Louis S. Constine MD, Nancy J. Tarbell MD, Edward C. Halperin MD - Pediatric Radiation Oncology (2016, LWW) PDF

Table of Contents
1. Pediatric Radiation Oncology

1. Cover
2. Title Page
3. Copy right Information
4. Dedication
5. Contributors
6. Preface
7. Acknowledgments
2. Chapter 1: The Cancer Problem in Children
1. Chapter 1 Introduction
1. Table 1.1: The Five Leading Causes of Death in the
United States in 2011 for 1- to 19-Year-Olds
2. Relative Frequency of the Various Ty pes of Childhood Cancer
1. Table 1.2: The Five Most Common Forms of Cancer in
Adults in the United States Compared with the Five Most
Common Forms of Cancer in Children
2. Table 1.3: The Incidence Rates of Cancer in the United
States for 0- to 19-Year-Olds Expressed as a Percentage
of the Total Number of Cancer Cases in This Age Group,
2006–2010
3. Table 1.4: The Most Common Causes of Pediatric Cancer
Death in the United States, 2007–2011, by Primary
Cancer Site for Ages 0–19
3. Trends in Childhood Cancer Mortality Rates
1. Table 1.5: Trends in 5-Year Relative Survival Rates for
Children with Cancer (0–14 Years of Age) in the United
States at the Approximate Midpoint of the Last Four
Decades
4. Funding of Pediatric Cancer Research
1. Table 1.6: Percentage of Total Dollars Spent by Scientific
Area in Pediatric Cancer Research by the United States
National Cancer Institute for Fiscal Year 2013
2. Table 1.7: The Yearly Investment of the United States
National Cancer Institute in Pediatric Cancer Research
5. Is the Incidence of Childhood Cancer Increasing?
6. What Does Cure Mean in Pediatric Oncology ?
7. The Growing Population of Childhood Cancer Survivors
1. Exhibit 22
2. Exhibit 23
3. Exhibit 24
4. Table 1.8: Marriage, Employ ment, and Health Insurance
in Adult Survivors of Childhood Cancer: A Survey of
1437 Survivors >18 Years of Age and >10 Years
Postdiagnosis Treated at St. Jude Children’s Research
Hospital
8. Site of Care and the Pediatric Cancer Team
1. Table 1.9: Requirements for a Pediatric Cancer Center
9. Postgraduate Training in Pediatric Radiation Oncology
10. The Problem of Evil and Childhood Cancer
11. Common Responses to the Problem of Evil
12. References
3. Chapter 2: Leukemias in Children
1. Figure 2.1
2. Acute Ly mphoblastic Leukemia
1. Biology
2. Clinical Presentation
3. Staging: Risk Categories for ALL
4. Staging: CNS Involvement in ALL
5. Treatment: Chemotherapy
6. Treatment: CNS Preventive Therapy
1. Evolution of CNS Preventive Therapy in
ALL
2. Current Recommendations for Preventive
CNS Therapy
7. Radiotherapeutic Management
1. Volume
2. Dosage
8. Treatment of Established CNS Leukemia
1. CNS Leukemia at Diagnosis
3. CNS Relapse
4. Volume and Dose
9. Treatment of Other Extramedullary Sites
1. Testicular Leukemia
1. Other Sites of Extramedullary Disease
11. Figure 2.2
12. Figure 2.3
13. Figure 2.4
14. Figure 2.5
15. Table 2.1: Indications for Preventive Cranial Irradiation
(pCrI)–Contemporary Studies (2009)
3. Acute My elogenous Leukemia
1. Extramedullary Disease
2. CNS Disease: Radiation Therapy
3. Hematopoietic Stem Cell Transplantation (HSCT)
4. HSCT in Children and Adolescents
1. Acute My eloblastic Leukemia
2. Acute Ly mphoblastic Leukemia
3. Other Hematologic Diseases
1. Volume
2. Dosage (Hematologic Malignancies)
6. Figure 2.6
4. References
4. Chapter 3: Supratentorial Brain Tumors
1. Table 3.1: Histopathologic Classification of CNS Tumors
—WHO Classification 2007
2. Figure 3.1
2. Etiology
1. Table 3.2: Genetic Sy ndromes Related to Pediatric CNS
Tumors
4. Low-Grade Supratentorial Astrocy tomas
1. Therapy
1. Surgery
2. Radiation Therapy
3. Chemotherapy
1. Volume
2. Dosage
3. Technique
3. Results
4. Figure 3.2
5. Figure 3.3
6. Figure 3.4
7. Figure 3.5
8. Figure 3.6
5. Optic Pathway Tumors
1. Therapy
1. Surgery
3. Chemotherapy
1. Volume and Technique
2. Dosage
6. Oligodendroglioma
7. Ganglioglioma
8. Rare Low-Grade Neoplasms
9. Malignant Gliomas
1. Therapy
1. Surgery
1. Chemotherapy
2. Dosage
3. Results
4. Figure 3.7
11. Embry onal CNS Tumors (Primitive Neuroectodermal Tumors or
Spnet and Pineoblastoma)
1. Therapy
2. Dosage
3. Figure 3.8
12. Craniophary ngioma
1. Therapy
3. Dosage
4. Results
5. Figure 3.9
6. Figure 3.10
7. Table 3.3: Craniophary ngioma—Outcome in Children
13. Intracranial Germ Cell Tumors
1. Therapy
1. Surgery
3. Chemotherapy
4. Radiotherapy Management
2. Dosage
5. Results
6. Figure 3.11
7. Table 3.4: Pineal Region Tumors—Relative Incidence
8. Table 3.5: Intracranial Germinoma—Outcome
9. Figure 3.12
10. Figure 3.13
14. References
5. Chapter 4: Tumors of the Posterior Fossa and the Spinal Canal
2. Medulloblastoma
1. Therapy
1. Surgery
3. Chemotherapy
1. Volume
2. Dosage
3. Technique
4. Delivery
3. Results
4. Figure 4.1
5. Table 4.1: Chang Staging for Medulloblastomaa
6. Table 4.2: Medulloblastoma—Results of Postoperative
Radiation Therapy (No Chemotherapy )
7. Table 4.3: Selected Major Medulloblastomas Studies
Reporting Outcome with Postoperative Irradiation
Combined with Chemotherapy
8. Table 4.4: Medulloblastoma—Radiation Therapy (Data
Reporting Reduced Tumor/Target Volume Techniques)
9. Figure 4.2
10. Figure 4.3
11. Figure 4.4
12. Figure 4.5
13. Figure 4.6
14. Figure 4.7
3. Embry onal and Malignant Glial Tumors in Infants and Young
Children
1. Therapy
1. Surgery
3. Chemotherapy
2. Dosage
3. Results
4. Table 4.5: Malignant Infant Brain Tumors—Outcome in
Selected Prospective Primary Management Trials
4. Ependy momas (Infants, Children, and Adolescents)
1. Therapy
1. Surgery
3. Chemotherapy
1. Volume
2. Dosage
3. Technique
3. Figure 4.8
4. Table 4.6: Molecular Subgroups of Ependy moma
5. Table 4.7: Ependy moma—Outcome Following Surgery
and Irradiation
6. Figure 4.9
5. Brainstem Glioma
1. Therapy
1. Surgery
3. Chemotherapy
1. Volume
2. Dosage
3. Technique
3. Results
4. Figure 4.10
5. Figure 4.11
6. Figure 4.12
7. Figure 4.13
8. Figure 4.14
6. Cerebellar Astrocy tomas
1. Therapy
1. Surgery
3. Chemotherapy
3. Results
7. Spinal Cord Neoplasms
1. Therapy
1. Surgery
2. Chemotherapy
1. Volume
2. Dosage
3. Technique
3. Results
4. Figure 4.15
5. Figure 4.16
8. References
6. Chapter 5: Retinoblastoma
1. Incidence
2. Genetics
3. Clinical Assessment
1. Figure 5.1
2. Figure 5.2
3. Figure 5.3
4. Table 5.1: The Reese–Ellsworth Sy stem of Classify ing
Retinoblastoma
5. Table 5.2: International Classification Sy stem for
Intraocular Retinoblastoma (Children’s Oncology Group
Version)
4. Treatment of Intraocular Retinoblastoma
1. Enucleation
2. Focal Therapy
3. Laser
4. Cry otherapy
5. Radioactive Plaque Application
6. External Beam Radiotherapy
7. Figure 5.4
8. Figure 5.5
9. Figure 5.6
10. Table 5.3: Ey e Preservation Following External Beam
Irradiation: Selected Series Reese–Ellsworth Group
11. Figure 5.7
5. Chemotherapy for Intraocular Disease
1. Intravenous Chemotherapy
2. Ophthalmic Artery Chemosurgery
3. Periocular Chemotherapy
4. Intravitreal Chemotherapy
5. Figure 5.8
6. Extraocular Retinoblastoma
1. Table 5.4: International Retinoblastoma Staging Sy stem
7. Treatment due to High-Risk Enucleation Pathology
8. Treatment of Overt Extraocular Disease
1. Regional Extraocular Disease
2. Stage 4a Disease
3. CNS Retinoblastoma: Stage 4b and Trilateral Disease
9. Palliation of Metastases
10. Late Effects
1. Secondary Nonocular Tumors
2. Cataracts
3. Orbital Development
4. Ocular Surface Dry ness
11. References
7. Chapter 6: Neuroblastoma
1. Neuroblastoma
2. Epidemiology and Screening
1. Figure 6.1
2. Figure 6.2
3. Biology
1. Table 6.1: Genetic Aberrations in Neuroblastoma That
Are Found at Diagnosis
4. Pathology
1. Figure 6.3
2. Figure 6.4
3. Table 6.2: International Neuroblastoma Pathology
Committee Sy stem
5. Clinical Presentation and Evaluation
1. Table 6.3: Clinical Evaluation of Neuroblastoma
(Minimum Recommended Studies to Determine the
Extent of Disease)
2. Figure 6.5
6. Staging and Prognostic Factors
1. Staging
2. Response Criteria
3. Prognostic Factors
1. Clinical
2. Biologic
4. Table 6.4: International Neuroblastoma Staging Sy stem
5. Table 6.5: International Neuroblastoma Risk Group
(INRG) Staging Sy stem
6. Table 6.6: International Neuroblastoma Response Criteria
7. Figure 6.6
8. Table 6.7: International Neuroblastoma Risk Group
Working Committee Modified Response Criteria
9. Figure 6.7
10. Table 6.8: Children’s Oncology Group Neuroblastoma
Risk Groups for Treatment
11. Table 6.9: INRG Risk Classification
7. Selection of Therapy
1. Chemotherapy
1. My eloablative Therapy with Hematopoietic
Stem Cell Support
2. Table 6.10: Induction Regimens for High-Risk
Neuroblastoma Since 1985 (More Than 50 Patients)
3. Table 6.11: EFS for High-Risk Neuroblastoma in First
Remission Using My eloablative Therapy and
Hematopoietic Cell Transplant for Studies of More than
20 Patients
4. Figure 6.8
8. Therapy for Minimal Residual Disease
1. Figure 6.9
9. Surgery
1. Low-Risk Disease
2. Stage 4S and Hepatomegaly
3. Intermediate-Risk Disease
4. High-Risk Disease
5. CNS Metastases
6. Metastatic Disease Treated with Palliative Intent
7. Table 6.12: Effect of Radiation in Local Control of
Advanced (INSS 3 and 4) Neuroblastoma
11. Adolescent and Adult Neuroblastoma
1. Volume
2. Dose
3. Figure 6.10
13. Techniques of Radiation
1. Figure 6.11
2. Figure 6.12
14. Intraoperative Radiation Therapy
1. Table 6.13: Intraoperative Radiotherapy for
Neuroblastoma
15. Complications
16. Targeted Radionuclides
17. Molecularly Targeted Agents and Radiosensitizers
18. Future Investigations
19. References
8. Chapter 7: Hodgkin Ly mphoma
2. Biology
1. Figure 7.1
3. Epidemiology
1. Table 7.1: Ann Arbor Staging Sy stem with Cotswold
Modifications for Hodgkin Ly mphoma
5. Pathologic Classification
1. Figure 7.2
2. Table 7.2: WHO Classification of Hodgkin Ly mphoma
6. Staging
1. Table 7.3: Demographic and Clinical Characteristics at
Presentation of Pediatric Hodgkin Ly mphoma
7. Diagnostic Evaluation
1. Figure 7.3
10. Evolution of Combination Chemotherapy
11. Risk and Response-Adapted Therapy
1. Treatment of Early -Stage Disease
2. Treatment of Advanced and Unfavorable Disease
3. Figure 7.4
4. Figure 7.5
5. Table 7.4: Summary of Treatment Results for Pediatric
Hodgkin Ly mphoma Trials
12. Refractory and Relapsed Disease
13. Targeted Therapies
15. Volume Considerations
1. Involved-Site Radiotherapy (ISRT)
2. Involved-Node Radiotherapy
3. PET/CT Radiation Planning
4. Figure 7.6
5. Table 7.5: Involved Site Radiation Therapy (ISRT)
Guidelines
6. Figure 7.7
7. Figure 7.8
16. Conformal Radiation Planning
1. Figure 7.9
2. Figure 7.10
17. Dosage Considerations
18. Sequence of Therapy
19. Results
1. Figure 7.11
20. Complications
1. Acute Side Effects
2. Long-Term Side Effects
21. Future Investigations
22. References
9. Chapter 8: Non-Hodgkin Ly mphoma
1. Figure 8.1
2. Epidemiology and Etiology
1. Table 8.1: Clinical and Biologic Features of NHL in
Children
4. Evaluation
5. Staging and Classification
1. Table 8.2: Murphy and St. Jude Children’s Research
Hospital Staging Sy stem for Childhood NHL
2. Table 8.3: Clinical Staging of B-Cell Ly mphomas
1. Chemotherapy
2. Table 8.4: Low-Stage/Low-Risk Patients
3. Table 8.5: Advanced-Stage/High-Risk Patients
9. Surgical Management
10. Results of Therapy
11. References
10. Chapter 9: Ewing Sarcoma
1. Figure 9.1
2. Pathology
1. Table 9.1: Clinical Evaluation of the Patient with Ewing
Sarcoma
2. Figure 9.2
3. Figure 9.3
4. Table 9.2: Prognostic Factors in Ewing Sarcoma
4. Selection of Treatment
1. Local Control
2. Surgery
3. Chemotherapy
1. Volume
2. Dosage
3. Technique
5. Radiation Therapy for Metastatic Disease
6. Total-Body Irradiation and Stem Cell Transplantation
7. Table 9.3: National Cancer Institute Protocol INT-0091
(Children’s Cancer Group Study 7881 and Pediatric
Oncology Group Study 8850)
8. Figure 9.4
9. Table 9.4: Influence of Chemotherapy on Local Control
of Ewing Sarcoma in CCG-7881 and POG-8850
10. Figure 9.5
5. Cure Rates and Side Effects of Treatment
1. Table 9.5: Second Malignancies in Patients Treated in the
German Cooperative Ewing Sarcoma Studies CESS-81
and CESS-86
6. References
11. Chapter 10: Osteosarcoma, Chordoma, and Chondrosarcoma
1. Figure 10.1
2. Figure 10.2
2. Signs, Sy mptoms, Evaluation, and Staging
1. Figure 10.3
2. Figure 10.4
3. Table 10.1: A Sy stem for Osteosarcoma Subclassification
by Histology and Origin
4. Figure 10.5
5. Table 10.2: The Enneking Staging Sy stem for
Osteosarcoma
6. Table 10.3: Influence of the Histologic Response to
Neoadjuvant Chemotherapy on Survival in
Osteosarcoma
1. Surgery
1. Local Disease
2. Metastatic Disease
1. Prebiopsy
3. Primary and Preoperative Treatment
1. The Cade Technique
2. Modern Series of Primary Photon Radiation
Therapy
4. Maxilla and Mandible
5. Lung
6. The Role of Adjuvant Whole-Lung Irradiation (WLI) in
Osteosarcoma in Nonrandomized Studies
1. Evidence from Randomized Studies
2. WLI for Advanced Osteosarcoma
7. Extracorporeal Irradiation (ECI)
8. Chemotherapy
9. Table 10.4: Local Recurrence Rates for Osteosarcoma as
a Function of the Extent of Surgery
10. Table 10.5: Factors Predicting Event-Free Survival in
Patients with Primary Metastatic Osteosarcoma in the
German–Swiss–Austrian Cooperative Osteosarcoma
Study Group Clinical Trials
11. Figure 10.6
12. Table 10.6: The Cade Technique: Management of
Osteosarcoma with Primary Irradiation or Primary
Irradiation and Selected Delay ed Amputation (Excluding
Parosteal Tumors)
13. Table 10.7: Significant Recent Cooperative Group Trials
Addressing the Management of Localized Osteosarcoma
14. Table 10.8: Prophy lactic Lung Irradiation in the
Treatment of Osteogenic Sarcoma
15. Figure 10.7
16. Figure 10.8
4. Radiotherapeutic Technique
1. Dosage
2. Volume
3. Technique
4. Neutron Therapy
5. Charged Particle Therapy
6. Intraoperative Radiation Therapy (IORT)
7. Radioisotope Therapy
8. Palliation
9. Chordoma and Chondrosarcoma
1. Treatment
10. Table 10.9: Literature Review of the Local Control Rates
for Osteosarcomas after Neutron Therapy
11. Figure 10.9
12. Figure 10.10
13. Figure 10.11
5. References
12. Chapter 11: Rhabdomy osarcoma
1. Figure 11.1
2. Epidemiology
1. Figure 11.2
3. Biology
1. Cy togenetics
2. Cell Cy cle Control
3. Proto-oncogenes
4. Tumor Suppressor Genes
1. Diagnostic Evaluation
2. Prognostic Features
1. Histology
2. Favorable: Embry onal, Botry oid, and Spindle
Cell Variants
3. Unfavorable: Alveolar
4. Stage
5. Group
6. Primary Site
7. Other Factors
3. Table 11.1: International Classification of
Rhabdomy osarcoma
4. Table 11.2: Tumor, Node, Metastasis Pretreatment
Staging Classification
5. Table 11.3: The IRS Grouping Sy stem
6. Figure 11.3
7. Figure 11.4
8. Table 11.4: Ly mph Node Metastasis by Primary Site for
592 Patients with Visibly Resected Diseasea from IRS-I
and IRS-II
5. General Principles of Therapy
1. Surgery
2. Chemotherapy
4. Figure 11.5
5. Table 11.5: Design and Results of IRS-I, 1972–1978 (686
Patients)
6. Table 11.6: Design and Results of IRS-II, 1978–1984
(1003 Patients)
7. Table 11.7: Therapy and Outcomes According to
Specific Patient Subgroups in IRS-III, 1984–1991 (1032
Patients)
8. Table 11.8: Outcome for Patient with Group II Tumors
According to Histology, Primary Site, and IRS Study
9. Table 11.9: Estimated Cumulative Incidence at 5 Years of
Local, Regional, and Distant Failure by Primary Site and
Therapy for Patients Who Received Their Randomized
Therapy on IRS-IV
6. Specific Sites
1. Bladder and Prostate Rhabdomy osarcoma
2. Paratesticular
3. Vagina and Vulva
4. Uterus and Cervix
5. Extremity
6. Parameningeal
7. Orbit
8. Other Head and Neck Sites
9. Trunk
10. Retroperitoneal
11. Perineal
12. Hepatobiliary Tree
14. Figure 11.6
15. Figure 11.7
16. Figure 11.8
17. Figure 11.9
18. Figure 11.10
19. Figure 11.11
20. Figure 11.12
21. Figure 11.13
7. Recurrent Disease
8. Future Directions
9. References
13. Chapter 12: Soft Tissue Sarcomas Other Than Rhabdomy osarcoma; Desmoid
Tumor
1. Table 12.1: Common Cy togenetic Changes in
Nonrhabdomy osarcoma Soft Tissue Sarcomas
2. Pathology
1. Table 12.2: The Most Common Ty pes of Childhood
Nonrhabdomy osarcoma Soft Tissue Sarcoma in Recent
Clinical Seriesa
2. Figure 12.1
3. Figure 12.2
4. Table 12.3: Cells of Origin of Nonrhabdomy osarcoma
Soft Tissue Sarcoma of Childhood
5. Exhibit 307
6. Figure 12.3
7. Figure 12.4
8. Exhibit 310
9. Exhibit 311
10. Figure 12.5
3. Presentation, Workup, and Staging
1. Figure 12.6
2. Table 12.4: The 2012 American Joint Committee on
Cancer Staging Sy stem for Sarcoma of Soft Tissuea
3. Table 12.5: POG Grading Sy stem for Pediatric
Nonrhabdomy osarcoma Soft Tissue Sarcomas
4. Table 12.6: Tumor Differentiation Scores of Sarcoma in
the French Federation of Cancer Centers Sy stem of
Grading Soft Tissue Sarcomas
5. Table 12.7: French Federation of Cancer Centres Sy stem
of Grading Soft Tissue Sarcomas
1. Surgery
2. Radiotherapy
3. Chemotherapy
1. Cooperative Group Studies of Chemotherapy
and NRSTS Exclusive of PNET, EOES, and
Askin Tumor
2. Large-Scale Studies of Adjuvant
Chemotherapy in Adults with NRSTS
3. Modern USA and European Pediatric
Cooperative Group Trials for NRSTS with
Selective Use of Adjuvant Therapies Based
on Risk
4. Table 12.8: POG Protocol 8653: Local Control by
Surgical Margins and Radiotherapy
5. Table 12.9: Factors Affecting Local Relapse in NRSTS in
the St. Jude Children’s Research Hospital Retrospective
Reviews
6. Figure 12.7
7. Figure 12.8
1. Volume
2. Dosage
3. Brachy therapy and Intraoperative Radiation Therapy
4. High–Linear Energy Transfer Radiotherapy (e.g.,
Neutrons)
5. Figure 12.9
6. Figure 12.10
7. Figure 12.11
6. Results
7. Desmoid Tumors
1. Figure 12.12
2. Table 12.10: Local Control of Desmoid Tumors with
Three Forms of Therapy
3. Figure 12.13
4. Table 12.11: Local Control Rates in Combined Pediatric
and Adult Series of Radiotherapy with or without Surgery
for the Management of Desmoid Tumors
8. References
14. Chapter 13: Wilms Tumor
1. History
1. Figure 13.1
2. Epidemiology
3. Molecular Biology
1. Table 13.1: Analy sis for the Joint Effect of LOH at 1p
and 16q for (A) Stage I/II and (B) Stage III/IV Favorable
Histology Patients (29)
2. Table 13.2: COG Risk-Stratification Schema for Renal
Tumor Protocols
4. Pathology
1. Mesoblastic Nephroma
2. Nodular Renal Blastemas and Nephrogenic Rests
3. Wilms Tumor
4. Rhabdoid Tumor of the Kidney
5. Clear Cell Sarcoma of the Kidney
6. Table 13.3: Classification of Pediatric Renal Tumors
7. Table 13.4: International Society of Pediatric Oncology
National Wilms Tumor Study
8. Table 13.5: Children’s Oncology Group Classification of
Renal Tumors
9. Figure 13.2
10. Figure 13.3
11. Figure 13.4
12. Figure 13.5
5. Clinical Presentation and Workup
1. Figure 13.6
6. Staging
1. Table 13.6: Children’s Oncology Group Staging of Wilms
Tumor
2. Table 13.7: Staging Sy stem Used in SIOP Wilms Tumor
Trial 1
7. Nwts, Siop, and the Management of Wilms Tumor
1. The NWTS and SIOP Strategies
2. The National Wilms Tumor Studies
3. Children’s Oncology Group Studies
4. AREN03B2
5. AREN0321
6. AREN0532
7. AREN0533
8. AREN0534
9. SIOP Wilms Tumor Studies
10. Table 13.8: NWTS-1 Results
11. Figure 13.7
13. Figure 13.8
14. Figure 13.9
16. Table 13.11: NWTS-3 Relapse Rates
17. Figure 13.10
19. Table 13.13: Comparing Results: NWTS-4 and UK
Children’s Cancer Study Group Wilms Tumor Study 2
20. Table 13.14: Risk of Local Recurrence in NWTS-4
21. Table 13.15: COG Radiation Therapy Guidelines
22. Table 13.16: COG Chemotherapy Regimens
23. Table 13.17: Results of the Treatment of New Cases of
Historically Confirmed Wilms Tumor, with More Than 2
Years of Follow-Up, As Reported by Schweisguth and
Bamberger of the Institut Gustave Roussy in 1963
24. Table 13.18: SIOP 1 Wilms Tumor Treatment Protocol
25. Table 13.19: SIOP 1 Results
30. Table 13.24: Effect of Preoperative Treatment: SIOP
Trial 5
34. Table 13.28: SIOP 9: Stage IV Protocol
36. Table 13.30: SIOP 93-01 Wilms Tumor Treatment:
Postoperative Treatment Strategies for Unilateral Wilms
Tumor
37. Table 13.31: SIOP 93-01 Stage IV Protocol
38. Table 13.32: SIOP 93-01 Results
39. Table 13.33: SIOP 93-01 Results
40. Table 13.34: SIOP 2001 Postoperative Treatment
Strategies for Localized Tumors
41. Table 13.35: SIOP 2001 Stage IV Postoperative
Treatment
42. Table 13.36: SIOP 2001 Indications for Radiotherapy
43. Table 13.37: SIOP 2001 Radiation Therapy Dosage (Total
Dose/Dose per Fraction)
1. Surgery
3. Chemotherapy
1. Volume
2. Figure 13.11
3. Figure 13.12
4. Figure 13.13
10. Dosage for Abdominal Disease
1. Intensity -Modulated Radiation Therapy in Wilms Tumor
2. Bilateral Wilms Tumor
4. Recurrent Wilms Tumor
5. Renal Tumors in Very Young Children
11. Toxicities
1. Hematologic Toxicity
2. Hepatic Effects
3. Orthopedic Effects
4. Renal Effects
5. Cardiac Effects
6. Pulmonary Effects
7. Pregnancy Outcome
8. Treatment-Induced Neoplasms
9. Growth Abnormalities
10. Table 13.38: Long-Term Complications of Renal Function
11. Table 13.39: Long-Term Complications of Cardiac
Function (99)
12. Table 13.40: Pregnancy Outcome
13. Table 13.41: Predicted Deficit in Height at Age 18 Years
after Flank Irradiation at Selected Ages and Dosages
12. Future Developments
13. References
15. Chapter 14: Liver Tumors in Children
1. Table 14.1: Incidence of Primary Hepatic Tumors in
Childhood
2. Benign Tumors
1. Vascular Tumors
2. Mesenchy mal Hamartoma
3. Focal Nodular Hy perplasia and Hepatic Adenomas
3. Primary Malignant Liver Tumors
1. Hepatoblastoma
2. Hepatocellular Carcinoma
3. Undifferentiated Embry onal Sarcoma of the Liver
4. Table 14.2: Histologic Classification of Hepatoblastoma
5. Figure 14.1
6. Figure 14.2
7. Figure 14.3
4. Diagnosis
1. Genomic Abnormality
2. Figure 14.4
5. Staging
1. Table 14.3: Staging Sy stem of Hepatoblastoma by the
Children’s Oncology Group
2. Figure 14.5
1. Surgery
2. Chemotherapy
4. Table 14.4: Hepatoblastoma Staging and Risk
Stratification
5. Table 14.5: Multicenter Studies in Hepatoblastoma—
Comparison of Results
6. Table 14.6: Results of the Pediatric Intergroup Hepatoma
Study for Hepatoblastoma (CCG-8881 and POG-8945)
7. Table 14.7: Summary of Recent Hepatoblastoma
Multicenter Trials (12,25,31,36,53,54,55,59,60,66,67,68)
8. Figure 14.6
9. Table 14.8: Current Chemotherapy Recommendations of
the Different Study Groups (66,68,73,74,75)
7. Results and Future Directions
8. References
16. Chapter 15: Germ and Stromal Cell Tumors of the Gonads and Extragonadal
Germ Cell Tumors
1. Figure 15.1
2. Table 15.1: Biologic Characteristics of Pediatric Germ
Cell Tumors
3. Table 15.2: Grading of Immature Teratomas
2. General Aspects of Clinical Presentation, Staging, and Workup
1. Ovary
2. Testis
3. Extragonadal
1. Sacrococcy geal Tumor (SCT)
2. Mediastinal GCT
3. The Role of Radiotherapy
4. Figure 15.2
5. Table 15.3: Children’s Oncology Group Surgical
Guidelines for Ovarian Germ Cell Tumor in Pediatric
Patients
6. Table 15.4: Children’s Oncology Group Staging for
Pediatric Ovarian Germ Cell Tumors
7. Figure 15.3
Pediatric Testicular Germ Cell Tumor
9. Figure 15.4
10. Table 15.6: TNM Classification (UICC 2009)
Pediatric Malignant Extragonadal Germ Cell Tumors
12. Figure 15.5
3. Results
4. References
17. Chapter 16: Endocrine, Aerodigestive Tract, and Breast Tumors
1. Adrenocortical Carcinoma
1. Histology
2. Epidemiology
3. Genetics
4. Clinical Aspects
5. Biology
6. Molecular Biology
8. Imaging
9. Treatment
1. Surgery
2. Chemotherapy
3. Radiotherapy
10. Follow-Up
11. Results
12. Table 16.1: Constitutional Genetic Abnormalities
Associated with Adrenal Cortical Tumors (ACT)
13. Figure 16.1
2. Pheochromocy toma and Paraganglioma
1. Definition
2. Histology
3. Epidemiology
4. Genetics
5. Clinical Aspect
6. Biology
7. Imaging
8. Treatment
9. Results
3. Thy roid Carcinoma
1. Histology /Epidemiology
2. Follicular, Papillary, and Poorly Differentiated
Carcinomas
1. Risk Factors
2. Clinical Aspects
3. Imaging
4. Prognostic Factor
5. Treatment
3. Follow-Up
4. Results
5. Table 16.2: Differentiated Thy roid Cancer in Children
from 11 Pediatric Series
4. Radiation-Associated Thy roid Cancer in Children
1. Cancer Survivors
2. The Chernoby l Accident
5. Medullary Thy roid Carcinoma
1. Clinical Aspect
2. Genetics
3. Treatment
6. Aerodigestive Tract
1. Juvenile Nasophary ngeal Angiofibroma
1. Epidemiology
2. Histology
3. Clinical Aspect
4. Imaging
6. Classification
7. Treatment
2. Nasophary ngeal Carcinoma (NPC)
1. Histology
2. Epidemiology
3. Genetics
4. Clinical Aspects
5. Biology
6. Imaging
8. Classification
9. Treatment
10. Results
11. Late Effects
3. Esthesioneuroblastoma (or Olfactory Neuroblastoma)
1. Epidemiology
2. Histology
3. Clinical Aspect
4. Imagery
5. Classification
6. Treatment
7. Results
4. Table 16.3: Radiotherapy for Juvenile Nasophary ngeal
Angiofibroma: Most Recent Studies
5. Figure 16.2
6. Table 16.4: Staging Sy stem for Carcinoma of the
Nasophary nx
7. Table 16.5: Survival in Childhood Nasophary ngeal
Carcinomas: Studies During the 1990s and 2000s
8. Table 16.6: Kadish Staging Sy stem
9. Table 16.7: Local Recurrence Rates in Retrospective
Series of the Treatment of Esthesioneuroblastoma:
Combined Adult and Pediatric Series
7. Malignancies of the Oral Cavity, Orophary nx, Hy pophary nx, and
Lary nx
1. Epidemiology
8. Salivary Gland Tumors
1. Epidemiology
2. Pathology
1. Mucoepidermoid Carcinoma As Second
Tumors
3. Clinical Aspects
4. Treatment
9. Infantile Subglottic Hemangiomas
1. Treatment
10. Esophageal Cancers
11. Gastrointestinal Malignancies
12. Pulmonary Neoplasm
1. Epidemiology
2. Pathology
1. Pleuropulmonary Blastoma (PPB)
4. Genetics
5. Diagnosis
6. Treatment
7. Results
13. Carcinoid and Mucoepidermoid Bronchial Tumors
14. Neoplasms of the Pancreas
15. Pancreatoblastoma
1. Histology
2. Diagnosis
3. Treatment
16. Colorectal Malignancies
17. Breast Cancer
18. References
18. Chapter 17: Langerhans Cell Histiocy tosis
1. Historical Background
1. Figure 17.1
2. Definition, Pathogenesis, and Pathology
1. Figure 17.2
2. Figure 17.3
3. Table 17.1: Immunophenoty pe of Langerhans Cell
Histiocy tosis
3. Clinical Presentation, Diagnostic Evaluation, and Staging
1. Table 17.2: An Overview of the Clinical Presentation of
Langerhans Cell Histiocy tosis in Several Recent Clinical
Series
2. Table 17.3: Sites of Bone Involvement in Langerhans Cell
Histiocy tosis: A Summary from the Published Literature
3. Figure 17.4
4. Figure 17.5
5. Table 17.4: Treatment of Localized Langerhans Cell
Histiocy tosis of Bone with Intralesional Corticosteroid
Injection
1. Surgery
2. Bone Sites Not Appropriate for Surgery
3. Direct Injection of Steroids
5. Chemotherapy
1. AIEOP-CNR-HX*83
2. DAL-HX83
3. DAL-HX90
4. LCH 1
5. LCH2
6. JLSG-96
7. LCH3
8. Salvage Therapy
9. Skin Therapy
6. Liver and Bone Marrow Transplantation
7. Table 17.5: A Treatment Algorithm for Langerhans Cell
Histiocy tosis
8. Table 17.6: Results of External Beam Radiation Therapy
for Langerhans Cell Histiocy tosis of Bone
9. Figure 17.6
1. Dosage
2. Volume
3. Figure 17.7
4. Figure 17.8
5. Figure 17.9
6. Long-Term Sequelae of LCH and Its Treatment
7. Results
8. References
19. Chapter 18: Vascular Neoplasms and Skin Cancer
1. Vascular Neoplasms
1. Table 18.1: Vascular Malformations
2. Table 18.2: Vascular Neoplasms
2. Vasculoproliferative Tumors
3. Vascular Malformations
4. Basal and Squamous Cell Carcinomas
5. Malignant Melanoma
1. Table 18.3: Classification of the Primary Lesion in
Malignant Melanoma
2. Figure 18.1
3. Figure 18.2
6. References
20. Chapter 19: Late Effects of Cancer Treatment
1. Figure 19.1
2. Figure 19.2
3. Figure 19.3
2. Effects of Chemotherapy and Radiotherapy on Normal Tissue
1. Table 19.1: Tolerance Dosages, TD5–TD50 (Fractionated
Dosage, Whole or Partial Organ)
2. Table 19.2: Common Chemotherapy Late Effects
3. Influence of the Developmental Stage of the Target Organ on Its
Sensitivity to Therapy
1. Figure 19.4
2. Table 19.3: Anatomy and Phy siology : Relative Rate of
Development
3. Figure 19.5
4. Late Effects by Organ Sy stem
1. Central Nervous Sy stem
1. Pathophy siology
2. Clinical Manifestations
3. Cerebrovascular Disease
4. Additional Manifestations
5. Psy chosocial
2. Neuroendocrine
1. Growth Hormone
3. Non–Growth Hormone Tropins
3. Thy roid
1. Pathophy siology
2. Hy pothy roidism
3. Hy perthy roidism
4. Detection and Screening
5. Management
4. Bone and Body Composition
1. Pathophy siology
3. Other Skeletal Abnormalities
5. Cardiac
1. Pericarditis
2. Cardiomy opathy
3. Valvular Disease
4. Arrhy thmia
5. Coronary Artery Disease
6. Lungs
1. Pathophy siology
3. Radiation and Chemotherapy Effects on the
Lung
7. Ovary
1. Pathophy siology
8. Breast
9. Testes
1. Pathophy siology
3. Reproduction and Offspring
10. Urinary Sy stem
11. Kidney
1. Pathophy siology
12. Urinary Bladder
13. Digestive Tract
14. Pancreas
15. Liver
16. Ey e
1. Retina
2. Lacrimal Apparatus
3. Lens
4. Optic Nerve
5. Lid
6. Orbit
17. Hearing
18. Teeth and Salivary Glands
19. Bone Marrow
20. Figure 19.6
21. Figure 19.7
22. Table 19.4: Evaluation of Patients at Risk for Late Effects:
Central Nervous Sy stem
23. Figure 19.8
24. Figure 19.9
Neuroendocrine
26. Figure 19.10
Thy roid
28. Figure 19.11
Musculoskeletal
30. Figure 19.12
31. Figure 19.13
32. Figure 19.14
Cardiac
34. Figure 19.15
Pulmonary
36. Table 19.10: Effect of Fractionated Irradiation on
Ovarian Function in Women of Reproductive Age
37. Figure 19.16
38. Table 19.11: Evaluation of Patients at Risk for Late
Effects: Ovarian
39. Table 19.12: Effect of Fractionated Testicular Irradiation
on Spermatogenesis and Ley dig Cell Function
Effects: Testicular
41. Figure 19.17
Effects: Genitourinary
Effects: Gastrointestinal
44. Figure 19.18
Effects: Ey e
46. Figure 19.19
Effects: Ear
48. Figure 19.20
Effects: Dental and Salivary
50. Figure 19.21
51. Table 19.19: Antineoplastic Drug Category and Agent
with Their Relative Degree and Duration of
My elosuppression
5. Conclusions and Future Directions
6. References
21. Chapter 20: Second Primary Cancers
2. Second Primary Cancers: The Scope of the Problem
1. Figure 20.1
3. Risk Factors for Second Primary Cancers
1. Primary Diagnosis
2. Host-Related Risk Factors
1. Age at Diagnosis of Primary Cancer
2. Sex
3. Therapy -Related Risk Factors
1. Radiation
2. Chemotherapeutic Agents
4. Environmental and Lifesty le Factors
5. Characteristics of Second Primary Cancers
1. Alky lating Agent–Associated Acute My eloid
Leukemia and My elody splasia
2. Topoisomerase II Inhibitor–Associated Acute
My eloid Leukemia
6. Musculoskeletal Tumors
7. Breast Cancer
8. Thy roid Cancer
9. Brain Tumor
10. Other Carcinomas
11. Lung Cancer
12. Skin Cancer
1. Nonmelanoma skin cancer (NMSC)
2. Melanoma
13. Bladder
14. Renal Cell Carcinoma
15. Salivary Gland Tumors
16. Molecular Underpinnings of Second Primary Cancers
17. Drug Metabolism and Disposition
18. DNA Repair
19. Role of Genetic Susceptibility in Therapy -Related
Leukemia
1. Drug Metabolism and Risk of t-MDS/AML
2. DNA Damage and Repair and t-MDS/AML
3. Impact of Antimetabolite Drugs and DNA
Sy nthesis/Repair on t-MDS/AML Risk
20. Role of Genetic Susceptibility in Therapy -Related Solid
SPCs
1. Breast cancer
2. Meningioma
3. Thy roid cancer
21. Table 20.1: Second Primary Cancers and their
Relationship with Primary Cancers
22. Figure 20.2
23. Figure 20.3
24. Table 20.2: Characteristics of Therapy -Related
My elody splasia or Acute My eloid Leukemia after
Treatment with Alky lating Agents and Topoisomerase II
Inhibitors
25. Figure 20.4
26. Table 20.3: Risk of Breast Cancer in Hodgkin Ly mphoma
Survivors by Age and Latency
27. Table 20.4: Role of Genetic Susceptibility in the
Development of Therapy -Related My elody splasia/Acute
My eloid Leukemia
28. Table 20.5: Role of Genetic Susceptibility in the
Development of Therapy -Related Solid Subsequent
Malignant Neoplasms
4. Primary Cancers Associated with Second Primary Cancers
1. Retinoblastoma
1. Hodgkin Ly mphoma
2. Prevention Strategies
3. Future Directions
4. Figure 20.5
5. Figure 20.6
6. Figure 20.7
5. References
22. Chapter 21: Anesthesia for External Beam Radiotherapy
2. Behavioral Techniques to Avoid Anesthesia
3. Frequency of Anesthesia for Pediatric Radiotherapy
1. Table 21.1: Need for Anesthesia in Children as a Function
of Age at Initiation of Irradiation
4. Goals of Anesthesia for Radiotherapy
1. Table 21.2: Goals for Ideal Anesthesia for Outpatient
Pediatric Radiation Therapy
5. Inhaled Anesthetics
1. Table 21.3: Inhalation Anesthetic Agents Commonly
Used in Pediatric Radiation Therapy
2. Figure 21.1
3. Figure 21.2
4. Figure 21.3
5. Figure 21.4
6. Intravenous Anesthetics
7. Sedation or Anesthesia?
8. Anesthesia Monitoring
1. Figure 21.5
2. Figure 21.6
3. Figure 21.7
4. Figure 21.8
9. Anesthetic Implications of Underly ing Disease
1. Figure 21.9
10. References
23. Chapter 22: Psy chosocial Aspects of Radiotherapy for the Child and Family with
Cancer
2. Cognitive Effects of Radiotherapy
1. Effects of RT on Intelligence
2. Effects of RT on Specific Cognitive Functions
3. Further Factors Involved in Cognitive Functioning
4. Table 22.1: Studies about the Effects of RT on IQ Scores
3. Social and Behavioral Effects of RT
1. Table 22.2: Behavioral and Social Effects of RT
4. Children’s Distress in the Course of RT
1. Effects of RT on the Children’s Quality of Life
2. Intervention Procedures for Reducing Distress during RT
3. Figure 22.1
5. Interview
1. The Views of the Children and the Parents about RT
2. Results Based on Interviewing Parents
3. Results Based on Interviewing the Children
4. Some Comments Concerning the Interviews
5. Figure 22.2
6. Summary
7. References
24. Appendix
1. Remarks
Pediatric Radiation Oncology
SIXTH ED ITION
Louis S. Constine, MD, FASTRO
The Philip Rubin Professor of Radiation Oncology and Pediatrics
Vice Chair
Department of Radiation Oncology
Director
The Judy DiMarzo Cancer Survivorship Program
James P. Wilmot Cancer Institute
University of Rochester Medical Center
Rochester, New York
Nancy J. Tarbell, MD, FASTRO

CC Wang Professor of Radiation Oncology
Massachusetts General Hospital
Dean for Academic and Clinical Affairs
Harvard Medical School
Boston, Massachusetts
Edward C. Halperin, MD, MA

Chancellor/Chief Executive Officer
Professor of Radiation Oncology, Pediatrics, and History
New York Medical College
Provost for Biomedical Affairs
Touro College and University
Valhalla, New York
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Library of Congress Cataloging-in-Publication Data
Names: Constine, Louis S., editor. | Tarbell, Nancy J., 1951- editor. |
Halperin, Edward C., editor.
Title: Pediatric radiation oncology / editors, Louis S. Constine, Nancy J.
Tarbell, Edward C. Halperin.
Description: Sixth edition. | Philadelphia, PA : Wolters Kluwer, [2016] |
Includes bibliographical references and index.
Identifiers: LCCN 2016020698 | ISBN 9781496342867
Subjects: | MESH: Neoplasms—radiotherapy | Child
Classification: LCC RC281.C4 | NLM QZ 275 | DDC 618.92/9920642—dc23 LC record a
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Dedication
This book is dedicated both to our own children and to all those children diagnosed with
cancer. These children have taught us about life, bravery, pain, openness, innocence,
resilience, as well as clinical pediatric radiation oncology. To them we are forever grateful.
Through our patients we have learned to more profoundly appreciate our own families. We
pause to recognize those children who succumbed to cancer, and to feel gratitude for those
fortunate to have survived while retaining a childlike enthusiasm for living despite the burden
of malignancy. We hope that the sixth edition of Pediatric Radiation Oncology will serve as
some small reciprocation for what our patients have given to us.
Louis S. Constine
Nancy J. Tarbell
Edward C. Halperin
Contributors
David H. Abramson, MD, FACS

Chief
Ophthalmic Oncology Service
Memorial Sloan Kettering Cancer Center
Professor
Department of Ophthalmology
Weill-Cornell Medical Center
New York, New York
James E. Bates, MD
Resident
University of Florida
Gainesville, Florida
Myriam Weyl Ben Arush, MD

Professor
Department of Pediatrics
Professor
Division of Pediatric Hematology Oncology
Rappaport Faculty of Medicine
Technion - Israel Institute of Technology
Chief
Division of Pediatric Hematology and Oncology
The Ruth Rappaport Children’s Hospital
Rambam Health Care Campus
Haifa, Israel
Smita Bhatia, MD, MPH

Professor
Director
Institute of Cancer Outcomes and Survivorship
School of Medicine
University of Alabama
Birmingham, Alabama
Steve E. Braunstein, MD, PhD

Assistant Professor
University of California
San Francisco, California
Christian Carrie, MD
Chief
Department of Radiotherapy
Centre Léon Bérard
Ly on, France
Bow-Wen Chen, MD
Senior Pediatrician
Medical Director
Hematopoietic Stem Cell Research Laboratory
Koo Foundation Sun Ya-Sen Cancer Center
Taipei, Taiwan
Skye H. Cheng, MD
Chief
Director
Clinical Research Office
Deputy Chief
Department of Research
Koo Foundation Sun Yat-Sen Cancer Center
Taipei, Taiwan
Line Claude, MD
Assistant Head
Centre Léon Bérard
Ly on, France
Louis S. Constine, MD, FASTRO

The Philip Rubin Professor of Radiation Oncology and Pediatrics
Vice Chair
Director
The Judy DiMarzo Cancer Survivorship Program
James P. Wilmot Cancer Institute
Rochester, New York
Sughosh Dhakal, MD
Assistant Professor
Medical Director
James P. Wilmot Cancer Institute/Strong Memorial Hospital
Rochester, New York
Xavier Druet
Internship Department of Radiotherapy
Institut du cancer de Montpellier(ICM)
Montpellier, France
Ira J. Dunkel, MD
Associate Attending Phy sician
New York, New York
Bree R. Eaton, MD
Assistant Professor
Winship Cancer Institute
Emory University
Atlanta, Georgia
Natia Esiashvili, MD
Associate Professor
Woodruff Health Sciences Center
Emory University
Atlanta, Georgia
Marla B. Ferschl, MD
Associate Professor
Department of Anesthesia and Perioperative Care
Division of Pediatric Anesthesia
Program Director
Pediatric Anesthesia Fellowship Program
Jasmine H. Francis, MD, FACS

Assistant Attending Phy sician
Ophthalmic Oncology Service
Department of Surgery
New York, New York
Heather J. Frederick, MD, MHSc

Assistant Professor
Department of Anesthesiology
Duke University Medical Center
Durham, North Carolina
Debra L. Friedman, MD
Associate Professor of Pediatrics
E. Bronson Ingram Chair in Pediatric Oncology
Vanderbilt-Ingram Cancer Center
Cancer Control and Prevention Program
Director
Division of Hematology -Oncology
Vanderbilt University
Nashville, Tennessee
Alison M. Friedmann, MD, MSc

Assistant Professor
Hana Golan, MD
Department of Pediatric Hematology and Oncology
The Edmond and Lily Safra Children’s Hospital
Sheba Medical Center
Tel Hashomer, Israel
Daphne Haas-Kogan, MD
Professor and Chair
Brigham and Women’s Hospital
Dana-Farber Cancer Institute
Boston Children’s Hospital
Edward C. Halperin, MD, MA

Chancellor/Chief Executive Officer
Professor of Radiation Oncology, Pediatrics, and History
New York Medical College
Provost for Biomedical Affairs
Touro College and University
Valhalla, New York
Andrew T. Huang, MD
Professor
Department of Medicine
Duke University Medical School
Durham, North Carolina
President and CEO
Koo Foundation Sun Yat-Sen Cancer Center
Taipei, Taiwan
Mary S. Huang, MD
Assistant Professor
Pediatric Hematology and Oncology Unit
Massachusetts General Hospital for Children
John A. Kalapurakal, MD, FACR

Professor and Vice Chair
Northwestern University Feinberg School of Medicine
Chicago, Illinois
Shulamith Kreitler, PhD

Professor
School of Psy chological Sciences
Tel-Aviv University
Tel-Aviv, Israel
Director
Psy chooncology Research Center
Elena Abigail Krivoy, MSc

Senior Clinical and Medical Psy chologist
Department of Pediatric Hematology and Oncology
The Ruth Rappaport Children’s Hospital
Rambam Health Care Campus
Haifa, Israel
Larry E. Kun, MD
Clinical Director
St Jude Children’s Research Hospital
Chair
Department of Radiological Sciences
Memphis, Tennessee
Anne Laprie, MD, PhD

Assistant Professor
Department of Radiotherapy
Institut Universtaire du Cancer de Toulouse-Oncopole
Toulouse, France
Shannon M. MacDonald, MD
Associate Professor
Radiation Oncologist
Anita Mahajan, MD
Professor
Division of Radiation Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas
Monika Metzger, MD, MSc

Regional Director
South and Central American Regions
Member
Department of Oncology and Global Pediatric Medicine
St Jude Children’s Research Hospital
Memphis, Tennessee
Brandon R. Mancini, MD
Chief Resident
Department of Therapeutic Radiology
Yale School of Medicine
Yale University
New Haven, Connecticut
Karen J. Marcus, MD
Associate Professor
Division Chief
Division of Radiation Oncology
Boston Children’s Hospital
Katherine K. Matthay, MD
Mildred V. Strouss Professor of Translational Research in Childhood Cancer
Chief
Leader
Pediatric Malignancies Program
School of Medicine
UCSF Benioff Children’s Hospital
Ronica H. Nanda, MD
Chief Resident
Emory University
Atlanta, Georgia
Kenneth B. Roberts, MD
Professor
Department of Therapeutic Radiology
Yale School of Medicine
Yale University
Associate Chief
Yale-New Haven Hospital
New Haven, Connecticut
Scott R. Schulman, MD, MHSc

Professor
Department of Anesthesiology, Pediatrics and Surgery
Director
Department of Pediatric Cardiac Anesthesiology
Benioff Children’s Hospital
Eric Yi-Liang Shen, MD

Attending Phy sician
Chang Gung Memorial Hospital
Linkou, Taiwan
Nancy J. Tarbell, MD, FASTRO

CC Wang Professor
Dean for Academic and Clinical Affairs
Stephanie A. Terezakis, MD
Associate Professor
Department of Radiation Oncology and Molecular Radiation Sciences
Johns Hopkins School of Medicine
Baltimore, Mary land
Amos Toren, MD, PhD, MHA

Professor
Director
Division of Pediatric Hemato-Oncology
The Edmond and Lily Safra Children’s Hospital
Tel Hashomer
Tel-Aviv University
Tel-Aviv, Israel
Howard J. Weinstein, MD
Chief
Massachusetts General Hospital for Children
Professor of Pediatrics
Suzanne L. Wolden, MD, FACR

Member
New York, New York
Tel-Aviv University
Hopkins Hospital
Baltimore, Mary land
Michal Yalon Oren, MD, PhD

Head of Pediatric Neuro-Oncology Service
Department of Pediatric Hemato-Oncology
Torunn I. Yock, MD, MCH

Director
Department of Pediatric Radiation Oncology
Associate Professor
Chair
Radiation Oncology Quality Assurance
Quality Improvement Chair
Francis H Burr Proton Therapy Center
Preface
“Every child begins the world again.”

Henry David Thoreau
Evil spirits, the disharmony of celestial bodies, and the wrath of the gods were all invoked as
etiologies for what we today recognize as cancinos or carcinoma (coined by Hippocrates).
Ultimately, cancer was understood to be a my riad of diseases, but those afflicted were shut
away to die if surgical approaches (and those for children were pioneered in the 19th
century ) failed. In the art of antiquity, children were often depicted as small versions of
adults; similarly our treatment approaches were adapted from those suitable for adults. The
vulnerability of children to the effects of our therapies required visibility before substantial
progress could be made in curing without unacceptable harm. As radiation oncologists, we
are fortunate to spend our lives striving to help patients with cancer, curing them when
possible, and improving their quality of life when cure is bey ond reach.
Marie Curie said: “Nothing in life is to be feared. It is only to be understood.” She could
well have been alluding to the historic fears engendered by the my sterious force that was
radiation, but this axiom surely embodies the progress we have made with these diseases. It
was the compassion and passionate determination to cure children with cancer that permitted
the metamorphosis from hopelessness to optimism in its treatment, and this required the
unrelenting efforts of our professional predecessors.
In 1986, one of us (Edward C. Halperin) conceived the idea of a new textbook of
pediatric radiation oncology. While several general textbooks in radiation oncology existed,
none were specifically devoted to the use of radiation therapy in the treatment of childhood
cancer. When Dr. Halperin first proposed such a book, most publishing companies rejected it
on the grounds that the market was too small to sustain a book of this ty pe. After several
rejections, Raven Press of New York City had the foresight to agree. Dr. Halperin, at that time
a 32-y ear-old assistant professor, invited and persuaded his colleague Larry E. Kun, at St.
Jude Children’s Research Hospital in Memphis, Tennessee, to join him in the project. Drs. Kun
and Halperin then drew up the outline for the proposed book and completed the team with
Drs. Nancy J. Tarbell of Boston and Louis S. Constine of Rochester.
We had a very specific vision for this book. Most clinical radiation oncology textbooks
were massive tomes perfectly appropriate for propping a door open or lifting up the slide
projector for the morning lecture. Our goal for Pediatric Radiation Oncology was
considerably different because we wanted it to be manageable and engaging for y oung
phy sicians who had little time for exhaustive investigation in order to understand and propose
treatment for a new patient. We sought to write chapters that could be read in one sitting. We
envisioned a resident-in-training, the night before morning teaching conference, needing a
reliable book to turn to and read a chapter that would render him or her able to reasonably
defend a rational treatment approach for their patient. Furthermore, when we first envisioned
this book, it was well before the age of computer-augmented searches for journal articles or
expert (and trusted) summary information. We intended to sy nthesize data on pathogenesis,
pathology, diagnostic workup, staging, treatment approaches (particularly radiation therapy —
indications, doses, volumes, treatment planning), and toxic outcomes. We also intended to
provide rational judgment for decision making when data was lacking.
It is hard to believe that three decades have passed since Dr. Halperin’s concept both
germinated and blossomed into what will now be the sixth edition. Our founding principles
remain steadfast. We have tried to compose all of the chapters with a common voice,
avoiding repetition and maintaining uniformity of sty le. We have paid respect to historical
information and have paid due deference to the many controversies in the field. The passage
of time has allowed us to witness considerable evolution in pediatric radiation oncology. When
we wrote the first edition of this book, the role of radiation therapy in the treatment of
childhood leukemia, retinoblastoma, neuroblastoma, Hodgkin disease, Wilms tumor, and
Langerhans histiocy tosis were all vastly different than they are now. The information that we
were able to present to our readers about the late effects of cancer treatment (including
second malignant neoplasms) was also in its infancy.
The challenge of pediatric radiation oncology derives from the broad spectrum of
complex diseases, all with their own biology and natural history. The optimal and creative
integration of radiation therapy into their management requires a sophisticated understanding
of the disease as well as the adverse consequences of all treatment modalities. Pediatric
oncology scares many radiation oncologists because each new patient opens a foreign world
into which the doctor must not only enter but be successful. The stakes are high since most
childhood cancers are curable, but the child can be injured and live a long time with the
injury.
We have all aged (gracefully and wisely, we hope) through these 30 y ears together, and
through these editions. The reader will see evidence of the original authors having passed the
torch to the new generation of pediatric radiation oncologists in the writing of these chapters.
Passing the torch is an energy -requiring process since many radiation oncologists do not
become experts in pediatrics since the patient numbers are small, obtaining expertise requires
a huge investment of time, and there is little personal financial reward in return for the
investment.
The response to this book has been gratify ing. We never imagined in 1986 that there
would be six editions of this book and that it would have assumed a niche in the medical
literature. Indeed, we have sat at medical meetings and heard this text referred to simply as
“the book.”
We hope that all six editions of this book have contributed to an improved understanding
of the benefits and risks of radiotherapy for children. We remain resolute in our belief that the
dissemination of knowledge about pediatric radiation oncology will improve the quality and
quantity of life for children afflicted with cancer. We hope that this book helps to demy stify
pediatric cancer and its treatment.
Louis S. Constine
Nancy J. Tarbell
Edward C. Halperin
January 2, 2016
Acknowledgments
The preparation and collation of the sixth edition of this book is grounded in the multiple
previous editions that resulted from the dedication of the late Ruth Aultman in North Carolina
and Kentucky, Rebecca Bunker in Memphis, Laura Finger in Rochester, Erin Cromack and
Heidi Fliegauf in Boston, and Vera Rosario and Vilma Bordonaro in Valhalla. Emilie Moy er
and the staff of Lippincott Williams & Wilkins were, at all times, courteous and bey ond
helpful. The conscientiousness and skill of this staff has again given life to our book.
We are indebted to our mentors and teachers: J. Robert Cassady, Juan A. del Regato,
Sarah Donaldson, Samuel Hellman, Henry Kaplan, Rita M. Linggood, Jay Loeffler, Donald
Pinkel, Leon Rosenberg, Philip Rubin, Herman Suit, Samuel Thier, and John Truman.
The love of our families has been a source of constant strength to us.
CH A P TER 1
The Cancer Problem in Children
Edward C. Halperin
Page 1In 1900, cancer trailed ty phoid fever, malaria, smallpox, measles, scarlet fever,
whooping cough, diphtheria, croup, influenza, dy sentery, ery sipelas, tuberculosis, sexually
transmitted disease, meningitis, acute bronchitis, pneumonia, accidents, birth injuries, and
violence as a cause of death in children in the United States (1,2). Cancer mortality
constituted only 0.43% of mortality from all causes for children (1).
At the beginning of the 21st century, in
economically developed countries, many
children die every y ear from preventable
incidents such as traffic accidents, intentional
injuries, drowning, falls, fire, and poisoning. The
leading causes of death in infants are congenital
anomalies, disorders related to short gestation
and low birth weight, and sudden infant death
sy ndrome (3). The leading cause of death in
children older than 1 y ear is murder by a close Table 1.1 The Five Leading Causes of
relative. Cancer in children, however, has Death in the United States in 2011 for 1-
become a significant problem compared with to 19-Year-Olds
other causes of childhood mortality (4) (Table
1.1 ). In the United States, 1 in 285 children will be diagnosed with cancer before age 20
(5). In 2014, there were 10,450 new cases of cancer among children of age 0–14 y ears and
5330 new cases among children of age 15–19 y ears in the United States (5,6,7). Cancer is
now the leading natural cause of death among children between the ages of 1 and 14 y ears in
the United States (3). In late adolescence, homicide surpasses cancer as a cause of death.
Although cancer is a major cause of childhood death in developed countries, it continues
to trail infections as a cause of mortality in developing countries (6,8). In many parts of the
world, nutrition, housing, climate, and sanitation conditions create childhood mortality
statistics similar to those reported for industrialized countries in the early 20th century.
However, it is likely that future improvements in the standard of living, the success of
immunization programs, and dissemination of medical services will make inroads against
infectious disease, and thereby make childhood cancer a major cause of death in developing
nations.
Figure: The Five Leading Causes of Death in
the United States in 2011 for 1- to 19-Year-
Olds
RELATIVE FREQUENCY OF THE VARIOUS TYPES OF CHILDHOOD
CANCER
Adults generally get cancer of places where

their bodies interact with the environment; for
the most part, children do not. Whereas adults
often get cancer as a result of tobacco
consumption, dietary habits, and sun exposure of
the epithelial surfaces of the body, children get
cancer as a result of intrinsically occurring
mutations provoking oncogene and tumor
suppressor gene activity or inactivity (Table
1.2 ).
The relative frequency of the various ty pes
of childhood cancer is influenced by whether we
are examining incidence or mortality and by
how we stratify by age, sex, or nationality.
Table 1.2 The Five Most Common
Among the most commonly used data are those
Forms of Cancer in Adults in the United
of the Surveillance, Epidemiology, and End
States Compared with the Five Most
Results (SEER) program. SEER is a project of
Common Forms of Cancer in Children
the Biometry Branch of the U.S. National
Cancer Institute (NCI). The program draws data
from several population-based cancer reporting sy stems covering approximately 10% of the
total population of the United States (7,9) (Table 1.3 ). Leukemias, brain and spinal tumors,
ly mphomas, sy mpathetic nervous sy stem tumors (neuroblastoma), kidney (Wilms) tumors,
and soft tissue and bone sarcomas are the most common childhood cancers, whereas the
common epithelial tumors of adults are rare in children. Cancers that arise from embry onic
cells or in developing tissues and organ sy stems are characteristic of children and are rarely
seen in adults. Examples of embry onal cancers are neuroblastoma, Wilms tumor or
nephroblastoma, medulloblastoma (brain), hepatoblastoma (liver), retinoblastoma (ey e), and
rhabdomy sarcoma (muscle) (5,10).
Page 2Of the cancers that do afflict children, some are more common in specific age
groups. For example, neuroblastomas are more common in infancy. The ratio of non-
Hodgkin ly mphoma to Hodgkin disease favors non-Hodgkin ly mphoma in y ounger children,
but the reverse is true in adolescents. There is a steep rise in bone cancers among children
aged 11 through 15, which coincides with the adolescent growth spurt. The most common
tumors of neonates (y ounger than 28 day s of
age) are teratomas, retinoblastoma,
rhabdomy osarcoma, and neuroblastoma
(11,12). In 15-to-19-y ear-olds, the most
common forms of cancer are malignancies of
the brain and central nervous sy stem (20%),
followed by leukemia (13%), Hodgkin
ly mphoma (13%), thy roid carcinoma (10%),
gonadal germ cell tumors (9%), and melanoma
(5%) (6).
In general, approximately one-third of
childhood cancer deaths are caused by leukemia
and about one-fifth of these deaths are caused
by brain tumors (5,6,10,13,14) (Table 1.4 ). In
0-to-14-y ear-olds, U.S. cancer incidence and
mortality rates are lower in girls, whereas in 15-
to-19-y ear-olds, boy s and girls have similar
cancer incidence rates, with girls having lower
mortality rates. This may be related to
differences in the frequency of ty pes of cancer
in boy s versus girls. Non-Hispanic white and
Table 1.3 The Incidence Rates of
Hispanic children have the highest cancer
Cancer in the United States for 0- to 19-
incidence rates. African American children
Year-Olds Expressed as a Percentage of
have lower cancer survival rates (5).
the Total Number of Cancer Cases in This
About 175,000 cases of cancer are
Age Group, 2006–2010
diagnosed annually in children <15 y ears of age
worldwide. Less than 40% of these children are
adequately diagnosed and treated (5). Childhood cancer incidence varies throughout the
world. This may be related in part to fundamental issues of biology and demographics. It can
also be related to the reporting sy stem of a country and its level of economic development.
For example, the distribution of childhood cancers in Uruguay is very similar to that of North
America. Uruguay has a per capita income much higher than that of the rest of Latin
America and the Caribbean (15). However, the frequency of malignant solid tumors in
children in a report from Pakistan was distinctly
different from that in the rest of the world (16).
In Cuba, the most common childhood tumor is
leukemia (31%), followed by ly mphoma (18%),
central nervous sy stem (CNS) tumors (15%),
sy mpathetic nervous sy stem tumors (7%), soft
tissue sarcomas (6%), and renal tumors (5%)
(17). In Thailand, leukemias are most common
(40%), followed by CNS tumors (14%),
ly mphoma (12%), bone tumors (4%), and soft
tissue sarcomas (4%) (18). In Eastern Nigeria,
ly mphoma leads the list (19). Although the
absolute frequency of certain tumors is reported Table 1.4 The Most Common Causes
to be higher in developing countries than in of Pediatric Cancer Death in the United
industrialized states, there is likely to be variation States, 2007–2011, by Primary Cancer
in reporting standards, diagnostic techniques, and Site for Ages 0–19
histopathologic review (20,21).
Figure: The Five Most Common Forms of
Cancer in Adults in the United States
Compared with the Five Most Common
Forms of Cancer in Children
Figure: The Incidence Rates of Cancer in the
United States for 0- to 19-Year-Olds
Expressed as a Percentage of the Total
Number of Cancer Cases in This Age Group,
2006–2010
Figure: The Most Common Causes of
Pediatric Cancer Death in the United States,
2007–2011, by Primary Cancer Site for Ages
0–19
TRENDS IN CHILDHOOD CANCER MORTALITY RATES
Page 3The mortality rate from childhood cancer has fallen dramatically in the United States.
Particularly impressive gains have been posted for acute ly mphocy tic leukemia (ALL), bone
tumors (predominantly osteosarcoma and Ewing sarcoma), Hodgkin disease, non-Hodgkin
ly mphoma, soft tissue sarcomas (including rhabdomy osarcoma and nonrhabdomy osarcoma
soft tissue sarcomas), and Wilms tumor. Although gains have also been achieved for acute
my elocy tic leukemia (AML), neuroblastoma, and brain tumors, the improvements have been
less dramatic or confined to certain subgroups or stages (Table 1.5 ). In general, however,
the diagnosis and treatment of childhood cancer has been one of the success stories of
modern medicine.
Table 1.5 Trends in 5-Year Relative Survival Rates for Children with Cancer (0–14 Years
of Age) in the United States at the Approximate Midpoint of the Last Four Decades
An estimated 1350 cancer deaths in children 0–14 y ears of age and 610 cancer deaths in
15-to-19-y ear-olds occurred in the United States in 2014. It is clear that when compared with
adult cancer, childhood cancer is a vanishingly rare event. For example, in 2015 there were
158,000 estimated deaths from lung cancer alone in the United States (6). The comparative
infrequency of childhood cancer is highlighted by the fact that more people in the United
States die of lung cancer in 1 week than children die of all forms of cancer in 1 y ear. Looking
at the impact of cancer solely in this manner is insufficient. If one looks at a death from
cancer in terms of potential y ears of life lost, then the death of an 8-y ear-old from ALL has a
greater statistical weight than the death of an 82-y ear-old from small cell carcinoma of the
lung. Therefore, the success of medical treatment of childhood cancer has a significant public
health impact when considered in terms of the person-y ears of potential life lost or lifetime
earnings saved. A lifetime is saved for every child cured of cancer.
Figure: Trends in 5-Year Relative Survival
Rates for Children with Cancer (0–14 Years
of Age) in the United States at the
Approximate Midpoint of the Last Four
Decades
FUNDING OF PEDIATRIC CANCER RESEARCH
In the United States, there is a significant federally funded pediatric cancer research
program. Research focuses on treatment in cancer biology and the management of long-
term cancer survivors (Table 1.6 ). We know very little about pediatric cancer prevention
in contrast to the extensive efforts in tobacco and alcohol consumption control, reduction in
sun exposure, and dietary interventions promoted to reduce adult cancer. Unfortunately, the
amount of U.S. federal inflation-adjusted dollars spent on pediatric cancer research has fallen
in recent y ears (Table 1.7 ).
Table 1.6 Percentage of Total Dollars Spent by Scientific Area in Pediatric Cancer
Research by the United States National Cancer Institute for Fiscal Year 2013
Table 1.7 The Yearly Investment of the United States National Cancer Institute in
Pediatric Cancer Research
Figure: Percentage of Total Dollars Spent by
Scientific Area in Pediatric Cancer Research
by the United States National Cancer
Institute for Fiscal Year 2013
Figure: The Yearly Investment of the United
States National Cancer Institute in Pediatric
Cancer Research
IS THE INCIDENCE OF CHILDHOOD CANCER INCREASING?
From 2007 to 2011, the overall incidence rate for childhood cancer has increased by 0.6%
per y ear for children <15 y ears of age and has remained stable for 15-to-19-y ear-olds. From
1970 to 2011, the death rate for childhood cancer decreased by 67% for children <15 y ears
of age and decreased by 58% for 15-to-19-y ear-olds (6). Incidence rates in the United States
and Europe have increased for ALL and AML, non-Hodgkin ly mphoma, and testicular germ
cell tumors and decreased for Hodgkin disease; they are stable for other tumors (5). Experts
disagree about what might account for these data. Some have asserted that new diagnostic
techniques such as computed tomography (CT), magnetic resonance imaging (MRI), needle
biopsy, and serum chemical markers are increasing the rate of diagnosis of childhood cancer.
This would render the increase in childhood cancer as merely an artifact of improved
diagnostic techniques. The counterargument is that the rise in the incidence of childhood
cancer continues unabated even when new techniques are not introduced, and the rise in
incidence may be linked to environmental toxins. So far, alleged links include pelvic
radiography of mothers during pregnancy, the use of radioactive nucleotides during
pregnancy, radon, solvents, parental occupational exposure, diet, environmental tobacco
smoke, alcohol, and infection. The alleged link to agricultural and home pesticide use is weak,
and many studies find no correlation (22,23). While it has been suggested that exposure to
magnetic fields emanating from electric transmission and distribution lines and certain
electrical household appliances may be associated with some childhood tumors, studies are
contradictory (24).
Page 4SEER, the Manchester Children’s Tumor Registry in northwestern England, a
registry for Queensland, Australia, the Greater Delaware Valley Pediatric Tumor Registry,
and a study from Canada indicate an increase in cancer incidence in children of
approximately 1% per y ear, although a study in Denmark did not find a rising incidence
(24,25,26,27,28).
If we accept the premise that the overall incidence of childhood cancer is rising, then we
must bear in mind two potential confounding factors. First, the frequency of childhood cancer
is so low that it takes only a few cases, in registries covering a small population base, to
suggest a change in incidence (28). Second, as previously suggested, with the improvement in
diagnostic tools in modern medicine, more children will be correctly diagnosed with cancer
as opposed to another diagnosis. This effect may be particularly important for brain tumors
(27).
WHAT DOES CURE MEAN IN PEDIATRIC ONCOLOGY?
The English word cure is derived from the Latin term cura and the Old French term cure,
both meaning “care.” The generally accepted definition in medicine for cure is “successful
medical treatment; the action or process of healing a wound, a disease, or a sick person;
restoration to health” (29). There are several mathematical and statistical definitions of cure.
In 1963, Easson and Russel (30) suggested a definition for cure that was a modification of an
earlier definition proposed in 1929 by Greenwood (31): “We can speak of cure when in time
—probably a decade or so after treatment—there remains a group of disease-free survivors
whose progressive death rates from all causes is similar to that of a normal population of the
same sex and age constitution.” Patients and clinicians, during the 1960s and 1970s, became
comfortable with transitioning from the concept of “indefinite remission” to “cure” (32).
Frei and Gehan (33) suggested that survival should also be associated with continuing
morbidity from the disease or its treatment. Cure is not achieved when treatment stops or
even after a 5-y ear disease-free period. For each child with cancer and his or her family, the
meaning of cure is different. For some patients, it is the knowledge that the disease is gone and
never coming back. To others, it is the statement that they are well today and want to be so
tomorrow. For all children with cancer, hope is the common denominator and getting on with
life is the goal (34).
One way of expressing the probability of survival is a relative survival rate. The relative
survival rate is the ratio of the observed percentage of survival to the percentage expected on
the basis of general population experience, adjusted for age, sex, race, and calendar y ear.
Using this definition, a population of patients would be cured when a graph plotting relative
survival rate showed a horizontal line (32).
Pinkel (35) summarizes the criteria of biologic cure as completion of all cancer
treatment, continuous freedom from cancer relapse, and minimal or no risk of subsequent
relapse. It is important to consider the continuous cancer-free survival (other commonly used
terms are relapse-free survival and event-free survival) and the overall survival in
constructing survival curves. Overall survival rates reflect factors other than biologic
curability, including death caused by complications of treatment and subjective factors such
as the patient’s will to continue living with cancer or its repeated relapses, the phy sician’s
determination to keep the patient alive, and the technical and financial resources available to
the phy sician and the patient.
Page 5The reported cure rates in pediatric cancer may be affected by artifacts of data
acquisition and analy sis. The zero-time shift or lead-time bias will extend the statistical length
of survival without prolonging life. This phenomenon occurs when a new screening test or
imaging study leads to the detection of a previously unknown tumor. Even if therapy is
ineffectual, survival is increased by the interval provided by the earlier detection of the
cancer. The Will Rogers effect occurs when there are improved techniques for detecting
cancer metastases. These new detection techniques allow patients to migrate from lower
stages of cancer to higher stages. Such migration improves survival in lower stages by
eliminating those with metastatic disease. Survival also improves in higher stages because of
the addition of people with minimal metastatic disease. Survival improves in each stage, but
overall survival for the cancer is unaffected. This phenomenon is named after the American
humorist Will Rogers (1879–1935) who is reputed to have remarked during the economic
depression of the 1930s that “when the Okies left Oklahoma and moved to California, they
raised the average intelligence in both states” (36) (see Sidebar).
THE GROWING POPULATION OF CHILDHOOD CANCER SURVIVORS
With improving cure rates in childhood cancer, it is apparent that we must move bey ond the
statistical definition of cure (14,37). Cure is more than the absence of disease. It is important
to provide the child with a functional cure, regaining or retaining the ability to make one’s way
in society without major handicaps and minimizing the need for a significant support. The
U.S. prevalence estimate for individuals diagnosed with cancer at <20 y ears of age who are
now living ≥15 y ears and <36 y ears after diagnosis is approximately 113,000 (7). About 1 in
530 y oung adults between the ages of 20 and 39 y ears of age is a childhood cancer survivor
(5). This means that the average adult primary care phy sician will have several long-term
survivors of childhood cancer in his or her practice.
The Childhood Cancer Survivor Study is a multicenter study funded by the NCI. This
study of more than 14,000 survivors of childhood cancer shows that survivors are at a higher
risk of impaired pulmonary function, growth abnormalities, endocrine dy sfunction, obesity,
phy sical limitations, infertility, cardiac problems, reduced quality of life, depression, special
educational needs, and second malignant neoplasms (38,39). Pulmonary complications may
develop y ears after treatment. Cancer survivors have higher rates of lung fibrosis,
emphy sema, pneumonia, pleurisy, and a need for oxy gen compared with sibling control
subjects. Survivors of childhood ALL treated with >20 Gy of cranial radiotherapy were
significantly more likely to be overweight or obese than sibling control subjects (39,40).
T H E WI L L ROG E RS E F F E CT
The Will Rogers effect occurs when a new staging test, such as diagnostic imaging, is
introduced into cancer management (44). Assume that you evaluate 100 children
with a specific histologic type of cancer. After they complete a staging workup, they
are assigned a stage. For example, Stage I—localized; Stage II— regional spread; Stage
III—metastatic. Let’s say the 100 patients are distributed as follows.
Now, we will enter the 5-year survival probabilities and determine the overall
survival, in this case 44 of the 100 patients.
Then a new staging test is discovered. By detecting small foci of tumor spread, some
patients are moved from Stage I to Stages II or III. By removing these bad prognosis
patients from Stage I, the survival for Stage I rises—even if therapy is not improving.
Some patients who were formerly Stage II are reassigned to Stage III because of the
detection of tumor spread. Similarly, the survival rate of Stage II rises by extracting
these “bad actors” from the pool of Stage II patients. The Stage III patient group
enlarges—having acquired patients with minimal-volume metastatic disease. These
patients with low-volume metastatic disease do better than the traditional patient
with metastatic disease. (Imagine the difference between lung metastases detected
by CT, for example, vs. conventional chest x-ray.)
The survival rates of Stages I–III have risen as a result of restaging with new
technology and stage redistribution, but not as a result of improved therapy.
Interestingly, although the survival probability for every stage of disease rose, the
overall survival is still 44 out of 100 patients. The introduction of a new test that more
precisely stages patients has deceived us into thinking that our therapy has improved
—but it has not. As described in the text, this is “The Will Rogers effect.”
Page 6Late mortality rates are declining among pediatric cancer survivors. Armstrong
et al. studied 34,033 patients who were y ounger than 21 y ears of age at the time of diagnosis
of cancer and were at least 5-y ear cancer survivors. Median follow-up was 21 y ears.
Overall, there were 3958 deaths in the population. The most common causes of death were
secondary cancers (46%), heart disease (15%), and lung disease (8%). When comparing the
all-cause mortality rates for patients treated for cancer from 1970 to 1974 to those treated
from 1990 to 1994, the rate fell substantially (12% vs. 6%, p < 0.001). A likely explanation for
this decline in late mortality is a combination of refinement in therapy to reduce treatment
intensity when it is not warranted and better supportive care when late ill effects of cancer
treatment occur. Of particular note is the decline in the use of cranial radiotherapy in the
treatment of ALL (86% in the 1970s to 54% in the 1980s to 22% in the 1980s), Wilms tumor
(77% vs. 54% vs. 49%), and Hodgkin ly mphoma (96% vs. 88% vs. 77%) (41,42).
Overtime there has also been a decrease in exposure of many patients to cardiotoxic
chemotherapy. Patients treated for Hodgkin disease in the 1970s had an average
anthracy cline exposure of 295 mg/m 2, which dropped to 193 mg/m 2 in the 1990s.
Planning for adequate limb function, ambulation, and activities of daily living is crucial
in planning a course of treatment. Rehabilitation, including phy sical, occupational, and
recreational therapy, play s an important part in follow-up care. A comprehensive pediatric
cancer rehabilitation program requires people with expertise in prosthetics, orthoses, ostomy
care, gait training, and pain management (43,44,45,46).
Attention to the child’s emotional status is also important. This includes preserving and
nurturing a sense of well-being on the part of the child and his or her family. Childhood
cancer survivors are more likely than their siblings to suffer sy mptoms of depression and
somatic distress (48). The family should be given every measure of support in dealing with
illness and restoring health. The diagnosis and treatment of cancer exert severe emotional and
financial strains on a family. The term psychological cure refers to the ability to put cancer
behind y ou and move on with life (30).
Parental separation and divorce, sibling behavior problems, and the weight of family
responsibilities during adversity complicate the treatment and rehabilitation of the child with
cancer (49,50). The pediatric radiation oncologist should ensure an ongoing relationship with
the child and family after treatment to contribute to rehabilitation. As the survival rates for
pediatric cancers improve, we will have an increasing population of y oung adults who are
cancer survivors. These people will pose new problems for medicine and society : What will
be appropriate medical surveillance for late effects of treatment, including secondary
malignancy ? How will these patients be counseled concerning reproduction? What special
needs will such people have concerning employ ment, disability and health insurance, and
psy chological support? (44). A survey of 1437 childhood cancer survivors, >18 y ears old and
>10 y ears postdiagnosis, showed decreased marriage rates in irradiated hematologic
malignancy survivors and generally lower rates of employ ment (Table 1.8 ) (51). The
pediatric radiation oncologist will play an important role in understanding these issues and
implementing solutions (52).
Table 1.8 Marriage, Employment, and Health Insurance in Adult Survivors of Childhood
Cancer: A Survey of 1437 Survivors >18 Years of Age and >10 Years Postdiagnosis Treated at
St. Jude Children’s Research Hospital
Figure:
Figure:
Figure:
Figure: Marriage, Employment, and Health
Insurance in Adult Survivors of Childhood
Cancer: A Survey of 1437 Survivors >18 Years
of Age and >10 Years Postdiagnosis Treated
at St. Jude Children’s Research Hospital
SITE OF CARE AND THE PEDIATRIC CANCER TEAM
The 1969 edition of Nelson Textbook of Pediatrics reported that childhood “leukemia is a
uniformly fatal malignant disease.” Advances in the treatment of pediatric malignancies in
the subsequent four decades have been remarkable. This success is the result of a complex,
multidisciplinary process administered by a team of professionals (53).
Combined-modality therapy has been a rewarding approach. In the United States, about
90% of children with cancer are cared for at a member institution of the Children’s Oncology
Group (COG), an NCI-supported clinical trials group with about 100 trials open at any time
(5). A coordinated group of medical and surgical specialists with expertise in the clinical care
of children with cancer and in basic and clinical research best direct the child’s care. The
complete pediatric cancer center participates in clinical trials and is staffed by a pediatric
medical oncologist, specially trained nurses, a pediatric diagnostic radiologist, surgeons with
expertise in pediatric oncology, anesthesiologists, psy chiatrists, phy siotherapists, phy sicians
assistants, and social workers. The group must also include a radiation oncologist committed to
pediatric care and with experience in radiotherapy for children (52,53) (Table 1.9 ).
Table 1.9 Requirements for a Pediatric Cancer Center
Participation of the patient’s parents and other significant family members is an integral
part of the team approach. Parents will soon become extremely knowledgeable about their
child’s illness, its treatment, and the associated complications. They will become careful
observers of phy sical signs and sy mptoms, and their report of changes in the child’s well-
being will be invaluable to caregivers. Parents often develop important skills such as the care
of indwelling venous access devices. Parents may be taught to administer medications, titrate
their dosages, and oversee sy mptom management.
Going to school is the normal day time activity for most children. The child with cancer
should be encouraged to live as normally as possible. Participation in school is encouraged to
whatever degree is reasonable. Many hospitals maintain a program for schooling children
during their cancer care. In some states, the hospital itself is accredited as a public school and
certified teachers are on staff. These teachers, working closely with the local school districts,
can help children keep up with their studies and be more readily integrated back into their
classrooms at home.
There is evidence that the diagnosis and treatment of some pediatric malignancies,
particularly those dependent on complex radiotherapy, are better conducted at university -
affiliated medical centers. The available data suggest that there is a benefit to treatment at a
university -based or regional cancer center when the treatment is rapidly evolving and when
complex treatment approaches with technically difficult surgery or radiotherapy are needed.
However, it appears that the site of treatment does not alter survival rates for patients in
whom a cure may be achieved with surgical intervention alone, for tumors for which there is
no significant curative treatment, and for tumors necessitating multimodality therapy when
the most up-to-date protocol information and the services of a consulting expert are available
in the community hospital (54,55,56,57,58,59,60).
Figure: Requirements for a Pediatric Cancer
Center
POSTGRADUATE TRAINING IN PEDIATRIC RADIATION ONCOLOGY
Page 8There are serious gaps in residency training in pediatric radiation oncology in the
United States. The incidence of childhood cancer is low. In addition, only a portion of
childhood cancer cases are appropriate for radiotherapy. When one also considers the fact
that pediatric cancer cases are not uniformly distributed among the radiation oncology
training programs in the United States, one can readily understand why many residency
programs see less than five pediatric cancer cases per y ear. In some residency programs, the
few pediatric radiation oncology cases that are seen are heavily weighted toward palliative
cases, total body irradiation for bone marrow transplantation, or late adolescents with Hodgkin
disease. Therefore, it is very likely that a person could go through 4 or 5 y ears of
postgraduate training in radiation oncology and never see a case of retinoblastoma,
neuroblastoma, Wilms tumor, or Langerhans cell histiocy tosis.
There is an intrinsic problem with the way academic medical centers count the number
of pediatric radiation oncology cases for U.S. residency training accreditation. In adult
radiation oncology, guidelines exist for the appropriate number of lung, colorectal, breast,
head and neck, and genitourinary malignancies necessary for training. In the case of
pediatric cancer, however, all forms of cancer are lumped together to reach an acceptable
number. Such a policy would never be acceptable in taking an inventory of the appropriate
number of adult cases for training.
Some residency programs try to solve the problem by sending residents for away
rotations. With a 1-month rotation at another center, residents are expected to acquire
sufficient pediatric training for the 4 or 5 y ears of the residency program. In 1 month, it is
entirely likely that a resident would never see a patient taken from consultation through
simulation and all the way through completion of a course of treatment. Long-term follow-up
is also impossible.
Some have proposed eliminating pediatric radiation oncology training from general
radiation oncology training. By this line of argument, pediatric radiation oncology would
become a subspecialty, which would entail a separate fellowship at the end of a residency.
Another proposed solution is to designate only certain residency programs as capable of
providing pediatric radiation oncology training by virtue of the adequate number of cases and
faculty with sufficient expertise. It is highly unlikely that there will be approved subspecialty
training in pediatric radiation oncology in the near future. The designated accrediting boards
in the United States have a series of requirements for subspecialty designation that are too
formidable to be met in the case of pediatric radiation oncology. Therefore, it remains likely
that for the foreseeable future, pediatric radiation oncology residency training will continue to
be inadequate (61,62). Insofar as the burden of childhood cancer is far higher in low- and
middle-income countries (LMIC) than it is in high-income countries, one might envision
residency education being benefited by trainees taking clinical rotations in these LMIC.
THE PROBLEM OF EVIL AND CHILDHOOD CANCER
Phy sicians have a tendency to be comforted by scientific and/or epidemiological

explanations for the misfortunes which befall their patients. These explanations help the
doctor get through the day by convey ing the message that the world is an orderly and rational
place. By way of example, let us imagine that an adult primary care internal medicine
phy sician has arrived at her morning clinic. The first patient she sees is a long-term patient
who, today, is gasping for breath because of emphy sema.
“It’s terrible,” the doctor say s to the medical student who is following her in the clinic,
“but the patient smoked three packs of cigarettes for fifty y ears.”
The internist’s next patient has a gangrenous toe and will require hospitalization for
amputation and antibiotics.
“A great shame,” the doctor tells the student. “Of course she is very poorly compliant
with weight control and monitoring her blood sugar.”
The third patient of the morning is an 80-y ear-old with known bronchogenic carcinoma.
He has severe right hip pain. The doctor orders a plain X-ray of the hip, and there is clearly a
focus of metastatic cancer in the right ilium.
“Well,” the doctor tells the student, “it is most unfortunate and we’ll have to make a plan
for pain control and treatment of the site. Like the first patient of the day, however, this man
has been a heavy smoker, and I have never been able to get him to give it up.”
What has the doctor done, repeatedly, this morning? She has given a rational explanation
for why bad things happen to her patients. These explanations include chronic use of a known
carcinogen (cigarettes), a lifesty le that increases the risk of bad consequences of disease
(being overweight), and/or failure to heed medical advice (not monitoring blood sugar,
refusal to stop smoking). These explanations help make the pains and disappointments of
clinical medicine tolerable and make it easier for the doctor to get through the day.
Let us contrast this hy pothetical primary care internal medicine doctor with some of my
clinical experiences over the past y ear as a pediatric radiation oncologist. Last y ear, I
consulted on an elementary school student who developed visual changes. Imaging studies
supported the diagnosis of a large craniophary ngioma. An attempt at surgical resection both
failed to achieve complete excision and was complicated by a massive intraoperative bleed
and postoperative vasospasm and recurrent bacterial meningitis. Referred for radiotherapy
with residual tumor, the child had been unresponsive for months, imaging studies indicated
severe brain injury unlikely to improve, and she seems destined for life in a chronic care
facility.
Page 9Last month, I received word that a high school student whom I had consulted on
for the role of radiotherapy in the management of acute ly mphoblastic leukemia, the child of
a faculty colleague, had died after multiple relapses of leukemia and unsuccessful salvage
procedures.
Last week, I consulted on a high school student with ly mphoepithelioma of the
nasophary nx who, in addition to dealing with the vicissitudes of the tumor and the severe
mucositis attendant to radiotherapy and chemotherapy, has one biologic parent who is
incarcerated, another who is in and out of his life because, apparently, of substance abuse,
shuttles between the homes of relatives, and was not registered for any form of state-
supported health insurance because he does not have a fixed address in any one state.
What are the alleged rational explanations for why horrific things have happened to
these innocent children? Can y ou blame it on too much smoking, too much drinking, unsafe
sexual practice resulting in a viral infection, or failure to heed the doctor’s orders? Certainly
not! Being unable to explain pediatric tumors other than invoking the actions or inactions of
invisible oncogenes and tumor suppressor genes, I, the other caregivers in the three cases, and
the parents and relatives of the children have no one and nothing to blame. “Why did bad
things happen to these children?”, some people cry out. “I am angry with God.” (63)
The Prophet Isaiah say s that a monotheistic God gets the credit for good in the world and
the blame for evil. “I form the light and create darkness. I made peace and create evil. I The
Lord do all these things.” (Isaiah 45:7) (64) Why would an all-knowing, all-just, all-powerful,
and all-merciful monotheistic Divinity create such a world? Is there some discernible purpose
to it? Albert Camus writes in The Plague that he cannot conceive of a god worth believing in
who would permit the sufferings and death of innocent children. (65) Epicurus (341 BCE–270
BCE) is credited with a succinct summary of the theological problem of evil via what is often
referred to as “The Epicurean Paradox.”
Is God willing to prevent evil, but not able?

The He is not omnipotent.
Is He able, but not willing?
Then He is malevolent.
Is He both able and willing?
Then whence cometh evil?
Is He neither able nor willing?
Then why call him God? (66,67,68)
The great biologist Charles Darwin (1809–1882) grappled with the concept that the
human mind could discern a rational explanation for evil in the world. In an 1860 letter to the
American botanist Asa Gray (1810–1888), Darwin wrote
…I cannot see as plainly as others do, and as I should wish to do, evidence of
design and beneficence on all sides of us. There seems to me too much misery
in the world. I cannot persuade myself that a beneficent and omnipotent G-d
would have designedly created the Ichneumonidae with the express intention
of their feeding within the living bodies of Caterpillars, or that a cat should
play with mice. Not believing this, I see no necessity in the belief that the eye
was expressly designed. On the other hand, I cannot anyhow be contented to
view this wonderful universe, and especially the nature of man, and to
conclude that everything is the result of brute force. I am inclined to look at
everything as resulting from designed laws, with the details, whether good or
bad, left to the working out of what we may call chance. Not that this notion
at all satisfies me. I feel most deeply that the whole subject is too profound for
the human intellect. A dog might as well speculate on the mind of Newton
(69).
The insolubility of the theological problem of evil, and the way in which it makes many
people turn away from a belief in a monotheistic God, was recognized by the great Jewish
phy sician-philosopher living and working in The Golden Age of Islamic Medicine,
Maimonides (1135–1204).
It is something which pains the heart and troubles the mind. From it alone
many throughout the generations have been drawn to completely reject belief.
It is the fact that we see in the world crooked judgment, the righteous
suffering while the wicked enjoy a good life. People say: “Why do these men
succeed in their ways, while that one and that one, who appear to be
righteous, are destroyed?” This is the root of rebellion within every nation and
tongue (70)
COMMON RESPONSES TO THE PROBLEM OF EVIL
Any practicing pediatric radiation oncologist will have heard and will accumulate, over their
career, an extensive collection of responses to the theological problem of evil. These
responses include:
There is no monotheistic God. Instead we live in a world of, at the least, Dualism. There
is a good god and a bad god—or there are multiple good gods and bad gods. They might
have names like God and Satan or may be we’ll call them something else but, whatever
we call them, sometimes one force is prevailing over the other and sometimes the
reverse. When there are floods, epidemics, and when innocent children die of cancer,
the evil force or evil god is in the driver’s seat. When people fall in love, when people
recover from illness, and when we financially prosper, we thank a good god for his/her
manifold blessings.
There is no monotheistic God. Instead, there is no God at all. Humans are on this earth
because of a collection of random events which, through the processes of evolution,
resulted in us being here. This same set of evolutionary processes made oncogenes and
tumor suppressor genes. Bad stuff happens. It just does and there is no point in asking the
“Why ?” question because there is no answer other than “Because it just does.” Bridges
collapse, a speeding car kills y our pet dog when he runs out into the street, and y our
patient dies of acute my elocy tic leukemia after a bone marrow transplant. Put on y our
big boy underwear and deal with it.
There is a God and He/She maintains a grand balance scale of justice. When y ou do
something wrong the Divine bean counter tallies it. Eventually y ou or y our descendants,
including y our children, are going to pay the piper for the misdeed—including y our
children or grandchildren getting cancer. Sometimes the misdeeds are not y ours as an
individual, but ours as a society or culture. If we act sufficiently badly as a city, then we
will be wiped out like Sodom and Gomorrah. If we act badly as a society, but not
sufficiently badly to be wiped out, then we’ll be punished by pestilence, including
childhood cancer.
Page 10There is a God and we achieve a greater knowledge of Him/Her and closeness
to the Divine via suffering. Suffering is redemptive because it educates and purifies. It is
a way to achieve true self-understanding and Divine Grace.
There is a God and He/She knows best. We don’t. Every thing happens for a reason. G-d
decided to have the sun come up this morning and go down tonight. God decided that y ou
would find y our life partner and marry him/her. God decided y ou would get into
medical school. God decided that a 9-y ear-old should get an aggressive pontine glioma.
There is a God, and He/She is doing the best He/She can under the circumstances.
He/She is unable to prevent the suffering of the innocent. Therefore, God joins with His
people in their suffering.
There is a God and He/She doesn’t get involved in the affairs of humankind. The good
and bad that happens to people is either of their doing or the result of evolution. You’re
free to pray if y ou want but y ou’re alway s going to get the Divine answering machine.
The pediatric radiation oncologist can be paraly zed into immobility by the question
“Why does this innocent child, who did nothing to deserve this, have cancer?” The child
with cancer, however, does not need a phy sician rendered numb by the cruelty of the
world, they need a phy sician prepared and capable of taking action. I have found that the
most satisfy ing response to the problem of evil is to be found in the writings of Joseph
Solovetchik. It is difficult to do justice to the breadth and depth of his extraordinary
exposition of the issue in a few sentences but, in essence, he say s the following: When
faced with evil in the world it is human nature to ask “Why ?” However, if one believes in
the existence of a God who exceeds all human comprehension, then there is no
imaginable language one can use to engage in a conversation with Him/Her about
“Why ?” Do not spend y our time and energy posing and seeking answers to an
unanswerable question. Rather, the only correct action for an ethical person is to expend
their time and energy to take action dealing with evil (71).
It is in taking action to diagnose, treat, and comfort his/her patients that the pediatric
radiation oncologist can best respond to the theological problem of evil.
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CH A P TER 2
Leukemias in Children
Larry E. Kun
Page 12Leukemias are the most common cancer ty pes in children, representing nearly 30%
of all childhood cancers in North America. The most common leukemia is acute
ly mphoblastic leukemia (ALL), accounting for 80% of childhood leukemia and nearly 24%
of all cancers in children. Approximately 3000 children present with ALL annually in the
United States. ALL was the prototy pe childhood cancer documenting response and,
subsequently, cure with chemotherapy and the importance of combined modality therapy
that incorporated irradiation or site-specific chemotherapy for “sanctuary sites.” The
development of therapeutic approaches in ALL set another precedent in oncology,
demonstrating the value of serial, prospective clinical trials to introduce progressively more
successful treatment regimens. It is no exaggeration to attribute the early success in leukemia
control to the introduction of central nervous sy stem (CNS) irradiation, a fundamental
component of the earliest successful leukemia regimens developed in the 1960s that has been
extensively studied in serial intervals, identify ing subsets of ALL at higher risk for CNS
disease and weighing relative effectiveness and toxicities of CNS-directed chemotherapy or
irradiation (Fig. 2.1 ).
Approximately 20% of childhood leukemia presentations are acute my eloblastic
leukemia (AML), a disease that is more common in adults. Successful management of AML
has lagged behind that of ALL historically, and the role of radiation therapy remains poorly
identified. However, AML has been one of the more common indications for bone marrow
transplant (BMT) in children, and the use of total body irradiation (TBI) in this setting has
been rather common. Transplant regimens continue to evolve, with increasing indications for
radiation immunosuppression, as the host pool
for allogeneic transplants now commonly
includes matched unrelated and haploidentical
donors.
Figure 2.1 Outcome in childhood ALL

serial “total” therapy studies at St. Jude
Children’s Research Hospital 1962–
2013;2007. EFS (top) and OS (bottom) for
2628 children treated on 15 consecutive
trials. Reprinted from Pui CH, Evans WE.
A 50-year journey to cure childhood acute
lymphoblastic leukemia. Semin Hematol.
2013;50(3):185–196. doi:
10.1053/j.seminhematol.2013.06.007 .
Figure:
Outcome in childhood ALL serial “total” therapy studies at St. Jude Children’s Research
Hospital 1962–2013;2007. EFS (top) and OS (bottom) for 2628 children treated on 15
consecutive trials.
Reprinted from Pui CH, Evans WE. A 50-year journey to cure childhood acute lymphoblastic
leukemia. Semin Hematol. 2013;50(3):185–196. doi: 10.1053/j.seminhematol.2013.06.007.
ACUTE LYMPHOBLASTIC LEUKEMIA
Biology
ALL results from a clonal expansion of dy sregulated, immature ly mphoid cells. The linkage
of ALL subty pes to the major immunophenoty pic ly mphocy te lines provided the first
biologic understanding of the disease ty pes that correlate biologic characteristics with
common clinical features. B-precursor leukemias account for 85% of ALL cases in children.
Most cases of B-precursor ALL consist of leukemic clones from early pre–B-cell lines (55%;
cy toplasmic immunoglobulin [cIg] negative) or pre–B-cell lines (25%; cIg-positive). T-
precursor ALL accounts for 15% of cases of childhood ALL (1). B-cell-derived ALL
ty pically occurs in y oung children, associated with a wide range of clinical manifestations
and initial white blood cell (WBC) counts. Classically, T-cell ALL occurs in boy s over 10
y ears old and is more often associated with extramedullary involvement (mediastinal ly mph
nodes and the CNS) and high presenting WBC (2).
Page 13Enormous advances in the understanding of ALL have accompanied studies of
the cy togenetics and genome sequencing of this disease (3,4)(Fig. 2.2 ). Translocation
t(1;19) is ty pical of pre–B-cell immunophenoty pe, while translocation t(11;14) is often
present in T-cell immunophenoty pe. The earliest distinct molecular characteristic in
childhood leukemia was the demonstration of Philadelphia chromosome Ph+, associated with
chronic my elogenous leukemia in adults, in up to 5% of children with B-precursor ALL. Ph+
cases have translocation t(9;22) often in the presence of the BCR–ABL1 fusion gene; the
genoty pe has been associated with a relatively high risk of relapse, especially in adolescents
(3,5). Other genoty pes are also associated with relatively more aggressive disease requiring
intensive chemotherapy regimens to enjoy outcomes more comparable to the broad
category of B-cell leukemias. BCR–ABL1-like (Ph+ like) B-cell ALL accounts for 10% of B-
lineage leukemia, and those also showing IZKF1 have a less favorable prognosis. Between 5%
and 7% of B-lineage ALL express CRLFZ, including 50% of those with Down sy ndrome–
associated ALL; such presentations also require relatively intensive chemotherapy to
overcome a less favorable outcome (4). Pre–B-cell disease with t(1;19)(q23;p13) and
expression of TCF3–PBX1 fusion is associated with an increased risk of CNS relapse (6).
Infants less than 1 y ear old often show MLL rearrangement; high expression of FLT3 is
apparent in most infants not showing the MLL findings (4). Among the children and
adolescents presenting with T-cell ALL, the 15% with early T-cell precursor ALL have been
at relatively high risk and show immunologic, gene expression, and mutation findings all
suggestive of a my eloid leukemia, suggesting a stem cell leukemia (7).
Figure 2.2 Genotypes in childhood ALL, including genetic findings in B-cell lineage or all
ALL immunophenotypes; genetic findings unique to T-cell ALL are in purple shades. Reprinted
from Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med.
2004;350(15):1535–1548, with permission.
Pharmacokinetics and pharmacogenetics impact tolerance and efficacy of

chemotherapy, key to management of ALL. Inherited poly morphisms of the gene
responsible for expression of thiopurine methy ltransferase (TPMT) are related to
mercaptopurine (6-MP) use, one of the standard agents in this disease. Unstable or diminished
TPMT function results in increased hematotoxicity and secondary leukemias associated with
6-MP dosing; in addition, use of 6-MP concurrently with cranial irradiation has been related
to increased incidence of secondary brain tumors in the TPMT-deficient population (4,8,9).
Clinical Presentation
The median age at presentation for ALL is 4 y ears, with a peak occurrence between 2 and 4
y ears. Boy s are more commonly affected than girls, particularly with T-cell ALL. ALL is
less common in African-American children. Earlier studies demonstrated unfavorable
outcome in adolescents and in African-American children; more recent results are similar
among children with standard-risk ALL (10). More aggressive disease has also been
associated with >10% Native American genetic ancestry (4).
Page 14The most common presenting sy mptoms include fever, bleeding, and bone pain.
Findings at diagnosis include ecchy moses or petechiae, signs of ly mph node enlargement,
and hepatosplenomegaly. The diagnosis is suspected with a complete blood count (CBC)
demonstrating the presence of immature ly mphoblasts in the peripheral blood or elevated
WBC (WBC is less than 10,000/mL in 50% of presentations, 10,000–50,000/mL in 30%, and
more than 50,000/mL in 15–20% at diagnosis). Less often, clinical sy mptoms or signs are
associated with extramedullary involvement of the CNS, testis, or kidney.
ALL is a sy stemic disease by definition, usually involving the bone marrow diffusely
and associated with ly mphoblastic infiltration, either microscopic or overt, in a number of
organ sy stems (e.g., ly mph nodes, liver, and spleen). CNS leukemia is usually asy mptomatic;
extensive leptomeningeal disease may be manifest clinically by irritability, headaches,
sometimes vomiting or unanticipated weight gain (the hy pothalamic sy ndrome), cranial
nerve palsies (especially VII; less often VI, III), or seizures. Advanced disease sometimes is
manifest by papilledema and diffuse retinal infiltration (Fig. 2.3 ). The pathophy siology
was demonstrated in Price and Johnson’s classic description of leukemic cells filling the
subarachnoid space well into Virchow–Robin spaces and throughout the basal cisterns (11).
Staging: Risk Categories for ALL

The clinical criteria used in determining risk group for pediatric ALL were agreed upon at an
NIH-sponsored Consensus Conference in 1995. Low risk has been defined as B-precursor
ALL in children between 1 and 10 y ears presenting with WBC <50 × 109/L (50,000/mL)
(12). Other features currently identified as low risk include DNA index of >1.16 or presence
of TEL–AML1 fusion (13). The standard (intermediate) risk patients include infants below 1
y ear, children 10 y ears or older, B-cell lineage with WBC over 50,000/mL, all those with T-
cell lineage, and cases with t(1;19)/E2A–PBX1 fusion, overt CNS disease (CNS 3), or
testicular involvement (13). High-risk disease at diagnosis is limited to those with t(9;22)/BCR–
ABL1 fusion with Philadelphia chromosome–positive ALL or BCR–ABL1-like fusion (with
Ph+ like ALL) (13,14,15). In addition to clinical and biologic features at diagnosis, one of the
most important predictors of outcome is early response to induction chemotherapy : patients
with residual bone marrow leukemia (minimal residual disease or MRD, quantitatively
defined by immunohistochemistry or poly merase chain reaction [PCR]-identified blasts at
≥1% on day 19 of induction therapy or ≥0.01% at completion of 6 weeks of induction therapy )
are at higher risk for relapse and are treated as standard risk (despite low-risk presenting
features); those with ≥1% residual at the latter interval are all treated as high risk (13,15,16).
Recent studies show 45–50% of cases treated as low risk, 40–45% as standard risk, and 8–10%
as high risk (13,17). With more aggressive, risk-adapted therapy, many of the previously
identified outcome correlates are no longer significant, including mature B-cell or T-cell
immunophenoty pes, race, and gender (13,18,19).
Staging: CNS Involvement in ALL

The diagnosis of CNS disease in leukemia was
standardized by the Rome Workshop as the
presence of ≥5 WBC/µL in the cerebrospinal
fluid (CSF) with identifiable blasts or the
presence of cranial nerve palsies believed to be
related to CNS infiltration (20,21). CNS disease is
classified as CNS 1 (no blasts), CNS 2 (blasts
with <5 WBC/µL), or CNS 3 (as above: ≥5 WBC/
µL and cy tologic or biologic evidence of blasts
in the CSF, and/or the presence of cranial nerve
palsies) (20). Studies at St. Jude Children’s
Research Hospital (SJCRH) showed that a
traumatic lumbar puncture early in
diagnosis/therapy (iatrogenic introduction of
circulating blasts into the CSF) is equivalent to
CNS 2 disease (22). At diagnosis, overt CNS
disease (CNS 3) is documented in no more than Figure 2.3 The retinal photograph
3–5% of children; the proportion with CNS 2 demonstrates advanced CNS leukemia
status has varied between 5% and 10–30% (23). with papilledema and retinal infiltrate
CNS 2 or CNS 3 at diagnosis was associated with typical of ocular disease.
a less favorable outcome; more intensive
sy stemic and IT chemotherapy has essentially eliminated the impact of CNS 2, y et
identify ing CNS 3 as a negative finding at diagnosis (13,24,25).
Treatment: Chemotherapy
Therapy for ALL includes remission induction, CNS- directed therapy, intensification (or
consolidation), and continuation therapy. Ty pical remission induction combines corticosteroids
(prednisone), vincristine, and asparaginase. Dexamethasone is often substituted for
prednisone during CNS-directed therapy only (due to greater CNS penetration)(4,18).
Intensification (or consolidation) follows remission induction and incorporates aggressive
drugs and regimens to continue maximal early cy toreduction. The most commonly used
agents include methotrexate (MTX; at high dosages, ty pically 1–5 g/m 2 repeatedly during
this phase), 6-mercaptopurine (6-MP), and asparaginase. Reinduction is also a component of
consolidation, shown to improve disease control (25,26). Patients with BCR–ABL1 fusion gene
(Ph+) deficit and poor initial response (with positive MRD) appear to benefit from allogeneic
BMT in intensification (27). More recently, studies in the United Kingdom (UK) have shown
that augmented postremission chemotherapy can obviate the need for hematopoietic stem
cell transplant for clinical low- and standard-risk leukemia and positive MRD (28). In addition,
children with low-risk ALL and negative postinduction MRD can be successfully treated with
reduced therapy (29).
Page 15Continuation therapy is a routine part of therapy for ALL presentations
administered for ≥2 y ears (5,30). It is ty pically weekly low-dose MTX and 6-MP. The goal of
continuation therapy is to eliminate residual, slowly replicating leukemic blasts or to
sufficiently suppress leukemic cell division to allow programmed cell death to intervene.
Active CNS-directed therapy is given early during remission induction, consisting most
often today of intrathecal (IT) chemotherapy (methotrexate alone or as triple-IT therapy,
also including cy tarabine and hy drocortisone) along with intermediate-dose intravenous
methotrexate (and delay ed leucovorin rescue to diminish sy stemic toxicity of exposure to IT
methotrexate as it elutes into the sy stemic circulation). There is a balance of IT therapy, triple
agent versus methotrexate alone, and the use of higher dose intravenous methotrexate with
the latter to more directly address sy stemic disease. Studies have shown relatively more
effective CNS control with the TIT approach, but suggestions of better control of hematologic
and extramedullary (e.g., testicular) sites with the latter. (4,31) Selective use of preventive
CNS irradiation is addressed below.
Long-term leukemia-free survival is now achieved in over 85–90+% of children with
ALL (4,8,31,32,33,34). Low-risk ALL can be cured in 90–95% of cases, while standard-risk
patients can anticipate disease-free survival rates greater than 80%; children with high-risk
features are reported to show EFS of 50–70% depending on the threshold for defining high
risk (13,18,24,32,33).
Treatment: CNS Preventive Therapy

Evolution of CNS Preventive Therapy in ALL
The initial concept for preventive CNS irradiation was derived from animal experiments with
the mouse L1210 leukemia model: “leukemia control” was possible only when CNS
irradiation was added to intraperitoneal chemotherapy (35). Investigators at SJCRH first
applied the experimental model to children with ALL in the 1960s. Taking a “total” approach
to the disease, they used induction chemotherapy (vincristine, prednisone) in sequence with
prolonged, nonaggressive maintenance therapy (oral MTX and 6-MP) (36,37,38).
Craniospinal irradiation (CSI, at 5–12 Gy ) was added following the observation that CNS
relapse was the dominant event once hematologic remission extended bey ond 6–12 months
(36). CNS preventive therapy evolved through serial studies at SJCRH and in Cancer and
Leukemia Group B (CALGB). CSI or cranial irradiation (CrI) at 24 Gy (CrI with intrathecal
methotrexate [IT-MTX]) reduced the incidence of CNS relapse from >60% to <5–10%
(36,39). When randomized to preventive CSI (pCSI; 24 Gy ) versus equivalent therapeutic CSI
at overt CNS relapse, markedly higher event-free and overall survival and quality of life
were noted with pCSI (40,41). Subsequent trials proved the advantage of CrI at 18 Gy (1.5–
1.8 Gy per fraction) combined with IT-MTX as the “standard” preventive regimen
(42,43,44,45).
Other approaches to preventive CNS therapy have included high-dose sy stemic MTX
and increased IT-MTX or TIT as above (43,44,46,47). More recent trials have limited CrI by
defining cohorts at progressively higher risk for CNS relapse as most likely to benefit from
CrI—seeking to balance the efficacy of CrI with radiation-related toxicities (in particular
neurocognitive deficits and secondary neoplasms) (2,14,23). The Dana-Farber Cancer
Institute (DFCI) Childhood ALL Consortium Protocol 95-01 included preventive CrI for 60%
of children: all high risk (defined by WBC >50,000/mL, T-cell ALL, Ph+ or t(9;22)) and, by
randomization, half the standard risk (randomized to CrI vs. more intensive IT
chemotherapy ); girls with WBC <20,000/mL were assigned to the IT arm. The high-risk
cohort was randomized between 18 Gy in 10 fractions (180 cGy once daily ) or in 20
fractions (90 cGy twice daily ). The EFS and OS at 5 y ears were 82% and 90%, respectively ;
the rate of CNS relapse was 3% overall and 0.6% as an isolated event. CrI was associated
with zero isolated or combined CNS relapses in the standard-risk group; the IT group was not
different, with <2% combined and 1% isolated CNS failures (2). There were no differences
in neurocognitive function when intensive IT was compared to CrI18 Gy (48). The German
Austrian Swiss ALL-BFM-95 study limited preventive CrI (dose = 12 Gy ) to those > 1 y.o.
with T-cell ALL and high-risk disease (high early MRD, t(9;22) or BCR–ABL1, or t(14;11) or
MLL–AF4). Compared to the earlier ALL-BFM-90 trial, CrI was used in 10% instead of >50%
of cases, with EFS in BFM-95 of 80% and OS of 87% at 6 y ears; CNS relapse was 1.8%
isolated and 4.1% overall (49). The cohort of medium risk, age >1 y ear with pre–B-cell
disease who received 12 Gy CrI on BFM-90 showed equivalent EFS but superior CNS control
when no CrI was given in BFM-95: overall CNS relapse 4.4% versus 1.9%, and isolated CNS
failure rates 2.2% versus 0.5%—statistically superior, if perhaps not clinically meaningful
(49).
Secondary disease control following CNS relapse in BFM-95 trial was 58% at 6 y ears
postrelapse (14).
St. Jude Total XV trial was designed specifically to test eliminating CrI even with CNS 3
involvement at diagnosis, the first major US prospective trial assessing intensive TIT and
sy stemic chemotherapy to totally replace CrI (13). The impetus was based on the high rate
of secondary neoplasms identified in the preceding St. Jude Total XII trial (12–20%)
(9,32,50,51) (Fig. 2.4 ). Trials XIIIA and XIIIB had shown CNS relapse rates of 1.2% and
1.7%, respectively, with thresholds for preventive CrI resulting in 22% and 12% of
participants receiving CrI, respectively (26). Total XV was powered to document a low rate
of CNS relapse even in the highest-risk category, defined in the key Italian-BFM report as T-
cell ALL with WBC >100,000/mL at diagnosis (13,52). On comparing the highest-risk cohort
regarding CNS disease in Total XV trial with the 12% of similarly presenting patients who had
received CrI on the earlier Total XIIIA-B studies, EFS was statistically equal or better in the
Total XV group without CrI (13). Despite the high overall EFS and low rate of CNS relapse,
one must note the low rate of overall disease control (43%) in the CNS 3 cohort without use of
CrI (13,23,53).
Figure 2.4 Craniospinal irradiation for CNS leukemia. A: Sagittal CT simulation
reconstruction showing eye (yellow) and optic nerve (blue) at the midorbital level; cranial
irradiation for CNS leukemia includes the subarachnoid extension along the optic nerve
sheath and the posterior retina (see Fig. 2.6 ). B: Midline sagittal CT simulation
reconstruction showing the cribriform plate (red) volume providing margin at key anatomic
regions (A and B) for craniospinal therapy in ALL.
Standard-risk ALL can be treated without CrI (14,42,43,45,47). The group for which CrI
may be beneficial is the cohort with T-cell ALL and presenting with WBC greater than
100,000/µL. Approximately 20% of children with T-cell ALL (or 2% of all children with
ALL) present with high WBC and seem to benefit from preventive CrI (14,54). Because HD-
MTX and IT-MTX have been associated with neurologic sequelae, there is also interest in
considering further CrI dosage reduction (12 Gy /8 fractions in the more recent BFM studies)
(43).
Page 16Current Recommendations for Preventive CNS Therapy

It is unclear whether absolute avoidance of CrI (preventive or “therapeutically ” for overt
CNS disease at diagnosis) reflects the best current understanding of the relative effectiveness
and major toxicities of CrI and the more intensive MTX (sy stemic and IT) required in high-
risk settings when not using CrI (55,56,57,58). Contemporary ALL regimens include
indications for preventive CrI in 0–20% of children (13,23,25,59,60). There remain cohorts
with T-cell disease and high WBC, Ph+ (t(9;22)) presentations, and B-cell precursor ALL with
t(1;19) where the risk of CNS relapse may exceed 5–10%, and the use of 18 (or 12) Gy CrI
may offer superior CNS control, but data do not currently substantiate a CrI-related benefit in
EFS or overall survival (13,59,60,61). Other studies show a benefit in those with CNS 3 at
diagnosis in T-cell ALL, a group otherwise at high risk for competing events that have
diminished over time with the introduction of more intensive IT and sy stemic methotrexate
and the use of intensive asparaginase, but show no difference when analy zed by sy stematic,
risk-directed, CNS-positive only, or complete absence of CrI (60,61).
Radiotherapeutic Management
Volume
For cranial irradiation, the target volume
includes the entire intracranial subarachnoid
space. The key margins are at the skull base: the
cribriform plate (the lowest point of the anterior
cranial fossa, located in the midline at a level
that is ty pically below the orbital roof) and the
lower limit of the temporal fossa. It is a good
practice to outline the cribriform plate to ensure
adequate coverage (Fig. 2.5 ) (62). By
convention, the lower border is at the inferior
margin of the second cervical vertebra.
Documentation of retinal involvement as a
rare manifestation of markedly advanced CNS
leukemia has led to a standard requirement to
Figure 2.5 Lateral field for cranial
include the posterior retina and orbital apex in
irradiation in ALL. Note margin below
the target volume, subtending the extension of
cribriform plate (pink) and middle cranial
the subarachnoid space around the optic nerves.
fossa (blue). Targeted volume includes
Several techniques allow one to encompass the
posterior eye (yellow) and orbit.
posterior orbits and globes while sparing the
sensitive anterior aspect of the globe and lens,
from geometric 2D approaches to IMRT. One may need to accept a dose in the lens
approximating 20% of the projected target volume dose in order to adequately cover the
cribriform plate (63).
Dosage
Dosages for preventive CrI range from 12 to 18 Gy in current practice, with meta-analy ses
suggesting no difference between 18 and 24 Gy. Fractionation ty pically is at 150–180 cGy
once daily (2,23,25,59).
Treatment of Established CNS Leukemia

CNS Leukemia at Diagnosis
CNS leukemia is present at diagnosis in 2–5% of children (20,49,64). Under the “CNS staging”
sy stem, up to 20% of children at diagnosis show positive CSF cy tology, but the incidence of
true CNS leukemia (CNS 3: positive CSF cy tology and WBC ≥5/µL) is approximately 5%
(20,25,42,49,65). Earlier trials found CNS leukemia at diagnosis associated with a negative
outcome. More intensive sy stemic and IT chemotherapy have successfully eliminated CNS
relapse in children with CNS 2 disease (positive CSF cy tology and WBC <5/L)
(20,25,42,49,65). Therapeutic CrI or CSI has been used in most series for children with CNS 3
disease; the impact of CNS involvement on outcome has been diminished and, in some series,
eliminated with such intervention (49,64,66). Nevertheless, the ALL-BFM-95 trial showed 6-
y ear EFS of only 58% with CNS 3 at diagnosis (following therapeutic CrI sy stematically at 18
Gy ) compared to 80% overall 6-y ear EFS, and SJCRH Total XV trial showed 5-y ear EFS of
43% (with CrI only for residual CNS disease after induction) compared to 86% overall 5-
y ear EFS (13,14). The latter series (obviating irradiation except with residual CSF positivity
after induction therapy ) showed excess CNS and hematologic relapse and death (13).
Page 17Radiotherapeutic Management

Most current protocols include consolidative CrI after intensification therapy for children with
CNS 3 disease at diagnosis (Table 2.1 ). The recommended dosage of CrI is 18 Gy, based
on 150–180 cGy fractions daily. Evolving studies are y et unclear re direction for CrI in CNS 3
disease at diagnosis, the overall results in the St. Jude Total XV trial showing a significant
increase in adverse events (isolated CNS relapse and combined hematologic-CNS relapse and
death) absent radiation consolidation, y et the difference in B-cell precursor ALL alone is not
significant for any adverse event or isolated CNS relapse (13).
Table 2.1 Indications for Preventive Cranial Irradiation (pCrI)–Contemporary Studies
(2009)
CNS Relapse
Despite CNS preventive therapy, 1–8% of children sustain an isolated CNS relapse (i.e., in the
presence of continuous, maintained hematologic remission) (23). CNS relapse is
asy mptomatic at diagnosis in 75% of cases (i.e., detected by routine surveillance lumbar
puncture). Sy mptoms and signs are apparent in 25% of children with CNS involvement and
include headaches with or without vomiting, papilledema, cranial nerve palsies (most often
VI and VII; also V), hy perphagia, and CNS hemorrhage (presenting with headaches,
seizures, change in mental status, and/or focal neurologic signs) (23,67,68).
Therapy for isolated CNS relapse includes sy stemic chemotherapy for reinduction, IT
chemotherapy (MTX alone or TIT) to clear the CSF, and irradiation. Clinical trials
documented CNS control following neuraxis irradiation, but overall disease control was
observed in only 50–70% of children after isolated CNS relapse following reinduction and
consolidation chemotherapy with CNS irradiation (67,69,70,71,72,73,74).
Page 18Serial trials in the Pediatric Oncology Group (POG) confirmed the benefit of
initial sy stemic and IT chemotherapy for isolated CNS relapse: POG 9061 interposed 6
months of chemotherapy prior to CSI (24 Gy /16 fx CrI, 15 Gy /10 fx SpI); secondary EFS
was 71% (67). The study also documented that early CNS relapse (<18 months postdiagnosis)
was much more aggressive, with secondary 4-y ear EFS 46% compared to 83% for those
who relapsed later than 18 months (67). As in most series after 1985, failures were
predominantly in the bone marrow, leading to POG 9412 that tested 1 y ear of sy stemic and
IT chemotherapy followed by delay ed “risk-adapted” CNS irradiation: CrI to 18 Gy for CNS
relapse >18 months after diagnosis, and CSI to 24 Gy CrI & 15 Gy SpI for earlier CNS
relapse (75). Results were similar to the earlier trial: 52% 4-y ear EFS with early CNS relapse
versus 78% with relapse ≥18 months postdiagnosis (75). The other significant factor related to
outcome was the NCI risk group (high risk: age <1 or >10 y ears; WBC >50,000 mL at
diagnosis); children in the high-risk group had a four-time greater likelihood of relapse
following isolated CNS relapse (75).
Volume and Dose

CrI, as described above, is adequate for CNS relapse occurring bey ond 18 months after
diagnosis; the current standard is 18 Gy (at 150 cGy once daily ). There is an ongoing
assessment of further reducing the cranial dose in late-relapsing CNS leukemia to 12 Gy, but it
is y et premature to use the data as a standard for management. For those with early relapse,
CSI is standard with 24 Gy to the cranium and 15 Gy to the spine. Ongoing trials testing 18 Gy
in the latter setting are y et inconclusive.
Techniques are identical to that described earlier in this chapter for CrI. For CSI, the
basic technique is summarized in Chapter 4 ; noteworthy is the modification of the cranial
volume to include the posterior ocular globe (unique to leukemia; an area not included with
primary CNS tumors treated with CSI). Coordination of neuraxis irradiation and TBI during
BMT is considered below.
Treatment of Other Extramedullary Sites

Testicular Leukemia
Treatment of ALL in the 1980s was associated with a significant risk of testicular relapse.
Approximately 5–10% of boy s presented with overt testicular leukemia representing 10–20%
of all failures (73,76). Testicular relapse was ty pically a late event, occurring at a median of
3 y ears postdiagnosis (73,76). The occurrence was related to high-risk features (e.g., T-cell
phenoty pe and high WBC at diagnosis) (73). Testicular relapse seems to represent a sign of
inadequate sy stemic disease control rather than a true “sanctuary site” analogous to the CNS.
Enhanced sy stemic disease control, particularly the introduction of high-dose MTX into
prolonged intensification regimens, has largely eliminated the occurrence of testicular
relapse since 1990 (77).
Treatment of testicular relapse involves sy stemic chemotherapy. Sy stematic testicular
irradiation has been eliminated from most current treatment regimens, reserving irradiation
for documented residual testicular infiltration following reinduction chemotherapy (73,78).
More recent national COG trials reserve irradiation for disease persistent after high-dose
MTX and induction chemotherapy (documented by biopsy of testes enlarged at completion
of induction). The Dutch Late Effects Study Group has reported successful management of
testicular relapse without local irradiation (78), and the approach in the more recent Total
ALL trials at St. Jude offer orchiectomy or testicular irradiation depending upon age and
testicular response to initial chemotherapy. Although late failure may be present with
unilateral disease, evidence of bilateral infiltration is usually apparent (76). When indicated,
irradiation is directed to both testes, usually by en face electron beam, calculating the energy
to deliver 90% of the dose to the posterior aspect of the testes based on measurements in the
treatment position. Attention to daily positioning is important, ensuring the descent of the testes
into the scrotum during therapy. The recommended dosage is 20–24 Gy, usually given at 200
cGy per fraction (76). The interest in limiting use of irradiation reflects sterility and Ley dig
cell hy pofunction following irradiation. There is y et preliminary data using chemotherapy
alone, reserving orchiectomy for local disease control in boy s who do not show prompt,
histologically verified disease control.
Other Sites of Extramedullary Disease

Other sites of extramedullary relapse are uncommon, representing less than 2% of failures
(73). An unusual pattern of involvement is disease confined to the anterior chamber of the
ey e. Unlike diffuse retinal disease that is associated with CNS leukemia, limited anterior
chamber leukemia seems to be an isolated phenomenon. Management with en face electrons
superficially irradiating the ey e has been successful at dosages of 12 Gy /6 fractions (79,80).
Other sites of extramedullary involvement have included ly mph nodes, ovaries or uterus, and
bone (73). In the uncommon situation in which local extramedullary disease fails to respond
to reinduction chemotherapy, or in the rare patient with truly sizable local disease, it is
appropriate to consider local irradiation as consolidation either after intensification
chemotherapy or in conjunction with BMT.
Figure:
Genotypes in childhood ALL, including genetic findings in B-cell lineage or all ALL
immunophenotypes; genetic findings unique to T-cell ALL are in purple shades.
Reprinted from Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J
Med. 2004;350(15):1535–1548, with permission.
Figure:
The retinal photograph demonstrates advanced CNS leukemia with papilledema and retinal
infiltrate typical of ocular disease.
Figure:
Craniospinal irradiation for CNS leukemia. A: Sagittal CT simulation reconstruction showing
eye (yellow) and optic nerve (blue) at the midorbital level; cranial irradiation for CNS
leukemia includes the subarachnoid extension along the optic nerve sheath and the posterior
retina (see Fig. 2.6). B: Midline sagittal CT simulation reconstruction showing the cribriform
plate (red) volume providing margin at key anatomic regions (A and B) for craniospinal
therapy in ALL.
Figure:
Lateral field for cranial irradiation in ALL. Note margin below cribriform plate (pink) and
middle cranial fossa (blue). Targeted volume includes posterior eye (yellow) and orbit.
Figure: Indications for Preventive Cranial
Irradiation (pCrI)–Contemporary Studies
(2009)
ACUTE MYELOGENOUS LEUKEMIA
Approximately 20% of children with leukemia present with AML, representing nearly 500
children per y ear in the United States; nearly 40% of leukemic deaths in US children occur
with this form of leukemia (81). The disease occurs throughout the pediatric age range, with
greatest frequency in newborns and y oung children approximating 2 y ears old and a later
“peak” during adolescence. There is a high incidence of AML among y oung children with
Down sy ndrome (81). Presenting sy mptoms include sy mptoms and signs of pancy topenia
(pallor, fatigue, bleeding, infection, and fever) or leukostasis. Localized extramedullary tumor
deposits (chloromas or “granulocy tic sarcomas”) can present as sy mptomatic masses
involving the head and neck region, spinal cord, or brain. The initial WBC ty pically is below
50,000/mL; about 20% present with hy perleukocy tosis (WBC >100,000/mL). Clinical features
associated with outcome include ethnicity, age, and body weight: African Americans, older
age (>2 y ears and increasing age), and overweight habitus are associated with poorer
outcome (82,83,84,85). Unlike adults, it is rare for children to show initial my elody splasia
preceding actual AML. Secondary AML (ty pically due to alky lating agents or high doses of
topoisomerase II inhibitors (e.g., cy tarabine) also have poor prognosis (86).
Page 19CNS disease is documented at presentation in 10–15% of cases (23). CNS
disease at diagnosis is associated with high peripheral WBC, age <2 y ears, and ironically
favorable cy togenetic characteristics (t(l;11), t(8;21), inv(16)) (87).
AML has classically been categorized by cy tomorphology, based on the French-
American-British (FAB) classification and increasingly by molecular characteristics (82).
The common morphologic feature is the presence of Auer rods in cy toplasm of leukemic
blasts. Cell ty pes indicate primarily my eloblastic, monoblastic, or megakary ocy tic AML; the
megakary ocy tic form is common with Down sy ndrome and associated with favorable
response and prognosis, if traditional therapy resulted in acute toxicities and early toxic
deaths, recently ameliorated with dose reductions providing greater tolerance (81).
Cy togenetic abnormalities have been documented in a majority of children with AML. One
of the most common findings is translocation t(8;21), associated with AML1, a gene encoding
AML1CBF, a transcription factor essential for normal hematopoietic development (82,88).
The t(8;21) is often combined with inversion of chromosome 16(inv(16)) as “core binding
factor” AML, commonly present in AML M2; the t(8;21) translocation and inv(16) identify
favorable disease (82,88,89). The t(9;22) translocation is associated with a poor outcome.
Favorable AML (with t(8;21), inv(16), wild-ty pe FLT3, mutations of NPM1 or CEPBA; MRD
<0.1% after induction), high-risk disease (t(6;9), −7, −5, −5q; FAB M0 or M6, FAB M7; MRD
>5% after the first induction or >1% after the second induction), and intermediate-risk AML
(all others) are associated with 78%, 42%, and 55% 5-y ear survival, respectively
(10,11,81,82,90,91,92).
The mainstay of treatment for AML has been induction with daunorubicin (or idarubicin
or mitaxantrone) in conjunction with cy tarabine and etoposide; chlofarabine or gemtuzumab
may be included (82,86,93,94,95,96). Current regimens result in 80% remission but only 40–
50% event-free survival rates in children and 50–60% overall survival. Even more so than in
ALL, the finding of MRD upon completion of induction, by molecular or genetic analy sis, is
associated with a poor outcome (92). Postinduction therapy is somewhat controversial, data
suggesting the use of matched sibling or matched unrelated stem cell transplant (SCT) may
add to overall survival in high-risk and, potentially, standard risk AML (97). Although early
experience in pediatric AML had failed to prospectively identify a benefit with marrow
transplant, trials in POG and CCG demonstrated an apparent survival advantage for
allogeneic transplant (matched sibling SCT) when compared with chemotherapy alone or
autologous transplant (94,95,97). Conflicting data from the UK MRC studies show that even
matched sibling donor SCT reduced the frequency of relapse without improving survival (96).
In acute megakary ocy tic leukemias, the AML-BRM 04 study showed overall 5-y ear survival
of 70%, equivalent with or without SCT (98) Summary recommendations currently indicate
use of SCT (matched, related donor; increasingly, also matched unrelated/haploidentical
donor) with high-risk AML in first remission; indications in intermediate (or standard) risk
bey ond poor early responses are controversial (82,99).
Extramedullary Disease
Extramedullary disease is relatively common in AML at diagnosis. A Japanese cooperative
group series found signs of extramedullary leukemia in 23% of children. Disease was most
often epithelial (skin as nodules or infiltration in 26% or gingival, 14%; CNS, 14%; bone, 10%;
orbital, 8%). (100). The incidence of extramedullary disease in all sites in earlier BFM studies
was similar, while POG reported only 7–10% with extramedullary AML outside the CNS
(100,101,102). Extramedullary involvement is associated with high WBC and
my elomonoblastic or monoblastic subty pes (FAB M4, M5) (100,103). The incidence of CNS
involvement at diagnosis (10–15%) exceeds that seen with ALL (23,50,87,104). In serial St.
Jude trials, the incidence of CNS 2 disease (blasts present but WBC <5 mL in the CSF) was
12% (87). The combination of CNS disease at diagnosis with other extramedullary
involvement and WBC > 100,000 mL has been related to a high frequency of relapse (100).
The overall outcome in patients with CNS leukemia initially varies in the literature; the
outcome over four consecutive St. Jude trials suggests better survival for those with CNS 3 at
diagnosis, many of whom received CrI therapeutically as a part of primary therapy (87).
More recent experience, with limited numbers, suggests similarly favorable outcome may
relate more to associated favorable cy togenetics seen in the CNS cohort than an impact of
therapy (87,100). Overall survival in AML is now approaching the 70% level with wide
variations amongst demographic characteristics and genetic identifications.
CNS Disease: Radiation Therapy

Preventive CrI is not used in North American AML protocols. The BFM group studied the
impact of CrI prospectively in AML-BFM-87, randomizing children without CNS disease to
18 Gy CrI or enhanced sy stemic chemotherapy. The randomization was stopped early due to
the lack of excess CNS relapse in the nonirradiated group, but final analy sis actually showed a
higher rate of both CNS and sy stemic relapse in the cohort who did not receive CrI. BFM
trials then incorporated CrI for children >1 y ear old. Other studies without CrI over the same
interval failed to show excessive CNS failure in AML (23,96,105,106). In the St. Jude trials
using CrI only when blasts were present in the CSF, the incidence of CNS relapse was 3% for
those with CNS 1 disease and 6% for CNS 2 disease without CrI (87). In the larger CCG 2891
trial, the 8-y ear cumulative risk of CNS relapse absent CrI was 4.8%, (103).
Management of CNS relapse in AML is most often with intensified intrathecal cy tosine
arabinoside (ara-C, with or without MTX and hy drocortisone); it has been difficult to evaluate
the potential efficacy of CrI in a setting where bone marrow relapse rapidly follows
apparently isolated CNS failure (23,103). Treatment of focal infiltrates (“chloromas”) may
be required for sy mptom control or consolidation, the latter primarily a concern for larger
tumor-like infiltration in and around the CNS. AML is exquisitely sensitive to irradiation;
sy mptomatic and measurable response is often apparent after 12–15 Gy. Consolidative
therapy has been reported to be effective at 18 Gy ; lesions that show incomplete response to
chemotherapy may require 21–27 Gy focally in our experience (23,100).
Page 20Hematopoietic Stem Cell Transplantation (HSCT)

HSCT is a unique technique designed to allow higher dosages of antineoplastic agents
(chemotherapy, TBI) then “rescue” the attendant hematosuppression by engrafting new
hematopoietic stem cells from bone marrow or peripheral circulating cells to repopulate the
bone marrow. HSCT can also result in an immunotherapeutic antineoplastic effect by tumor
ly sis releasing antigens that stimulate host T cells or by donor cells attacking residual host
hematopoietic cells (107,108). Graft-versus-leukemia effects are associated with matched
unrelated or haploidentical transplants (and ty pically not with matched sibling HSCT)
(107,109). Developed initially by Donnell Thomas and colleagues at Fred Hutchinson Cancer
Research Center, BMT has been used predominantly in leukemias, malignant ly mphomas,
and other hematologic disorders in both children and adults, as well as in genetic diseases
(e.g., aplastic anemia, Fanconi sy ndrome, sickle cell disease, hemophilia, thalassemia, and
osteogenesis imperfecta) (107,108,109,110,111,112).
The principles of HSCT include a conditioning regimen (“supralethal” doses of
chemotherapy often with TBI) and successful engraftment of extrinsic hematopoietic stem
cells. Initial work in BMT focused entirely on allogeneic transplantation, ty pically rely ing on
a sibling or related donor found to be histocompatible based on human leukocy te antigen
(HLA) ty ping. In leukemias, the cy tolethal therapy is intended both to eliminate residual
ly mphoblasts or my eloblasts and to immunosuppress the host so that the donor marrow is
accepted (108,109,110). The use of HLA-matched, unrelated donors requires more potent
immunosuppression while providing greater antineoplastic immunotherapeutic effect to
patients who lack a matched sibling donor (111,112,113). Unrelated donor transplants are
more problematic in that the greater degree of immunosuppression needed to ensure
engraftment and associated anti–host immunoreactivity (graft-versus-host disease, GVHD) is
associated with decreased relapse but increased treatment-related mortality (107,113,114).
Sy ngeneic transplants (in which an identical twin is the donor) and matched sibling donor
allogeneic transplants are better tolerated (i.e., less often associated with GVHD), but show
higher rates of relapse (107,108).
Autologous transplants use the patient’s own HSC (either from bone marrow or
peripheral circulating stem cells), harvested and stored before the conditioning regimen, to
repopulate the patient’s own bone marrow following high-dose chemotherapy. Autologous
procedures are used in hematologic malignant diseases and increasingly selected “solid
tumors” in children and adults where drug intensity has been associated with improved
outcome (97,99,107,112).
The “standard” conditioning regimen is high-dose cy clophosphamide (CY) and TBI
(CY/TBI); alternative chemotherapeutic agents include thiotepa, etoposide, and
cy tarabinoside (30,102,107,109,113). The most commonly used non-TBI alternative is
busulfan (BU) and cy clophosphamide (BU/CY) (113,115,116,117). Management of AML in
remission and relapsed ALL are the most common indications for HSCT in children and
adolescents; data suggest that CY/TBI is superior to BU/CY in the first or subsequent relapse
of ALL, including a randomized trial showing 2-y ear EFS of 58% with TBI versus 29% with
BU, differences favoring TBI being more significant with matched unrelated than sibling
matched transplant (113,115). Large retrospective “evidence-based” reviews using data from
the Center for International Blood & Bone Marrow Transplant Research (Milwaukee) have
shown improved leukemia control and overall survival in children with first relapse of ALL
occurring “early (<3 y ears postdiagnosis) when using a TBI-containing regimen in HLA-
matched allogeneic transplant than with chemotherapy alone (118,119) The findings are
similar with bone marrow relapse alone with or without concurrent extramedullary relapse
(118,119).
HSCT in Children and Adolescents

Acute Myeloblastic Leukemia
Consolidation of remission in childhood AML was one of the earlier successes in BMT (120).
The overall disease-free survival rates of AML approximate 50–60%. There has been a
debate over the impact of postinduction intensification. Recent trials suggest a relationship
between drug intensity and survival after remission (81,82,93,94,95,96,112,121). Recent data
further substantiate the advantage of my eloablative therapy with SCT (bone marrow or
peripheral circulating stem cells) in children and adolescents with (1) intermediate- or high-
risk presenting biologic features (presence of isochromosome 7 or 5 [or −5q], or FCT3
mutation), or (2) low-risk disease (inv(16) or t(8;21)) but clinical factors (age > 10 y ears,
WBC > 50,000/mL) or response to induction therapy (MRD or >15% blasts at the end of
induction, initial CR <1 y ear at relapse) requiring management as high-risk (82,83,91,95,112).
Initial intensive sy stemic induction chemotherapy induces remission in 80–90% of
children/adolescents (82,93,94,96,121). AML treated in first remission (CrI) with matched
sibling donor HSCT enjoy up to 70–75% 5-y ear EFS and OS; results are superior to those with
autologous stem cell rescue (99,112,116,122). There appears to be advantage to matched
unrelated donors where the inherent graft-versus-leukemia immunoregulation decreases the
incidence of relapse; higher rates of treatment-related mortality in the latter setting limits the
advantage in overall survival (112,116,117). For children with residual leukemia after
induction or postinduction relapse, the only curative approach is transplantation. Allogeneic
transplants (in second remission) result in survival rates of approximately 20–40%, depending
on the length of first remission (88,122,123).
Acute Lymphoblastic Leukemia

The role of HSCT in pediatric ALL is ty pically limited to management of first or subsequent
relapse; use in first relapse when confined to extramedullary disease (especially isolated CNS
relapse) is controversial (107,119,124). With isolated CNS relapse, there is no proven benefit
to HCST versus chemotherapy and irradiation alone in the large retrospective “evidence-
based report” from the Center for International Blood & Bone Marrow Transplant Research
(CIBBMTR; Milwaukee) (119,125).
Page 21HSCT is considered in children with early relapse (within 3 y ears of initial
remission). Large retrospective “evidence-based” reviews using data from the CIBBMTR
have shown improved leukemia control and overall survival in children with first relapse of
ALL occurring “early ” (<3 y ears postdiagnosis) when using a TBI-containing regimen in
HLA-matched allogeneic transplant than with chemotherapy alone (118,119). The findings
are similar with bone marrow relapse alone with or without concurrent extramedullary
relapse (118,119). The use of higher-dose chemotherapy with HSCT prior to documented
relapse is considered appropriate with poor initial response to induction therapy or genetic
determinants of high-risk disease (Ph+, t(9;22) or BRC–ABL or MLL–AF4 fusion genes, or
t(4;11)) (13,107,126,127). Outcome depends on disease state; several studies demonstrate
long-term survival rates greater than 65% for high-risk ALL transplanted in first relapse
(118,119,127,128,129,130).
Allogeneic transplantation in ALL results in low rates of transplant-related mortality
following matched sibling transplant and low rates of relapse with matched unrelated or
haploidentical transplants (107,113,114,126,128).
The role of TBI has been addressed in children with ALL treated with allogeneic
transplant using HLA-matched sibling donors. Retrospective comparisons using data from the
CIBBMTR have reported CY/TBI to be superior to BU/CY in preventing relapse, reducing
treatment-related mortality, improving overall treatment failure, and reducing overall rate of
mortality (113,119). The addition of etoposide to CY/TBI may further improve disease
control and overall survival (131). For patients with extra medullary relapse (i.e., CNS, testis),
the addition of local irradiation before (cranial) or during (testicular) the conditioning regimen
results in excellent local disease control and outcomes equivalent to or better than those with
hematologic relapse alone (119,124,127,128,132). Overall disease control following TBI-
based HSCT has been excellent with isolated CNS relapse; series show 0–20% posttransplant
relapse and 0–13% treatment-related mortality (both figures superior to HSCT data for
hematologic response); the influence of timing of CNS relapse (prior to or later than 18
months after initial remission) is also documented in HSCT series (119,124,128). Continuing
the controversy, though, large retrospective evidence-based review from the CIBBMTR
shows no difference between TBI-containing HSCT based therapy and chemotherapy with
irradiation alone; as well, the addition of cranial irradiation boost to the TBI regimen has not
been shown to statistically improve survival (118,125,133,134).
Other Hematologic Diseases
Fanconi anemia is an autosomal recessive disease characterized by progressive
pancy topenia, growth retardation, urinary tract abnormalities, microthalmia, and cardiac
malformations. The disease is associated with a number of chromosomal aberrations and is
invariably fatal as a result of progressive marrow aplasia or the development of leukemia
(135). HSCT is potentially curative as genetic therapy, reversing the underly ing genetic clone
and reintroducing normal hematopoiesis in approximately half the children without leukemic
conversion (135,136,137). Transplant programs at some institutions rely on
cy clophosphamide alone for those without overt leukemia based on greater radiation
sensitivity in children with Fanconi anemia. Other institutions use thoracoabdominal
irradiation at reduced dose (ty pically 5 Gy in one fraction) (137). Patients with leukemic
conversion are treated with TBI at standard or reduced dosages similar to techniques used in
other acute childhood leukemia settings.
Aplastic anemia is characterized by marrow hy poplasia and pancy topenia. The disease
may be associated with chemical exposures or abnormal response to infectious or other
agents; often, the origin is not apparent. Allogeneic HSCT can be curative (116,138,139,140).
Because it is a nonmalignant disorder, the conditioning regimen often is chemotherapy alone
(cy clophosphamide with an additional alky lating agent). When additional immunosuppression
is needed (e.g., initial failure at engraftment, incompletely matched donor), TBI or,
preferably, total ly mphoid irradiation (TLI) is a part of the conditioning regimen
(116,138,140). The latter has the advantage of sparing significant pulmonary irradiation while
including sufficient volumes of the marrow and immune sy stem to ensure engraftment (138).
Volume
TBI is a central component of HSCT in most malignant hematologic and many genetic
disease states. The target volume encompasses the entire body. Techniques include a variety
of phy sical configurations to achieve a field size adequate to subtend the entire body. For
infants and small children, an anterior–posterior (AP:PA) configuration on the floor often
allows sufficient field size and easy reproducibility. For larger children and adolescents, one
of the extended distance techniques uses opposed lateral fields, providing table positioning and
some degree of tissue compensation from the arms to reduce the excess lung dose secondary
to increased transmission through the lungs. AP:PA techniques (achieved with sitting or
standing positions or with the supine or prone body rotated to be roughly perpendicular to the
incident beam) offer the advantage of partial blocking for compensation or diminution of dose
to critical structures (most often lungs; in some instances, kidney s) (141,142) (Fig. 2.6 ).
The incidence of interstitial pneumonitis is one of the major dose-limiting, regimen-
related, often fatal acute toxicities; the cause is multifactorial including transplant mode
(sy ngeneic associated with the lowest incidence, allogeneic associated with an incidence that
parallels the severity of acute GVHD), the combined conditioning regimen, and the radiation
dose, dose rate, and fractionation (129,141,142,143,144,145,146,147,148). Most current
techniques compensate for added transmission through the measured lung volume and also
deliver a dosage to the midplane of the lungs 10–15% lower than the dose to the total body ;
heterogeneity corrected dose levels are suggested to reduce serious pulmonary complications
when planning approximately 12 Gy TBI (128,141,142,144,145,148,149). Lung blocks should
include the pulmonary volumes identified on
AP:PA radiographs, ty pically excluding the
upper mediastinum (i.e., thy mus) from the lung
shields. In lateral body techniques, the added
width of the thorax in most children and
adolescents compensates for the lung
transmission. Tomotherapy has been used to
deliver total marrow/total ly mphoid irradiation,
the helical techniques providing targeted
marrow/ly mphoid doses while delivering 50–
80% less dose to critical viscera (146,150,151).
Page 22Based on an initial testicular failure
rate in 4 of 28 boy s, Shank and colleagues at
Memorial/Sloan Kettering Cancer Center (152)
recommended the addition of a testicular boost
in TBI. The use of a 4-Gy testicular boost
essentially eliminated testicular relapse. A
subsequent French experience (with TBI and
high-dose cy tosine arabinoside and busulfan)
used 12 Gy TBI in six fractions or 9–10 Gy as a Figure 2.6 A: “AP:PA” technique using
single fraction with no testicular “boost” in two- supine/prone positioning, respectively, on
thirds of the boy s treated; no testicular failures rotating couch (St. Jude), patient secured
were recorded (128). with whole body Vac-Loc and rotated 90º
Children with isolated CNS relapse may to provide incident lateral beam. Shown,
benefit from CrI given immediately before the PA with lung compensators. B: Simple
start of the conditioning regimen; data is “AP:PA” on-the-floor technique for infants
controversial. CrI to 6–12 Gy in 4–8 fractions
timed to be in close temporal subtended by vertical beam. Shown, PA
proximity /continuity with TBI has resulted in with lung compensators.
essentially eliminating second relapse without
transplant-related mortality in series reporting HSCT for isolated CNS relapse
(119,124,125,133,134).
Dosage (Hematologic Malignancies)

The initial experience with TBI was based on a single fraction of 9–10 Gy (143,153,154).
Modifications in TBI delivery were stimulated by the occurrence of interstitial pneumonitis.
Early studies indicated a relative sparing by reducing the dose rate below 10 cGy per minute;
in parallel, a change to fractionated TBI was suggested (122,143,145,155,156,157).
Subsequent trials have generally indicated improvement in the therapeutic ratio with
fractionated delivery based on one or two fractions per day (110,120,144,158). The most
commonly used schedules include 2 Gy administered twice daily to 12 Gy at an
instantaneous dose rate of 5–10 cGy per minute (120,128,144,158). Somewhat higher dosages
have been used in study settings: 225 cGy once daily to 15.5 Gy or 1.75 Gy twice daily to 14
Gy (142,158). The range of fractionation regimens attests to the flexibility apparent at low-
dose levels for TBI (i.e., 8–10 Gy single fraction or 10–12 Gy fractionated). Suggestions that
more fractionated regimens are better tolerated in terms of acute pulmonary and late
visceral effects are difficult to prove across institutions and trials; correlations between
radiation parameters and lower rates of untoward renal effects, for example, identify both
increased fractionation and instantaneous lower dose rate (143,159). Higher doses are
ty pically used with matched unrelated donor BMT (160). Doses bey ond 14 Gy seem to be
associated with greater risks of TBI-related toxicities (158,161). A low-intensity TBI regimen
(2 Gy total in one fraction) is used in nonmy eloablative regimens rely ing on graft-versus-
leukemia effect with chimerism (107).
Figure:
A: “AP:PA” technique using supine/prone positioning, respectively, on rotating couch (St.
Jude), patient secured with whole body Vac-Loc and rotated 90º to provide incident lateral
beam. Shown, PA with lung compensators. B: Simple “AP:PA” on-the-floor technique for
infants subtended by vertical beam. Shown, PA with lung compensators.
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CH A P TER 3
Supratentorial Brain Tumors
Bree R. Eaton, Shannon M. MacDonald, Larry E. Kun, and Nancy J. Tarbell
Page 27Twenty percent of all neoplasms in children arise in the central nervous sy stem
(CNS). The incidence of CNS tumors in children has increased over the past three decades
(1). The current World Health Organization (WHO) classification of CNS neoplasms is
summarized in Table 3.1 (2,3); a new WHO classification scheme, with major emphasis
on genomic diagnoses and classification, will be released in 2016.
Over half of pediatric CNS tumors arise in the supratentorial brain. Anatomically, the
supratentorial cranial compartment (Fig. 3.1 ) includes the cerebral hemispheres (frontal,
parietal, temporal, and occipital lobes), the diencephalon (hy pothalamus, the optic chiasm,
and the thalamic, caudate nucleus, putamen, and basal ganglion structures, the latter
generally considered together as the thalamic region), the pineal region (pineal gland and
posterior third ventricular region), and the sellar/suprasellar region. Tumors can be
categorized by anatomic region, correlating with clinical signs and specific histioty pes:
suprasellar lesions (including glial tumors of the optic chiasm and adjacent hy pothalamic
area, craniophary ngioma, and germ cell tumors [GCTs]), central deep-seated lesions
(gliomas of the thalamic region and tumors of the pineal region, including germ cell,
embry onal, and glial neoplasms), and peripheral lesions (gliomas, ependy momas, and
embry onal tumors of the cerebral hemispheres).
Table 3.1 Histopathologic
Classification of CNS Tumors—WHO
Classification 2007
Figure 3.1 A: Axial MRI demonstrating key anatomic sites from the interorbital frontal
lobes, through the superior suprasellar region (optic tracts, hypothalamus), midbrain, and
superior cerebellar vermis (posterior to midbrain). B: Coronal MRI through central
suprasellar location with posterior chiasm, hypothalamic nuclei, anterior aspect of third
ventricle (between R and L hypothalamic nuclei), lateral ventricles (above third), and mid-
temporal lobes. C: Sagittal MRI demonstrating supratentorial brain, tentorium and
underlying cerebellum (with central fourth ventricle), brainstem (pons with medulla below
and tegmentum of midbrain contiguously above), tectal plate (cerebral aqueduct delineates
this in midline from anteroinferior tegmentum), pineal gland, and suprasellar structures
(optic chiasm and infundibulum of pituitary–hypothalamic stalk).
Advances in neuroimaging have improved the accuracy of diagnosis in CNS tumors,

with perfusion, diffusion, and diffusion tensor MR imaging adding to diagnostic capabilities. In
suprasellar and pineal region lesions, computed tomography (CT) may be helpful to delineate
calcification ty pically seen in craniophary ngioma and malignant GCTs. Positron emission
tomography (PET), single photon emission tomography (SPECT), magnetic resonance
spectroscopy (MRS), and magnetoencephalography are of potential value in assessing tumor
ty pe or grade and may be helpful in differentiating tumor progression from radiation-related
changes (e.g., intralesional necrosis) (5).
Modern neurosurgical techniques have largely eliminated multidisciplinary therapy
without a histologic diagnosis. Central lesions within or around the third ventricle (suprasellar,
thalamic, or pineal region tumors) can be biopsied endoscopically at the time of third
ventriculostomy, often indicated to decompress the ventricular sy stem in preference to a
ventriculoperitoneal shunt. Histology may not be required for diagnosis of malignant GCTs
(where elevated levels of alpha-fetoprotein [AFP] or beta-human chorionic gonadotropin
[beta-HCG] may be diagnostic) and optic pathway tumors (OPTs) that involve the optic
nerve alone or the chiasm in conjunction with adjacent optic pathway structures. For
craniophary ngioma, the imaging diagnosis can be confirmed by cy st aspiration, documenting
the presence of diagnostic squamous cells or cholesterol cry stals in the cy st fluid.
Figure: Histopathologic Classification of
CNS Tumors—WHO Classification 2007
Figure:
A: Axial MRI demonstrating key anatomic sites from the interorbital frontal lobes, through
the superior suprasellar region (optic tracts, hypothalamus), midbrain, and superior
cerebellar vermis (posterior to midbrain). B: Coronal MRI through central suprasellar
location with posterior chiasm, hypothalamic nuclei, anterior aspect of third ventricle
(between R and L hypothalamic nuclei), lateral ventricles (above third), and mid-temporal
lobes. C: Sagittal MRI demonstrating supratentorial brain, tentorium and underlying
cerebellum (with central fourth ventricle), brainstem (pons with medulla below and
tegmentum of midbrain contiguously above), tectal plate (cerebral aqueduct delineates this
in midline from anteroinferior tegmentum), pineal gland, and suprasellar structures (optic
chiasm and infundibulum of pituitary–hypothalamic stalk).
ETIOLOGY
Although most brain tumors are sporadic, a number of pediatric brain tumor presentations are
associated with recognized neurocutaneous or other genetic sy ndromes, as outlined in Table
3.2 (6).
Table 3.2 Genetic Syndromes Related to Pediatric CNS Tumors
Neurofibromatosis is a common congenital disorder associated with CNS tumors.

Clinical criteria for ty pe I neurofibromatosis (NF1) include six or more café au lait spots and
peripheral neurofibromas among other characteristic features. NF1 is an autosomal dominant
sy ndrome linked to a 17q11 chromosomal defect. Fifteen to twenty percent of children with
neurofibromatosis ultimately present with CNS neoplasms, usually gliomas of the optic
pathway s or low-grade tumors of the diencephalon, cerebral hemispheres, or posterior fossa.
Low-grade gliomas associated with NF1 may respond better to chemotherapy and be less
aggressive than similar gliomas in the general population (6).
The indolent subependy mal giant cell astrocy toma occurs in children with tuberous
sclerosis, a hereditary disorder signified also by cutaneous acneiform lesions and
hamartomatous angiofibromas in the skin, brain, heart, and kidney s, mental retardation, and
renal insufficiency ; CNS findings include hamartomatous periventricular lesions known as
tubers. The disease is marked by the tuberous sclerosis complex gene 1 (TSC1), identified as a
9q34 mutation (6).
Page 28Childhood brain tumors (and sarcomas) are frequently noted in families with the
Li–Fraumeni familial tumor sy ndrome; the entity is also associated with breast cancer,
sarcomas, and brain tumors in adults, commonly occurring before the age of 35–40 y ears.
The sy ndrome is associated with germline TP53 mutations and a high incidence of
astrocy toma (low and high grades), gliosarcoma, medulloblastoma, and primitive
neuroectodermal tumor (PNET) (6). Those with the sy ndrome are also at high risk for
secondary, treatment-related neoplasms.
Radiation-induced benign and malignant brain tumors have long been recognized. Data
from long-term survivors of the Childhood Cancer Survivor Study have demonstrated a linear
relationship between the dose of cranial irradiation received and the excess relative risk of
secondary gliomas and meningiomas (7). Among patients who received 50 Gy or more, the
cumulative incidence of a secondary malignant brain tumor was 7.1% at 25 y ears (8).
Figure: Genetic Syndromes Related to
Pediatric CNS Tumors
CLINICAL PRESENTATION
Page 29Supratentorial tumors generally present with localizing neurologic sy mptoms;

sy mptoms and signs may develop over extended time intervals and are often protean.
Seizures are the most common sy mptom in cerebral hemispheric lesions, especially with
tumors arising in the temporal lobe. Lateralizing neurologic signs (motor and/or sensory )
occur in thalamic region tumors, often associated with sy mptoms of increased intracranial
pressure (i.e., headaches, vomiting). Suprasellar tumors ty pically occlude the foramen of
Monro, also resulting in sy mptoms of elevated intracranial pressure. Visual signs (visual field
deficits and/or decreased acuity ) and endocrine abnormalities (diminished growth hormone,
cortisol or thy roid production; diabetes insipidus; delay ed or precocious puberty ) are often
apparent with midline suprasellar lesions. Youngsters with suprasellar tumors may show
features of the diencephalic sy ndrome (hy peractivity and asthenia, the latter despite normal
or high food intake). Pineal region tumors produce hy drocephalus by compressing the
aqueduct of Sy lvius; specific ocular signs (i.e., the Parinaud sy ndrome: decreased upward
gaze, near-light dissociation of the pupillary response, convergence ny stagmus) are
classically noted.
LOW-GRADE SUPRATENTORIAL ASTROCYTOMAS
Low-grade astrocy tomas are a diverse group of tumors that collectively represent the most
common category of pediatric brain tumors (1). Management is variable and dependent on
tumor location, patient age, presence of a genetic mutation, and, often, phy sician and parental
preference. Outcomes are generally favorable; the goal of treatment is durable disease
control or cure with preservation of function. The most frequent site of origin is in the
cerebellum (see Chapter 4 ) followed by the deep midline diencephalon (thalamus,
hy pothalamus, optic chiasm and nerves, basal ganglia, and related structures) and the
cerebral hemispheres. In contrast to adults who are most commonly diagnosed with high-
grade astrocy tomas, the majority of supratentorial tumors occurring in childhood are low-
grade astrocy tomas. Low-grade gliomas of the optic pathway and hy pothalamus have
distinct features and are discussed below as a separate group.
Page 30A subset of diffuse low-grade tumors extends across two or three lobes, often
with no obvious or dominant mass lesion; the diffuse pattern of involvement is classified as
gliomatosis cerebri (9). Ty pical unifocal low-grade gliomas occasionally present with
subarachnoid dissemination; the incidence is approximately 3%, most often seen in tumors
located in the diencephalon (9,10).
Diagnostic imaging generally reveals a lesion that is isointense on CT and T1 MRI
sequences and hy perintense on T2 sequence (5). Pilocy tic astrocy tomas (PAs) enhance
briskly and diffusely, but most other low-grade tumors show little or no enhancement with
gadolinium (5). Scattered calcifications may be present. Tumors may include small or
dominant cy sts; some degree of cy st formation is common in JPAs. MRI is the imaging
modality of choice. Due to the variability of enhancement, T1 sequences may not provide
the best demarcation of the tumor borders; post-gadolinium T2-FLAIR images are often
preferred (Fig. 3.2B ).
Histopathology of low-grade astrocy tomas is characterized by low cellularity, little
nuclear aty pia, and few, if any, mitotic figures. Although the term “low grade” applies to all
pediatric gliomas that are not anaplastic, the various histioty pes differ in the degree of
infiltration, relative aggressiveness, and prognosis. JPAs and diffuse fibrillary astrocy tomas
comprise the majority of pediatric low-grade gliomas. Figure 3.3 depicts histologic
features of these two most commonly encountered low-grade astrocy tomas. Less common
low-grade astrocy tomas include gemistocy tic astrocy tomas, pleomorphic
xanthoastrocy tomas, desmoplastic infantile astrocy tomas, protoplasmic astrocy tomas, and
subependy mal giant cell astrocy tomas. These tumors are generally classified by the WHO
histologic criteria (2). The WHO sy stem categorizes PA as grade I and other differentiated
astrocy tomas including all diffuse astrocy tomas, as grade II; anaplastic astrocy toma and
glioblastoma multiforme are coded as grade III and grade IV, respectively (2). Broniscer et
al. (11) reported a cumulative rate of malignant transformation amongst pediatric grade II
astrocy tomas of 7% at 15 y ears postdiagnosis, a
much lower frequency than has been reported in
adults. PAs almost uniformly retain low-grade
characteristics even when uncontrolled or
recurrent (11).
Figure 3.2 A: JPA of (L) thalamus,

presenting in a 4-year-old boy—cystic and
solid, largely enhancing tumor on T1-
gadolinium MRI. B: JPA visualized on T2-
FLAIR sequence postcontrast. Note even
better tumor definition. C: Note
leptomeningeal metastasis in
hypothalamus/chiasmatic JPA, a finding
largely at diagnosis in <10% of cases.
Figure 3.3 Histologic features of the most common pediatric low-grade gliomas: JPA (L)
and diffuse fibrillary astrocytoma (R). JPAs (WHO grade I) show biphasic architecture with
more cellular areas that tend to have the Rosenthal fibers and loose areas with microcysts.
Cells are elongated, bilpolar, and have thin “hair-like” processes. Diffuse fibrillary
astrocytomas (WHO grade II) consist of long, thin cells highlighted by a crisscrossing
background of cytoplasmic glial filaments; nuclear atypia often apparent.
PAs are characterized by elongated bipolar astrocy tes organized in a parallel array of
glial fibers, giving a hairlike or piloid appearance. The sparsely cellular tumors are signified
by microcy sts and Rosenthal fibers (amorphous eosinophilic material formed by plump,
degenerating astrocy tes). Macroscopically, visible cy stic components often are present,
sometimes with less prominent solid tumor components. The tumors may be circumscribed
or may extend along white matter tracts, depending on the location (Fig. 3.4 ). PA is the
most common tumor in the diencephalic region and comprises 25% of hemispheric
astrocy tomas. The tumor ty pically is nonaggressive, although multifocal presentation, rapid
progression, and dissemination may occur (12).
Page 31
Figure 3.4 A: A 7-year-old boy with JPA of optic chiasm and optic tracts (without
neurofibromatosis), involving and distorting chiasm (A, top) with spread along optic tracts
(A, bottom). B: Increased tumor size, enhancement along optic tracts noted 7 months
postradiotherapy (post-RT), attributed to transient posttherapy effects (B, top and bottom).
C: Same levels with marked, spontaneous reduction in tumor volume compared to
preirradiation or MRI 7 months post-RT (Figures B); note normal chiasm (C, top). Patient
now 5.5 years post-RT, with intervening (R) middle cerebral infarct (C, bottom; same time
as C, top).
Pilomy xoid tumors have recently been defined as a subset of low-grade gliomas,
previously classified with pilocy tic astrocy tomas. Pilomy xoid tumors have a my xoid matrix
with highly monomorphic piloid cells; they may demonstrate an arrangement resembling
perivascular rosettes; they are usually solid with less prominent cy stic components and lack
Rosenthal fibers (13). These tumors are considered to be more aggressive than classical
pilocy tic astrocy tomas and are categorized by the WHO as grade II, although little data y et
confirm the clinical implications of this diagnosis (2).
Grade II astrocy tomas are characterized by a greater degree of infiltration; the
proliferation index may exceed that of the PA, and a greater number of molecular
aberrations are apparent. Diffuse fibrillary astrocy tomas consist of long, thin cells highlighted
by a crisscrossing background matrix of cy toplasmic glial filaments. Gemistocy tic
astrocy tomas are less common, presenting as benign-appearing, often circumscribed lesions
with a high rate of recurrence; these tumors often demonstrate malignant degeneration within
several y ears after initial presentation and are associated with worse survival than other grade
II astrocy tomas (14,15). Protoplasmic astrocy tomas are characterized by large, rounded
astrocy tes with abundant cy toplasm and a background largely devoid of fibrils. Grade II
astrocy tomas are more often associated with local recurrence and may present with
malignant progression (11).
Pleomorphic xanthoastrocy tomas present as superficial tumors in the cerebral
hemispheres. Despite an aggressive histologic appearance with cellular pleomorphism and
numerous mitoses, the behavior of pleomorphic xanthoastrocy tomas is quite benign; the
tumor is classified as grade II. Long-term disease control usually is obtained through surgery
alone; a proportion of cases does recur late and occasionally shows malignant degeneration
(16). A small percentage of these lesions show mitotic activity, areas of necrosis, and a high
proliferative index at initial diagnosis and are designated as anaplastic pleomorphic
xanthoastrocy toma. The latter may be somewhat more aggressive clinically (16).
Subependy mal giant cell astrocy tomas are a distinct subty pe of sharply marginated
tumors that occur along the linings of the lateral ventricles. The lesions occur in the setting of
tuberous sclerosis; children often have seizures and show significant developmental delay s
(17). Subependy mal giant cell tumors are almost alway s managed with surgical resection
alone.
Genomic alterations involving BRAF are common in low-grade astrocy tomas and
gangliogliomas, carry prognostic significance, and provide options for targeted therapy (18).
BRAF-activating mutations are common in sporadic PAs, most often in infratentorial or
midline-located tumors, and are associated with a more favorable prognosis and reduced risk
of progression to high-grade gliomas. Approximately two-thirds of pleomorphic cases and up
to 40% of gangliogliomas carry the BRAFV600E point mutation. This mutation has been
recognized as a poor prognostic factor and is found in tumors that progress to HGG (18).
Page 32Therapy
Surgery
For low-grade gliomas amenable to complete surgical resection, surgery is generally the first
and sole intervention providing excellent control of disease. Total resection is usually feasible
for tumors arising in the cerebral hemispheres with reports indicating gross total resection
(GTR) in 90% of cerebral hemispheric and cerebellar astrocy tomas (19). Low recurrence
rates are reported for both PA and other astrocy tomas after total resection. Data from the
Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) study of primary
surgery in low-grade gliomas reported a 5-y ear progression free survival of 92% after GTR,
ranging from 95-100% for PAs and gangliogiomas to 80% for diffuse astrocy tomas (20).
Resection of tumors involving the dominant medial temporal lobe, motor strip region, or the
Broca speech cortex may not be possible without inducing severe neurologic deficits. Partial
resection may provide initial intervention for decompression and histopathologic diagnosis.
Low-grade gliomas of the diencephalon and optic pathway are technically challenging
due to the deep location and eloquent area; however, contemporary series report successful
resection for selected tumors in this region (21,22). Long-term disease control is ty pically
achieved by total resection. The CCG–POG study notes a progression-free survival after
surgery alone of 50–60% for diencephalic tumors, much lower than for lesions originating in
the cerebellum or cerebral hemispheres where GTR is more common (20).
Radiation Therapy
Radiation therapy is an established, effective treatment for low-grade gliomas, achieving
tumor response and durable disease control in a significant proportion of pediatric cases
(19,23,24) (Fig. 3.2 ). An analy sis from Pollack et al. (19) showed improved disease
control at 10 y ears after irradiation following incomplete resection of cerebral hemispheric
astrocy tomas: 82% progression-free survival with irradiation versus 42% after surgery alone;
there was no significant benefit in overall survival. A phase II prospective study published by
Merchant et al. (24) demonstrated excellent event-free survival (87% and 74% at 5 and 10
y ears, respectively ) and overall survival (over 90% at 10 y ears) for children treated with
three-dimensional (3D) conformal irradiation to the MRI-defined tumor volume. These
outcomes compared favorably to the literature and have been associated with excellent
functional outcomes (25). Proton therapy also provides an opportunity to minimize radiation
associated sequelae by further reducing the dose delivered to the normal brain in these
patients (26). The decreased volume of normal brain exposed to moderate or high radiation
doses using conformal techniques with small margins may significantly decrease some of the
serious radiation-induced side effects (27). A study from Greenberger et al. (28)
demonstrated excellent results with the use of proton therapy for low-grade gliomas, with a 6-
y ear PFS rate of 89.7%. Treatment toxicity was minimal, with no significant declines in
neurocognitive functioning among patients age 7 y ears and older, and visual acuity stabilized
or improved in 83% of patients at risk for radiation-induced injury to the optic pathway s (28).
Care must be taken to accurately delineate tumor volumes, addressing white matter
tracts in defining the clinical tumor volume (CTV). Merchant et al. (24) suggest a minimal
margin (as small as 5 mm) may be adequate for well-demarcated tumors. The recently
completed Children’s Oncology Group (COG) study ACNS0221 utilized a 5-mm
anatomically limited CTV margin around the gross tumor volume (GTV) in a multi-
institutional trial; the trial has y et to be reported.
There are no contemporary data suggesting a benefit to postoperative irradiation for
completely resected low-grade astrocy tomas. Current indications for radiation therapy after
a near total resection (with imaging evidence of disease residual) include sy mptoms or signs
that might improve with irradiation or postsurgical progression in a location not amenable to
safe, definitive second resection. Other factors that are taken into consideration are histologic
subty pe and biology (29). Chemotherapy is ty pically considered prior to irradiation for
y oung children or for patients with neurofibromatosis (NF1) or cognitive delay.
For incompletely resected low-grade astrocy tomas, early administration of irradiation
may not benefit the patient (30). Reports from the large CCG–POG low-grade trial confirm
previous institutional data suggesting that a significant proportion of incompletely resected
astrocy tomas remain indolent over 3–5 y ears; progression-free survival rate at 5 y ears is
55% after near total or subtotal resection (20). A decision to observe children with residual
astrocy toma should involve all subspecialties (neurosurgery, radiation oncology, pediatric
neuro-oncology ) indicating the obligation for regular clinical follow-up and imaging that
allows one to comfortably observe a child with the anticipation that treatment can be initiated
upon documented tumor progression. Such an approach balances the recognized efficacy of
radiation therapy with potential toxicities related, in part, to the anatomic location and volume
of the tumor and the age of the patient. Inherent in such an approach is the commitment to
intervene appropriately with documented disease progression, including use of primary
radiation therapy, additional surgery, or chemotherapy as indicated.
PAs predominate in hy pothalamic and OPTs. Prolonged progression-free survival after
irradiation alone for these tumors reflects both the indolent nature of tumors in this site and the
efficacy of irradiation. Survival rates in excess of 80% at 10 y ears after irradiation are
common for these tumors (24,31). In thalamic astrocy tomas, pilocy tic histology is less
prevalent; 10-y ear survival results range from 33% to 60% after therapy (24,31,32).
Page 33Gliomatosis cerebri and bithalamic astrocy tomas represent supratentorial
counterparts of the more common, diffusely infiltrating pontine astrocy tomas. The infiltrating
supratentorial tumors respond to radiation therapy both sy mptomatically and by imaging, but
recurrence and progression are ty pically apparent within a y ear (9,32).
Chemotherapy
Chemotherapy has been used with increasing frequency for low-grade gliomas as a strategy
to delay or avoid radiation therapy ; with the availability of molecularly targeting agents (e.g.,
vemurafenib) for the low-grade gliomas that harbor the BRAFV600E mutation, there is more
interest in preirradiation pharmacologic approaches. Primary chemotherapy for low-grade
gliomas was studied initially in centrally located tumors that tend to occur in y ounger patients
and are not amenable to resection. Cy totoxic chemotherapy provides disease control for
months to y ears with stable disease or partial response; most tumors progress within 3–4
y ears, often requiring radiation therapy at that time. The age below which chemotherapy is
more appropriate is controversial and dependent on factors such as tumor size and location,
presence of NF mutation, or developmental or neurocognitive delay s. Packer et al. (33)
reported age to be the only significant prognostic factor, with 3-y ear progression-free
survival rate of 74% for children ≤5 y ears old versus 39% for older children. In COG, the age
of ≤10 y ears was chosen for trial eligibility in studies evaluating chemotherapy as initial
treatment.
Favorable control rates and relative absence of serious toxicity have established
carboplatin and vincristine as the “standard” first-line chemotherapy for low-grade gliomas
in y ounger children (33). Carboplatin hy persensitivity occurs over time, often limiting further
administration of this regimen (34). Temozolomide, an alky lating agent with modest
responsiveness in recurrent low-grade gliomas, has been used with carboplatin/vincristine to
prolong drug tolerance (35). The five-drug University of California at San Francisco (UCSF)
regimen (6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine, TPCV) is
similarly efficacious. A randomized trial comparing carboplatin/vincristine to this regimen
has been completed by COG, suggesting equal or greater efficacy with this five-drug
regimen: 5-y ear event-free survival was 39% with carboplatin and vincristine versus 52%
with TPCV, not a statistically significant difference, and toxicity was greater with TPCV (36).
The 5-y ear OS for the entire population was 86%, with y ounger age, larger tumor size, and
thalamus location predicted for worse outcomes (36). Bevacizumab in combination with
irinotecan has been investigated for recurrent low-grade glioma with promising response
rates in heavily pretreated patients (37). Other sy stemic therapies for recurrent or refractory
low-grade gliomas include vinblastine, temozolamide, and lenolidomide alone or in
combination with other chemotherapeutic agents. Novel targeted therapies are also under
investigation.
The decision to proceed with chemotherapy or irradiation relates to patient age and
clinical presentation; consideration should involve consultation with and discussion amongst a
multidisciplinary team reviewing relative risks and benefits with the patient’s family. Factors
bey ond age alone include sy mptoms and signs, potential for additional neurocognitive
deficits, the likelihood of durable benefit from respective chemotherapeutic regimens, and the
radiation volume and modality -specific dosimetry related to relative potential toxicities.
Although not proven to be problematic, there is no confirmation that the response rate and
durability of disease control following radiation therapy are independent of prior failure on
chemotherapy.
Volume
Fusion of MRI with CT imaging is critical to determine the extent of disease defining the GTV
for treatment planning. T1 gadolinium-enhanced imaging may be ideal for PA; for diffuse
astrocy toma (grade II) and the less common low-grade neoplasms, T2-FLAIR or T2
sequences are most useful as the tumor rarely shows contrast enhancement throughout,
though all MRI sequences should be reviewed. The CTV may be defined as a 5- to 10-mm
anatomic expansion; a prospective study at St. Jude indicated a dearth of marginal
recurrences with a 1-cm anatomic expansion of the GTV to define the CTV (24), and a
recent prospective COG study has been completed using a 5-mm anatomic expansion. An
additional 3–5 mm geometric expansion defines the planning target volume (PTV). The use
of small margins requires a careful review of all neuroimaging with great attention to detail
including all cy stic and solid components of the tumor in the GTV, as well as daily image
guidance to minimize setup uncertainty. Similar guidelines appear to be appropriate for grade
II (fibrillary ) astrocy tomas, recognizing that most such tumors in children have apparent
margins on imaging. Shrinking fields ty pically are not used in PAs; when target volumes for
infiltrating fibrillary astrocy tomas are used, fields may be reduced to more narrowly
encompass the obvious tumor after delivery of 50.4 Gy. For tumors with a cy stic component,
a CT or limited sequence MRI during radiation therapy may prove useful to evaluate changes
in the cy stic portion of the tumor during treatment. Diffuse low-grade gliomas can be
associated with gliomatosis cerebri or bithalamic astrocy tomas; both may be histologically
WHO grade II, but the pattern of growth indicates a degree of aggressiveness and infiltration
requiring large-volume irradiation based on guidelines for malignant gliomas (9,32). For
gliomatosis cerebri that is bilateral and involving much of the cerebral hemispheres, corpus
callosum, and, sometimes, thalamic nuclei, volumes defined by disease extent may approach
the whole brain; use of an imaging-defined “boost” or partial brain irradiation where possible
initially remain the accepted standards (9,38).
Astrocy tomas with multifocal presentations or subarachnoid seeding generally are
treated with craniospinal irradiation (CSI), although the need to cover the entire neuraxis is
controversial and unproven (10,39).
Dosage
There is little definitive dose–response data specific for pediatric astrocy tomas. The adult
low-grade glioma trials have established no clear benefit for dosage levels greater than 45 Gy
(40,41). Pediatric national trials employ doses approaching the established tolerance of
critical CNS structures (i.e., 50–54 Gy ). The primary justification is the long-term disease
control rates documented in studies of pediatric PA and other low-grade astrocy tomas. For
children y ounger than 5 y ears, a delay in irradiation is appropriate as clinical signs permit,
and when radiation therapy is needed, a dose of 50–54 Gy with optimal conformality is
standard.
Page 34Technique
Ideal techniques achieve close conformation of the high-dose region to a well-defined local
target volume. 3D conformal or intensity -modulated photon irradiation, or use of intensity -
modulated proton beam therapy is ideal to achieve conformality, with potential differences in
sparing adjacent dose-limiting structures (e.g., optic chiasm, ey e, and pituitary –hy pothalamic
region) and in intralesional homogeneity. Given the nature of low-grade gliomas and
recognized dose-related toxicities, attention to dose–volume histograms (DVH) and a 3D
image-based radiation plan is critical in designing treatment techniques. Multiple fields, based
on single-plane or noncoplanar techniques, may be used to achieve a dose distribution
maximally conformed to the target volume (Fig. 3.5 ). The impact of low-dose irradiation
on broader regions of the developing brain has not y et been fully explored; dose–volume
modeling suggests correlations between low-dose volumes and cognitive deficits (42). Early
results suggest that 3D conformal techniques achieve greater sparing of neuropsy chological
function, for example, than past experience has shown for conventional therapies (43). The
phy sical properties of protons allow for further reduction in the amount of brain exposed to
low-dose irradiation (26)(Fig. 3.6 ). The optimal conformality of intensity -modulated,
photon or proton therapy is likely to be associated with less pronounced late toxicities as a
result of diminished high- and low-dose exposure of normal tissue volumes (26,27,28).
Figure 3.5 Optic chiasm/hypothalamic glioma presenting for radiation therapy at 4 years
old following imaging evidence of progression after two chemotherapy regimens (A1–A3) B:
target volumes for this case depicted for axial (B1), sagittal (B2), and coronal (B3) planes.
Note CT dosimetry using IMRT 6 MeV photons with: GTV (green) with 5–10 mm anatomic
expansion for CTV (blue); geometric 3-mm expansion for PTV (red).
Figure 3.6 A: DVH derived as a composite plan from 10 cases of optic chiasm gliomas,
comparing 3D conformal RT (photon is red/dashed) and scanning proton beam (blue/solid). B:
Estimated IQ change based upon dose–volume effect models, depicting Wechslar Individual
Achievement Test (WIAT) spelling for 3D conformal RT (photon, red/dotted) and scanning
protons (blue/solid). (From Merchant TE, Hua CH, Shukla H, et al. Proton versus photon
radiotherapy for common pediatric brain tumors: comparison of models of dose
characteristics and their relationship to cognitive function. Pediatr Blood Cancer.
2008;51:110–117, with permission.)
The use of single-fraction radiosurgery for primary management of pediatric low-grade

gliomas has been reported in institutional series (44). There is little data to document the
potential risks and benefits of this approach; however, in the rare instances where small
lesions distant from critical structures can be targeted, especially in children with NF1 where
subsequent development of additional CNS tumors is relatively common, data suggest
reasonable efficacy and intermediate-term tolerance (44).
Results
Overall, outcomes for low-grade gliomas are quite favorable. Prognosis is related to age at
diagnosis and degree of surgical resection; older children usually enjoy more favorable
outcome. GTR is consistently linked to improved progression-free survival (19,20). Although
low-grade gliomas are often considered one entity for the purposes of clinical trials and
management, they represent diverse histioty pes with variable prognoses as documented in
series reporting detailed histopathologic analy ses. Advances in pathology, particularly better
molecular and genetic classification, should further categorize tumors and lead to the
development of targeted agents and modifications in treatment.
Long-term disease-free survival has been reported in 90% of children after complete
resection of cerebral hemispheric tumors; for similarly managed thalamic tumors, smaller
series report 60–90% survival (19, 22,23,24,32). Incomplete resection alone results in
approximately 50% progression-free survival at 5 y ears (20). The addition of therapeutic
irradiation has been shown to achieve progression-free survival in hemispheric astrocy tomas
in approximately 80% of children measured at 10 y ears (19,24). For thalamic tumors treated
primarily with irradiation, 40–50% survive free of progression (31,32). Hy pothalamic tumors
have a favorable outcome after primary irradiation, with 10-y ear progression-free survival
rates of 70–85% (31,45,46). Particularly when one is treating central (diencephalic) PAs, it is
noteworthy that tumor size may appear to increase approximately 3–12 months after
irradiation, often by apparent intralesional necrosis or cy st formation; such changes ty pically
remit over several months. The majority of lesions respond by imaging criteria after
radiation therapy (both by size and gradual loss of enhancement), but the median time to
objective response is greater than 15 months (Fig. 3.4 ) (45). Low-grade gliomas involving
both right and left thalamic regions (i.e., bithalamic tumors) have an aggressive course
similar to that of the more diffuse gliomatosis cerebri or pontine gliomas (32).
Figure:
A: JPA of (L) thalamus, presenting in a 4-year-old boy—cystic and solid, largely enhancing
tumor on T1-gadolinium MRI. B: JPA visualized on T2-FLAIR sequence postcontrast. Note
even better tumor definition. C: Note leptomeningeal metastasis in
hypothalamus/chiasmatic JPA, a finding largely at diagnosis in <10% of cases.
Figure:
Histologic features of the most common pediatric low-grade gliomas: JPA (L) and diffuse
fibrillary astrocytoma (R). JPAs (WHO grade I) show biphasic architecture with more cellular
areas that tend to have the Rosenthal fibers and loose areas with microcysts. Cells are
elongated, bilpolar, and have thin “hair-like” processes. Diffuse fibrillary astrocytomas (WHO
grade II) consist of long, thin cells highlighted by a crisscrossing background of cytoplasmic
glial filaments; nuclear atypia often apparent.
Figure:
A: A 7-year-old boy with JPA of optic chiasm and optic tracts (without neurofibromatosis),
involving and distorting chiasm (A, top) with spread along optic tracts (A, bottom). B:
Increased tumor size, enhancement along optic tracts noted 7 months postradiotherapy
(post-RT), attributed to transient posttherapy effects (B, top and bottom). C: Same levels
with marked, spontaneous reduction in tumor volume compared to preirradiation or MRI 7
months post-RT (Figures B); note normal chiasm (C, top). Patient now 5.5 years post-RT,
with intervening (R) middle cerebral infarct (C, bottom; same time as C, top).
Figure:
Optic chiasm/hypothalamic glioma presenting for radiation therapy at 4 years old following
imaging evidence of progression after two chemotherapy regimens (A1–A3) B: target
volumes for this case depicted for axial (B1), sagittal (B2), and coronal (B3) planes. Note CT
dosimetry using IMRT 6 MeV photons with: GTV (green) with 5–10 mm anatomic expansion
for CTV (blue); geometric 3-mm expansion for PTV (red).
Figure:
A: DVH derived as a composite plan from 10 cases of optic chiasm gliomas, comparing 3D
conformal RT (photon is red/dashed) and scanning proton beam (blue/solid). B: Estimated IQ
change based upon dose–volume effect models, depicting Wechslar Individual Achievement
Test (WIAT) spelling for 3D conformal RT (photon, red/dotted) and scanning protons
(blue/solid).
(From Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common
pediatric brain tumors: comparison of models of dose characteristics and their relationship
to cognitive function. Pediatr Blood Cancer. 2008;51:110–117, with permission.)
OPTIC PATHWAY TUMORS
OPTs represent 5% of childhood brain tumors. OPTs may involve one or several anatomic
sections of the optic sy stem (optic nerves, optic chiasm, optic radiations) (Fig. 3.4 ). They
can be small and localized or extensive and infiltrative. Chiasmatic gliomas are commonly
grouped with hy pothalamic gliomas as a single entity. OPTs occur predominantly in y oung
children; 25% present before 18 months of age, and 50% present before 5 y ears (45,46). Up
to 25% of childhood OPTs occur in children with NF1 (47,48). Careful neuro-ophthalmologic
examination ± screening MRIs should be standard for patients with NF1 (47,49) where 20%
develop OPT’s (48,49).
Clinical presentation is most often with diminished vision. In y oung children, increased
intracranial pressure, endocrinopathies, and diencephalic sy ndrome may predominate.
Histologically, more than 90% of OPTs are low-grade astrocy tomas, most often PAs (more
than 65% of cases) and grade II astrocy tomas (25%), with infrequent gangliogliomas or
hamartomas; malignant gliomas are uncommon (45,46).
The nature of OPTs has been debated. While acknowledging the sometimes indolent
nature of OPTs, disease progression is documented in 75–85% of children, ty pically within 2
y ears of initial presentation (46,50,51). Tumors confined to the optic nerve(s) may behave in
a more hamartomatous fashion. Children with NF1 have a more indolent course with lower
rates of progression and longer latency intervals (51). Signs of a more malignant behavior of
OPTs include extension to or invasion of the adjacent hy pothalamus and posterior extension to
the optic tracts (up to and including the lateral geniculate bodies) and optic radiations.
Infrequently, optic chiasmatic and hy pothalamic tumors demonstrate diffuse leptomeningeal
disease (19,39). Mortality within 10 y ears of diagnosis is uncommon, although ultimate
disease-related mortality has been documented in 10% of cases (46,50). Also to be noted is
the rare but documented occurrence of spontaneous regression of OPTs (52).
Page 36Lesions extending to or originating in the hy pothalamus may be somewhat more
aggressive than lesions confined to the visual pathway s (46,53). Preliminary data suggest
adequate retrieval with secondary therapy at the time of progression during observation
(46,53).
Therapy
Surgery
Surgery has been the preferred treatment for unilateral tumors of the optic nerve amenable
to surgical resection with acceptable morbidity. In a series of 623 optic gliomas reported by
Alvord and Lofton (54), complete surgical excision was performed in 60% of the optic nerve
tumors; the failure rate was 15% among this population at 20 y ears. Progression occurred in
70% of children with untreated lesions within 6 y ears of diagnosis, although it was rarely
associated with tumor-related mortality (54). Observation may be selected, especially if
there is residual vision associated with a lesion confined to the intraorbital optic nerve. Most
series indicate more indolent, perhaps truly hamartomatous behavior in children with
neurofibromatosis (46,48).
Page 37For lesions involving the optic chiasm, there are limited data suggesting a role for
surgical resection, though decompression or limited resection may be successful in restoring
vision (55). Series from the Hospital for Sick Children, Toronto, and New York University
suggest a somewhat broader role for local excision in selected presentations. The latter
authors indicate removal of lesions of partially infiltrating low-grade optic pathway
astrocy tomas with surprisingly little added visual compromise; approximately 50% of such
cases have remained stable without further intervention for 3–5 y ears (21,22). Care should be
taken to avoid visual compromise or other surgical complications as alternative therapies are
quite successful.
Ty pical chiasmatic lesions that involve components of the visual pathway s bey ond the
optic chiasm and hy pothalamic region (i.e., with imaging extension to the optic nerves, optic
tracts, or optic radiation) may be managed without biopsy confirmation. Most of these tumors
are low-grade astrocy tomas and can be managed based on the clinical and imaging
diagnosis. Globular tumors that involve the chiasm and hy pothalamus are best biopsied if this
can be performed safely ; a small percentage of these lesions may be GCTs, unusual ty pes of
low-grade neoplasms, or more aggressive malignant gliomas.
Radiation Therapy
Irradiation is indicated for significant visual or neurologic deficits at presentation or
documented progression by clinical evaluation or neuroimaging after observation, surgery, or
chemotherapy. Radiation therapy is highly effective for OPTs: 10-y ear progression-free
survival rates exceed 80% (28,45,56,57). Although overall survival at 10 y ears is unaffected
by the initial therapeutic approach (i.e., observation, resection, chemotherapy, or irradiation),
progression-free survival rates at 5 and 10 y ears are higher after radiation therapy (31,46).
Serial imaging studies document significant tumor response in more than 50% of children
after irradiation (45). Transient postirradiation tumor enlargement, often in the setting of
central cy stic degeneration, has been well documented (45). Close observation and medical
management (i.e., steroids) rather than aggressive intervention for presumed tumor
progression is advised, particularly for lesions that may appear to progress within 3–12
months after radiation. Visual improvement has been reported in 25–35% of children after
irradiation (28,45). Visual deterioration is reported in 10–20% of children after irradiation,
largely related to cy stic degeneration (and consequent increased mass effect at the chiasm)
or unrecognized elevated intracranial pressure (45,46). Vision should be monitored closely
during the radiation course and in the months following completion.
Balancing the indications for radiation therapy and the timing requires judgment and,
often, serial evaluations to determine the nature of the disease process. OPTs are associated
with unique late radiation-related sequelae. The y oung age at diagnosis, central location, and
often extensive anatomic involvement challenge the ability to deliver adequate radiation
therapy while preserving neurocognitive function; the problem is further accentuated in
children with NF1, itself associated with cognitive delay s. There is also concern about late
vascular events: the incidence of occlusive vasculopathy at the circle of Willis in children
with brain tumors is highest among those with OPTs, especially in y ounger children (58).
Moy amoy a sy ndrome is characterized by obliteration of the major vessels at the circle of
Willis; incomplete brain perfusion is provided by collaterals and peripheral meningeal
vessels. The sy ndrome has been noted after irradiation, perhaps related to cicatricial
constriction of vessels tracking through chiasmal and hy pothalamic gliomas. An incidence of
at least 18% has been reported, especially noted among children less than 2–3 y ears and
those with NF1 (58). A baseline magnetic resonance angiography (MRA) prior to irradiation
to document vascular status is important, often revealing occult vascular compromise due to
the tumor itself; the baseline is important to more easily detect changes after treatment.
There is also a heightened concern regarding the risk of second malignancy in patients with
NF1 (59). Hormonal dy sfunction is also a long-term concern with the use of radiotherapy for
tumors in this location.
Chemotherapy
Because of the radiation-associated morbidities in y oung children with OPT, chemotherapy is
the accepted first line therapy used in effort to delay radiation therapy (46, 53,60). In a
French Society of Pediatric Oncology Study, patients >1 y ear old or with a CR/PR to
chemotherapy had a 3-y ear PFS of 66% (60). Lack of a response to chemotherapy and age
<1 y ear were factors that predicted for an inferior outcome with chemotherapy alone, with
3-y ear PFS ranging from 44–53%. Chemotherapy in this study consisted of alternating
carboplatin/procarbazine, etoposide/cisplatin, and vincristine/cy clophosphamide. Second-line
chemotherapy was offered at tumor progression, resulting in a radiotherapy -free survival of
61% at 5 y ears (60). An 18-month regimen of carboplatin and vincristine for low-grade
gliomas including those of the hy pothalamic region and OPTs reported significant objective
tumor response (greater than 50% tumor reduction in one-third of patients), early progression
in only 10%, and 3-y ear progression-free survival that ranged from 75% for children
y ounger than 5 y ears to 39% for those older than 5 y ears (33,61). Similar results have been
reported with the UCSF five-drug regimen (36).
Early experience suggests favorable outcome with secondary irradiation following post-
chemotherapy progression; recent observations suggest that long-term radiation disease
control and function are not diminished with prolonged preirradiation intervals (46, 53, 57,60).
Toxicity with carboplatin and vincristine has been limited, and early data suggest continued
intellectual development during chemotherapy (33). There is a balance between duration of
disease control (clearly superior with radiation therapy ) and less durable control with
chemotherapy, but apparently without the serious morbidities associated with irradiation in the
y ounger age group. Data from St. Jude has demonstrated that visual acuity in the worse ey e
is negatively impacted by the receipt of chemotherapy or tumor progression prior to the
delivery of radiation (62). In current practice, most children below 5–10 y ears receive
chemotherapy as the initial intervention, with some centers extending this to all prepubertal
children. It is important not to avoid irradiation, even in y ounger children, when progressive
visual loss is apparent despite chemotherapy.

Volume and Technique
The volume of disease is quite variable for OPTs. The target volume includes only the
radiographically involved aspects of the optic pathway. Tumors are often confined to the
suprasellar region for lesions that are limited to the chiasm with or without hy pothalamic
involvement. Central lesions require optimized intensity -modulated radiation therapy (IMRT),
limiting the dosage to the surrounding cerebral hemispheres and minimizing intralesional
inhomogeneity of dose (24,56). Proton radiation therapy provides a dosimetric benefit for
such tumors by reducing the dose delivered to the contralateral optic nerve, optic chiasm and
pituitary gland at clinically relevant levels (63). Optic nerve involvement, most often in NF1,
necessitates inclusion of the nerve to the posterior aspect of the globe in defining the target
volume. For lesions extending along the optic tracts or bey ond (occasionally to involve the
optic radiation, toward or to the occipital lobes), it is key to discern where apparent neoplastic
changes differ from edema.
Dosage
The extensive literature on radiation therapy for OPTs ty pically calls for dose levels of 50–54
Gy, most often at 180 cGy per fraction (24,28,45,57). Reduction to 50 Gy at 150 cGy daily
may be considered for children y ounger than 3 y ears (31).
OLIGODENDROGLIOMA
Oligodendrogliomas in children are rare, with only 6% of these tumors occurring in the
pediatric population (64). The generally circumscribed tumors occur most often in the
cerebral hemispheres. In adults, loss of chromosome 1p or 19q and isocitrate dehy drogenase
(IDH1) mutation are noted in 50–80% of cases, and each are both prognostic and predictive
of response to treatment (65,66,67). In pediatric oligodendrogliomas 1p19q codeletion was
noted in 25% of cases, primarily in adolescents (68,69,70). Treatment recommendations are
based largely on adult experience with surgery and irradiation. Adults show excellent
response to procarbazine, lomustine, and vincristine (PCV) or to temozolomide
chemotherapy, particularly in oligodendrogliomas with 1p19q codeletion, IDH1 mutations, or
p53 mutations (66,67,71). Given differences in biology, it is unclear whether chemosensitivity
can be extrapolated to children.
Total surgical resection is the treatment of choice for accessible lesions. GTR has been
documented in 25–56% of all cases, and has been associated with significantly improved PFS
and OS, apparently more so in children and adolescents (72,73). The 5-y ear progression-free
survival rate after total excision is reported at 100% in the Washington University School of
Medicine Series (72).
For incompletely resected oligodendrogliomas, a short-term benefit for radiation
therapy has been documented. In a randomized trial evaluating the use of early versus
delay ed irradiation, adjuvant therapy (54 Gy ) was shown to significantly improve PFS to 5.3
y ears versus 3.4 y ears, though there was no significant difference in OS (74). Adjuvant
irradiation ty pically is withheld for differentiated oligodendrogliomas in children, even with
incomplete resection. Anaplastic oligodendrogliomas are managed similarly to other
malignant supratentorial gliomas in children, although the outcome tends to be superior to
those with anaplastic astrocy toma and glioblastoma.
Combined radiation therapy and PCV has been associated with excellent disease control
in adults, resulting in improved overall survival compared with radiation therapy alone among
patients with 1p19q codeleted or IDH1 mutated anaplastic oligodendroglioma (66,67,71). The
addition of PCV has also been demonstrated to benefit grade II gliomas (75). Temozolomide
has demonstrated efficacy in both low- and high-grade oligodendrogliomas and is often used
in preference to PCV (76,77).
GANGLIOGLIOMA
Gangliogliomas are uncommon, biologically benign neoplasms comprised of neuronal and

glial elements (ganglion cells and astrocy tes, respectively ) (2). The tumors occur primarily
in children and y oung adults, with a median age approximating 25 y ears (78).
Gangliogliomas present most often in the mesial aspect of the temporal lobes, with seizures as
the dominant sy mptom (78,79). Pediatric tumors uncommonly present in the posterior fossa.
The lesions are ty pically well circumscribed and surgically resectable. Gangliogliomas are
classically coded as WHO grade I, well differentiated histologically with no aty pia or
anaplasia (2). Surgery alone is the standard initial intervention with survival >92% 10 y ears
after surgery (78). Malignant transformation at progression or recurrence is rare; at most
10% of cases show nuclear aty pia or anaplastic components (grade II or III, respectively )
(80). Malignant degeneration to high-grade histology is decidedly uncommon in children and
adolescents (80). Prolonged progression-free survival has been noted in small series with
irradiation following incomplete resection or recurrence; the efficacy following malignant
degeneration is less apparent (81).
RARE LOW-GRADE NEOPLASMS
Neurocy tomas are clinically indolent tumors that present as intraventricular lesions, usually
in the lateral ventricles with attachment to the midline septum pellucidum; most are diagnosed
in adolescents and y oung adults. Neurocy tomas are composed of small neuronal cells thought
to represent a benign neoplasm derived from cells midway in the maturation process of
neuronal differentiation (82). These tumors are genetically distinct from the
oligodendrogliomas and dy sembry oplastic neuroepithelial tumors (DNETs), with which they
can be confused both clinically and histologically (82). Neurocy tomas are generally
resectable. Prognosis has been related to the rate of proliferation (83). These tumors respond
to irradiation; small series have suggested improved outcome in cases with less than total
resection when followed by radiation therapy (local or anatomically defined target volume;
dose ≥54 Gy in 30 fractions reported to be superior to lower doses) (81,83).
Page 39DNETs are biologically indolent, often large cerebral cortical tumors ty pically
presenting with a long-standing seizure history (84). Sy mptoms ty pically arise in children
y ounger than 12 y ears; the mean age at diagnosis is 14 y ears (84). The tumors may be
considered quasi-hamartomatous, classically are well demarcated, and show no contrast on
MRI; uncommonly, DNETs present as complex solid and cy stic lesions with enhancement,
calcification, and intralesional hemorrhage (85). These tumors may be followed, but surgery
often is needed for seizure control; although they appear to be responsive to irradiation, there
is no documented role for postoperative therapy.
MALIGNANT GLIOMAS
Supratentorial malignant gliomas represent approximately 6% of brain tumors in children.

Histologic grading identifies high-grade (or malignant) gliomas as anaplastic astrocy toma
(WHO grade III) or glioblastoma (WHO grade IV) (2). Children have a higher proportion of
anaplastic astrocy tomas and arguably longer survival intervals in comparison to adults, and
are biologically separate from the more common adult malignant gliomas (86,87). Adult
primary malignant gliomas appear to arise de novo and are associated with amplification of
the epidermal growth factor receptor (EGFR) gene and PTEN; less common secondary
malignant gliomas evolve from low-grade tumors (primarily infiltrating astrocy tomas, WHO
grade II) and ty pically have TP53 mutations (88). In contrast, PDGFRA is the predominant
target of focal amplification in pediatric high-grade gliomas (89). Overexpression of p53 and
mutations in TP53 have been noted in pediatric malignant glial tumors; EGFR amplification
and PTEN deletions are less common (89,90).
Supratentorial malignant gliomas arise primarily as cerebral hemispheric tumors; 20–
30% present centrally in the thalamus or basal ganglia (91). Imaging characteristics are
similar to those in adults, with often poorly marginated, peripherally enhancing lesions on
MRI associated with surrounding white matter changes (edema); the enhancing components
correlate with the cellular, vascularized periphery of the tumor complex. Adult studies have
shown infiltration of the small, round anaplastic cells well into the T2 and T2 FLAIR areas of
perilesional abnormal white matter (92). Even with acknowledged infiltration at a distance
from the “overt” tumor, clinical data shows both a direct relationship between the degree of
resection and relative duration of “tumor control” as well as a pattern of failure that is
overwhelmingly within the primary target volume after high-dose focal irradiation (93,94).
The large prospective CCG trial (CCG-945) showed disease bey ond the primary site (as
multifocal or leptomeningeal spread) only anecdotally (94).
The diagnosis of high-grade glioma in children has often been challenging to the
neuropathologist. Central review of pathology in the CCG-945 trial showed 36% of cases
entered based on an institutional diagnosis of anaplastic astrocy tomas or glioblastoma were
felt to have a discordant diagnosis, primarily low-grade gliomas, based on the reviewers’
interpretation (95). In addition to confusion with pleomorphic xanthoastrocy toma and
embry onal tumors in y ounger children, the newly identified “glioneuronal tumor” may
present with an apparently malignant phenoty pe despite sometimes benign natural history
(96). Genomic analy sis can now be used in conjunction with histopathologic analy sis to
improve diagnostic accuracy ; the K27M or G34 mutation in the H3F3A gene has been
demonstrated to occur exclusively in pediatric high-grade gliomas (30% in GBM and 20% in
AA) (97) and also carries prognostic significance (97,98).
Therapy
Surgery
Surgical resection often has been limited in extent by the poorly circumscribed nature of the
tumor and the attendant lack of aggressive neurosurgical intent. The large CCG series
indicated that more than 90% resection (gross total and near total, by definition) was achieved
in only 37% of cases: 49% of lesions arising in the superficial cerebral hemispheres, 45% of
lesions arising in the cerebellum, and 8% of those arising in the central structures
(diencephalons, midbrain) (94). There is a significant relationship between degree of
resection and outcome. Five-y ear progression-free survival in the initially reported CCG-945
experience was 44% and 26% for anaplastic astrocy tomas and glioblastoma, respectively,
after more than 90% removal, compared with 22% and 4%, respectively, after less
aggressive resection (94).
RADIATION THERAPY
Radiation therapy is a primary component of initial management of pediatric malignant

gliomas. Adult studies have documented the impact of adequate radiation therapy on survival,
although survival bey ond 2 y ears occurs almost entirely among those with anaplastic
astrocy toma rather than glioblastoma. Treatment has evolved to local irradiation, with
margins reflecting the known pattern of microscopic extension and, increasingly, functional
imaging to guide evolving therapeutic approaches. A series of dose-escalating trials have y et
to demonstrate a convincing impact on disease control (99). Current trials use 3D conformal
radiation therapy or IMRT to dosage levels approximating 59–60 Gy, similar to those used in
adults.
Chemotherapy
The large EORTC–NCIC prospective adult trial has convincingly shown the advantage of
temozolomide in conjunction with surgery and irradiation in adult glioblastoma: 2-y ear
survival rate increased from 11% to 27%, and 5-y ear survival rate, from 2% to 10% (100).
The advantage of chemotherapy was apparent in all clinical settings (age, extent of resection,
performance status; the impact of chemotherapy correlated most closely with the presence
or absence of MGMT methy lation). Unfortunately, the pediatric experience has not been as
favorable with temozolomide: the rate of objective response in phase II trials with recurrent
malignant gliomas has been quite disappointing (12%), and prospective primary management
phase II trials of temozolomide following surgery and radiation have shown no benefit in
progression-free survival (PFS) or overall survival (OS) in comparison with historical controls
(2-y ear OS 21%) (101,102). An early pediatric trial of 58 patients, CCG 943, reported an
apparent benefit when pCV chemotherapy (vincristine, lomustine, and prednisone) was
added after radiation therapy, with 5-y ear event-free survival (EFS) approaching 45% with
chemotherapy compared with 17% for those who received irradiation alone (103). The
subsequent CCG-945 trial, compared pCV chemotherapy to eight drugs in 1 day (8-in-1) and
found no significant difference in outcome according to the two chemotherapy regimens with
5-y ear OS and PFS of 33% and 36%, respectively, and greater toxicity with the 8-in-1
regimen (104). Later follow-up of this study with central independent review by five
neuropathologists reclassified a significant number of the tumors as low-grade gliomas (86).
After central review, overall survival at 5 y ears was 79% among children with low-grade
gliomas and 22% among children with high-grade gliomas, a finding similar to the
radiotherapy only arm of previous studies (86). The COG study ACNS 0126 examined the
effect of temozolomide delivered concurrently and adjuvantly with radiation in comparison
with historical controls from the CCG-945 trial. The 3-y ear EFS rate for AA was 13% in
ACNS 0126 compared with 22% in CCG-945, and the 3-y ear EFS rate for GBM was 7% in
ACNS0126 compared with 15% in CCG-945 (105). The results of ACNS 0126 demonstrated
that temozolomide failed to improve outcomes for children with high-grade gliomas.
However, EFS was significantly greater among patients without overexpression of the O6-
methy ltransferase gene (MGMT) in both studies (105,106) and methy lation (silencing) of the
MGMT has been associated with improved response to temozolomide in pediatric GBM (107).
MGMT methy lation status may be a useful marker to select patients for temozolamide
treatment.
Page 40Interest in overcoming the theoretical blood–brain barrier and the potential
advantage of dosage intensification have stimulated investigation of high-dose chemotherapy
with autologous bone marrow rescue in childhood malignant gliomas (108,109). Attempts to
utilize relatively high-dose therapy with granulocy te-colony stimulating factor (GCSF)
support (short of doses requiring peripheral stem cell support) in CCG resulted in 42%
progression prior to irradiation and an additional 15% failing to complete 12 weeks of
chemotherapy due to toxicities; over 20% of cases were unable to proceed to scheduled
radiation therapy (109).
Current trials in COG and the Pediatric Brain Tumor Consortium (PBTC) focus on the
addition of molecular targeting agents such as anti-angiogenic compounds targeting VEGF
and related angiogenesis pathway s, as well as EGFR, PDGF, and mTOR inhibitors
administered concurrently or sequentially with irradiation. Integrin inhibitors and dendritic
cell vaccines are also currently being investigated (110).
The target volume is best defined by the enhancing lesion and surrounding low-density
change using both pre- and postoperative MRI that includes gadolinium-enhanced T1
sequence and the larger region often identified only on T2 (or T2 FLAIR). Detailed reviews
of imaging and histologic extent in malignant gliomas and clinical patterns of failure have
suggested that a 1- to 2-cm margin bey ond the tumor/tumor bed and associated T2 (or
FLAIR) abnormality define the initial CTV, with
subsequent reduction to the residual enhancing
tumor and/or tumor bed (on postoperative MRI)
with 0.5–1 cm expansion define the “boost” CTV
(Fig. 3.7 ). Imaging guidelines reflect findings
of histologic infiltration in the “surrounding
edema” in most supratentorial malignant glioma
cases (92). Despite this, most studies indicate that
central failures (within the high-dose volume)
y et predominate in these cases (111). The use of
image-guided radiation planning in pediatric
malignant gliomas is important in sparing the
normal brain. IMRT is the current standard to
better spare critical normal structures (e.g., optic
chiasm and nerves, brainstem) (112).
Dosage
The conventional dose–volume relationships in
children have favored levels of approximately
45–54 Gy to the initial CTV, with a total of 60 Gy
to the “boost” volume as defined above based on
adult guidelines. Figure 3.7 Glioblastoma multiforme
presenting in an 8-year-old boy, involving
Page 41Results (L) thalamus in a “nodular” pattern, status
post minimal resection (A–C). D: MR
Median survival times for pediatric malignant
spectroscopy map demonstrates
gliomas are 18–24 months (86,104). Event-free
quantitative ratio of choline:NAA. E: 3D
survival rate at 3–5 y ears is as high as 45%
conformal plan with GTV (green), 2-cm 3D
among the minority of patients in whom GTR is
anatomic expansion to CTV (blue), and 3-
confirmed by postoperative neuroimaging and
mm geometric expansion to PTV (red).
treated subsequently with both irradiation and
chemotherapy (20, 94,104). For the 65–75% of
childhood malignant gliomas with residual disease identifiable after surgery, the progression-
free survival rate at 3–5 y ears is only 5–20%, slightly higher among the anaplastic
astrocy tomas than the glioblastomas (95). Infants with high-grade gliomas have considerably
better long-term survival than older patients, with 5-y ear OS reaching 66%, suggesting a
different tumor biology among this age group (113).
Figure:
Glioblastoma multiforme presenting in an 8-year-old boy, involving (L) thalamus in a
“nodular” pattern, status post minimal resection (A–C). D: MR spectroscopy map
demonstrates quantitative ratio of choline:NAA. E: 3D conformal plan with GTV (green), 2-cm
3D anatomic expansion to CTV (blue), and 3-mm geometric expansion to PTV (red).
EMBRYONAL CNS TUMORS (PRIMITIVE NEUROECTODERMAL
TUMORS OR SPNET AND PINEOBLASTOMA)
The WHO classification of embry onal CNS tumors clarifies earlier controversies regarding
PNETs (2). The tumor consists of undifferentiated neuroepithelial cells with areas of
divergent differentiation toward glial, neuronal, and mesenchy mal lines. In 1983, Rorke
introduced the PNET as a unify ing concept, grouping together the “small round blue cell”
CNS tumors, with or without specific differentiation but sharing common histologic and
clinical features (e.g., tendency to seed along the CSF pathway s and relative responsiveness
to irradiation and chemotherapy (114). Recent biologic studies and gene profiling have
demonstrated markers specific for medulloblastomas (e.g., isochromosome 17p), separating
the classical posterior fossa embry onal tumor from the several supratentorial PNET
“subty pes” (115).
The current WHO classification outlines specific embry onal histioty pes (Table 3.1 ).
Medulloepithelioma is the most primitive embry onal tumor, histologically showing features
of primitive medullary epithelium and primitive tubular structures; focal differentiation
toward glial, neuronal, or mesenchy mal lines is often present. Ependy moblastoma is a poorly
differentiated embry onal tumor with ependy mal differentiation marked by multilay ered
rosettes similar to those seen in retinoblastoma (Flexner–Wintersteiner rosettes) (2),
classically felt to be a specific embry onal neoplasm, different from the differentiated and
anaplastic ependy momas (discussed in Chapter 4 ). Cerebral neuroblastoma ranges
histologically from an undifferentiated tumor similar to the extra-CNS childhood
neuroblastoma, to lesions demonstrating ganglionic differentiation (115). The recent
molecular classification will likely redefine sPNET’s for the upcoming WHO modification to
include major subgroups: embry onal tumor with multi-lay ered rosettes (ETMR); MYCN-
amplified and IDH/H3F3A expressing, respectively, high-grade gliomas; ependy moblastoma,
and the aty pical teratoid/rhabdoid tumor (AT/RT). The new classification identifies 30% of
tumors expressing high-grade glioma features, 15% intra-CNS counterparts of
neuroblastoma, and 10% as ETMR characterized (4,117,118). AT/RT is a biologically and
clinically unique embry onal tumor that is discussed in Chapter 4 with infant neoplasms.
Pineoblastoma is categorized as a pineal parenchy mal tumor by the WHO, though
ty pically (as here) grouped with embry onal tumors and managed similarly to other sPNETs
(2). The tumor is believed to arise from pineal parenchy mal cells, histologically signified by
undifferentiated small round cells, usually including scattered Homer–Wright rosettes. The
tumor may mimic retinoblastoma, including fleurettes and Flexner–Wintersteiner rosettes
(116).
The clinical outcomes of the supratentorial embry onal tumors have been inferior to
those of medulloblastoma; the different supratentorial entities show vary ing survival rates
dependent on subty pe as well as age, disease extent, and therapy ; recent reports that
pineoblastoma enjoy s favorable outcome compared to other supratentorial PNETs require
further substantiation (119).
The supratentorial embry onal tumors occur
more commonly in y ounger children.
Embry onal tumors ty pically present as solid or
partially cy stic lesions (Fig. 3.8 ). Although
sPNET and cerebral neuroblastoma may
present as well-demarcated lesions, most
embry onal tumors are generally invasive.
Leptomeningeal dissemination is apparent at the
time of diagnosis or at the time of initial tumor Figure 3.8 Classical pineoblastoma
recurrence or progression in approximately one- presenting in a 3-year-old child with
third of children (119,120,121); there is some large, complex solid, and cystic pineal
controversy regarding the frequency of CSF tumor.
failure in initially localized cerebral
neuroblastoma, but most reports indicate CNS
dissemination at a rate similar to that of the other embry onal tumor ty pes (120,121).
Therapy
Surgical resection is the first step in the management of sPNET, which may be resectable in
up to 50–60% of cases (119,120). A report from the COG demonstrated the complete
resection is associated with improved survival among patients with sPNET receiving adjuvant
craniospinal irradiation and chemotherapy (122). Pineoblastomas are generally approached
for stereotactic biopsy or limited resection (123).
Postoperative irradiation is indicated for the embry onal CNS tumors. Classic studies
indicate disease control in less than 25% of cases with sPNET and pineoblastoma without
adjuvant treatment (124). A review of the SIOP/UKCCSG experience showed high rates of
disease control with CSI for pineoblastomas with or without chemotherapy (125). The use of
immediate postoperative irradiation and subsequent chemotherapy in CCG resulted in a 60%
survival rate in children over 1.5–3 y ears with pineoblastomas (123). For children age 3 y ears
and older, 5-y ear survival rates approach 80% for patients with pineoblastoma and 45% for
nonpineal sPNETs treated with craniospinal irradiation with concurrent carboplatin and
adjuvant cy clophosphamide-based chemotherapy (122). Results in other series highlight
interest in high-dose chemotherapy (e.g., high-dose methotrexate in the HIT regimens from
the German studies or high-dose therapy with peripheral stem cell rescue) following
irradiation (126,127).

CSI has been the standard for embry onal CNS tumors in children older than 3–4 y ears. The
technique for CSI is discussed in Chapter 4 . For supratentorial embry onal tumors, the local
boost is defined by the preoperative tumor volume, corrected for tissue shifts that occur with
resection of often sizable lesions; in practice, the preoperative volume is diminished to the
tumor bed and residual neoplasm to identify the GTV. Anatomic expansion by approximately
1 cm is utilized to define the CTV for all but the most circumscribed tumors; more diffuse
tumors requiring further expansion. As in other supratentorial lesions, the use of intensity
modulated photon irradiation or proton therapy (128) offers a potential advantage in coverage
and limits the dosage to adjacent critical brain volumes.
Dosage
The dosage of CSI is comparable to that used in high-risk medulloblastoma, with full neuraxis
dosages of 35–36 Gy in children older than 3–5 y ears (122,129,130). The HIT 2000 trial
showed no advantage to hy perfractionated irradiation to higher numerical doses (131). Data
from St. Jude suggest that reduced neuraxis irradiation (23.4 Gy ) may be appropriate in
localized sPNET with limited or no postoperative residual when combined with dose-intensive
chemotherapy (126). The primary tumor volume is treated to a cumulative dose of 54 Gy
with volume reduction at 45–50.4 Gy if necessary, as above.
Figure:
Classical pineoblastoma presenting in a 3-year-old child with large, complex solid, and cystic
pineal tumor.
CRANIOPHARYNGIOMA
Craniophary ngiomas are benign tumors of epithelial origin believed to arise from remnants
of Rathke’s pouch in the suprasellar region. The ty pical adamantinomatous
craniophary ngioma is a calcified, cy stic tumor derived from embry onic cell rests of enamel
organs located adjacent to the tuber cinereum along the pituitary stalk. The
adamantinomatous craniophary ngioma seen in children and adolescents includes solid
components and often large, complex cy sts filled with fluid containing high lipid content and
cholesterol granules, described as “crankcase oil.” Up to 10% may present as purely cy stic
lesions (132). The less common papillary craniophary ngioma occurs almost exclusively in
adults, is rarely calcified, and often presents as a solid lesion without cy st formation.
Papillary craniophary ngiomas commonly carry a BRAF V600E mutation and may respond
well to targeted therapy (133).
Craniophary ngiomas are well-circumscribed, encapsulated extra-axial lesions. The
tumor has an interdigitating pattern of adhesion to adjacent neurologic structures, including
the optic chiasm, major vessels at the circle of Willis, the tuber cinereum (along the pituitary
stalk), and the hy pothalamus. Infiltration into the tuber cinereum and the presence of small
tumor islets in the adjacent hy pothalamus document the potential for local invasiveness.
Grading sy stems proposed for craniophary ngioma are based largely on the degree of
hy pothalamic involvement (e.g., none vs. abutting/displacing vs. involving/infiltrating, the
latter marked by absence of the hy pothalamus on imaging) (132).
Anatomically, 70–90% of childhood craniophary ngiomas involve the retrochiasmatic
region, usually extending superiorly into the third ventricle and along the hy pothalamus (Fig.
3.9 ) (132). The multicy stic lesion may include cy stic extension into the basal cisterns,
even into the posterior fossa. In 10–30% of cases, the tumor presents in a prechiasmatic
location between the optic nerves, pushing the chiasm posteriorly (132). Prechiasmatic
tumors are more surgically accessible and less adherent to vital suprasellar structures.
Figure 3.9 A (column on L): Craniopharyngioma in a 5-year-old boy showing typical solid
component in region of tuber cinereum (suprasellar cistern) and cystic components
extending into the third ventricle/interpeduncular region and upper sella; T1-gadolinium
imaging. B (column on R): 3.5 years following simple drainage of the superior cyst and 54
Gy per 30 fractions using 3D conformal RT. Small residual solid component off inferior tuber
cinereum just posterior to optic chiasm shown in sagittal (top) and axial MRI (middle),
largely calcified as noted in accompanying CT without contrast (bottom).
Children present with visual field deficits and/or impaired acuity and sy mptoms of
elevated intracranial pressure (headaches, nausea, vomiting). Endocrine deficits at diagnosis
are apparent in 50–90% of children studied, most often diminished growth hormone, but also
diabetes insipidus (10–20% of cases preoperatively ), and decreased gonadotropin, thy roid-
stimulating hormone, or adrenocorticotropic hormone (25% incidence) (134). Changes in
personality and altered cognitive function have been noted in up to 50% of children at
presentation (135).
Therapy
The treatment of craniophary ngiomas is one of the most controversial issues in pediatric
neuro-oncology. Total resection is often curative in this technically “benign” neoplasm.
Numerous contemporary series reporting primary surgical intent in children note attempted
total resection in 50–80% of cases (136,137,138). Postoperative imaging indicates residual
calcification or obvious tumor in 15–50% of “totally resected” cases (132,136,137,138). The
rate of clinical recurrence even after imaging confirmed total resection is 15–30%, linked to
tumor volume and location (136,137,138).
Balanced against the low failure rate after aggressive surgery are risks of perioperative
mortality (1–3%) and major postoperative morbidity (significant visual loss, vascular events,
or added neurologic deficits) in 10–20% of cases (135,136,137,138). The skill and experience
of the surgeon are important; tumor control and morbidity rates correlate with the number of
cases performed annually. Extensive resection is associated with a 90% incidence of diabetes
insipidus, a relatively difficult endocrine deficit to manage, and often marked hy pothalamic
obesity in ≥50% of cases (137,139). Hy pothalamic obesity is associated with uncontrollable
appetite and correlated with a 15–20% incidence of behavioral problems (e.g., anger or
aggressive behavior including rage or violence) related to hy pothalamic damage (135).
Transphenoidal resection may be favored over open resection as it has been associated with a
reduced risk of serious perioperative complications (136,138).
Page 43Given the morbidity associated with aggressive surgical resection, biopsy or
limited resection followed by adjuvant radiation therapy may be the preferred primary
approach. The literature confirms long-term disease control in 75–90% of children with
primary radiation therapy following limited surgery (137,140). In a sy stematic review of 109
studies of children with craniophary ngioma, there was no difference in disease control
among patients treated with GTR versus STR followed by radiotherapy ; 5-y ear PFS 77% for
GTR alone versus 73% for STR and radiotherapy (140). The use of adjuvant irradiation
following subtotal resection in contemporary, image-based radiation series results in PFS as
high as 98% at 5 y ears, outcomes that are markedly improved compared with STR alone (5-
y ear PFS of 43%, although longer term follow-up can show late recurrences between 5 and
10 y ears in a significant proportion of cases) (140,141). Limited resection followed by
adjuvant RT is associated with a reduced risk of diabetes insipidus and panhy popituitarism
compared with aggressive surgery ; obesity may be slower in onset and less dramatic, if still
problematic with the combined modality approach (137). Early reports of proton beam
therapy for craniophary ngioma demonstrate good clinical outcomes and favorable late
affects (142,143). Single-fraction radiosurgery has been used for postoperative residual when
limited in size and anatomically positioned to allow avoidance of the chiasm and
hy pothalamus (144).
Acute reactions are rare during or after limited volume brain irradiation, while
anticipated endocrine changes reflect initial tumor- or surgery -related damage to the
hy pothalamic region; later endocrinopathies include growth hormone deficiency and less
frequent accelerated or delay ed sexual development; diminished thy roid-stimulating
hormone or adrenocorticotropic hormone secretion. Radiation-related diabetes insipidus is
distinctly uncommon. Comparative reports of neurocognitive and overall functional levels
favor children treated by limited surgery and irradiation compared to those with aggressive
total resection (145). Late vascular events are well documented in more than 20% of
survivors, related to surgery and irradiation and ranging from localized vascular narrowing to
moy amoy a sy ndrome with occlusion of major vessels of the circle of Willis (146).
The option of incomplete resection and observation, delay ing irradiation until later
progression, is unattractive in most instances. Despite the low-grade histology of
craniophary ngiomas, clinically detectable progression is apparent in up to 70% of
incompletely removed tumors within 3 y ears (140,147). Second surgery is associated with
less likelihood of GTR and higher surgical morbidity (148). Results of delay ed irradiation at
the time of recurrent disease are reported to be inferior to those achieved with planned
postoperative irradiation (149).
Cy st enlargement within the first y ear or so of irradiation may not represent progressive
tumor. A majority of children with early cy stic enlargement ultimately have stabilization and
later regression of the cy st or need simple cy st aspiration for associated neurologic
sy mptoms. Progressive but isolated cy stic enlargement following surgery or more than 1–2
y ears following irradiation may require therapy for durable control. There have been
positive results with intracy stic bleomy cin (more as a caustic agent) or irradiation using 32P
or 186Re, pure beta emitters. Use of interferon-alpha has been reported of value in a small
series in y oung children with largely cy stic presentations (150,151,152).
The controversy regarding primary treatment includes the balance of high rates of
immediate postsurgical sequelae and recognized rates of late postirradiation sequelae. Long
debated among neurosurgeons and radiation oncologists, recent statements often converge on
a judgmental approach reserving “radical” resection for cases with prechiasmatic or limited
retrochiasmatic lesions (in particular, avoiding surgery likely to result in hy pothalamic
damage) while pursuing limited surgery and irradiation in the more common, sizable
posterior and superior lesions. Coordinated care is important, and there is increasing
recognition that the overall quality of life in children with craniophary ngioma is challenging
as these children face multiple limitations related to visual, neurovascular, intellectual,
behavioral, and endocrine deficits.

The volume of irradiation is limited to the well-marginated tumor, including its cy stic
components. It is important to accurately map out the cy stic areas; cy stic extensions
posteriorly or inferiorly may be obscured by the basal cisterns. With close margins and
image-guided radiation planning and delivery, it may be fruitful to surgically decompress, or
resect, cy stic extensions to minimize the radiation volume, especially components growing
superiorly within the third ventricle (145). Craniophary ngiomas often interdigitate or invade
at the hy pothalamic and chiasmatic regions; it is unusual to see invasion at other sites.
Accordingly, one can define the GTV as the residual solid tumor and diminished cy st volume
after surgical intervention. Definition should include both MRI (for soft tissue and cy st extent)
and CT (for calcified residual tumor). The CTV has been defined as narrowly as the GTV
itself in an experience from Heidelberg reporting preliminary results with fractionated
stereotactic radiotherapy using CTV equal to GTV and an additional margin of 2 mm to
identify the PTV (153). The prospective experience at St. Jude has been based on a GTV
defined as the minimal postoperative residual (including the cy st wall), a CTV derived from a
5-mm 3D anatomic expansion of the GTV, and a PTV 3–5 mm geometrically expanding the
CTV (141) (Fig. 3.10 ). In this study, there was no detriment to local control with the use of
reduced margin expansions (141). Caution is warranted in documenting the sometimes
significant reexpansion of cy stic components during the 6-week course of irradiation, with
modification of radiation planning as needed or cy st aspiration through indwelling Ommay a
reservoirs or stereotactic access for sy mptomatic patients. Repeat MRI to monitor cy st
changes every 1–2 weeks during radiation, as needed, is recommended.
Figure 3.10 A: Craniopharyngioma with extensive cyst formation. Note extension to
prepontine cistern and anterior third ventricle in three planes (A1–A3). B: Following
craniotomy with microscopic resection of inferior/prepontine cyst and reduction of superior
component within third ventricle B1, B2. C: RT plan for 3D conformal treatment in three
planes: GTV (heavy blue line) defined by postoperative reduction in prepontine component;
CTV (lighter blue line) defined by 5–10 mm expansion of GTV, with 5-mm PTV (heavy red line).
Daily fraction of 180 cGy delivered to PTV (C1–C3).
Stereotactic or 3D conformal techniques (photon or proton IMRT) based on image-

guided planning are the standard. These techniques decrease the volume of normal tissue
irradiated and offer the promise of reduced neuropsy chological sequelae of irradiation (145).
Experience with proton beam IMRT is early, with apparent improvement in dose
conformality, particularly when comparing the volume of normal brain exposed to lower, but
potentially meaningful, doses (154).
Single-fraction radiosurgery has been used largely in the context of minimal residual
solid tumor components (i.e., after attempted complete resection with minimal residual in the
sella or in areas of tumor not adherent to the chiasm or hy pothalamus) or limited, localized
recurrence. The target volume for such interventions is limited to residual solid tumor,
ty pically smaller than 2 cm in diameter (153).
Intracavitary radionuclide insertion, in an effort to delay primary surgery or external
irradiation (e.g., in children y ounger than 4–5 y ears) or to treat residual or recurrent cy st
formation after definitive surgery or radiation therapy, is a valid approach for tumors that are
largely cy stic in centers with experience in this approach. A catheter is passed into the cy st at
craniotomy or by stereotactic guidance. Based on the cy st volume, an appropriate dosage of
isotope in diluent is instilled into the cavity. Most contemporary experience is with beta
emitters such as 32P, 186Re, or 90Yt, delivering a high dosage (i.e., 200 Gy ) to the cy st wall
(151).
Dosage
A radiation dose response has been documented at 50–54 Gy using 180-cGy fractions daily,
noting apparent improvement with dose levels approximating 54 Gy compared to levels of
<50 Gy (31,155,156). Data supporting dose levels above 55 Gy is less convincing and late
complications, including chiasmal injury, are increased with dosages greater than 60 Gy
(157).
Results
Disease control rates for craniophary ngioma are reported at 80–90% 5 y ears after surgery
or limited surgery and irradiation, with a poorly quantified late decrement in disease-free
survival bey ond 5 y ears. Such results are achievable among those selected for surgery who
have successfully undergone GTR or who receive limited resection followed by irradiation
(Table 3.3 ). Late recurrences and rare treatment-related mortality (largely
neuroendocrine or vascular following surgery or irradiation, or postirradiation
carcinogenesis) are reported well bey ond 5–10 y ears (158). Most data suggest that
postoperative irradiation is indicated with imaging evidence of residual disease (136,138,140).
Control rates after limited surgery and irradiation are equivalent to those of radical resection
(137,140). Quality of life is particularly important in a tumor setting marked by significant
potential neurologic deficits (vision, integrity of major cerebral vasculature), hy pothalamic
dy sfunction, and neurocognitive compromise.
Table 3.3 Craniopharyngioma—Outcome in Children

Figure:
A (column on L): Craniopharyngioma in a 5-year-old boy showing typical solid component in
region of tuber cinereum (suprasellar cistern) and cystic components extending into the third
ventricle/interpeduncular region and upper sella; T1-gadolinium imaging. B (column on R):
3.5 years following simple drainage of the superior cyst and 54 Gy per 30 fractions using 3D
conformal RT. Small residual solid component off inferior tuber cinereum just posterior to
optic chiasm shown in sagittal (top) and axial MRI (middle), largely calcified as noted in
accompanying CT without contrast (bottom).
Figure:
A: Craniopharyngioma with extensive cyst formation. Note extension to prepontine cistern
and anterior third ventricle in three planes (A1–A3). B: Following craniotomy with
microscopic resection of inferior/prepontine cyst and reduction of superior component
within third ventricle B1, B2. C: RT plan for 3D conformal treatment in three planes: GTV
(heavy blue line) defined by postoperative reduction in prepontine component; CTV (lighter
blue line) defined by 5–10 mm expansion of GTV, with 5-mm PTV (heavy red line). Daily
fraction of 180 cGy delivered to PTV (C1–C3).
Figure: Craniopharyngioma—Outcome in
Children
INTRACRANIAL GERM CELL TUMORS
Intracranial GCTs are rare in North America and Europe, representing less than 2–4% of
pediatric CNS neoplasms; in Japan and Taiwan, they are reported to represent up to 11% of
childhood brain tumors (159). The full range of germ cell histioty pes presents as primary
CNS tumors: pure germinomas (60–70% of intracranial GCTs), “malignant” germ cell ty pes
(embry onal carcinomas, endodermal sinus tumors, and choriocarcinomas, collectively 15–
20% of CNS GCTs), and teratomas (benign, immature, and malignant ty pes, 15–20%) (159).
Malignant teratomas are admixtures of benign teratomatous lesions with one or more
malignant germ cell lines such as embry onal carcinoma, endodermal sinus tumor, or
choriocarcinoma or with malignant elements of rhabdomy osarcoma, neuroblastoma, or
epithelial carcinoma. GCTs are conventionally categorized into two highly prognostic
histologic subgroups: pure germinomas and nongerminomatous (or “malignant”) germ cell
tumors (NGGCTs). NGGCTs include GCTs with any malignant germ cell component and/or
any tumor that secretes AFP or high levels of beta-HCG (levels >100–200 IU considered
“high”). Some international trials have classified these tumors simply as “secreting” and
“nonsecreting” based on the high likelihood of secretion from malignant germ cell
components and lack thereof from pure germinomas. Pure germinomas carry a much more
favorable prognosis, and require less aggressive therapy than NGGCTs.
Page 45CNS GCTs usually occur as midline third ventricular lesions. These tumors most
often arise in the pineal region at the posterior third ventricle (50–60% of presentations) or
from the infundibulum/pituitary stalk in the suprasellar region at the anterior recess of the
third ventricle (30–35% of cases) (160). Less common locations for primary intracranial
GCTs include the basal ganglia or thalamic nuclei. Involvement of multiple tumor sites around
the third ventricle is common, most often the pineal and suprasellar regions concurrently ;
such tumors are referred to as “multiple midline germinomas” and appear to represent
multicentric tumor development or subependy mal infiltration around the ventricle rather than
subarachnoid or CSF pathway metastasis. Up to 20% of intracranial germinomas present as
multiple midline tumors, especially noted in adolescent males (Fig. 3.11 ). This
phenomenon is much more frequently encountered with pure germinomas, but has been
reported with NGGCTs. Leptomeningeal spread through the cerebrospinal axis may be seen,
but is much less common.
Pineal germinomas occur with a higher prevalence in adolescent males. Suprasellar
germinomas occur throughout the first two decades; there is no gender predilection for this
location. Teratomas tend to occur in y ounger children, and other malignant histioty pes (e.g.,
embry onal carcinoma, endodermal sinus tumor) generally present in older children,
adolescents, and y oung adults.
Page 46GCTs are the most common tumors arising in the pineal region. A unique
spectrum of neoplasms presents a broad
differential diagnosis for tumors arising in the
posterior third ventricular region (Table 3.4 ).
Approximately 80% of the pineal region tumors
in children and adolescents are GCTs (60–70%)
or pineal parenchy mal tumors (10–20%). In
very y oung children, the most common tumor
ty pe is the pineoblastoma. Less common
histioty pes include glial tumors (astrocy tomas,
ependy momas), arachnoid cy sts and the
embry onal pineoblastomas. Pineocy tomas are
“mature” parenchy mal cell neoplasms which
are rare in children, clinically benign in
adolescents but potentially malignant in y ounger Figure 3.11 Midline multifocal
children. The differential diagnosis for germinoma involving suprasellar
suprasellar tumors is rather broad, including (anterior arrow) and pineal gland
astrocy tomas and craniophary ngiomas (posterior arrow) regions. This
(together, more than 80% of lesions in this phenomenon is typically seen with pure
location) as well as GCTs. germinomas in adolescent males.
Table 3.4 Pineal Region Tumors—Relative Incidence
Pineal GCTs present most often with increased intracranial pressure caused by
compression of the adjacent Sy lvian aqueduct. Ocular signs are classically noted as the
Parinaud sy ndrome: a triad of decreased upward gaze, abnormal pupillary responses
described as near-light dissociation (limited constriction to light but retained pupillary
response to accommodation; otherwise known as the Argy ll–Robertson pupil), and
convergence ny stagmus. Findings occur as a result of pressure from the pineal tumor on the
superior colliculus of the tectum. In suprasellar GCTs, the classic triad of presenting
sy mptoms is diabetes insipidus, precocious or delay ed sexual development, and visual
deficits. Diabetes insipidus or other sy mptoms of suprasellar disease in conjunction with an
apparently isolated pineal tumor are virtually diagnostic of a multiple midline germinoma
and should be treated as such (161). Conversely, care should be taken in evaluating the pineal
region with suprasellar tumors (162).
Page 47Evaluation for GCT should include MRI of the brain with and without gadolinium
with thin cuts (≤2.5 mm thickness, no skip) through the suprasellar and pineal regions. A
screening MRI of the spine should be obtained with axial images through any regions
suspicious for disease. Lumbar puncture with CSF cy tology and CSF AFP and beta-HCG
should be obtained with caution, especially in children with large pineal tumors or potentially
persistent increased intracranial pressure. Serum AFP and beta-HCG should also be
measured. AFP is usually present in serum and CSF in embry onal carcinoma, endodermal
sinus tumor, or malignant teratoma. beta-HCG is elevated in a subset of germinomas: 10–
20% of pure germinomas show levels above 10 IU, up to 70–100 IU; levels above 100–200
IU are found in germinomas with sy ncy tiotrophoblastic giant cells); significant elevation
(ty pically more than 1000 IU) is diagnostic of choriocarcinoma (159,163). COG ultimately
recognized values > 100 IU/L as indicative of NGGCT; this may be a conservative number. If
there is any detectable elevation of AFP above institutional norm (generally, serum >5–10
ng/dL; CSF >2–5 ng/dL), this is diagnostic of malignant germ cell histioty pes; the tumor is
classified as an NGGCT. Additional baseline studies should include a full evaluation of
hy pothalamic and pituitary function, ophthalmologic examination, and baseline
neuropsy chological testing. Diagnostic studies, implications regarding disease ty pe and extent,
and therapeutic decisions are outlined in an “international consensus” statement,
unfortunately devoid of authorship from radiation oncologists (164).
Therapy
Treatment of CNS GCTs is controversial, from the decision to establish histology to the role of
surgery, radiation parameters, and the role of chemotherapy. Although excellent disease
control has been reported in series based on clinical and imaging diagnosis (i.e., without
histologic confirmation), specific radiation, chemotherapy, and surgical interventions are best
guided by a histologic diagnosis (Table 3.5 ). At present, clinicians routinely recommend
confirmation of pathology for all GCTs when attainable, and particularly for those with
negative markers in serum and CSF. When there is a significant elevation of tumor markers in
serum or CSF (any clear elevation of AFP or marked elevation of beta-HCG, ty pically more
than 100 IU), clinicians may consider the diagnosis of an NGGCT without a biopsy. Similarly,
a classical imaging presentation with beta-HCG above normal but <100 IU, or appearance of
multiple midline tumors without AFP elevation are considered pathognomonic of
germinomas by many clinical investigators. Others advocate for histologic verification in all
settings, as some studies indicate important prognostic implications based on histologic
subty pes (159,164). Recent COG studies allow enrollment onto germinoma treatment without
histologic confirmation if serum and/or CSF beta-HCG is ≤ 50 and AFP is ≤ 10 (or institutional
norm), or in the setting of bifocal involvement, normal AFP and beta-HCG is ≤ 100.
Table 3.5 Intracranial Germinoma—Outcome
Radiation therapy has for long been the standard sole treatment or an essential element
of treatment for pure germinomas; it is an important component of multimodality therapy for
NGGCTs (170,173,174) Intracranial pure germinomas are quite chemoresponsive; the use of
combined chemotherapy and whole-ventricle and reduced-dose irradiation is now the
standard approach in treating these tumors (171,174). The use of chemotherapy alone has
been associated with unacceptable recurrence and mortality rates for GCTs (175). For
NGGCTs, irradiation alone has achieved disease control in only 20–45% of tumors, and
combined-modality therapy, also including chemotherapy and potential surgical resection, is
standard (176,177).
Surgery
The goal of surgical resection or biopsy is to provide accurate diagnosis, and in some cases,
improve disease control. For patients with suspected GCT without elevation of tumor markers,
biopsy is mandatory to confirm diagnosis of germinoma and to attempt to rule out malignant
germ cell components. Contemporary surgical techniques permit stereotactic or open biopsy
for both suprasellar and pineal region tumors with low rates of morbidity and mortality (178).
Although it is clear that limited tissue sampling may lead to misdiagnosis for some patients,
particularly in the setting of a mixed histology tumor, aggressive upfront resection is not
advocated by the majority of institutions in Europe and North America as higher rates of
morbidity and mortality have been encountered; delay ed surgery for persistent disease after
chemotherapy is preferred (179). However, more aggressive resection is advocated by some
authors for therapeutic and prognostic implications and is routinely performed in Japan. In the
past, there was some suggestion that surgery or biopsy predisposed the patient to a higher risk
of subarachnoid dissemination; this has been refuted.
Page 48There is no known advantage to achieving a GTR for pure germinomas.
However, a benefit of surgical resection for NGGCT has been suggested if y et somewhat
controversial (176,177). Some series have shown a trend toward improved control with more
aggressive resection for malignant histioty pes. As stated above, others advocate initial
chemotherapy with consideration of second-look surgery for tumors or components of
tumors that do not respond. Often, teratoma components of these tumors do not respond to
chemotherapy and may even grow during chemotherapy. For these cases, surgical resection
is therapeutic and provides local control.
For patients with pineal region tumors that present with hy drocephalus, decompression of
the ventricles is required, often urgently. The placement of a ventriculoperitoneal shunt or
external ventricular drain can provide relief of hy drocephalus. Endoscopic third
ventriculostomy (ETV) is a particularly attractive, alternative method of treating
hy drocephalus by diverting CSF flow and obtaining a biopsy under direct visualization. This
procedure is performed by inserting and guiding a ventriculoscope through the lateral and
third ventricles and then carefully creating a hole in the thin membrane of the floor of the
third ventricle and establishing flow between the third ventricle and the prepontine cistern
(Fig. 3.12 ). ETV also allows for close inspection of the ventricular sy stem and may be
more sensitive than MRI for detection of metastatic deposits (180).
Page 49Radiation Therapy
For pure germinomas, radiation therapy has
been the major curative modality. Long-term
disease control rates range from 80% to more
than 90–95% with the use of irradiation alone
(165,166,167,168,169,170, 173, 176,181).
Analy ses of radiation therapy volume have
demonstrated excellent outcomes with whole
ventricular irradiation for patients with localized
disease, and suggest a limited role for
craniospinal irradiation, while the use of focal
tumor bed irradiation alone has resulted in an Figure 3.12 Sagittal T1-gadolinium
unacceptable rate of ventricular failures image showing third ventriculostomy
(181,182,183). The current standard is whole defect. Endoscopic third ventriculoscopy
ventricular irradiation to a reduced dose (ETV) alleviates hydrocephalus by
followed by primary tumor bed boost for creating flow from the ventricle to the
prepontine space.
patients with localized disease; CSI is reserved
for patients with CNS dissemination (164).
Whether primary radiation therapy or combined chemotherapy and radiation is the best
course of treatment is often a complex decision based on tumor site and extent, the child’s
age, and the child’s functional status at presentation, presenting a choice between irradiation
alone or a combination of chemotherapy and reduced-dose, limited-volume irradiation. The
COG trial, ACNS 0232, attempted to determine the better treatment; radiation alone or
chemotherapy and response-based reduced volume and dose irradiation. Unfortunately, this
trial closed due to poor accrual leaving this important question unanswered. However, most
pediatric oncologists favor chemotherapy followed by reduced-dose RT in an effort to
minimize radiation-associated sequelae.
For NGGCTs, combined chemotherapy and irradiation is the standard, again with some
uncertainty regarding the appropriate radiation volume (local is not often advocated, while
series report favorable outcomes following whole ventricle, whole brain, or craniospinal
volumes) (176). The use of stereotactic radiosurgery to boost local disease visible on imaging
and persistent after chemotherapy and fractionated radiation therapy is rational, but
investigational for children with persistent NGGCT that cannot be safely removed by surgery
(184).
Chemotherapy
Intracranial GCTs are chemosensitive, with excellent objective response rates documented
for cy clophosphamide; carboplatin; cisplatin and etoposide; ifosfamide, carboplatin, and
etoposide; and cisplatin, etoposide, and bleomy cin (175,185). Objective response rates
approach 100% for germinomas.
Several series using preirradiation chemotherapy and limited-volume, “response-
adjusted” attenuation of radiation doses have shown excellent disease control rates
(164,165,171,172). Initially explored in the United States by Allen with the use of
cy clophosphamide and, later, platinating agents, this treatment has resulted in a large
proportion of complete or substantial responses, with long-term disease control after local
irradiation to reduced dose levels of 24–36 Gy (186,187). Carboplatin, most often in
combination with etoposide, has replaced cisplatin for germinomas because the drug is
associated with fewer long-term sequelae (172). The major short-term morbidity has been
difficulties handling fluid and electroly te balance in children with suprasellar tumors, often
associated with diabetes insipidus and/or salt-wasting sy ndromes. This has been associated
with early mortality during chemotherapy (175). The aim of combined chemotherapy and
irradiation has not been to improve disease control, but to potentially improve long-term
functional outcomes by decreasing radiation doses and/or volumes (188).
The use of chemotherapy alone for intracranial germinomas has been tested in the
international protocols coordinated by Balmaceda et al. (175) This trial included pure
germinomas and NGGCTs. The first drug regimen tested (carboplatin, etoposide, bleomy cin,
± cy clophosphamide) achieved high initial response rates, but disease progression or
recurrence occurred in 50% of patients (both pure germinomas and NGGCTs); unacceptable
chemotherapy -related mortality approximated 10% (175). Failures occurred primarily in the
primary site at the ventricular sy stem, with <5% in the spine. Although Merchant et al. (189)
reported sy stematic salvage following chemotherapy -alone failure with high-dose
cy clophosphamide and CSI, the more aggressive combined therapy regimen is excessive in a
significant cohort of children who would enjoy favorable outcome with less intensive initial
radiation therapy.
For NGGCTs, prognosis with irradiation alone is inadequate; overall long-term survival
rates approximate 20–40%. The addition of platinum-based chemotherapy has markedly
improved outcome, with short-term survival rates in excess of 70%. Chemotherapy has
become a standard component of therapy for these tumors prior to irradiation (176,177).
Chemotherapy on both the French Society of Pediatric Oncology (SFOP) and recent COG
protocols used alternating cy cles of carboplatin/etoposide and ifosphamide/etoposide (190).
The recently published COG ACNS 0122 study included six preirradiation cy cles of this
chemotherapy followed by craniospinal and boost irradiation in patients with a complete or
partial response after induction chemotherapy, with or without second look surgery ;
chemotherapy was well tolerated and 5-y ear EFS and OS were 84% and 93%, respectively
(190). Among patients with a complete or partial response to chemotherapy, EFS was 92%
and OS 98% (190).Given the excellent outcomes on ACNS 0122, the currently ongoing COG
trial ACNS 1123 utilizes the same induction chemotherapy backbone of six cy cles of
alternating carboplatin/etoposide and ifosphamide/etoposide, and offers whole ventricular
radiation rather than CSI in patients with complete or partial response to chemotherapy.
Page 50High-dose chemotherapy with stem cell rescue has shown promise for relapsed
GCTs (191). This strategy was recommended for patient without a CR or PR to induction
therapy on ACNS 0122. Two patients with residual disease received consolidation thiotepa and
etoposide chemotherapy with peripheral blood stem cell rescue followed by CSI and both
patients were without evidence of disease at the time of study reporting, 39 and 52 months
after treatment (190).
Radiotherapy Management
There has been continuing debate regarding the need for large-volume irradiation (full
cranial or CSI or, alternatively, the entire ventricular sy stem) for localized GCTs, both pure
germinomas and NGGCTs. The concept originated in the pre-CT era when Sung et al. (192)
showed a more than 10% risk of subarachnoid dissemination in pineal region GCTs; among
biopsied suprasellar germinomas, neuraxis dissemination occurred in 43%. Several more
recent studies have proposed limiting the radiation volume to the primary tumor alone, the
third ventricle, the whole ventricular sy stem, or the whole brain. When volumes are larger
than the involved field (i.e., ventricles, whole brain), a higher dose is administered as a
“boost” to the primary tumor.
Evidence of disease bey ond the primary site is apparent in 10–20% of intracranial
germinomas at diagnosis. Third ventricular disease occurs as multiple midline presentations,
classically involving the pineal and suprasellar recesses but sometimes showing multiple
subependy mal nodules along the linings of the ventricle (third and, less often, lateral). Overt
spinal seeding is rarely demonstrable by imaging. CSF involvement has been documented in
fewer than 15% of cases (192).
A large proportion of clinical series reporting disease control rates higher than 90% in the
past y ears have been based on low-dose CSI as a component of therapy (165,173,176,181).
Other series report nearly similar results following more limited radiation volumes
(166,181,182,183).The incidence of spinal failure, specifically, has been reported to be 0–
10% after irradiation to cranial volumes only (166,181). In light of these data, there is
recognition that CSI has only a marginal benefit for pure germinomas treated solely by
radiation therapy (182). The potential gain is controversial and must be weighed against the
potential added toxicities of 24–25 Gy to the neuraxis. In considering the debate on
therapeutic volume, some studies reporting functional outcome or quality of life among long-
term survivors of CSI in childhood and adolescence have shown remarkably normal
achievement (188). Perhaps the most concerning morbidities associated with low-dose CSI in
this setting are secondary neoplasms and cardiac dy sfunction, the latter y et difficult to
quantify.
Though somewhat older series report high rates of disease-free survival with vary ing
volumes identified as “local” without further description, radiation volumes limited to the
local tumor bed only, without inclusion of the ventricles, have been associated with significant
rates of ventricular or periventricular relapses in recent series (165,193). The most common
approach for localized germinomas has now migrated toward treatment of the full ventricular
sy stem (the “large field” component) followed by a boost to the site(s) of initial disease
(194).
All patients with metastatic disease at diagnosis require CSI: 24–30 Gy with irradiation
alone or 21–24 Gy with combined chemotherapy and irradiation; local doses to the primary
and large metastatic foci remain 45 Gy or 30–36 Gy, cumulative, the former for radiation
alone and the latter, combined therapy.
Whole-ventricular radiation is a sizable volume; however, using modern techniques
(IMRT or proton radiation therapy ), one can spare a substantial amount of cortical tissue
when compared with full cranial irradiation (Fig. 3.13 ). This whole-ventricular volume
can be challenging to define and should be done carefully and often with the help of a
neuroradiologist. The whole-ventricular volume should include the lateral, third, and fourth
ventricles as well as the suprasellar and pineal cisterns. Inclusion of the prepontine cistern is
also recommended for patients who have undergone a third ventriculostomy. A contouring
guideline for the whole ventricular volume is available on the COG and QARC websites. An
additional 3–5mm PTV margin is then applied to create the whole ventricular PTV. Current
COG protocols define the local “boost” volume as the MRI-defined residual disease at the
time of treatment planning and all tissue initially involved or in contact with tumor at the time
of diagnosis with a 5-mm anatomically confined margin and an additional 3–5 mm PTV
margin. For tumors with multiple midline involvement, the initial radiation volume should
include the neuraxis or the entire ventricular sy stem at a minimum. Local radiation volumes
have included the primary tumor only, using a 1- to 2-cm anatomic expansion to define the
CTV, or broader fields encompassing at least the third ventricle. Care should be taken to
ensure that the local volume is encompassed by the larger initial ventricular target volume.
Image-guided therapies using multiple (often noncoplanar) fields, stereotactic radiotherapy,
or proton beam are dosimetrically superior in treating midline GCTs.
Figure 3.13 A: Axial and sagittal images of intensity-modulated photon radiation therapy
(L) and proton therapy (R) plans for whole ventricular irradiation. Both techniques are highly
conformal; care should be taken to accurately define the whole ventricular volume. B:
Proton “stereotactic boost” to residual disease following chemotherapy and standard
radiation therapy for NGGCT of the pineal gland.
For NGGCTs, there seems to be consensus that even in the setting of chemotherapy, high
radiation doses are required. However, the appropriate volume is controversial. Studies using
chemotherapy followed by CSI plus a boost to the primary site have y ielded long-term
survival rates of 67–74% (163, 164). The recently reported Phase II COG study for NGGCT,
ACNS 0122, delivered six cy cles of alternating carboplatin/etoposide and
ifosphamide/etoposide followed by CSI to a dose of 36 Gy and an involved field boost to
deliver a total dose of 54 Gy to the tumor bed; results were excellent, with a 5-y ear EFS and
OS being 84% and 93%, respectively (190). Limited trials from Europe and Japan have
documented excellent disease-free survival for chemotherapy followed by whole ventricular
or local field irradiation for patients with NGGCT (186,195). Response to chemotherapy has
been found to be a prognostic factor for NGGCTs (190). The COG trial ACNS 1123 is testing
the use of reduced volume radiation for patients with a complete or partial response to
induction chemotherapy. These patients will receive 30.6 Gy of whole ventricle radiation
therapy followed by a local boost of an additional 23.4 Gy. Second-look surgery is also
recommended for patients without a complete response to chemotherapy. Patients with only
mature teratoma or fibrosis found at the time of second-look surgery are considered to have
had a complete response. For those who cannot safely undergo a second surgical, prognosis is
poor. Incorporation of a final stereotactic radiosurgical “boost” to the local tumor site may be
appropriate for persistent, unresectable NGGCTs.
Page 51Dosage
A total dosage of 40–45 Gy is appropriate for pure germinomas when radiotherapy is used
alone. The elective dose to the neuraxis (i.e., for M0 disease) is 21–24 Gy ; in patients with
positive cy tology, neuraxis levels of 24–30 Gy have been used successfully. Similarly, in
patients receiving full ventricular volumes, the dose to the initial volume is 21–24 Gy, though
the COG study ACNS 1123 has tested the use of 18 Gy whole ventricle radiation in patients
with localized germinoma and a complete response to chemotherapy. The primary area(s) of
tumor involvement require a total dose of approximately 45 Gy in the absence of
chemotherapy. In conjunction with chemotherapy, patients with pure germinoma receive
radiation doses of approximately 30 Gy after complete or near CR, with doses in the range of
36 Gy for patients with partial or incomplete response. Patients with less than partial response
receive full-dose irradiation (45 Gy ). Successful salvage (for patients with progressive or
recurrent disease during or after primary chemotherapy ) has been reported with 30 Gy to
the neuraxis and 45–50 Gy to the local tumor region (189).
Patients with NGGCT receive chemotherapy first. Consolidative irradiation generally
has been delivered in doses in excess of 50 Gy to the primary site of disease. The use of CSI
is somewhat controversial, but is considered the standard treatment in North America. Local
field radiation to a dose of 54–59.4 Gy is the standard in many European countries; it was the
standard treatment on the recently presented SFOP and SIOP studies (186). The ongoing
COG study for NGGCT is exploring reduced volume irradiation (whole ventricle to 30.6 Gy
followed by boost of 23.4 Gy ) for patients with a complete or partial response to induction
chemotherapy (180).
Results
Five-y ear disease-free survival rates of 90–95% are documented in pure germinomas treated
with primary radiation therapy (165,166,167,168,173,176,181). Comparable results are
reported with induction chemotherapy and more limited irradiation (164,165,171,172,187). It
is important to recognize a 10% incidence of late failure (between 5 and 15 y ears) (196).
Disease control with primary chemotherapy has been only about 50% (175). Treatment
choice is often based on tumor and patient characteristics and phy sician and/or parental
biases, though chemotherapy followed by reduced-dose WVRT and involved field boost is
favored by most pediatric oncologists (194).
For NGGCTs, survival after radiation alone is inadequate, and platinum-based
chemotherapy is standard for all patients (190,194). Volume remains controversial, with the
most recent standard in the United States being CSI followed by boost, but the current COG
protocol is testing reduced volume irradiation (whole ventricle followed by boost) for selected
patients. Malignant germ cell ty pes that do not respond completely to chemotherapy carry a
worse prognosis, and continue to be a therapeutic challenge. The use of combined-modality
therapy has been associated with EFS rates approaching 85% (190). With further
understanding of this disease and improvements in therapy, one would hope to bring the
outcomes of malignant germ cell ty pes closer to that of pure germinomas.
Figure:
Midline multifocal germinoma involving suprasellar (anterior arrow) and pineal gland
(posterior arrow) regions. This phenomenon is typically seen with pure germinomas in
adolescent males.
Figure: Pineal Region Tumors—Relative
Incidence
Figure: Intracranial Germinoma—Outcome
Figure:
Sagittal T1-gadolinium image showing third ventriculostomy defect. Endoscopic third
ventriculoscopy (ETV) alleviates hydrocephalus by creating flow from the ventricle to the
prepontine space.
Figure:
A: Axial and sagittal images of intensity-modulated photon radiation therapy (L) and proton
therapy (R) plans for whole ventricular irradiation. Both techniques are highly conformal;
care should be taken to accurately define the whole ventricular volume. B: Proton
“stereotactic boost” to residual disease following chemotherapy and standard radiation
therapy for NGGCT of the pineal gland.
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CH A P TER 4
Tumors of the Posterior Fossa and the
Spinal Canal
Torunn I. Yock, Larry E. Kun, Shannon M. MacDonald, and Nancy J. Tarbell
Page 57The posterior fossa occupies the lower half of the posterior cranial vault, bounded
anteriorly by the clivus and posterior clinoid and inferiorly by the occipital bone and foramen
magnum. Superiorly, the margin is defined by the tentorium cerebellae, that portion of the
dura mater extending from the basisphenoid adjacent to the posterior clinoid, rising to cover
the cerebellum, and extending posteriorly and inferiorly to insert at the level of the inion (the
prominent midline outpouching of the occipital bone). The cerebellum and brainstem are
located within the posterior fossa.
Nearly one-half of all childhood brain tumors arise in the posterior fossa. The most
common ty pes are medulloblastoma, low-grade astrocy tomas, and ependy momas (see
Table 3.1 ) (1,2,3).
MEDULLOBLASTOMA
Medulloblastoma is a primitive cerebellar tumor of neuroectodermal origin. The tumor is the

most common malignant brain tumor in children and adolescents, accounting for 20% of
pediatric brain tumors or approximately 480 cases per y ear in the United States (4).
Medulloblastoma was first identified in Bailey and Cushing’s 1925 classification of central
nervous sy stem (CNS) tumors (5,6). The classic description defined medulloblastoma as a
primitive (embry onal) tumor of the cerebellum, derived from undifferentiated progenitor
medulloblasts located in the cerebellar external granular lay er.
The World Health Organization (WHO) classification of CNS neoplasms identifies
embry onal tumors as a subset of the neuroepithelial neoplasms that are particularly
prominent among pediatric brain tumors (7). The current WHO classification is included in
Table 3.1 , separately identify ing the three major categories of embry onal CNS tumors:
(1) medulloblastoma and its subty pes; (2) CNS primitive neuroectodermal tumors (PNETs,
including supratentorial PNETs, CNS neuroblastoma, CNS ganglioneuroblastoma,
medulloepithelioma, and ependy moblastoma); and (3) aty pical teratoid/rhabdoid tumors.
Note that pineoblastoma, considered clinically as a ty pe of PNET, is listed separately as a
tumor of the pineal region (7).
The most common embry onal CNS tumor is medulloblastoma, by definition a malignant
embry onal tumor arising in the cerebellum, with predominantly neuronal differentiation. The
tumor is thought to arise from cerebellar stem cells in the superficial external germinal lay er
(giving rise to cerebellar granule cells) or the deep-seated subventricular zone in the midline
posterior medullary velum (generating cerebellar neuronal and glial cells) (8,9). DNA
microarray gene expression patterns reported by Pomeroy et al. (10) confirm the apparent
derivation of medulloblastoma from the molecularly similar cerebellar granule cells,
genetically distinct from supratentorial PNETs.
Histologically, medulloblastoma is a densely cellular neoplasm composed
predominantly of undifferentiated small, round, blue cells. Differentiation may be toward
neuronal or glial (astrocy tic, oligodendroglial, and, less commonly, ependy mal) lines in the
more common “classic variant.” (7,11). Approximately, 10–20% of medulloblastomas can
be categorized as desmoplastic ty pe, marked by relatively hy pocellular areas of prominent
nodularity in reticulin-free zones, occurring most often in the cerebellar hemispheres (7).
Desmoplastic medulloblastoma is associated with mutations within the sonic hedgehog
(SHH)-patched (PTCH) pathway and overexpression of IGF-2 (12,13,14). There is
considerable excitement about the SHH pathway as a target for newly developing molecular-
targeted therapies. Anaplastic tumors are marked by nuclear pleomorphism and high mitotic
rate; these tumors overlap with large cell medulloblastoma and are marked by chromosomal
loss (17p-), MYC amplification, and poor prognosis (14,15,16). The histologic characteristics
of medulloblastoma correlate with prognosis. Extensive nodularity or desmoplasia has been
correlated with favorable outcome (14,17,18). Large cell or anaplastic variants have been
associated with inferior survival rates (14,15,16,19).
Page 58Molecular characterization of medulloblastoma has been rapid over the last
decade and revealed four major subty pes: wingless (Wnt), sonic hedgehog (Shh), group 3,
and group 4 (20). Our understanding of the molecular and clinical features of each group
continues to evolve and be refined with time (21,22,23,24,25). The WNT subgroup comprises
10% of the medulloblastoma population and has a very good prognosis. It is ty pically
characterized by monosomy 6, nuclear beta-catenin staining, CTNNB1 mutation in exon 3
and is ty pically seen in older children and adults. The SHH or sonic hedgehog group
comprises about 30% of the population and has intermediate prognosis in the child and adult
population but a good prognosis in infants. It has somewhat heterogeneous molecular features
which are age dependent. It is ty pically characterized by PTCH1, SMO, and SUFU mutations
and GLI2 and n-MYC amplification and can also be associated with germline TP53
mutations. Group 3 or group C comprises approximately 25% of the population and has a
poor prognosis and is clinically associated with a high incidence of metastatic disease, a male
predominance, and y ounger age. It can often appear anaplastic or as a large cell variant, and
c-MYC amplification can often be found. Group 4 or Group D comprises approximately 35%
of patients and may have the most heterogeneous molecular characterization. This group has
a male predominance again and ty pically occurs in children, but infants and adults can
occasionally have this subty pe. It can have CDK6 and N-My c amplification and has an
intermediate-to-poor prognosis. However, the story continues to evolve with these subty pes
and what we as clinicians do with them. The next generation of cooperative group protocols is
planning to incorporate the subgroup classification as well as clinical features into its risk
stratification (20,26).
From the clinical genetics standpoint, medulloblastoma is the CNS tumor most often
associated with germline mutations and familial diseases (see Table 3.3 ). The most
frequent association is between Gorlin sy ndrome (nevoid basal cell carcinoma sy ndrome
[NBCCS]) and desmoplastic medulloblastoma, both related to the tumor suppressor gene
PTCH and the SHH receptor). In y ounger children, NBCCS is associated with extensive
nodularity (18). NBCCS is characterized by somatic abnormalities (cutaneous nevi and
palmar or plantar pits, odontogenic keratocy sts of the jaw, bifid or fused ribs, falx
calcifications) and development of numerous basal cell carcinomas, medulloblastoma, and
rhabdomy osarcoma (13,18,27). In addition, mutations of the SHH–PTCH pathway are found
in 10–20% of patients with “sporadic” medulloblastoma (12,28). TP53 mutations mark the Li–
Fraumeni sy ndrome, associated with a small percentage of medulloblastoma.
Mutations of the APC gene define Turcot sy ndrome of colonic poly posis, also seen in
conjunction with medulloblastoma (7). Mutations of the WNT pathway, developmentally
linked to proliferation of stem cells in the subventricular zone, were first noted in children with
Turcot sy ndrome. The pathway is activated in 5–10% of patients with sporadic
medulloblastoma with classic histopathology, manifest by accumulation of intranuclear beta-
catenin and associated with quite favorable prognosis; Wnt/Wg-active tumors are associated
with isochromosome 16 (14,19,28,29,30). Notch2 overexpression has also been noted in
medulloblastoma, interesting as hy poxia appears to promote neural stem cell proliferation
through Notch (31).
The median age at diagnosis is 5–6 y ears. Approximately 20% of patients with
medulloblastoma are infants y ounger than 2 y ears and 10% occur in y oung adults. Boy s are
affected more often than girls. Presenting sy mptoms are those classically associated with
posterior fossa lesions in children: sy mptoms related to elevated intracranial pressure
(headaches and vomiting, especially in the morning) and ataxia. Elevated intracranial
pressure results from the tumor obstructing CSF flow through the sy lvian aqueduct and the
fourth ventricle.
Approximately 75% of patients with medulloblastoma present in the midline cerebellar
vermis. The tumor characteristically grows into and fills the fourth ventricle. Infiltration
around the fourth ventricle is common, often involving the brachium pontis and extending
onto the ventricular floor (i.e., the brainstem). Nearly one in four tumors arises within the
cerebellar hemispheres, more commonly with desmoplastic histology. On magnetic
resonance imaging (MRI), medulloblastomas are ty pically well-marginated, solid lesions
with uniform or heterogeneous contrast enhancement. They are often restricted in diffusion
on diffusion-weighted sequences due to high cell density, and similarly on computed
tomography (CT) imaging they are hy perdense. Medulloblastoma is the classic CNS tumor
associated with CSF seeding or metastasis. The standard of care requires postoperative
staging, ty pically based on imaging of the brain to assess degree of resection and potential
subarachnoid metastasis (ideally within 24 hours, but acceptable up to 72 hours postsurgery ),
spinal MRI (gadolinium-enhanced study approximately 10–14 day s after surgery to assess
potential overt metastasis), and lumbar CSF cy tology (best obtained immediately after spinal
imaging). Subarachnoid dissemination has been reported at diagnosis in 20–35% of children
(32,33). A review of 106 consecutive cases staged at diagnosis showed leptomeningeal
disease in 32%, noted on both spinal MRI and CSF cy tology in 12%, positive CSF alone in 8%,
and MRI alone in 11% (19,33). Neuraxis disease ty pically involves the spinal subarachnoid
space; intracranial metastasis is less common, noted as isolated disease in the basal or
suprasellar cisterns (Fig. 4.1 ) or diffusely in the subarachnoid space (34).
Figure 4.1 Medulloblastoma, originating classically in the cerebellar vermis (A, B), with
signs of subarachnoid spread in the hypothalamic region (B) and along the spine (C).
The Chang (35) staging sy stem for medulloblastoma was developed in the pre-CT era
and includes both T stage, which is based on the size and invasiveness of the primary tumor at
surgery (“T stage”), and evidence of spread outside the posterior fossa (“M stage”) (Table
4.1 ). However, in the modern MRI and surgical era, T stage is no longer of prognostic
value and only the M staging is still used to stage medulloblastoma patients (36,37). M stage is
based on subarachnoid metastasis, progressively coding abnormal CSF cy tology (M1) or
imaging evidence of noncontiguous tumor in the cranium (M2) or spine (M3). Extraneural
disease (most often confined to the bone marrow or bone) is present in fewer than 2% of
cases at presentation, coded as M4. M stage remains a significant prognostic factor and is
incorporated into our risk stratification of patients, which affects intensity of therapy
(37,38,39,40).
Table 4.1 Chang Staging for Medulloblastomaa a A pre-CT era system described by
Chang (35), modified by J. Langston (personal communication, 1988).
Page 59Current clinical trials and standard management in North America define
clinical risk categories for medulloblastoma as average risk (children older than 3 y ears with
no metastatic disease after near total or total resection, with less than 1.5 cm 2 residual on
early postoperative imaging) or high risk (overt metastatic disease based on CSF cy tology or
neuroimaging, or the presence of more than 1.5 cm 2 residual on early postoperative
imaging). In 2008, recognition of the prognostic importance of histologic subty pe resulted in
the COG exclusion of children with diffuse anaplastic or large cell variant tumors (but
otherwise standard risk) from the national standard risk protocol, which randomized y oung
children to 23.4 Gy or 18 Gy CSI. Given the “intermediate risk,” the consensus was that such
patients should be eligible for the COG high-risk study. Thus, the high-risk study was renamed
“other than average risk.” There has been controversy on how best to treat these children
given the substantial late effects caused by full 36 Gy CSI dose in the y ounger children. A
current multicenter protocol led by St. Jude investigators includes “intermediate risk”
category that reflects this ty pe of patient (clinicaltrials.gov number NCT01878617). Children
y ounger than 3 y ears of age are classified as having infant medulloblastoma (41). With
appropriately aggressive surgical intent in most centers in the United States and Europe, more
than 65–75% of children above 3 y ears of age are staged as average risk. Of the 25–35%
staged as high risk, more than 85% present with metastatic disease at diagnosis: primarily M3
(60%), but also M1 (30%), and M2 (10%); significant residual tumor at the primary site is
present in >15% of cases (19,41,42).
Page 60Therapy
Surgery
Harvey Cushing’s (5) classic 1930 report of his experience with medulloblastoma
demonstrated the inability of surgery alone to cure this tumor; only 1 of 61 patients survived 3
y ears after surgery with or without limited irradiation.
Maximal judicious surgical resection underlies most contemporary series (37,38). Gross
total resection (GTR) is defined as no evidence of residual tumor seen at surgery and
negative postoperative imaging, and near-total resection (NTR) is defined as minimal residual
with more than 90% resection estimated by the surgeon and less than 1.5 cm 2 residual on
postoperative imaging. Combined results with GTR and NTR reveal superior outcome in
comparison to subtotal (51–90% resection) or partial (11–50% removal) resection and biopsy
only (less than 10% removal) (38). Data from the Children’s Cancer Group (CCG) indicate
gross total or near total resection in approximately 90% of children (37,38). Survival appears
to correlate significantly with amount of tumor residual as documented on immediate
postoperative imaging; data confirming the value of minimal residual disease are most
apparent among children with M0 disease (38,43). In an earlier CCG trial, 5-y ear event-free
survival (EFS) was 78% for children with M0 disease and less than 1.5 cm 2 residual,
compared with 54% for those with larger residual volumes (37). For tumors adherent to or
invading the brainstem, a report from St. Jude Children’s Research Hospital showed no
advantage to pursuing GTR compared with NTR, with none of the cases exhibiting more than
1.5 cm 2 residual; morbidity appeared to be greater with the more aggressive surgical
approach (44). With maximal safe resection a principle of therapy, the impact of minimal
residual tumor (<1.5 cm 2) is difficult to discern; key is the distinct advantage of treatment on
an average-risk regimen whenever possible, assuming such is a “given” for M0 disease
(19,38,45,46,47).
Operative mortality has been reduced to 2% or less in pediatric neurosurgical centers.
However, aggressive surgery may be associated with significant morbidity (38,48,49). The
posterior fossa sy ndrome has been described in 15–40% of children after posterior fossa
craniotomy (50,51,52). The sy ndrome is signified by difficulty swallowing, emotional
lability, truncal ataxia, mutism, and, less often, respiratory failure; recent imaging data
suggest that the etiology may be a cerebellocerebral diaschisis (51). Sy mptoms and signs
ty pically are noted after a 12- to 24-hour period of initially uneventful postoperative
recovery. Disabling neurologic signs can improve dramatically, but can take many months
after surgery. Those children with severe posterior fossa sy ndrome are less likely to make a
full recovery and may have late neurologic and neurocognitive consequences (52,53,54).
Significant neurologic recovery does not appear impaired by the use of radiotherapy despite
a lack of major improvement early in the course of irradiation (52,53,54).
The routine use of ventriculoperitoneal (VP) shunts to reduce intracranial pressure
before posterior fossa craniotomy resulted in significant improvement in operative morbidity
and mortality, when introduced 50 y ears ago. Children with VP shunts ty pically become
shunt dependent. Shunt failure or infection may complicate long-term survival, necessitating
revision or replacement in nearly 25% of children measured 5 y ears after insertion. In many
centers, it is standard to place a ventricular drain (ventriculostomy ), as needed, at the time of
surgery. The surgeon often can document reestablishment of CSF flow after fourth
ventricular tumor resection. Later, shunt insertion may be needed in 20–25% of children
(38,55,56). A delay ed shunt insertion approach provides phy siologic CSF dy namics for the
majority of children, avoiding potential late events related to an indwelling VP shunt.
Radiation Therapy
The efficacy of radiation therapy in medulloblastoma was reported within a decade of
Cushing’s initial description of the tumor. Cutler et al. (57) reported the radiation
responsiveness of medulloblastoma and the value of preventive irradiation of the entire
neuraxis based on Cushing’s clinical series. The seminal report documenting cure of
medulloblastoma with craniospinal irradiation (CSI) was published by Bloom et al. in 1969
(58), documenting 32% survival at 5 y ears and 25% disease-free survival at 10 y ears.
Numerous reports have subsequently confirmed increasing rates of disease control with
modern radiation techniques; at standard CSI dose levels, radiation therapy alone achieves
durable disease control in 65–75% of patients with average-risk disease (Table 4.2 )
(36,59). Modifications of radiation volume, dosage, and fractionation have been explored.
The outcome following postoperative irradiation alone in average-risk medulloblastoma using
conventional radiation parameters (Pediatric Oncology Group [POG]–CCG trial, one arm of
which used CSI to 36 Gy, posterior fossa boost to 54 Gy resulting in 65% 7-y ear EFS in a
large cohort evaluated largely by CT my elography rather than spinal MRI scans) has been
used as a basis for nonrandomized comparisons in establishing current standards for
combined modality therapy in North America. The result is sy stematic reduction in CSI
dosage (to 23.4 Gy ) with well-documented efficacy now in average-risk disease when
combined with contemporary cis-platinum–based chemotherapy (19,60,61,62). Agreement
on combined chemoradiation is based on disease control rates that appear to be superior to
those achieved with irradiation alone for both average-risk and high-risk presentations, a
randomized European trial demonstrating improved outcome with chemoradiation compared
to contemporary radiation therapy alone, and several studies suggesting improvement in the
risk:benefit ratio based on dose–volume modeling and evolving clinical data (61,
63,64,65,66,67).
Page 61
Table 4.2 Medulloblastoma—Results of Postoperative Radiation Therapy (No

Chemotherapy)
Chemotherapy
Phase II trials have documented the chemoresponsiveness of medulloblastoma to alky lating
agents (cy clophosphamide, CCNU [lomustine]), platinum compounds (cisplatin, carboplatin),
etoposide (administered orally or intravenously ), antimetabolites (methotrexate), and
camptothecins (topotecan) (68,69,70,71).
The sentinel trial documenting the efficacy of adjuvant chemotherapy was reported by
CCG, combining the attenuated CSI dose in average-risk patients that had just shown only
55% EFS at 5 y ears in the POG–CCG with concurrent vincristine and postirradiation cis-
platinum, vincristine, and CCNU; the 79% progression-free survival (PFS) at 5 y ears
confirmed earlier institutional experience to show among the best disease control rates in this
disease (36,39,60). The International Society for Pediatric Oncology (SIOP)/United Kingdom
Children’s Cancer Study Group (UKCCSG) PNET-3 trial showed improved EFS with limited
preirradiation chemotherapy and full-dose irradiation versus equivalent irradiation alone:
78% EFS at 5 y ears with preirradiation vincristine, etoposide, carboplatin, and
cy clophosphamide compared to 65% with irradiation alone (63). A large randomized trial
assessing reduced-dose CSI followed by cisplatin and vincristine with “standard” CCNU
versus cy clophosphamide confirmed overall EFS of more than 80% with no difference in
disease control on either chemotherapy arm; early analy sis suggests a larger number of
secondary neoplasms may be apparent in the cy clophosphamide arm (62). St. Jude reported
a sizable prospective trial using postirradiation “compressed” cy clophosphamide, vincristine,
and cisplatin; 83% EFS was obtained without vincristine during irradiation and with a reduction
in ototoxicity attending postirradiation cisplatin when the latter was given with amifostine
(19,72). The standard of care for children with average-risk medulloblastoma throughout
North America has been accepted as reduced-dose CSI (23.4 Gy ) followed by
chemotherapy including an alky lating agent, vincristine, and cisplatin (Table 4.3 ).
Table 4.3 Selected Major Medulloblastomas Studies Reporting Outcome with

Postoperative Irradiation Combined with Chemotherapy
For patients with high-risk disease, studies through the 1990s ty pically showed 5-y ear
EFS at the 40–50% level following full-dose irradiation and chemotherapy (46,47). St. Jude’s
SJMB96 study has shown 70% 5-y ear EFS following the same compressed chemotherapy
noted above, preceded by full-dose CSI (19). Randomized trials have shown somewhat
conflicting results regarding the sequence of postoperative therapy : POG showed >60% 5-
y ear EFS in high-risk medulloblastoma regardless of postoperative/preirradiation
chemotherapy (cy clophosphamide, vincristine, cisplatin) or the opposite sequence, both using
full-dose CSI (75). The German HIT’91 trial showed superior results with postoperative
irradiation followed by CCNU/vincristine/cisplatin compared to postoperative
ifosfamide/etoposide/high-dose methotrexate/cisplatin cy tosine arabinoside followed by
irradiation: 83% 5-y ear EFS compared to 53%, respectively, for M0 patients; no difference
was noted in the M2–3 cohort, both at <40% EFS (47). CCG 9931 documented a 17% PD rate
during a prolonged, 5-month preirradiation regimen, again showing only 43% EFS in high-risk
disease (67). Similar trials have noted that outcome in average-risk patients receiving
preirradiation chemotherapy correlates with response to chemotherapy ; in the Milan trial,
those with CR/PR to preirradiation chemotherapy enjoy ed 94% PFS compared to 61% if only
SD or PD attended chemotherapy (74). Several studies note the time to initiating irradiation is
conversely related to disease control (46,56).
For disease recurrent after radiation therapy (with or without chemotherapy ), numerous
studies demonstrate chemotherapy responsiveness to single agents, multiagent combinations,
and high-dose therapy with hematologic stem cell rescue. Except in the infant setting, best
defined as “radiation therapy naïve,” durable secondary disease control following initial CSI
has only rarely been achieved despite aggressive, high-dose chemotherapy and further
irradiation (76,77,78,79,80). Local irradiation can provide further control at the primary site
(81). Trials of intrathecal chemotherapy in this setting are of interest, but to date with only
limited phases I and II data (82).
Volume
Medulloblastoma is the seminal tumor identified with subarachnoid dissemination. The need
for full CSI has been recognized for more than five decades. In reviewing serial treatment
regimens in Sweden, Landberg et al. (83) noted serial improvements in survival rates with
increasing radiation volume: 5% 10-y ear survival after limited posterior fossa irradiation,
15% after irradiation to the posterior fossa and spinal canal, and 53% after CSI. Reported
failures in the subfrontal region additionally indicate the need to completely encompass the
cranial and spinal subarachnoid spaces; such failures clearly represent inadequate dosage to
the subfrontal area, a potential site of geographic miss even in the era of 3D, imaging-based
treatment planning (84,85,86,87). Other parameters key to appropriate CSI encompassing the
entire subarachnoid volume are discussed below (see Techniques, p. 61 –64 ).
Page 63Historically, the standard boost field included the whole posterior fossa. Use of
3D conformal radiation therapy (3D CRT) to the entire posterior fossa provided some
reduction in cochlear dose, important in children receiving cisplatin and at risk for both
chemotherapy - and radiation-related ototoxicity (Table 4.4 ) (66,72,91,92,93,94). The use
of conformal radiotherapy techniques such as IMRT, 3D conformal RT or proton therapy
targeting only the tumor bed has been shown to be equivalent to treatment encompassing the
entire posterior fossa, with in-field or posterior fossa recurrences at or below the 5% level
even with more limited boost volumes (45,61,66,90). Initial experience with a 2-cm
anatomically defined clinical target volume (CTV) expansion of the gross tumor volume
(GTV) (postoperative tumor bed) showed few if any posterior fossa failures outside the
targeted volume (91,95,88). The St. Jude SJMB96 trial confirmed local disease control in 95%
of cases with the 2-cm CTV; the recent MSFOP 98 and current COG trials are testing a 1.5-
cm CTV expansion, while a previous study from the University of Washington and the
current SJMB03 study have studied a 1-cm anatomically defined expansion to identify the
CTV (45,61,90). The recently closed COG trial (ACNS 0331) (ClinicalTrials.gov
Identifier:NCT00085735) randomized patients to either tumor bed boost or whole posterior
fossa boost, but the results of the trial have not y et been published as of the submission of this
book. However, preliminary results were reported at the spring COG meeting in 2016
indicated that the 18 Gy CSI arm met inferiority requirements but that there was no
difference between the boost arms.
Table 4.4 Medulloblastoma—Radiation Therapy (Data Reporting Reduced

Tumor/Target Volume Techniques)
Detailed reviews of actual dosimetry and dose modeling, including 3D CRT, intensity -
modulated radiation therapy (IMRT), and proton beam radiation therapy demonstrate
significant dose reduction to the cochlea and upper cervical spinal cord with tumor bed
targeting and 3D-planned therapy ; more narrowly defining the target volume and more
conformal treatment offer the potential to significantly spare the medial temporal lobes (and,
potentially, the hippocampus, both volumes related to cognitive function) in addition to
anterior cranial structures (optic chiasm, hy pothalamus) (61,66,67).
Although the earlier literature had suggested a predominance of posterior fossa failures
in medulloblastoma despite surgery and relatively high-dose irradiation to the entire posterior
fossa using broad 2D techniques, more recent studies consistently indicate a shift in the
pattern of failure toward diffuse leptomeningeal recurrences; failures limited to the posterior
fossa occur in less than 5–10% of patients (36,60,88,91,95,96,97). Although the results of the
randomized COG trial in standard risk patients (ClinicalTrials.gov Identifier: NCT00085735)
has not y et been published many pediatric radiation oncologists have moved to an involved
field tumor bed only boost approach in standard risk patients.
Dosage
Medulloblastoma is a radiosensitive tumor. In vitro studies by Fertil and Malaise (98)
demonstrated a favorable surviving fraction in vitro at 2 Gy (28%), comparable to most other
embry onal pediatric tumors and notably different from the clinically less responsive
malignant gliomas. Earlier data indicated a correlation between dosage to the primary tumor
site and the outcome; local disease control and survival were consistently related to posterior
fossa dosages of ≥50–55 Gy using conventional fractionation at 160–180 cGy per fraction
(55,96,99). The use of limited volume boost to 59.4 Gy for patients with imaging evidence of
residual disease at the primary site has been reported, with no clear evidence that escalation
bey ond 55 Gy is fruitful (91,88).
Page 64Recent trials support the use of 23.4 Gy (at 180 cGy /fraction) to the neuraxis for
average-risk presentations when combined with effective chemotherapy as discussed above
(62). Largely in response to age-related concerns regarding neurocognitive changes, a small
pilot study of 18-Gy CSI for 10 children y ounger than 10 y ears was undertaken at the
Children’s Hospital of Philadelphia and at the University of Pennsy lvania. Disease control in
seven of ten children was initially reported with apparently only minor neuropsy chologic
deficits (100). Subsequent reports suggest failures following the 18-Gy level may be more
apparent with time (73). The current COG average-risk medulloblastoma protocol
randomizes children with average-risk disease between 3- and 8-y ears-old to 23.4-Gy CSI or
18-Gy CSI, prospectively addressing the potential efficacy and relative toxicities of further
reduction in CSI dosage.
For patients with high-risk disease, particularly those with overt metastasis (including M1
in most studies in addition to M2–3), 36 Gy to the neuraxis remains the standard. Several
studies have used 39.6–40 Gy for cases with significant bulk disease through the intracranial
and spinal meninges (19).
Trials of hy perfractionated CSI include neuraxis dosages of 30–48.4 Gy at 100–110 cGy
per fraction twice daily, with an interfraction interval greater than 6 hours; cumulative
dosages for the posterior fossa have been 66–72 Gy with similar fractionation
(67,90,101,102). Long-term results of the French M-SFOP 98 trial showed 75% 6-y ear PFS in
average-risk medulloblastoma after hy perfractionated CSI (36 Gy in 36 fractions) with tumor
bed boost (cumulative dosage, 68 Gy in 68 fractions); the goal with equivalent total CSI dose
for average-risk disease treated with irradiation alone was to reduce toxicity while preserving
equivalent disease control (59,90). A concurrent Milan study used preirradiation
chemotherapy and hy perfractionated accelerated radiation therapy for M+ disease, with
1.36 Gy b.i.d. to 31.2–39 Gy (depending on age and response to chemotherapy ), with 1.5 Gy
b.i.d. to the posterior fossa to cumulative levels of 59–60 Gy ; at investigator’s option, cases
with overt primary residual or progressive tumor received additional treatment to a reduced
target volume to 9 Gy ; preliminary reports seem favorable albeit without details regarding
long-term toxicities to date (74). The potential value of altered fractionation has y et to be
demonstrated.
Technique
The goal of achieving uniform dosage throughout the subarachnoid space, encompassing the
entire intracranial vault and spinal canal, is one of the more technically demanding aspects of
radiation oncology. Several techniques are appropriate for CSI administration (103). The
fundamental is the use of opposed lateral fields including the cranium and upper cervical
spinal canal, matching a posterior spinal field including the full spinal subarachnoid space or,
in larger children, the upper one half of the spinal canal (with a separate, matched lower
posterior spinal field) (Figs. 4.2 and 4.3 ).
Figure 4.2 Consideration of spinal volume for craniospinal irradiation. A: Nerve root
seeding in medulloblastoma; this figure first appeared in the Bulletin of the Los Angeles
Neurological Society (8:1–10, 1943), representing advanced, diffuse leptomeningeal seeding.
B: Typical anatomy of the nerve roots demonstrating the extension of the subarachnoid
space laterally along the nerve root to a location in the neural foramen.
Figure 4.3 Craniospinal irradiation (CSI). Basic technique for CSI including lateral cranial
volume (A) and appropriately matched posterior spinal field(s) (B). C: Prone positioning with
aquaplast mask.
It is important to establish immobilization and reproducibility of setup. Prone positioning

has some advantages in that it allows greater immobilization and better extension of the chin
(minimizing potential bone growth changes caused by the exit of the posterior spinal field)
and simplifies technical maneuvers at the critical junction between the lateral craniocervical
fields and the posterior spinal field(s). Immobilization can be achieved through a customized
plaster cast, use of the Alpha Cradle sy stem, or a vacuum bag (discussed in Chapter 22 ).
CT simulation for CSI provides both accuracy and flexibility in aligning fields and junction
zones (104). Supine positioning also has some benefits with regards to airway management in
patients under anesthesia; detailed attention to the junction area is needed when one adapts the
more familiar prone geometry to supine CSI use (105,106,107).
Page 65CT simulation provides axial and sagittal anatomy to enable one to accurately
outline the key anatomic sites and plan rational junction areas (104). Key areas, already
discussed, include attention to the cribriform plate—outlining that structure on axial images
greatly facilitates accurate identification of target volumes at the “tight” interface of the
cribriform plate and the ey es (86) (Fig. 4.4 ). Other critical anatomic sites important in
designing full cranial volumes include the middle cranial fossa and a sufficient margin about
the calvarium to be certain to achieve full-dose levels within. In y ounger children, the margin
above the ey e may be extremely close but should permit coverage of the subfrontal area as
a first priority, minimizing dosage to the ey e and, in particular, the optic lens. For older
children, the pneumatized frontal sinuses allow sufficient margin to obviate concern for the
cribriform anatomy (Fig. 4.4 ).
Figure 4.4 Craniospinal irradiation (CSI). A: Lateral cranial volume defined to encompass
the subarachnoid space, with attention to the cribriform plate (blue), shown in (B). C:
Posterior spinal volume, here divided for upper (thoracic) spine with lateral margins to
dosimetrically include the neural foramina. D: Posterior spinal volume for lower
(lumbosacral) spine, including “flair” to encompass sacral neural foramina (see Fig. 4.2 ). E:
MRI depicting lower thecal sac.
Defining the lower border of the spinal field should alway s be based on the lowest level
of the thecal sac as determined by MRI, ty pically at or below S2 (Fig. 4.4E and 4.5 )
(108,109). The width of the spinal field should be sufficient to dosimetrically encompass the
full width of the spinal canal to the dorsal nerve roots laterally. Adequate lateral coverage at
the lower sacral margin is appropriate to cover the sacral foramina (Fig. 4.2 ) (109).
Several institutions have reported the relative advantage in using intensity -modulated photon
irradiation or, more recently, proton beam approaches (Fig. 4.5 ) (110,111). Proton spinal
irradiation significantly spares the underly ing heart, breasts, and soft tissues; long-term
follow-up is not available as y et documenting late effects (110,112,113,114). Homogeneity in
planning and delivering CSI with protons is
challenging; introduction of scanning beam
technology seems to provide more optimal
dosimetry (Fig. 4.6 ) (115).
Page 66The brain and upper cervical spine
are treated with lateral fields. The collimators
for the lateral fields are angled to match the
divergence of the posterior spinal field
(Fig.4.3 ). The cranial fields must Figure 4.5 Craniospinal irradiation.
accommodate serial decreases in length to Use of multiple “IMRT minibeam”
feather the junction zone; discrete readjustments compensates for diameters in lateral
of the junction by 5–10 mm/week are ty pical, if cranial volumes and depths in posterior
there is some literature regarding daily spinal volumes to provide relatively
modulation of the junction (116). A table angle homogeneous dose distribution for photon
generally is used to correct for caudal CSI. Note lateral dosimetric projection
divergence of the craniocervical fields confirms adequacy of lower thecal sac
(Fig.4.3 ). Although detailed analy sis shows coverage (see Fig. 4.4A ).
only minimal inhomogeneity if a correcting
table angle is not used (103), full 3D attention at the junction zone permits more confident
abutting of the lateral craniocervical and posterior spinal fields. Even with the ideal
craniocervical match using asy mmetric jaws, it is important to feather all junctional zones,
shifting the anatomic junction site by at least 5 mm every 8–9 Gy, effectively once a week
(117). Helical tomotherapy has been used, with excellent handling of the complex, full
neuraxis (118).
The cranial fields include the entire intracranial subarachnoid space. The most difficult
area is at the level of the cribriform plate, where there is often little margin to allow one to
block the ey es and dosimetrically encompass the critical subfrontal cribriform site (86). With
passively scattered proton therapy, oblique beam configurations are required to reduce
incidental lens dose (120) which can also be used for pencil beam techniques. Although a
single PA cranial field is another viable alternative for pencil beam proton therapy as well.
Boost techniques ty pically include either (1) 3D CRT or IMRT to encompass the posterior
fossa, or (2) using similar techniques to encompass the tumor bed alone, using anatomically
corrected 3D expansion by 1–2 cm to define the CTV (45,61,66,90,88,120). With photon
irradiation, the differences between IMRT or 3D CRT and conventionally planned 2D therapy
are impressive in relatively sparing the cochlea, temporal lobes, and brainstem (12,45,61,66).
The recently closed COG trial in average-risk medulloblastoma randomized all cohorts
between 3D based therapy to the posterior fossa or to the tumor bed (using a 1.5-cm
anatomic expansion → CTV and a 3- to 5-mm
geometric expansion → PTV (COG:
ACNS0331). In nonprotocol settings, there is now
sufficient information to suggest the adequacy of
boost volumes confined to the tumor bed
(61,66,90,88). This sophisticated approach entails
analy zing the initial tumor extent based upon
preoperative MRI and identify ing margins of the
posterior fossa tumor bed using CT and, ideally,
fused preoperative MR imaging. Figure 4.7
demonstrates boost confined to the tumor bed).
The goal of image-guided irradiation and narrow
margins in targeting the tumor bed is to diminish
the dosage to the cochlea which remains
especially important with combined irradiation
and cisplatin, as well as the temporal lobes, and
the hy pothalamic–pituitary region (Fig. 4.7 ).
Several reports document the theoretical
Figure 4.6 Spinal irradiation (CSI). A:
advantage of proton beam therapy for the
Comparison of dosimetry with single PA
“boost” volume, based on significant further
field, PBRT versus photon. B: PBRT
reduction in normal tissue doses to the key
dosimetry closely conforming to spinal
anatomic regions noted: cochlea, temporal lobes,
canal and vertebral body (to ensure
and pituitary –hy pothalamic region (12,112,121).
relatively “normal” growth).
Page 67
Figure 4.7 Tumor bed boost for resected medulloblastoma. GTV = tumor bed (green) with
1-cm anatomic 3D expansion to provide protocol-specified (SJMB03) CTV (blue) and further 3-
mm geometric expansion to establish PTV (red). Shown are transverse planes (A = MRI, B =
CT at level of cochlea, shown in blue) and sagittal plane (C = MRI in midline showing spinal
cord, brainstem, chiasm in yellow, and pituitary in green).
The quality of radiation therapy has been correlated with improved outcome, based on
both volume adequacy (in several but not all prospective cooperative group reviews) and
duration of therapy (with several reports indicating inferior disease control when the interval
to complete irradiation exceeds 45 day s) (55,63,96,122,123,124).
Delivery
CSI results in acute changes in the peripheral blood counts. Monitoring for neutropenia or
thrombocy topenia, most often noted during or after the third week of CSI without preceding
chemotherapy, is critically important. CSI is currently interrupted if absolute neutrophil count
falls below 1000 cells per milliliter, and the child is also febrile. Overall radiation treatment
time must be kept short (<45–50 day s) or there will be a decrement in disease control
(122,123). When necessary to permit completion of neuraxis irradiation, granulocy te colony -
stimulating factor may be used to correct neutropenia; thrombocy topenia may necessitate
platelet transfusion (125). Irradiation is ty pically initiated with CSI. Nausea and vomiting are
generally more pronounced in older children and in those with significant postoperative
emesis. Use of antiemetics is important in preventing and treating nausea and vomiting, which
may be more difficult to control. Ondansetron usually is successful. Rarely, corticosteroids
may be necessary at low dosage levels, particularly early in the postoperative period.
Nutritional support during CSI is mandatory as children often go from completion of
irradiation to adjuvant chemotherapy.
Page 68Results
Long-term disease-free survival after surgery and irradiation should approach the 70% level
overall (Tables 4.2 and 4.3 ). Factors associated with more favorable outcome include
age greater than 3 y ears, localized presentations (i.e., M0), and tumors amenable to near total
or total resection. The more effective combinations of radiation therapy and chemotherapy
for children older than 3 y ears show long-term disease control in 80% of those with average-
risk disease, and 60–70% of those with high-risk medulloblastoma (Table 4.3 )
(19,59,62,74). The impact of histology, biologic findings, and genetic analy ses is increasingly
important, as summarized above. Future studies seek improvement in disease control and
reduction in functional limitations attendant to therapy.
Figure:
Medulloblastoma, originating classically in the cerebellar vermis (A, B), with signs of
subarachnoid spread in the hypothalamic region (B) and along the spine (C).
Figure: Chang Staging for
Medulloblastomaa
a A pre-CT era system described by Chang (35), modified by J. Langston (personal
communication, 1988).
Figure: Medulloblastoma—Results of
Postoperative Radiation Therapy (No
Chemotherapy)
Figure: Selected Major Medulloblastomas
Studies Reporting Outcome with
Postoperative Irradiation Combined with
Chemotherapy
Figure: Medulloblastoma—Radiation
Therapy (Data Reporting Reduced
Tumor/Target Volume Techniques)
Figure:
Consideration of spinal volume for craniospinal irradiation. A: Nerve root seeding in
medulloblastoma; this figure first appeared in the Bulletin of the Los Angeles Neurological
Society (8:1–10, 1943), representing advanced, diffuse leptomeningeal seeding. B: Typical
anatomy of the nerve roots demonstrating the extension of the subarachnoid space laterally
along the nerve root to a location in the neural foramen.
Figure:
Craniospinal irradiation (CSI). Basic technique for CSI including lateral cranial volume (A)
and appropriately matched posterior spinal field(s) (B). C: Prone positioning with aquaplast
mask.
Figure:
Craniospinal irradiation (CSI). A: Lateral cranial volume defined to encompass the
subarachnoid space, with attention to the cribriform plate (blue), shown in (B). C: Posterior
spinal volume, here divided for upper (thoracic) spine with lateral margins to dosimetrically
include the neural foramina. D: Posterior spinal volume for lower (lumbosacral) spine,
including “flair” to encompass sacral neural foramina (see Fig. 4.2). E: MRI depicting lower
thecal sac.
Figure:
Craniospinal irradiation. Use of multiple “IMRT minibeam” compensates for diameters in
lateral cranial volumes and depths in posterior spinal volumes to provide relatively
homogeneous dose distribution for photon CSI. Note lateral dosimetric projection confirms
adequacy of lower thecal sac coverage (see Fig. 4.4A).
Figure:
Spinal irradiation (CSI). A: Comparison of dosimetry with single PA field, PBRT versus photon.
B: PBRT dosimetry closely conforming to spinal canal and vertebral body (to ensure
relatively “normal” growth).
Figure:
Tumor bed boost for resected medulloblastoma. GTV = tumor bed (green) with 1-cm
anatomic 3D expansion to provide protocol-specified (SJMB03) CTV (blue) and further 3-mm
geometric expansion to establish PTV (red). Shown are transverse planes (A = MRI, B = CT at
level of cochlea, shown in blue) and sagittal plane (C = MRI in midline showing spinal cord,
brainstem, chiasm in yellow, and pituitary in green).
EMBRYONAL AND MALIGNANT GLIAL TUMORS IN INFANTS AND
YOUNG CHILDREN
Children y ounger than 3 y ears account for 15–25% of pediatric CNS neoplasms (1,126,127).
Sy mptoms in this age group usually include enlarged head, lethargy, and vomiting. Tumors
are predominantly supratentorial; in comparison to older children, infant tumors are more
often malignant and may be more frequently metastatic at diagnosis (129). The most
common tumor ty pes include astroglial tumors (primarily low grade; among infants <1 y ear
old, up to 25% are high-grade malignant gliomas), the embry onal neoplasms
(medulloblastoma and the supratentorial embry onal tumors, including PNETs and
pineoblastomas), and ependy momas (129,130,131). Aty pical teratoid/rhabdoid tumors
(AT/RTs) occur predominantly in this age group (7,132,133). A significant proportion of
intracranial teratomas and choroid plexus tumors present in y oung children below 12–18
months of age (127,130). Infantile desmoplastic neuroepithelial tumors (desmoplastic
infantile gangliogliomas and astrocy tomas) also arise predominantly in the very y oung.
These lesions often are quite large, are peripherally located, and appear aggressive
histologically, but ty pically display rather “benign,” low-grade behavior, rarely recurring
after primary resection (7,134,135).
Survival rates for the embry onal brain tumors presenting in children y ounger than 3–4
y ears are lower than for older children (130,131,136,137). Tumor ty pe, pattern of growth,
and the therapeutic ratio for both surgery and radiation therapy are unfavorable when
compared to older children (38,138,139). Operative morbidity and mortality rates are higher
in infants than in older children; after radiation therapy, cognitive dy sfunction, somatic
alterations, endocrine deficits, and neurotoxicity are more pronounced than in older children
(64,65,130,140).
For malignant gliomas, however, y oung age portents a better prognosis than that of older
children and adults, based on apparent differences in biology and disease response to
chemotherapy (141,142,143,144).
Therapy
For embry onal tumors with long-established chemosensitivity, a number of trials between
1985 and 2000 explored the use of prolonged primary postoperative chemotherapy using
delay ed, diminished, or no irradiation (depending on the goals and philosophy of the group or
institution) (Table 4.5 ). Several large series documented a high rate of
chemoresponsiveness to a “standard” four-drug regimen (including cy clophosphamide,
cisplatin, vincristine, etoposide) or to sy stemic methotrexate; durable disease control without
irradiation was limited to 25–35% of cases in most trials, ty pically in those with localized
disease amenable to complete resection at diagnosis
(128,130,131,140,146,147,149,150,155,156,157).
Table 4.5 Malignant Infant Brain Tumors—Outcome in Selected Prospective Primary

Management Trials
Two different directions have proven more successful, at least in selected settings, over
the past 10–15 y ears. Successive trials from the German POG tested progressively more
intense sy stemic and intrathecal methotrexate with an alternating drug program incorporating
the agents noted above. While overall PFS in the HIT SKK 87 trial (1987–1993) was 53% in
the favorable resected, M0 cohort (with identical overall survival [OS]), the study showed
y oungsters with desmoplastic medulloblastoma enjoy ed nearly 90% PFS. The SKK 92 study
(1992–1997) intensified methotrexate and noted overall 5-y ear PFS of 58%; among the
resected M0 group, 5-y ear PFS was 82% (with 14 of 17 survivors treated with surgery and
chemotherapy only, absent irradiation which was used only for residual/progressive disease
during chemotherapy ). Once again, the results with desmoplastic histology were exceptional:
85% PFS (95% OS) compared to 34% PFS (41% OS) in those with classic medulloblastoma
(156,148).
The second direction was suggested by Khalifa and the French group (SFOP), where
primary chemotherapy showed only 29% PFS at 5 y ears even among the most favorable,
resected M0 cohort. Notable was the OS rate of 73%, reflecting excellent “salvage” therapy
with high-dose chemotherapy, busulfan–thiotepa, and local irradiation; among 39 patients
treated, 5-y ear postsecondary treatment survival was 77% for those with M0 disease initially
and at failure (147,158). Although the St. Jude group had also documented excellent salvage
with CSI alone, the improved functional outcomes of more limited irradiation in this age
group are clearly more attractive (140,150). Both POG and the Pediatric Brain Tumor
Consortium (PBTC) initiated trials in the late 1990s testing chemotherapy (including
intrathecal mafosfamide, an activated form of cy clophosphamide, in the PBTC study ) with
planned, localized irradiation after the initial 4 months of chemotherapy. Progression Free
Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive
neuroectodermal tumor (PNET, n = 9), and aty pical teratoid rhabdoid tumor (ATRT, n = 12)
was 65 ± 19%, 37 ± 29%, and 0 ± 0%, respectively (159).
Page 70All infant trials to date have shown poor outcome for the 20% of patients
presenting with neuraxis dissemination, OS rates rarely exceeding 10–25%
(146,147,156,148). Although CSI is curative in a significant proportion of such children, the
consequences of CSI at effective dose levels are not considered acceptable (140). Alternative
use of aggressive, high-dose chemotherapy alone has been fraught with significant toxicity
(including toxic deaths) and EFS for favorable (M0, resected) presentations approximating
50%; outcome in the M+ cohort has been essentially zero (149).
Separate from medulloblastoma is the immature, highly aggressive AT/RT (7,160).
AT/RTs occur predominantly in y oung children, presenting in the posterior fossa; those
occurring in children older than 3 y ears are more often supratentorial lesions (137,160,161).
The lesions are histologically distinctive, and diagnosis by light microscopy and
immunohistochemistry (especially documenting positive epithelial membrane antigen and
vimentin) is often definitive. The tumor is associated with monosomy of chromosome 22, a
finding in common with extraneural primary rhabdoid tumors (162). Genetically, the tumor is
associated with loss of the tumor suppressor gene hSNF5/INI1 in more than 75% of cases;
absence of INI1 by FISH is diagnostic (137,161,163). Tumors with documented loss of INI1
are considered AT/RT and should be treated as such. Up to 15–25% of cases show
leptomeningeal dissemination at diagnosis (163,164). Although AT/RTs often respond to
chemotherapy (especially carboplatin-containing regimens), the disease course has been
marked by rapid recurrence and neuraxis dissemination (160,161). There is increasing
evidence that the outcome is improved with postoperative irradiation (165). Recent US trials
incorporate early local irradiation for children as y oung as 12–18 months old, ideally limiting
postoperative chemotherapy to 4–6 weeks (133,137,161,166), although one trial from Vienna
showed very good outcomes with intensive dose dense chemotherapy followed by high dose
regimen with localized radiation at the end with 5-y ear EFS and OS of 89% and 100% (167).
For children older than 3 y ears of age, use of postoperative CSI followed by chemotherapy
has resulted in 78% 2-y ear EFS compared to 11% for y ounger children in whom irradiation
was delay ed or avoided (137).
Surgery
As in older children, complete resection is often the primary predictor of disease control; for
infant medulloblastoma, the differences in outcome strongly favor attempted GTR in every
major series regardless of the ty pe and intensity of postoperative management
(128,130,131,146,147,148,149). In the initial Baby POG study, OS for medulloblastoma was
40%, compared with 60% for the one third of children who had undergone GTR and 69% for
those with GTR and localized disease (128). In the latest published GHOP trial, PFS among all
M0 cases falls from 82% to 50% based on the absence or presence of residual tumor
postsurgery, respectively (148).
Delay ed definitive surgery has been utilized for sizable medulloblastomas or
supratentorial PNETs in this age group. After initial chemotherapy, tumors may be reduced in
size and vascularity, resulting in more successful tumor resection (131,150).
Choroid plexus tumors are often malignant carcinomas in this age group. The tumors
ty pically arise in the lateral ventricles; histology can be uncertain in predicting benign or
malignant behavior, with carcinomas marked largely by brain invasiveness and aty pia.
Complete resection alone appears to be adequate therapy, with few recurrent tumors
following imaging-confirmed removal even without added chemotherapy or irradiation
(168,169,170). Young children with choroid plexus carcinoma (CPC) may have a p53
germline mutation and a recent analy sis shows those patients with a germline mutation who
received radiotherapy faire worse than those whose regimens omit radiotherapy (171).
Radiation Therapy
Evolving combinations of sy stematic or selected consolidative irradiation, “standard”
irradiation for disease progression, or multimodality salvage regimens incorporating low or
high-dose radiation therapy have resulted in radiation therapy as a component of therapy for
nearly half of all surviving children in this admittedly “vulnerable” age group
(128,140,147,149,150,158). Important in the context of current strategies is identification of
those cases most likely to benefit from local irradiation, with consensus developing toward
noting those with classic (nondesmoplastic) histology and localized medulloblastoma or those
with incompletely resected M0 desmoplastic medulloblastoma. Using “early ” planned
irradiation, ty pically within the first 4 months of postoperative chemotherapy, is key to
avoiding the scenario of requiring more aggressive irradiation (volume and dose) and
chemotherapy (dose) for those who progress during or after more prolonged chemotherapy.
In AT/RT, even earlier initiation of radiation therapy (4–8 weeks) may be key to improving
outcome depending on the chemotherapy, as noted above.
Although salvage CSI (at therapeutic dosage levels of 30–36 Gy using 180-cGy daily
fractions) has been successful in controlling more than 40% of recurrent medulloblastomas,
the ultimate 40–60% disease control was balanced by a median IQ of only 62 at 7 y ears
(140). The latter finding has dampened enthusiasm for salvage CSI, at least at dosage levels
greater than 24 Gy, in this age group.
Chemotherapy
The initial van Ey s study of primary mechlorethamine (nitrogen mustard), vincristine,
procarbazine, and prednisone (MOPP) chemotherapy at M.D. Anderson Cancer Center
showed long-term survival in 8 of 11 infants with medulloblastoma; 6 had not received
radiation therapy (172).
The first POG trial with initial postoperative chemotherapy was reported in 1993 (131).
The regimen included cy cles of cy clophosphamide with vincristine and cisplatin with
etoposide; response rates varied between medulloblastoma (48% partial and complete
response rate among those with imaging residual) and malignant gliomas (60%) (131). PFS
and OS rates, respectively, at 5 y ears were 32% and 40% for medulloblastoma, 43% and
50% for malignant gliomas, and 0% and 0% for pineoblastomas; overall 5-y ear survival was
27% for supratentorial PNETs (128). As in subsequent infant trials, failures bey ond 2 y ears
have been uncommon except with ependy momas (130,140,149,150,155).
Page 71Most of the subsequent infant studies have used variations of the four-drug
regimens noted in the first POG trial; more intensive regimens have shown benefit in specific
subsets of infant malignant tumors (146,173). The Head Start series of dose-intensive
chemotherapy have evolved to similar four-drug induction with second surgery for residual
local tumor, followed by my eloablative doses of thiotepa, etoposide, and carboplatin. In the
selected M0 resected medulloblastoma cohort, EFS at 5 y ears was 52%; OS of 70% those
requiring irradiation for disease progression; toxicity has remained a problem with this
approach (149). The French experience with high-dose chemotherapy, reported excellent
disease control with busulfan–thiotepa and local irradiation for children with progressive
disease following conventional chemotherapy alone (157). Results from CCG-99703 phase
I/II dose escalation study of thiotepa for infants with malignant tumors revealed that
medulloblastoma patients with M0 disease had 5-y ear EFS and OS of 72% and 76%, whereas
M+ patients had rates of 30% and 51%, respectively. Five-y ear EFS for AT/RT was 37.5%
and for pineal and nonpineal supratentorial PNET, it was 35% and 29%, respectively (174).
Recently completed studies in COG and PBTC have sought to confirm the role for local
irradiation in “high-risk” infant medulloblastoma, a group defined as those with localized
disease (M0) following incomplete resection (“R1” in the developing terminology for this
setting) or with classical histology M0 disease following complete resection (“R0”: imaging-
confirmed GTR) or R1 (175). Data from these trials, suggest excellent overall disease control
with the addition of posterior fossa irradiation for the M0 medulloblastoma cohort (176).
Given data in older children restricting “boost” volumes to the tumor bed, tumor bed
irradiation in the infant or y oung children trials is now currently used. Recent and current
infant studies in COG incorporate local tumor bed volume for AT/RT and allow elective local
tumor bed irradiation in high-risk medulloblastoma (ACNS0333, ACNS0334); a similar trial in
PBTC requires local irradiation as well in the M0 setting (PBTC 026). Guidelines for radiation
volume in the ongoing clinical trials parallel to those noted above for medulloblastoma and in
Chapter 3 for supratentorial PNETs. The GTV is defined as the tumor bed and residual
tumor following initial resection, ideally requiring fusion of preoperative MRI and the
planning set of CT and MRI imaging (Fig. 4.7 ). Changes in tumor residual may be
apparent after induction chemotherapy or, selectively, where second surgery has preceded
irradiation; in such instances, changes in areas of the normal brain that were contiguous with
the primary tumor need to be traced through sequential preoperative and intervening image
sets to the time of simulation. In the infant population, the current trials define the CTV as a 1-
cm anatomic expansion of the GTV and require an additional 3–5 mm or greater geometric
expansion to identify the PTV, depending on immobilization and repositioning in a cohort
requiring daily sedation/anesthesia for proper radiation therapy.
3D, IMRT, and now proton therapy are commonly used to diminish dose to the critical
medial temporal lobe–hippocampus region (important with regard to intellectual
development), the cochlea, and the pituitary –hy pothalamic regions. With any technique, it is
important to account for inhomogeneity and avoid overdosage or hot spots to the upper
cervical spine or brainstem especially with primary posterior fossa tumors. It is clear that
potent adjuvant and neoadjuvant chemotherapy affects tolerance to the neural structures and
some injury has been reported (177,178,179,180,181). The potential advantage for proton
beam irradiation may be best realized in the setting of infant tumors, reflecting both
intralesional homogeneity and further sparing of critical normal structures
(111,112,113,114,182).
The use of CSI in this age group has been discouraged since conventional dosages to the
neuraxis (30–36 Gy ) result in unacceptable functional consequences in children y ounger than
3 y ears of age (130,140). Efficacy is not y et demonstrated for this intervention,
recommended in AT/RTs, for example, for children older than 12–18 months of age
(108,146,150,183).
Dosage
For infant embry onal CNS tumors, response-adjusted irradiation is a component of most open
trials in North America. Most regimens use 45–50 Gy to the planning target volume (PTV)
for children up to 18–24 months of age and 54 Gy for those bey ond 18–24 months old. Note
that the French series that combined high-dose chemotherapy and local posterior fossa
consolidation for progressive medulloblastoma used only 36-Gy total dosage to the posterior
fossa (158,183). Although dose:response data are unavailable, AT/RTs are treated with similar
dose regimens, the ongoing COG trial calling for a reduced CTV at 45–50 Gy with an
additional 5.4 Gy to a reduced CTV2 derived from a 5-mm anatomic expansion of the GTV.
The indications for CSI in this age group are discussed above. When used for consolidation in
a protocol setting following complete response to chemotherapy, an age-adjusted regimen of
18- to 23.4-Gy CSI has been recommended.
Results
The most positive results in more recent infant medulloblastoma studies show OS rates
approaching 45–76%, notably more positive for those with M0 presentations, desmoplastic
histology, and initial complete resection (Table 4.5 ) (146,147,148,150). Supratentorial
PNET and AT/RTs in this age group have done less well, with few survivors in the older studies
(128,131,145,155,184). However, recent results from CCG-99703 demonstrate 5-y ear OS
rates of 41% and 63%, respectively (174).
Figure: Malignant Infant Brain Tumors—
Outcome in Selected Prospective Primary
Management Trials
EPENDYMOMAS (INFANTS, CHILDREN, AND ADOLESCENTS)
Intracranial ependy momas represent 5–8% of intracranial neoplasms in children. More than
90% of pediatric ependy momas occur as intracranial tumors; primary spinal cord tumors are
relatively uncommon in children, where ependy momas represent 25% of primary spinal
tumors. Two-thirds of ependy momas in children present as posterior fossa lesions, arising
along the linings of the fourth ventricle or at the cerebellopontine angle (CPA). Tumors
originate from the ventricular floor as midline neoplasms, where attachment is commonly
noted at the level of the obex (the caudal most aspect of the fourth ventricle along the
posterior surface of the medulla, where the fourth ventricle ends and the central spinal canal
begins). It is quite common for such tumors to grow into the foramina of Luschka (on either
side of the brainstem) toward and to the CPA (185,186,187,188). Presentation in the CPA is
noted less commonly, occurring particularly in very y oung children (189). Fourth ventricular
tumors also extend caudally bey ond foramen magnum and into the upper cervical spine;
extension is either from caudal growth from foramen of Luschka or, more commonly,
through the foramen of Magendie and then posteriorly from the cervicomedullary junction
caudally (190). Growth below the foramen magnum marks nearly 50% of fourth ventricular
lesions (Fig. 4.8 ) (185,186,188). Supratentorial ependy momas account for one-third of
childhood presentations, occurring predominantly as extraventricular cerebral hemispheric
tumors; growth is commonly adjacent to the third or lateral ventricular regions (190,191).
Page 72
Figure 4.8 Posterior fossa ependymoma, typically extending from the region of the fourth
ventricle, through the right foramen of Luschka (A) and caudally beyond the
cerebellopontine angle along the cervicomedullary junction to a level below the foramen
magnum (B).
Ependy momas consist histologically of poly gonal cells with large vesicular nuclei and
cy toplasmic granules. Characteristic are ependy mal rosettes, formed by tumor cells oriented
radially around a central lumen; cells also have a tendency to orient themselves around blood
vessels, forming perivascular pseudorosettes (7,192). Molecular genetic analy ses highlight the
origin of ependy momas from populations of neural progenitor cells that are genetically
distinct in the supratentorial, posterior fossa, and spinal regions—anatomically related patterns
of gene expression and regions of chromosomal loss or gain mark the three sites
independently (193).
There has been much debate over the clinical significance of the histologic classification
or grading of ependy momas in the past (7,192). The WHO classification now defines
ependy momas as grade 1 (subependy momas or my xopapillary spinal ependy momas),
grade 2 (“classical ependy momas,” including cellular, papillary, clear cell, and tancy tic
ty pes), and grade 3 (anaplastic) (7,192). Subependy momas are benign neoplasms most often
arising beneath the fourth ventricular wall, but also similarly adjacent to the lateral ventricles.
My xopapillary tumors are “often indolent” lesions occurring primarily in y oung adults,
specifically in the region of the cauda equina. Cellular tumors occur in extraventricular
regions with a relatively low mitotic rate. Papillary ependy momas present along the
ventricular surfaces. Clear cell tumors mimic oligodendrogliomas histologically, occurring
primarily as supratentorial lesions; there is a suggestion that this variant is somewhat
aggressive. Tancy tic tumors grow as fascicles, usually within the spinal cord. Anaplastic
ependy momas are marked by high mitotic rate, microvascular proliferation, and
pseudopalisading necrosis (7,192). Ependy moblastoma are extremely rare, highly malignant
primitive embry onal tumors occurring in infants as supratentorial lesions with features of an
ependy mal neoplasm; they are not considered in the classification of ependy momas, but
rather as embry onal tumors and have been renamed as embry onal tumor with abundant
neuropil and true rosettes (ETANTR) (194).
There have been conflicting reports regarding the correlation between tumor grade
(ependy moma vs. anaplastic ependy moma) and survival. Three of the most prominent
neuropathologists in the 1980s reported no correlation between anaplasia or grade and clinical
behavior (195,196,197). More recent series identify histology as one of the dominant features
related to disease control after aggressive surgery and irradiation (192,198,199). Merchant et
al. (199) report the St. Jude historical experience, noting 5-y ear EFS of 86% among the
children with grade II ependy momas and 61% in patients with anaplastic tumors (p = 0.005).
Extent of surgical resection was the primary driver of prognosis, however, with 5-y ear EFS
of 82% in those with a gross total resection and 41% in those with a subtotal resection. A large
proton series also found that the predominant driver of disease control was surgical resection.
Merchant’s report similarly documents a significant correlation between anaplastic histology
and a higher rate of distant failure (199).
Page 73The biology of ependy momas has been of considerable interest and much work
has been done in this arena. However, again, this is an evolving story and the number of
subgroups of ependy moma appears less well defined than in medulloblastoma. See the table
below for molecular and clinical features of subgroups that are starting to take shape (Table
4.6 ).
Table 4.6 Molecular Subgroups of Ependymoma
Ependy momas are somewhat more common in boy s, although y oung children show
equal sex distribution or even a slight female predominance. The median age at diagnosis is
4–5 y ears; one-third occur in children y ounger than 3 y ears, with ty pically inferior likelihood
of disease control (185,186,200,201). Ependy momas represent a somewhat higher proportion
of CNS tumors in infants and y oung children (127).
Sy mptoms usually are nonspecific and related to fourth ventricular obstruction with
headaches, vomiting, and ataxia. Children with disease involving the CPA often show torticollis
or cranial nerve signs (including unilateral hearing loss and facial weakness) (189). MRI often
shows a nonhomogeneously enhancing lesion, diagnostic when there is characteristic
involvement through the foramen of Luschka EP.4. The patterns of extension in and around
the cervicomedullary region are noted above (190,202). CT often shows stippled
calcification.
Therapy
Surgery
Extent of resection is the dominant factor influencing outcome
(152,185,186,189,200,201,203,204). Fourth ventricular lesions usually are adherent along the
brainstem, especially at the level of the obex, where surgical damage can result in significant
cardiorespiratory compromise. Total or near total resection is achievable in approximately
two-thirds or more in the more recent series (199,205) realized in the majority of cases
(152,185,186,201,202,203,204). Current image-guided neurosurgical techniques and
recognition of the importance of gross total resection have allowed some major referral
centers to achieve gross total resection in 80% or more of instances, sometimes requiring a
second procedure to complete surgery before adjuvant irradiation (188,189,191,199). Even in
very y oung children, complete or near complete resection is often feasible prior to initiating
further therapy. The relationship between extent of resection (or degree of residual on
postoperative MRI) and disease control has been apparent for several decades, with EFS
averaging 50–75% after gross total resection compared with 30–45% with incomplete
removal (Table 4.7 ) (186,189,191,200,201,202,203). Even in cases with metastatic disease
at diagnosis, the impact of GTR on both 5-y ear EFS and OS is impressive, with 35% and 59%
reported in a retrospective multi-institutional review (207).
Table 4.7 Ependymoma—Outcome Following Surgery and Irradiation
Total resection is associated with a low but acknowledged rate of operative mortality
(2.5% or less) and morbidity (10–25% incidence of new neurologic deficits postoperatively )
(152). Postoperative cranial nerve deficits are common, including components of the
posterior fossa sy ndrome (e.g., significant difficulties with speech, swallowing, and balance)
(49,152,185,186,189). The proximity of vital centers makes gross total resection in the fourth
ventricle rather challenging, particularly for those arising in or extending to the CPA
(153,190,208). Total resection of supratentorial ependy momas is more readily achieved
(191,208). The St. Jude experience with gross total resection in 96% of tumors originating in
the CPA is marked by a 30% major complication rate, including need for tracheostomy
(almost alway s transient, with removal between 3 and 12 months postsurgery ), gastrostomy
feeding tube (similarly ), or major cranial nerve palsies (189). The rationale, continued
improvement in neurologic function over time, and overall functional status of often y oung
children has encouraged the neurosurgical team to continue aggressive resection for primary
presentations, second surgery before irradiation, or for local recurrence (188,199). In y oung
children with moderate disease residual, the option of initial chemotherapy with delay ed
surgery prior to irradiation has been noted for some time and is still under exploration
(151,209).

Radiation therapy has been a routine component of therapy for ependy momas since the
1950s. The favorable results summarized above following gross total resection are based on
the addition of postoperative irradiation in almost all the instances (152,185,186,189,201,202).
Earlier, two classic retrospective series confirmed the contribution of radiation therapy : (1)
Pollack et al. (201) recorded overall 5-y ear survival of 45% with surgery and irradiation,
compared with 13% with surgery alone, while (2) Rousseau et al. (202) noted 63% survival at
5 y ears after irradiation and 23% without. Although there are limited data from Epstein’s New
York University experience suggesting disease control for differentiated supratentorial
ependy momas following surgery alone, there are very little data documenting favorable
disease control rates absent irradiation for posterior fossa presentations, patients with
anaplastic histology, or those with any degree of residual disease (206). The prospective
Italian Association for Pediatric Hematology and Oncology protocol reports inferior outcome
when irradiation is deferred following surgery alone, with both inferior disease control and
greater morbidity attendant to requisite second surgery (153).
The excellent results with complete resection and postoperative irradiation, even in
children as y oung as 12–18 months of age, are best demonstrated by Merchant’s series from
St. Jude, where assiduously contoured target volumes for 3D CRT to relatively high-dose
levels resulted in 74% EFS at 5 y ears, with 87% local tumor control and 85% OS; the rate of
local failure is 16% at 7 y ears (Table 4.6 ) (199). The series shows little decrement in
outcome at 7 y ears, recognizing that longer-term data reporting results from Children’s
Hospital of Philadelphia (CHOP), University of Pennsy lvania; and Washington University, St.
Louis, both show a 10% or greater decline in EFS and OS between 5 and 10 y ears
postirradiation (210,211). The coordination of aggressive surgical resection and prompt
postoperative irradiation, even in the y ounger age cohort, resulted in an excellent rate of
tumor control and survival with noted but relatively low rates of acute and subacute
morbidities from surgery and radiation therapy ; prospective data suggest relatively limited
functional morbidities to date (212,213,214). Disease control rates (both EFS and OS) and
local tumor control are equivalent in cohorts y ounger than 3 y ears or ≥3 y ears in the St. Jude
data, based largely on surgery and irradiation (199). The completed COG trial (ACNS0121)
studied children more than 12 months of age with postoperative irradiation for those with
complete or near total resection except supratentorial differentiated ependy momas, the latter
to be observed after confirmed GTR; children with significant local residual had the option of
initial chemotherapy followed by second-look surgery prior to irradiation. This study has not
been published in manuscript form, but was presented in abstract form at the 2015 annual
meeting of ASTRO. The results of the 378 patients divided into four strata include the
following: Stratum 1: patients with a grade II supratentorial ependy moma who had had a
GTR (n = 11) 5-y ear EFS was 61%. Stratum 2 had children who had an initial STR and were
treated with chemotherapy prior to a second attempt at surgery. Five-y ear EFS was 39%.
Stratum 3 entailed patients with a near total resection and their 5-y ear EFS was 67%. Stratum
4 patients had a gross total resection microscopically with a 5-y ear EFS of 70%. Five-y ear
EFS was 75% for patients with a grade II ependy moma and 61% for grade II ependy momas
as according to central pathology review (p = 0.0047) (215). There is a modest literature
regarding retreatment for ependy momas recurrent following prior surgery and irradiation,
with or without chemotherapy. Resection and full-dose local reirradiation to 50–54 Gy
resulted in secondary disease control for 10 of 13 children following local recurrence at St.
Jude; among 12 children with metastatic recurrence retreated with CSI, the 4-y ear secondary
EFS was 53% (prior therapy had included only local irradiation) (216). Bouffet et al. (217)
reported a combined Canadian experience with recurrent ependy moma and also found that
incorporating radiation in the recurrence treatment plan statistically significantly improved 3-
y ear OS from 7% in 29 patients who were not irradiated at recurrence versus 81% in the 19
patients that were irradiated at the time of recurrence. MGH reported their salvage rates with
proton reirradiation and found that in 20 patients 3-y ear OS and PFS are 78.6% and 28.1%,
but that patients with resection of the recurrent lesions did better. Toxicity was acceptable but
with three patients having grade 2 toxicities (218). Tolerance has been reasonably good, as
reported in more eclectic series with stereotactic radiosurgery used for reirradiation in
children and adults (216,219). Messahel et al. (220) reviews the topic and finds that key to
salvage is both surgery and radiotherapy.
Page 75Chemotherapy
Ependy momas are only modestly chemosensitive tumors, with objective responses most
apparent after exposure to cisplatin and oral etoposide (186,188,209,221,222). The only
prospective, randomized trial that tested adjuvant chemotherapy (CCNU, vincristine,
prednisone) after surgery and irradiation was completed by CCG in the early 1980s and
tested adjuvant (223). The trial was small, but there was no suggestion of improved disease
control with chemotherapy ; a subsequent randomized trial of adjuvant
CCNU/vincristine/prednisone versus the “8-in-1” regimen showed no improvement in either
arm of the trial; the group concluded that local tumor control was the dominant issue,
inadequately addressed sy stemically (221). Needle reported a limited-institution pilot study in
children 3 to 14 y ears old, where moderately aggressive carboplatin/vincristine alternating
with ifosfamide/etoposide resulted in a 74% 5-y ear PFS rate, noting half the cohort had
incomplete resection; the data reflect a combination intentionally derived from infant
protocols, and it is in the latter setting that further assessment of dose-intensive chemotherapy
is ongoing (224).
Gilbertson’s documentation of ERBB2 and ERBB4 coexpression in >75% of
ependy momas specimens has prompted studies in the PBTC testing lapatinib, a molecular
targeting agent active in preclinical models against ERBB expressing xenografts (225).
Preliminary reports have not been encouraging with this approach, but trials of molecular
agents are ongoing.
Infant studies may be interpreted positively in documenting that approximately 20–25%
of children with ependy momas can be controlled with surgery and chemotherapy, absent
radiation therapy ; the more recent UKCCSG/SIOP study alone shows radiation-free EFS at 5
y ears of 42% (151,204,209,217). The CCG 9921 experience resulted in postoperative,
postchemotherapy 5-y ear EFS of 32% with OS of 59% (146). The multidrug regimens have
included the traditional four-drug combination (cisplatin, etoposide, vincristine, and
cy clophosphamide) or, more recently, the UKCCSG/SIOP dose-intensive regime including
sequential carboplatin and vincristine, high-dose methotrexate and vincristine,
cy clophosphamide, and cisplatin (151,209). The St. Jude experience with a carboplatin-based
regimen showed 33% 5-y ear PFS and 62% OS in a series utilizing postchemotherapy
irradiation with any imaging evidence of residual (150). The impact of irradiation on disease
control in y oung children had early been suggested in the first POG infant brain tumor study :
children 2 to 3 y ears old received irradiation after 1 y ear of chemotherapy, and those
y ounger than 2 y ears old were scheduled to receive irradiation after 2 y ears of
chemotherapy. Long-term disease control was significantly higher in the older cohort,
interpreted as likely to be related to earlier irradiation (209). Part of the rationale for
continuing primary chemotherapy in this age group is the potential ability for
postchemotherapy (including postprogression) surgery and irradiation to achieve ultimate
disease control: the overall 5-y ear survival in the SFOP series was 59% despite the 22% rate
of PFS (204). Timmermann et al. (226) concluded that the 27% EFS at 3 y ears following HIT
SKK 87 and 92 chemotherapy (highly high-dose methotrexate based, both sy stemic and
intrathecal) is inadequate, resulting in local failures in 75% of cases prior to irradiation and an
early OS rate (at 3 y ears) of 56%.
Volume
Target volumes for postoperative irradiation have evolved from whole brain to posterior fossa
to outlining the local tumor bed only over the past two decades, from full posterior fossa
therapy to local tumor bed volumes and consideration of high-dose volumes restricted to
residual tumor sites (129,185,186,202,203,227,228). Posterior fossa ependy momas tend to
adhere to the floor of the fourth ventricle and to cranial nerves and vessels rather than
invading the brainstem or adjacent normal brain, suggesting that limited margins may be
appropriate for this tumor. Recurrence patterns are predominantly local, within the high-dose
volume; detailed patterns of failure analy ses show 50–70% of failures confined to the
primary site, an additional 10–20% involving the primary site and the neuraxis, and 10–40%
involving the neuraxis alone (185,201,202,210,211,227,228,229,230). As local control rates
improve, recently noted at more than 85% at 5–7 y ears with aggressive surgery and optimal
radiation therapy, the percentage of failures involving the neuraxis or limited to the neuraxis
has increased (152,199). For the 85–90% of children presenting with localized ependy momas,
current recommendations for the GTV include the tumor bed and residual tumor based on
both pre- and postoperative imaging. Optimal planning requires fusion of MRI studies to the
planning CT, carefully assessing common patterns of disease extension (foramina of Luschka,
circumferentially around the brainstem to encase the basilar artery, into foramen of
Magendie and bey ond foramen magnum to the upper spinal canal (189,190,199). The GTV is
expanded anatomically by 1 cm to form the CTV, curtailed at fixed anatomic borders; a final
3D geometric expansion of 3–10 mm provides the PTV (203,231) (Fig. 4.9 ).
Page 76
Figure 4.9 Ependymoma, fourth ventricle, following near total resection: (A, B) RT
planning for 6-MeV photons using IMRT (L) compared to scatter-beam protons (center) and
intensity-modulated proton beam therapy (IMPT, R). Axial imaging through level of cochlea
(A) and pituitary (B). GTV (red) and 1-cm anatomic expansion to CTV (yellow); brainstem
(green), cochlea (red), and pituitary (red) shown. C: Comparative DVH for three modalities
showing coverage of GTV, cochlea (RC, LC), brainstem (BS), whole brain (WB). D: DVH showing
coverage of GTV, pituitary (PT) and hypothalamus (HT) and temporal lobes (TL).
The incidence of neuraxis dissemination at diagnosis varies between 7% and 15% in the
recent literature (154,186,210,232). Bloom et al. initially reported a high frequency of
seeding among high-grade posterior fossa ependy momas, recommending CSI for such
presentations (233,234). Late follow-up of Bloom’s Roy al Marsden experience reported
neuraxis dissemination in only 2 of 33 children with local posterior fossa tumor control, also
noting no difference between children who had received CSI and those treated with only local
volumes (234). Although vary ing significantly among recent reports, the prospective St. Jude
series noted a 12% rate of failure limited to the neuraxis (i.e., with primary tumor control),
notably related to histology : 5% for differentiated ependy momas versus 17% for anaplastic
tumors, data that remarkably reproduced Bloom’s earlier experience (129,199,228,232,234).
Except for patients with neuraxis dissemination at diagnosis, no ongoing trial incorporates CSI
as primary management.
Page 77Dosage
It has been difficult to define a dose–response relationship in ependy momas, largely
reflecting differences in the proportion of completely resected cases and other factors (age,
histology ) that impact local tumor control. Data from CHOP suggest improved disease
control with doses of >54 Gy (210). The excellent local control noted in Merchant’s series was
based largely on 59.4 Gy, although the infant cohort y ounger than 18 months in that series
received only 54 Gy ; no statistical difference was noted in tumor control related to dose.
Awaiting the larger, multi-institutional COG trial, one is tempted to recommend 59/4 Gy,
noting that the technique should spare the chiasm and upper spinal cord dose bey ond the 54-
Gy level (152,188,199,). There have been trials of hy perfractionated delivery, with doses of
60–66 Gy delivered as 100 cGy twice daily through the SFOP; although readily tolerated, no
advantage in outcome measures was apparent (235).
Technique
The standard of practice now entails use of 3D CRT or IMRT or proton therapy to target the
tumor bed with a CTV expansion of 1–1.5 cm and a PTV expanded by an additional 5–7 mm,
depending on the immobilization techniques and experience of the treating institution (Fig.
4.9 ). Comparative dosimetry reveals advantages in normal tissue sparing at the cochlea
and in the nearby optic chiasm and upper spinal cord with IMRT or proton therapy
(188,236,230). The potential advantage of PBRT is apparent in considerable dose sparing;
prospective clinical data are anticipated as the experience matures at MGH and begins at
other PBRT facilities in the United States and abroad. Important in the very y oung population
is dose to critical structures such as the brainstem. Excellent work by Indelicato et al. (178) at
the University of Florida has helped delineate dose constraints to the brainstem with proton
radiotherapy which is especially relevant in the very y oung population who suffer a
disproportionate burden of the treatment related radiation injury. They recommend that when
possible to try to keep the mean dose to the brainstem below 52.4 Gy and that the maximum
dose to the brain stem should not exceed 56.6 Gy. A commentary that accompanies this
article nicely reviews the literature in this area and is a helpful adjunct to this study as well
(180).
Figure:
Posterior fossa ependymoma, typically extending from the region of the fourth ventricle,
through the right foramen of Luschka (A) and caudally beyond the cerebellopontine angle
along the cervicomedullary junction to a level below the foramen magnum (B).
Figure: Molecular Subgroups of
Ependymoma
Figure: Ependymoma—Outcome Following
Surgery and Irradiation
Figure:
Ependymoma, fourth ventricle, following near total resection: (A, B) RT planning for 6-MeV
photons using IMRT (L) compared to scatter-beam protons (center) and intensity-modulated
proton beam therapy (IMPT, R). Axial imaging through level of cochlea (A) and pituitary (B).
GTV (red) and 1-cm anatomic expansion to CTV (yellow); brainstem (green), cochlea (red), and
pituitary (red) shown. C: Comparative DVH for three modalities showing coverage of GTV,
cochlea (RC, LC), brainstem (BS), whole brain (WB). D: DVH showing coverage of GTV, pituitary
(PT) and hypothalamus (HT) and temporal lobes (TL).
BRAINSTEM GLIOMA
The brainstem is the connecting structure that

joins the long tracts from the cerebral
hemispheres and midline diencephalic nuclei
with the cerebellar tracks; the white matter tracts
course in all directions within aspects of the
brainstem while converging caudally to form the
spinal cord as the tracts exit through foramen
magnum. Within the brainstem are the nuclei of
the cranial nerves; coursing dorsally along the
length of the brainstem is the reticular activating
sy stem, controlling vital functions (respiration, Figure 4.10 A lower pontine glioma
blood pressure), and general consciousness. The interferes with motor function on one
brainstem includes three anatomic segments: the side of the body and with contralateral
midbrain rostrally, the pons, and the medulla function of the sixth and seventh cranial
caudally. The midbrain includes the cerebral nerves. These two cranial nerves are
peduncles (long tracts) and the reticular most commonly affected by brainstem
formation in the anterior tegmentum, as well as tumors. Ataxia can result from
the nuclei of the third and fourth nerves; involvement of the fibers of the middle
posterior to the cerebral aqueduct is the tectal cerebellar peduncle.
plate, centers of coordination of ocular
movements and both visual and auditory processing. Nuclei within the pons include cranial
nerves V, VI, VII, and VIII; long tracts are organized longitudinally with broad connections
laterally (cerebellopontine peduncles). Tracts are largely longitudinal through the medulla,
which includes nuclei for cranial nerves IX, X, XI, XII, and centers controlling the vital
functions (respiration, blood pressure) (Fig. 4.10 ).
Brainstem tumors are a heterogeneous group of tumors that share common astrocy tic
histologies but evidence divergent neoplastic behavior (growth and invasiveness) and degrees
of differentiation related to the anatomic region of involvement. Brainstem tumors are
classified by the anatomic area(s) involved and the macroscopic appearance or pattern of
growth: focal lesions are tumors that are discrete or distinctly marginated on imaging (without
apparent infiltration bey ond the primary lesion), relatively limited in volume, and histology
which is low grade, usually juvenile pilocy tic astrocy toma (JPA, grade 1), less often
fibrillary astrocy toma (grade 2) (Fig. 4.11 ) (237,238). Focal tumors occur most often in
the tectal plate and adjacent to pontine nuclei, sharing low-grade histology with the largely
exophy tic tumors arising dorsally exophy tic at the pontomedullary junction or in other
“peripheral” locations of the brainstem (239,240). The more common diffusely infiltrating
brainstem gliomas (DIBSG) arise in the pons, diffusely expanding the pons and extending
rostrally to the cerebral peduncles of the midbrain and sometimes through the internal
capsule of the thalamic region, or growing caudally to the medulla or upper spinal cord, less
often through the peduncles into the cerebellum (Fig. 4.12 ). DIBSG account for 75–85%
of brainstem neoplasms in children and adolescents; focal and “exophy tic” tumors in sum
represent 15–25% of cases (237,238,241,242).
Figure 4.11 Focal, intrinsic pontomedullary juvenile pilocytic astrocytoma, after biopsy
(3/12/99). Appearance 6 weeks after radiation therapy (54 Gy in 30 fractions): symptoms
progressed from isolated right sixth nerve palsy with subtle left hyperreflexia to complete
right seventh nerve palsy and dense left hemiparesis, associated with intralesional necrosis
and expansion of the lesion (6/24/99). Patient treated supportively, with gradual
improvement of left hemiparesis but persistent right seventh and sixth nerve palsies,
associated with virtual resolution of lesion showing residual area of focal encephalomalacia
on late imaging follow-up (3/12/03).
Figure 4.12 Brainstem gliomas: classic and most common
diffusely infiltrating pontine glioma.
The duration of sy mptoms correlates with the ty pe of brainstem glioma. Children with
DIBSG report a consistently brief history of neurologic sy mptoms, ty pically measured in
weeks and certainly less than 6 months. Neurologic signs associated with the pontine DIBSGs
include cranial nerve deficits, long tract signs, and ataxia; dy spraxia and dy sphagia are also
rather common (241,242). Elevated intracranial pressure secondary to obstructive
hy drocephalus is often present in midbrain tumors or the expansile dorsally exophy tic tumors
that fill the fourth ventricle, but noted in fewer than 15% of children with pontine DIBSGs
(Fig. 4.13 ). The focal brainstem tumors are often associated with prolonged, more limited
sy mptoms, findings confined to deficits in one or two cranial nerves alone, ataxia, or
dy spraxia, ty pically with minor long tract signs and a history measured in months or y ears
(233,237,238,240,242,243,244,245).
Figure 4.13 Brainstem astrocytomas. A: Dorsally exophytic brainstem juvenile pilocytic
astrocytoma presents as a sizable lesion filling the fourth ventricle but is attached only along
the floor at the level of the pontomedullary junction (B, postoperative); appearance 4 years
after irradiation for documented postsurgical progression shows decreased mass effect and
lack of enhancement.
Page 78MRI is the definitive test for diagnosis and delineation of tumor extent and ty pe
(Figs. 4.11 –4.13 ). The ty pical diffusely infiltrating pontine glioma is homogeneous and
hy pointense on T1 imaging but readily appreciated on T2 sequence. DIBSGs expand the
pons, often showing exophy tic growth in the ventral, dorsal, and/or lateral directions as
infiltrating lesions with indistinct margins; gadolinium enhancement is usually absent or
minimal, occasionally noted in a ring-enhancing manner. Diffusion tensor imaging (DTI) and
tractography often show sparing of the dorsal columns of the pons with infiltration splay ing
the longitudinal tracts. Focal brainstem tumors by definition show distinct margins, ty pically
enhancing briskly. 18FDG PET is hy permetabolic in DIBSG; imaging–histologic correlations
show hy peractivity only among grade 4 or glioblastoma cases; anaplastic astrocy tomas were
isometabolic with normal brain or hy pometabolic, while low-grade fibrillary gliomas (grade
2) were isometabolic (246,247,248).
As a group, brainstem tumors constitute approximately 10% of intracranial tumors in
children. The peak incidence occurs between the ages of 5 and 9 y ears; boy s are affected
more commonly than girls. The most common presenting sy mptoms for DIBSGs include
diplopia, lateralizing motor weakness, and difficulty with speech, swallowing, and walking.
Neurologic signs include ataxia, cranial nerve palsies (most common are the pontine nerves,
VI and VII, followed by the medullary nerves, IX, X, XI, and XII, and, less often, the
midbrain nerves, III, IV, and V), and long tract signs (motor weakness, most often
hemiparesis) (238,241). A review of the anatomy of the brainstem readily demonstrates why
this constellation of signs occurs (Fig. 4.10 ).
Page 79Tumors of the midbrain and medulla may be diffuse or focal; even diffuse
tumors ty pically show much less infiltration and expansion of the brainstem than seen with
the pontine gliomas. Focal intrinsic tumors do occur in the pons, often as localized tumors of a
cranial nerve nucleus or along the cerebellopontine peduncle.
Biopsy of the classic, diffusely infiltrating pontine glioma is generally unnecessary
(238,241,242,244,245,246,247,248,249). Following trials in the 1980s of sy stematic open
biopsy that y ielded some of the basic knowledge correlating imaging and histopathology,
biopsy -related neurologic compromise has led most US and European centers to biopsy only
the 15–20% of “aty pical” brainstem tumors, often demonstrating JPA or fibrillary grade 2
astrocy toma (246). Stereotactic guidance has resulted in a rather safe approach to the
brainstem tumors, with series from Paris, Germany, and Brussels showing current
histopathology and clinic-imaging correlations while reporting only minor, ty pically transient
new neurologic deficits in approximately 10% of instances (246,250,251). The more recent
biopsy series shows rather divergent histopathology, clearly dependent on selection criteria
for biopsy : 22 of 24 children showed anaplastic astrocy toma or glioblastoma, with 1 PNET
and 1 JPA reported from Hospital Necker-Enfants, compared to 10 of 20 in a more selected
series from Brussels, the remainder showing grade 2 low-grade fibrillary astrocy toma, JPA,
PNET, or germ cell tumor (250,251). There is no consistent correlation between histology and
outcome; all diffusely infiltrating pontine tumors show extremely poor duration of response to
irradiation and median survival of less than 1 y ear (241,245,252,253). Brainstem tumors have
been shown to express ERBB1, with the degree of overexpression or less common
amplification proportional to increasing histologic grade (254). The finding suggests that ErbB
or EGFR inhibitors may be worth study ing in these tumors, allowing “selected” therapeutic
interventions. A trial of an EGFR inhibitor showed a little efficacy with 1-y ear PFS of 21%
and 1-y ear overall survival of 56%, but in most studies median OS is less than 1 y ear (255). A
small subset of DIBSG may show CNS dissemination. Gururangan et al. (256) described
neuraxis metastasis in 17% of 96 patients at a median of 15 months after diagnosis, presenting
as parenchy mal dissemination (e.g., apparently noncontiguous disease extending from the
pontine primary site to the internal capsule), leptomeningeal metastasis, or subependy mal
spread.
Hoffman et al. (243) identified a highly specific brainstem tumor: the dorsally exophy tic
“benign” brainstem tumor. The lesion characteristically fills the fourth ventricle, presenting
with sy mptoms and signs of elevated intracranial pressure. In most cases, the tumor enhances
briskly with gadolinium (Fig. 4.13 ). The origin from the floor of the fourth ventricle (the
dorsal surface of the pons or medulla, with the tumor often arising at the pontomedullary
junction) may be suggested by MRI but is usually apparent only at the time of surgery. These
tumors are almost alway s JPA histologically ; the prognosis has been quite favorable
(249,257,258).
Focal tumors of the pons are uncommon. One specific presentation includes isolated
facial nerve palsy or similar, limited neurologic dy sfunction associated with a small,
enhancing intrapontine lesion (233). Such tumors are JPAs and enjoy a favorable prognosis
(Fig. 4.11 ) (241,259).
Page 80Tumors of the midbrain may involve the tegmentum or the tectal plate.
Tegmental tumors usually are fibrillary astrocy tomas (WHO, grade 2). The tumors may
involve the tegmentum focally or may infiltrate through much of the midbrain. Lesions may
show uniform enhancement or little contrast enhancement. Presenting signs include
extraocular muscle palsy or long track involvement. Biopsy is preferred, especially for
lesions contiguous with the pineal region.
Tectal plate tumors usually are quite small and well demarcated, confined to the tectal
plate (Fig. 4.14 ). MRI shows the focal nature of tectal lesions, most often signified by brisk
enhancement; biopsy generally confirms juvenile pilocy tic histology (WHO, grade 1). These
tumors ty pically are indolent; observation alone usually is the treatment of choice
(240,241,248,260). If the tumor is anatomically confined to the tectum and stable over an
initial 3- to 6-month period of observation, biopsy may be deferred unless there is evidence
of tumor progression necessitating therapy (241,259). When lesions are aty pical (e.g.,
cy stic), larger than 10 cc in volume, or when there is some question whether the lesion
originated in the adjacent pineal region, biopsy may be needed at diagnosis. If it is confirmed
as a low-grade astrocy toma, observation is appropriate.
Figure 4.14 Tectal plate glioma. A: A sagittal postcontrast MRI image of a child with a
juvenile pilocytic astrocytoma of the tectum. The tumor (T) is nonenhancing. A third
ventriculostomy defect is seen (arrow). B: Typical signal characteristics and enhancement
pattern of low-grade gliomas, here in tectal plate. Low-grade gliomas are hypointense on T1
MRI sequences and may not enhance with gadolinium (a and b, left). They are hyperintense
on T2 sequences (b, center). These tumors remain hyperintense on T2 FLAIR images (c, right),
but CSF hyperintensity is suppressed. C: Proton plan for JPA of the tectum. Axial and sagittal
images demonstrate the high conformality of proton radiation. DVH (D) and images
demonstrate the minimal dose delivered to surrounding critical structures including the
hypothalamus, pituitary gland, optic chiasm, and temporal lobes.
Therapy
Surgery
The role of surgery in classic pontine gliomas is limited. Interest in biopsy in the current era is
largely to define the biology of the more common DIBSG and to document diagnosis for the
aty pical brainstem tumors, both intrinsic and exophy tic (249,261,262).
For dorsally exophy tic tumors, judicious incomplete resection will establish the diagnosis
(by surgical observation of the origin from the brainstem and histology ) and reduce the
obstructing mass in the fourth ventricular region. Although there is no documented advantage
to aggressive surgery, it may be advantageous to remove the bulk of the lesion posteriorly,
establishing CSF flow and reducing the bulk of tumor when it can be reasonably separated
from the underly ing margin of normal, functioning brainstem. Aggressive resection as a
primary intervention is often associated with unnecessary morbidity (257,258). Partial
resection alone is associated with 50–70% freedom from progression at 5–10 y ears
(243,244,257,258).
Page 81Small focal lesions intrinsic to the pons may be biopsied if safely approachable;
one cannot insist on biopsy if the differential diagnosis is limited and the biopsy -associated
morbidity is high (233,241).
Lesions in the tegmentum should be biopsied, although the potential morbidity of
stereotactic biopsy is recognized because of the proximity of the central veins. Occasional
resection has been reported for midbrain tumors (239,262). Tumors of the lower medulla or
cervicomedullary region are similar to low-grade astrocy tomas of the spinal cord. Biopsy
and attempted gross total resection have been reported; results after surgery alone have been
impressive but limited to a small number of neurosurgical centers (239,261,263). Histology
usually is low-grade astrocy toma (WHO, grade 2). Malignant gliomas have been reported
(261).
Radiation Therapy
Children with diffusely infiltrating pontine gliomas often respond impressively to irradiation.
Up to 70% show improvement in neurologic sy mptoms and signs over the course of
irradiation; objective reduction in tumor on MRI is apparent within 8–12 weeks of initiating
irradiation. Unfortunately, signs of progressive disease are apparent sy stematically within 6–
12 months (241,264).
Clinical response has also been noted in tegmental midbrain lesions and tumors of the
medulla, where radiation therapy is more likely to achieve long-term disease control
(241,265). For tectal plate or dorsally exophy tic pontomedullary astrocy tomas, irradiation is
ty pically deferred until signs of disease progression are apparent on imaging
(240,244,248,257,258). Once progression has been documented on serial imaging (noted in
25–40% of dorsally exophy tic tumors), there has been almost uniform disease control
measured out to more than 5 y ears after local irradiation (244,257,258). Intrinsic focal
pontine lesions often require irradiation at diagnosis to control attendant neurologic signs
(233). With the availability of precision volume techniques (i.e., 3D CRT or fractionated
radiosurgery ), the risk:benefit ratio may favor earlier radiation intervention in localized, low-
grade brainstem lesions (266,267).
Chemotherapy
Despite documented transient response, there is little evidence of efficacy for chemotherapy
in brainstem tumors. An earlier prospective, randomized trial of CCNU, vincristine, and
prednisone showed no benefit in these tumors despite purported efficacy in supratentorial
high-grade gliomas (268). Adjuvant studies with concurrent or sequential chemotherapy or,
more recently, trials incorporating molecular targeting agents (inhibitors of EGFR, PDGFR;
HDAC (histone deacety lase inhibitors) and VEGF inhibitors) have failed to alter the PFS or
OS data in this disease (269,270,271,272,273). Despite efficacy in adults with hemispheric
malignant gliomas, temozolomide has shown no advantage in DIBSG in children (274).
Preirradiation chemotherapy regimens have shown some responsiveness, but early disease
progression during chemotherapy and a lack of objective benefit in postirradiation intervals to
progression have largely dampened enthusiasm for this approach, if a limited recent French
trial testing preirradiation BCNU, cisplatin, and high-dose methotrexate continues to generate
interest (275,276,277,278).
Recently, there has been better biologic and molecular understanding of diffuse intrinsic
pontine gliomas that may provide targets for drug therapy. Genomic interrogation of DIPG
tumors from biopsies and autopsies, have revealed histone mutations specifically K27M
H3.3/H3.1 mutations in 80% and activin A receptor, ty pe 1 (ACVR1) mutations in 25% of
diffuse intrinsic pontine gliomas, providing renewed hope for future success in identify ing
effective therapies as both appear to be driver mutations (279,280).
For focal, low-grade gliomas, the use of chemotherapy before irradiation is an
extrapolation from diencephalic low-grade tumors, which may be rational in selected settings
(281). For the majority of children, even those y ounger than 4 y ears old, sy mptomatic or
progressive dorsally exophy tic or focal pontine lesions can be treated effectively with focal
radiation techniques. It is difficult to anticipate any significant advantage in delay ing
definitive therapy with intervening chemotherapy.
Volume
MRI and autopsy studies document contiguous extension of pontine gliomas linearly through
the adjacent medulla or midbrain and axially into the brachium pontis, the CPA, and adjacent
portions of the cerebellar hemispheres (237,242,282). Neuraxis metastasis has been noted in
up to 15% of children with DIBSG, involving the subarachnoid space (primarily about the
brainstem, the basal cistern, or the upper cervical cord, but also into the spinal canal), direct
or noncontiguous appearance cephalad into thalamic white matter, or subependy mally within
the ventricular sy stem (241,256,283,284). A small proportion of focal, low-grade brainstem
lesions (often JPAs) are associated with neuraxis dissemination, most often noted at diagnosis
(233,285). In almost all instances, the pattern of failure for DIBSG includes the primary
pontine tumor alone or in conjunction with other sites as above (282,286). Local irradiation is
indicated, with target volumes subtending both the pons and the contiguous regions both
linearly (adjacent midbrain and medulla) and axially (adjacent peduncles and, where
indicated, contiguous anterior cerebellum). The best estimate of tumor extent is ty pically on
T2 or T2 flair sequences to define the GTV (242,266). Microscopic margins along the white
matter tracts provide a 1- to 2-cm anatomic expansion to identify the CTV. It is important to
note that tumors extending rostrally into the midbrain or higher will show larger axial CTVs at
the upper midbrain and contiguous internal capsules than at the primary pontine level, simply
a matter of anatomically covering sites of direct extension. For infiltrating tumors of the
midbrain and medulla, margins of 1–1.5 cm along white matter tracts bey ond the T2 or flair
extent are appropriate.
Focal lesions of the tectum can be treated with limited target volumes; treatment of
discrete lesions generally entails treating only the identifiable tumor with a 1 cm or less CTV
for 3D conformal or IMRT (241,266). Fractionated stereotactic radiosurgery (also called
stereotactic radiotherapy ) and radiosurgery have been used for the latter tumor ty pes
(197,266,267).
Page 82For dorsally exophy tic tumors, the volume can conform to the disease process
based on MRI; the anterior margin at the brainstem should encompass at least 5 mm of
apparently normal brainstem ventral to the tumor as documented on MRI. A 3D CRT or IMRT
approach can spare radiation dosage to the temporal lobes, especially important in this y oung
age group.
Dosage
A decade-long series of trials in the 1980s and 1990s explored the impact of high-dose,
hy perfractionated irradiation for brainstem gliomas. Despite dosage escalations from 66 Gy
to 70 to 72 Gy and ultimately to 75.6–78 Gy (with twice-daily fractions of 100–126 cGy ), no
durable improvement was documented in disease control or survival. The outcome after
conventionally fractionated irradiation to 54–55.8 Gy (180 cGy once daily ) or
hy perfractionated irradiation to between 70 and 78 Gy has been consistently documented at
median times to progression of only 6–8 months, median survival approaching 1-y ear, and 2-
y ear survival rates of only 10% (241,245,264,265,287). A randomized trial ultimately
documented the equivalence of conventional and hy perfractionated schedules (288). A trial
of accelerated fractionation in Europe, using 180 cGy twice daily with interfraction intervals
of 8 hours to 48.6 and 50.4 Gy, showed similar results, with 32% survival at 1 y ear and 11% at
2 y ears (289). It is unclear whether paucifractionated approaches with fraction sizes of 3 Gy
(to 39 Gy /13 fractions) or 5.5 Gy (to 33 Gy /6 fractions) achieve equivalent or inferior results
compared to conventionally fractionated regimens (290).
Technique
Radiotherapy for these tumors employ s a CT scan for planning and a fusion MRI and the use
of either 3D conformal RT or IMRT that enable one to spare the temporal lobes and aspects of
the cochlea. GTV encompasses all of the enhancing and T2 or Flair signal abnormality. The
CTV is a 1- to 2-cm expansion superiorly and inferiorly with a 1-cm anatomically confined
expansion axially, which means likely the CTV will be trimmed to stay within the boney
confines of the posterior fossa anteriorly but extend posteriorly to tracks of the cerebellar
peduncles to cover microscopic spread. With usual immobilization and repositioning, one
ty pically identifies an additional 3 to 5 mm geometric expansion to define the PTV.
For focal brainstem gliomas (including tectal plate lesions, dorsally exophy tic
pontomedullary tumors, and focal intrinsic lesions of the midbrain, pons, or medulla), tumor
size, margination, and location demand highly conformal 3D CRT, IMRT, or proton
radiotherapy approaches to minimize dosage bey ond the primary target volume while
maintaining intralesional homogeneity in the CTV within 5% (246) (Fig. 4.14 ).
Radiosurgery for focal brainstem gliomas is not recommended. CT-based planning with a
fusion MRI should encompass all gross residual disease based on T2, Flair and T1 post
gadolinium sequences and coverage of the tumor bed as well if resection was employ ed.
CTV margins should be 5 to 10 mm and anatomically confined.
Children with DIBSGs usually need corticosteroids at diagnosis to control neurologic
sy mptoms. For those not receiving corticosteroids at the initiation of radiation therapy, one
should consider initiating a low-dose regimen (e.g., dexamethasone at 2–4 mg twice daily )
only for children with large intrinsic tumors or early development of additional or progressive
neurologic signs. Irradiation generally is well tolerated, and one can commonly taper
dexamethasone during the course of irradiation, often discontinuing steroid support by the
fifth or sixth week of therapy. Reducing the dexamethasone dose is important both for
secondary drug effects and to control cushingoid features that can make repositioning in
immobilizing masks problematic as the face expands secondary to steroids. The newer
biologic agents often show cutaneous reactions that require management within and well
bey ond the radiation volumes (291,292).
A significant proportion of patients with brainstem tumors demonstrate clinical and
imaging evidence of apparent progressive tumor within 1–4 months of completing radiation
therapy (263,293). MR spectroscopy and PET studies may be of help in differentiating early
tumor progression from the “pseudoprogression” often comparable to that seen in adults with
hemispheric glioblastoma (242,294). Imaging changes during this interval include focal
enhancement (often in a previously nonenhancing lesion), cy st formation (or cy stic
degeneration), or intralesional hemorrhage and necrosis (242,289,293). The problem is
recognized in cooperative group trials, where patients may be coded formally as “disease
progression,” but maintained on study without interruption of postirradiation therapy until
resolution or progression is ultimately clear. Similar changes, with apparent tumor progression
and worsening of neurologic signs, can occur 1–4 months after irradiation for focal intrinsic
JPAs (Fig. 4.11 ). Medical support, including corticosteroids, may be necessary until the
lesion regresses over several months.
Results
Approximately 60–70% of patients with classic pontine gliomas show improvement in
functional status after irradiation. Time to progression may be difficult to document in this
tumor sy stem; cooperative group studies report median time to progression of 6–8 months.
Overall survival is the primary endpoint for comparing therapies, providing an objective
parameter reflecting primary management and recognizing that little prolonged secondary
benefit has been documented from secondary therapies. Median survival is 8–12 months in
patients selected for high-risk DIBSG studies, and the proportion surviving at 2 y ears is less
than 10–20% (241,242,245,264,265,273,286,287). There is some suggestion that y ounger
children (<3 y ears old) may show superior outcome, perhaps related to the biology of such
uncommon presentations (295).
Children with focal, intrinsic tumors of the midbrain or medulla show long-term survival
after irradiation of 50–70% (237,240,241,265). Survival at 10 y ears after surgery with or
without necessary irradiation for dorsally exophy tic brainstem gliomas approaches 75%
(241,243,257,258). Similar rates are quoted for the focal pontine lesions of limited size after
localized irradiation (235).
Figure:
A lower pontine glioma interferes with motor function on one side of the body and with
contralateral function of the sixth and seventh cranial nerves. These two cranial nerves are
most commonly affected by brainstem tumors. Ataxia can result from involvement of the
fibers of the middle cerebellar peduncle.
Figure:
Focal, intrinsic pontomedullary juvenile pilocytic astrocytoma, after biopsy (3/12/99).
Appearance 6 weeks after radiation therapy (54 Gy in 30 fractions): symptoms progressed
from isolated right sixth nerve palsy with subtle left hyperreflexia to complete right seventh
nerve palsy and dense left hemiparesis, associated with intralesional necrosis and expansion
of the lesion (6/24/99). Patient treated supportively, with gradual improvement of left
hemiparesis but persistent right seventh and sixth nerve palsies, associated with virtual
resolution of lesion showing residual area of focal encephalomalacia on late imaging follow-
up (3/12/03).
Figure:
Brainstem gliomas: classic and most common diffusely infiltrating pontine glioma.
Figure:
Brainstem astrocytomas. A: Dorsally exophytic brainstem juvenile pilocytic astrocytoma
presents as a sizable lesion filling the fourth ventricle but is attached only along the floor at
the level of the pontomedullary junction (B, postoperative); appearance 4 years after
irradiation for documented postsurgical progression shows decreased mass effect and lack of
enhancement.
Figure:
Tectal plate glioma. A: A sagittal postcontrast MRI image of a child with a juvenile pilocytic
astrocytoma of the tectum. The tumor (T) is nonenhancing. A third ventriculostomy defect is
seen (arrow). B: Typical signal characteristics and enhancement pattern of low-grade
gliomas, here in tectal plate. Low-grade gliomas are hypointense on T1 MRI sequences and
may not enhance with gadolinium (a and b, left). They are hyperintense on T2 sequences (b,
center). These tumors remain hyperintense on T2 FLAIR images (c, right), but CSF
hyperintensity is suppressed. C: Proton plan for JPA of the tectum. Axial and sagittal images
demonstrate the high conformality of proton radiation. DVH (D) and images demonstrate the
minimal dose delivered to surrounding critical structures including the hypothalamus,
pituitary gland, optic chiasm, and temporal lobes.
CEREBELLAR ASTROCYTOMAS
Page 83Cerebellar astrocy tomas make up 10–15% of childhood brain tumors and 25% of
posterior fossa neoplasms. These tumors are ty pically low grade, well circumscribed, and
slowly growing with prominent cy st formation (296,297). Cushing (191) was the first to
describe the entity in 1931, commenting on the “benign” nature of cerebellar astrocy tomas,
associated with low morbidity and mortality.
The cerebellum is one of the most common sites of origin for low-grade gliomas in
children. The vast majority of cerebellar astrocy tomas are low grade: JPAs (WHO, grade 1)
comprise 80–95% of cases, and diffuse fibrillary astrocy tomas (WHO, grade 2) account for
5–15% (298,299,300,301). Biphasic architecture is characteristic of JPAs, with more cellular
areas that tend to have Rosenthal fibers (degenerating astrocy tic processes and loose areas
with microcy sts). Cells are elongated, bilpolar, and have thin “hair-like” processes (hence,
piloid) (298). Diffuse fibrillary astrocy tomas tend to be less circumscribed, more infiltrative
and expansile, with a less favorable prognosis relative to JPA; the diffuse tumors arise
specified, or as oligoastrocy tomas (298,299,302,303). Malignant gliomas are quite
uncommon in the childhood cerebellum.
The median age at diagnosis is 5–6 y ears, with 20% of cases y ounger than 3 y ears old;
astrocy tomas of this location are rarely found in infants (296,300,304). Presenting sy mptoms
often are confined to those associated with elevated intracranial pressure (headaches,
vomiting, etc.), with less frequent altered cerebellar function (primarily ataxia, poor
coordination, or dy spraxic speech); cranial nerve deficits are uncommon.
The majority of tumors arise in the cerebellar hemispheres; approximately one-third
are primary vermis lesions. Most tumors are confined to the cerebellum; a minority extends
to the cerebellopontine peduncle or the posterior aspect of the brainstem
(296,297,300,304,305). The most characteristic appearance on CT or MRI is a large, well-
circumscribed tumor with prominent cy sts (unilocular or multilocular). The nodular or solid
portion of the tumor characteristically enhances briskly. The cy st wall may or may not
demonstrate contrast enhancement. The nodular and cy stic components are considered part
of the tumor; both components should be addressed at the time of surgery (300,304,306).
Cerebellar JPAs have uncommonly been associated with multifocal CNS involvement,
representing either neuraxis dissemination or concurrent multifocal presentation (307,308).
Therapy
Surgery
Surgical resection is the treatment of choice for cerebellar astrocy tomas. The amount or
degree of resection has been found to be the most important prognostic factor for outcome in
patients with low-grade gliomas (137). For classic cy stic cerebellar astrocy tomas, gross total
resection has been reported in 70–90% of cases (299,300,302,309). PFS for these children is
in excess of 90%. Even in the setting of documented residual, many tumors remain indolent.
After surgery - and imaging-confirmed gross total resection, recurrence is uncommon, noted
at 5–10% in major series (300,302,303,304,305,309,310). After incomplete resection, disease
progression has been reported in 30–60% of cases at 5 y ears or more. Importantly, long-term
survival remains above 65% (297,300,302,309). Infiltrative tumors and diffuse fibrillary
astrocy tomas are less likely to be amenable to gross total resection and are associated with a
higher rate of disease progression or recurrence (300,311). Despite the indolent nature of
these tumors, the median time to recurrence is about 2 y ears (297,300,302,305). Children
who experience tumor recurrence amenable to surgery may benefit from a second surgery.
This is generally recommended if the tumor can be totally resected or substantially debulked
without great risk of neurologic compromise.
Radiation Therapy
There is no established role for radiation therapy in the primary management of cerebellar
astrocy tomas that are amenable to gross total resection. Prognostic factors that may predict
relapse after initial surgery alone should be considered. Most series indicate greater risk of
later disease progression in recurrent tumors, infiltrative tumors, astrocy tomas that cannot be
completely resected, and tumors with diffuse fibrillary histology or more aggressive
histologic subty pes (296,297,299,300,304,309).
Indications for radiation therapy include progression of incompletely resected tumors
that are not amenable to second surgery and incomplete surgical resection following
recurrence. This is an uncommon situation for JPA, but is seen more frequently in tumors
with diffuse fibrillary histology (300,303). Chemotherapy is the preferred initial adjuvant
treatment for these more aggressive presentations in very y oung children (312). There are no
data substantiating improvement in disease control with postoperative irradiation following a
complete resection (304,309,313). Infrequent malignant gliomas seem to benefit from
immediate postoperative irradiation, but overall prognosis in these cases is poor (311).
Chemotherapy
Because most low-grade gliomas located in the cerebellum are amenable to surgical
resection and do not require adjuvant therapy, it is relatively rare to use chemotherapy for
this specific tumor site. Multiple chemotherapeutic agents have been shown to delay
progression (312,314,315,316). The most commonly administered regimen is the
combination of carboplatin and vincristine. A more extensive review of the use of
chemotherapy for low-grade gliomas is included in the “Low-Grade Supratentorial
Astrocy tomas” section in Chapter 3 .
Indications for radiation therapy are generally limited to documented progressive or
recurrent disease after or on chemotherapy in the y ounger patients or progressive or
recurrent disease in the older children (300,313). Lesions with an infiltrative pattern involving
the peduncle or brainstem may require early radiation therapy when sy mptomatic or
progressive. Such lesions are targeted with limited anatomic expansion of 0.5–1 cm around
the GTV as defined on MRI with image registration to include immediate preoperative
disease and residual at the tumor bed (317). The prescription dose is generally 50–54 Gy
(318).
Page 84The treatment of high-grade cerebellar astrocy tomas generally includes
multiple modalities. Postoperative irradiation to the local tumor is recognized as the standard
of care (300,313). CSF dissemination is a recognized pattern of failure; neuraxis irradiation is
ty pically considered only when overt CNS metastasis is documented (300,307,308,313).
Results
OS rates in childhood cerebellar astrocy tomas are more than 80% at 10–20 y ears
(296,297,300,304). Survival rates are highest among those with tumors confined to the
cerebellar hemispheres or vermis, JPA histology, and those amenable to gross total resection.
For incompletely resected diffuse astrocy tomas, long-term survival rates of 50–80% have
been reported (296,299,300,302,305). It is interesting that children with cerebellar
astrocy tomas demonstrate cognitive and adaptive deficits despite posterior fossa location and
therapy limited to surgery alone (319). This risk does not seem to be associated with surgical
or medical complications.
SPINAL CORD NEOPLASMS
Spinal cord neoplasms are uncommon in children. These tumors are divided into two main
groups: intradural and extradural. Intradural lesions are further classified into those involving
the spinal cord itself (intramedullary ) or arising outside of the spinal cord parenchy ma from
the cauda equina or intradural components of the nerve roots (extramedullary ). Extradural
tumors are by definition neoplasms that arise outside the nervous sy stem with extension into
the spinal canal through the neural foramina. Extradural tumors that gain access to the spinal
canal can then extend linearly bey ond the cord segment of entry, accounting for the
“dumbbell” description; such presentations are most common in neuroblastomas,
paravertebral soft tissue tumors of the Ewing ty pe (i.e., peripheral PNET), or neurofibromas
(320). Management of extradural presentations is discussed in Chapters 9 , 11 and
12 .
Primary (intramedullary ) spinal cord neoplasms account for approximately 5% of CNS
neoplasms in children (321). The median age is between 8 and 9 y ears with a slight male
predominance (322,323). The relative histologic and anatomic frequencies of spinal cord
tumors in children are almost mirror image proportions of those in adults: astrocy tomas
account for approximately 60% of primary spinal cord tumors in children, while
ependy momas account for 30% (321,324,325,326). Other gliomas (gangliogliomas,
oligodendrogliomas) and neurilemomas (neurofibromas usually associated with
neurofibromatosis ty pe I) comprise the remaining 10% (321,324,327,328,329).
More than 80% of pediatric spinal cord astrocy tomas are low-grade neoplasms, most
often fibrillary and less commonly juvenile pilocy tic in ty pe. Astrocy tomas occur primarily
in the cervical and thoracic regions of the cord, presenting as circumscribed or more
infiltrating lesions (Fig. 4.15 ). The tumors diffusely widen the involved cord; tumor length
averages six spinal cord segments (321). More than 30% are associated with sizable
intraspinal cy sts (324,327,329). The cy sts ty pically extend in cephalad and caudal directions
from the solid tumor, representing fluid-filled components that may be more than double the
overall length of the lesion. Differentiating true tumor-derived cy sts from common sy rinx
formation related to obstruction of the central canal is often difficult. Malignant gliomas
(high-grade astrocy tomas: anaplastic astrocy toma and glioblastoma multiforme) account for
fewer than 20% of astrocy tic lesions. Spinal malignant gliomas are clinically aggressive
lesions and carry a poor prognosis. The literature suggests that such tumors may be more
common in infants (324,326,327,329). Holocord astrocy tomas extend over much of the
length of the cervicothoracic cord. The majority of these tumors are infiltrating (fibrillary )
astrocy tomas and often represent lengthy cy stic extensions of relatively more localized
neoplasms, recognizing the solid tumor components may y et involve a significant length of
the spinal cord (325,330,331). Less common glial tumors include oligodendrogliomas and
gangliogliomas. These tumors usually are discrete and well-circumscribed intraspinal lesions
that occur in the cervical, thoracic, or cervicomedullary junction regions. Presenting
characteristics are similar to those of the astrocy tomas (325,332,333).
Figure 4.15 Intramedullary spinal cord astrocytoma. A: Lesion involving the

cervicothoracic cord. B: The child is free of disease after subtotal resection and irradiation.
Page 85Spinal cord tumors represent 5% or less of all ependy momas in children
(324,334). The majority arise in the low thoraco-lumbar region, involving the conus
medullaris or the cauda equina. Most such ependy mal lesions are histologically differentiated
ependy momas, most often grade 1 my xopapillary ependy moma (334). These tumors are
low-grade, indolent lesions signified histologically by papillary growth and mucin formation
(335). Two thirds occur in the cauda equina, presumably arising from the filum; 30% present
as tumors of the conus medullaris and 5% as aty pical my xopapillary tumors of the cervical
or thoracic cord (335) (Fig. 4.16 ). Despite their benign histology and tendency for slow
growth, local recurrence and dissemination superiorly in the spine and sometime brain is not
uncommon, particularly after incomplete resection. As compared to adults, children have
been shown to have a more aggressive disease course with a greater risk of recurrence and
dissemination to other regions of the spine (336). In contrast, ependy momas of the cervical or
thoracic cord tend to be discrete, focal intramedullary lesions (328,337).
Figure 4.16 Myxopa-pillary ependymoma of the cauda equina, documenting extensive
disease that involves the cauda and nerve roots (A); postoperative imaging shows residual
and subarachnoid deposits (B) and (C). Disease controlled at 5 years following surgery and
CSI.
Spinal cord tumors usually present with slowly progressive sy mptoms. The average
duration of sy mptoms in most studies is 2–9 months, but some children report sy mptoms for
y ears prior to diagnosis (320,338,339). The most common sy mptoms include pain and
weakness corresponding to the level of the lesion. Pain is classically greater at night, when the
child is recumbent (331,332). Younger children may present with torticollis or hy potonia
and/or variability of reflexes on examination (339). It is not rare to see lower thoracic cord
pain evaluated as an intra-abdominal process, including by laparotomy for suspected
appendicitis. Numbness or sphincter dy sfunction occurs in 10% of cases (324,325,330).
Sy mptoms and signs of elevated intracranial pressure may be noted at diagnosis of a
primary, localized spinal cord tumor (340).
MRI is the standard imaging mode for assessment of spinal cord neoplasms. One can
usually distinguish intramedullary from extramedullary lesions; tumor extent is generally
well appreciated. It is sometimes difficult to discern subtle cy stic changes from solid tumor
extension; intraoperative ultrasound can be a more sensitive tool in this regard. Fibrillary
astrocy tomas and gangliogliomas usually are nonenhancing tumors, best delineated on T2
sequences. JPAs enhance uniformly. Ependy momas ty pically are enhancing lesions. In
evaluating spinal cord tumors, it is important to image the entire length of the spinal canal; one
can see “skip” intramedullary involvement uncommonly in astrocy tomas. In ependy momas,
it is standard to image the entire neuraxis; rarely, intracranial ependy momas can present
sy mptomatically as a “primary ” intraspinal or cauda equina tumor with an occult
intracranial primary. Subarachnoid dissemination can occur in malignant gliomas and
ependy momas (327,337).
Page 86Therapy
Surgery
The primary management for most intradural spinal tumors is surgery. Current technology
and experience with intramedullary lesions have greatly facilitated gross total resection for a
large percentage of pediatric intraspinal neoplasms. The use of midline my elotomy and
ultrasonic dissection has allowed discrete dissection of intraspinal gliomas. Pediatric
neurosurgeons report low rates of long-term morbidity after judicious complete resection,
often technically approached from just outside the tumor margin, rather than after biopsy
with attendant intralesional swelling or potential hemorrhage (325,326,328,330,333,334,341).
Spinal evoked potentials guide the surgical procedure, allowing intraoperative monitoring to
confirm preservation of long tract function (330,333). Postoperative increased neurologic
deficit is reported to be limited and often transient for tumors above the T9 level; intraspinal
astrocy tomas at the T9–T12 level may be associated with greater postoperative morbidity, in
part due to complexities of the vascular supply in this region (325,326,328,330).
The goal of surgery for spinal cord tumors is to establish a pathologic diagnosis and
perform a complete excision without major compromise of neurologic function; when
complete excision is not possible, maximal safe removal will often relieve sy mptoms with
less compromise postoperatively than biopsy alone. Summary data from 10 earlier studies
combining pediatric and adult experience indicated total excision in 16% of low-grade spinal
gliomas (primarily astrocy toma) (327,330,331,341). For low-grade histologies, Epstein’s New
York experience indicates PFS after surgery alone exceeding 90% at more than 5 y ears in
spinal cord and cervicomedullary junction tumors, data that have been confirmed in smaller
studies (241,324,329,330,334). The high rates of disease control after surgery, with acceptable
morbidity, confirm the role for primary surgical management for low-grade astrocytomas in
experienced neurosurgical centers, most data suggesting a correlation between degree of
resection and outcome (338,342). For incompletely resected tumors, second surgery may be
considered immediately (when anatomically approachable, before postoperative gliosis sets
in) or at relapse when added risks may seem more justified. For high-grade gliomas outcome
is poor regardless of degree of resection, with only anecdotal survival bey ond 3 y ears for
anaplastic astrocy tomas or glioblastomas (324,327,328,329).
For spinal ependy momas, gross total resection has been documented in 25–100% of
cases in series often combining pediatric and adult experience (325,328,335,336,337,343).
My xopapillary ependy momas in children are often amenable to gross total resection.
Although detailed dissection often is necessary for lesions that adhere to numerous nerve
roots comprising the cauda, earlier data from the Roy al Marsden Hospital indicate total
resection in 42% of 24 cases of cauda equina tumors, with 92% PFS at 5 y ears (337). For
lesions of the conus medullaris, the earlier studies indicated resection in only 2 of 14 cases
(337). By contrast, McCormick et al. (343) indicated resection in all 23 children and adults
with intramedullary tumors, only 1 of whom experienced recurrence. A recent study
indicates a higher rate of recurrence in children (64% vs. 32% in adults at a median follow-up
of 6.1 y ears) (336). Surgery alone has been associated with survival rates at 5 y ears of 86–
100% (263,325,333,334,337).
Chemotherapy
Experience using chemotherapy is limited, but small series do report apparent efficacy for
carboplatin and vincristine in low-grade spinal astrocy tomas (344). The combination of
irinotecan and cisplatin was also found to be safe and effective in a small cohort of children
under the age of 3 y ears with progressive disease after administration of carboplatin and
vincristine (345). Currently, there is no clear role for chemotherapy for the treatment of
spinal cord ependy momas. For high-grade tumors of the spinal cord multimodality therapy
including chemotherapy is generally used, but despite aggressive treatment, prognosis is poor
(346).
Radiation Therapy
The use of postoperative irradiation for spinal cord tumors has been controversial and largely
inconsistent. With improved neurosurgical methods, there appears to be no clear benefit from
sy stematic postoperative radiation therapy for low-grade spinal gliomas or ependy momas in
children (325,326,327,334).
The literature documents 50–60% survival rates at 5 y ears after surgery and irradiation
for largely incompletely resected spinal astrocy tomas (324,327,334,347,348). Lacking
comparative data, a rational approach includes maximal surgical resection. For incompletely
resected tumors, one can support observation for low-grade gliomas (especially pilocy tic
histologies, but also other low-grade gliomas in prepubertal children where the risk:benefit
ratio may favor delay ing radiation intervention). Although long-term freedom from
progression has been documented after incomplete surgery alone, postoperative radiation
therapy is generally indicated for sizable residual tumors that are unlikely to be amenable to
later, more complete resection (324,326,334,347,349). If one elects to follow a child with
suspected or definite residual disease, it is important to commit to later second surgery (when
feasible) and irradiation (unless the second surgery results in imaging-confirmed total
resection) with evidence of progressive disease (based on imaging or on changes in
sy mptoms or neurologic signs).
Page 87For spinal cord ependy momas, there is evidence supporting surgery alone for
intramedullary tumors and for initial management of cauda equina tumors
(325,328,333,343,348). The indolent nature of my xopapillary tumors favors observation in
the setting of total resection or minimal residual disease (327,334,337,349). Recurrence rates
after complete resection are relatively low, but disease progression after incomplete resection
for children may be high (327,328,337). In the setting of recurrence or tumor progression,
treatment generally consists of second surgery followed by irradiation. Although the impact
of histologic grade in ependy momas is apparent in adult studies, anaplastic ependy momas of
the spine are uncommon in children; extrapolation from the adult data suggests a role for
postoperative irradiation for such lesions (328,337,347).
Volume
Neuraxis staging is an important component of preirradiation assessment for intramedullary
tumors of all ty pes. When radiation is indicated, local irradiation is used for most spinal cord
tumors. Localized intramedullary astrocy tomas and ependy momas are generally treated to
the tumor bed, based on preoperative and postoperative MRI; a margin of 1–2 cm
longitudinally is indicated for low-grade, focal lesions. For astrocy tomas, one ty pically sees
decompression or obliteration of the rostral and caudal cy stic components after resection of
the solid tumor. In such instances, it appears that radiation therapy can be limited to the solid
tumor bed (327,329,330,334,337,341). For spinal ependy momas, local volumes are also
indicated (327,334,337). For cauda equina tumors, there is some debate regarding the use of
local or craniospinal volumes. Recent studies suggest regional irradiation that includes a 2- to
3-cm margin above the initial tumor volume (ty pically into the conus), and caudal coverage
to include the proximal sacral nerve roots axially and the bottom of the thecal sac
longitudinally (334,335,337). For patients with disseminated low-grade astrocy tomas, the
radiation volume is controversial with some advocating the use of local irradiation and others
recommending inclusion of the entire craniospinal axis (350,351). Age-dependent
consideration of full neuraxis irradiation is indicated when the pattern of involvement is truly
leptomeningeal. Careful consideration of tumor and patient characteristics in these cases is
paramount.
Dosage
The local radiation dose for spinal cord astrocy tomas and other glial histioty pes has ty pically
been reported as 50.4 Gy using daily fractions of 180 cGy. This is based at least as much on
estimated cord tolerance as it is on documentation of dose to achieve local control. Single-
institution and collected studies indicate no apparent dose–response relationship bey ond 50
Gy ; it is difficult to find data differentiating outcome at 50 versus 54 Gy for astrocy tomas
(327,348). For ependy momas, similar analy ses indicate a response at the 45- to 50.4-Gy
level, although recent studies have favored a dose of 50.4 Gy (327,348,349). With current
localization techniques, the use of 50.4–54 Gy at 180 cGy per fraction is considered
acceptable to target volumes discussed above (334). In cases of disseminated disease, 36–
39.6 Gy is common for areas that are not involved with imaging evident disease.
Technique
Current techniques for spinal cord tumors use image-guided definition of the target volume,
with 3D CRT or IMRT or proton radiotherapy approaches to avoid excessive irradiation of the
underly ing viscera, especially the kidney s, lung, or heart. Electrons have also been used.
Protons provide excellent sparing of tissues anterior to the spinal canal or vertebral body and
should decrease rates of acute and long-term toxicities to these anterior organs (Figure
4.6B ). Among the planning parameters should be reasonably homogeneous irradiation of
the vertebral bodies for children who have not reached full height.
Results
OS in spinal cord astrocy tomas is estimated as 80% at 5 y ears and 55% at 10 y ears
(324,329,333). Prognosis is affected by histologic grade and the extent of surgical resection.
For ependy momas, OS is comparable, with recent figures indicating 90% 5-y ear survival.
Outcome depends on the site of origin (with long-term survival rates greater than 90% for
cauda equina tumors and 60% for intramedullary tumors or those arising in the conus
medullaris) (325,326,328,337,349). Patients with complete resection appear to enjoy a
favorable outcome in some studies (326,327,328,337).
Figure:
Intramedullary spinal cord astrocytoma. A: Lesion involving the cervicothoracic cord. B: The
child is free of disease after subtotal resection and irradiation.
Figure:
Myxopa-pillary ependymoma of the cauda equina, documenting extensive disease that
involves the cauda and nerve roots (A); postoperative imaging shows residual and
subarachnoid deposits (B) and (C). Disease controlled at 5 years following surgery and CSI.
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CH A P TER 5
Retinoblastoma
Jasmine H. Francis, Suzanne L. Wolden, David H. Abramson, and Ira J.
Dunkel
PAGE 96INCIDENCE
Retinoblastoma (RB) is the most common primary ey e tumor in children and usually afflicts
children less than 5 y ears of age. It occurs in about 1/20,000 live births, resulting in about 250–
350 new cases per y ear in the United States. In the higher-income nations, retinoblastoma
almost alway s presents with intraocular disease that may threaten the ey e and vision, but
extraocular disease is uncommon, occurring in less than 5% of cases. In contrast, extraocular
retinoblastoma remains a common problem in lower-income countries and is usually fatal.
Many phy sicians believe that retinoblastoma is more common in lower- or middle-
income countries, but a population-based study in Argentina determined that the incidence
there is comparable to that of higher-income countries (1).
GENETICS
Retinoblastoma was one of the first examples demonstrating the potential genetic etiology of
cancer. Hereditary retinoblastoma presents in a Mendelian autosomal dominant pattern with
90% penetrance, but only 10% of patients have a family history of the disease.
Retinoblastoma occurs in two forms: Patients with unilateral disease present with a single
focus of tumor at a median age of about 24 months, while patients with bilateral disease
present with multifocal tumors at a median age of about 12 months. Knudson proposed his
classical two-hit model in 1971 after noting that the timing of tumor development (earlier
diagnosis of bilateral tumors than of unilateral tumors) suggested that at least two events
would be responsible for the development of the tumor. Patients with multifocal bilateral
disease are germline carriers for the first hit, with only one second hit necessary to develop
retinoblastoma in a susceptible cell. Unilateral unifocal patients usually have a normal
germline genome, but develop both hits in the progenitor tumor cell (2).
The nature of these hits was suggested by kary oty pic abnormalities on the long arm of
chromosome 13 in tumors. In 1986, the “hit” was discovered to be a mutation in the RB1 gene
on chromosome 13q14 (3). It is likely that most patients with bilateral or multifocal disease
have a germline RB1 mutation (as mosaicism may be as common as 15% of patients), while
most (85%) patients with unilateral disease have a sporadic RB1 mutation only in the
retinoblastoma tumor cells. The first hits are usually point mutations or small deletions, while
the second hit is usually loss of the normal allele (loss of heterozy gosity ) (4).
DNA-based mutation identification can be performed at specialized laboratories, and
genetic counseling regarding RB1 genetic testing is part of the standard care of retinoblastoma
patients. Testing is clinically useful to identify the approximately 15% of unilateral survivors
at risk for secondary malignancy and/or transmission of the disease to their offspring, to
determine which relatives or offspring of survivors inherited the mutation and need to be
carefully clinically screened, and to allow bilateral survivors the option of considering
preimplantation genetic diagnosis and in vitro fertilization to avoid the risk of their child
inheriting their mutated RB1 gene (5).
An important recent discovery was that N-my c amplification appears to be an
alternative mechanism to retinoblastoma development that is responsible for about 1% of
unilateral cases (6). The current understanding regarding the molecular genetics of
retinoblastoma is impressive, but we still are not able to answer the question frequently posed
by parents of a child newly diagnosed with retinoblastoma in the absence of a family history :
Why did this happen to my child? It remains unclear whether this is an uncommon random
event or whether environmental exposures may be contributory (7).
CLINICAL ASSESSMENT
Retinoblastoma commonly presents with a white

pupillary light reflex (called leukocoria) in
developed countries (8). The parents may notice
this abnormal appearance in a flash photograph
(Fig. 5.1 ). Normally, in an unprocessed
photograph, a photographic flash bounces light
through the pupil and reflects a red reflection of
the fundus to produce a red dot in the central Figure 5.1 Right eye leukocoria
pupil. However, large retinoblastoma, or a demonstrated in a photograph.
retinoblastoma-producing retinal detachment,
produces a white reflex. This effect can also be seen as a phy siologic effect of the light
reflecting from the optic nerve, particularly in certain angles of light. Over half the patients
with retinoblastoma are diagnosed due to leukocoria, which is initially noticed by a parent or
another family member the vast majority of the time (9). Other presenting signs include
strabismus, decreased vision, and occasionally orbital pseudo-cellulitis.
Page 97On phy sical examination one notes
a raised white, white-y ellow, or white-pink mass
(10). Tortuous vessels may be seen either
feeding or intrinsic to the tumor. Cells may break
off from the main tumor mass and grow as
small vitreous seeds (Fig. 5.2 ). Because
retinoblastoma may be multifocal, it is
necessary to examine the entire retina of both
ey es with a scleral depressed exam, generally
with the patient under anesthesia. Due to the
occurrence of new tumors, both ey es continue to
Figure 5.2 Vitreous seeds.
be examined on a monthly basis until 44 months
of age in unilateral cases and 7 y ears with bilateral disease.
When retinoblastoma presents as a mass, the differential diagnosis includes astrocy tic
hamartoma, Toxocara canis granuloma, medulloepithelioma or the infected emboli of
subacute bacterial endocarditis or toxoplasmosis, and other ty pes of severe uveitis. When
retinoblastoma causes retinal detachment, the differential diagnosis includes Coats disease,
retinopathy of prematurity, incontinentia pigmenti, and persistent hy perplastic vitreous.
Biopsy of a suspected retinoblastoma tumor is contraindicated because of the risk of
extraocular dissemination (11).
During the examination, the intraocular
pressures and corneal diameters are initially
measured. Following this, the tumors are
visualized with indirect ophthalmoscopy and
documented with retinal drawings and
photographs (Fig. 5.3 ). Ultrasonography can
be used to further depict the tumors and evaluate
for extraocular extension or orbital involvement.
Ultrasonic biomicroscopy captures the anterior
structures of the ey e and can assess involvement
of the ciliary body and anterior segment.
Figure 5.3 Fundus image of an eye
Electroretinography can be used to determine
containing retinoblastoma.
the electric response of the retina as an
indication of retinal function. Brain–orbit
magnetic resonance imaging is generally obtained at the time of diagnosis to evaluate for
optic nerve, orbital and intracranial involvement of disease. Computed tomography imaging
is not recommended in children with retinoblastoma, particularly those children with a
germline mutation in RB1, due to (theoretical) concern about increased risk of radiation-
induced cancers (12).
A number of classification and staging sy stems have been developed for intraocular and
extraocular retinoblastoma. In the 1960s, the Reese–Ellsworth (RE) sy stem was used to group
intraocular retinoblastoma ey es (13) (Table 5.1 ). It was developed during a time when
external beam radiation therapy (EBRT) was widely used and assigned a higher grouping to
ey es with features associated with inferior ocular survival after radiation treatment (size,
location, and seeding). In the mid-1990s, the primary treatment for retinoblastoma shifted
from EBRT and enucleation to chemoreduction and focal therapies. With the evolution in
treatment approach, a new classification sy stem was developed and named the International
Classification of Retinoblastoma (ICRB) (14) (Table 5.2 ). It was generated with the
intention of predicting treatment success following chemoreduction and focal therapies. A
number of iterations have been developed, and as a result, inconsistencies between the
different versions limit comparisons between reports.
Table 5.1 The Reese–Ellsworth

System of Classifying Retinoblastoma
Table 5.2 International Classification System for Intraocular Retinoblastoma (Children’s
Oncology Group Version)
Figure:
Right eye leukocoria demonstrated in a photograph.
Figure:
Vitreous seeds.
Figure:
Fundus image of an eye containing retinoblastoma.
Figure: The Reese–Ellsworth System of
Classifying Retinoblastoma
Figure: International Classification System
for Intraocular Retinoblastoma (Children’s
Oncology Group Version)
TREATMENT OF INTRAOCULAR RETINOBLASTOMA
Page 98The three goals of treatment for retinoblastoma include preservation of life, ey e, and
vision. In the majority of the world, the priorities follow in this order. However, in some
countries, the cultural beliefs may necessitate the need to preserve the ey e at the expense of
risking life. Worldwide, half of the children diagnosed with retinoblastoma in 2015 will die of
disease that has metastasized. However, in North America, Europe, Japan, and other higher-
income parts of the world, the survival rate of retinoblastoma is greater than 95%. Treatment
modalities have changed with time and continue to evolve. We will outline below the current
treatment approaches.
Enucleation
An enucleation involves removing the ey e and retaining the orbital contents. It is a reasonable
and commonly used treatment for retinoblastoma, particularly in advanced cases and when
the intraocular pressure is elevated. In an enucleation, the six extraocular muscles are
detached from the globe and the optic nerve is severed near its exit at the optic foramen.
Obtaining a long segment of nerve is important, particularly if the tumor is within the nerve
since tumor at the cut section is associated with central nervous sy stem (CNS) metastasis and
a poor prognosis.
Once the ey e is removed, it is replaced with a spherical orbital implant and the
conjunctiva and Tenons are closed over this. Approximately 4 weeks after the surgery, the
socket is measured for a prosthesis which fits like a contact lens between the lids. It is
cosmetically similar to the fellow ey e, but may not move to the same degree. In y oung
children, orbital growth slows after enucleation and as the rest of the child grows, the orbit
may appear small (this is more common when the ey e is removed at a very y oung age)
(Fig. 5.4 ).
Page 99Focal Therapy

The focal therapies for retinoblastoma include cry otherapy, laser, and radioactive plaque
applications. Focal therapies can serve as primary treatment of small tumors or they can be
an adjunct to other modalities including the various delivery methods for chemotherapy (to
be discussed in a later section). Specifics regarding each focal treatment are outlined below.
Laser
Laser can be applied as photocoagulation or as hy perthermia. Laser hy perthermia is
generated by a diode laser (810 nm) on continuous mode. A single spot, 0.8–2.0 mm in
diameter, is aimed at the tumor, ty pically with
an indirect ophthalmoscope and 20 diopter lens.
A power setting range between 100 and 2000
mW is selected based on the tumor response.
Intravenous indocy anine green may be used to
enhance the laser response (15). Tumors are
treated for a variable amount of time depending
on response: ty pically fundi or tumors with more
pigment will respond more rapidly and at lower
power settings. Tumors in the posterior pole or
posterior part of the ey e are more easily
accessible to laser compared to anteriorly Figure 5.4 Bilateral retinoblastoma
located tumors, which may require scleral treated with enucleation on one side with
indentation for adequate visualization. Laser is a prosthesis in place. A calcified fundus
particularly effective as a primary treatment for lesion is seen in the remaining eye.
tumors less than 3 mm in size, and requires an
average of 1.8 laser applications to cure a tumor.
Cryotherapy
Cry otherapy is the focal use of freezing temperatures to create intracellular ice formation to
treat retinoblastoma tumors. A tumor is localized and indented through the wall of the ey e
with a nitrous oxide cry oprobe (Fig. 5.5 ). The freeze (–90°C) is then applied until the
tumor is completely covered. The freeze–thaw cy cle is repeated at least three times (16).
Cry otherapy is most accessible to small tumors anterior to the equator, which can be reached
with the cry oprobe (posterior tumors are difficult to reach, and the risks of freezing the
macula or nerve increase posteriorly ).
Cry otherapy can induce acute retinal edema and accumulation of subretinal fluid. To
avoid retinal detachment, some ophthalmologists use laser to create a retinal barrier to fluid
leakage. Disruption of the retina by cry otherapy has the advantage of increasing the
intravitreal permeation of chemotherapy. Cry otherapy can cause a local inflammatory
reaction and pain, which may be mitigated with local anesthetics or topical steroids.
Radioactive Plaque Application

Brachy therapy with insertion of radon seeds was first described for the treatment of
retinoblastoma in 1930 (17). Refinements in
technique led to the development of curved discs
or “plaques” loaded with radioactive isotopes
and placed on the outer sclera overly ing the
tumor (18). Due to the exquisite radiosensitivity
of retinoblastoma, episcleral plaque
brachy therapy was highly successful in
eradicating focal tumors while preserving the
ey e (19). In recent y ears, radioactive plaques
have been used in the adjuvant or salvage
setting. Tumors suitable for treatment with
brachy therapy ty pically have a largest base Figure 5.5 Cryotherapy for
diameter no more than 16 mm and a maximum retinoblastoma.
depth of 10 mm. Vitreous seeding should be
absent or within 2 mm of the tumor surface (20). Tumor measurements should be obtained
from ultrasonography at the time of dilated ey e examination under anesthesia. The planned
dose is prescribed to the maximal tumor thickness or apex plus the thickness of the sclera
which is ty pically 1 mm or less.
Surgery for plaque placement (Fig. 5.6 ) is done under general anesthesia and begins
with a dilated examination using the indirect ophthalmoscope to confirm tumor location. The
conjunctiva is then opened and muscle hooks are used to hold rectus muscles and rotate the
ey e. It is often necessary to disinsert a rectus muscle to gain access and traction sutures may
be used to hold the ey e in place. The tumor location can be verified by visualization with
indirect ophthalmoscopy along with scleral indentation and marking with a light pipe
diathermy can be used. A clear dummy plaque of identical size and shape to the radioactive
plaque is placed over the tumor. This dummy plaque is sutured in place with scleral bites and
perfect placement is once again confirmed. These preplaced sutures are left in the sclera
while the dummy plaque is replaced with the radioactive plaque. The sutures are then
tightened, the ey e is rotated back in place and conjunctiva is closed. Due to radiation safety
precautions, patients are generally kept in the
hospital for the duration of the radiation delivery
(1–4 day s). Once the plaque is removed, patients
are ty pically discharged to home with an ey e
patch.
Page 100A number of isotopes are available
for plaque brachy therapy. 60Co has been an
economical and highly effective choice in the
past. The dosimetry is relatively forgiving so that
there is a low risk of underdosing tumor.
However, 60Co plaques have fallen out of favor Figure 5.6 Placement of 125I
primarily because of radiation safety concerns radioactive plaque.
for the patient as well as hospital staff. 192Ir and
103Pd have also been used but 125I followed by 106Ru are most commonly used today.
Advantages of 125I and 106Ru plaques include the ability to easily shield the patient as well
as staff from radioactivity. Because of the relatively short half-life of approximately 2
months, 125I plaques are assembled with a customized assortment of seeds for each case.
They also require shielding around the periphery of the plaque which necessitates very
precise placement. 106Ru plaques are preloaded in standard sizes and may be used
repeatedly owing to a half-life of just over 1 y ear. However, there is less control over
treatment time since the plaques are not custom loaded. They are thinner than other plaques
which can be an advantage for placement in y oung children. In experienced hands, all ty pes
of plaques have an excellent record of efficacy for retinoblastoma.
One of the most significant experiences with plaque brachy therapy for retinoblastoma is
from the Wills Ey e Hospital (21). They reported long-term outcomes for 208 tumors with an
overall 5-y ear control rate of 79%. The majority of patients (71%) had received previous
therapy and 35% had relapsed prior to brachy therapy. The vast majority of plaques were
125I and the median prescribed dose was 40 Gy. Risk factors for plaque failure included
vitreous and subretinal seeding as well as increased patient age. Complications at 5 y ears
included cataract in 31%, retinopathy in 27%, papillopathy in 26%, maculopathy in 25%, and
glaucoma in 11%. There were no cases of scleral necrosis and only one case of second
cancer in the field of plaque irradiation.
A team from Toky o reported a series of 101 retinoblastoma tumors in 85 patients treated
with 106Ru plaques as first- and second-line treatment (22). The median prescribed dose at
the apex was 47 Gy with a corresponding dose to the outer sclera of 162 Gy. Many patients
had advanced disease with vitreous (42%) and subretinal (36%) seeding. Local control and
ocular retention were 34% and 59%, respectively, at 2 y ears. Larger tumor size, tumor
seeding, and lower radiation doses were associated with local failure. The rate of
complications was low and included retinal detachment (13%), retinopathy (7%), rubeosis iris
(2%), and cataract (26%). There were no cases of secondary cancer attributable to
brachy therapy.
Plaque brachy therapy is increasingly used as an adjuvant or focal salvage after
sy stemic and/or intra-arterial chemotherapy. A recent report from Memorial Sloan Kettering
detailed the successful use of plaque therapy in 15 patients following ophthalmic artery
chemosurgery (23). Brachy therapy was an adjuvant in 2 patients and as salvage therapy in
13 patients. Twelve cases had localized vitreous seeding. Ocular retention was 79% with six
patients requiring enucleation and six ey es required additional treatment for relapse outside of
the target volume. Electroretinogram demonstrated stable or improved retinal function in the
majority of ey es following plaque therapy.
Plaque brachy therapy remains a useful tool in the treatment of focal retinoblastoma.
With proper patient selection and an experienced team, high rates of control are achieved in
the up-front and salvage setting. The major advantage over external beam therapy is that
plaques are not associated with bone hy poplasia or a significant risk of secondary cancers.
Apex doses of 40–45 Gy have been used traditionally, but most now advocate for lower doses
of 30–40 Gy, especially in patients who have received prior chemotherapy. A current
Children’s Oncology Group (COG) protocol, ARET12P1, calls for an apical dose of 36 Gy
when plaque brachy therapy is used following intra-arterial chemotherapy (24).
External Beam Radiotherapy

EBRT has been used to treat retinoblastoma for over a century and was the vision-sparing
treatment of choice for many y ears (25,26,27). Ey e-preservation rates ranged from 50% to
100% in large series and varied according to Reese–Ellsworth group (Table 5.3 ). The use
of EBRT has decreased dramatically in recent y ears with the introduction of effective intra-
arterial chemotherapy and focal techniques. This major shift away from EBRT was driven
by concerns about the long-term complications of radiation including orbital bone hy poplasia
and second malignancy, especially in patients with a germline RB1 gene mutation.
The use of EBRT is now generally reserved for patients with persistent or relapsed
diffuse disease after chemotherapy and focal therapies (39). EBRT has been the best option
for vision sparing when tumor is multifocal, close to the macula or optic nerve, or with diffuse
vitreous seeding though in the past 9 y ears the success of intra-arterial chemotherapy has
largely replaced even these indications.
Page 101Radiation treatment techniques have evolved dramatically over the decades. In
the era of 2-dimensional therapy, fields were set up based upon detailed knowledge of
standard orbital and bony anatomy. When lateral fields were used, the anterior border of the
ty pical D-shaped field was set at the limbus of the ey e (junction of the cornea and sclera).
This is the way to adjust for differing degrees of ocular protrusion based on orbit volume and
ey e size. The isodose was set at the anterior field edge to avoid divergence and unnecessary
dose to the opposite lens. The phy sician would check the field setup daily prior to treatment.
This technique was criticized because of the potential for poor coverage of the anterior retina
which could result in relapse for patients with very extensive disease. Other techniques were
developed which often included an anterior field with placement of a lens block. Numerous
institutional series have compared techniques
retrospectively but the largest is from Memorial
Sloan Kettering, reporting results for primary
EBRT for 182 ey es in 123 children (35). Their
modified lateral technique set the beam edge 2–
3 mm behind the limbus to avoid anterior
failures. They showed that 8-y ear local control
for Reese–Ellsworth group I–III ey es was
significantly better with a modified lateral beam
technique compared to the anterior lens-sparing
technique, 84% versus 38%, p < 0.0001. For
Reese–Ellsworth group IV–V ey es, the
improvement was not significant. The doses used
in this series ranged from 38 to 46 Gy in 2–2.5
Gy fractions. It was notable that the long-term
rate of cataract was 22% and no ey es required
enucleation for ocular complications.
With the advent of more sophisticated
photon treatment delivery sy stems, the Table 5.3 Eye Preservation Following
previously described techniques are rarely used. External Beam Irradiation: Selected
A dosimetric study from McGill University Series Reese–Ellsworth Group
compared 10 photon and electron techniques,
showing the best conformity for retinoblastoma was achieved with intensity -modulated
radiation therapy (IMRT), volumetric arc therapy (VMAT) and helical tomotherapy (40). A
recent clinical report from Children’s Hospital Los Angeles (CHLA) included 24 ey es treated
with IMRT as salvage after failure of sy stemic chemotherapy (41). Prescription dose was 36
Gy for 22 ey es and 24 Gy for 2 ey es with low tumor burden. With mean follow-up of 63
months, 79% of ey es were preserved. Enucleation was required following IMRT because of
tumor progression in four cases and blindness with pain in one. The cataract rate was 79%
and 17% developed retinopathy. No solid tumors developed during the relatively short follow-
up period.
While IMRT can deliver very conformal therapy to the target, this is at the expense of
low-dose exposure to a larger volume of normal tissue (42,43). There is ongoing debate about
whether this will pose any increase in risk for second cancer in the general population of
oncology patients. IMRT is a reasonable and appropriate therapy for patients with unilateral
retinoblastoma without an RB1 germline mutation because their risk of secondary cancer is
low. However, unnecessary low-dose exposure is a serious concern for patients with a
germline RB1 mutation. These patients have a high rate of secondary cancer which is
increased threefold by treatment with EBRT (44). Since these patients are exquisitely
sensitive to radiation-induced carcinogenesis, it is imperative to treat them with as much
normal tissue sparing as possible.
Patients with germline RB1 mutations comprise the most compelling case for clinical
benefit with proton therapy over other EBRT modalities (Fig. 5.7 ). A recent report from
Massachusetts General Hospital provided promising results for a series of 60 ey es in 49
patients treated with proton radiotherapy (45). With a median 8-y ear follow-up, the ocular
retention rate was 82%. The majority of patients (84%) had bilateral disease and no in-field
second malignancies have developed, though follow-up is relatively short. Vision was
maintained in the majority of patients for whom ophthalmologic follow-up was available and
the radiation complication rate was 20%. With the rapidly increasing availability of proton
therapy, it is expected that the use of protons for retinoblastoma will rise. Longer follow-up
will help to define the risk reduction of proton therapy over photons, which is expected to be
greatest in children with a germline RB1 mutation.
Figure 5.7 Radiation dosimetry comparison for a retinoblastoma treated with protons
versus intensity-modulated (IMRT) photons.
As radiation technique has been debated and evolved over decades, so has radiation
dose. Retinoblastoma is clearly a very radiosensitive tumor as it can be cured with modest
doses of radiotherapy alone. A large number of dosage and fractionation schedules have been
proposed for external beam treatment, ranging from 1.2 to 3.8 Gy per fraction with total
doses of 30–60 Gy. Many retrospective clinical series have been published, showing
conflicting data regarding dose–response relationship and the impact of tumor size and dose
on local control. The most traditional approach to EBRT dose has been 40–45 Gy in once
daily fractions of 1.8–2 Gy. This dose range has reliably produced excellent tumor control
with acceptable complication rates in the definitive treatment of retinoblastoma.
Page 103Now that radiotherapy is most often used after cy toreduction with sy stemic
chemotherapy, modification of EBRT dose should be considered. There is concern that the
complication rate, especially retinopathy, may be greater with the combination of
chemotherapy and radiation. In the CHLA series, 24–36 Gy was successfully used as salvage
after failure of chemotherapy (41). Additional study is needed to determine the optimal dose
of radiotherapy following chemotherapy but in the absence of a clinical trial, 36 Gy seems
appropriate based on currently available data.
Figure:
Bilateral retinoblastoma treated with enucleation on one side with a prosthesis in place. A
calcified fundus lesion is seen in the remaining eye.
Figure:
Cryotherapy for retinoblastoma.
Figure:
Placement of 125I radioactive plaque.
Figure: Eye Preservation Following External
Beam Irradiation: Selected Series Reese–
Ellsworth Group
Figure:
Radiation dosimetry comparison for a retinoblastoma treated with protons versus intensity-
modulated (IMRT) photons.
CHEMOTHERAPY FOR INTRAOCULAR DISEASE
In the mid-1990s, it became clear that chemotherapy was effective against retinoblastoma
and it provided an alternative to enucleation and external beam radiation. As the treatment of
retinoblastoma has evolved over the y ears, so too has the delivery method of chemotherapy :
becoming increasing more localized, and some would argue, more invasive. The following
section will describe the delivery of intravenous, periocular, intra-arterial, and intravitreal
chemotherapy for the treatment of retinoblastoma.
Intravenous Chemotherapy
Sy stemic chemotherapy was first reported to be effective against retinoblastoma in 1953. It
was intermittently used at first, but finally adopted by many centers in the 1990s as an
alternative to enucleation and external beam radiation (46). The most commonly used
regimen consists of vincristine, carboplatin, and etoposide, and in conjunction with focal
therapy (laser, cry otherapy, and/or plaque brachy therapy ) has been associated with about a
90% chance of radiation and enucleation-free survival for ey es with less advanced disease
(RE group I–III) versus about a 30% chance for ey e with more advanced disease (RE group
IV–V) (47).
Investigators from Philadelphia described their experience in several papers. Seventy -
five ey es in 47 patients were treated with six cy cles of vincristine, carboplatin and etoposide
with local therapies and all 39 RE group I to III ey es were cured without EBRT (48). Thirty
Reese–Ellsworth group V ey es were treated and 53% required EBRT and/or enucleation.
Subsequently they reported that this strategy produced inferior results in 30 patients with
unilateral retinoblastoma (49). For RE group I to IV ey es, 38% required EBRT and/or
enucleation by 5 y ears, while 100% of group V ey es required one or both. Finally, this group
also reported the outcome of 158 retinoblastoma-containing ey es in 103 patients treated with
six cy cles of vincristine, carboplatin, and etoposide (39). EBRT was used in 10% of RE group
I–IV ey es and 47% of RE group V ey es. Ey e survival was 85% for RE group I–IV ey es and
47% for RE group V ey es.
Some centers will use single-agent carboplatin, particularly in y oung children less than 3
months of age, in order to bridge them until they are of an optimal age and size for other
delivery methods (such as ophthalmic artery chemosurgery ) (50).
The most important potential acute side effect of intravenous chemotherapy is
my elosuppression, which may be associated with need for admission for fever and
neutropenia and/or and blood product transfusions. Ototoxicity is uncommon, but may be
more frequent in y oung infants (51,52). A rare, but potentially very serious side effect is
secondary acute my eloid leukemia (AML), and the risk of secondary malignancy in patients
with a germline RB1 mutation receiving this treatment is not y et completely elucidated.
Ophthalmic Artery Chemosurgery

Ophthalmic artery chemosurgery (OAC) is a
treatment that involves gaining access via the
femoral artery and placing a microcatheter at
the ostium of the ophthalmic artery, where
chemotherapy is infused into the ey e (53). (Fig.
5.8 ) It allows for a localized, concentrated
delivery of drug to the ey e while minimizing
sy stemic exposure and toxic effects. It was
initially used to treat only ey es that were
destined for enucleation, but it has since become
the first-line treatment for intraocular Figure 5.8 Angiogram during intra-
retinoblastoma at more than 70% of centers arterial chemotherapy procedure.
worldwide. It has enabled advanced ey es, ey es
that have failed previous sy stemic chemotherapy, ey es with subretinal seeding to all be
treated without enucleation or EBRT. For example, our group reported treatment of 95 ey es
(87% advanced disease, 55% previously treated with intravenous chemotherapy and/or
EBRT) in our first 78 patients treated with intra-arterial melphalan +/− topotecan (54). The
catheterization was successful in 98.5% of the procedures. Patients received a median of 3
treatments per ey e and the Kaplan–Meier estimates of 2-y ear ocular event-free survival
were 81.7% for previously untreated ey es and 58.4% for previously treated ey es.
Neutropenia (usually grade 3) is the most commonly seen acute nonocular toxicity. We have
noted it to occur following 29% of treatment cy cles and the risk is greater if the melphalan
dose is >0.40 mg/kg (55). Blood product transfusions and admission for febrile neutropenia
have been very uncommon. OAC is also an effective treatment for less advanced disease
and bilateral retinoblastoma, which necessitates sequential administration of each ey e during
the same infusion (56,57).
Page 104OAC infusions are ty pically administered on an outpatient, monthly basis an
average of three times. The most frequently used agent is melphalan, either alone or in
combination with carboplatin and/or topotecan. The dose selection is a dy namic process that
considers many factors (54). For example, y ounger children, ey es with inflammatory
reaction on previous infusions or ey es with wedge flow may receive lower doses of drug,
while ey es with large nonocular branches or inadequate response from prior OAC may
receive higher doses. Electroretinogram monitoring is used as an evaluation of retinal toxicity.
A 6-y ear study of electroretinogram responses following OAC concluded that the toxic
effects to the retina are slightly more pronounced with melphalan compared to topotecan or
carboplatin, but are generally minimal (estimated to result in a 1% decline of retinal response
with each melphalan-containing infusion) (58).
Periocular Chemotherapy
Periocular chemotherapy is a method of injecting chemotherapy (1-2 mL) under one of the
lay ers of tissue (Tenon’s) that surrounds the ey e. The needle does not enter into the ey e.
Instead, the chemotherapy bathes the outside of the ey e, transitions through the wall, and into
the vitreous. This treatment may be given in conjunction with other therapies (intra-arterial
chemotherapy or intravitreal chemotherapy ). Ty pically, treatments are given weekly, one to
eight times. Occasionally, patients may experience swelling and redness of their ey e and
ey elids, which resolves with time.
Carboplatin is the mostly widely used drug for periocular injection (59). In a nonhuman
primate model, it was demonstrated that in comparison with intravenous administration, the
drug levels after periocular injection were seven to nine times higher in the ey e and 90% less
in the blood (60). Though there were fewer effects on bone marrow, periocular injections of
carboplatin cause (in 50% of cases) severe local reactions including scarring and, rarely, loss
of vision (61,62). Recently, topotecan has been administered as a periocular injection: while
its local toxicity profile is more favorable to carboplatin (63), its efficacy is questionable.
Intravitreal Chemotherapy
Intravitreal chemotherapy involves injecting a small amount (approximately 0.05–0.1 mL)
of chemotherapy through the wall of the ey e and into the vitreous (64). The procedure is
done on an outpatient basis while the child is under anesthesia. Injections are ty pically given
weekly to monthly for one to approximately eight times. There is no pain associated with this
treatment, although the sclera and conjunctiva may appear red for a couple of day s to weeks.
This method is particularly useful at treating vitreous seeds, which are little fragments of
tumor that break off and float in the jelly (vitreous) of the ey e. Melphalan is the most
frequently injected medication, although other drugs have been used. Recent published
evidence demonstrates that 25–30 mcg of intravitreous melphalan can result in ocular
survival rates of 83–100% (64,65). While intravitreal melphalan can cause toxic effects to the
retina and even the anterior segment of the ey e (66), it saves ey es with vitreous seeding that
once would have been enucleated.
Figure:
Angiogram during intra-arterial chemotherapy procedure.
EXTRAOCULAR RETINOBLASTOMA
Retinoblastoma may potentially spread outside the ey e via different routes. It may grow
contiguously through the choroid and sclera into the orbit, hematogenously metastasize to the
bone, bone marrow, and/or liver, extend directly through the optic nerve to the brain, and/or
invade the subarachnoid space surrounding the optic nerve and disseminate to the
leptomeninges via the cerebrospinal fluid (CSF). The ey e has limited ly mphatic drainage
(through the conjunctiva), so ly mphatic spread is rare, but regional nodal metastasis may
rarely occur.
Extraocular retinoblastoma may be present at initial diagnosis in lower-income
countries, but in higher-income countries it is almost alway s a later event, occurring several
months postenucleation. The presenting signs and sy mptoms can vary, depending on the
affected sites. Orbital recurrences are often diagnosed following a parent’s observation that
the child’s ocular prosthesis is no longer fitting well or may present as a visible mass. Bone
disease may present with pain or a mass. Bone marrow disease is often asy mptomatic, but
may be suspected if the patient has abnormal low blood counts. Liver metastases are usually
asy mptomatic and discovered only upon evaluation of extent of the disease. CNS disease,
either directly due to the metastases or indirectly via hy drocephalus, may cause headache,
irritability, emesis, and/or focal neurologic signs.
When a child is suspected or known to have extraocular retinoblastoma, a thorough
evaluation to determine the extent of disease should be expeditiously performed. It should
include brain and orbit MRI with and without contrast, spine MRI with and without contrast (if
the brain MRI or CSF cy tology are positive or CNS disease is otherwise suspected), lumbar
puncture for CSF cy tology, bone marrow aspirate and biopsy, bone scan and abdominal
computed tomography (CT) with IV contrast. The results allow assignment of a stage via
International Retinoblastoma Staging Sy stem (67) (Table 5.4 ).
Table 5.4 International
Retinoblastoma Staging System
Figure: International Retinoblastoma
Staging System
TREATMENT DUE TO HIGH-RISK ENUCLEATION PATHOLOGY
Page 105In higher-income countries, enucleation is usually curative for patients with
intraocular retinoblastoma, but a small proportion will suffer an extraocular recurrence.
Many investigators have attempted to correlate the histopathologic features of the enucleation
specimen with risk of extraocular recurrence, usually focusing on invasion of the postlaminar
optic nerve, choroid, and sclera. Which findings warrant prescription of postenucleation
adjuvant chemotherapy in an attempt to decrease the risk of later development of overt
metastatic disease remains controversial.
The Children’s Oncology Group completed a study (COG ARET0332) that attempted to
prospectively determine the prevalence of high-risk histopathologic features such as choroidal
involvement, optic nerve invasion, scleral and anterior segment involvement in patients with
unilateral retinoblastoma treated with enucleation. They also aimed to estimate the event-free
survival (extraocular or metastatic disease) and survival of patients with unilateral
retinoblastoma with and without high-risk features. Patients with (1) massive choroid
replacement, (2) any posterior uveal involvement with any optic nerve involvement or (3)
optic nerve involvement posterior to the lamina cribrosa were treated with six cy cles of
intravenous carboplatin, vincristine, and etoposide given once every 4 weeks, while the other
patients were followed without postenucleation therapy. Preliminary results (published in
abstract form) indicate that 2 of 93 (2.2%) patients treated with chemotherapy suffered
extraocular recurrences (68).
While the COG ARET0332 results are very impressive, it was a nonrandomized trial and
the risk to similar patients observed without chemotherapy might be comparable. For
example, Argentine investigators reported 167 patients with isolated choroidal invasion (35
with massive invasion) encountered from 1989 to 2010. Most (n = 136) did not receive
adjuvant therapy and the probabilities of 5-y ear event-free and overall survival were 98.1%
and 98.7%, respectively. Children with massive invasion had statistically significantly lower
event-free survival than those with lesser invasion (94.2% vs. 99.2%), but that did not impact
overall survival (98.7% vs. 99.2%) (69).
Similarly, patients with isolated postlaminar optic nerve invasion may fare well without
adjuvant therapy. We and the Buenos Aires group reviewed our experiences regarding 224
patients with unilateral retinoblastoma whose ey e had been enucleated as the primary
therapy from 1980 to 2001. Twenty -five patients had isolated postlaminar optic nerve
invasion, without major choroidal and/or sclera invasion. Four received chemotherapy and 21
were observed and no patient suffered a recurrence (70).
We believe that it remains unclear whether patients with isolated choroidal or
postlaminar optic nerve invasion should receive adjuvant chemotherapy. While it is possible
that adjuvant therapy may reduce the risk of development of overt extraocular disease, at
best it is likely to be a small reduction and whether or not that outweighs the risks and
inconvenience of unnecessary treatment for the others remains controversial.
TREATMENT OF OVERT EXTRAOCULAR DISEASE
Regional Extraocular Disease

Patients with stage 2 or 3 disease (optic nerve margin positivity, orbital or regional nodal
disease) may be cured with sy stemic chemotherapy and EBRT.
Patients with orbital disease historically had a poor prognosis when treated with surgery
with or without radiation therapy (71), but the addition of sy stemic chemotherapy was
associated with an improved outcome (1-y ear event-free survival of 40%) (72,73). More
recent publications have confirmed that patients with stage 2 or 3 retinoblastoma may be
cured with conventional chemotherapy and EBRT. Argentine investigators at the Garrahan
Children’s Hospital treated 15 patients with orbital or preauricular nodal disease on two
consecutive protocols. Treatment included chemotherapy (vincristine, doxorubicin, and
cy clophosphamide on local protocol 87 or vincristine, idarubicin, cy clophosphamide,
carboplatin, and etoposide on local protocol 94) followed by EBRT (45 Gy administered up to
the chiasm for patients with orbital disease and to the involved nodes in patients with
preauricular adenopathy ). The 5-y ear event-free survival was 84%. A combined report from
the Garrahan and New York groups reported the results of 12 patients with optic nerve margin
positivity treated with the chemotherapy regimens above and orbital radiation therapy (40–45
Gy ). All 12 were event-free survivors (70).
Similar results were reported by investigators from Sao Paulo, Brazil. Their patients
were treated with chemotherapy (vincristine, doxorubicin, cy clophosphamide, cisplatin, and
teniposide from 1987 to 1991, or ifosfamide, etoposide, cisplatin, and teniposide from 1992 to
2000) followed by EBRT (40–50 Gy to the orbit). Triple intrathecal therapy was also
administered. The treatment was successful in 20 of 32 patients (63%) with orbital disease
and 22 of 29 (76%) with optic nerve margin positivity (74).
We recently reported a large experience regarding orbital disease, although it does
include patients with stage 4 disease (75). We retrospectively reviewed 1674 consecutive
patients undergoing enucleations between 1914 and 2006. Seventy -one patients (4.2%)
suffered an orbital recurrence at a mean of 6 months (range 1–24 months) postenucleation.
Fifty patients died of metastatic retinoblastoma, but 10 of 11 patients (91%) diagnosed with
orbital disease after 1984 were alive and well.
Stage 4a Disease
In contrast to patients with stage 2 or 3 disease, patients with stage 4a or 4b metastatic
retinoblastoma fare poorly when treated with conventional chemotherapy and EBRT. Two
reports from Argentina and Brazil noted that only 1 of 40 patients survived following
treatment with conventional dose chemotherapy and radiation therapy (74,76).
However, patients with stage 4a retinoblastoma are potentially curable when their
treatment is intensified to include high-dose chemotherapy with autologous stem cell rescue
(ASCR). A number of groups from around the world have demonstrated in small series that
various high-dose chemotherapy regimens with ASCR appeared promising with
approximately two-thirds of patients achieving event-free survival (77,78,79,80,81,82).
Page 106Our group has reported the largest experience that we are aware of regarding
the use of intensive multimodality therapy for patients with stage 4a retinoblastoma (83). We
treated 15 patients with bone marrow (n = 14), bone (n = 10), orbit (n = 9), and/or liver (n =
4) disease. Induction chemotherapy usually consisted of vincristine, cy clophosphamide,
cisplatin, and etoposide. The high-dose chemotherapy regimen included carboplatin and
thiotepa alone (n = 1) or with etoposide (n = 5) or topotecan (n = 7). Bone marrow cleared at
first postinitiation of chemotherapy examination in all patients and stem cells were harvested
after a median of 3.5 cy cles of chemotherapy (range 3–6 cy cles). Two patients progressed
prior to high-dose chemotherapy and died. Thirteen received high-dose chemotherapy at a
median of 6 months postdiagnosis of metastases (range 4–8 months). Ten were
retinoblastoma-free in first remission at a median follow-up of 103 months (range 34–202
months) while three recurred (two in the CNS, one in the mandible) 14–20 months
postdiagnosis of metastases. Retinoblastoma-free and event-free survival at 5 y ears were
67% (95% confidence interval 38–85%) and 59% (95% confidence interval 31–79%). Six of
the 10 survivors received radiation therapy, and three developed secondary osteosarcoma 14,
4, and 9 y ears after diagnosis of metastatic disease. We concluded that intensive
multimodality therapy including high-dose chemotherapy with autologous hematopoietic
stem cell rescue was curative for the majority of patients with stage 4a metastatic
retinoblastoma treated and that the contribution of EBRT is unclear.
CNS Retinoblastoma: Stage 4b and Trilateral Disease

Retinoblastoma may metastasize to the CNS (stage 4b disease), but may also develop as an
independent focus of tumor in the pineal or suprasellar region, known as trilateral
retinoblastoma. About 1.5% of bilateral patients develop trilateral disease, though children
with a family history of retinoblastoma who receive EBRT in the first month of life appear to
have a significantly higher risk (84).
Trilateral retinoblastoma had invariably been fatal in patients who presented with
sy mptoms and/or a tumor greater than 15 mm in size when treated with conventional
chemotherapy and/or EBRT (85), but their prognosis appears to have improved when
intensified therapy including high-dose chemotherapy with ASCR was introduced (86). We
conducted a multicenter retrospective review of 13 patients treated with intensive
chemotherapy, defined as the intention to include high-dose chemotherapy with autologous
hematopoietic stem cell rescue. Their sites of disease were pineal (n = 11) and suprasellar (n
= 2). Seven patients had localized (M-0) disease and six had leptomeningeal dissemination
(M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intraocular
retinoblastoma while eight later developed trilateral disease at a median of 35 months (range
3–60 months) following diagnosis of intraocular retinoblastoma. Their induction
chemotherapy generally included vincristine, cisplatin or carboplatin, cy clophosphamide,
and etoposide. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan
and cy clophosphamide (n = 3). One patient died of toxicity (septicemia and multi–organ
sy stem failure) during induction and three developed disease progression prior to high-dose
chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months
(range 4–9 months) postdiagnosis of trilateral disease. Five patients were event-free survivors
at a median of 77 months (range 36–104 months) and never received EBRT. Four of seven
patients with M-0 disease were event-free versus only one of six patients with M-1+ disease.
We concluded that intensive chemotherapy is potentially curative for some patients with
trilateral retinoblastoma, especially those with M-0 disease and a recent meta-analy sis of
trilateral retinoblastoma concurs (87).
Similarly, stage 4b retinoblastoma (CNS metastatic disease) had been lethal in virtually
all cases reported. Our retrospective series included eight patients, seven of whom had
leptomeningeal disease and one patient with only direct extension to the CNS via the optic
nerve (88). Three patients had stage 4b disease at the time of original diagnosis of the
intraocular retinoblastoma while five had later onset at a median of 12 months (range 3–69
months). Induction chemotherapy included cy clophosphamide and/or carboplatin with a
topoisomerase inhibitor. High-dose chemotherapy regimens were carboplatin and thiotepa
with or without etoposide (n = 3) or carboplatin, etoposide, and cy clophosphamide (n = 2).
One patient died of toxicity (septicemia and multiorgan sy stem failure) during induction and
two had disease progression prior to high-dose chemotherapy. Five patients received high-
dose chemotherapy at a median of 6 months (range 4–6 months) postdiagnosis of stage 4b
disease. Two patients survive event-free at 40 and 101 months; one was irradiated following
recovery from the high-dose chemotherapy. We concluded that intensive multimodality
therapy may be beneficial for some patients with stage 4b retinoblastoma.
These experiences were the basis for a recently completed Children’s Oncology Group
prospective, multi-institutional and international treatment protocol (COG ARET 0321) (24).
Patients with stage 2 or 3 regional extraocular retinoblastoma (orbital disease, regional nodal
disease, and/or optic nerve margin positivity ) were treated with aggressive conventional
chemotherapy (vincristine, cisplatin, cy clophosphamide, etoposide) and involved-field EBRT.
Those with stage 4a or 4b or trilateral retinoblastoma received the same aggressive
conventional induction chemotherapy, had autologous stem cells harvested, received high-
dose carboplatin, thiotepa and etoposide with ASCR, and, depending on response to induction,
were considered for involved-field EBRT. The study has completed accrual and the outcome
results are expected to be released in 2016.
PALLIATION OF METASTASES
For painful bone metastases, palliative radiotherapy is appropriate and highly effective.
Depending upon field size, location, and life expectancy, ty pical palliative regimens of 3 Gy
× 10 fractions, 4 Gy × 5 fractions, or 8 Gy × 1 fraction may be used. Because retinoblastoma
is a highly radiosensitive tumor, high-dose stereotactic body radiotherapy (SBRT) is not
necessary. In the palliative setting, radiotherapy may be used liberally to relieve sy mptoms
since secondary cancers are no longer a concern.
LATE EFFECTS
Page 107Secondary Nonocular Tumors

Retinoblastoma patients are at very high risk of developing second neoplasms and this is a
consequence of a combination of genes and environment (89). Ten y ears before the RB1
gene was cloned it was recognized that despite unilateral retinoblastoma being more common
worldwide, the majority of patients who developed subsequent neoplasms had been treated
for bilateral retinoblastoma (90). The risk appeared similar for unilateral patients with the
genetic form (those with multifocal tumors, positive family history, molecular identification
of a germline mutation and often in children diagnosed in the first y ear of life) which was
much higher than unilateral patients without the genetic form (91). These patients were at risk
even if only enucleations had been done and there was no exposure to EBRT or
chemotherapy (92). Without exposure to EBRT one-third of the subsequent neoplasms were
in the head and two-thirds elsewhere and the mean latent period many y ears after
retinoblastoma diagnosis.
EBRT, however, altered the timing, location, and survival of these patients. With EBRT,
two-thirds of the neoplasms developed in the head in a shorter latency period, and mortality
from these exceeds 50% (93,94). A dose response curve for second cancers exists (95), and
at doses of 60 Gy, the incidence of second cancers was increased by more than tenfold (96).
Retinoblastoma patients who had lipomas were also at higher risk for the development of
second cancers (97). There is a significant relationship between age at exposure to EBRT and
incidence of second neoplasms. Children treated with EBRT in the first y ear of life are at a 2-
to-8-times increased risk for developing these second neoplasms in the head (44,98). The
most common second malignancy in children receiving EBRT is a soft tissue sarcoma
(leiomy osarcoma) with osteosarcoma the next most common (99). Sarcomas are the most
common malignancy seen in tumors outside the field of radiation and in nonirradiated
children with a germline RB1 mutation.
Although sarcomas represent the majority of second cancers in retinoblastoma patients,
more than 50 distinct tumors have been reported, and cutaneous melanoma is one that
appears to be unrelated to radiation exposure. It may be more common in patients with the
hereditary form of bilateral retinoblastoma than the sporadic form of retinoblastoma (100). It
is not known if these melanomas are related to ultraviolet exposure. EBRT may also play a
role in the development of breast cancer in girls who do not have germline disease as an
increase in breast cancer has been shown in this group (101).
Exposure to chemotherapy (especially topoisomerase inhibitors) in patients with or
without germline disease increases the chance of secondary AML (102) and that has not been
reported in retinoblastoma patients who have not been exposed to sy stemic chemotherapy. A
number of reports have suggested that children who receive EBRT and chemotherapy (and
different chemotherapies from different centers) are at a higher risk for the development of
second cancers (mostly sarcomas) (96).
Overall 50% of patients with a second malignancy die from their second cancer. Those
who survive are at risk to develop a third (103), fourth, and even fifth malignancy —often of
the same histology but in different locations (104).
Some centers have screening programs for second cancers but there is not universal
agreement on the modality, frequency, or body part to be screened. At Memorial Sloan
Kettering Cancer Center (MSKCC), we perform MRI of the brain–orbit at diagnosis and then
y early until teenage y ears when we do whole body bone marrow MRI scans (105).
Following that, we again do y early MR of the brain–orbit and encourage skin exams and
gy necologic evaluation.
Cataracts
The natural lens of the ey e is particularly sensitive to radiation and cataracts (mainly
subcapsular) are a well-known consequence of treatment. The link between exposure to
ionizing radiation and cataract formation was first recognized in survivors of the atomic
bomb, nuclear plant workers, and later in patients treated with radiation for head and neck
cancers. The mechanism of damage is unclear but is speculated to involve free-radical
formation and inefficient dissipation of heat. Studies suggest that a minimum of a single 2 Gy
dose or a cumulative dose of 5.5 Gy over 3 months is sufficient to cause a cataract. Delivery
method, energy of the source, dose per fraction, location and size of tumor, and age of patient
heavily influence development of a lenticular opacity. The latency of cataract formation
ranges from 6 months to 30 y ears, and an average of 2–3 y ears.
Radiation-induced cataracts after EBRT for retinoblastoma can be removed successfully
and vision can be corrected. Brooks et al. (106) removed cataracts in 38 patients with
retinoblastoma (42 ey es) from 1973 to 1989. Nineteen ey es (45%) had final visual acuities of
20/20 to 20/50, while the 12 ey es (29%) with macular tumors had postoperative visual acuities
of 20/80 to counting fingers. The risks of cataract removal after retinoblastoma treatment
include ambly opia, retinal detachment, and the risk of tumor dissemination if retinoblastoma
was not controlled.
Orbital Development
Children treated with EBRT or enucleation are at significant risk for orbital and midfacial
growth retardation. Radiation to the ossification centers may cause bone growth arrest,
necrosis of cartilaginous structures, and bony deformities. In long-term survivors of
retinoblastoma, these orbital growth abnormalities may be apparent. Over the y ears,
investigators have sought to quantify the changes in orbital development. Imhof et al. (107)
examined children treated at Utrecht University Hospital in the Netherlands and followed for
a mean of approximately 8 y ears. Direct measurements were made of the orbital width and
height and the orbital–tragus distance. In general, high-dose-per-fraction EBRT had been used
(3 Gy per fraction × 15 = 45 Gy, 8-MV photons). The mean orbital width, height, and
distance between the tragus and the outer orbital edge were significantly shorter in irradiated
orbits compared with nonirradiated orbits in patients with unilateral retinoblastoma and
compared with control ey es. Enucleation with EBRT was not worse than EBRT alone. Other
groups have reported similar findings.
Page 108Hy potelorism, enophthalmos, depressed temporal bones, atrophy of the
temporalis muscle, anophthalmic socket sy ndrome, and narrow and deep orbits have been
reported (108). These effects are accentuated if EBRT is used in the very y oung (less than 6
months of age) and at dosages greater than 35 Gy (109).
Ocular Surface Dryness

EBRT may disrupt many of the key structures that produce the tear film constituents, and
places the patient at risk for dry ey es. For example, EBRT-induced atrophy of the lacrimal
gland and meibomian glands/conjunctival goblet cells occur at 50–60 Gy and 30 Gy,
respectively. This is turn causes reductions in the aqueous, lipid, and mucin components of the
tear film. When all three elements of the tear film are dy sfunctional, it is inevitable that dry
ey es will result.
Imhof et al. (110) studied lacrimal function in 45 ey es of 34 irradiated patients who
underwent tear function tests, with a mean of 86 months after irradiation. Irradiated ey es had
significantly less tear production and significantly less tear protein production than a control
group. Although many radiation oncologists attempt to shield the lacrimal gland, some long-
term survivors of retinoblastoma have diminished tears and diminished stability of the tear
film. Such children may be prone to keratopathies. Keratitis as a side effect of irradiation for
retinoblastoma has been reported with vary ing frequencies: 28% by Imhof et al., 3 of 30
patients (10%) treated at less than 1 y ear of age, and 2 of 15 patients (13%) treated after 1
y ear of age by Fontanesi et al. (32).
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CH A P TER 6
Neuroblastoma
Katherine K. Matthay, Steve E. Braunstein, Daphne Haas-Kogan, and Louis S.
Constine
PAGE 111NEUROBLASTOMA
Neuroblastoma (NB) is a malignancy derived from embry onic neural crest cells of the
peripheral sy mpathetic nervous sy stem. It is the most common extracranial solid tumor of
childhood, accounting for 15% of cancer-related deaths. The behavior of NB is marked by
clinical heterogeneity that leads to differences in behavior ranging from spontaneous
maturation in some patients to inexorable rapid metastatic progression in others. It was noted
as early as 1927 to be a tumor in which spontaneous maturation could occur, when Cushing
and Wolbach (1) reported the case of a 2-y ear-old boy whose thoracic paravertebral
sy mpathetic NB, over the course of 10 y ears, transformed into a completely differentiated
ganglioneuroma. However, advanced NB is the most lethal of childhood solid tumors, often
resistant to all attempts at disease eradication. The enigmatic behavior of this tumor is
beginning to be elucidated by new research into the genetic and biologic diversity, but the
treatment of advanced disease is a continuing challenge. This chapter discusses the biologic
features of NB associated with differing behavior, the evaluation and staging, and a risk-based
approach to therapy, with an emphasis on local control issues.
EPIDEMIOLOGY AND SCREENING
There are approximately 710 cases of NB annually in the United States, with an overall
incidence of 10.3 per million per y ear from birth to the age of 15 y ears. NB accounts for
nearly 10% of pediatric cancer in children y ounger than 15 y ears, making it the fourth most
common malignancy in children after leukemias, brain tumors, and ly mphomas. However, it
is the most common malignancy of children y ounger than 1 y ear, with an incidence of
nearly 60 per million, and about 20 per million in those aged 1–5 y ears (2). Ninety percent of
patients with NB are diagnosed by 10 y ears, 79% before 4 y ears, and 36% are infants
y ounger than 1 y ear. The incidence is slightly higher in boy s than in girls and is more
common in whites than in other race or ethnicities. The median age at diagnosis is 22 months.
NB is responsible for 15% of childhood cancer mortality, with an annual mortality rate of 5
per million for all children and 9 per million for the 0- to 4-y ear-old subgroup, although the
survival has increased over the past two decades (2).
NB arises from primitive (fetal) adrenergic neuroblasts of neural crest tissue, which
may explain its high incidence in infancy. In the embry o, continuous columns of neural crest
tissue form dorsolateral to the developing neural tissue. These columns are the precursors of
the spinal ganglia, the dorsal spinal nerve roots, and the chromaffin cells, which flank the
abdominal aorta. The largest of these masses is the adrenal medulla (Fig. 6.1 ). Most cases
of NB occur in an anatomic distribution consistent with the location of neural crest tissue (Fig.
6.2 ).
Page 112Several studies using sy stematic screening of neonates for NB have confirmed
the results of earlier autopsy studies by suggesting a much higher incidence of NB than is
clinically evident. More than 90% of NBs secrete vanilly lmandelic acid (VMA) or
homovanillic acid (HVA) in the urine, for which rapid quantitative screening methods have
been developed that have a high degree of sensitivity and specificity. Urinary catecholamine
screening for NB was initially proposed because the incidence of 8.7 per 1 million children
per y ear is comparable to or higher than that of other congenital diseases for which screening
is already in place, such as hy pothy roidism, galactosemia, and pheny lketonuria. The poor
prognosis for advanced NB in children older than
12 months at diagnosis compared with the
favorable outcome for those diagnosed in
infancy raised the expectation that diagnosis at
an earlier age might improve overall outcome.
However, the cumulative data from 30 y ears of
screening in Japan, the Quebec Neuroblastoma
Screening Project, and screening projects in
Europe have shown that screening infants by 6
months of age results in a significant increase in
the overall incidence of NB but fails to reduce
the incidence of advanced-stage disease with
poor prognosis. A publication from the Quebec
project conclusively showed that screening at 3 Figure 6.1 Migration of the neural
weeks and 6 months in a cohort of 476,654 crest in the human embryo.
infants born over a 5-y ear period had no impact
on overall mortality for the screened cohort compared with multiple control populations from
Minnesota, the Delaware Valley, Florida, and the rest of Canada, verify ing the results of the
earlier studies (3). A second study screened 1,475,773 children at 1 y ear of age in German
states and similarly revealed no impact on outcome (4). The screened group and children in
the control area had a similar incidence of stage 4 NB (3.7 cases per 100,000 screened
children and 3.8 per 100,000 controls) and a similar rate of death among children with NB
(1.3 deaths per 100,000 screened children and 1.2 per 100,000 control subjects). There was a
substantial rate of overdiagnosis in the screened group of children without benefit from the
screening.
The environmental and inherited factors involved in the pathogenesis of NB are largely
unknown, despite extensive epidemiologic and genetic studies. Given the y oung age at which
most NBs present, it has been suggested that environmental exposures before conception or
during pregnancy increase the risk of NB. Epidemiologic investigations have implicated fetal
exposure to diuretics, tranquilizers, hormones, pheny toin, alcohol, and tobacco as increasing
the risk of NB. However, these studies have lacked the statistical power to convincingly
demonstrate that these drugs are etiologic risk factors or have not been confirmed by
subsequent studies.
Although NB usually occurs sporadically, 1–2% of patients have a family history of the
disease. Familial NB is inherited in an autosomal dominant Mendelian fashion with
incomplete penetrance. Affected children from these families differ from those with
sporadic disease in that they are often diagnosed at an earlier age (usually infancy ) or they
have multiple primary tumors. Both germline
mutation and different hereditary -predisposition
loci may predispose to neuroblastoma. Multiple
groups have recently identified the anaplastic
ly mphocy te kinase (ALK) gene as a
predisposition gene in familial NB, responsible
for 80% of the familial cases, which is also
mutated in 10 to 15% of tumors from sporadic
NB (5). Other possible predisposition genes
include germline p53 mutations, as well as SNPs
identified in GWAS studies, including CASC15,
FLJ44180, BARD1, LMO1, HSD17B12,
DDX4/IL31RA, DUSP12, HACE1, LIN28B, and Figure 6.2 Common locations of
NBPF23. NB cases are also detected in other primary tumors in neuroblastoma. The
familial cancer congenital sy ndromes, including percentage is derived from data on 8369
Beckwith–Wiedemann sy ndrome, Li–Fraumeni tumors from the International
sy ndrome, Noonan sy ndrome (PTPN11), some Neuroblastoma Risk Group project.
subty pes of Fanconi anemia, and some Tumors arising in the neck and thorax
chromosomal breakage sy ndromes (6). NB has were significantly more common in
also been seen in several patients with children <18 months of age. (Data are
constitutional chromosomal rearrangements, from Vo KT, Matthay KK, Neuhaus J, et
including deletions overlapping putative tumor al. Clinical, biologic, and prognostic
suppressor loci at chromosome bands 1p36 and differences on the basis of primary tumor
11q14–23 (7). NB has been reported in patients site in neuroblastoma: a report from the
with other neural crest disorders such as the international neuroblastoma risk group
Hirschsprung disease and central hy poventilation project. J Clin Oncol. 2014;32:3169–76.)
sy ndrome; these cases are associated with a
germline mutation at chromosome 4p12 (PHOX2B gene) (6).
Figure:
Migration of the neural crest in the human embryo.
Figure:
Common locations of primary tumors in neuroblastoma. The percentage is derived from
data on 8369 tumors from the International Neuroblastoma Risk Group project. Tumors
arising in the neck and thorax were significantly more common in children <18 months of
age.
(Data are from Vo KT, Matthay KK, Neuhaus J, et al. Clinical, biologic, and prognostic
differences on the basis of primary tumor site in neuroblastoma: a report from the
international neuroblastoma risk group project. J Clin Oncol. 2014;32:3169–76.)
BIOLOGY
Page 113Cy togenetic and molecular studies in NB are providing new insights into its biology
and prognosis. Unfavorable biologic features include amplification of MYCN, deletion or loss
of heterozy gosity of chromosome 1p or 11q, and gains at 17q. In addition, any segmental
losses have been shown to be unfavorable in MYCN-nonamplified tumors (8). Favorable
biologic features include hy perdiploidy and overexpression of Trk A (9). Recognizing these
biologic pathway s in NB has improved the ability to treat children with risk-based therapy and
may lead to novel therapeutic approaches in the near future (Table 6.1 ).
Table 6.1 Genetic Aberrations in Neuroblastoma That Are Found at Diagnosis
MYCN amplification was the first, and is now the most widely accepted, biologic marker
of prognosis for NB (10). MYCN is in the family of MYC oncogenes that encode
transcriptional regulatory factors involved in the control of other genes. The amplification is
generally a consequence of an aberrant gain of multiple copies of the MYCN gene.
Homogeneously staining regions (HSRs, nonbanding regions of metaphase chromosomes that
stain homogeneously ) and double-minute chromatin bodies (fragments of HSRs) are a
manifestation of gene amplification. They are derived from the distal short arms of
chromosome 2, which contains the proto-oncogene MYCN. The excess number of MYCN
genes leads to overexpression of the n-my c protein and subsequent overproduction of growth-
promoting signals and stimulation of proliferation and tumorigenesis. Mice with aberrant
overexpression of MYCN develop NB, providing evidence that MYCN play s a prominent role
in NB development (11). MYCN amplification is most easily detected on fluorescent in situ
hy bridization of fresh tumor imprints, although it may also be tested by
immunohistochemistry, Southern blot, or poly merase chain reaction. Recent studies also show
that circulating MYCN DNA can be detected in advanced-stage NB with MYCN amplification
with a sensitivity of 75–85% (12).
Amplification of MYCN in primary NB has been shown to correlate with advanced stage
and a poor prognosis. Such amplification occurs in 30–40% of advanced-stage NB but in only
5–10% of low-stage or 4S disease and not at all in benign ganglioneuromas (13). Children who
have MYCN amplification in their tumor need more intensive or novel therapy to control the
disease. MYCN usually is an independent prognostic factor such that amplification portends an
unfavorable outcome, even in disease settings that would otherwise be favorable. MYCN
amplification is seldom identified in localized-stage disease (stage 1 and 2) or in stage 4S, but
may predict a poor outcome in these patients when present (14). Amplified MYCN is more
common in tumors from children older than 1 y ear with advanced stage and elevated ferritin,
neuron-specific enolase, lactate dehy drogenase, and chromosome 1p deletion (13).
Page 114DNA ploidy is also an important discriminator of response to chemotherapy for
NB. In infants with metastatic disease, the progression-free survival (PFS) was more than
90% for those with hy perdiploid tumors and 0% in diploid cases. Hy perdiploid tumors also
appear to counteract the unfavorable impact of MYCN amplification in low-stage tumors (14).
Ploidy is probably less useful as a prognostic marker in children older than 24 months, in
whom most tumors are diploid.
Specific chromosomal deletions often are present in NB. Deletion of the short arm of
chromosome 1 occurs in 30–50% of primary tumors and usually occurs at the distal end of
chromosome 1 in the area of 1p36. Loss of chromosome 1p strongly correlates with MYCN
amplification and is also associated with a poor prognosis. Loss of heterozy gosity of 1p in
tumors without MYCN amplification is an independent prognostic marker of outcome,
although this prognostic value is lost in MYCN-amplified tumors (15).
Partial gains at chromosome 17q are another common genetic alteration and are
associated with an adverse outcome. Gains on chromosome 17q have been linked to several
prognostic factors: age greater than 1 y ear, advanced-stage disease, deletion of chromosome
1p, and amplification of MYCN. It is the most common genetic alteration found in NB,
occurring in 50% of cases. However, whether 17q gain is an important independent marker of
prognosis has not y et been verified in a larger prospective multivariate analy sis.
In addition to gains and losses of genetic material, other genes that have been identified
as prognostically important include nerve growth factor receptor expression, telomerase
activity, and genes involved in invasion and metastasis, though currently these are not used in
clinical risk stratification. High levels of telomerase activity or rearrangements in the TERT
gene may also predict an aggressive tumor phenoty pe (16). Specific mutations are rare in
neuroblastoma, present in only about 10% of 240 tumors at diagnosis studied with next-
generation sequencing. The most commonly affected gene was ALK, mutated in nearly 10%
of cases. Other mutations found in 7 and 6 tumors, respectively, were PTPN11 and ATRX (17).
Figure: Genetic Aberrations in
Neuroblastoma That Are Found at Diagnosis
PATHOLOGY
NB is one of the small blue round cell tumors, along with the non-Hodgkin ly mphoma, Ewing
sarcoma, rhabdomy osarcoma, undifferentiated soft tissue sarcomas, and primitive
neuroectodermal tumors. The classic histologic subty pes of neuroblastic tumors include NB,
ganglioneuroblastoma, and ganglioneuroma, reflecting a pattern of increasing maturation and
differentiation (18). The cells of NB are small and uniformly sized, with dense
hy perchromatic nuclei and scant cy toplasm (Fig. 6.3 ). The cells may be densely packed,
separated by thin fibrils or bundles, and necrosis and calcification can occur. Neuritic
processes can be demonstrated in most cases, and pseudorosettes can be seen in 15–50% of
cases. The other end of the spectrum, ganglioneuroma, has mature ganglion cells, neuritic
processes, and Schwann cells and has more fibrillary material. Patients with ganglioneuroma
or ganglioneuroblastoma generally have localized tumors with favorable biologic
characteristics, explaining the excellent associated prognosis.
The most widely accepted sy stem of histologic classification is now the International
Neuroblastoma Pathology Committee Classification (INPC) (18), summarized in Table
6.2 . It is based on the highly prognostic sy stem developed by Shimada et al. (18) using
patient age, the presence of stroma (“rich” or “poor”) and nodularity, the degree of
differentiation, and the mitosis–kary orrhexis index (MKI). Differences between the original
Shimada classification and the INPC are (1) to subdivide the “undifferentiated” subty pe in the
former classification into two subty pes of undifferentiated and poorly differentiated in the
latter classification, based on the degree of cellular density and the number of tumor cells and
MKI (Fig. 6.4 ); and (2) to change the name of “stroma-rich, well differentiated” in the
former classification to “ganglioneuroma, maturing.” The INPC, based largely on the
Shimada sy stem, is now being used in protocols worldwide to facilitate comparisons of patient
groups. A retrospective analy sis of the Children’s Cancer Group (CCG) validated the
prognostic value of this sy stem combined with age (19). An additional modification in 2003
clarified the favorable and unfavorable subsets of ganglioneuroblastoma, nodular (20).
Finally, by international consensus, it was shown
that even if age were taken out of the INPC,
diagnostic category, MKI, and grade of
differentiation each had independent prognostic
significance (9).
Figure 6.3 A: Fine-needle aspirate of

neuroblastoma, showing typical Homer–
Wright pseudorosettes with
neurofibrillary material in the center. B:
Differentiating neuroblastoma,
Schwannian stroma-poor. C:
Neuroblastoma (Schwannian stroma-
poor), poorly differentiated subtype,
composed of undifferentiated
neuroblastic cells with clearly
recognizable neuropil. (From Shimada H,
Ambros IM, Dehner LP, et al. Terminology
and morphologic criteria of neuroblastic
tumors: recommendations by the
International Neuroblastoma Pathology
Committee. Cancer. 1999;86(2):349–363,
with permission.) (See color plate.)
Figure 6.4 The computed tomography

scan shows a large retroperitoneal
neuroblastoma that encases the
abdominal aorta and displaces the
inferior vena cava. The left kidney is
pushed laterally, and calcifications are
evident.
Page 115
Table 6.2 International Neuroblastoma Pathology Committee System

Figure:
A: Fine-needle aspirate of neuroblastoma, showing typical Homer–Wright pseudorosettes
with neurofibrillary material in the center. B: Differentiating neuroblastoma, Schwannian
stroma-poor. C: Neuroblastoma (Schwannian stroma-poor), poorly differentiated subtype,
composed of undifferentiated neuroblastic cells with clearly recognizable neuropil.
(From Shimada H, Ambros IM, Dehner LP, et al. Terminology and morphologic criteria of
neuroblastic tumors: recommendations by the International Neuroblastoma Pathology
Committee. Cancer. 1999;86(2):349–363, with permission.) (See color plate.)
Figure:
The computed tomography scan shows a large retroperitoneal neuroblastoma that encases
the abdominal aorta and displaces the inferior vena cava. The left kidney is pushed laterally,
and calcifications are evident.
Figure: International Neuroblastoma
Pathology Committee System
CLINICAL PRESENTATION AND EVALUATION
The clinical presentation of NB depends on the site along the sy mpathetic nervous sy stem
chain from which the primary tumor develops (Fig. 6.2 ) and on the manifestations of
metastatic disease. This varies according to patient age. The abdomen is the most common
primary tumor location (50–80% of cases), and is most likely to have a less favorable
prognosis (21). Intra-abdominal primary tumors arise in the adrenals or in a paraspinal
location. The paraspinal tumors may have a dumbbell configuration wherein tumor extends
through the neural foramina and presents with a mass lesion in the spinal canal; extradural
spinal cord compression may occur. Extra-abdominal locations of the primary tumor, which
rarely exhibit MYCN amplification and have a more favorable prognosis, include sy mpathetic
ganglia in the neck (often initially thought to be ly mphadenitis), posterior mediastinum, and
pelvis (21).
Page 116The earliest sy mptoms or signs of NB may be a palpable abdominal mass
(often large, firm, irregular, and crossing the midline), a unilateral neck mass often causing
the Horner sy ndrome, spinal cord compression, respiratory compromise caused by thoracic
disease or hepatic metastases placing upward pressure on the diaphragm, or bowel and
bladder disturbances caused by compression from a pelvic mass. About 60% of children with
NB have metastatic disease (either ly mphatic or hematogenous) at the time of clinical
presentation. The sy mptoms in this setting are those of sy stemic illness: fever, weight loss,
weakness, or a general failure to thrive. In a few patients, the presenting sy mptoms are
related to secretory products of the tumor. For example, intractable diarrhea (from
vasoactive intestinal poly peptide) may rarely occur, usually in children with
ganglioneuroblastoma or ganglioneuroma. In another rare paraneoplastic sy ndrome, seen in
about 3% of patients, a child with NB presents with the opsoclonus (rapid multidirectional ey e
movements)–my oclonus–truncal ataxia sy ndrome. This paraneoplastic sy ndrome is
associated with early -stage NB; it is probably caused by development of antineuronal
antibodies, and neurologic deficits usually persist despite cure of the tumor (22). Bone
metastases present as pain, refusal to walk, skull masses, or proptosis with orbital ecchy mosis.
Skin metastases are common in neonates and generally have a blue tinge (the “blueberry
muffin” sign). NB may infiltrate the marrow and cause pancy topenia with resulting
complications (infection, pallor, lethargy, bleeding). Intracranial metastatic disease is rare,
seen in less than 2% of patients at diagnosis, and may be parenchy mal or meningeal, and in
infants it may cause cranial suture separation (23).
The standard diagnostic evaluation of NB
(Table 6.3 ) includes imaging and laboratory
testing with the goals of determining disease
extent and prognosis and identify ing markers of
disease activity. The primary tumor ty pically is
imaged radiographically and with computed
tomography (CT) scan or magnetic resonance
imaging (MRI). The classical radiographic sign
of adrenal NB is calcification in a suprarenal soft
tissue mass (Fig. 6.4 ). In the thorax, a plain
radiograph demonstrates a posterior mediastinal
mass. In both abdomen and chest, CT scan and
MRI are helpful in assessing possible ly mph
node metastases and intraspinal extension (24).
The search for distant, usually bony
metastasis must include scanning with 123I-
metaiodobenzy lguanidine (MIBG) or 18F-
fluorodeoxy glucose scan (for patients whose
tumor does not take up MIBG), with conventional Table 6.3 Clinical Evaluation of
radiographs as indicated. Bone metastases are Neuroblastoma (Minimum
most often periorbital, metaphy seal, and axial in Recommended Studies to Determine
location (Fig. 6.5 ). Bone scintigraphy is more the Extent of Disease)
sensitive than conventional radiographs but is
sometimes difficult to interpret in infants y ounger than 1 y ear. MIBG is a guanethidine
derivative that is similar in structure to norepinephrine and epinephrine. The compound is
taken up via the norepinephrine transporter into catecholaminergic cells and stored in the
chromaffin granules. It is highly sensitive and specific for skeletal and soft tissue metastases
of NB, taken up in more than 90% of primary and metastatic tumors (25). The MIBG is
labeled with 123I and scintigraphy is performed for imaging. Because MIBG depends on
functional uptake by tumor cells, it is also useful in distinguishing residual active tumor after
treatment from masses composed of scar tissue and may complement CT scans (Fig.
6.5 ). More recently, response by MIBG scan has been shown to be a useful prognostic
marker of response and survival (26). 99m Tc-diphosphonate bone scans continue to be used to
detect metastatic foci in the skeleton, in patients who are negative by MIBG, though positron
emission tomography scans with 18F-fluorodeoxy glucose are a newer modality that
complement MIBG for determination of tumor viability. Several studies have demonstrated
that positron emission tomography scanning can visualize NB, even in some cases where
MIBG is negative, although in other cases the converse is true (27).
Liver involvement may be evaluated by CT, ultrasound, or MIBG or PET scan in older
children because it is usually focal or nodular. In
infants it may be diffuse and not apparent by
imaging. For this reason, some authorities
recommend liver biopsies for diagnostic workup
of infants. Pulmonary parenchy mal metastases
rarely occur at diagnosis in NB, although at
relapse they may be seen in 7% of cases and
should be sought with CT scan. At diagnosis, lung
metastases are associated with MYCN
amplification and high lactic dehy drogenase
(LDH), and predict a worse outcome (23). In
contrast, metastases limited only to distant
ly mph nodes denote a favorable prognosis (28).
Page 117There may be extensive
involvement of the bone marrow by tumor
without a change in the peripheral blood counts,
with some bone marrow tumor present at
diagnosis in 80% of children with metastatic
disease (23). Therefore, bilateral bone marrow
aspiration and biopsy are performed routinely,
with some centers using 4–10 core biopsies to Figure 6.5 This 123I-
minimize sampling error. Small amounts of NB metaiodobenzylguanidine scan shows
cells may be difficult to distinguish from intense localization in the primary
hematopoietic elements. The diagnosis of NB in retroperitoneal mass. Widespread bone
the bone marrow can be confirmed when only metastases are evident, with large
small amounts of tumor are present with lesions in the distal right femur and
immunohistochemical stains on the core biopsy, proximal left humerus, but multiple other
often using neuron-specific enolase (NSE) as a lesions are seen on the dome of the skull,
marker, or with immunostaining on a right humerus, right rib, pelvis, and both
concentrated cy tology specimen from the femurs and tibias, and in a few
aspirate. This technology clearly is more retroperitoneal areas, probably
sensitive than conventional analy ses, detecting representing nodal spread. Physiologic
one tumor cell per 105–106 normal uptake is seen in the salivary glands,
mononuclear marrow cells. At present, tumor liver, and thyroid gland, which was
detected by immunocy tology that is not insufficiently blocked with potassium
extensive enough to be diagnosed by iodide drops.
conventional bone marrow microscopy does not
affect staging or risk group at diagnosis. Reverse transcriptase poly merase chain reaction (RT-
PCR) is being used in a number of prospective studies to further quantify the prognostic
impact of minimal residual disease (MRD) detected in blood or bone marrow after therapy.
Standardized methods for both immunocy tology and RT-PCR have been agreed upon by
international consensus (29).
NB is associated with elevated or abnormal production, secretion, and catabolism of
catecholamines (or metabolites) in 90% of cases. Catecholamines and metabolites may be
measured in the urine: norepinephrine, VMA, 3-methoxy -4-hy droxy pheny lgly col, or HVA.
Dopamine may be measured in urine or serum. Urinary catecholamines ty pically are
presented as ratios to urinary creatinine. The sy mptoms associated with excess
catecholamine production include flushing and sweating, pallor, headache, and hy pertension.
Figure: Clinical Evaluation of
Neuroblastoma (Minimum Recommended
Studies to Determine the Extent of Disease)
Figure:
This 123I-metaiodobenzylguanidine scan shows intense localization in the primary
retroperitoneal mass. Widespread bone metastases are evident, with large lesions in the
distal right femur and proximal left humerus, but multiple other lesions are seen on the
dome of the skull, right humerus, right rib, pelvis, and both femurs and tibias, and in a few
retroperitoneal areas, probably representing nodal spread. Physiologic uptake is seen in the
salivary glands, liver, and thyroid gland, which was insufficiently blocked with potassium
iodide drops.
STAGING AND PROGNOSTIC FACTORS
The criteria for diagnosis of NB recommended by the second International Neuroblastoma

Staging Sy stem (INSS) Conference are unequivocal pathologic diagnosis from tumor tissue
by light microscopy, with or without immunohistology, electron microscopy, elevated urine or
serum catecholamines or metabolites (dopamine, HVA, or VMA greater than 3.0 SD above
the mean per milligram creatinine for age); or bone marrow aspirate or biopsy containing
unequivocal tumor cells (e.g., sy ncy tia or immunocy tologically positive clumps of cells) and
elevated urine or serum catecholamines or metabolites (30). A diagnosis of NB based only on
compatible radiographic findings and elevated urinary catecholamine metabolites is
insufficient because of possible confusion with ganglioneuroma or pheochromocy toma or
even other solid tumors (e.g., primitive neuroectodermal tumor, rhabdomy osarcoma), which
can have false positive urinary findings.
Staging
Subsequent to 1993, most investigators have used the staging sy stem internationally developed
in 1989 and modified in 1993, the INSS (Table 6.4 ), in an attempt to improve and unify the
previous definitions (30). Most recently, a further modification was introduced by consensus
of the International Neuroblastoma Risk Group (INRG) Task Force (Table 6.5 ) (20).
Understanding the nuances of these sy stems is important for interpreting and accurately
comparing data from various reports and determining therapy.
The INSS was developed in order to have a uniform staging so that studies could be
compared. In classify ing tumors that cross the midline, infiltration (extending by contiguous
invasion to or bey ond the opposite side of the vertebral bodies) was chosen to identify tumors
presumably less favorable than those that are pedunculated and simply drape over the
midline. The INSS used Arabic numbers to distinguish it from the letters and Roman numerals
of the prior sy stems. However, some inconsistencies were noted due to the fact that it was a
postsurgical staging sy stem with substantial reliance on the assessment of tumor resectability
and surgical examination of ly mph node involvement. In fact, many patients with stage 3
disease do not actually undergo surgical resection at diagnosis, and many stage 2 patients do
not have extensive ly mph node sampling, resulting in possibly inaccurate staging.
Furthermore, the separation of stage 2A and 2B depending on ly mph node involvement is of
questionable prognostic value for OS, unless the tumor has unfavorable biology (31).
Therefore, four further international conferences were held from 2004 to 2006, and a new
international staging sy stem was proposed by the INRG task force in which anatomic staging
was performed by radiologic imaging, rather than surgery. In the INRGSS (International
Neuroblastoma Staging Sy stem), locoregional tumors are staged L1 or L2 based on the
absence or presence of 1 or more of 20 image-defined risk factors (IDRFs) (32),
respectively. Metastatic tumors are defined as stage M, except for stage MS, in which
metastases are confined to the skin, liver, and/or bone marrow in children y ounger than 18
months of age. Within a 661-patient European clinical trial cohort, IDRFs were present (i.e.,
stage L2) in 21% of patients with INSS 1, 45% of
patients with INSS 2, and 94% of patients with
INSS 3 disease. Patients with INRGSS stage L2
disease had significantly lower 5-y ear event-
free survival than those with INRGSS stage L1
disease (78% ± 4% vs. 90% ± 3%; p = 0.0010)
(33).
Page 118Response Criteria

International Neuroblastoma Response Criteria
(INRC) from the first international conference
are still generally used, shown in Table 6.6 ,
which takes into account some of the unique
characteristics of this tumor, such as MIBG
uptake, catecholamine excretion, and propensity
for bone and bone marrow involvement. This is
currently the best accepted method for reporting
response to treatment, which supplements the
National Institutes of Health criteria generally
used for evaluating response in phase I and II
studies, the Response Evaluation Criteria in Solid
Tumors Group. As recurrence in NB is most
often in metastatic sites in bone and bone Table 6.4 International
marrow, it is critical to be able to evaluate Neuroblastoma Staging System
response in these sites in addition to solid masses.
Further consensus conferences of the INRG
have defined quantization of response in bone
sites with a semi-quantitative MIBG score, (25),
incorporation of RECIST criteria rather than
tumor volume change, and more precise sy stem
for grading response in bone marrow by percent
tumor.
Table 6.5 International

Neuroblastoma Risk Group (INRG)
Staging System
Table 6.6 International Neuroblastoma Response Criteria

Prognostic Factors
Several clinical and biologic characteristics of NB are associated with prognosis. A study of
an international database of 8800 NB patients by the INRG showed that patients could be
stratified into four different risk groups for 5-y ear event-free survival (EFS) using age, stage,
histologic category, grade of differentiation, MYCN, 11q aberration, and ploidy. The lowest
group had an estimated 5-y ear EFS greater than 85%, while the highest risk group had an EFS
below 50% (9). However, for current practical risk stratification on cooperative clinical trials,
the most useful and independent variables are stage, age, histology, ploidy, MYCN copy
number, and loss of heterozy gosity for 1p or 11q or other segmental chromosome losses.
Clinical
Stage and age continue to be critical determinants of outcome. The disease stage strongly
influences prognosis (Fig. 6.6 ). With surgery as primary therapy, more than 90% of
children with stage 1 and 2 disease survive and 85% of children with stage 4S survive,
whereas with multimodality therapy, the survival is 60–90% for INSS stage 3 disease but only
40% for stage 4 disease (34). However, age at diagnosis is another strong determinant of
outcome, which must be factored in with stage. Originally 12 months was recognized as the
cut-off for a favorable outcome, even in advanced disease, but more recently it has been
shown that this can be extended to 18 months as long as the biology of the tumor is favorable.
Infants y ounger than 18 months of age do better than older children with the same disease
stage, an effect that is dramatic for patients with advanced stage 3 and 4 disease (35). Infants
and toddlers without MYCN gene amplification and with stage 4 disease have more than 80%
long-term survival with modest chemotherapy, whereas children older than 18 months at
diagnosis with stage 4 have less than 40% survival with very intensive therapy. This may be
related to a higher rate of spontaneous tumor regression or tumor maturation in infants (35).
On the other hand, adults and adolescents with NB have a particularly poor long-term
survival, even with disease presenting without metastases, although their course may be
prolonged (36). Response to therapy is another important clinical prognostic factor for
patients with advanced disease (26).
Page 119
Figure 6.6 Overall survival according to International NB Staging System (INSS) stage of
1034 children with neuroblastoma treated on Children’s Cancer Group protocols from 1991
to 1995. INSS stage 1, n = 195; INSS stage 2, n = 117; INSS stage 3, n = 184; INSS stage 4S, n =
64; INSS stage 4, n = 474. (Courtesy of the Children’s Cancer Group Statistical Office.)
Page 120Biologic
Several nonspecific inflammatory serum markers have prognostic value in NB, including
ferritin, LDH, and NSE. All the three are more likely to be elevated in advanced disease and
are predictive of a worse outcome in univariate analy sis. Ferritin may be produced by NB
cells and thus reflects tumor burden or growth, or it may be necessary for NB cell growth.
An elevated serum ferritin level (more than 92 ng/mL) is found in up to half of patients with
advanced-stage disease but rarely in children with localized disease. PFS is lower for children
with elevated levels (9). NSE may be useful as a marker for following the response to
treatment. LDH may reflect tumor cell burden or turnover, and serum elevations (750–1500
IU/mL) have been found in some studies to be independently associated with a worse
prognosis (9).Two neural markers found in the serum of NB patients may also be markers of
disease activity and prognosis, including GD2 and chromogranin A, though these are not part
of the standard risk stratification criteria. In summary, numerous clinical, biochemical, and
genetic risk factors have been shown to have prognostic value in various studies, but the recent
multivariate analy sis by the INRG has shown
that for practical purposes patients can be
effectively placed into risk groups for
therapeutic assignment using the readily
available clinical and genetic factors. Those that
have appeared to be consistent over many y ears
and readily available to the clinician have been
combined to form a framework for risk
stratification in current therapeutic studies. Age,
INSS stage, histopathology, tumor cell ploidy,
MYCN gene copy number, LOH 1p and 11q are Figure 6.7 Event-free survival based
the factors used in risk stratification and therapy on COG risk stratification. The event-free
assignment for the current COG clinical trials in Kaplan–Meier survival curves calculated
North America, with very similar guidelines from the time of diagnosis for 5,829
used internationally (Tables 6.8 and 6.9 ). children enrolled onto ANBL00B1 (>2001)
The survival for low and intermediate risk or onto Children’s Cancer Group,
patients by this classification is more than 90% Pediatric Oncology Group studies (<2001)
(31,35,37), and that of the high-risk group between 1990 and 2010 were classified as
remains at about 40% (Fig. 6.7 ) (34,38) low-, intermediate-, and high-risk NBL at
(Tables 6.8 and 6.9 ). diagnosis based upon clinical and biologic
factors (age, International Neuroblastoma
Staging System stage, MYCN status, DNA
copy number and histologic grading).
(Reproduced from Park JR, Bagatell R,
London WB, et al. Children’s Oncology
Group’s 2013 blueprint for research:
neuroblastoma. Pediatr Blood Cancer.
Table 6.7 International Neuroblastoma Risk Group Working Committee Modified
Response Criteria
Table 6.8 Children’s Oncology Group Neuroblastoma Risk Groups for Treatment
Table 6.9 INRG Risk Classification
Staging System
Figure: International Neuroblastoma Risk
Group (INRG) Staging System
Response Criteria
Figure:
Overall survival according to International NB Staging System (INSS) stage of 1034 children
with neuroblastoma treated on Children’s Cancer Group protocols from 1991 to 1995. INSS
stage 1, n = 195; INSS stage 2, n = 117; INSS stage 3, n = 184; INSS stage 4S, n = 64; INSS stage
4, n = 474.
(Courtesy of the Children’s Cancer Group Statistical Office.)

Figure: International Neuroblastoma Risk
Group Working Committee Modified
Response Criteria
Figure:
Event-free survival based on COG risk stratification. The event-free Kaplan–Meier survival
curves calculated from the time of diagnosis for 5,829 children enrolled onto ANBL00B1
(>2001) or onto Children’s Cancer Group, Pediatric Oncology Group studies (<2001) between
1990 and 2010 were classified as low-, intermediate-, and high-risk NBL at diagnosis based
upon clinical and biologic factors (age, International Neuroblastoma Staging System stage,
MYCN status, DNA copy number and histologic grading).
(Reproduced from Park JR, Bagatell R, London WB, et al. Children’s Oncology Group’s 2013
blueprint for research: neuroblastoma. Pediatr Blood Cancer. 2013;60:985–993, with
permission.)
Figure: Children’s Oncology Group
Neuroblastoma Risk Groups for Treatment
Figure: INRG Risk Classification
SELECTION OF THERAPY
Low-risk tumors are managed with surgery alone unless sy mptomatic cord compression or
respiratory compromise necessitates a short course of chemotherapy. Patients in the low-risk
group with stage 1 or 2 disease have an expected 4-y ear survival of more than 95% with
surgery only, whereas infants with INSS 4S have more than 90% survival with supportive
care or a short course of chemotherapy (31,39). The smaller intermediate-risk group consists
of infants and toddlers with stage 4 disease (but no tumor MYCN amplification), favorable
biology stage 3, or INSS 4S with unfavorable histology or DNA index. Patients in this group
have been shown to have an estimated survival of more than 90% with moderate dosages of
chemotherapy for 4–8 months and primary tumor resection (35,37). Radiotherapy (RT) is
rarely used in the low- or intermediate-risk groups because of their favorable prognosis and
the fact that many of these patients are y ounger than 1 y ear. It is reserved for use in life- or
function-threatening situations. It is occasionally needed for cases of unresectable primary
disease remaining after chemotherapy or regional recurrences not controlled with
chemotherapy.
Page 121The high-risk group in NB consists primarily of patients with stage 4 disease of
any age who have MYCN amplified tumors, or children age 12–18 months (365–547 day s)
with any of the following three unfavorable biologic features (MYCN amplification,
unfavorable pathology and/or DNA index = 1), and all those with stage 4 disease who are
greater than 18 months of age at diagnosis. Also included are stage 3 with either tumor MYCN
amplification or those older than 18 months with unfavorable histopathology, stage 2 above 1
y ear of age with MYCN amplification, and stage 4S infants with MYCN gene amplification.
Despite the use of increasingly aggressive combined-modality treatments, which have higher
remission rates and durations, the long-term survival for INSS stage 4 disease in children who
are older than 18 months at diagnosis has remained less than 15% until the early 1990s. The
most recent phase III studies indicate that the 3-y ear EFS of this group has steadily increased
in the past decade to up to 50% with the use of my eloablative therapy and treatment for MRD
but is still far below the desired outcome (34).
Page 122Therapy for high-risk NB is divided into three phases: intensive induction
treatment, marrow ablative therapy, and management of MRD. The goal of induction
therapy is to achieve maximum reduction of tumor burden, including reduction of bone
marrow tumor (in vivo purging), within a timeframe that will minimize the risk of resistant
tumor clones and clinical progression. During or at the end of this phase, local control of bulky
disease is accomplished with delay ed surgery and local RT, which is usually given after
my eloablative therapy. Subsequently, very high dose marrow ablative therapy may be used
to try to overcome residual and potentially resistant tumor, followed by hematopoietic cell
transplant (HCT). The relapse rate of more than 40% even after such treatment has led to the
approach of using tumor-targeted therapies after my eloablative treatment to try to eliminate
microscopic resistant clones (minimal residual disease) (34).
Chemotherapy
As indicated earlier, chemotherapy is used in low-risk disease only for recurrence or for
sy mptomatic patients with compromised organ function. Intermediate-risk patients can
achieve long-term survival with moderate combination chemotherapy for 4–8 months (35).
The most effective induction regimens for obtaining complete or partial response are
combination of platinum-based regimens including other active drugs such as
cy clophosphamide, doxorubicin, etoposide, vincristine, and ifosfamide. Induction regimens
used in recent large cooperative studies are shown in Table 6.10 , with overall response
rates generally ranging from about 60% to 80% at the end of 5–6 months of treatment
(38,40,41). Most recently, the COG has incorporated two cy cles of topotecan with
cy clophosphamide into the N7 ty pe induction, with similar response rates and successful
peripheral blood stem cell harvests (42). The European group has tested a dose-intensive
schedule in a randomized trial of 262 patients that randomly assigned 132 patients to standard
and 130 patients to rapid treatment. The relative dose intensity of the rapid regimen was 1.94
compared with the standard regimen. My eloablation was given a median of 55 day s earlier
in patients assigned to the rapid regimen. Although OS did not differ, the 5-y ear EFS was
18.2% in the standard group and 30.2% in the rapid group, representing a difference of 12.0%
(1.8–22.3), p = 0.022 (43). However, the EFS in this study was apparently not different from
other recent protocols using less dose intensive regimens. Most of these regimens also include
surgery for residual disease, although the overall impact of complete resection on survival in
stage 4 disease is still contradictory.
Table 6.10 Induction Regimens for High-Risk Neuroblastoma Since 1985 (More Than 50
Patients)
Page 123Myeloablative Therapy with Hematopoietic Stem Cell Support

My eloablative high-dose chemotherapy with or without total body irradiation (TBI) has been
incorporated as consolidation treatment for high-risk NB for the past two decades, beginning
with early studies using melphalan ablation. Numerous single arm studies using vary ing
my eloablative regimens from 1985 to about 1995 showed an apparent improvement in EFS,
usually reported from the time of transplantation. The 3-y ear EFS ranged from 26% to 62%,
with an average of about 40% for the large studies (more than 20 patients) shown in Table
6.11 (44,45,46,47,48,49,50). This approach introduced some bias into the interpretation of
results because only patients who survived for 5–6 months and responded to induction
chemotherapy were able to receive the high-dose my eloablative treatment with autologous
or allogeneic transplantation.
Table 6.11 EFS for High-Risk Neuroblastoma in First Remission Using Myeloablative
Therapy and Hematopoietic Cell Transplant for Studies of More than 20 Patients
Several retrospective comparisons of concomitant and similar groups of patients treated

with standard dosages of chemotherapy and those treated with high-dose therapy and
autologous bone marrow transplantation (ABMT) have been performed, with conflicting
assessments of the value of my eloablative therapy. Some studies showed a significantly
better outcome for patients treated with my eloablative therapy, while others did not report a
difference (49,51,52,53). A randomized prospective trial was necessary to eliminate the bias
inherent in such retrospective comparisons. The European Neuroblastoma Study Group
(ENSG) reported the earliest attempt at a randomized trial of high-dose therapy with
autologous bone marrow support for NB, with improvement noted for ABMT in the final
report (54). However, this report included only 65 randomized patients, with widely vary ing
times to ABMT. A randomized trial in Germany of my eloablative consolidation therapy
compared to a low-dose oral maintenance therapy in 295 patients again showed an advantage
for high-dose consolidation, with estimated 3-y ear EFS of 47% versus 31% (p = 0.0221) (55).
The CCG conducted the first large
prospective, randomized study from 1991 to
1996, comparing a single course of
my eloablative chemoradiotherapy supported by
purged ABMT with three cy cles of a dose-
intensive, nonmy eloablative, continuous-infusion
consolidation chemotherapy. Randomized
patients were assigned equally to ABMT (n =
189) or consolidation chemotherapy (n = 190).
Overall toxicity and total mean hospital day s
were similar between the two randomized arms.
The 3-y ear EFS was 27% for all patients, 34% ±
4% for those assigned to ABMT, and 22% ± 4%
for the cases randomly assigned to consolidation
chemotherapy (p = 0.034) (Fig. 6.8 ) (40).
The outcome advantage noted with ABMT was
also significant in the subgroups of patients with
MYCN-amplified tumors and in those who were
more than 2 y ears old at diagnosis. The 3-y ear
EFS from the time of transplantation for those
129 patients actually receiving ABMT (as-
treated analy sis) is shown to be 43% ± 6%,
similar to that of previous single-arm studies and
significantly higher than the 27% ±5% EFS of the
150 patients receiving the chemotherapy Figure 6.8 Results of CCG 3891, a
consolidation. A recent update with 8 y ears of randomized study comparing
follow-up confirmed that the EFS for patients
randomly assigned to ABMT was significantly myeloablative chemoradiotherapy and
higher than those randomly assigned to purged autologous bone marrow
chemotherapy ; the 5-y ear EFS (mean ± SE) was transplantation with intensive
30% ± 4% versus 19% ± 3%, respectively (p = nonmyeloablative therapy. A second
0.04) (56). randomization was performed on all
Page 126Different my eloablative regimens consenting patients completing the
have been used, although most are melphalan- consolidation therapy without
based. The very first my eloablative regimen progression to test the efficacy of 13-cis-
used to treat NB was high-dose melphalan alone. retinoic acid for minimal residual disease.
This progressed to various combinations of other A: Superior event-free survival (79) with
agents, including cisplatin, etoposide, and myeloablative therapy compared with
doxorubicin, melphalan with busulfan (BuMel), standard-dose chemotherapy. The
and melphalan with carboplatin and etoposide difference in 5-year EFS for the 379
(CEM). Other centers used a thiotepa base randomized patients was 30% versus
coupled with cy clophosphamide, or etoposide, or 19%, respectively (p = 0.04). B: The
busulfan combined with cy clophosphamide. difference in 5-year overall survival was
Subsequently other pilot regimens have 39% versus 30%, respectively (p = 0.39);
incorporated topotecan into the conditioning however, in patients who survived more
regimen in combination with thiotepa and than 3 years, there appears to be a
carboplatin (57). benefit of ABMT. (From Matthay KK,
Few studies have tried to compare two Reynolds CP, Seeger RC, et al. Long-term
my eloablative regimens in a randomized results for children with high-risk
fashion. However, the retrospective analy sis by neuroblastoma treated on a randomized
the European Group for Blood and Marrow trial of myeloablative therapy followed
Transplantation failed to show any difference in by 13-cis-retinoic acid: a Children’s
EFS using different high-dose regimens. An Oncology Group study. J Clin Oncol.
analy sis, from the European Bone Marrow 2009;27(7):1007–1013, with permission.)
Transplant Registry has shown that patients
treated with busulfan and melphalan appeared to have better EFS than those on other
conditioning regimens (58).
These data may depend on the chronology of the protocols and the fact that the busulfan
regimen was compared with a combination of a variety of other regimens. The European
Cooperative Neuroblastoma Group (HR-ESIOP) tested this hy pothesis in a randomized study,
comparing the COG regimen of CEM with the BuMel regimen, and showed that BuMel
resulted in a significantly superior EFS (59) although this did not appear to be a better EFS
than reported in a concurrent COG study with CEM (38). Other pilot studies have suggested
that additional benefit may be obtained from double or triple tandem transplants (60). A
recent COG trial (ANBL0532) tested the value of double tandem transplant with
thiotepa/cy clophosphamide followed by CEM compared to single ablative regimen with CEM
in a randomized phase III study. Preliminary results showed significant improvement in EFS
with the tandem approach. Phase I and II studies have now shown the tolerability and possible
benefit of combining the targeted radiopharmaceutical 131I-MIBG with carboplatin,
etoposide, and melphalan for a my eloablative regimen with responses and some long-term
survivors in patients with relapsed or refractory NB (61). A pilot trial of MIBG followed by
BuMel is underway in the COG for newly diagnosed high-risk NB (ANBL09P1).
Bone marrow involvement is present in 70–90% of stage 4 patients at diagnosis, and
residual tumor cells can still be detected in bone marrow samples by sensitive
immunodetection methods even after several cy cles of induction therapy. For this reason,
allogeneic bone marrow transplantation (BMT) has been proposed as an alternative to ABMT.
It is also hoped that the allogeneic cells will provide a further “graft=versus-NB” effect,
although the rationale for this concept is weak because NB cells express little human
leukocy te antigen (HLA) class I. To date, lack of evidence of any immunologic benefit,
coupled with the problems with frequent lack of a HLA- compatible sibling donor and the
significantly higher toxic death rates, has discouraged extensive use of allogeneic BMT. Two
reports directly compared allogeneic and autologous transplantation in NB. A CCG study
compared 36 patients receiving an autologous purged BMT and 20 patients receiving the
same induction who received allogeneic matched-sibling BMT. There was no significant
difference in relapse rate and an apparently higher toxicity in the allogeneic group. Four of
20 patients died of causes other than relapse in the allogeneic group, compared with 3 of 36 in
the autologous group (not significant); the estimated PFS was 25% for the allogeneic group
versus 49% for the autologous group (p = 0.051) (62). In a comparison from the European
Bone Marrow Transplant Registry, the 5-y ear OS favored autologous transplant: 37% for
autologous and 25% for allogeneic at 2 y ears, respectively (58).
Page 127The other way to overcome the problem of possible tumor contamination of
autologous bone marrow or stem cells is with ex vivo purging of the hematopoietic cells.
Although bone marrow and peripheral blood often show gross disappearance of tumor cells
after a few courses of chemotherapy, sensitive methods of detection with immunocy tology
and RT-PCR have shown persistence of low levels of tumor in 10–40% of hematopoietic cell
collections (38). The most common method for removal of NB cells currently employ ed is
either with immunomagnetic beads (40) or using positive CD34 selection, which has been
shown to reduce tumor cell content but may rarely lead to later ly mphoproliferative
disorders. The most widely tested and validated method with 4–6 logs of tumor cell removal
and no impairment of engraftment is immunomagnetic purging. COG studies showed that
bone marrow can be successfully harvested; shipped at room temperature overnight; purged
using sedimentation, filtration, and immunomagnetic bead separation; and cry opreserved
without injury and with successful tumor cell removal and engraftment (40). Recently, the
COG study (A3973) tested in a randomized fashion the impact of immunomagnetic purging
of peripheral blood stem cells, collected after only two cy cles of induction therapy, on
patients subsequently receiving my eloablative therapy and treatment of MRD with cis-
retinoic acid. The results of this study showed no benefit to EFS for the group undergoing the
tumor cell removal (38). Thus, due to the increased cost and apparent lack of benefit, stem
cell purging is not currently considered essential.
Figure: Induction Regimens for High-Risk
Neuroblastoma Since 1985 (More Than 50
Patients)
Figure: EFS for High-Risk Neuroblastoma in
First Remission Using Myeloablative
Therapy and Hematopoietic Cell Transplant
for Studies of More than 20 Patients
Figure:
Results of CCG 3891, a randomized study comparing myeloablative chemoradiotherapy and
purged autologous bone marrow transplantation with intensive nonmyeloablative therapy. A
second randomization was performed on all consenting patients completing the
consolidation therapy without progression to test the efficacy of 13-cis-retinoic acid for
minimal residual disease. A: Superior event-free survival (79) with myeloablative therapy
compared with standard-dose chemotherapy. The difference in 5-year EFS for the 379
randomized patients was 30% versus 19%, respectively (p = 0.04). B: The difference in 5-year
overall survival was 39% versus 30%, respectively (p = 0.39); however, in patients who
survived more than 3 years, there appears to be a benefit of ABMT.
(From Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-
risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-
cis-retinoic acid: a Children’s Oncology Group study. J Clin Oncol. 2009;27(7):1007–1013, with
permission.)
THERAPY FOR MINIMAL RESIDUAL DISEASE
Despite improvements in EFS using my eloablative therapy, the relapse rate, even for patients
transplanted in complete response, remains high (34). For this reason, it has become
increasingly important to find new approaches to eliminate MRD with agents that will be
tolerable after my eloablative therapy. Immediately after HCT, when disease is likely to be
minimal, is the ideal window of time to eradicate resistant clones that are still present using
novel therapies not dependent on standard cy totoxic mechanisms.
In vitro, both all-trans-retinoic acid and 13-cis-retinoic acid cause decreased
proliferation and differentiation in NB cell lines, including some established from refractory
tumors. A phase II trial in children with relapsed NB using 13-cis-retinoic acid on a single
daily administration schedule of 100 mg/m 2 showed only 2 of 22 responses (63). However,
based on in vitro experiments with higher intermittent dosing, a phase I trial in children with
high-risk NB after HCT determined that a high-dose intermittent schedule of 13-cis-retinoic
acid after BMT had minimal toxicity, achieved levels that were effective against NB cell lines
in vitro, and resulted in complete bone marrow responses in 3 of 10 patients. A subsequent
phase III randomized trial by the CCG of children with high-risk NB completing consolidation
chemotherapy or ABMT showed that the 3-y ear EFS from the time of randomization was
significantly better for the patients randomized to receive 13-cis-retinoic acid (46% ± 6%)
than for those randomized to receive no further therapy (29% ± 5%; p < 0.03) (Fig. 6.9 )
(40). A European randomized trial of very low-dose continuous 13-cis-retinoic acid given
after transplant did not show any benefit (64). Other investigational retinoids, such as
fenretinide, are under investigation for use in MRD (65).
Figure 6.9 Event-free survival from posttransplant randomization for high-risk
neuroblastoma treated with chimeric anti-GD2 monoclonal antibody (ch14.18) with IL-2, GM-
CSF and isotretinoin (RA) versus isotretinoin alone for treatment of minimal residual disease.
The difference in 2-year EFS was 66.5% for the randomized immunotherapy arm, compared
to 46.5% for isotretinoin alone (p = 0.01). (Reproduced from Yu AL, Gilman AL, Ozkaynak MF,
et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N
Engl J Med. 2010;363:1324–1334, with permission.)
Multiple phase I and II trials testing anti-GD2 monoclonal antibodies in murine,

chimeric, and humanized versions have shown activity and tolerability in relapsed and MRD
settings, finally leading to a phase III randomized trial in the COG comparing posttransplant
maintenance therapy with 13-cis-retinoic acid for six cy cles to the addition of five
interspersed cy cles of ch14.18 with GM-CSF and IL-2. The arm including the anti-GD2
chimeric antibody (ch14.18) compared to 13-cis-retinoic acid alone showed a significant
improvement in 2-y ear EFS after transplant, 66% versus 46%, (p = 0.01) (Fig. 6.9 ) (66).
Further attempts to improve immunotherapy approaches to MRD have included using
the anti-GD2 monoclonal antibody with cy tokines or a fusion protein of Hu14.18-IL2. Phase I
trials using a fusion protein of the humanized form of the anti-GD2 antibody, Hu14.18 with
IL-2 has the advantage of working simultaneously through both antibody -dependent
cy totoxicity and natural killer cell mechanisms. A murine NB model showed superior activity
of the immunocy tokine to the phy sical mixture of the antibody and cy tokine, and phase I and
II trials showed some activity and tolerability (67). Ongoing phase I trials include the addition
of autologous expanded natural killer cells to anti-GD2 antibody, anti-GD2 vaccines, and CAR
T cells (68,69).
Other approaches to MRD in the future may use genetically targeted agents such as
ALK inhibitors in patients with mutations (70) or other activated genetic pathway s (71).
Another possible avenue would use antiangiogenic therapy after transplantation. Angiogenesis
appears to play a major role in progression of NB in that multiple proteins associated with
angiogenesis have been shown to be associated with more advanced disease or worse
prognosis, and preclinical models support activity via suppression of angiogenesis.
Figure:
Event-free survival from posttransplant randomization for high-risk neuroblastoma treated
with chimeric anti-GD2 monoclonal antibody (ch14.18) with IL-2, GM-CSF and isotretinoin
(RA) versus isotretinoin alone for treatment of minimal residual disease. The difference in 2-
year EFS was 66.5% for the randomized immunotherapy arm, compared to 46.5% for
isotretinoin alone (p = 0.01).
(Reproduced from Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF,
interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–1334, with
permission.)
SURGERY
Surgery has both a diagnostic and a therapeutic role. If the diagnosis has not been established
by bone marrow aspirate, biochemical testing, or skin biopsy, surgery provides histologic
confirmation of malignancy. Even in the presence of a clear, nonsurgically determined
diagnosis of NB, a tissue sample is important for biologic analy sis.
As previously stated, 20–40% of children present with localized disease. In children
without evidence of metastatic disease, an attempt at resection is warranted if substantial
morbidity (sacrifice of vital structures) can be avoided. Complete gross excision of the
primary tumor in localized disease is associated with a very high likelihood of cure
irrespective of the patient’s age. For patients with stage 1 or 2 disease, the cure rate exceeds
90% as stated above (31). The LNESG1 study in localized neuroblastoma (72) demonstrated
significantly worse overall survival (89% vs. 98%) and event-free survival (79% vs. 92%) for
patients with IDRF (L2 vs. L1). Moreover, L2 patients had higher surgical complication rates
versus L1 (17% vs. 5%). If the tumor is localized but unresectable because of its intimate
relationship with major blood vessels or other characteristics, the proper extent of surgery
may depend on tumor biology. In a study of 228 patients with INSS stage 3 NB, for children
who had elevated serum ferritin or tumors with unfavorable histopathology or MYCN
amplification, the EFS was improved by complete gross resection, whereas the extent of
resection did not appear to affect the children with biologically favorable tumors treated with
standard dose chemotherapy (73). Similar results were observed in the 427 patients on the
LNESG1 study (74), where MYCN amplification led to poor outcomes with surgery alone.
The optimal timing of the surgery is still under debate; it is possible that the advantages of
early resection are outweighed by a higher complication rate before chemotherapy
reduction followed by delay ed surgery. However, even when the primary tumor is
unresectable, defining its extent remains important for staging and determining optimal
additional local therapy with radiation. Employ ment of preoperative IDRFs as part of the
newer INRG staging sy stem has been shown predictive of completeness of resection (75).
Page 128Recurrence in the local or regional area of primary disease is a component of
relapse in a large proportion of children with high-risk NB, at rates ranging from 20% to 80%
in reports that often include local RT and my eloablative therapy. Both single-arm studies and
one randomized study demonstrate the benefit of local control measures for children with
advanced but nonmetastatic NB (73,76), but the impact of resection in stage 4 disease in the
past were mixed. However, as therapy intensity has improved control of metastatic disease
and survival, the importance of local control of the primary disease via gross total resection
and radiation therapy seems to have increased (77). A recent meta-analy sis shows for stage 3
NB GTR versus STR 5-y ear OS odds-ratio of 2.4 (95% CI 1.19–4.85) and 1.65 (95% CI 0.96–
1.91) for stage 4 disease (78). A series of 104 high-risk NB patients treated with resection prior
to HSCT at Duke university demonstrated no significant OS benefit to GTR, but there was
improved OS with >90% resection versus <90% (p < 0.008) (79). Current consensus still
supports that more extensive resection is associated with better survival outcomes, which may
be of greatest importance in the presence of high-risk disease features such as MYCN
amplification. As with early stage disease, data from NB97 for stage 4 patients demonstrate
IDRFs are predictive of extent of resection (80).
Second-look surgical procedures are commonly used in NB. Chemotherapy and
irradiation may produce significant interval regression of a bulky primary tumor. For patients
with residual tumor, surgery may then be performed to achieve a complete response.
Children who have localized NB converted to a resectable status by interval therapy and who
undergo complete excision have a better prognosis (76). Completely resecting the primary
tumor also appears feasible for patients with advanced disease; eventual complete excision
can be accomplished in up to 65% of patients (81). Resection after chemotherapy appears to
be associated with fewer complications than resection before chemotherapy. The Italian
Cooperative Group for Neuroblastoma has reported 145 patients with localized inoperable NB
or primary tumor excised with a tumor residue more than 2 mL. Ninety -four of the 145
(65%) achieved a complete or partial response with chemotherapy, and 75 (52%)
subsequently underwent complete resection (82).
Although the prognostic value of ly mph nodes has been controversial, and nodes
adherent to or removed with the primary tumor do not appear to predict prognosis, ly mph
nodes that are distinct (usually superior or inferior, but especially if bilateral or contralateral)
from the tumor are ideally sampled for complete staging and later considerations for RT
(28,32). However, this may be difficult for some patients with cervical or thoracic tumors or
infiltrative unresectable abdominal primaries. The utility of other prognostic factors suggests
that aggressive attempts to acquire this information are unwarranted. If RT is contemplated,
clips should be used to mark the tumor.
If treated surgically, dumbbell tumors are dealt with by a two-stage procedure. The
extraspinal component of the tumor is removed at a first operation. The extradural, intraspinal
portion of the tumor is removed later. However, if there is evidence of spinal cord
compression and if surgery is used, the laminectomy is performed first. Osteoplastic
laminotomy is preferable to minimize later deformity (83). Many institutions prefer to treat
spinal cord compression with chemotherapy to try to minimize late deformities. A study of
576 NB patients treated at Children’s Cancer Hospital of Egy pt reported 51 patients (9%) with
spinal cord compression at presentation, the majority of whom were treated nonsurgically,
with chemotherapy ± steroids with improved neurologic outcomes in the subset who were
sy mptomatic, driven only by the initial duration of sy mptoms (93% vs. 70%, ≤4 weeks vs. >4
weeks, p = 0.008) (84).
On occasion, infants with a small primary tumor and extensive liver metastases (stage
4S) warrant special surgical considerations. The enlarging liver may compromise respiratory
function from upward pressure on the diaphragm or compress the inferior vena cava or renal
vein. If chemotherapy or local irradiation does not adequately reduce hepatic size, a silastic
sheet may be inserted in the abdominal wall to allow room for liver expansion and reduce
compression of vital structures. Resection of the primary tumor does not influence survival in
stage 4S (39,85).
RADIATION THERAPY
Indications concerning the use of RT in children with NB continue to be refined by progress in

devising effective chemotherapy and the desire to avoid unnecessarily aggressive treatment
regimens in y oung children, all on the backdrop of the recalcitrant nature of NB in many
children. NB cells in culture are generally radiosensitive, although radiation responsiveness of
NB in patients is less predictable, and we are learning that radiotherapy may have pleotropic
effects including stimulation of angiogenesis and invasion (86). In discerning the optimal use
of RT in NB, reports must be interpreted cautiously because of the differences in staging
sy stems and lack of information about tumor biology. In general radiation therapy is
employ ed less commonly for low risk disease and reserved for high-risk or refractory
disease. A SEER study examining use of radiotherapy from 1973 to 2008 in pediatric
malignancies demonstrated a decline in RT use from 60–25% (87).
Page 129Low-Risk Disease

There is no role for postoperative RT in INSS stage 1 and 2 NB, since numerous cooperative
studies have reported more than 90% survival with surgery alone or surgery with
chemotherapy. Gross surgical excision cures the majority of these children, regardless of
age, urinary VMA and HVA ratios, and histologic patterns, as mentioned in the “Surgery ”
section (31,88). Matthay et al. (89) reported outcomes of 156 patients with INSS stage 2A NB.
No significant benefit was associated with the use of chemotherapy or radiation. The
outcomes for 75 patients treated with surgery alone were similar to those of 66 patients
receiving RT with 6-y ear PFS of 89% versus 94%, respectively. For the subgroup of patients
with residual (postsurgical) gross or microscopic disease, survival was not influenced by the
use of radiation. A subsequent prospective CCG study by Perez et al. (88) demonstrated more
than 98% survival for 374 children with stage 1 and 2 NB with surgery alone as primary
therapy. COG study P9641 enrolled 915 patients with predominantly INSS stage 1, 2a, and 2b
disease treated primarily with maximal safe resection with chemotherapy reserved for
sy mptomatic disease or for limited resection with 5-y ear OS 97% (31). Thus, cooperative
group studies of localized NB dictate surgery as the primary treatment modality.
Chemotherapy is generally reserved for recurrent or progressive tumors that cannot be
resected successfully. RT is reserved for the very rare instances of local recurrence in spite
of surgery and chemotherapy or for instances in which function is urgently threatened, such
as in spinal cord compression or in respiratory insufficiency caused by hepatomegaly.
Stage 4S and Hepatomegaly

Stage 4S NB was initially proposed as separate from stage 4 in light of the observation that
infants with a localized primary NB with metastases to liver, bone marrow, or skin without
cortical bone involvement had a surprisingly good outcome compared with other infants with
metastatic disease. In fact, patients with stage 4S NB who have favorable biology have an
excellent prognosis, with 85–90% needing little or no therapy (39,85). Therefore, RT should
be reserved for palliation of life-threatening conditions such as marked, sy mptomatic
hepatomegaly (90). The indication for radiation must be balanced against the need for such
therapy and the risk of late sequelae of irradiation in infancy (91). Certainly, routine RT is
inappropriate in stage 4S disease and should be instituted only when disease progression
threatens vital organ function. This occurs most commonly in infants 1–2 months old, a risk
factor for death in several series (39,85,90,92). An enlarging liver may induce respiratory
compromise from upward pressure on the diaphragm, produce inferior vena cava
obstruction, compromise renal perfusion, and occasionally result in gastrointestinal
compromise or disseminated intravascular coagulation. When sy mptoms are early, low-dose
chemotherapy can be attempted for sy mptom reduction. However, often in very y oung
infants the progression is too rapid and local irradiation in stage 4S NB is indicated for acute
reduction of hepatic enlargement. A radiation of 2–6 Gy is usually sufficient to reduce
hepatic tumor burden and is well within the accepted limit of hepatic radiation tolerance.
Intermediate-Risk Disease
For children with regional NB on the less favorable end of the spectrum (i.e., INSS stage 3),
several reports support a survival advantage from the use of RT (Table 6.11 ).
Unfortunately, because of the previous multiple staging sy stems, many reports have
combined INSS stage 2B and INSS stage 3, making it difficult to discern whether radiation is
beneficial in both of these groups. As noted above, recent studies suggest that INSS stage 2B
disease does not necessitate RT, despite older reports showing improved survival with RT.
Patients with stage 3 disease who are more than 1 y ear old with MYCN amplification or
unfavorable pathology need additional treatment. For these children EFS is only 50–60%,
even with aggressive multimodality therapy (73). Only one randomized study of RT has
clearly delineated results for unresectable nonmetastatic disease. This POG study
randomized patients more than 1 y ear old with stage C NB to receive postoperative
chemotherapy or chemotherapy with regional RT (24–30 Gy, 16–20 fractions). Of 62 eligible
patients, in the chemotherapy arm 45% and 31% achieved complete remission and remained
disease-free, respectively, at a median of 35 months, and in the chemotherapy and RT arm
67% and 58% achieved complete remission and remain disease-free, respectively, at a
median of 23 months. Unfortunately, the chemotherapy used in this 10-y ear study was much
less dose intensive than current protocols, and there were no biologic risk factors reported,
rendering these results nearly impossible to interpret in the context of current therapy (93).
However, current reports seem to support the importance of local control in biologically
unfavorable high-risk stage 3 disease, although no further randomized trials have been
performed (76). All current protocols prescribe RT for residual disease after chemotherapy,
with the exception of infants and children with favorable biology (nonamplified MYCN,
favorable histology, hy perdiploid) (Table 6.12 ).
Table 6.12 Effect of Radiation in Local Control of Advanced (INSS 3 and 4)

Neuroblastoma
The completed COG study for intermediate risk disease (A3961), including stage 3 with
favorable biology and infant stage 4, used surgery to provide diagnostic material at
presentation and to attempt safe maximal resection of the primary tumor after
chemotherapy. Chemotherapy included cy clophosphamide, doxorubicin, carboplatin, and
etoposide. The duration of chemotherapy was based on the biologic risk factors. RT was
limited to situations in which there was clinical deterioration despite chemotherapy and
surgery or persistent tumor after chemotherapy and second-look surgery. This treatment
resulted in >90% survival for this group (35).
High-Risk Disease
Nearly half of all patients diagnosed with NB present with high-risk disease. Despite
concerted clinical and scientific efforts, the prognosis of children with high-risk NB remains
poor. Less than 30% of patients with high-risk disease who are more than 1 y ear old survive
more than 5 y ears. Historically, early attempts to use radiation to cure children with
advanced NB focused on large-volume RT, “segmental” or “sequential” fields administered
as fractionated or single doses. Mixed results in the face of significant toxicities diminished
enthusiasm for such radiation approaches, and they ultimately fell out of favor.
Page 130Although large-field RT has not proven efficacious, the concept of aggressive
sy stemic therapy has prevailed and has proven successful at improving outcomes for high-
risk patients. The randomized CCG 3891 trial showed superior clinical outcomes for patients
with high-risk NB who were treated with my eloablative chemotherapy and TBI with
transplantation of purged autologous bone marrow (40). Indeed, TBI has play ed a prominent
role in many my eloablative regimens. Table 6.10 summarizes studies that use autologous
or allogeneic BMT either with or without TBI as a component of their preparatory regimens.
For most reports EFS rates are on the order of 20–40%, although mortality continues to
increase as follow-up lengthens. As with older TBI protocols, trends in conditioning regimens
for stem cell transplantation have favored omitting TBI because it limits dosages of
my eloablative chemotherapy that can be administered and because of the increase in late
effects in y oung children.
Although the use of TBI for NB is nearly obsolete, an enlarging body of evidence
supports the use of local RT to the primary site and bulky metastatic sites. Disease recurrence
after BMT for NB is most common at previous sites of disease. Local radiation delivered
either in preparation for transplant or afterwards appears to reduce the risk of relapse at these
sites (81,94). Indeed, the current standard of care dictates that patients with high-risk disease
receive radiation to the primary disease site regardless of the extent of surgical resection and
to sites of metastatic disease that display persistent 131I-MIBG avidity on the pre–stem cell
transplant scans.
Several reports have specifically tackled the role of radiation to the primary tumor site in
uniform cohorts of patients with advanced NB. Such results strongly support the
administration of radiation to the primary site in high risk disease. These single-institution and
small consortium studies have reported excellent local control rates after treatment regimens
that consist of induction chemotherapy, delay ed primary surgery with attempted resection of
primary and bulky metastatic lesions, external beam radiation to the primary tumor site and
persistent metastatic areas, my eloablative chemotherapy, and infusion of stem cells. A report
from Japan describes a program of intensive chemotherapy and treatment of primary
disease with surgery and radiation for a group of children more than 1 y ear old with stage 4
disease, although a few patients with stage 3 disease and children y ounger than 1 y ear were
included. The 5-y ear EFS was 39% (50). CCG protocol 321P3 used a dose-intensive
combination of four chemotherapeutic agents followed by autologous purged BMT and
enrolled 99 children more than 1 y ear old with stage 4 and high-risk stage 3 disease. The 4-
y ear PFS was 40% (51). Despite TBI and local RT to residual disease, the primary site was
involved in more than 50% of the relapses (45). Better primary control was seen at Memorial
Sloan–Kettering Cancer Center in patients with stage 4 NB, who received higher dose local
radiation to primary tumor sites regardless of resection and had an actuarial locoregional
control rate of 84% at 5 y ears (94). An update of this single-institution experience reported a
10.1% probability of primary site failure among 99 patients, 92 of whom had no evidence of
disease in the primary site at the time of irradiation (95). Children received 1.5 Gy twice a
day to 21 Gy to the prechemotherapy, presurgery primary tumor volume and regional
ly mph nodes. Among seven patients with disease at the primary site at the time of irradiation,
three had disease that recurred locally. A similar treatment regimen was used by the German
multicenter NB trial in which 14 of 26 patients with advanced disease had disease that
relapsed, with 4 (29%) including the primary sites (96). Comparable regimens have resulted
in decreased local relapse rates, ranging from 0% to 17%. A report from St. Jude Children’s
Research Hospital on 63 patients with metastatic neuroblastoma demonstrated comparable 5-
y ear rates of local failure (35%) among patients receiving radiotherapy for local control
versus those who did not, despite higher rates of residual disease prior to consolidation therapy
(88% vs. 70%, p = 0.008) (97).
Page 131Although favorable local control rates have been reported in single-institution
and small consortium studies, large multi-institutional studies have lower rates of complete
total resections and differing chemotherapy regimens that limit direct comparisons of clinical
results. Therefore, it is not surprising that large, modern multi-institutional trials report higher
rates of local relapse. The CCG trial (CCG 3891) showed superior EFS for patients with high-
risk NB who were treated with my eloablative chemotherapy and TBI with transplantation of
purged autologous bone marrow, followed by treatment with 13-cis-retinoic acid. External
beam RT (EBRT) was prescribed for all patients with gross residual disease after induction
chemotherapy and surgery. Patients randomly assigned to the transplantation arm received
additional TBI as a component of the ablative regimen (40).
In CCG 3891, recurrence at the primary disease site was a major component of relapse.
Among 539 patients, 349 had recurrences, including 31 with isolated locoregional relapses,
148 with simultaneous local and distant recurrences, and 150 with distant relapses. At 5 y ears,
the estimated regional recurrence rate was 51% ± 5% among patients who received
continuation chemotherapy and 33% ± 7% among patients who received transplantation. The
difference in local relapse rates between the continuation chemotherapy and ABMT groups
was most pronounced in patients with MYCN-amplified tumors. Among patients with MYCN
amplification, the estimated 5-y ear local recurrence rate was 70% ± 10% for those who
received continuation chemotherapy and 25% ± 15% for patients who received ABMT (81).
Although CCG 3891 did not examine the benefit of local EBRT in a randomized fashion,
some conclusions were evident from an analy sis of RT administered in this trial. For patients
who received 10 Gy of EBRT to the primary site, the addition of 10 Gy of TBI and ABMT
resulted in lower local recurrence rates than continuation chemotherapy. The benefit of RT
was particularly evident when sy stemic treatment was optimized with my eloablative therapy
and 13-cis-retinoic acid (81). For patients with high-risk NB, we recommend EBRT to the
primary tumor site in the context of a my eloablative regimen that does not include TBI but
incorporates posttransplant therapy for MRD.
For patients with metastatic sites that do not warrant early sy mptomatic palliative
radiotherapy, current consensus on North American protocols specifies radiation of up to five
metastatic sites with persistent active disease demonstrated at the time of evaluation prior to
high-dose consolidative chemotherapy, as demonstrated on 131I-MIBG scan. A multi-
institutional analy sis of 43 patients with metastatic NB, including bone and soft-tissue sites of
metastasis, reported a reduced risk of relapse at bony sites with irradiation (25% vs. 17%, p =
ns) (98). A study from Bay lor examining EBRT to the primary tumor bed and metastatic sites
that remained MIBG-avid after induction chemotherapy included 21 sites of metastatic
disease that received 24 Gy and demonstrated local control of 74% (99).
CNS Metastases
Some controversy exists regarding whether increasingly aggressive multimodality therapy
for stage 4 disease has altered patterns of metastases. Some metastatic sites, although perhaps
rare in NB patients, pose unique therapeutic challenges, exemplified by CNS metastases. The
incidence of CNS metastases in children with high-risk stage 4 NB varies depending on
whether reporting at diagnosis (2%) or relapse (8–12%) (23,100).
In a COG study, all 648 patients with stage 4 NB in CCG 3881 and 3891 were analy zed
for sites of metastases. At diagnosis, the most common sites of metastases were bone
marrow, bone, ly mph nodes, and liver. The distribution of metastatic sites differed between
patients at diagnosis and those at first progression. Whereas the frequencies of bone, bone
marrow, liver, ly mph nodes, and skin metastases were lower at first progression than at
diagnosis, frequencies of adrenal, lung, and CNS metastases exhibited the opposite propensity.
Whereas CNS involvement was almost never seen at diagnosis, at first progression, CNS
metastases were more common in all age groups. Of all patients with stage 4 disease and
relapse, 11% of children y ounger than 1 y ear and 3% of children 1 y ear or older had CNS
metastases at relapse. Although the number of patients with CNS metastases was small, a few
trends were evident. All patients with CNS metastases were more than 1 y ear old, died within
1 y ear of diagnosis, and had both MYCN amplification (among those tested) and unfavorable
Shimada histopathology. Among patients with CNS metastases at diagnosis and those y ounger
than 1 y ear who progressed with CNS metastases, hematogenous spread to parenchy mal sites
was nearly absent. In contrast, for patients older than 1 y ear, CNS metastases at progression
appeared to result from hematogenous routes of spread (23).
A similar analy sis at the Institute Curie and Institute Gustave-Roussy confirmed that CNS
metastases at diagnosis are extremely rare but revealed an estimated 3-y ear risk of CNS
recurrence of 8% among patients with stage 4 disease, a rate that was stable over 15 y ears
(100). Patients with CNS recurrences were equally distributed among those with
parenchy mal lesions, those with only meningeal involvement, and those with a combination
thereof. Of note, 131I-MIBG scans did not reliably identify CNS recurrences, detecting
lesions in only 43% of those with known CNS metastases (100).
In contrast to the aforementioned studies, investigators at Memorial Sloan–Kettering
Cancer Center found more CNS metastases associated with increased intensity of curative
protocols for patients with stage 4 disease (101). In patients treated with earlier N4–5
protocols, 2% recurred in the CNS, whereas in those treated with more intensive N6–7
protocols, 12% experienced CNS metastases, perhaps reflecting the longer median survival
times in patients treated on N6–7. As patients live longer, metastases to sanctuary sites such as
the CNS may become more evident.
Although prospective head CT or MRI scans may better quantify the true incidence of
CNS metastases, the infrequent occurrence of such metastases does not justify routine CNS
imaging. Furthermore, although most studies do not support an increase in frequency of CNS
metastases in the past two decades, it is unclear whether the movement away from TBI for
stage 4 NB will result in increased metastases to sanctuary sites such as the CNS. The rarity
of CNS metastases does not justify prophy lactic CNS radiation; however, for a patient with
CNS recurrence the appropriate field of radiation remains unclear. In some instances, highly
localized stereotactic radiotherapy may provide durable control of intracranial metastases
(102).
Page 132CNS parenchy mal or meningeal metastatic relapse has portended a very short
survival in prior studies, with median survival of 3–6 months. However, with aggressive
surgery and local radiation, survival may be extended in some instances. Memorial Sloan
Kettering Cancer Center reported on a series of 29 children with NB and CNS relapse who
received either focal RT (13 patients) or low-dose craniospinal RT (CSI) ± intra-Ommay a
radioimmunotherapy (16 patients). Intrathecal radioimmunotherapy consisted of 131I-
monoclonal antibodies targeting GD2 or B7H3. At a median follow up of 28 months, 75% had
no evidence of CNS disease whereas all the patients in the focal radiotherapy group had died
(101).
Metastatic Disease Treated with Palliative Intent

Most children with NB have metastatic disease at presentation, which may occasionally
threaten function, such as an orbital metastasis affecting vision, an epidural metastasis causing
cord compression, or severe pain caused by bone lesions. RT is effective in palliating
sy mptoms secondary to bone and soft tissue metastases, although in a newly diagnosed,
chemotherapy -naive patient, sy stemic treatment usually is initiated first, except in extreme
circumstances. A Duke study assessed the value of palliative RT for NB by retrospectively
study ing 40 irradiated bony sites. Pain completely or partially responded at 65% of treated
sites. A subsequent recurrence of pain was seen in 23% of initially responding sites. Complete
or partial palliation of soft tissue mass effect was seen in 67% of treated sites. A subsequent
relapse of mass effect was seen in 28% of initially responding sites (103). Palliative RT for
pain or other sy mptoms in the refractory relapsed patient can generally be administered
rapidly with good relief. There are also extensive phase I and II data concerning palliative
treatment of metastatic disease with 131I-MIBG (104,105).
Figure: Effect of Radiation in Local Control
of Advanced (INSS 3 and 4) Neuroblastoma
ADOLESCENT AND ADULT NEUROBLASTOMA
NB occurs only rarely in adolescents and adults. More than one-third of patients are
diagnosed before the age of 1 y ear, whereas less than 5% of patients present after the age of
10 y ears (19). NB in adolescents and adults presents unique challenges that necessitate distinct
analy ses and therapeutic approaches.
NB in adolescents and adults is characterized by an indolent course, persistent disease,
multiple recurrences, and poor outcome (36). In studies examining patients who were
diagnosed with NB between the ages of 15 and 75 y ears, less than 5% of patients are long-
term survivors, without evidence of disease (106). Most aspects of clinical presentation are
similar to those of y ounger patients. For example, sites of metastatic disease are similar in
adolescents and y ounger children, most commonly found in bone marrow, ly mph nodes,
bone, and liver. However, distinct differences occur between y ounger patients and
adolescents with NB. Such differences in tumor histology and secretion of catecholamine
metabolites may reflect the unique entity of NB in adolescents and adults. The lower
frequency of MYCN amplification and secretion of catecholamine metabolites probably go
hand in hand with the more chronic nature of the disease in this age group (106).
Franks et al. (106) reported the experience of the CCG with NB in adults and adolescents.
This study examined 16 patients from the University of California, San Francisco (UCSF),
and 38 patients registered in the CCG, all 13 y ears or older. They found that older patients
experienced multiple recurrences; chronic, prolonged courses; and poor outcome regardless
of stage or site of disease. For example, although 25% of patients in the UCSF series had
pelvic primaries, a site that in y ounger patients is associated with more favorable outcome,
pelvic primaries were associated with outcomes as poor as those for adults and adolescents
with other primary sites (106). The indolent, chronic nature of NB in adults and adolescents
was reflected with a long median time to progression of 32 months. Although stage IV disease
recurred within a y ear from diagnosis in most patients, late recurrences were observed, as
long as 83 months after diagnosis. Furthermore, although y ounger patients with stage IV NB
have only a 3- to 4-month median survival after their first recurrence, similarly staged
adolescents experienced multiple recurrences and persistent disease after their first
recurrence. After their first recurrence, adolescents and adults had a median survival of 17
months, with a significant proportion surviving more than 4 y ears after recurrence (106).
Whereas the CCG and UCSF experiences demonstrate poor outcome for all adolescents,
regardless of stage, the French Society of Pediatric Oncology found that patients with stage I–
II disease fared well and had survival rates comparable to those of y ounger patients with
early stage disease (107). None of six patients with stage I–II disease experienced
recurrence. In contrast, adolescents with stage III disease experienced multiple recurrences,
with prolonged and chronic clinical courses. This is reflected in discordant PFS and OS rates
at 5 y ears, which were 28% and 86%, respectively. Adolescents with metastatic NB had low
PFS and OS rates of 18% and 27%, respectively, and exhibited poor responses to intensive
chemotherapy (107).
The poor outcome for adults and adolescents, even with localized disease, calls into
question the usual risk-based treatment in this age group. Aggressive multimodality therapy
may be appropriate even for patients with low-stage disease but certainly for patients with
INSS stage 3 and 4 disease. In the analy sis of the INRG database, the older patients who
received my eloablative therapy had a significantly better outcome than those treated with
nonmy eloablative therapy (36). In addition, higher radiation doses are appropriate. Doses to
the primary tumor site should be maximized, tailored to the individual disease sites, and
constrained by tolerance of adjacent normal tissues. For example, abdominal primary
tumors should be treated with 45 Gy, which constitutes small bowel tolerance, as long as the
dosage to the kidney s and liver can be kept within tolerance. Given the poor clinical outcome
for adults and adolescents with NB, creative approaches are warranted in the treatment of
such patients, including immunotherapy, differentiating agents, targeted RT using 131I-MIBG,
and biologic agents.
RADIOTHERAPEUTIC MANAGEMENT
Page 133Volume
The volume for radiation of regional NB is determined by imaging studies and by the
operating surgeon’s description. If ly mph node involvement is suspected or proven, a wide
field that covers the primary tumor site and involved ly mph nodes is appropriate. If the field
must cover a portion of the vertebral body, the full width of the bone should be encompassed
in preadolescent children. This will y ield uniform vertebral growth impairment and reduce
the severity of subsequent scoliosis as well as ensure coverage of the regional ly mph nodes.
Controversy surrounds the issue of whether next-echelon ly mph nodes (i.e., mediastinal
ly mph nodes with an upper abdominal primary tumor) need be radiated. Relapse in
nonradiated next echelon nodes can occur, albeit usually in conjunction with local or distant
failure. In the Duke experience of 33 patients with stage A to C, 12 relapsed. Only 1 of the 21
irradiated patients (5%) experienced an in-field failure, whereas 7 of the 12 not receiving RT
(58%) experienced local failures at the time of recurrence (p = 0.001). Routine next-echelon
nodal irradiation was not given. Five of the 12 patients who suffered a relapse had next-
echelon nodal failure as a component of relapse; only one case was an isolated next-echelon
nodal failure (103). Current analy sis of LN irradiation from A3973 did not show
improvement in local control or survival with extensive nodal irradiation (manuscript in
progress). Extensive nodal fields may contribute to late morbidity and limit the ability to give
chemotherapy, so most treatment approaches cover only the primary tumor volume and
involved nodal groups. With a dumbbell-shaped tumor, careful attention must be paid to the
intraspinal and extravertebral components of the tumor to ensure full coverage.
As previously discussed, RT may be used for INSS stage 4S–associated sy mptomatic
hepatomegaly. The entire liver need not be irradiated to induce tumor regression. The
therapist may use portals designed to avoid the kidney s and, in girls, the ovaries. One may use
a simple conventional setup with two lateral fields, parallel opposed or slightly angled
anteriorly, to treat the majority of the liver but spare the kidney s. Placing the posterior border
of the lateral field at the anterior aspect of the vertebral body accomplishes this objective.
The ovaries are generally avoided by keeping the inferior border of the field at or above the
superior iliac crest. Radiation doses for stage 4S hepatomegaly are low, usually 2–6 Gy in two
to four fractions, so it could be argued that the kidney s are in little danger of chronic injury
and that the liver could be treated with parallel, opposed anterior and posterior fields or a
single anterior field. Although these are acceptable field arrangement options, the infant
kidney is more sensitive to radiation than kidney s in older children. Children with stage 4S
disease have high likelihood of survival and, if possible, should not be subjected to risks of
lifetime reductions of glomerular filtration rates. Stage 4 NB with hepatomegaly may also be
treated for palliation with ports designed to cover the entire liver, using the opposed lateral
beams. NB metastases occur in a wide variety of locations. Bone and soft tissue sites are
irradiated with moderate margins using a variety of beam arrangements to minimize dose to
uninvolved regional tissues.
Dose
Classic radiobiologic analy ses reflect the relative radiosensitivity of NB cell lines in vitro but
produce conflicting results regarding the most appropriate fractionation schedules. The D0 for
most mammalian tumor cell lines is between 1.3 and 1.5 Gy. The n is usually between 1.5
and 10. The n is the extrapolation number and measures the width of the survival curve
shoulder. The D0 describes the final slope of the cell survival curve and is the dose required to
reduce survival from 0.1 to 0.037. Collated data on 11 NB cell lines derived from 7 patients
indicate moderate cellular radiosensitivity bey ond that seen for many other mammalian
tumors. The median n for NB is 1.36, and the D0 is 1.04 Gy (108). This low repair capacity
for radiation damage implies that little sparing would result from dose fractionation. Wheldon
et al. (109) used human NB grown as multicellular tumor spheroids (MTS) to confirm this
hy pothesis. There was no significant difference in the killing ability of single-dose and split-
dose irradiation. The absence of substantial interfraction repair capacity of MTS may provide
a radiobiologic rationale for treating NB with multiple fractions per day. Some NB cell lines
have a rapid doubling time. This would also suggest that the overall treatment time of a
fractionated course of radiation should be kept short to prevent tumor repopulation between
fractions. However, Deacon et al. (110) performed in vitro split-dose radiation of an NB cell
line and found a small but finite capacity for sublethal damage repair. There may be intrinsic
variability in repair capabilities between NB cell lines.
Although NB is radiosensitive in the laboratory, its clinical response to radiation is
variable, and in-field recurrences, although rare, do occur. Possible reasons for this
discrepancy include the following. First, the in vitro data may not reflect clinical NB because
cell culture techniques may select more radiosensitive cell lines. Second, NB, characterized
by certain microscopic and biochemical characteristics, may actually be a spectrum of
diseases. Genomic amplification of MYCN has been correlated with the stage and prognosis of
NB, suggesting that MYCN may have a role in determining the aggressiveness of human NB.
Clinical variability in radiosensitivity may reflect the variation in oncogene amplification in
NB. In defining the role of radiation for high-risk NB, adequate doses have been defined
empirically. Studies on patients now known not to have the needed radiation shaped standard
radiation dosages that were then translated into doses adequate for high-risk disease.
Historically, RT was administered to most patients with NB, with the exception of those with
stage I tumors. Radiation doses ranged from 10 to 45 Gy and were dictated by patient age
rather than stage of disease. In this era, in which patients with early -stage disease received
radiation, two studies examined the radiation dose of NB (111). Doses below 20 Gy were
deemed sufficient to achieve local control. However, the majority of patients included in both
studies probably would not receive RT in the current era. Nonetheless, the adequacy of doses
of less than 20 Gy was adopted for all stages of disease.
Page 134Emerging data suggest that although 20 Gy may be adequate for controlling
completely resected tumors, gross residual disease may necessitate higher dosages. The Joint
Center for Radiation Therapy analy zed radiation dosage and local control and concluded that
higher doses are necessary for local control of NB in older patients (111). The protocol design
of CCG 3891 also allowed a limited dose–response analy sis, suggesting that the combined
effect of external beam radiation and TBI improved local control (81).
Whereas the majority of patients on CCG 3891 had mediastinal and intra-abdominal
tumors and therefore received 10 Gy to the primary site, a subgroup of patients received 20
Gy delivered to extra-abdominal primary tumors. Of 36 patients with extra-abdominal
primaries, 6 patients received 20 Gy EBRT (2 also received TBI) and 30 patients received no
EBRT (10 of these received TBI). Local relapse rates at 5 y ears were 0% ± 0% and 44% ±
15% for patients with and without EBRT, respectively (p = 0.09). Thus, the data suggest a
dose–response relationship for local EBRT, although the optimal dosage to primary tumor sites
has not been established (81). In a series of 34 high-risk NB patients from Emory, 3-y ear
local control was 94%, suggesting EBRT doses in the range of 21 to 24 Gy as sufficient for
adequate local control (112).
As a basic guide for patients with high-risk NB, a minimum dose of 21 Gy, in either 1.8
Gy daily fractions or 1.5 Gy twice-daily fractions, should be delivered to the tumor volume
present before surgical resection. This dosage should be adequate for patients with a complete
surgical resection, but patients with incomplete surgical resections may benefit from higher
radiation dosages directed at gross residual disease in an attempt to improve upon poor local
control rates reported in the literature.
Several publications suggest that current local therapy for incompletely resected patients
is inadequate. Wolden et al. (94) reported on a series of patients with stage 4 NB receiving 1.5
Gy twice a day to 21 Gy to prechemotherapy, presurgery primary tumor volume and
regional ly mph nodes. The actuarial locoregional control rate at 5 y ears was 84%. An update
of this experience reported a 10.1% probability of primary site failure among 99 patients,
most of whom (92 patients) had no evidence of disease in the primary site at the time of
irradiation (95). Among seven patients with disease at the primary site at the time of
irradiation, three had disease that recurred locally. EBRT did not increase acute toxicity,
except for increased total parenteral nutrition administration.
An analy sis from the University Children’s Hospital in Cologne, Germany, reported that
36 Gy of EBRT administered to patients with incompletely resected primary tumors could
compensate for “the disadvantage of incomplete response to induction chemotherapy.” In this
report of the NB97 trial for patients 1 y ear of age or older with stage 4 NB, patients with
isolated localized residual disease had improved outcome following EBRT (3-y ear-EFS 100%,
3-y ear-OS 100%) compared to those not receiving EBRT despite residual tumor tissue (3-
y ear-EFS 20 ± 18%, p < 0.001; 3-y ear-OS 20 ± 18%, p < 0.001) (113).
Given high rates of local recurrence, particularly following an incomplete surgical
resection, and tolerable side effects of EBRT evident in multi-institutional trials, the current
COG high-risk study is assessing whether a boost to residual primary tumor in patients with
less than gross total resection will improve the 3-y ear local control rate compared to historical
controls. Thus, patients enrolled on ANBL0532 who have an incomplete surgical resection of
the primary tumor receive 21.6 Gy EBRT to the postinduction chemotherapy, preoperative
primary tumor volume and an additional boost of 14.4 Gy EBRT to the gross residual volume
(total dose of 36 Gy to gross residual tumor volume). A dose of 36 Gy is well within normal
tissue tolerance for most organs within the field of radiation, and kidney s and liver will likely
prove to be the dose-limiting structures. It should be noted that the volume that receives 36 Gy
is generally substantially smaller than the original preoperative tumor volume that receives
21.6 Gy. An example of a patient treated with such a radiation regimen is shown in Figure
6.10 .
Figure 6.10 A and B: Two axial sections demonstrating dose distributions to the primary
tumor volume (shown in red). CTV shown in red represents the postinduction chemotherapy,
preoperative tumor volume that received 21.6 Gy; CTV shown in light blue is the
postoperative residual disease that, per the COG ANBL0532 protocol, received a boost of 14.4
Gy for a total dose of 36 Gy. An IMRT plan was used and the isodose lines shown are 21.6 Gy
(dark blue) and 18.0 Gy (yellow) highlighting the relative sparing of the bony pelvis as well as
liver and kidneys. A and B: Two axial sections demonstrating isodose lines encompassing the
gross residual postoperative tumor volume that received an additional boost of 14.4 Gy to a
total dose of 36.0 Gy, as per the COG ANBL0532 protocol. The isodose line shown is 14.4 Gy
(green) and shows the volume that received a total dose of 36.0 Gy. This child is without
evidence of disease 2 years after radiation therapy. (With gratitude to Tarek Halabi, PhD,
Hospital Physicist.)
Several investigators have published recommendations for time and dose fractionation
schedules for the radiation of metastatic NB in bone or soft tissues with a wide range of daily
fractions of 2–8.5 Gy and total doses of 4–32 Gy. In a retrospective evaluation of palliative RT
for NB at Duke, there was no evidence of a dose–response relationship (114). However, all
total doses used in this study were low. The clinician must avoid selecting too low a dose for
palliation of painful bony or soft tissue lesions. Although most children with stage 4 NB die
from the malignancy, some live for 1 y ear or more after palliative local treatment. The dose
should be adequate to control the sy mptom for the remainder of the patient’s lifetime y et not
be so high as to have a significant likelihood of complications. Fractionation depends on
volume. Small fields may be treated with 16–20 Gy in four or five fractions, whereas large
volumes are better treated with 2–3 Gy per fraction to 20–30 Gy so as to allow for regional
normal tissue repair and recovery. In the preterminal case, where timely pain control is
desired with minimal trips to the RT department, one may administer 6–8 Gy once or twice
with moderate success. Palliation of hepatomegaly in stage 4S disease usually can be
accomplished by 2–6 Gy in two to four fractions. However, regression of the liver may be
slow. It is occasionally necessary to repeat the dose. If possible, one should allow a 2- to 3-
week interval to gauge response. If the dose is repeated such that the cumulative dosage
reaches 12 Gy, the infant’s kidney should be out of the field of irradiation.
Figure:
A and B: Two axial sections demonstrating dose distributions to the primary tumor volume
(shown in red). CTV shown in red represents the postinduction chemotherapy, preoperative
tumor volume that received 21.6 Gy; CTV shown in light blue is the postoperative residual
disease that, per the COG ANBL0532 protocol, received a boost of 14.4 Gy for a total dose of
36 Gy. An IMRT plan was used and the isodose lines shown are 21.6 Gy (dark blue) and 18.0 Gy
(yellow) highlighting the relative sparing of the bony pelvis as well as liver and kidneys. A and
B: Two axial sections demonstrating isodose lines encompassing the gross residual
postoperative tumor volume that received an additional boost of 14.4 Gy to a total dose of
36.0 Gy, as per the COG ANBL0532 protocol. The isodose line shown is 14.4 Gy (green) and
shows the volume that received a total dose of 36.0 Gy. This child is without evidence of
disease 2 years after radiation therapy. (With gratitude to Tarek Halabi, PhD, Hospital
Physicist.)
TECHNIQUES OF RADIATION
Some abdominal and pelvic sites are best treated with parallel, opposed anterior and posterior
portals. When possible, multiple fields should be used to spare normal tissues. We have often
found three-dimensional (3D) reconstruction of bulky localized disease useful. After
reconstruction of the tumor volume, conformal fields or intensity -modulated RT may be
used. A key benefit of computer planning in the treatment of abdominal NB is related to the
ability to localize the kidney s and liver in addition to the precise delineation of the areas at risk
for recurrent disease. Field position and blocking are used to minimize the dosage to normal
tissue. However, often anteroposterior/posteroanterior or minimally obliqued fields prove to
be best.
Page 135Improved imaging technology, specifically MRI and CT, and biologic,
metabolic imaging such as radiolabeled MIBG have improved delineation of tumor and
surrounding critical structures. Novel techniques capitalize on an improved definition of tumor
volumes, allowing clinicians to decrease the dosages delivered to critical structures while
maintaining or increasing the dose to tumor. The advent of other technical advances such as
multileaf collimation (MLC), digitally reconstructed radiographs (DRRs), and electronic
portal imaging have contributed to the integration of conformal radiation delivery. Intensity -
modulated radiotherapy (IMRT) has the potential to reduce morbidity (e.g., spare liver,
kidney s).
CT images are analy zed jointly by radiation oncologists, diagnostic radiologists, pediatric
oncologists, and pediatric surgeons. Once target volumes and critical structures are defined,
beam geometry and weighting are defined and dose distribution is calculated. Selection of
beam angles can be done by referencing axial images or by using beam’s ey e view (BEV).
BEV allows visualization of the relationship of tumor volumes to the volumes of critical
normal tissues as if looking from the origin of the beam. This allows beam angles and beam
shaping to be selected more intelligently. Once an initial plan has been developed, the
resulting dose distributions are calculated and evaluated by the clinician. The plan can then be
altered to improve on initial results, if necessary. The beam directions as well as their relative
weights and shapes are modified finally to optimize the 3D plan.
The last decade has seen rapid development of novel technical approaches to RT and its
application to pediatric malignancies in general and NB in particular. These include 3D
conformal RT (3D-CRT), IMRT, proton beam RT, intraoperative RT, and radiosurgery. In
particular circumstances, such cutting-edge technical innovations can be of great help, as
exemplified in Figure 6.11 . Shown is a paravertebral mass with extension into the spinal
canal that recurred locally after prior radiation therapy. Radiosurgery using the Cy berKnife
allowed sparing of the previously irradiated spinal cord.
Page 136
Figure 6.11 CyberKnife isodose lines and plan for the treatment of a paravertebral mass
with extension into the spinal canal. Red line denotes the tumor volume shown on sagittal
(A), and axial (B). This locally recurrent mass after prior radiation therapy required sparing
of the spinal cord that was achievable by CyberKnife treatment planning, as shown in the
figure. A total dose of 30 Gy in five 6 Gy fractions was prescribed to the dark blue isodose line.
The light blue and green lines denote the 20 and 35 Gy isodose lines, respectively.
Paulino et al. (115) compared the use of conventional techniques to IMRT specifically
for treatment of primary abdominal NBs. They found that although IMRT was superior to
parallel, opposed anteroposterior/posteroanterior fields prescribed to midplane with respect to
kidney doses, this advantage was at cost of higher mean doses to the liver, stomach, and
spleen. Furthermore, IMRT was not found to be superior to conventional
anteroposterior/posteroanterior field arrangements for lateralized tumors (115). However,
another report from St. Jude’s using IMRT for abdominal tumors, employ ed 4DCT to account
for phy siologic organ motion during the breathing cy cle and demonstrated 100% local control
while maintaining normal tissue constraints with minimal significant acute toxicity (116).
Thus, although IMRT has advantages of dose conformity that are particularly appealing in the
treatment of children, each case must be individualized and the best plan be utilized for each
individual patient. Excellent conformity is shown in Figure 6.12 in which IMRT allowed
sparing of ears and contralateral ey e while treating a maxillary sinus metastasis.
Figure 6.12 Axial (A), coronal (B), and sagittal (C) sections showing the dose distribution
for a right maxillary sinus metastasis that showed persistent 131I-MIBG uptake on the
pretransplant MIBG scan and therefore received 21.6 Gy. Radiation was administered using
an IMRT plan. Isodose lines, 21.6 Gy in blue and 18.0 Gy in yellow, demonstrate excellent
conformity with the tumor volume (shown in red) while sparing of the ears and contralateral
eye. (With gratitude to Tarek Halabi, PhD, Hospital Physicist.)
Proton beam therapy has been increasingly employ ed in the management of a variety
of pediatric cancers due to its characteristic Bragg peak, y ielding very steep dose gradients,
with the ability to decrease exit dose and thus advantageous in application of CSI, for
example, where organs anterior to the vertebral column can receive minimal dose. However,
practical benefits of application of proton beam radiation to other anatomic sites remain
controversial and are dependent upon the technique of proton beam generation, geometry of
beam angles, and volume of target (117). A Japanese series employ ed proton beam
radiotherapy for 14 patients with high-risk NB with the goal of regional organ sparing. Three-
y ear locoregional control was 82% with no severe acute toxicity reported (118). A dosimetric
study of five patients who underwent proton beam radiotherapy for retroperitoneal
neuroblastoma compared the proton plans with generated 3D conformal and IMRT plans and
concluded significant dose reduction to regional organs with the proton plan as compared to
IMRT or 3D. Moreover, upon modeling secondary cancer risks, the authors concluded risk
reduction of 24–83% with proton radiotherapy over 3D or IMRT (119).
Page 137Proton beam therapy is permitted on most current NB protocols, with the dose
reported as Gy Radiobiologic Equivalent (Gy E) where 1 Gy E equals the proton dose in Gy ×
1.1. The potential benefits of proton beam radiation must be weighed against recent
publications that highlight potentially higher toxicities observed after treatment of CNS tumors
with protons than with photons. In this context, one must acknowledge persistent uncertainties
related to proton dose deposition and biologic effects. A study examining imaging changes
following proton- or photon-based (IMRT) radiotherapy demonstrated more imaging changes
following proton-based radiation compared to photons-based IMRT. Furthermore, only proton
treated patients experienced grade 3 or 4 changes and had persistent sy mptoms, including one
grade 5 toxicity related to radiation necrosis documented at autopsy (120). A similar study
assessing brainstem toxicity following proton radiotherapy for pediatric brain or skull-base
tumors reported a 2-y ear cumulative incidence of grade 3 or higher brainstem toxicity of
2.1% ± 0.9%, with one grade 5 toxicity (121).
Figure:
CyberKnife isodose lines and plan for the treatment of a paravertebral mass with extension
into the spinal canal. Red line denotes the tumor volume shown on sagittal (A), and axial
(B). This locally recurrent mass after prior radiation therapy required sparing of the spinal
cord that was achievable by CyberKnife treatment planning, as shown in the figure. A total
dose of 30 Gy in five 6 Gy fractions was prescribed to the dark blue isodose line. The light blue
and green lines denote the 20 and 35 Gy isodose lines, respectively.
Figure:
Axial (A), coronal (B), and sagittal (C) sections showing the dose distribution for a right
maxillary sinus metastasis that showed persistent 131I-MIBG uptake on the pretransplant
MIBG scan and therefore received 21.6 Gy. Radiation was administered using an IMRT plan.
Isodose lines, 21.6 Gy in blue and 18.0 Gy in yellow, demonstrate excellent conformity with
the tumor volume (shown in red) while sparing of the ears and contralateral eye. (With
gratitude to Tarek Halabi, PhD, Hospital Physicist.)
INTRAOPERATIVE RADIATION THERAPY
Patients with high-risk disease often present with large abdominal primary tumors, abutting or
invading many dose-limiting normal tissues. External beam radiation to these tumors often
entails treatment of a large volume of normal tissue, including bowel, liver, kidney, bony
structures, and spinal cord. RT to NB occurring at other primary sites, including the thorax and
pelvis, similarly exposes normal tissues to the risk of long-term side effects. Long-term
toxicities associated with EBRT may be particularly severe in children (91,114,122,123,124).
Furthermore, EBRT may decrease renal function, resulting in diminished tolerance to high-
dose chemotherapy with stem cell transplant, as well as adjuvant immunotherapies.
Although EBRT play s a key role in NB treatment, several institutions have explored
intraoperative RT (IORT) (Table 6.13 ) as an effective radiation modality that may
minimize acute and long-term side effects. In contrast to conventional EBRT, IORT allows
treatment of high-risk areas at the time of primary resection. Critical structures can be
directly visualized and manipulated at the time of surgery, allowing their exclusion from the
radiation field if they are at low risk for microscopic disease. A high radiation dosage can be
delivered to residual tumor and areas at high risk for microscopic disease with minimal
radiation dosage to nearby normal tissues. A small number of studies have established the
potential for IORT as a treatment modality in infants and children, including patients with NB
(125,126,127,128). IORT in these studies is extremely well tolerated and may improve local
disease control.
Table 6.13 Intraoperative Radiotherapy for Neuroblastoma
UCSF reported on a cohort of 31 consecutive patients treated with IORT for newly
diagnosed high-risk NB. With follow-up ranging from 1.5 to 16.7 y ears (median 44 months), 1
of the 22 patients who had gross total resections experienced local recurrence. In contrast,
three of nine patients who had subtotal resections experienced local recurrence, despite
additional EBRT to the primary site postoperatively in two of these patients (129). The 3-y ear
estimate of local control, PFS, and OS rates were 85%, 47%, and 60%, respectively. Side
effects attributable to either the disease process or multimodality treatment were observed in
seven patients who developed either hy pertension or vascular stenosis. These late
complications resulted in the death of two patients; however, additional analy sis is needed to
determine the relative contributions of the disease process and specific components of the
multimodality treatment to these adverse events. Similarly, a series of 27 advanced-stage NB
patients treated with IORT in Japan, demonstrated excellent rates of local control with three
“in-field” recurrences in the absence of further EBRT, attributed to deep location,
displacement or shielding of tissues which ultimately evidenced disease involvement (130). In
another Japanese series, examination of long-term toxicity in neuroblastoma patients living
>4 y ears following IORT demonstrated spinal column deformity in 5 of 9 patients, though
only one patient was sy mptomatic (131).
Page 138IORT at the time of primary resection achieves excellent local control in
patients with high-risk NB and is well tolerated. IORT achieves control and survival rates
comparable to those of historical controls while avoiding the use of sy stematic EBRT.
Additional therapy with EBRT may not be warranted in high-risk patients with gross total
resection treated with IORT who have only microscopic residual disease, although more
conclusive evidence requires larger patient numbers and longer follow-up. Higher local
failure rates in patients with high-risk NB after incomplete resections or multiple positive
ly mph nodes warrant additional therapy with EBRT.
Figure: Intraoperative Radiotherapy for
Neuroblastoma
COMPLICATIONS
Patients with high-risk NB often present with large abdominal primaries, abutting or invading
many dose-limiting normal tissues. EBRT to these tumors often entails treating a large volume
of normal tissue, including bowel, liver, kidney, bony structures, and spinal cord. RT to NB
occurring at other primary sites, including the thorax and pelvis, similarly exposes normal
tissues to the risk of long-term side effects. Long-term toxicities associated with radiation are
particularly severe in children (129,132,133). EBRT may also decrease renal function,
resulting in diminished tolerance to high-dose chemotherapy with stem cell transplant.
Acute side effects during RT depend on the precise normal tissues included in the
radiation field. In the treatment of most primary tumors, whether thoracic or abdominal,
radiation to the gastrointestinal tract, particularly the small bowel, may cause nausea and
vomiting. Antiemetic medications are very effective in ameliorating such sy mptoms.
Diarrhea and abdominal pain occur less often, and dietary counseling is generally sufficient
to control such side effects. Some primary tumors and metastatic sites necessitate the
inclusion of significant regions of bone marrow, resulting in a fall in blood counts that
necessitates regular monitoring.
Long-term sequelae of radiation are of particular concern because most patients with
NB are very y oung and prone to such toxicities (123,132,133). Doses of approximately 20
Gy to bones produce only minimal deficits, although specific effects depend on the ty pe of
bone growth: radiation to epiphy ses of tubular bones leads to bone shortening, whereas
radiation to diaphy ses impairs bone modeling and thickness. Effects on bone are highly
dependent on patient age and radiation dose (91). Substantial impairment in bone growth has
been reported for doses greater than 30 Gy, and although doses of 10–20 Gy probably affect
all cell ty pes in maturing bones, such lower doses probably will produce more subtle clinical
sequelae. A report of the long-term side effects from localized NB studies NB90 and NB94
noted 73% late effects in patients receiving multimodal therapy with 50% within the RT field,
most commonly musculoskeletal abnormalities with doses greater than 31 Gy (134). For all
patients, regardless of delivered dose, shielding of bone growth plates will minimize potential
growth arrest and skeletal abnormalities. When one is treating regions close to vertebrae,
radiation of the entire vertebral bodies reduces the risk of scoliosis and other musculoskeletal
abnormalities.
A high incidence of spinal deformity has been seen in long-term survivors of NB.
Among the most common abnormalities are postsurgery or postradiation ky phosis or scoliosis
(103). The incidence of these abnormalities in 5-y ear survivors of NB with paraspinal tumors
ranges from 25% to 50%. Factors associated with development of spinal deformity include
irradiation at a very y oung age, orthovoltage irradiation, asy mmetric irradiation of the spine,
epidural spread of tumor, and laminectomy. In y oung children, a laminectomy may result in
growth abnormality, gibbus formation, and instability of the spine. Therefore, the y oung child
with a dumbbell-shaped tumor is at risk for spinal deformity, and every effort should be made
to minimize this and other late sequelae with the use of chemotherapy when possible as first-
line treatment for cord compression or surgical decompression using osteoplastic laminotomy
rather than traditional laminectomy (83).
In addition to musculoskeletal toxicities, local radiation may cause organ dy sfunction if
tolerance dosages are exceeded. Whole organ tolerance levels generally are presented as
dosages that cause a severe complication rate of 5% within 5 y ears of radiation completion.
These include the lungs (17.5 Gy ), kidney s (20 Gy ), liver (30 Gy ), small bowel (40 Gy ),
ovaries (10 Gy ), and testes (2 Gy ). These tolerance dosages are general guidelines and may
be lower in children and in patients who are also receiving chemotherapy. Skull and orbital
metastases are common in NB, often necessitating irradiation of normal brain tissue. The risks
of neurocognitive dy sfunction and endocrine abnormalities increase with higher dosages of
radiation, larger volumes of irradiated normal brain, and y ounger age at time of radiation.
Lens tolerance is as low as 10 Gy, and dosages to the lens should be minimized to prevent
cataract formation. Permanent alopecia is extremely rare after dosages of 21 Gy or less, but
permanent hair thinning may occur in a small proportion of children.
Investigators at Memorial Sloan–Kettering Cancer Center have described the spectrum
of long-term complications in a population of survivors of advanced-stage NB (133). The
study included 63 survivors with a median age at diagnosis of 3.0 y ears and a median follow-
up from diagnosis of 7.06 y ears. All patients had surgery and received chemotherapy, 89%
received RT, 62% immunotherapy, and 56% autologous stem cell transplant. The vast
majority of survivors (95%) experienced late complications that included hearing loss (62%),
primary hy pothy roidism (24%), ovarian failure (41% of females), musculoskeletal (19%),
and pulmonary (19%) abnormalities. As would be expected based on known toxicities of
specific drugs, survivors who received cisplatin were at greater risk for developing hearing
loss, and greater total doses of cy clophosphamide were associated with ovarian failure.
Although the majority of complications were moderate, 4% were deemed life-threatening.
Page 139Another report investigates potential post treatment complications of aortic
growth inhibition and Middle Aortic Sy ndrome in patients with NB. These investigators used
CT to analy ze effects of RT on the growth of the aorta in NB patients. Abdominal CT scans of
31 patients with intra-abdominal NB (stages II–IV), treated with RT (n = 20 IORT/EBRT, n =
11 EBRT alone), were analy zed retrospectively. The diameter of the abdominal aorta was
measured before and after RT in 31 patients with intra-abdominal NB (stages II–IV) (n = 20
IORT/EBRT, n = 11 EBRT alone). These data were compared to normal, predicted aortic
diameters of children and to a control group of children who did not undergo irradiation. They
found that mean aortic diameters pre-RT and post-RT and the growth of the aorta were
significantly lower than expected for patients with NB and when compared to the growth in a
control group with normal and nonradiated aorta. However, among the radiated patients,
there was no difference due to the ty pe of RT—IORT/EBRT versus EBRT alone. Seven
patients from the IORT ± EBRT group developed vascular complications that included
hy pertension, middle aortic sy ndrome, or death due to mesenteric ischemia, and critical
aortic stenosis that required aortic by pass surgery. These finds led the authors to recommend
that CT evaluations of RT-treated NB patients should include not only reports of changes in
tumor extension, but also documentation of perfusion, size, and growth of the aorta and its
branches over time (135).
Whereas side effects of local radiation depend on the exposed normal structures, TBI
carries inherent toxicities that, like local radiation, worsen with increasing radiation dosage
and decreasing patient age. Long-term side effects of TBI include risks of impaired growth,
chronic interstitial lung disease, cataracts, neurocognitive deficits, chronic renal insufficiency,
dental disturbances, and endocrinopathies (123,133,136,137). After fractionated TBI, a
majority of patients experience diminished height and endocrine deficits, most commonly
manifest by delay ed puberty, but only a minority of patients experience other major organ
toxicities.
Both local RT and TBI carry the risk of second malignancies. Intensive my eloablative
chemotherapy regimens may further potentiate risk of secondary cancers (138). In the
treatment of a malignancy with guarded prognosis such as high-risk NB, the risk of death
from recurrent disease clearly outweighs the risk of death from a second malignancy. One
may extrapolate from a large body of literature in pediatric Hodgkin disease survivors and
assume that children who are cured after receiving radiation for NB will develop additional
cancers 10–20 y ears later (139). Recent data from a SEER database analy sis from 1973 to
2006 of 2801 patients with neuroblastoma demonstrated an overall incidence of 1.2% (34
patients) secondary cancers, 47% of whom had radiation. However, for high-risk patients, the
cumulative incidence of secondary cancers was 10.4% at 30 y ears, as compared to 3.6% for
non–high-risk patients, p < 0.001 (140). Common radiation-related malignancies may include
breast cancer, sarcomas, ly mphomas, and other solid tumors. Long-term survivors of NB
need lifelong screening for late sequelae of RT.
TARGETED RADIONUCLIDES
Targeted radioisotope therapy using anti-GD2 antibody or MIBG for delivery of radiation in
the form of 131I has also been tested in clinical trials in relapsed and newly diagnosed NB
(105). Although responses were reported, 131I-MIBG has only recently advanced into
cooperative or phase III trials, possibly due to the my elosuppression and the lack of an
available commercialized form. MIBG is a guanethidine derivative that is structurally similar
to norepinephrine and therefore concentrates in the neurosecretory granules of
catecholamine secreting cells. Radiolabeled MIBG provides very sensitive and specific
visualization of primary and metastatic NB in 90% of tumors by scintigraphy (25). In an
attempt to deliver higher doses of tumor-specific RT and avoid normal organ toxicity, 131I-
MIBG therapy has been used in pilot trials since the mid-1980s, with more than 500 children
reported in the literature. Initially, it was shown to induce a 30–40% response rate in highly
refractory relapsed patients, without significant nonhematologic toxicity. At low and
moderate doses, up to 12 mCi/kg of 131I-MIBG, the main toxicity has been
thrombocy topenia, usually self-limited. Phase I dosage escalation studies showed that higher
doses, up to 18 mCi/kg, could be administered with bone marrow or peripheral blood stem cell
support to mitigate the neutropenia and thrombocy topenia, but still without other organ
toxicity, excepting a 10–15% incidence of hy pothy roidism caused by an uptake of some free
iodide by the thy roid gland (105). There are a few reports of patients with secondary
leukemia developing after MIBG therapy, but the estimated risk of this problem at 5 y ears
after therapy is only 4%, lower than with some chemotherapy regimens (105). Recent
studies are investigating the use of low-dose 131I-MIBG at diagnosis combined with
chemotherapy before surgical resection (141) or high-dose my eloablative chemotherapy
(61). The response rate in 22 patients treated in the phase I dose escalation of 131I-MIBG
with CEM my eloablative chemotherapy was 27%, and there were 5 patients surviving more
than 3 y ears. A phase II study confirmed the tolerability at 12 mCi/kg, the maximum
tolerable dose combined with CEM. A pilot COG study (ANBL09P1) is currently open testing
the use of 131I-MIBG after five cy cles of induction chemotherapy in newly diagnosed
patients, and preceding my eloablative therapy with BuMel. Additional investigations are
needed to determine the optimal timing and use of this targeted approach.
MOLECULARLY TARGETED AGENTS AND RADIOSENSITIZERS
Initially, irinotecan was tested with MIBG as a radiosensitizer, due to its known activity in
neuroblastoma and radiosensitizing properties in other solid tumors (142). Two studies
combining vincristine and irinotecan in two different schedules with MIBG showed efficacy
and tolerability up to the MTD of 18 mCi/kg, with a response rate of 25% (143). Another
recent example of a radiosensitizer with MIBG therapy is combining with histone deacety lase
inhibitors (HDACIs) that have emerged as a new concept in cancer therapy. Among
HDACIs, vorinostat is furthest along in clinical development and is the first agent in its class to
be approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T-
cell ly mphoma. Several studies have shown that HDACIs, including vorinostat, have
radiosensitizing functions in a variety of cancer models. The underly ing mechanism for
radiosensitization is not fully understood but studies show that vorinostat inhibits expression of
double-strand break repair enzy mes like Rad51 and Ku87.
Page 140Consortium studies, including those within COG, have examined vorinostat as a
single agent and in combination with additional agents (e.g., combined with isotretinoin in the
COG study ). These trials have demonstrated favorable safety profiles in adults and children.
Recent research lends considerable enthusiasm to combining vorinostat and 131I-MIBG
therapy for the treatment of NB. This study finds that not only does vorinostat sensitize NB
cells to radiation in vitro and in vivo, but also it increases expression of the norepinephrine
transporter (NET), which in turn enhances MIBG uptake by NB cells in a dose-dependent
fashion and increased efficacy of radiation in an NB xenograft model (144). Based on these
promising results, NANT conducted a phase I clinical trial (NANT 2007–03) in which
vorinostat was combined with 131I-MIBG therapy for resistant/relapsed NB. The overall
response rate was 17%, and the maximum tolerated dose was 18 mCi/kg of 131I-MIBG and
180 mg/m 2 of vorinostat for 14 day s (145).
Other targeted agents under investigation include inhibitors of specific activated genetic
pathway s, including ALK, Trk B, PI3 kinase, IGF1R, Aurora A kinase, and mTor (6,71).
FUTURE INVESTIGATIONS
Current treatment regimens for NB are risk-based; that is, the biologic characteristics of the
tumor are considered together with traditional clinical prognostic factors in determining the
optimal therapy. As data are accumulated, the most powerful independent prognostic
determinants will be clarified. Areas of active investigation include the following:
Efforts to develop chemotherapeutic agents with new mechanisms of action.

Megatherapy (high-dose chemotherapy with or without RT) followed by hematopoietic
stem cell rescue.
Targeted therapy using radiolabeled MIBG or monoclonal antibodies.
The use of biologic response modifiers or immunotherapy, such as IL-2, IL-12, or
dendritic cells and vaccines. The retinoids, such as 13-cis-retinoic acid and fenretinide,
can decrease tumor cell proliferation, morphologic differentiation, expression of N-myc,
or apoptosis.
Targeted inhibitors of activated critical genetic pathway s.
Clinical studies are in progress to assess the potential benefit of these agents.
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CH A P TER 7
Hodgkin Lymphoma
Stephanie A. Terezakis, Monika Metzger, and Louis S. Constine
Page 145The clinical challenge in pediatric Hodgkin ly mphoma (HL) is to continue the
progress of achieving curability while diminishing the risk for the morbidities that
compromise quality of life and survival. The history of pediatric HL is, of course, the history
of Hodgkin ly mphoma. In 1832, Thomas Hodgkin (1) described seven patients with enlarged
absorbent (ly mphatic) glands not thought to result from inflammation. At the turn of the
century, Sternberg and Reed each described the multinucleated giant cell characteristic of HL
(2). Shortly after the discovery of X-ray s in 1902, Pusey (3) demonstrated the
radioresponsiveness of HL. In the 1930s, Gilbert (4) laid the foundation for definitive
treatment of HL with radiotherapy (RT), and Peters (5) provided additional definition of
important principles. During World Wars I and II, the ly mpholy tic effects of nitrogen mustard
were recognized (6), and over the next two decades, progress in safely combining multiple
chemotherapeutic agents to treat HL led to DeVita’s (7) report on the use of nitrogen mustard,
vincristine (Oncovin), procarbazine, and prednisone (MOPP) chemotherapy. Kaplan (2)
sy stematically studied the role of RT for HL during these decades. Concurrently, advances
were made in identify ing different pathologic subty pes, determining staging criteria,
improving diagnostic imaging capabilities, and developing effective chemotherapeutic
regimens. When the clonality of the Hodgkin–Reed–Sternberg (HRS) cell was finally
established in the 1960s, controversy over the malignant or inflammatory nature of HL
abated (8).
Although the biology and natural history of HL in children are similar to that in adults,
when irradiation techniques and dosages suitable for controlling disease in adults were
translated to the pediatric setting, substantial morbidities (primarily musculoskeletal growth
inhibition) were the result (9,10). It is in this context, new strategies for the treatment of
pediatric HL were developed by Donaldson and others (11,12,13,14,15,16,17,18,19).
Historically, children were thought to have a worse prognosis than adults (2). It is now
apparent that the reverse is true (20,21,22).
BIOLOGY
For many y ears, the rarity and distribution of malignant cells in pathologic material
precluded elucidation of the origin and evolution of the HRS cell. Advances in
immunohistology and molecular biology subsequently revealed that the HRS cell and its
variants most commonly derive from a neoplastic clone that originates from B ly mphocy tes
in ly mphoid germinal centers. Clonality can be demonstrated at diagnosis and relapse through
detection of unique nucleotide sequences, which molecularly fingerprint the HRS cell clone;
these sequences represent rearrangements of immunoglobulin variable-region (V) genes,
which are B-cell derived (23,24). Complicating this scenario is the finding by Kanzler et al.
(24) that flawed V genes, which would be lethal for normal B cells, are present in HRS cells
and prevent them from expressing immunoglobulin. Such cells would be expected to die of
apoptosis. Therefore, the genesis of classic HL (CHL) probably involves evasion by the HRS
cell of the apoptotic pathway. Deregulation of the nuclear transcription factor (NF-κB) in the
HRS cells has been hy pothesized as a mechanism that prevents apoptosis (25). Epstein–Barr
virus (EBV) and genes that monitor cell damage, such as p53, may play a role in the rescue
and repair of the HRS cells (24,26). EBV genome fragments can be found in HRS cells in 30–
50% of HL specimens, most commonly in the mixed-cellularity HL (MCHL) subty pe and
rarely in the nodular ly mphocy te-predominant HL (NLPHL) subty pe (27,28). The EBV
genome is temporally stable because it can be found at diagnosis and relapse. Finally, the
HRS cell can also have characteristics of T ly mphocy tes and the interdigitating reticulum
cell. Such evidence of a multilineage origin of the HRS cell may be explained by postulating
that the HRS cell is a hy bridoma resulting from fusion of different cell lines, provoked by a
virus or other agent. Cy togenetic data also show an unexpected frequency of B-cell
translocation (14:18) and bcl-2 gene involvement in HL, but these may derive from
by stander normal ly mphocy tes rather than the HRS cell (29). The complexity of elucidating
the etiology of HL continues to unfold and is illustrated by data that not only support the
association of infectious mononucleosis with EBV-positive HL, but also suggest that EBV-
negative HL has a different etiology (30). A pathogenetic model for HL is depicted in (Fig.
7.1 ), which suggests that the HRS cells arise in a germinal ly mphoid center from a clone
of antigen-stimulated B cells and through genetic changes achieve immortality and malignant
properties (31).
Figure 7.1 The derivation of Hodgkin and Reed–Sternberg cells in classic Hodgkin
lymphoma and lymphocytic and histiocytic cells in nodular lymphocyte-predominant
Hodgkin lymphoma. (From Thomas RK, Re D, Wolf J, et al. Part 1: Hodgkin’s lymphoma–
molecular biology of Hodgkin and Reed–Sternberg cells. Lancet Oncol. 2004;5:11–18.)
Page 146A curious characteristic of HL is the rarity (about 1%) of the malignant HRS
cell in specimens and the abundant reactive cellular infiltrate of ly mphocy tes, macrophages,
granulocy tes, and eosinophils. The histologic features and clinical sy mptoms of HL have
been attributed to the numerous cy tokines secreted by the HRS cells, which include interleukin
(IL)-1 and IL-6, and tumor necrosis factor (TNF) (32,33). IL-5 could be responsible for the
eosinophilia in MCHL, and transforming growth factor beta could be responsible for the
fibrosis in the nodular sclerosis subty pe. These cy tokines also enable the cells to evade
immunologic surveillance and promote their own replication (32).
Evidence that HL comprises a family of diseases includes the observation that HRS cells
can rarely be derivatives of cy totoxic T cells and that NLPHL is a distinctive and uncommon
ly mphoproliferative disorder. The ly mphocy tic and histiocy tic (L&H) cells characteristic of
NLPHL have folded and lobate nuclei among small ly mphocy tes and histiocy tes. The L&H
cells are also B-cell–derived but harbor V gene alterations, which differ from those in HRS
cells; whether the L&H cells are monoclonal is unclear (34,35). The clinical characteristics
of NLPHL differ from those of the subty pes of CHL by virtue of its indolence, excellent
prognosis, epidemiology, and response to chemotherapy. In the 2008 World Health
Organization (WHO)/Revised European–American Classification of Ly mphoid Neoplasia
(REAL) there is a clear distinction of NLPHL from CHL (36).
Several aspects of the biology of HL continue to unfold, and many have prognostic
applicability. For example, loss of CD15 expression may be a prognostic factor for PHL
clinical outcomes, although CD15 expression has been inconsistent possibly due to biologic or
technical variability (37,38). A high proliferative index (PI) may suggest
chemoresponsiveness and, as a result, a low pretreatment PI may be associated with poor
outcomes (37,38). Increased CD68 and CD163 expression in the microenvironment have also
been reported as predictors of inferior outcome in classicl HL (39,40). However, this finding
has not y et been confirmed in a pediatric cohort (41).
Figure:
The derivation of Hodgkin and Reed–Sternberg cells in classic Hodgkin lymphoma and
lymphocytic and histiocytic cells in nodular lymphocyte-predominant Hodgkin lymphoma.
(From Thomas RK, Re D, Wolf J, et al. Part 1: Hodgkin’s lymphoma–molecular biology of

Hodgkin and Reed–Sternberg cells. Lancet Oncol. 2004;5:11–18.)
EPIDEMIOLOGY
HL makes up 6% of childhood cancers. A striking male:female predominance is found among

children, with a ratio of 4:1 for 3- to 7-y ear-olds, 3:1 for 7- to 9-y ear-olds, and 1.3:1 (a ratio
more similar to that of adults) for older children (20,42,43). The age-specific incidence
curves for HL in the United States and other developed countries are bimodal, peaking in the
20s and then again after the age of 50 (44). The disease is uncommon before age 5 and,
among children, is most common in adolescence. Not only does the incidence of pediatric
HL vary in y ounger children versus adolescents, but the histologic subty pes and associations
with EBV also vary (45).
Page 147Although evidence that HL is infectious or contagious was suggested by reports
of case clusters (46), confirmatory data are lacking. However, the role of EBV in the
pathogenesis of EBV-positive HL is well established (30). EBV early RNA1 is expressed in
HRS cells in 58% of childhood cases (47). Of particular interest, expression was age-
dependent: 75% of children under the age of 10 y ears compared with 20% of older children.
In addition, a history of infectious mononucleosis increases the risk for HL, and anti-EBV
titers are elevated before the diagnosis of HL.
In a large population-based study, infectious mononucleosis was associated with an
increased risk of EBV-positive HL with an odds ratio of 3, but did not increase risk for EBV-
negative HL (30). EBV latent membrane protein (LMP-1) is expressed in CHL and has been
correlated with serum IL-10 levels (48). LAG-3 expression, a marker for regulatory T cells,
is also associated with EBV positivity and related to impairment of LMP-1 function (49).
Several reports have suggested that EBV positivity is most common in the MCHL subty pe
(50,51,52,53). There has been conflicting evidence as to whether latent EBV infection carries
prognostic significance. LMP-1 positivity has been associated with inferior survival in patients
with nodular sclerosis cellular subty pe Bennett II and those with advanced-stage disease
despite a lack of influence on failure-free survival. LMP-1 emerged as an independent
prognostic factor for overall survival (OS) on multivariate analy sis in a study by Claviez et al.
(50). EBV positivity has also been associated with inferior OS in patients greater than the age
of 50 when adjusting for stage, sex, and B sy mptoms, although it was not associated with
inferior disease-specific survival (51). The analy sis by Herling et al. (52) revealed no
significant differences associated with expression of LMP-1 in failure-free survival or OS
after adjustment for stage and age. Current data suggest that in EBV-positive pediatric HL, an
effective immune response directed against viral or tumor antigens may be triggered in the
tumor microenvironment. That microenvironment may be altered by age and phy siologic
changes. For example, children <10 y ears old with EBV-positive CHL were found to have a
more intense T-cell infiltrate with higher numbers of CD3+ , CD8+ , TIA1+, and TBET+
ly mphocy tes (53). Understanding the pathogenesis and prognostic implications of EBV-
associated HL may help to improve immune-directed therapeutic strategies.
Evidence of a genetic predisposition exists and is relevant when counseling families. The
incidence of HL is two to five times higher in the siblings of affected children and nine times
higher in same-sex siblings than in the general population. Parent–child associations have
been reported (30,54). Mack et al. (55) reported a 99-fold increased risk in monozy gotic twins
of patients but no increased risk in dizy gotic twins. The Children’s Oncology Group (COG)
performed a study demonstrating that pediatric/adolescent HL was associated with a positive
family history, particularly in those with early -onset cancers and those in the paternal
lineage. There were no patterns noted between EBV (+) and EBV (−) HL (56). The status of
the immune sy stem in patients with HL also deserves comment. A complex deficiency in
cellular immunity exists, which includes a deficiency in naive T cells and an elevated
sensitivity of effector T cells to suppressor monocy tes and T-suppressor cells (57). Of interest
is that radiation results in a long-term dy sregulation of T-cell subset homeostasis. Finally, it is
unclear whether HL is more common in patients with either congenital (e.g., ataxia–
telangiectasia) or acquired immunodeficiency states, including acquired immunodeficiency
sy ndrome (43,58), but HL is rarely seen as a second malignancy. In patients with the HIV,
the disease more commonly presents in an advanced stage with sy stemic sy mptoms,
extranodal involvement, and a poor response to therapy (59).
HL appears to be unifocal in origin, with 90% of patients presenting in a pattern that suggests
contiguous ly mphatic spread (2,60). Most children are diagnosed on the basis of
supradiaphragmatic ly mph nodes, with mostly painless cervical adenopathy in 80%. The
nodes are generally firm and may be occasionally be tender. Mediastinal involvement occurs
in 76% of adolescents but in only 33% of 1- to 10-y ear-olds. Mediastinal disease may
produce sy mptoms such as dy spnea, cough, and superior vena cava sy ndrome. Axillary
adenopathy is less common (2). Associations exist between the mediastinum and the neck, the
neck and the ipsilateral axilla, the mediastinum and the hilum, and the spleen and abdominal
ly mph nodes (60). Isolated mediastinal or infradiaphragmatic HL is rare, occurring in fewer
than 5% of patients. About one-third of the patients have sy stemic “B” sy mptoms, as defined
in Table 7.1 (2,61).
Table 7.1 Ann Arbor Staging System with Cotswold Modifications for Hodgkin
Lymphoma
Figure: Ann Arbor Staging System with
Cotswold Modifications for Hodgkin
Lymphoma
PATHOLOGIC CLASSIFICATION
The HRS cell is the essential malignant cell in

HL (Fig. 7.2 ). It is large, with abundant
cy toplasm, two or three nuclei, and a prominent
nucleolus. However, its frequency in pathologic
specimens is greatly variable (1–2%) because of
the presence of numerous reactive cells
including ly mphocy tes, eosinophils, and plasma Figure 7.2 Reed–Sternberg cell.
cells. Moreover, the HRS cell, particularly its
mononuclear variant, is not pathognomonic for
HL because cells simulating it can be found in
other disorders that are reactive, infectious, or
malignant (62). The diagnosis of HL must be
established by excisional ly mph node biopsy.
Aspiration cy tology alone is not recommended
because of the lack of stromal tissue, the small
number of cells present in the specimen, and the
difficulty of classify ing HL into one of the WHO
classifications. The WHO classification Table 7.2 WHO Classification of
subcategorizes CHL into nodular sclerosing Hodgkin Lymphoma
(NSHL), MCHL, ly mphocy te rich (LRHL), and
ly mphocy te depleted (LDHL) ty pes, and then there is NLPHL (see Table 7.2 ) (36). With
modern treatment the prognostic significance of these subty pes has diminished, although the
presenting characteristics and natural history remain evident, particularly for the nodular
subty pe of NLPHL. The clinicopathologic characteristics in adults are briefly described here.
Page 148NLPHL (63): The distinctive cell is the L&H “popcorn” cell, which is CD20
(B-ly mphocy te marker) positive and CD15 negative. Classic HRS cells (which are
usually CD15 and CD30) are rare, as is the detection of EBV. Progressive transformation
of the germinal centers of ly mph nodes is often seen, and, in fact, can occur in the
absence of NLPHL. Therefore, it is important to distinguish these entities. NLPHL has a
long natural history, in its time to diagnosis and to relapse, reminiscent of that of indolent
non-Hodgkin ly mphomas (NHL). It is more common in y oung children (33% of all
patients are y ounger than 15 y ears), has a high male:female ratio (4:1), and commonly
involves a single ly mph node region with sparing of the mediastinum (64).
Ly mphocy te-rich (classic) HL: HRS cells (CD15) are identifiable against a background
predominantly of ly mphocy tes. Clinical behavior is similar to that of MCHL.
Mixed-cellularity (classic) HL: HRS cells (CD15) are common against a background of
abundant normal reactive cells (ly mphocy tes, plasma cells, eosinophils, histiocy tes).
This subty pe can be confused with peripheral T-cell NHL.
Nodular sclerosis (classic) HL: This subty pe is distinctive because of the presence of
collagenous bands that divide the ly mph node into nodules, which often contain an HRS
cell variant called the lacunar cell. NSHL often occurs in children, involves
supradiaphragmatic nodes, and spreads in an orderly manner along contiguous nodal
chains.
Ly mphocy te-depleted (classic) HL: This subty pe is rare and commonly confused with
NHL, particularly of the anaplastic large cell ty pe. HRS and pleomorphic variants are
common relative to the number of background ly mphocy tes. LDHL often is advanced at
diagnosis and has a poor prognosis.
Page 149Although the pathologic and immunohistochemical characteristics of HL generally

are sufficiently clear to establish a diagnosis, confusion with select subty pes of NHL is
problematic. In particular, CHL can be confused with anaplastic large cell NHL, and NLPHL
can be confused with T-cell–rich B-cell NHL (32).
The relative distribution of the subty pes in y ounger children differs from that in
adolescents and adults, as reported from Stanford University (20). NLPHL is more common
(13%) in y ounger children (y ounger than 10 y ears), whereas LDHL is exceedingly rare.
Although NSHL is the most common subty pe in all age groups, it is more common in
adolescents (77%) and adults (72%) than in y ounger children (44%). Conversely, MCHL is
more common in y ounger children (33%) than in adolescents (11%) or adults (17%).
Figure:
Reed–Sternberg cell.
Figure: WHO Classification of Hodgkin
Lymphoma
STAGING
Using anatomic groups of regional ly mph nodes, the staging sy stem was designed for all age
groups, according to a modification of the sy stem devised at the 1970 Ann Arbor
Sy mposium. This was subsequently revised at the Cotswold’s Meeting, although not all
suggestions from those recommendations are consistently used (61).
A weakness of the Ann Arbor sy stem is its failure to consider disease bulk (either
dimension or number of involved sites) or specific patterns of involvement. For this reason,
subclassifications of the Ann Arbor staging sy stem have been proposed, particularly for
patients with large mediastinal adenopathy (LMA). LMA, most commonly defined as a mass
exceeding one-third the transverse diameter of the chest (intrathoracic width measured at the
dome of the diaphragm) on a standard upright posteroanterior (PA) chest radiograph, places a
patient at a greater risk for disease recurrence after radiation alone. Despite the requirement
to obtain chest CT scan for staging, bulk is still determined on current COG protocols by PA
upright chest radiograph. In the European Pediatric Hodgkin ly mphoma consortium
(EuroNet-PHL), bulk is defined by volumetric assessment of the mass and any mass >200
mL is considered bulky whether in the mediastinum or a peripheral nodal group.
The distribution of stages observed in children is somewhat different from that observed
in adults. Table 7.3 summarizes the demographic and clinical features of children,
adolescents, and y oung adults presenting with HL (65). Among 3571 consecutive patients with
HL treated at three pediatric centers, 18.1% were y ounger than 10 y ears and 81.4% were
11–16 y ears old. Stage I or II disease was present in 65.8% of children.
Table 7.3 Demographic and Clinical Characteristics at Presentation of Pediatric
Hodgkin Lymphoma
Figure: Demographic and Clinical
Characteristics at Presentation of Pediatric
Hodgkin Lymphoma
DIAGNOSTIC EVALUATION
Page 150After pathologic confirmation, the patient undergoes an extensive clinical staging.
This begins with a detailed history of sy stemic sy mptoms and evidence of cardiorespiratory
compromise or organ dy sfunction. The phy sical examination carefully records the location
and size of all palpable ly mph nodes. An evaluation of Waldey er ring, cardiorespiratory
status, and organomegaly is vital. Laboratory studies include complete blood count with
platelets and biochemical evaluation of renal and liver function. Acute phase reactants,
including ery throcy te sedimentation rate, C-reactive protein serum copper, and ferritin, may
be elevated at diagnosis and can be used as nonspecific marker of disease activity. Elevated
serum CD30 and CD25 have been correlated with advanced stage, the presence of
constitutional sy mptoms, and poor prognosis; however, these studies have not been widely
used to risk stratify and monitor patients during therapy (66,67,68). Patients with “B”
sy mptoms (fevers of unexplained origin, >10% unintended weight loss within the last 6
months and drenching night sweats) or stage III–IV disease historically underwent bone
marrow biopsy for routine staging (69). HL may present focally in the bone marrow and
bone marrow biopsy may miss the site of involvement. Thus, FDG-PET may evaluate all the
bone marrow at once and has been shown to have increased sensitivity and specificity
relative to bone marrow biopsy (70). The low y ield of a bone marrow evaluation in
asy mptomatic patients with localized disease (stage I and II) does not support routine use of
the procedure.
Imaging studies of the thorax should include a chest radiograph with a PA and lateral
view. It should be noted that the LMA ratio, if based on computed tomography (CT) scan
measurements, would increase the frequency of patient’s LMA since a mediastinal mass will
splay bilaterally in a reclined child. CT scans with contrast are essential for delineation of the
status of intrathoracic ly mph node groups (including the hila and cardiophrenic angle), lung
parenchy ma, pericardium, pleura, and the chest wall, demonstrating abnormalities in about
one half of patients with unremarkable chest radiographs (22,71). Distinguishing normal (or
hy perplastic) thy mus from nodes in children can be difficult.
Imaging of the abdomen and pelvis may involve an abdominal and pelvic CT scan or
magnetic resonance imaging (MRI). If CT is used, oral and intravenous contrast
administration is needed to accurately distinguish retroperitoneal and pelvic ly mph nodes
from other infradiaphragmatic structures. In cases with suboptimal contrast resolution of the
bowel, MRI may provide a better evaluation of the fat-encased retroperitoneal nodes (72). In
previous German and Pediatric Oncology Group (POG) trials using CT or MRI for staging,
the size of abdominal and pelvic ly mph nodes was used to define the extent of disease
involvement. Abdominal nodes less than 1.5 cm in diameter and pelvic nodes less than 2 cm
were considered negative, whereas abdominal nodes more than 2 cm in diameter and pelvic
nodes more than 3 cm were considered positive. This is no longer used in the positron
emission tomography (PET) era but an understanding is needed to interpret results of older
trials and ultimately, indeterminate nodes may require biopsy.
HL involving the liver and spleen is suggested by CT or MRI findings of organomegaly
with areas of abnormal density representing ly mphomatous deposits. Organ size alone does
not predict ly mphomatous involvement. PET scans are very sensitive at identify ing
involvement of liver and spleen.
Nuclear imaging with gallium-67 was historically used to stage and monitor treatment
response in children with HL. However, gallium had limitations because of its low resolution
and phy siologic bio-distribution, causing difficulties in evaluating abdominal and pelvic ly mph
nodes and necessitates delay ed imaging. PET is now recognized as an integral staging
modality for ly mphoma (73,74,75). Uptake of the radioactive glucose analog
fluorodeoxy glucose (FDG) correlates with proliferative activity in tumors undergoing
anaerobic gly coly sis. FDG-PET provides full-body imaging in which areas of abnormal
avidity have been correlated with treatment outcomes. PET does have limitations in the
pediatric setting (e.g., tracer avidity in nonmalignant thy mic rebound commonly observed
after completion of therapy for HL and uptake in the case of benign brown fat) (76). The
Deauville criteria is a scoring sy stem now used to assess the level of FDG uptake relative to
uptake in the liver and mediastinum. These criteria are used to give patients a “score” both
upfront in staging and to classify response, either interim or at completion of therapy (Fig.
7.3 ). Current clinical trials are intensify ing or de-escalating therapy based on
chemotherapy response scored by the Deauville criteria.
Figure 7.3 A: Deauville Criteria (images below courtesy of Steve Cho MD, University of
Wisconsin). B: Baseline FDG PET/CT—Coronal. Deauville 5, Lymphoma Multiple mediastinal
and abdominal retroperitoneal disease [Markedly increased uptake]. C: Postcycle-2 FDG
PET/CT—Coronal, Deauville 5, Residual Lymphoma.
Figure:
A: Deauville Criteria (images below courtesy of Steve Cho MD, University of Wisconsin). B:
Baseline FDG PET/CT—Coronal. Deauville 5, Lymphoma Multiple mediastinal and abdominal
retroperitoneal disease [Markedly increased uptake]. C: Postcycle-2 FDG PET/CT—Coronal,
Deauville 5, Residual Lymphoma.
PROGNOSTIC FACTORS
As the treatment of HL has improved, characteristics that influence outcome have diminished
in importance. However, several factors continue to influence the success and certainly the
choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and
biologic aggressiveness often are codependent. Also complicating the determination of
prognostic factors is that relevant variables often depend on staging evaluation and treatment.
Most data are based on reports that include primarily adults.
The disease stage persists as the most important prognostic variable. Patients with
advanced-stage disease, especially stage IV, have a worse outlook than those with early -stage
disease (77).
The bulk of disease is reflected by the disease stage and is determined more specifically
by the volume of distinct areas of involvement and the number of disease sites. LMA places a
patient at a greater risk for disease recurrence. While OS remains high due to the
effectiveness of salvage chemotherapy (2,22,78), patients with LMA have a somewhat lower
survival rate in most, but not all series (2,22,79). Patients with several sites of involvement,
generally defined as more than three sites, fare less well (22). Patients with stage IV disease
who have multiple organs involved fare especially poorly.
Page 152Nonwhite pediatric patients presented more frequently with advanced-stage
disease based on a study population derived from two South African hospitals although white
children had a lower OS (80). In this report, nonwhite pediatric patients had better survival
when compared to white pediatric patients of the same stage. However, in a study from St.
Jude Children’s Research Hospital, black pediatric patients had lower event-free survival
(EFS), but equivalent 5-y ear OS to white pediatric patients (81). The impact of race on
prognosis remains unclear particularly given the potential impact of socioeconomic, cultural,
and environmental differences between white and nonwhite populations that may play a role
in clinical outcomes.
Systemic (“B”) symptoms, which result from cy tokine secretion, reflect biologic
aggressiveness and confer a worse prognosis.
Laboratory studies/biologic markers, including the ery throcy te sedimentation rate, serum
ferritin, hemoglobin level, serum albumin, and serum CD8 antigen levels, have been reported
to predict a worse outcome (66,67,82,83). This could reflect disease biology or bulk. Other
investigational serum markers associated with an adverse outcome include soluble vascular
cell adhesion molecule-1 (84), TNF (85), soluble CD30 (28,86), beta-2-microglobulin (87),
transferrin, and serum IL-10 (88). Beta-2-microglobulin is the most commonly altered gene
in Reed–Sternberg cells with the majority of cases having inactivating mutations that lead to
the loss of major histocompatibility complex class I (MHC-1) expression. The absence of the
beta-2-microglobulin protein was associated with lower-stage disease, y ounger age at
diagnosis, and better clinical outcomes, including better survival and progression-free survival
(89). High levels of caspase 3 in HRS cells have been correlated with a favorable outcome
(90). Serum vascular endothelial growth factor (VEGF) levels may also have prognostic
implications. VEGF is a proangiogenic molecule involved in neovascularization of tumors.
Increased microvessel density associated with increased VEGF level expression has been
demonstrated in HL progression (91) and VEGF expression has been identified in HRS cells
(92). Pretreatment levels of angiogenic factors have been found to be significantly elevated
in HL patients compared to controls and high levels of VEGF have been associated with poor
survival (93). Serum VEGF levels have also been associated with treatment response in
children with HL (94). In a study by Ben Arush et al. (94), serum VEGF levels correlated
with treatment response in seven of nine children with HL. A significant reduction in serum
VEGF level was identified in patients with a partial or complete response based on an
assessment using PET-CT. The identification of angiogenic factors that play a role in the
clinical course of HL may have therapeutic implications for the use of anti-angiogenic agents
in the future. Other biologic factors that may enable prognostic modeling continue to be
discerned (95,96). A study from the Groupe d’Etude des Ly mphomes de l’Adulte (GELA)
prospectively analy zed the prognostic value of TNF, soluble receptors TNF-R1 and TNF-R2,
IL-10, IL1-RA, IL-6, and sCD30 in patients with an initial diagnosis of CHL. Five-y ear EFS
probability was predicted by segregating combinations of serum marker levels into four
prognostic classes, suggesting that a plasma cy tokine signature may predict clinical outcomes
in CHL (96).
Histologic subtype is relevant but may differ in children versus adults. For example,
adults with clinical stage I or II MCHL have a higher frequency of subdiaphragmatic relapse
which may indirectly influence survival (22). NSHL histology has conferred poor outcome in
some but not all studies (97). Patients with LDHL fare poorly. A report from the United
Kingdom Children’s Cancer Study Group assessing the relevance of histology in 331 children
is revealing. Fewer than 1% had LDHL, obviating any meaningful assessment of its
prognostic significance. For patients with other histologies treated with combined therapy, no
difference in outcome was observed (98). As previously discussed, patients with NLPHL
have distinctive differences in disease-free survival and OS.
Age is a significant prognostic factor in some studies. Survival rates for children with HL
approach 95%. In a report from Stanford, the 5- and 10-y ear survival rates for children
y ounger than 10 y ears with HL are 94% and 92%, respectively, compared with 93% and
86% for adolescents (11–16 y ears old) and 84% and 73% for adults (20). Although children
y ounger than 4 y ears with HL are uncommon, even these children appear to have an
excellent prognosis (21).
Imaging The rapidity of response to initial therapy is an important prognostic variable in
many forms of cancer, including HL. In some trials, the rapidity of response to
chemotherapy is used to determine subsequent therapy (99). There have been a number of
recent investigations evaluating early response to therapy, as measured by FDG-PET
imaging, as a possible marker of prognosis. The NPV of PET was evaluated in the GHSG
HD15 trial. After patients received BEACOPP-based chemotherapy, PET was used to assess
residual disease measuring greater than or equal to 2.5 cm in diameter. Progression-free
survival was significantly improved in PET negative patients (96%) as compared to PET
positive patients (86%) (p = 0.011) (100). PET done at the completion of chemotherapy
successfully guided the need for additional radiotherapy in this combined modality setting
(101). The relapse patterns suggested that local RT to PET-positive residual disease was
sufficient for patients with advanced stage HL with only 16% of patients who received
adequate RT relapsing compared to 24% with inadequate RT (102). In the setting of stem cell
transplant for refractory /recurrent HL, pretransplant functional imaging response has been
found to predict outcome. Patients with positive PET or gallium scans prior to undergoing
high-dose chemotherapy with autologous stem cell transplant had a significantly lower 3-
y ear PFS and OS rates than patients with negative functional imaging (103).
Most recently, attention has been paid to developing an International Prognostic Score
(IPS) for children (e.g., CHIPS). About 1721 patients with intermediate risk HL were treated
on Children’s Oncology Group protocol, AHOD0031 and 770 patients were randomized or
assigned to receive treatment with four cy cles of ABVE-PC and IFRT. Of the variables
examined, four were found to be predictive of adverse event-free survival (EFS) including
stage IV disease, large mediastinal adenopathy, albumin <3.5 and fever. Patients with CHIPS
0 or 1 (N = 589) had an EFS of nearly 90% compared to 78% with CHIPS 2 (N = 141) and
62% with CHIPS 3 (N = 32) (104).
Page 153Prognostic factors will continue to be influenced by choice of therapy ;
parameters such as disease, bulk, number of involved sites, and sy stemic sy mptoms are likely
to remain relevant to outcome. Nonetheless, as therapy becomes increasingly tailored to
prognostic factors and therapeutic response, overall outcome should become less affected by
those parameters.
HL is one of the pediatric malignancies that has an adult counterpart with a similar natural
history and biology. The overall 5-y ear relative survival from the SEER database for 2002–
2008 was reported to be 84.7% with children and adolescents having a significantly better
HL-specific 5-y ear survival (96%) than adults (88%) (p < 0.001) (105). However, devising
the optimal therapeutic approach for children with this disease is complicated by their greater
risk for adverse effects. In particular, RT dosages and fields used in adults can cause profound
musculoskeletal retardation, including intraclavicular narrowing, shortened sitting height,
decreased mandibular growth, and decreased muscle development in the treated volume (see
Chapter 19 ) (9,10). Adults with early -stage HL were historically treated with full-dose
radiation as a single modality (22). However, in prepubertal children, despite a similar
success rate, this approach produced unacceptable sequelae (10,19,74,106). Additionally
complicating the treatment of children are sex-specific differences in chemotherapy -induced
gonadal injury. The desire to cure y oung children with minimal side effects has stimulated
attempts to reduce staging procedures, the intensity and ty pes of chemotherapy, and the
radiation dosage and volume. Because of the differences in the age-related developmental
status of children and the sex-related sensitivity to chemotherapy, no single treatment method
is ideal for all children.
Important studies using chemotherapy and low-dose radiation in children to effect cure
with tolerable sequelae were first undertaken at Stanford University. These trials used
chemotherapy in combination with lower dosages of RT for y oung children with early -stage
disease (2,11,12). An important sequence of studies performed by the German-Austrian
Pediatric Hodgkin’s Disease Study Group progressively refined the extent of staging and the
intensity of chemotherapy and radiation (14,16,107). Stage dependent chemotherapy and
radiation dosage and volume were used and these studies served as the paradigm for
refinement of the risk-adapted treatment approach that is currently used at most pediatric
treatment centers.
In general, the use of radiation and chemotherapy broadens the spectrum of potential
toxicities while reducing the severity of individual (drug- or radiation-related) toxicities. The
volume of radiation and the intensity and duration of chemotherapy are risk adapted, or
determined by prognostic factors at presentation, including presence of constitutional
sy mptoms, disease stage, and bulk.
EVOLUTION OF COMBINATION CHEMOTHERAPY
MOPP was the standard chemotherapy regimen used in the United States for many y ears
after DeVita et al.’s 1972 report (108). The major toxicities include an associated risk of acute
my eloid leukemia, azoospermia in more than 90% of boy s treated at any age, and a risk of
sterility in girls, which increases with age (109,110). Subsequently, the effectiveness of
Adriamy cin, bleomy cin, vinblastine, and dacarbazine (ABVD) as front-line chemotherapy
was established (111,112,113). Second malignancies and sterility were less common with
ABVD than with MOPP (114). The predominant adverse effects of ABVD are pulmonary
toxicity related to bleomy cin and cardiovascular toxicity secondary to Adriamy cin. These
side effects may be exacerbated by the addition of irradiation (115). Over the y ears, the
MOPP and ABVD regimens have undergone a variety of modifications, but the majority of
the chemotherapeutic regimens used today are derived from these two combinations.
The current era of risk-adapted response-based therapy for PHL presents several critical
issues regarding the role of RT.
For patients with PHL, is chemotherapy alone adequate without administering excessive
amounts or using overly aggressive combinations in terms of potential morbidities?
Embedded in this question are the relative toxicities of curative chemotherapy versus
less chemotherapy plus RT.
Can the rapidity and the completeness of the response to chemotherapy define the use of
RT, and how will functional imaging enhance the precision of this approach?
When RT is administered, then what is the appropriate target volume? Can RT be
restricted to initially involved ly mph nodes rather than chains (or regions) of nodes? In
what settings should RT be directed to areas of initial bulk disease or residual
postchemotherapy disease? Should involved organs, such as the liver, lung, and heart,
ever be irradiated?
If we use RT, what is the appropriate dose? Should this be dependent on the initial or
postchemotherapy extent of disease, bulk of disease, organ at risk, and age of the patient?
Inherent in these questions is the recognition that RT is effective in locally controlling PHL but
provokes a dose-dependent spectrum of toxicities. Most profound are musculoskeletal growth
inhibition, coronary artery disease and cardiomy opathy, pulmonary fibrosis, infertility, and
subsequent malignancies. However, eliminating RT necessitates more toxic chemotherapy
(either agents or amounts). Discerning the ideal balance will maximize cure while minimizing
toxicity. We address these questions in upcoming sections.
Few randomized controlled trials have prospectively compared chemotherapy alone
with combined-modality therapy in children and adolescents with HL (112,113,116,117,118).
In an important CCG trial reported by Nachman et al. (116), chemotherapy alone using the
COPP and ABV hy brid regimen was compared with combined-modality therapy including
low-dose involved-field radiation treatment (IFRT). Treatment assignment was risk-adapted
based on the presence of clinical features including the presence of “B” sy mptoms, hilar
adenopathy, mediastinal and peripheral ly mph node bulk, and the number of involved nodal
regions. Patients with favorable disease presentations received four cy cles of COPP and
ABV; those with unfavorable risk features received six cy cles of COPP and ABV. Patients
with stage IV HL received sequential cy cles of high-dose cy tarabine and etoposide, COPP
and ABV, and cy clophosphamide, vincristine, doxorubicin, and methy lprednisolone. Patients
achieving a complete response to chemotherapy were eligible for randomization to receive
low-dose IFRT or no further therapy. The trial was terminated prematurely because results
indicated a significantly higher number of relapses among patients treated with
chemotherapy alone. The 3-y ear EFS estimates according to patient randomization were
92% for patients treated with combined-modality therapy and 87% for those treated with
chemotherapy alone; the benefit of IFRT remained significant in the as-treated analy sis. The
difference was most marked in patients with stage IV disease, who had 90% EFS if
randomized to receive IFRT and 81% if randomized to receive chemotherapy alone. In a
recent update, Wolden et al. (119) reported 10-y ear clinical outcomes of the study after a
median follow-up of 7.7 y ears. Ten-y ear EFS and OS rates for the entire patient population
were 83.5% and 92.5%. In the as-treated analy sis for randomly assigned patients, the 10-
y ear EFS was 91.2% for patients who received IFRT and 82.9% for those that received no
further therapy (p = 0.004). There was no difference in OS for the two groups (97.1% for
those who received RT vs. 95.9% for no further therapy, p = 0.50). Inferior EFS was
associated with bulk disease, B sy mptoms, and nodular sclerosing histology.
Page 154Because of successful salvage therapy after relapse, estimates of OS do not
differ between the randomized groups in early follow-up. However, other investigations of
long-term outcomes after treatment for PHL implicate retrieval therapy after relapse as a
significant risk factor for neoplastic complications and early mortality (120,121). In the
German-Austrian Pediatric Hodgkin’s Disease Study Group (GPOH) HD-95 trial, relapse-
free survival rates were higher for patients treated with RT after partial response (93%) than
for those without RT after complete response (89%) (122). The difference was significant for
patients treated for advanced-stage but not early -stage disease. Kaplan–Meier analy sis after
5 y ears demonstrated that the DFS was lower in nonirradiated patients than in irradiated
patients (p = 0.049). Again, there was no difference in DFS with or without RT in favorable
patients. In the TG2 group (intermediate risk), DFS was 92% in patients who received RT
versus 78% in patients who did not. In the combined TG2+ TG3 (intermediate + high risk),
there was also a significant improvement in DFS for patients who received RT (91% vs. 79%).
Therefore, the omission of RT was only possible for early stage patients without sacrificing
DFS. OS rates remained stable as compared to prior studies suggesting that therapy reduction
was feasible (123).
These results were confirmed in the GPOH-HD 2002 study. In this study, all patients
received IFRT to 19.8 Gy except those in the early -stage (IA/B and IIA without extranodal
involvement) disease category who achieved an anatomic CR after induction therapy as
defined in GPOH-HD 95. In regions with <75% volume reduction, patients received a boost
to approximately 30 Gy, and residual masses >100 mL were boosted to approximately 35 Gy
(124). In this study, two to six cy cles of OEPA/ COPDAC in combination with IFRT produced
excellent results, with a 5-y ear EFS rate of approximately 89%.
Patients with stage I, IIA, or IIIA HL were randomized in a study conducted by the POG
to six courses of alternating MOPP/ABVD or four courses of MOPP/ABVD and IFRT to 25.5
Gy. At a median follow-up of 8.25 y ears, there were no significant differences in EFS or OS
rates between either arm. Eight-y ear EFS rates were 83% for chemotherapy alone and 91%
for combined-modality therapy (p = 0.151) while 8-y ear OS rates were 93.6% for
chemotherapy alone and 96.8% for chemotherapy and radiation (p = 0.785) (125).
Retrospective analy sis of the data showed that patients with early response to therapy had a
significantly better outcome, which supports the paradigm of response-based treatment.
In summary, numerous investigations have confirmed that chemotherapy alone is an
effective treatment approach for PHL. However, the higher cumulative dosages used in these
protocols predispose survivors to greater risks of acute and late toxicity associated with
alky lating agents, anthracy clines, and bleomy cin. Conversely, these protocols decrease the
potential for radiation-associated treatment complications including musculoskeletal growth
impairment, cardiopulmonary dy sfunction, and solid tumor carcinogenesis. Current
information suggests that children with advanced and unfavorable sy mptomatic or bulky
disease at presentation have better outcomes using a combined-modality approach.
Identify ing the prognostic features of patients who need radiation to optimize disease control
is a focus of many ongoing pediatric trials.
RISK AND RESPONSE-ADAPTED THERAPY
Numerous investigations published in the 1990s supported the use of a risk-adapted treatment
assignment based on clinical features at disease presentation
(14,16,64,107,116,117,122,123,124,125,126,127,128,129,130). Parameters have varied
according to individual studies, but those used most often in risk assessments include the
presence of “B” sy mptoms, mediastinal and peripheral ly mph node bulk, number of involved
nodal regions, and Ann Arbor stage. These studies uniformly evaluated treatment outcomes
using a lower number of multiagent chemotherapy cy cles in clinically staged patients with
favorable clinical presentations.
Revised International Workshop Criteria have also recently been proposed for response
assessment to incorporate imaging with PET in addition to CT given the increased specificity
and sensitivity of PET compared to CT (131,132). A recent study conducted by Brepoels et
al. (133) compared these revised criteria incorporating PET versus the criteria using CT alone
to predict clinical outcome and found that the revised criteria predicted response more
accurately.
Treatment of Early-Stage Disease

Early -stage disease may present with favorable or unfavorable features. A favorable clinical
presentation is ty pically defined as localized (stage I or II) nodal involvement in the absence
of “B” sy mptoms and nodal bulk. The involvement of more than three nodal regions ty pically
moves the patient into an intermediate- or high-risk group. Children and adolescents with
early -stage, favorable presentations of HL are excellent candidates for reduced therapy.
Several multiagent regimens and a variety of nonalky lator regimens have proven effective
(10,12,14,16,64,98,106,107,116,117,126,127,128,129). Treatment for patients with a favorable
clinical presentation ty pically involves two to four cy cles of chemotherapy with or without
low-dose radiation based on a favorable response to chemotherapy.
Page 155The German pediatric Hodgkin ly mphoma investigators pioneered the use of
risk- and sex-adapted therapy featuring the OPPA regimen for girls and OEPA for boy s
(16,107). The GPOH HD-95 trial investigated whether RT could be omitted in patients
achieving a complete response at the end of all chemotherapy. Results at 6 y ears indicated a
97% EFS for favorable-risk patients and no difference in outcome in favorable risk patients
treated with chemotherapy alone or combined modality therapy (123). Notably, bulky
ly mphadenopathy is not used in the GPOH risk assessment because bulk has not influenced
outcome in the German trials, which prescribe a 5- to 10-Gy boost in cases with an
insufficient remission after chemotherapy (134).
Several North American investigators have observed excellent treatment results in
combined-modality trials for favorable-risk HL. Pediatric Hodgkin Consortium investigators
from Stanford, St. Jude Children’s Research Hospital, and Dana Farber Cancer Institute have
reported treatment results using a novel nonalky lator regimen, vinblastine, adriamy cin,
methotrexate, and prednisone (VAMP), for children with clinical stage I or II, nonbulky HL
(126,135,136). Patients received four cy cles of VAMP chemotherapy and IFRT; the radiation
dosage was determined by early response after two cy cles of chemotherapy. Patients
achieving a complete response received 15 Gy, and those achieving a partial response
received 25.5 Gy. At a median follow-up of 9.6 y ears, 5- and 10-y ear EFS were 92.7% and
89.4%, respectively ; 5- and 10-y ear OS were 99.1% and 96.1%, respectively. Long-term
toxicity has been limited to 42% of irradiated patients with hy pothy roidism, one patient with
cardiac dy sfunction, and two malignant tumors (135). Patients were also able to maintain
fertility with 17 healthy babies born to 106 patients. More recently, a study using VAMP in a
response-based approach evaluated the need for radiotherapy in patients who achieved CR
after two of four cy cles of chemotherapy. CR was defined as negative gallium or FDG-PET
scan and ≥75% reduction in size on CT. In this trial, favorable patients received four cy cles of
VAMP and response assessment after two cy cles. Patients in CR after two cy cles received no
radiotherapy as compared to patients with less than a CR who received 25.5 Gy IFRT. Two-
y ear EFS was 89.4% in patients who did not receive RT compared to 92.5% in patients who
did (p = 0.61). Thus, therapy could be successfully tailored to reduce intensity while still
maintaining a high EFS (136).
Very good early treatment results have also been observed by POG investigators using
response-based doxorubicin, bleomy cin, vincristine, and etoposide (DBVE) chemotherapy
and low-dose (25.5 Gy ) IFRT. Tebbi et al. (137,138) reported on P9426 in which stage IA,
IIA, and IIIA patients received two cy cles of DBVE and then evaluated for response. Those
in CR received 25.5 Gy of IFRT and those with partial response or stable disease received two
additional cy cles of chemotherapy and IFRT at 25.5 Gy. There was no difference in EFS by
histology, rapidity of response or number of cy cles of chemotherapy. Eight-y ear EFS was
86.3% and OS was 96.5%. Eight second malignancies were identified. EFS and OS were
similar to other reported studies despite significantly reduced chemotherapy.
A recent COG study AHOD0431 evaluated a lower intensity regimen using doxorubicin,
vincristine, prednisone, and cy clophosphamide (AV-PC) for patients with low risk (e.g. IA and
IIA) disease. Patients in a CR after three cy cles of chemotherapy received no further
therapy compared to those with less than a CR who received IFRT with 21 Gy. CR in this
study was defined as resolution of gallium or PET activity and at least 80% reduction in
tumor volume. The relapse rate in patients whose CR was not confirmed by FDG-PET
exceeded stopping rules and accrual to the study was suspended in 2008. Four-y ear EFS and
OS was 79.6% and 99.6%, respectively. There were no significant differences in outcomes
between patients with and without a CR. However, patients with a negative FDG-PET scan
had a significantly better EFS than patients with a positive PET scan so much so that patients
with a positive PET after one cy cle returned for RT if they were within 1 y ear of completing
chemotherapy even if they achieved CR (139).
Treatment of Advanced and Unfavorable Disease

In risk-adapted treatment regimens, early disease presenting with unfavorable features
sometimes is treated similarly to advanced-stage disease. Alternatively, an intermediate
designation is given in some risk categorizations to patients with localized (stage IA or IIA)
disease presentations that have one or more of the unfavorable features and to patients with
stage IIIA disease. For example, the GPOH studies prescribe four cy cles of chemotherapy
(two OPPA or two OEPA and two COPP or COPDac) for patients with intermediate risk
(designated as stage IIEA, IIB, or IIIA) and six cy cles (two OPPA or two OEPA and four
COPP or COPDac) for patients with unfavorable and advanced disease (123,124). Criteria
for unfavorable clinical presentations vary between investigations but ty pically include the
presence of “B” sy mptoms, bulky ly mphadenopathy, involvement of three or more nodal
regions, extranodal extension to contiguous structures, or advanced stage (IIIB–IV).
RT for unfavorable and advanced HL is variable and protocol dependent. Although focal
RT, historically IFRT and now ISRT, remains the standard in patients treated with combined-
modality therapy, restricting RT to areas of initial bulky disease (generally defined as larger
than 5 cm at the time of disease presentation), slow-responding disease or postchemotherapy
residual disease (generally defined as larger than 2 cm, or residual PET avidity ) is under
investigation without clear consensus amongst protocols.
(10,12,15,16,17,19,107,116,122,123,124,129,140).
Hudson et al. (141) evaluated the combined-modality regimen of VAMP/COP followed
by response-based involved-field radiation in advanced or unfavorable HL patients. Patients
achieving a complete response received 15 Gy and patients achieving a partial response after
two cy cles of chemotherapy received 25.5 Gy. Five-y ear OS and EFS rates were 92.7% and
75.6%, respectively. Given the low rates of EFS, combined modality therapy with
VAMP/COP and response-based involved-field radiation was not considered efficacious for
unfavorable PHL patients.
Page 156The Children’s Oncology Group conducted a study evaluating early -response
adapted therapy using ABVE-PC chemotherapy with 216 eligible patients less than 22 y ears
old who presented with intermediate- or high-risk HL. ABVE-PC is advantageous in the
pediatric population as the cumulative chemotherapy doses are below the doses ty pically
associated with long-term toxicities. In this study, patients with a rapid early response to three
cy cles of ABVE-PC received 21 Gy of regional field radiation (mantle, para-aortic, or
pelvis). Slow early responders received an additional two cy cles of ABVE-PC and then
received involved-field radiation to 21 Gy. The 5-y ear EFS was 86% for rapid early
responders and 83% for slow early responders (p = 0.85) and the five-y ear OS was 95%.
This protocol has provided encouraging clinical outcomes using risk-adapted therapy in a
high-risk group of patients (140).
The COG AHOD0031 trial assessed an early response-based approach for intermediate-
risk patients including patients of all stages except IA, IIA and IIIB, and IVB. In this study,
patients received two cy cles of ABVE-PC followed by response assessment (Fig. 7.4 ).
Patients had a rapid early response (RER) after cy cle 2 if they met CT-based criteria defined
by at least 60% reduction in tumor volume. Patients who had an RER went on to receive an
additional two cy cles of ABVE-PC. At that point, they were reassessed for response and if in
CR (defined as at least 80% reduction in tumor volume and gallium or FDG-PET negative)
were randomized to either receive IFRT to 21 Gy or no further therapy. Those patients who
had a slow early response (SER, approximately 18% of total cohort) received an additional
two cy cles of ABVE-PC with or without DECA (dexamethasone, etoposide, cisplatin, and
cy tarabine). All patients with a slow early response received IFRT to 21 Gy. Four-y ear EFS
was 85% and OS was 97.8%. EFS and OS were not statistically different in patients who
achieved RER and CR whether they received RT or no further therapy (141) (see Fig. 7.5
for graphical depiction of clinical outcomes). Of patients who relapsed, the relapses generally
occurred at nodal sites of initial bulk, and nonbulky sites and the first site of relapse were
rarely new sites or outside the IFRT field (142).
Figure 7.4 Schema for AHOD0031.
Figure 7.5 Clinical outcomes in AHOD0031. (A) EFS and OS for entire study cohort (B) EFS
and OS for two-cycle rapid early responders (RERs) and slow early responders (SERs) (C) EFS
and OS by IFRT randomized for RERs in CR. (D) EFS and OS by dexamethasone, etoposide,
cisplatin, and cytarabine (DECA) randomization for SERs. (E) EFS by IFRT randomization for
RERs with CR and negative cycle-2 PET results and for RERs with CR and positive/equivocal
cycle-2 PET results. (F) EFS by DECA assignment for SERs with negative cycle-2 PET and for
SERs with positive/equivocal cycle-2 PET results. (From Friedman DL, Chen L, Wolden S, et
al. Dose-intensive response-based chemotherapy and radiation therapy for children and
adolescents with newly diagnosed intermediate-risk Hodgkin lymphoma: a report from the
Children’s Oncology Group Study AHOD0031. J Clin Oncol. 2014;32(32):3651–3658, with
permission.)
The COG completed a study evaluating a dose-intense, response-based regimen using

BEACOPP (bleomy cin, etoposide, doxorubicin, cy clophosphamide, vincristine, procarbazine,
and prednisone). Females with a rapid response received four cy cles of COPP/ABV
following BEACOPP without IFRT, and males received two cy cles of ABVD and IFRT. All
patients with a slow response received four additional cy cles of BEACOPP and IFRT. A high
5-y ear EFS rate of 94% was achieved, and the 5-y ear OS rate was 97% (143). The GPOH
also demonstrated that six cy cles of OEPA/COPDAC together with 20–30 Gy IFRT y ields a
high 5-y ear EFS rate of approximately 87% (124).
The most recent COG protocol AHOD0831 also evaluated a response-based approach
where patients received two cy cles of ABVE-PC. Rapid early responders were treated with
two additional cy cles of ABVE-PC and risk-adapted radiation therapy. Slow early responders
receive two cy cles of ifosfamide/vinorelbine in addition to two additional cy cles of ABVE-
PC and risk-adapted radiation. This study was closed early due to lower than expected clinical
outcomes and the final results are still pending.
A summary of treatment results for recent major published clinical trials is provided in
Table 7.4 . Optimal treatment planning involves a multidisciplinary approach beginning at
diagnosis. This is best accomplished if the pediatric and radiation oncologist can meet to
review staging studies after examining the patient. The treatment approach should consider
host factors, such as age and sex, which may increase the risk of specific treatment
complications, and disease factors (e.g., presence of “B” sy mptoms, bulky
ly mphadenopathy, and stage).
Table 7.4 Summary of Treatment Results for Pediatric Hodgkin Lymphoma Trials
Figure:
Schema for AHOD0031.
Figure:
Clinical outcomes in AHOD0031. (A) EFS and OS for entire study cohort (B) EFS and OS for
two-cycle rapid early responders (RERs) and slow early responders (SERs) (C) EFS and OS by
IFRT randomized for RERs in CR. (D) EFS and OS by dexamethasone, etoposide, cisplatin, and
cytarabine (DECA) randomization for SERs. (E) EFS by IFRT randomization for RERs with CR
and negative cycle-2 PET results and for RERs with CR and positive/equivocal cycle-2 PET
results. (F) EFS by DECA assignment for SERs with negative cycle-2 PET and for SERs with
positive/equivocal cycle-2 PET results.
(From Friedman DL, Chen L, Wolden S, et al. Dose-intensive response-based chemotherapy

and radiation therapy for children and adolescents with newly diagnosed intermediate-risk
Hodgkin lymphoma: a report from the Children’s Oncology Group Study AHOD0031. J Clin
Oncol. 2014;32(32):3651–3658, with permission.)
Figure: Summary of Treatment Results for
Pediatric Hodgkin Lymphoma Trials
REFRACTORY AND RELAPSED DISEASE
HL may still be cured even after initial treatment programs fail. Relapse usually occurs
within 4 y ears, and usually in 1–2 y ears but late relapse is not rare. The choice of therapy for
such patients depends on the initial treatment and the disease characteristics at the time of
relapse. A spectrum of treatment options exist (144). This section focuses on the role of
radiation in the setting of refractory or relapsed therapy.
Page 158For children who relapse after treatment that includes chemotherapy,
conventional (standard-dose) salvage chemotherapy regimens are of limited success,
increasing disease-free survival and OS in only 10–50% (144). Fortunately, other strategies
can be effective. The selection of the most appropriate salvage regimen is based on several
considerations, including the following:
Did the patient achieve a complete remission, or was the disease refractory ?
If a complete response was achieved, was it durable (longer than 1 y ear)?
Did the relapse occur in nodal or extranodal sites, and, as a corollary, was the stage at
relapse early or advanced?
The patients with the most favorable prognosis are those who have disease recurrence only at
a prolonged interval after an initial complete response and in a limited nodal pattern. In fact,
these patients may have a superior outcome (EFS as high as 80%) if treated with high-dose
chemotherapy and autologous stem cell rescue (145,146). In addition, a recent review by
Harker–Murray et al. (147) suggests that a non–stem cell transplant approach for patients with
late relapse >12 months, absent extranodal disease, no B sy mptoms, and CR to reinduction
chemotherapy could be efficacious. On the opposite end of the spectrum are patients who
have chemotherapy -refractory disease and are never cured by conventional salvage
chemotherapy.
Patients who relapse after regimens that include chemotherapy have been treated with
high-dose chemotherapy and hematopoietic stem cell rescue (144,145,148). Three- to 5-y ear
survival probabilities of 25–80%, depending on characteristics at relapse, have been reported
(primarily in adults) after such treatment (146,149,150). Only one prospective study
randomizing refractory or relapsed patients with HL to high-dose chemotherapy and stem
cell rescue or conventional-dose chemotherapy has been performed. Data specific to
children with recurrent HL are limited. However, an analy sis of 81 pediatric patients with HL
who underwent ABMT and were reported to the European Bone Marrow Transplant Group
demonstrated a similar outcome to a case matched group of adults similarly treated (151).
Claviez et al. (152) found an increased risk of relapse and lower progression-free survival
bey ond 9 months when pediatric patients received reduced intensity compared to a
my eloablative conditioning regimen prior to undergoing allogeneic stem cell transplant,
although OS was not different between the two groups. The United Kingdom Children’s
Cancer Study Group performed a review of 51 pediatric patients with relapsed or refractory
HL who underwent autologous stem cell transplant and 78 patients who underwent
conventional salvage treatment without stem cell transplant. There were no statistically
significant differences in OS between the two cohorts including those patients who had a short
initial remission after primary therapy (153). Prognostic factors for unfavorable outcome
include the duration of initial response to chemotherapy, “B” sy mptoms at relapse,
disseminated pulmonary or bone marrow disease at relapse, and more than minimal disease
at the time of transplantation (146,150). Patients with poor prognostic factors have a reported
5- to 10-y ear OS of 20–25% (154). Female sex, lactate dehy drogenase level ratio (the
absolute LDH level divided by the upper limit of the laboratory normal value) of greater than
one and short interval from diagnosis to autologous stem cell transplant (≤15 months) have
also been reported as negative predictive factors in pediatric patients (155). A variety of
preparative regimens provide similar outcome (148,156).
Page 159The basis for including RT in the setting of high-dose chemotherapy and stem
cell rescue for HL is twofold: These aggressive salvage programs still fail to cure a large
proportion of patients, and ample data show that many patients with progressive, recurrent
HL after chemotherapy do not exhibit a cross-resistance to radiation (144,157,158).
Moreover, most patients relapse in sites of previous involvement, mostly nodal (146,159,160).
The majority of patients undergoing auto stem cell transplant are conditioned with
carmustine, etoposide, cy tarabine (Ara-C), and melphalan (BEAM). ISRT may be given
after recovery for localized relapse particularly in patients who have not y et received
radiation as part of their primary therapy.
In considering the role of ISRT in the setting of high-dose chemotherapy and stem cell
rescue, three essential questions must be answered: Does RT to sites of recurrent or
refractory HL diminish relapse at these sites? If so, then what is the impact on freedom from
relapse, EFS, and OS? Is the associated morbidity of ISRT acceptable? Data from several
series support an affirmative answer to these questions (145,148,161,162).
In a Stanford report, patients with stage I–III disease at relapse who received ABMT and
IFRT had a 3-y ear freedom from relapse of 100% and OS of 85%, compared with 67% and
60%, respectively, for patients not receiving IFRT (162). For patients not previously irradiated,
IFRT was associated with an improved freedom from relapse of 85% and OS of 93%, in
contrast to 57% and 55%, respectively, for those previously irradiated. Morbidity was similar
to that of those not irradiated, although RT may have contributed to the peri-transplant death
of two patients.
Central issues relating to the use of RT are the dosage, target volume, and timing with
respect to transplantation. RT dosages generally are 20–36 Gy, in 1.5- to 2.0-Gy fractions.
This variation relates to potential normal tissue toxicity and the value of higher radiation
dosages in patients with identifiable tumor that demonstrates radiation responsiveness (148).
Radiation volume can vary and include treatment to all sites of initial disease, recurrent
disease, persistent disease after salvage chemotherapy, persistent disease after the
preparative regimen for transplantation, or all nodal sites (145,146,148). RT can be
administered before high-dose chemotherapy to place patients in a minimal disease state. RT
can also be administered after high-dose chemotherapy in patients that are high risk for
sy stemic relapse if BMT is delay ed in any way and to reduce RT-related peri-transplant
morbidity such as esophagitis, pneumonitis, cardiomy opathy, and veno-occlusive disease.
Possible disadvantages of this approach include the loss of the pretransplant cy toreductive
effect and the theoretical carcinogenic effect of RT on the newly proliferating hematopoietic
sy stem (145,146,148).
Retrieval therapies for higher risk relapse have been evaluated in combination with stem
cell transplant, primarily autologous stem cell transplant. COG study AHOD00P1 evaluated a
combination of ifosfamide and vinorelbine for pediatric patients in first relapse showing a
good overall response rate of 72% and the majority of patients were able to undergo stem
cell transplant (163). For patients who relapsed after transplant or are refractory in the
upfront setting, a combination of gemcitabine and vinorelbine has been studied and was found
to have an overall response rate of 76% (164).
Because of the historically high transplant-related mortality associated with allogeneic
transplantation, autologous hematopoietic stem cell transplantation has been preferred for
patients with relapsed HL. However, reduced-intensity allogeneic transplantation has
demonstrated acceptable rates of transplant-related mortality (165). Nonmy eloablative
conditioning regimens have varied, but most often they use fludarabine or low-dose TBI to
provide a nontoxic immunosuppression. If successful, the procedure establishes a graft-
versus-ly mphoma effect and provides a platform for adoptive cellular immunotherapy.
Evaluation of the effectiveness of this approach has been limited by reports describing
treatment outcomes in small heterogeneous patient cohorts assigned to a variety of
conditioning regimens in a nonrandom fashion. A longer follow-up period is needed to
determine the efficacy of this approach.
Future study for relapsed/refractory disease will focus on risk-stratify ing patients in the
relapsed setting. In the COG, patients will be grouped into low, intermediate, and high risk
groups based on CHIPs score at initial diagnosis, duration of initial CR, and initial response to
prior therapy. Long-term OS is markedly different for patients with relapsed disease
depending on these factors and ranges from <30% for the highest risk to >95% for the lowest
risk patients (166) and therefore, retrieval therapies will be de-escalated or intensified
according to patient group.
TARGETED THERAPIES
Novel sy stemic therapy combinations with the use of monoclonal antibody immunotherapy
targeting cell surface antigens has found its way into the primary and relapsed setting. CD30
is a transmembrane gly coprotein that is present on Reed–Sternberg cells. Brentuximab
vedotin is an antibody drug conjugate that links an anti-mitotic agent (MMAE) and an anti-
CD30 antibody. The release of MMAE intracellularly results in the disruption of the
microtubule network and results in G2/M cell cy cle arrest and apoptosis. An initial study by
Younes et al. (167) demonstrated evidence of regression in relapsed CD30+ malignancies in
85% of patients (167). A phase II study evaluating brentuximab in the relapsed HL setting
demonstrated 75% response rate of which 34% had a CR (168). However, the combination of
brentuximab and ABVD resulted in increased pulmonary toxicity due to the inclusion of
bleomy cin. Thus, in the pediatric setting, brentuximab is currently being combined with AVE-
PC regimen in high-risk disease in combination with radiation for LMA and slow responding
disease. Brentuximab is also being used in high-risk patients in the St Jude–Stanford–Dana–
Farber consortium substituting vincristine in the OEPA/COPDac combination.
Page 160The curability of PHL, the complexity of current treatment approaches, and the
vulnerability of the developing child to radiation and chemotherapy require the involved
radiation oncologist to thoroughly understand the role of radiation and to deliver it with skill.
As discussed earlier, most newly diagnosed children are treated with risk-adapted
chemotherapy alone or combined modality therapy including low-dose radiation. Because
most children are treated in institutional (or multi-institutional) studies, the radiation oncologist
should confirm all aspects of the diagnostic workup and staging and must also understand
study requirements in order to deliver appropriate radiation. In a review of the DAL-HD-90
trial (German–Austrian pediatric multicenter trial), up-front centralized review of patients in
the study altered the treatment approach in a large number of children (169). Central review
can identify deviations quickly and institutions that modify their treatment fields based upon
such review can almost entirely eliminate deviations (170). Unpublished data from the POG
also support the superior outcome of children treated with appropriate radiation fields and
dosages, in contrast to cases in which protocol violations occurred.
VOLUME CONSIDERATIONS
Most children with HL are treated with combined chemotherapy and low-dose radiation.
Meticulous and judiciously designed fields are necessary for optimizing disease control and
tissue damage. The definitions of such fields depend on the anatomy of the region in terms of
ly mph node distribution, patterns of disease extension into regional areas, and consideration
for match line problems should disease recur. Historically, involved fields ty pically included
not just the identifiably abnormal ly mph nodes but the entire ly mph node region containing
the involved nodes. The traditional definitions of ly mph node regions can be helpful but are
not necessarily sufficient. For example, the cervical and supraclavicular ly mph nodes were
historically treated when abnormal nodes were located any where in this area; this is
consistent with the anatomic definition of ly mph node regions used for staging purposes (171).
Care must be taken to shield relevant normal tissues such as the breast and ovaries. Radiation
field definition is evolving. For example, it is appropriate to treat the axilla or mediastinum
without the supraclavicular volume and the inguinal nodes without the iliacs depending on the
size and distribution of involved nodes at presentation. Field definitions often are protocol-
specific, but excessively small fields usually are inappropriate. Every effort should be made
to exclude unnecessary normal tissues (e.g., breast tissue in a child with isolated mediastinal
disease and no axillary involvement). Treatment of involved supradiaphragmatic fields
requires precision because of the distribution of ly mph nodes and the critical adjacent normal
tissues. These fields can be simulated with the arms up over the head or down with hands on
the hips. The former pulls the axillary ly mph nodes away from the lungs, allowing greater
lung shielding. However, the axillary ly mph nodes then move into the vicinity of the humeral
heads, which should be blocked in growing children. Therefore, the position chosen involves
weighing concerns regarding ly mph nodes, lung, and humeral heads. Attempts should be
made to exclude or position breast tissue. When the decision is made to include some or all of
a critical organ in the radiation field, such as liver, kidney, or heart, then normal tissue
constraints, depending on the chemotherapy used and patient age, are critical.
Three-dimensional conformal therapy is now utilized routinely. Equally weighted
anterior and posterior fields are still used appropriately for daily treatment depending on the
clinical scenario. Anteriorly weighted fields
excessively irradiate the anterior heart, with
associated cardiac morbidity (172). Dosage
calculations should be based on the patient
separation at the central axis. A full mantle field
is rarely required but when treated, nodes in the
neck and axilla receive a higher dosage because
the patient’s body is thinner than at the mid-
thorax. Therefore, separate axillary, neck, and
low mediastinal dosimetry should be performed,
and compensating filters or other modifications
should be used to minimize inhomogeneity with
3D conformal approaches. Extended source-to- Figure 7.6 Coronal view on CT
skin distances decrease dosage inhomogeneity in simulation scan of ISRT field in the
these different areas. With 3D-based planning, mediastinum including contours
appropriate target coverage can be assessed depicting the postchemotherapy GTV
while minimizing doses to normal structures. If (green); CTV (pink); PTV (blue).
chemotherapy has been given, then the width of
the field generally is based on the postchemotherapy residual disease, whereas the cephalad–
caudad dimension respects the original disease extent (Fig. 7.6 ). As previously stated,
humeral head blocks are appropriate unless bulky axillary adenopathy would thereby be
shielded.
The entire heart and lungs are rarely treated and when treated, dosages tend not to
exceed 10–16 Gy, depending on the distribution of disease and chemotherapy used. More
specifically, whole heart and whole lung irradiation is generally no longer recommended.
Current protocols omit whole lung in the setting of complete response to chemotherapy
(171). The approaches to radiotherapy in pediatric HL are highly protocol dependent because
some children treated for advanced-stage HL receive RT only to areas of initial bulk disease
or post chemotherapy residual disease. When the subdiaphragmatic region is being treated,
the radiation dosage to the kidney s must be minimized. Usually the upper pole of the left
kidney is within the irradiated volume when treating the spleen. A treatment planning CT with
IV contrast, and diagnostic information obtained from the CT or MRI (coronal slices from a
thoracic MRI will reveal the relationship of the spleen to the kidney ) are helpful in drawing
the blocks. Four-dimensional CT scan should be obtained to assess spleen organ motion with
respiration to allow for a margin. When the pelvis is being treated, special attention must be
given to the ovaries and testes. The ovaries should be relocated, marked with surgical clips,
laterally along the iliac wings or centrally behind the uterus if there is concern for their
location within the field. In this manner, appropriate shielding may be used. The testes
receive 5–10% of the administered pelvic dosage, which is sufficient to cause transient or
permanent azoospermia, depending on the total pelvic dosage. The greatest shielding can be
afforded to the testes if the patient is placed in a frog-legged position with an individually
fitted testes shield. If multileaf collimation is available, the multileaf can be placed over the
testes, additionally decreasing the transmitted dosage. Clearly, careful planning and judgment
are necessary. As previously stated, RT for unfavorable and advanced HL is variable and
protocol dependent. Although RT remains the standard when patients are treated with
combined-modality therapy, restricting RT to areas of initial bulky disease (generally defined
as larger than 5 cm at the time of disease presentation) or postchemotherapy residual disease
(generally defined as larger than 2 cm or residual PET avidity ) is under investigation.
Page 161Involved-Site Radiotherapy (ISRT)

Radiation treatment fields have been successfully reduced in size to include an involved site
alone in combination with chemotherapy without sacrificing clinical outcomes. Smaller
treatment fields are expected to decrease long-term toxicities given the increased sparing of
normal structures. Patients with early -stage HL treated with chemotherapy alone most
frequently relapse in the initially involved ly mph node(s) (160). Therefore, an effort has
been made to reduce treatment field size further to include the initially involved ly mph
node(s) with a smaller margin than used in design of the involved fields which included
prophy lactic uninvolved ly mph node regions. Guidelines for the delineation of volumes for
ISRT are summarized in Table 7.5 (173). Fusion of prechemotherapy FDG-PET/CT
imaging from staging and response assessment to the planning CT scan is recommended to
delineate the nodal areas at risk. Thus, target volumes are delineated using nodal anatomy
rather than bony landmarks, as used in IFRT. ICRU guidelines are used to contour treatment
volumes for ISRT (Fig. 7.7 ) and image guidance is utilized to reduce margins by reducing
daily setup uncertainty. 3D and 4D treatment planning is encouraged to replace the approach
with IFRT when field design was based on bony anatomy using 2D treatment planning. ISRT
fields are generally smaller than the historical IFRT field (Fig. 7.8 ) but larger than the
involved node radiotherapy (INRT) field. INRT requires that imaging, including FDG-PET, be
obtained in the treatment position prior to chemotherapy and this is difficult to achieve.
Table 7.5 Involved Site Radiation Therapy (ISRT) Guidelines
Figure 7.7 Digitally reconstructed radiographs (DRRs) of an ISRT field (A) treating
involved inguinal nodes compared to a historical IFRT field (B) treating the inguinal nodes
based on bony landmarks.
Figure 7.8 INRT based on CT contours of the mediastinum incorporating the
prechemotherapy extent of disease in the superior and inferior direction and the
postchemotherapy width of disease plus a margin to achieve the final PTV.
Involved-Node Radiotherapy
The EORTC-GELA introduced the concept of involved-node radiotherapy (INRT) (174). This
uses all available clinical information including pre- and postchemotherapy imaging with CT
and FDG-PET scan to define the treatment field according to the prechemotherapy extent of
disease. Based on the EORTC-GELA guidelines, any visualized ly mph node after CRu should
be included in the clinical target volume (CTV) and normal structures displaced by enlarged
ly mph nodes should not be included in the CTV. The GHSG defines the margin of the
planning target volume (PTV) as 2 cm in the axial direction and 3 cm in the craniocaudal
direction although the EORTC-GELA group reduces this margin to 1–1.5 cm (175).
Controversy still exists regarding the optimum margins for the application of INRT
(174,175,176,177).
To apply the INRT concept and the high precision required to cover the full extent of
disease using INRT, both pre- and postchemotherapy CT and FDG-PET scans should be
performed in the treatment position (177). In a study of early -stage HL patients by Girinsky
et al. (178), PET identified 36% of involved ly mph nodes that were radiographically occult
on CT scan. Therefore, evaluation with FDG-PET scan prior to chemotherapy may help to
delineate the complete extent of clinical disease. Initial clinical data with the use of INRT is
emerging. Campbell et al. (179) reviewed clinical outcomes of patients with limited stage HL
treated with EFRT, IFRT, and INRT ≤5cm, similar to ISRT. No marginal recurrences or
locoregional failures occurred with INRT.
The application of INRT requires that all available clinical information is utilized to
appropriately reduce treatment field size without sacrificing the excellent clinical outcomes
that are attainable with standard therapy (Fig. 7.6 ).
Page 162PET/CT Radiation Planning

CT-based treatment planning has replaced conventional radiographic simulation, which is
limited in its two-dimensional (2D) rendering of bony landmarks. CT simulation enables 3D
visualization of the patient in the treatment position to allow increased precision for targeting
tumor and normal structures. The Hounsfield units acquired from CT images are also
proportional to electron density used to perform dose calculations. FDG-PET complements
CT by providing functional information to help delineate the tumor volume and normal
structures. FDG-PET and CT have been used in combination for radiation planning.
Dedicated PET/CT scanners for simulation allow the immediate co-registration of FDG-PET
and CT scan images while the patient is in the treatment planning position. An FDG-PET scan
obtained separately can also be fused to a CT treatment planning scan obtained in a radiation
oncology department. It is recommended that the patient be placed in the treatment planning
position for both scans with an appropriate immobilization device to enhance reproducibility.
Several studies have specifically assessed the changes in tumor volume and
management when PET is acquired at the time of simulation for adult patients with
ly mphoma (178,180,181). Hutchings et al. (181) studied 30 patients with early -stage HL who
underwent a staging FDG-PET/CT. After a short course of ABVD, patients were treated with
an involved field with tumor volumes delineated on the CT treatment planning scan. These
patients were then re-planned with incorporation of FDG-PET findings. The treated volume
increased in seven patients and decreased in two patients. Given the potential expansion of the
treated volume, the authors concluded that PET/CT treatment planning should be used with
caution. Thirty pediatric patients with HL who received chemotherapy and ABVD were
evaluated with 546 regions analy zed by both PET and CT modalities. Integration of PET
information resulted in a change in staging in 50% of patients and IFRT volumes were
adjusted as a result in 70% of patients. There were four patients who relapsed, one outside the
IFRT field, and all were successfully salvaged. Thus, the incorporation of PET had a
meaningful impact in staging and radiation treatment target delineation (182). Pre-
chemotherapy PET/CT scans were also acquired in the treatment position in 20 children with
HL and then registered to post-chemotherapy planning CT scans. In this study, registration of
FDG-PET and planning CT images resulted in significantly better consistency in contouring
treatment volumes than using the planning CT only in children with HL (183).
Page 163PET/CT treatment planning has particular use in apply ing the INRT concept.
Prechemotherapy CT and FDG-PET scans were performed in the treatment position using
immobilization and fused to postchemotherapy CT planning scans for early -stage HL patients
in a study performed by Girinsky et al. (178). FDG-PET was useful in identify ing involved
nodes in 36% of patients in whom ly mph nodes were undetectable on CT scan. Therefore,
PET may be a valuable adjunct to CT treatment planning, if treatment field size is reduced, to
ensure adequate dose coverage to the tumor volume. In the clinical scenario where the use of
conformal RT is being considered, the addition of PET to CT planning may enhance the
accuracy of target volume definition. Given the potential for an increase in treatment volume
with the use of PET/CT radiation planning, this technology should be used judiciously,
enlisting the input of diagnostic specialists.
Figure:
Coronal view on CT simulation scan of ISRT field in the mediastinum including contours
depicting the postchemotherapy GTV (green); CTV (pink); PTV (blue).
Figure: Involved Site Radiation Therapy
(ISRT) Guidelines
Figure:
Digitally reconstructed radiographs (DRRs) of an ISRT field (A) treating involved inguinal
nodes compared to a historical IFRT field (B) treating the inguinal nodes based on bony
landmarks.
Figure:
INRT based on CT contours of the mediastinum incorporating the prechemotherapy extent of
disease in the superior and inferior direction and the postchemotherapy width of disease plus
a margin to achieve the final PTV.
CONFORMAL RADIATION PLANNING
CT scan imaging enables 3D planning and enhanced anatomic localization for treatment field
design and dose calculations. Three-dimensional conformal radiation (3D-CRT) and intensity -
modulated radiotherapy (IMRT) are methods used to deliver tightly conformal doses to the
tumor volume. Steep dose gradients are achieved to spare normal structures, particularly for
patients who are at risk for treatment complications. It is important to note that the use of
conformal approaches is based on delineation of the appropriate volume to be irradiated, and
not on anatomic definitions and structures as is true for traditional anterior/posterior (two-
field) approaches.
“Forward planning” is used to create 3D-CRT plans whereby the phy sician, phy sicist, or
dosimetrist determines the nature of the radiation beams that will accomplish a desirable
radiation dose distribution. Using IMRT, the delivery of a tightly conformal radiation dose with
a steep dose gradient to spare normal structures can be achieved. It is particularly
advantageous in its ability to create concavities to avoid treatment of surrounding tissues and
utilizes multiple treatment fields to accomplish this goal. Although an increased number of
treatment fields improve conformality, the radiation dose is spread over a larger volume of
tissue as a result. IMRT also requires additional monitor units to deliver treatment compared to
conventional methods. Therefore, total body dose is increased due to increased leakage
radiation. The impact of IMRT in children is a special consideration. Children are known to be
at higher risk for the development of secondary malignancies after radiation (ICRU 60). The
use of multiple beams with IMRT results in a larger area of the body receiving a low dose
compared to conventional techniques (“low-dose” bath effect). IMRT for the pediatric
population remains controversial given the concerns for long-term toxicities including late
growth disorders and the development of second malignancies. Increased radiation scatter
may have a greater impact on oncogenic risk given the smaller body habitus of children as a
result of the closer proximity of organs at risk and PTV compared to adults (184,185).
Page 164IMRT has been adopted as a standard treatment for various malignancies
including prostate and head and neck cancer. However, the role of IMRT has been limited in
the treatment of PHL due to the low doses required for treatment, the need to identify with
certainty the target ly mph nodes, as well as the limitations in the dosimetric advantage of
IMRT when treating a large field. However, it should alway s be a primary therapeutic goal to
minimize exposure to critical normal tissues even when the doses are already low enough to
be considered “safe.” The use of IMRT may result in a dosimetric advantage in select cases
particularly when apply ing the involved-site or involved-node approach. For example,
patients who are referred for RT before or after stem cell transplant may have received prior
radiation or have higher risk for radiation pneumonitis. In a patient who has received prior
radiation, IMRT may allow reirradiation of relapsed or refractory disease given the
proximity of previously irradiated normal structures. IMRT may also have a potential benefit
in highly select patients with bulky mediastinal disease or after bleomy cin administration for
the sparing of lung and heart (Fig. 7.9 ) Dose–volume histograms of conventional and
IMRT plans, respectively, in a patient with bulky mediastinal disease.
Figure 7.9 CT-based planning images depicting a historic mantle RT (A), compared to
standard involved-field radiation treatment (IFRT) (B), and involved-node RT (INRT) (C) for a
patient with stage I disease involving the mediastinum. The postchemotherapy volume of
initially involved paratracheal nodes is depicted in dark red and the cardiac silhouette is also
evident. Demonstration of the reduction in dose to breast, lung, heart, and thyroid for the
female patient shown in. (From Hodgson DC, Hudson MM, Constine LS. Pediatric Hodgkin
lymphoma: maximizing efficacy and minimizing toxicity. Semin Radiat Oncol.
2007;17(3):230–242, with permission.)
Page 165At Memorial Sloan–Kettering Cancer Center, a study was conducted

comparing conventional 2D radiation, 3D-CRT, and IMRT in patients with Hodgkin or non-
Hodgkin mediastinal disease who had received prior radiation or had large volume disease
(186). PTV coverage was improved with the use of conformal treatment compared to
conventional radiation. However, the volume of lung receiving at least 20 Gy (V20) was
increased with IMRT. The probability for pneumonitis was assessed with a biologic model
known as the fractional damage (Fdam) that evaluated damage to organ subunits. Both the
Fdam and mean lung dose were decreased with IMRT compared to conventional and 3D-CRT
plans. Although Yorke et al. (187) found that the Fdam and mean dose correlated significantly
with the development of radiation pneumonitis in non–small cell lung cancer, these findings
have not been verified in the ly mphoma population. Reduced median heart and lung doses
were achieved using IMRT in eight patients with mediastinal disease in a small study
conducted by Nieder et al. (188). Girinsky et al. also compared IMRT, 3D-CRT, and
conventional plans for HL patients presenting with mediastinal disease.
Anteroposterior/posteroanterior (AP/PA) fields resulted in a minimally lower lung mean dose
compared to 3D-CRT and IMRT plans. The V20 achieved with AP/PA fields was similar to an
IMRT plan but lower than 3D-CRT. The median dose to the breast was lower using AP/PA
fields although there was no difference in the breast V20. A reduction in acute grade 2
toxicities was also identified with IG-IMRT ISRT compared to 3D conformal for stage IIA
Hodgkin ly mphoma in the combined modality setting (189). Given the possible advantages of
IMRT in specific clinical scenarios, further study must be performed to further elucidate dose
constraints in the setting of low dose RT with advanced techniques. In addition, deep
inspiration breath hold (DIBH) may be used with advanced radiation techniques to increase
the lung volume and pull the heart caudally. In this way, dose to the lungs, heart, breast tissue,
and coronary arteries may be accomplished without compromising dose to the target. This is
particularly advantageous in treating large, bulky mediastinal masses when dose constraints
are difficult to achieve.
IMRT can also modify the intensity patterns through a planned treatment volume to
achieve escalated doses to specific regions. “Simultaneous integrated boost” IMRT (SIB-
IMRT) or “dose painting” can deliver higher doses to areas of gross disease while delivering a
lower dose to subclinical or microscopic disease. In this way, a boost treatment normally
delivered after conventional therapy is integrated and treated simultaneously with a higher
dose per fraction and an overall shorter treatment course. Dose painting may prove
advantageous in the treatment of certain clinical sites such as the head and neck region but
further investigation into the use of this technique in the pediatric population is warranted
particularly in the setting where boost radiation is required.
There is much interest in the use of proton therapy in the treatment of pediatric HL and
its use is currently being investigated. Early investigations suggest that normal tissue doses
may be further reduced compared with IMRT or 3DCRT (Fig. 7.10 ). Current small-scale
studies suggest that mean breast and heart dose may be reduced with protons (190,191).
Preliminary studies also suggest equivalent clinical outcomes for early -stage disease (191).
Figure 7.10 Radiation treatment plans (A) using 3DCRT (left), protons (middle), and IMRT
(right). The initial staging PET scan demonstrating extent of disease is depicted in (B) along
with the field borders in (C). (From Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node
proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2
study. Int J Radiat Oncol Biol Phys. 2014;89(5):1053–1059, with permission.)
Figure:
CT-based planning images depicting a historic mantle RT (A), compared to standard
involved-field radiation treatment (IFRT) (B), and involved-node RT (INRT) (C) for a patient
with stage I disease involving the mediastinum. The postchemotherapy volume of initially
involved paratracheal nodes is depicted in dark red and the cardiac silhouette is also evident.
Demonstration of the reduction in dose to breast, lung, heart, and thyroid for the female
patient shown in.
(From Hodgson DC, Hudson MM, Constine LS. Pediatric Hodgkin lymphoma: maximizing
efficacy and minimizing toxicity. Semin Radiat Oncol. 2007;17(3):230–242, with permission.)
Figure:
Radiation treatment plans (A) using 3DCRT (left), protons (middle), and IMRT (right). The
initial staging PET scan demonstrating extent of disease is depicted in (B) along with the
field borders in (C).
(From Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node proton therapy in combined
modality therapy for Hodgkin lymphoma: results of a phase 2 study. Int J Radiat Oncol Biol
Phys. 2014;89(5):1053–1059, with permission.)
DOSAGE CONSIDERATIONS
Kaplan (2) constructed a radiation dose–response curve for HL, but limitations of its current
applicability include its use of kilovoltage data. Reports demonstrate that lower radiation
dosages provide excellent local control, with variables including tumor size and fractionation
schedule (192,193). In the absence of chemotherapy, subclinical disease is reliably (95%)
controlled with 25–30 Gy, small bulk disease (variously defined but less than 5 cm in most
reports) necessitates 30–35 Gy, and large bulk disease an additional 5–10 Gy. The dosages per
fraction should be 1.5–1.8 Gy daily, five times a week. Patients treated with large volumes
may tolerate only 1.5-Gy fractions. In the setting of combined therapy, certainly the intensity
of the chemotherapy is important to consider in the choice of the radiation dosage and
volume. However, dosages of 15–25 Gy are ty pical, with shrinking fields and boosts
individualized. In general, dosages of more than 25 Gy are uncommon in pediatrics. Of
interest in this regard is the DAL-HD-90 trial, in which dosages of 20–25 Gy were
administered in combination with OEPA or OPPA, with or without COPP. The radiation
dosages administered were 20–25 Gy, with a local boost of 5–10 Gy for insufficient remission
after chemotherapy. Tumor burden, indicated by bulky disease or number of involved nodes,
proved not to be prognostically significant (134).
SEQUENCE OF THERAPY
The most effective sequence of therapy in the setting of combined chemotherapy and
irradiation has not been established. However, chemotherapy usually is the first modality.
This allows assessment of drug response, maximization of the amount of drug treatment, and
shrinkage of disease and more limited fields of irradiation. Occasionally, focal irradiation
before chemotherapy is necessary because of airway obstruction.
RESULTS
In assessing the results of therapy for HL, specific reports must be evaluated for the
following:
Definitions of survival (e.g., event-free, relapse-free, freedom from progression,

overall)
Characteristics of the patient population regarding evaluation and prognostic factors
Treatment regimens and techniques, including chemotherapy dosage intensity
Morbidity and mortality of therapy
The actuarial 10-y ear survival for children with early -stage disease is 85–95%, and for
children with advanced-stage disease it is 70–90% (106). However, the toxicities vary greatly
between the treatment strategies. In fact, in the current era, essentially all patients will be
treated with combined chemotherapy and radiation, or chemotherapy alone, with the rare
exception of fully mature adolescents with very limited NLPHD who may be candidates for
radiation alone.
Page 166Although relapse-free survival and OS are excellent for patients with favorable,
early -stage disease, patients with unfavorable disease continue to fare less well. It is critical to
appreciate the extent to which death from causes other than recurrence of HL compromises
OS. Several investigators have observed a greater risk of mortality in long term survivors of
PHL than in the general population (120,121,192). In the first 10 y ears after diagnosis, deaths
were most commonly attributable to HL; with subsequent follow-up, subsequent cancers and
cardiovascular disease contributed to higher mortality rates than in age- and sex-matched
population control subjects. This is illustrated in (Fig. 7.11 ), which demonstrates the
cumulative incidence functions for cause-specific deaths among survivors of PHL treated at
St. Jude Children’s Research Hospital (120). Standardized incidence ratios in this cohort
showed a 12-fold elevated risk for all second malignancies, 11-fold elevated risk for a second
solid tumor, and 33-fold elevated risk of breast cancer in female patients. Standardized
mortality ratios also indicated greater mortality from cardiovascular disease (22; 95% CI, 8–
48) and infection (18; 95% CI, 7–38). Importantly, HL consistently accounts for the majority
of events in studies of long-term survivors; furthermore, relapse of HL is associated with a
higher risk of subsequent events, including second cancers and cardiovascular disease. These
findings underscore the need to proceed cautiously with therapeutic modifications because a
reduced treatment intensity or duration may compromise disease control and promote late
treatment complications.
Figure 7.11 Cumulative incidence functions for cause-specific deaths among St. Jude
children’s research hospital cohort with Hodgkin disease from second malignancy, Hodgkin
disease, cardiac disease, infection, and accident or suicide. Ten- and 20-year estimates are
shown, with 95% confidence intervals in parentheses. (From Hudson MM, Poquette CA, Lee J,
et al. Increased mortality after successful treatment for Hodgkin’s disease. J Clin Oncol.
1998;16(11):3592–3600, with permission.)
Cumulative incidence of cause-specific deaths among St. Jude children’s research

hospital cohort with HL from second malignancy, HL, cardiac disease, infection, and
accident or suicide are depicted in Figure 7.11 . Ten- and 20-y ear estimates are shown,
with 95% confidence intervals in parentheses.
Figure:
Cumulative incidence functions for cause-specific deaths among St. Jude children’s research
hospital cohort with Hodgkin disease from second malignancy, Hodgkin disease, cardiac
disease, infection, and accident or suicide. Ten- and 20-year estimates are shown, with 95%
confidence intervals in parentheses.
(From Hudson MM, Poquette CA, Lee J, et al. Increased mortality after successful treatment
for Hodgkin’s disease. J Clin Oncol. 1998;16(11):3592–3600, with permission.)
COMPLICATIONS
Acute Side Effects

Acute side effects seen during RT include temporary loss or change in taste, low posterior
scalp epilation, xerostomia, skin ery thema (particularly on the neck and shoulders),
esophagitis, and occasional nausea and vomiting necessitating antiemetics. Acute effects of
para-aortic irradiation are uncommon, but nausea and vomiting can occur.
Page 167Long-Term Side Effects

Concerns for long-term adverse sequelae limit the acceptance of radiation in combined-
modality treatment programs despite the effectiveness of RT. Significant late effects are
expected to be less of a concern with the use of modern treatment programs combining
modern radiotherapy approaches and limited treatment volumes. However, it is still
important to understand the potential injury incurred by patients who received radiotherapy
before modern approaches were employ ed. Higher radiotherapy doses used in the past (up to
44 Gy ) resulted in impairment of muscle and bone development (9,188,189,190) and injury
to the lungs and heart (161, 192, 194,195,196,197,198,199), thy roid gland (200,201), and
reproductive organs (110,202,203,204,205,206,207,208,209). Cardiovascular dy sfunction and
secondary carcinogenesis result in early mortality in long-term survivors (120,161,198).
Pulmonary fibrosis can compromise the quality of life in survivors. Long-term complications
are discussed extensively in Chapter 20 and are briefly outlined here. These effects are
less common with the use of modern treatment approaches although not completely
eliminated (210).
Chronic pneumonitis and pulmonary fibrosis should be rare in the current era of
treatment for primary HL. Predisposing therapies include thoracic radiation and ABVD
chemotherapy (113,195,196,211,212,213). The bleomy cin in ABVD can cause both acute
pulmonary compromise and late pulmonary fibrosis and can be augmented by the fibrosis
that can be associated with pulmonary radiation. Keeping dosimetric parameters such as the
V5 to lung tissue to as low as reasonably achievable may be relevant for HL patients. Data,
for example, suggest that use of a mean lung dose constraint <15 Gy results in low rates of
radiation pneumonitis (214). A “radiation recall” phenomenon can be seen when RT is
administered after doxorubicin. Asy mptomatic pulmonary dy sfunction that improves over
time is observed after contemporary combined-modality treatment (213).
Cardiovascular disease is a major concern in survivors of PHL. Cardiac dy sfunction is
most commonly observed after anthracy cline therapy, particularly doxorubicin
(197,198,199,215). Young children may be at greater risk for anthracy cline injury than adults
because of an adverse effect on cardiac my ocy te growth. This is suggested by studies of
childhood leukemia survivors who demonstrate a high frequency of abnormalities of
afterload and contractility (216). Mediastinal irradiation and other chemotherapeutic agents
(e.g., cy clophosphamide) may predispose patients with PHL to anthracy cline-related
my ocardiopathy (198–199). The risk at delay ed time points (more than 20 y ears) has not
been established. An increased risk for inpatient care for cardiovascular disease was
identified in HL patients diagnosed with HL at age 40 y ears or y ounger. A family history of
congestive heart failure and coronary artery disease has also been shown to increase risk for
these conditions in HL survivors (217).
Radiation also injures the pericardium and my ocardium in a dose-related fashion
(197,199,215). Premature coronary artery disease and acute my ocardial infarction may also
increase mortality risk in patients treated with mediastinal radiation in dosages of more than
30 Gy before 20 y ears of age (198). Screening echocardiogram, exercise stress test, and
resting and 24-hour ECG identified numerous clinically significant cardiac abnormalities in
HL patients who had mediastinal irradiation at a median age of 16.5 y ears (range, 6.4–25
y ears). Significant valvular defects were detected in 42%, autonomic dy sfunction in 57%,
persistent tachy cardia in 31%, and reduced hemody namic response to exercise in 27% of
patients (218). With the introduction of techniques that reduce the radiation dosage to the
heart, the rates of radiation associated cardiac injury have declined dramatically. Likewise,
my ocardial infarctions have not been sy stematically reported in children treated with
combined-modality regimens using lower radiation dosages and volumes and protective
cardiac shielding. Again, the impact of subclinical cardiac injury after low-dose RT may not
become apparent until larger cohorts of survivors treated with these regimens begin to age.
Page 168Thy roid sequelae are common after RT for PHL. Hy pothy roidism,
hy perthy roidism, thy roid nodules, and thy roid cancer have been observed in long-term
survivors (200,201). Of these, hy pothy roidism, particularly compensated hy pothy roidism,
defined as thy roid-stimulating hormone (TSH) elevation in the presence of a normal
thy roxine (T4) level, is the most common thy roid abnormality. Risk factors for
hy pothy roidism include y ounger age at treatment and higher cumulative radiation dosage. As
many as 78% of patients treated with radiation dosages greater than 26 Gy demonstrate
thy roid dy sfunction, as indicated by elevated TSH levels (201,213). Because persistent TSH
elevation most often signals impending gland failure and may be a carcinogenic stimulus to
the gland, thy roid hormone replacement therapy should be instituted. Gland suppression with
thy roid hormone replacement is also recommended for patients who develop thy roid nodules
after radiation. Replacement therapy should suppress gland function, as indicated by a TSH
of 0.5–1.5 mIU/mL. Periodic withdrawal of hormonal therapy in asy mptomatic patients
permits assessment of gland recovery, which has been observed in some patients serially
monitored after RT. Persistent and enlarging nodules should be monitored with ultrasound and
periodic biopsies for malignant degeneration because thy roid carcinoma is a common second
malignancy after HL (200).
The risk of gonadal injury after HL is related to the ty pe and intensity of treatment. In
boy s, high-dose pelvic radiation may produce a transient oligospermia or azoospermia, but
spermatogenesis ty pically recovers (208,219). Six to eight cy cles of MOPP (or similar
hy brid chemotherapy -containing alky lators) produced irreversible sterility in 80–90% of
male patients; fertility may be preserved if treatment was limited to three or fewer cy cles
(206). Recovery of gonadal function 10–15 y ears after MOPP chemotherapy has been
rarely reported. COPP/ABV was also associated with male infertility in a majority of y oung
men in a study conducted by Hobbie et al. (220). In contrast, anthracy cline-based regimens
such as ABVD (or similar hy brid) usually are associated with full recovery of
spermatogenesis after a temporary period of azoospermia (203,221). Testicular Ley dig cell
function is more resistant to the effects of antineoplastic treatment, so growth and puberty are
adversely affected only in boy s treated with very high cumulative dosages of alky lating
agent chemotherapy. Risk-adapted therapies reducing or eliminating gonadotoxic alky lating
agent chemotherapy offer y oung men with newly diagnosed HL excellent prospects to
maintain fertility (204).
Young women have a higher chance of maintaining regular menses after treatment for
HL than older women. The risk of ovarian failure after pelvic radiation is high but can be
reduced by midline ovarian transposition (oophoropexy ) (202). Although most y oung women
maintained or resumed menses after MOPP (or similar hy brid) chemotherapy, they are
predisposed to early menopause, particularly if they also received abdominal-pelvic
radiation (110,205,209). In a report of female HL survivors by the Late Effects Study Group,
42% of women treated with alky lating agent chemotherapy and subdiaphragmatic radiation
had experienced menopause by the age of 31 y ears, compared with 5% of control subjects
(205). In a study of female HL patients treated at the Norwegian Radium Hospital, premature
ovarian failure was identified in 37.4% of patients. The risk was significantly higher if patients
received chemotherapy in addition to radiation. The risk was increased further if the
chemotherapy regimen included an alky lating agent. Women y ounger than 30 y ears
developed premature ovarian failure later in life but had the same cumulative risk as women
older than 30 y ears (222). Reports by other groups have not indicated an excessive risk of
premature menopause in y oung women treated with supradiaphragmatic RT alone (209).
Several studies have also demonstrated that ABVD is associated with significantly better
fertility preservation among males compared to alky lator-based regimens such as MOPP
(223,224). The Germans utilize OEPA and COPDac in place of the procarbazine containing
OPPA and COPDac for males due to the sensitivity of male gonadal function to procarbazine.
The overall cumulative risk of developing a subsequent malignancy after treatment for
PHL ranges from 7% to 8% at 15 y ears from diagnosis and rises to 16–28% by 20 y ears
(121,225). Tumor histologies comprise two main ty pes: acute my eloid leukemia (including a
pancy topenic my elody splastic sy ndrome) and solid tumors. Secondary leukemias exhibit a
brief latency with a peak frequency in the first 5–10 y ears after treatment. The risk decreases
to less than 2% after 10 y ears from diagnosis. Clinical and treatment factors correlated with
secondary leukemogenesis include older age at treatment, history of splenectomy,
presentation with advanced disease, treatment with high cumulative dosages of alky lating
agents, and history of relapse (121,226,227,228,229,230,231,232). In contrast to secondary
hematopoietic malignancies, the risk of developing a second solid tumor increases with the
passage of time from diagnosis, with a latency usually exceeding 8 y ears from diagnosis. A
variety of solid tumors have been observed, most commonly involving the breast, thy roid,
bone, and soft tissues (39,121,219,225,229,230,231,232,233,234,235,236,237). Female breast
cancer is a particular concern but is likely to be less common with current radiation doses and
techniques, since it is associated with RT fields that include breast tissue (especially mantle
fields), and higher radiation doses. In fact, secondary cancer risk is likely dose dependent with
patients receiving <25 Gy mediastinal RT experiencing a lower risk of breast cancer than
those that received higher doses (238). Thus, current pediatric protocols utilizing 21 Gy should
result in a lower incidence of secondary solid tumors. It is noteworthy that females may also
be at higher risk for non-breast secondary malignancies, primarily thy roid cancer, and this is
unexplained (236). Recent investigation into genetic poly morphisms suggests that certain
individuals may be predisposed to the development of secondary malignancies. Further study
into the genomic variability of this population may help to define an individual’s susceptibility
to develop a second cancer (239). Secondary malignancies in PHL are discussed in detail in
Chapter 20 .
FUTURE INVESTIGATIONS
Page 169Devising new strategies to treat children with HL is problematic because of the
overall success of current treatment regimens. However, grouping patients into different risk
categories allows investigators to construct protocols intended to diminish therapy -induced
toxicity for patients with favorable prognoses, improve treatment effectiveness for patients
with unfavorable prognoses, and aim for both goals in patients who are intermediate in their
prognosis. Unfortunately, the ability to conduct clinical trials in which the differences in
survival between treatment arms are likely to be small is compromised by the large patient
numbers necessary to detect such differences. If a reduction in treatment toxicity is the
intended goal of a new regimen, then many y ears of follow-up are necessary to prove
effectiveness. Some generalizations regarding ongoing efforts in clinical trials for PHL are as
follows:
Patients with early -stage disease (I, IIA without bulk disease) have an excellent
prognosis. Therefore, the intensity and duration of chemotherapy can be decreased
along with the use of RT. Evaluation of response-based paradigms can help tailor therapy
to de-escalate appropriately.
Patients with disease of an intermediate stage or with characteristics indicating that their
prognosis is intermediate (II with bulky disease, IIB, IIIA) are appropriate for studies
that intend to increase efficacy without increasing toxicity. By using response-based
paradigms, treatment can be tailored to optimize the chemoradiotherapeutic approach.
Patients with advanced-stage disease (IIIB, IV) need more effective treatment
regimens. These might include increasing dosage intensity or the rate of drug delivery
and combining agents into new regimens and incorporating targeted agents. The use of
hematopoietic growth factors may assist in drug delivery. Defining the role of RT in such
trials will continue to be an important objective and potential dose escalation for slow
responding or incompletely responding patients may be necessary.
Of interest, ongoing trials are continuing to evaluate the paradigm of early response using
functional imaging as a prognostic factor for therapy reduction or intensification.
Finally, immunotherapeutic approaches are under development and investigation, such
as the use of antiferritin antibody joined with y ttrium-90 (240), EBV-specific cy totoxic T
ly mphocy tes (241), and anti-PD1 monoclonal antibodies blocking ligand activation of the
PD1 receptor on activated T cells. If effective, these novel approaches will provide an
alternative to cy totoxic treatment approaches with potentially fewer adverse long-term
treatment effects.
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CH A P TER 8
Non-Hodgkin Lymphoma
Mary S. Huang, Nancy J. Tarbell, and Howard J. Weinstein
Page 175Malignant ly mphoma was described by Hodgkin in 1832 (1) and was distinguished
from leukemia by Virchow in 1845 (2). Progress in treating children with non-Hodgkin
ly mphoma (NHL) mirrors the recognition of the sy stemic spread of the disease and
underly ing biology. Response to therapy and overall prognosis depend on the underly ing
histologic subty pe, primary site, and the extent of disease (3,4). Historically, local therapy
resulted in an overall survival of 10–30% (4). Multiagent protocols including sy stemic therapy
result in overall survivals of 70–95% (5).
Childhood NHL is distinguished from adult NHL by differing frequencies of
histopathologic ty pes and by the greater frequency of extranodal presentations (6,7). The
pediatric NHLs are mostly (>95%) high grade and include the following four major
subty pes: B- and T-ly mphoblastic ly mphoma, Burkitt ly mphoma, diffuse large B-cell
ly mphoma, and anaplastic large-cell ly mphoma (ALCL) (Fig. 8.1 ). Many of these high-
grade ly mphomas disseminate noncontiguously, evolve into a leukemic phase, and may
involve the central nervous sy stem (CNS) (7). The more common low-grade ly mphomas
seen in adults, such as follicular and marginal zone ly mphomas, are rare in children (6).
Figure 8.1 Denis Parsons Burkitt
(1911–1993) was the son of an engineer. A
Protestant raised in Northern Ireland, he
lost an eye in a fight as a schoolboy. He
graduated as a physician in 1935 and
trained in surgery but had difficulty in
obtaining surgical positions because of his
visual loss. Eventually, he was posted as
an Army physician in Africa and
subsequently worked as a missionary
physician. He characterized a previously
undescribed aggressive head and neck
cancer of childhood. Michael Epstein
attended one of Burkitt’s lectures in
England, suspected a viral origin, and
requested a tissue sample. Epstein and
Yvonne M. Barr isolated the virus
(Epstein–Barr virus). Burkitt also
described the crucial influence of dietary
fiber on health and disease.
Figure:
Denis Parsons Burkitt (1911–1993) was the son of an engineer. A Protestant raised in
Northern Ireland, he lost an eye in a fight as a schoolboy. He graduated as a physician in 1935
and trained in surgery but had difficulty in obtaining surgical positions because of his visual
loss. Eventually, he was posted as an Army physician in Africa and subsequently worked as a
missionary physician. He characterized a previously undescribed aggressive head and neck
cancer of childhood. Michael Epstein attended one of Burkitt’s lectures in England, suspected
a viral origin, and requested a tissue sample. Epstein and Yvonne M. Barr isolated the virus
(Epstein–Barr virus). Burkitt also described the crucial influence of dietary fiber on health and
disease.
EPIDEMIOLOGY AND ETIOLOGY
The ly mphomas are the third most common malignancy in children below 15 y ears of age.
They are rare under the age of 3 y ears, peaking in incidence from age 7 to 11 y ears. There is
approximately a 3:1 male:female ratio (3,4). Ly mphomas account for approximately 10% of
all childhood cancers: 60% are NHL and 40% are Hodgkin disease (8). There is geographic
variation in the incidence of the NHLs. For example, in equatorial Africa, Burkitt ly mphoma
accounts for almost 50% of all childhood cancers. In this setting, endemic Burkitt ly mphoma
is invariably positive for Epstein–Barr virus (EBV), in contrast to about 10% of cases of
sporadic Burkitt ly mphoma. However, both endemic and sporadic cases of Burkitt ly mphoma
have the same chromosomal translocations involving one of the loci encoding
immunoglobulin heavy or light chains and the c-my c oncogene. The exact role of EBV in the
pathogenesis of Burkitt ly mphoma and other malignancies is unknown. NHL occurs in
association with congenital immunodeficiency sy ndromes such as X-linked
ly mphoproliferative sy ndrome, ataxia telangiectasia, Wiskott–Aldrich sy ndrome, and
common variable immune deficiency disease, presumably caused by host defects in
immunoregulation or gene rearrangement (9,10). Immunosuppressive therapy and acquired
immunologic disorders including HIV also increase the risk of developing NHL (10). These
are predominantly diffuse large B cell or Burkitt subty pes. Screening for HIV and other
immunodeficiencies should be considered for all children with NHL, especially for those with
B-cell ly mphomas.
Page 176Several subty pes of NHL in children are associated with distinct clinical
manifestations and sites of disease (Table 8.1 ). Sy mptoms leading to diagnosis usually are
of short duration. Approximately 25% of children with NHL have an anterior mediastinal
mass (usually T ly mphoblastic or diffuse large B cell) and present with wheezing, stridor, and
cough progressing to dy spnea. The majority of these patients are adolescents, and their
presentation may pose a medical emergency (11). Patients with large anterior mediastinal
masses are at risk of cardiac or respiratory arrest during general anesthesia or deep sedation.
A careful workup including a chest computed tomography (CT) scan with airway
measurements is essential (12) before attempting any procedures. The least invasive
procedure (e.g., biopsy of a peripheral ly mph node) should be carried out. If these
procedures are not successful in providing a diagnosis, then a CT-guided needle biopsy of the
mediastinal mass should be considered (13). In some clinical situations (e.g., orthopnea or
significant airway narrowing), preoperative or preprocedure steroids should be considered
for up to 48 hours. The use of steroids has largely replaced localized irradiation in this setting.
Primary gastrointestinal involvement occurs in about 30% (usually Burkitt histology ),
commonly presenting as an abdominal mass with ascites, an “acute abdomen” from an
intussusception, or rarely a malnutrition sy ndrome with colitis sy mptoms (14). The majority
of children with Burkitt ly mphoma presenting with an ileal–cecal intussusception have limited
gastrointestinal involvement that is amenable to complete surgical resection (Murphy stage 2
or group A). In 20–30% of children, the head and neck region, including the Waldey er ring or
cervical ly mph nodes, is the site of origin. The remainder of patients have miscellaneous
primary sites, including bone, breast, skin, epidural space, or noncervical ly mph nodes.
Involvement of the bone marrow at diagnosis occurs in 10–30% of patients with Burkitt and
ly mphoblastic ly mphomas. Overt CNS involvement at diagnosis is not common but is mostly
seen in children with advanced-stage Burkitt and ly mphoblastic ly mphomas. Children who
develop Burkitt ly mphoma in endemic areas of the world often have a mass in the head or
neck region (especially jaw) in contrast to the abdominal presentation ty pical of nonendemic
Burkitt ly mphoma.
Table 8.1 Clinical and Biologic Features of NHL in Children

Figure: Clinical and Biologic Features of
NHL in Children
EVALUATION
A biopsy of a ly mph node or mass or examination of pleural or ascitic fluid is necessary to

establish the diagnosis. Although histology continues to be the primary determinant of
therapy, morphology with immunohistochemistry is supplemented by cy togenetic and
molecular genetic studies. The workup includes complete blood cell count with differential,
routine chemistries with electroly tes, calcium, phosphorus, magnesium, uric acid, liver and
renal function tests, and lactate dehy drogenase (LDH). Lumbar puncture with
cy tocentrifugation and bone marrow sampling are indicated in most children with NHL and
Burkitt ly mphoma. Chest radiograph, as well as abdominal, thoracic, and head and neck CT
scans should be obtained and a magnetic resonance imaging (MRI) scan may provide
additional information depending on the presenting site (15). Positron emission tomography
(PET) imaging is now part of the initial staging for some patients with NHL and is particularly
helpful in assessing response to induction therapy for diffuse large B-cell ly mphoma,
primary mediastinal large B-cell ly mphoma, and ALCL (15,16). In PET avid disease, bone
marrow sampling may not be necessary. Laparotomy is not indicated for staging and is
performed only for abdominal presentations necessitating surgical intervention (e.g., ileal–
cecal intussusception). There are no data to support surgical debulking of NHL in children.
STAGING AND CLASSIFICATION
Page 177Originally, the Ann Arbor staging sy stem for the Hodgkin disease was used for NHL
(see Table 7.1 ) (15). The usefulness of this sy stem in pediatric NHL is limited, and an
alternative staging sy stem proposed by Murphy et al. has been widely accepted (Table
8.2 ). This sy stem recognizes ty pical patterns of disease presentation and has greater
prognostic utility than the Ann Arbor sy stem. In Burkitt ly mphoma and large B-cell
ly mphomas, another staging sy stem developed by Patte et al. (17) is also used (Table
8.3 ). It classifies patients according to tumor burden and surgical resection.
Table 8.2 Murphy and St. Jude Children’s Research Hospital Staging System for
Childhood NHL
Table 8.3 Clinical Staging of B-Cell Lymphomas
The current most widely accepted histologic classification sy stem is the World Health
Organization (WHO) classification that was updated most recently in 2008 (18,19). This
sy stem has been validated as highly reproducible in international studies and has evolved to
incorporate histology as well as immunohistochemistry, gene expression profiling, and
cy togenetic, molecular, and clinical features.
As previously discussed, over 95% of the pediatric NHLs are high grade and fall into
four major histologic subty pes (ly mphoblastic ly mphoma, Burkitt ly mphoma, diffuse large
B-cell ly mphoma, and ALCL). T- and B-cell ly mphoblastic ly mphomas comprise about 30%
of NHL in childhood; T cell is the more common ty pe. Mature B-cell ly mphoma includes
Burkitt ly mphoma (35–40% of cases) as well as diffuse large B-cell ly mphoma (DLBCL)
and primary mediastinal large B-cell ly mphoma (PMBL). Together, the latter two comprise
approximately 20% of NHL in childhood. In the current WHO classification, PMBL is
considered distinct from other DLBCLs based upon its unique clinical, histologic, and
molecular features. Other mature B-cell ly mphomas, including pediatric marginal zone
ly mphoma, pediatric follicular ly mphoma, and MALT ly mphoma, are also recognized as
distinct entities that rarely occur in childhood. Within the category of mature T-cell
ly mphoma, ALCL accounts for approximately 10% of NHL in childhood.
Page 178B-cell ly mphoblastic ly mphoma consists of cells with round or convoluted
nuclei, fine chromatin, inconspicuous nuclei, and scant, faintly basophilic cy toplasm. In B-
cell ly mphoblastic ly mphoma, the tumor cells characteristically express TdT, CD10, CD19,
and CD79a, which is identical to the most common immunophenoty pe of B-acute
ly mphoblastic leukemia (ALL) in childhood (20). The T-cell ly mphoblastic ly mphomas are
also TdT positive, but express a combination of T-cell antigens (CD2, CD3, CD4, CD5, and
CD8) similar to that of T-cell ALL. T-cell ly mphoblastic ly mphomas share many clinical and
biologic features with T-cell ALL (21). When the bone marrow is involved with ly mphoblasts
(>25%), the distinction between ly mphoma and leukemia becomes difficult. Subtle distinct
biologic differences between the blasts in T-ly mphoblastic leukemia and ly mphoma are being
recognized with newer molecular assay s (22).
Burkitt ly mphoma tumor cells are monomorphic, medium-sized cells with round nuclei,
multiple nucleoli, and basophilic cy toplasm. A “starry -sky ” pattern is the result of benign
macrophages that have ingested apoptotic tumor cells. Cells ty pically express sIgM, CD19,
CD20, CD22, CD79a, and CD10 (18). Most, but not all cases, have a cy togenetic abnormality
involving the MYC gene at band 8q24.
Diffuse large B-cell ly mphoma consists of tumor cells that are larger than ly mphocy tes
with vesicular nuclei, basophilic cy toplasm, and a moderate-to-high proliferation fraction
(19). The nuclear size is equal to or greater than that of a normal macrophage. DLBCL can
be subdivided into several subclasses based on either immunophenoty ping or DNA
microarray s (18). These large B-cell ly mphomas ty pically express CD19, CD20, and CD22,
and 50–75% express cy toplasmic or surface immunoglobulin. PMBLs in addition to
presenting in the mediastinum are ty pically associated with compartmentalizing alveolar
fibrosis and, in contrast to other DLBCLs, ty pically do not express immunoglobulin.
Alterations of oncogenes involved in adult DLBCL such as BCL6 and BCL2 are very rare in
children with DLBCL, whereas rearrangement of the MYC oncogene is more common in
pediatric compared to adult DLBCL (23,24).
Pediatric follicular ly mphoma is an interesting entity that was initially noted for
clinically indolent behavior, and limited disease at diagnosis, ty pically stage I. It occurs, as
well, in y oung adults and, in contrast to conventional adult follicular ly mphoma, is
characterized by a high proliferation index (>30% Ki67 fraction) and absence of BCL-2 gene
abnormalities (25).
ALCL consists of ly mphoid cells that are usually large with abundant cy toplasm and
pleomorphic, often horseshoe-shaped nuclei. The cells are CD30 positive, and the majority of
pediatric cases are also positive for the anaplastic ly mphoma kinase (ALK) protein and have
the chromosomal translocation t(2;5)(p23;q35) involving the nucleophosmin (NPM) and ALK
genes (18).
Figure: Murphy and St. Jude Children’s
Research Hospital Staging System for
Childhood NHL
Figure: Clinical Staging of B-Cell
Lymphomas
PROGNOSTIC FACTORS
The most prominent prognostic determinant in childhood NHL is the clinical stage. Tumor
burden, as measured in part by serum LDH, has been predictive of outcome in some series,
especially for Burkitt ly mphoma (17,26,27). In general, patients with localized Murphy stage
I and II ly mphomas have a better prognosis than those with more extensive stage III and IV
ly mphomas. However, stratified therapy has resulted in excellent outcomes for both low- and
high-stage disease. Site of involvement has also been prognostic. For example, presentation of
PMBLs has been recognized as having significantly higher risk for relapse than other DLBCLs
(17,28). In the past, bone marrow involvement was associated with a poor prognosis, but with
intensive chemotherapy it is no longer an adverse prognostic factor (17,26,27). Before the use
of preventive CNS therapy, CNS relapse developed in 30–40% of children with stage III and
IV Burkitt and ly mphoblastic ly mphomas. CNS relapses were also noted, albeit in a much
lower percentage, in children who had head and neck primary sites of other NHLs (29,30).
Overt CNS involvement at diagnosis is rare and is associated with a poorer prognosis. In this
situation, intrathecal (IT) chemotherapy and cranial irradiation may be indicated (27,31).
Chemotherapy
Because of the high likelihood of disseminated
disease at presentation, all children with the high-
grade subty pes of NHL, regardless of stage,
receive sy stemic, combination chemotherapy.
The four major histologic subty pes of childhood
NHL respond to a wide range of drugs including
steroids, anthracy clines, vinca alkaloids,
topoisomerase 2 inhibitors, and alky lating agents,
but different combinations and schedules are
optimal for particular histologies. Tables 8.4 Table 8.4 Low-Stage/Low-Risk
and 8.5 list some of the commonly used Patients
regimens and treatment outcomes.
For limited-stage ly mphoblastic ly mphoma, treatment with the use of ALL therapy is
effective, with approximately 85–90% disease-free survival (20,31). The use of more
intensive ALL chemotherapy regimens has also resulted in excellent outcomes for most
children with advanced-stage disease (disease-free survival of 80–85%) (30,31). Similar to
the case with ALL patients, there is evidence that poor initial response to treatment, most
notably steroids, appears to confer a worse prognosis with event-free survival (EFS) only in
the 50% range (31). The least toxic and most effective method of CNS prophy laxis for these
patients remains unclear. Both cranial irradiation and IT methotrexate have been very
effective but are associated with neurocognitive late effects. Data from recent studies
indicate that intensive IT methotrexate with or without sy stemic high-dose methotrexate is
adequate therapy to prevent CNS relapse (30,38). In many settings, patients with B- or T-
ly mphoblastic ly mphoma are eligible to participate in trials for B- or T-ALL, respectively,
thereby allowing for new agents or treatment strategies to be tested in this group of patients.
Page 179For the purposes of treatment,
high-grade mature B-cell ly mphomas have been
treated similarly. Burkitt ly mphoma, in contrast
to DLBCL, is much more likely to involve the
bone marrow and CNS and much more likely to
be complicated with a tumor ly sis sy ndrome.
Although histologically and clinically
distinct, both Burkitt ly mphoma and DLBCL
respond well to treatments as outlined below. For
low-stage Burkitt ly mphoma as well as DLBCL,
short-duration therapy with cy clophosphamide,
doxorubicin, vincristine (Oncovin), and
prednisone (CHOP) or cy clophosphamide,
vincristine (Oncovin), prednisolone, and Table 8.5 Advanced-Stage/High-Risk
doxorubicin (Adriamy cin) (COPAD) results in Patients
excellent relapse-free survivals of 90–98% and
85–90% (26,31,32), respectively. For higher-stage and higher-risk groups, the ly mphoma
malignant B ty pe (LMB)-96 protocol, a multiagent intensive chemotherapy regimen for B-
cell ly mphoma, has resulted in greater than 90% 4-y ear EFS. LMB-96 includes 3–5 months
of intensive cy cles of cy clophosphamide, vincristine, prednisone, high-dose methotrexate,
doxorubicin, cy tosine arabinoside (AraC), and etoposide (17,27). Promising results from pilot
trials show safety and efficacy of rituximab, CD20 targeted therapy, on an LMB therapy
backbone (39,40). A randomized trial with the addition of rituximab on standard therapy is
currently in progress.
As noted previously, within the high-grade mature B-cell ly mphoma group, PMBL
stands out clinically, with significantly inferior EFS, in the less than 70% range, using LMB
therapy (28). With the adriamy cin, prednisone, vincristine (oncovin), 6-mercaptopurine, and
methotrexate (APO) protocol, which does not include an alky lating agent but features
intensive doxorubicin, durable EFS of approximately 70% has also been seen (33). This
regimen has never been directly compared to an LMB approach. As a clinical entity, PMBL
ty pically affects adolescents and y oung adults with peak incidence in the third and fourth
decades. As such, the majority of patients and clinical trials have been pursued in patients
greater than 18 y ears of age. In contrast to pediatric follicular ly mphoma, we do not know
that PMBL in y ounger patients behaves in a distinct way. It may be reasonable to extrapolate
from adult experience with this tumor in planning treatment for adolescent patients. Good
results have been reported with rituximab containing regimens, including Rituximab+CHOP
(34,41) and DA-Epoch-R (dose-adjusted etoposide, doxorubicin, cy clophosphamide,
vincristine, prednisone, and rituximab) (35). The latter regimen is notable for substantial
potential cumulative exposure to anthracy cline. A current randomized trial in adults is
comparing these two regimens. In future, it may be beneficial to include adolescents with this
disease in collaborative trials with y oung adult patients to optimize therapy and characterize
the disease more fully.
Rare low-grade mature B-cell ly mphomas, pediatric follicular ly mphoma, pediatric
marginal zone ly mphoma, and MALT ly mphoma occur in childhood. For the former two
presenting with low-stage disease, many patients have done well with resection and
observation only (25,42). For ocular MALT ly mphoma, treatment has consisted of resection
followed by radiation therapy without adjuvant chemotherapy (43). Efforts to collect clinical
information and pathologic specimens to further characterize these rare pediatric ly mphomas
and determine best approaches are in progress.
For early -stage ALCL, CHOP is effective therapy (32). The APO regimen has also
been effective for higher-stage ALCL in children (disease-free survival 70–75%) (33). Other
regimens for ALCL have been modeled after B-cell protocols and report similar results (36).
Although vinblastine has been shown to be particularly effective as a single agent in ALCL
(44,45), recent efforts to bring this agent forward into frontline therapy did not show
significant benefit (37). Current trials attempt to incorporate therapies that target CD30 or ALK
mutations in this disease. The optimal strategy to incorporate new agents into existing
regimens remains unclear.
Page 180In recent y ears, outcomes for pediatric patients with NHL have improved
dramatically. Optimal combinations of agents, intensity, and duration of therapy have evolved
for disease groups. In the future, we anticipate further stratification of treatment regimens
and, as noted above, the addition of disease-specific agents, such as rituximab, in mature B-
cell ly mphomas or agents targeting ALK and CD30 in ALCL.
Figure: Low-Stage/Low-Risk Patients
Figure: Advanced-Stage/High-Risk Patients
The role of radiotherapy in the management of all childhood NHL has decreased as sy stemic
chemotherapeutic regimens have become more effective (5). As the overall survival
improved for children with all stages and subty pes of NHL, studies designed to assess the
need for regional radiation therapy followed. This has evolved on a background of significant
concerns for late effects of treatment, including neurocognitive effects of low-dose CNS
radiation as well as the risk for second malignancy, and cardiac and pulmonary toxicity in
patients receiving radiation therapy to the mediastinum and neck combined with
chemotherapy (46). Increasing reports demonstrate successful local and sy stemic control
with chemotherapy alone for children with NHL regardless of histology and stage (5).
As previously discussed, prophy lactic CNS treatment is needed in the majority of
children with NHL, thereby reducing the otherwise high risk of CNS relapse. The approach
for all ly mphoblastic histologies includes sy stemic and IT chemotherapy. It has become
evident that there is no benefit to adding radiation therapy for CNS prophy laxis in Burkitt
ly mphoma (29), (38). The current CNS preventive regimens for advanced-stage
ly mphoblastic ly mphoma include either cranial irradiation and IT chemotherapy or IT
chemotherapy and sy stemic chemotherapy only. The Berlin–Frankfurt–Munster (BFM)
group safely reduced the dosage of cranial radiation therapy to 12 Gy for ly mphoblastic
ly mphoma and eliminated it entirely from BFM-95 without increasing the CNS relapse rate
(30). Cranial irradiation (12–18 Gy ) is still warranted for the rare patient with ly mphoblastic
ly mphoma with initial CNS disease or a CNS relapse. Patients with cranial nerve palsies at
diagnosis, independent of cerebrospinal fluid findings, are treated in a similar fashion as
children with initial CNS ly mphoma.
The current indications for radiation therapy to involved sites of disease outside the CNS
in pediatric NHL have become somewhat limited. Involved-field radiation is considered for
patients who do not attain a complete remission after induction chemotherapy. This situation is
relatively rare, but more common in PMBL. Given the increased rate of local failure
compared to other pediatric NHLs, the role of involved-field radiation remains a topic of
some debate. Adult data suggest that with the addition of rituximab to prior regimens, the
number of patients who require involved-field radiation in PMBL patients may decrease
(34,35,47).
As noted previously, rarely, low-grade mature B-cell ly mphoma, such as pediatric
follicular ly mphoma, pediatric marginal zone ly mphoma, and ocular MALT ly mphoma,
occur. Limited data are available as to the best therapy for these patients. Historically, ocular
MALT in pediatrics has been approached as adult cases, with low-dose superficial radiation
therapy (43). No role for radiation therapy in low-stage pediatric follicular ly mphoma or
pediatric marginal zone ly mphoma has been established.
Involved-field radiation may also be considered for palliation of pain or mass effect, and
consolidation to regions of local disease before or after bone marrow transplantation in
patients with recurrent disease. Care should be taken to use modest fractionation schedules
and to avoid exceeding normal tissue tolerance dosages because patients may be eligible for
subsequent bone marrow transplantation necessitating total body irradiation (TBI) as a
component of the preparative regimen.
Children with refractory or relapsed NHL can experience prolonged disease-free
survival after treatment with high-dose chemotherapy or high-dose chemoradiotherapy
followed by autologous or allogeneic bone marrow transplant (48,49,50). When TBI is a
component of the preparatory regimen, fractionated courses to total dosages of 12–14 Gy are
common (see Chapter 2 ). Disease recurrence rather than the morbidity of transplant is
the predominant cause of failure in this setting. The strategy of irradiating the local sites of
initial disease recurrence before or after transplant, whether or not TBI is used, can be
considered (48). Dosages to these sites (usually at least 20 Gy ) are constrained by normal
tissue tolerances.
Historically, emergency radiation therapy for superior vena cava sy ndrome, acute
airway compromise, or spinal cord compression has been used to provide rapid sy mptom
relief. The response is particularly dramatic with ly mphoblastic ly mphoma and sy mptoms
are usually improved within 48 hours of treatment. Usually 1.5–2 Gy per fraction for a total
dosage of 6–7.5 Gy is adequate to relieve sy mptoms. Hy perfractionated regimens (1.2–1.5
Gy per fraction twice a day for a total dosage of 6–10 Gy ) can also be used. Sy stemic
steroids, particularly in the case of mediastinal mass, are more commonly used and
generally are equally effective. On rare occasions, emergency radiation therapy or
treatment with steroids is appropriate in the absence of a histologic diagnosis. Despite the
rapid response with either, this can be done without significantly compromising tissue
diagnosis if sampling can occur within 48 hours of treatment (13).
SURGICAL MANAGEMENT
Although surgical biopsy may be critical in the diagnosis of NHL, the role of surgery is
otherwise limited. It should be performed on patients in whom there is good reason to believe
that total resection can be achieved, such as in limited abdominal disease. As well, in patients
with rare low-grade ly mphoma, such as pediatric follicular ly mphoma or marginal zone
ly mphoma, complete surgical resection of stage I disease may be curative and eliminate the
need for any adjuvant therapy (42).
RESULTS OF THERAPY
Before 1975, when therapy was directed to the identifiable gross tumor, few children
survived. The small number of patients who did survive had favorable presentations, including
limited resectable abdominal disease or involvement of a single nodal region or extranodal
site. With current intensive multiagent regimens, survival is generally excellent for all
patients, including those with disseminated disease and adverse prognostic factors such as
bone marrow involvement, CNS involvement, and high-serum LDH. Most relapses occur
within 12 months of diagnosis for Burkitt ly mphomas and within the first 2–4 y ears for the
other histologic subty pes. Late relapse has been reported with ALCL and B-ly mphoblastic
ly mphoma.
Page 181Children with stage I to II disease have 2-y ear disease-free survival rates of
85–98% (5,31,32). Children with stage III disease have an 85–90% 2-y ear disease-free
survival. Those with stage IV disease and marrow involvement have an 85–90% disease-free
survival, and those with CNS disease (Burkitt ly mphoma) have an 80% EFS. Patients with
PMBL have had significantly worse EFS at 60–70% (27,28).
Patients undergoing transplantation early in their disease course (i.e., after first relapse
or second complete remission) have 2-y ear disease-free survival approaching 50%, whereas
those with refractory disease or early relapse fare less well (48,49,50).
With improvements in survival in many groups of patients, recent efforts have focused
on maintaining excellent EFS with reduced late toxicity. Incorporating more specific targeted
therapies for patients with less favorable subgroups, notably PMBL, may be helpful as a
focus of future development.
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CH A P TER 9
Ewing Sarcoma
Karen J. Marcus, Torunn I. Yock, and Nancy J. Tarbell
Page 183James Ewing (1866–1943) first described the bone tumor that bears his name in
1921 (1). He observed that the malignancy was most common in teenagers, occurred in the
metaphy seal and diaphy seal region of long bones or in the flat bones, was associated with
pain and often fever, had a histologic appearance of highly vascular sheets of small round
cells, and was quite sensitive to radiation (Fig. 9.1 ) (2).
Figure 9.1 A: In the fourth edition of his textbook Neoplastic Diseases: A Textbook on
Tumors (1940), James Ewing of the Memorial Hospital, New York, described a “diffuse
endothelioma of radius, diffuse absorption without destruction of shaft, spontaneous fracture,
wide invasion of muscle, duration 1 year.” Ewing wrote that “the first indication is for
treatment by radiation in full doses, and over considerable periods. This recommendation is
based on the reported cure of certain cases … by radiation alone, and on the clinical
disappearance of the disease by variable periods in many more cases. The response to
radiation also confirms the diagnosis. The danger of metastases occurring while this
treatment is in progress is probably negligible, since the tumor tissue generally undergoes
rapid liquefaction and necrosis.” B: Ewing illustrated the excellent response of the tumor to
radiotherapy.
Ewing was a leading authority on cancer. He became professor and chairperson of

pathology at Cornell Medical School in New York City and went on to serve as director of the
Memorial Hospital, play ing a crucial role in the growth of what is now known as the
Memorial Sloan–Kettering Cancer Center (2).
Page 184Ewing sarcoma is the second most common childhood primary bone tumor.
The tumor is slightly less common than osteosarcoma and represents 3% of pediatric
cancers. Approximately 200 cases occur annually in the United States. Although it presents in
the pubertal age range in 40% of patients, the age at diagnosis is more variable than that of
osteosarcoma: 30% of cases occur in children y ounger than 10 y ears and 5% occur in y oung
adults older than 20 y ears. Boy s are affected more often than girls, in the ratio of 1.5 to 2:1.
Age at diagnosis parallels the earlier onset of puberty in girls, with a median time of onset 3–4
y ears y ounger than in boy s. Ewing sarcoma is rare in children of Asian or African descent
(3).
Figure:
A: In the fourth edition of his textbook Neoplastic Diseases: A Textbook on Tumors (1940),
James Ewing of the Memorial Hospital, New York, described a “diffuse endothelioma of
radius, diffuse absorption without destruction of shaft, spontaneous fracture, wide invasion of
muscle, duration 1 year.” Ewing wrote that “the first indication is for treatment by radiation
in full doses, and over considerable periods. This recommendation is based on the reported
cure of certain cases … by radiation alone, and on the clinical disappearance of the disease
by variable periods in many more cases. The response to radiation also confirms the
diagnosis. The danger of metastases occurring while this treatment is in progress is probably
negligible, since the tumor tissue generally undergoes rapid liquefaction and necrosis.” B:
Ewing illustrated the excellent response of the tumor to radiotherapy.
PATHOLOGY
Ewing sarcoma consists of monomorphic sheets of small, round malignant cells with
hy perchromatic nuclei and little cy toplasm. There is a dearth of associated stroma. Cells
usually are periodic acid–Schiff (PAS) positive, indicating the presence of gly cogen granules.
Gly cogen in the tumor cells and the demonstration of the MIC2 gene product on the tumor
cell membrane help identify Ewing sarcoma (4,5). The tumor cells are also uniformly
vimentin positive and often cy tokeratin positive, indicating origin from epithelial and neuronal
elements (6).
Sarcomas are subdivided into two classes; the first class is composed of tumors
display ing complex kary oty pic abnormalities with no distinct pattern, and the second class
includes tumors associated with particular chromosomal translocations that result in specific
fusion genes. The Ewing sarcoma family is in the second class of sarcomas. Ewing sarcoma
and primitive neuroectodermal tumor (PNET) have been linked to the specific chromosomal
abnormalities involving a reciprocal translocation between chromosomes 11 and 22: t(11;22)
(q24;q12).
Advances in cy togenetic and molecular science provide insights into these abnormalities.
The key diagnostic feature in the Ewing sarcoma family is the detection of the translocation
involving the EWSR1 gene located on chromosome 22 band q12 and one of several partner
chromosomes (5). The EWSR1 gene is a member of the TET family of RNA-binding
proteins. Ty pically in Ewing sarcoma, the amino terminus of the EWSR1 gene is juxtaposed
with the carboxy -terminus of another gene. This genetic rearrangement is detectable in 86–
90% of tumors. Approximately 5–10% of Ewing sarcomas do not contain t(11;22) but instead
have a translocation between chromosomes 21 and 22: t(21;22) (q21;q12). However, this
alternate rearrangement has molecular consequences similar to those of t(11;22) (7).
The 11;22 translocation juxtaposes the EWS gene with the FLI gene, a member of the
ETS transcription factor family. The 21;22 translocation juxtaposes the EWS gene to another
ETS family member, ERG. There are structural similarities between these two translocations,
suggesting that they bind to similar DNA target sites. The EWS–FLI1 fusion was the first
sarcoma gene to be cloned (8). EWS–FLI can produce malignant transformation of some, but
not all, cell lines. The EWS/FLI gene appears to act as a transcription factor. Its mechanism of
action appears to be a modulation of transcription of target genes. Ewing sarcoma and PNET
translocation seem to fall in a developing class of tumor-associated chromosomal
translocations that form chimeric transcription factors (7). The formation of aberrant
transcription factors is associated with many human malignancies. We may conclude that the
probable mechanism of carcinogenesis in Ewing sarcoma is a translocation that produces an
aberrant transcription factor. These factors can cause deregulation of pathway s, resulting in
tumorigenesis. Using retroviral sy stems to biologically screen cDNA from cells transformed
by EWS/FLI1, platelet-derived growth factor-C (PDGF-C) has been identified as the target of
EWS/ETS transcriptional deregulation (9). Therefore, Ewing sarcoma cy togenetics may help
us to understand oncogenic mechanisms.
The EWS gene is a member of the ETS family of transcription factors defined by the
ETS domain. The FLI1 gene appears to be involved in early hematopoietic, vascular, and
perhaps neuroectodermal development (10). Evidence suggests that EWS–FLI1 fusion protein
is the key oncogenic lesion in Ewing sarcoma. EWS–FLI1 acts as the dominant oncogene
(11). The transcription factor resulting from the translocation replaces the EWS RNA-binding
domain by the FLI1–ETS domain with the resulting aberrant transcriptional effects. A number
of genes have been identified as direct or indirect regulatory targets of the aberrant protein
produced by the EWS–FLI1 translocation (9,12). A major hurdle in the attempts to generate
model sy stems of the Ewing family of tumors is the toxicity of the fusion gene. The identity
of the cells from which Ewing tumors originate has remained elusive. The observation of the
t(11;22) translocation leading to the EWS–FLI1 expression suggests the existence of a primary
cell transformed by EWS–FLI1. Evidence from a genetically defined EWS–FLI1 model
sy stem suggests a mesenchy mal origin of these tumors (13). Recent publications have shown
that the t(11;22) breakpoint location and therefore the exact amino acid composition of the
resultant EWS–FLI fusion oncoproteins might have prognostic relevance (13,14,15,16).
Despite some suggestion that the breakpoint location is prognostic, two recent large series
have shown that the EWSR1-ETS translocation breakpoint site is not an adverse prognostic
factor (14,15).
Pain is the most common presenting sy mptom, noted in approximately 90% of cases. Local
swelling or mass effect related to the bone tumor is apparent in a majority of children. A
distinct soft tissue mass can be appreciated clinically in one-third of cases. Significant
limitation of movement has been described in 25% of presentations. Neurologic sy mptoms or
signs occur in 15% of children, either as spinal cord compression or as peripheral nerve
compression. The latter is most often apparent with lesions of the pelvis or about the knee.
Fever is present in 10% of cases and has been related to tumor size and metastatic disease at
diagnosis.
The diagnostic evaluation of the patient with
Ewing sarcoma is shown in Table 9.1 .
Laboratory findings may include high leukocy te
count, a nonspecific finding indicative of tumor
bulk or extensive disease. A high leukocy te count
has been related to increased risk of tumor
recurrence (16,17). Pretreatment serum lactate
dehy drogenase (LDH) is of prognostic
significance, and the degree of LDH elevation
has been related to tumor volume (17).
Currently, FDG-PET and FDG-PET/CT are
optional staging modalities. However, they have
demonstrated high sensitivity and specificity in
Ewing sarcoma and may provide additional Table 9.1 Clinical Evaluation of the
information that alters therapy planning. Positron Patient with Ewing Sarcoma
emission tomography (PET) using fluorine-18
fluoro-deoxy glucose is being studied for detection of osseous metastases in bone tumors and
appears to be a sensitive and specific modality in Ewing sarcoma and PNET.
Page 185The diagnostic features of Ewing sarcoma are radiographically defined as a
permeative, destructive lesion of bone. In long bones, the tumor most often presents along the
metaphy seal region or within the diaphy sis (i.e., at the midshaft level). The periosteum often
is displaced by the underly ing tumor, resulting in the clinical sign of Codman triangle,
representing a bone expansile lesion. Although bone expansion is common, new bone
formation bey ond the periosteal margin is rare. An associated soft tissue mass is ty pical,
occurring in more than 50% of long bone neoplasms (18,19). Both computed tomography
(CT) and magnetic resonance imaging (MRI) appear necessary for most sites and are
complementary. Using both studies has added substantially to the determination of disease
extent, identify ing extraosseous involvement, and the degree of marrow infiltration linearly
(Fig. 9.2 ). CT has been valuable in outlining the bone and soft tissue extent of central
Ewing sarcoma. Better definition of tumor extent by CT scans is credited with improvement
in control of pelvic Ewing sarcoma (20). MRI has added to this definition of tumor (Fig.
9.3 ) (21). Radionuclide bone scan may also be of value, although it may exaggerate the
linear tumor extent. PET/CT is useful in combination with MRI for active tumor definition.
MRI may show edema. Whether direct microscopic extension of tumor is associated with the
edema is unknown at present.
Figure 9.2 Ewing sarcoma of the left radius (A) with (B) extensive infiltration of the
surrounding soft tissue.
Figure 9.3 A: Ewing sarcoma of the tibia seen on a plain radiograph shows cortical
disruption, “onion skinning,” and a suggestion of soft tissue involvement. B, C: Coronal and
axial magnetic resonance imaging show extensive soft tissue infiltration.
Approximately 53% of Ewing sarcomas have a primary site in an extremity, and 47%
have central primaries. Ewing sarcoma presents in the proximal extremities in 20–30% and
distal extremities in 30–40% of cases (22,23,24). Metastases are present at diagnosis in
approximately 20–25% of patients.
Primary lesions of the rib are associated with direct pleural extension and significant
extraosseous soft tissue mass in a majority of cases (25,26). The original description of
thoracopulmonary malignant tumors by Askin et al. (27) in 1979 characterized small round
cell tumors in this location as a separate clinicopathologic entity, often called Askin tumor. He
described a female predominance and a short median survival (8 months). These tumors tend
to have a large soft tissue component that can displace most of one lung with or without much
rib involvement. This patient group has special management issues (28,29).
Page 186The frequency of overt metastasis is estimated at 25–30% for pelvic primaries
and less than 10% for tumors of the extremities or ribs. The sites of metastatic disease at
diagnosis parallel the distribution noted with treatment failure, most often involving the lungs
(40%) or bones (40%), with less common disease involving the bone marrow, ly mph nodes,
soft tissue, visceral sites, or, rarely, the central nervous sy stem (30). No formal staging
sy stem has been recognized for Ewing sarcoma. The disease factors most recognized as
prognostically significant include the bone of origin or primary site, older age, tumor size,
presence or degree of soft tissue extension, and identification of hematogenous metastasis at
diagnosis (Table 9.2 ). Smaller tumors (less
than 200 mL in volume) and distal extremity
tumors tend to be favorable (24,31). At present,
the most important prognostic factor at diagnosis
appears to be the presence of metastasis (32,33).
Reports suggest that the response to initial
chemotherapy is significant as well (34).
Table 9.2 Prognostic Factors in Ewing
Sarcoma
Figure: Clinical Evaluation of the Patient
with Ewing Sarcoma
Figure:
Ewing sarcoma of the left radius (A) with (B) extensive infiltration of the surrounding soft
tissue.
Figure:
A: Ewing sarcoma of the tibia seen on a plain radiograph shows cortical disruption, “onion
skinning,” and a suggestion of soft tissue involvement. B, C: Coronal and axial magnetic
resonance imaging show extensive soft tissue infiltration.
Figure: Prognostic Factors in Ewing Sarcoma
SELECTION OF TREATMENT
Local Control
The relative roles of surgery and radiation therapy for local treatment of Ewing sarcoma
have long been debated. In 1953, Wang and Schulz (35) reported 5-y ear survival in 6 of 36
children treated with wide-field irradiation, as compared with 1 of the 14 treated by primary
surgical resection. Using 50 Gy to the entire bone, Phillips and Sheline documented survival in
5 of 21 cases in 1969 (36). After these reports, Ewing sarcoma was generally treated with
radiation therapy except for small tumors in expendable bones. Reviews have indicated an
overall rate of local tumor control of 75% to almost 95% after primary radiation therapy
(3,32,37,38,39,40,41).
Historically, the use of radiation therapy had been the local treatment of choice.
However, the role of surgery has increased because of several developments. These
important developments include the recognition that the local failure rate of radiotherapy for
Ewing sarcoma ranges from 9% to 25%. In addition, the development of innovative surgical
techniques allowing preservation of limb and structural bone function has promoted surgery
as an alternative to radiation. The routine use of cy toreductive chemotherapy, as discussed
later in this chapter, often produces a significant decrease in the soft tissue component,
rendering tumors more readily resectable. In addition, the concern over second malignancies
from radiation therapy has prompted the reevaluation of the role of surgery as well (42).
However, the data concerning local control with radiation therapy alone are difficult to
interpret. Difficulties in assessing response to radiation therapy are evident in the slow rate of
resolution of CT, MRI, and radionuclide bone scan findings after irradiation. The significance
of residual soft tissue abnormalities and persistent areas of increased uptake on technetium
scans is uncertain (22,23,34,43). In patients who have hematologic metastasis, the implication
of residual recurrent tumor at the primary site confirmed by biopsy or autopsy is uncertain
because of the possibility of reseeding from the primary tumor (20,44).
Page 187Several other fundamental factors make it difficult to interpret the data
comparing surgery and radiotherapy for local treatment. The local recurrence rate after
radiation is strongly correlated with the primary tumor site. Local failure of extremity lesions
is of the order of 5–10%, compared with a local failure rate for pelvic lesions of 15–70%.
Local recurrence after radiation therapy of pelvic lesions is expected to improve with
improved tumor imaging and the widespread use of computerized radiotherapy treatment
planning. Therefore, old data may be of more limited use in contemporary management. It
should be noted that tumor size affects local control. Local control for tumors more than 8 cm
in diameter is on the order of 80%, compared with 90% for those less than 8 cm in diameter.
The fact that larger tumors are more likely to be treated with radiation instead of surgery
influences the clinical results of these modalities.
Some patients are treated with a combination of surgery and radiation therapy. Several
factors make it difficult to interpret this data. These include the important effect of quality of
radiotherapy on local control. In many “surgical” series, the comparison is not surgery with
radiotherapy but rather radiotherapy compared with radiotherapy and surgery. This is
analogous to the treatment of many other solid tumors with radiation therapy with resection.
Many surgical series include patients who are at lower risk. They include people who
have undergone ray resection of the hands and feet, removal of the wing of the ileum, lower
sacrum (lower than the S3 bone), ribs, clavicle, or body of the scapula. One must also
consider the relative functional deficits that will be experienced during high-dose irradiation,
surgery alone, and surgery with irradiation. In this context, when selecting local treatment for
childhood Ewing sarcoma, one must consider the rehabilitation capacity and the
psy chological adjustment of the patient with these local treatments (25,45,46).
Fundamentally, when attempting to compare surgery with radiation therapy in the
management of Ewing sarcoma, there is the problem of case selection. Studies are not
strictly comparable, so surgery and radiation can be seen not as competitive but as
complementary. However, one additional matter must be considered in comparing radiation
therapy with surgery : the risk of second malignant neoplasms. As we will describe later in this
chapter, radiation and alky lating agents combine to increase the risk of second malignant
neoplasms after the treatment of Ewing sarcoma. Studies indicate that the relative risk of
sarcomas in the treatment field is related to the radiotherapy dosage and the extent of
exposure to alky lating agents.
In an attempt to eliminate selection bias and evaluate local control modalities, Dubois et
al. (47) reported on 979 patients with localized Ewing sarcoma treated on three consecutive
randomized trials in the Children’s Oncology Group. The patients received similar
chemotherapy regimens. Although local control was not randomized, the authors used logistic
regression to generated propensity scores which indicated the probability that each patient
would have been selected to receive radiotherapy, surgery, or combined radiotherapy and
surgery. The potential covariates assessed were age, sex, tumor site, tumor size, clinical trial,
and y ear of study entry. Tumor size was eliminated from the final model as tumor size was
not available for all patients. On multivariate analy sis, compared with surgery, radiation had a
higher risk of local failure (HR, 2.41; 95% CI, 1.24–4.68). However, there were no significant
differences in EFS (HR, 1.42; 95% CI, 0.94–2.14), overall survival (HR, 1.37; 95% CI, 0.83–
2.26), or distant failure (HR, 1.13; 95% CI, 0.70–1.84) between local control groups.
The relative functional deficits that will be experienced during high-dose irradiation,
surgery alone, and surgery with irradiation must also be considered. In this context, when one
is selecting local treatment for childhood Ewing sarcoma, the patient’s rehabilitation capacity
and psy chological adjustment should be considered (4,40,48).
Surgery
The role of surgical resection in combined-modality treatment was addressed by the
Memorial Sloan–Kettering Cancer Center (23,49). With overall disease-free survival
approaching 80% at 3.5 y ears, Rosen et al. (50) described local treatment failure in 34 (21%)
patients after radiation therapy and aggressive multiagent chemotherapy, compared with 0 of
33 patients who underwent surgical resection in addition to chemotherapy. In an influential
review of the May o Clinic experience with Ewing sarcoma, Wilkins et al. (51) related a
significant impact of surgical resection on overall survival: 74% at 5 y ears, compared with
27% in patients treated without surgery. Other reports have also described improvement in
local control with the addition of surgery (22,25,40,45,52,53,54). However, the studies
reflected selected surgical intervention. For example, in a review by Wilkins et al. (51) of 27
children with microscopically complete resection in a total series of 65 cases, the analy sis
included 11 patients treated with radiotherapy and no adjuvant chemotherapy. These 11
patients were included in the analy sis of the “nonoperated group” and were compared with
the patients receiving surgery plus chemotherapy, clearly biasing the results to favor the
surgical group. In a more balanced comparison, Brown et al. (22) described improvement in
local control with surgery in extremity lesions. There were local recurrences in 0 of 5
resected cases, compared with 3 of 15 patients treated with primary radiation therapy. Brown
et al.’s analy sis pointed out the selected use of surgery in 35 of 67 patients, clearly selecting
cases with distal and smaller lesions for surgery.
Treatment results after surgical resection when combined with chemotherapy have been
excellent, even considering the selection factors inherent in surgical subsets. In cases with
complete or good partial response to preoperative chemotherapy, Hay es et al. (55) described
disease-free survival in 11 of 11 cases with negative operative margins and no added
irradiation. Most other series addressing the impact of surgery have incorporated
postoperative radiation therapy, often at reduced dosage levels (48,50,51,54,56). The addition
of surgery for “dispensable bones” (e.g., fibula, rib, smaller lesions of the hands or feet) often
is considered a significant addition to therapy with little attendant functional deficit, although
excellent results have also been reported with irradiation (44). Options for surgical
management have also been considered primarily in the very y oung population, in whom
radiation late effects would be more significant (56,57,58,59).
Page 188Appropriate comparison of surgical results for Ewing sarcoma entails attention
to the adequacy of radiation therapy in the control arm (23,43). The German Cooperative
Ewing’s sarcoma Study (CESS) reported a significant difference in local control and survival
favoring the cases operated on in the CESS-81 trial (20,40,56). On review, the high rate of
local failure in the radiation therapy group was attributed to a substantial number of cases
with inadequate irradiation volume. In fact, a report by Sauer et al. (56), on the same cohort,
showed equivalent results of surgery or radiation therapy in small lesions. In addition, the
CESS initiated a quality assurance program in 1984. The results of the subsequent study
(CESS-86) demonstrate a marked improvement in local control with irradiation compared to
the previous trial. From 1986 to 1991, 177 patients with localized Ewing sarcoma were treated
with chemotherapy plus radical surgery or surgery plus radiation (45 Gy ) or irradiation alone
(60 Gy total), with a central treatment planning review for quality assurance. Results are now
comparable to those of the surgery group (3-y ear relapse-free survival 67% after irradiation,
65% after surgery, and 62% after resection plus irradiation) (37,41,43,52,60,61). If the
functional results are similar, the potential for second malignancies in patients treated with
irradiation for Ewing sarcoma would favor surgery as the treatment of choice for small
extremity lesions, dispensable bones, or very y oung children. High-risk lesions may benefit
from combined surgery and radiation (37,62).
Chemotherapy
Early studies established the role of chemotherapy in primary management of Ewing
sarcoma (17,51,63). Multiagent regimens incorporating vincristine, actinomy cin D,
cy clophosphamide, and adriamy cin (VACA) resulted in overall survival rates of 50–75% for
patients without metastasis at diagnosis (17,22,39,55,64). The Intergroup Ewing’s sarcoma
Study (IESS) I (1973–1978) demonstrated the importance of combining alky lating agents and
anthracy clines. The IESS-II (1978–1982) showed that early and intensive chemotherapy
combined with local treatment of the primary tumor was beneficial (17,38,65,66).
The 5-y ear relapse-free survival and overall survival improved from IESS-I to IESS-II.
The local control rate improved as well, with a local failure rate of 15% on IESS-I and 9% on
IESS-II.
CESS-81 was conducted from 1981 to 1985 (40,60,67,68). Patients received VACA for
two cy cles followed by local therapy and two additional cy cles of the four-drug
chemotherapy program. The result of this study of local therapy, which was not randomized,
showed a 5-y ear relapse-free survival of 54% for the patients treated with surgery only, 68%
for those treated with surgery and postoperative irradiation, and 43% for those treated with
radiotherapy alone. The local failure rate was strikingly different: 6% for surgery alone, 17%
for surgery and postoperative irradiation, and 50% for radiotherapy alone. The high local
failure rate in the radiotherapy alone arm was clearly secondary to major radiotherapy
volume deviations. Midway through the trial, central review of radiotherapy was instituted
resulting in a decline in local failure.
The response of the primary tumor to chemotherapy as an important prognostic factor
has been demonstrated in patients undergoing surgery after initial chemotherapy (69). Picci
et al. (59) studied 118 patients between 1983 and 1993 and graded the surgical specimens
from grade I to III, with grade I having gross visible tumor, grade II microscopic tumor, and
grade III specimens with total necrosis. The 5-y ear disease-free survival ranged from 34%
for grade I to 95% in the grade III group (59). Others have confirmed that tumor necrosis
after induction chemotherapy carries a favorable prognosis (32,69).
The proportion of patients with distant metastasis is another measure of
chemotherapeutic responsiveness. Marcus et al. (21) analy zed the impact of tumor size on
survival; the dominant pattern of failure for large tumors remained distant metastasis despite
aggressive chemotherapy. Jurgens et al. (40) described distant metastasis in 29% of the CESS-
81 cases; isolated distant metastasis occurred in 10%. The updated results of IESS-II
demonstrated a 63% survival at 5 y ears, with 25% of patients developing distant metastases
only (66).
The substitution of ifosfamide for cy clophosphamide was tested in the CESS-86, which
included 177 patients from 1986 to 1991 (20,40,60,67,68,70,71). Patients whose primary
tumors were judged to be smaller than 100 cm 3 received induction VACA. Those with larger
tumors received vincristine, actinomy cin, ifosfamide, and adriamy cin (VAIA). Local
therapy, at the discretion of the treating phy sician, was given at week 10. This was followed
by four courses of VACA for the smaller tumors and four courses of VAIA for the larger
tumors. When a curative resection was conducted, no additional radiation was given if there
were no significant risk factors for local recurrence, such as positive margins. However, if the
operative bed was at risk for local persistence of tumor, patients were randomized to once or
twice per day postoperative irradiation. For patients in whom a curative resection was
possible but there was only small residual disease after induction chemotherapy, surgery was
not performed and patients were randomized to once- or twice-a-day radiation. When a
tumor resection was not undertaken and there was substantial tumor, patients were
randomized to receive either 45 Gy of conventional irradiation once per day to a larger field
with a 15-Gy cone-down boost to a total of 60 Gy or 44.8 Gy of twice-daily radiation to a
larger field followed by a 16-Gy boost with twice-daily irradiation.
In CESS-86, 22% of the patients were treated locally with surgery, 53% with surgery and
radiation, and 25% with radiation alone. Although the patients treated with surgery alone had
a low rate of local failure, they had a higher rate of distant metastases. Local treatment did
not influence survival. In addition, there appeared to be no difference between once- and
twice-daily irradiation. Tumor volume greater than 200 mL and poor histologic response to
chemotherapy had a negative effect on outcome by both univariate and multivariate
analy ses (70).
The impact of local therapy modality for the 1058 patients enrolled in the CESS and the
European Intergroup Cooperative Ewing’s sarcoma Study (EICESS) trials was reported. After
induction chemotherapy patients with resectable tumors had excellent local control, with a
local relapse rate of 7.5%. Comparable local control was achieved in patients given
preoperative radiotherapy in the EICESS-92 trial to patients for whom there was a high
likelihood of close resection margins or in whom further tumor reduction was expected to
allow function-preserving surgery. For patients treated with definitive radiotherapy, local
relapse was 26%, significantly higher than for those able to undergo resection; however, this
cohort represented a negatively selected group of patients with unfavorable tumor sites.
Page 189The sy nergistic effectiveness of etoposide in combination with alky lators was
studied in the Children’s Cancer Group (CCG) Study 7881 and Pediatric Oncology Group
(POG) Study 8850 (71). This trial evaluated the use of VACA with and without ifosfamide and
etoposide to treat newly diagnosed Ewing sarcoma or PNETs. This phase III randomized trial
was open from 1983 to 1994. Patients were randomly assigned to receive 49 weeks of
standard chemotherapy with VACA or the experimental treatment, which alternated VACA
with the ifosfamide–etoposide combination. The trial demonstrated, in terms of both
increased survival and overall survival, the superiority of six-drug chemotherapy to four-drug
chemotherapy for localized disease (Table 9.3 ). There was an improvement in local
control for patients with localized pelvic Ewing sarcoma who received the ifosfamide–
etoposide combination (72). This improvement was irrespective of the local control modality
used. However, no benefit was attributable to six-drug chemotherapy for patients with
metastatic disease.
Intensification of chemotherapy to improve the outcome of patients with Ewing sarcoma
and PNET was tested in two trials. These two sequential prospective randomized trials tested
the hy pothesis that intensification of chemotherapy can improve the outcome over standard-
dose chemotherapy in patients with nonmetastatic tumor. The first such trial was open from
1995 to 1998, and the second from 2001 to 2005. Both trials used interval compression as the
method of dosage intensification and were limited to patients with newly diagnosed localized
disease. The analy ses of these studies included event-free and overall survival, toxicity, and
the relationship between the intensification achieved and outcome. The first trial failed to
show an improvement with dose intensification (73). However, the second trial, which
accrued 564 eligible patients randomized to either every -3-week or every -2-week
chemotherapy cy cles, demonstrated superior event-free and overall survival for the every -
2-week regimen (74). The differences for both event-free and overall survival were
statistically significant.
For patients with nonmetastatic Ewing sarcoma, the intergroup prospective randomized
trial discussed previously demonstrated that the regimen of alternating
vincristine/doxorubicin/cy clophosphamide and ifosphamide/etoposide was superior to the
vincristine/doxorubicin/cy clophosphamide alone. Following this trial, the interval compression
administration of chemotherapy demonstrated superiority to standard chemotherapy
delivery. The compressed alternating regimen became the current standard in North
America. Trials are ongoing to test the addition of other agents to this now standard regimen.
In the management of metastatic disease at presentation, little progress appears to have
been made during serial studies. For example, in IESS-I patients with metastatic disease were
treated with VACA for a 5-y ear survival of 30%.
In IESS-II drugs were VACA plus 5-fluorouracil,
and the 5-y ear survival was 28%. In the
aforementioned CCG–POG trial recently
completed, the 2-y ear survival was 22%.
The role of radiation therapy in primary
management of Ewing sarcoma is generally
evaluated in each patient with a team including
surgeons, medical oncologists, and radiation
oncologists. As previously discussed, there is
controversy concerning the relative advantages
of irradiation and surgery with preoperative or
postoperative irradiation (21,43,52,61,75).
Volume
Local control of tumor with irradiation improved
after the general acceptance of a target volume
encompassing the entire medullary cavity to
Table 9.3 National Cancer Institute
moderately high dosage levels (30,76). Suit (77)
Protocol INT-0091 (Children’s Cancer
summarized the experience of the 1950s and
Group Study 7881 and Pediatric
1960s in recommending irradiation to the entire
Oncology Group Study 8850)
involved bone with a higher-dose boost to the
primary tumor site. He noted few instances of
marginal or distant intramedullary recurrence with such treatment. However, subsequent
studies have reported irradiation results based largely on treatment techniques that have not
included the opposite epiphy sis, noting no marginal recurrences despite high variable rates of
local tumor control (21,52,78).
Page 190The importance of adequate treatment volume and radiation quality cannot be
overemphasized. The results of the CESS-81 study indicated an excessive rate of local
recurrence attributed to poor quality control for radiation therapy. Protocol modification to
include central planning for radiation therapy diminished the frequency of local failure
(56,78).
Brown et al. (22) analy zed the sites of local recurrence, describing consistent failure in
the primary tumor volume for patients with lesions of the extremities and pelvis. Marginal
failures occurred infrequently, limited to patients with rib primaries. In a study reducing
treatment volume and dosage, Hay es et al. (55) found a high rate of local recurrence (25%
isolated, 35% overall). However, treatment failures were localized within the primary target
volume in 13 of 14 instances using a limited, postchemotherapy tumor extent to define the
soft tissue component of the irradiation fields.
Data addressed the efficacy of diminished treatment volumes (31,79). Local or tailored
fields encompassing the primary tumor with a 3- to 5-cm margin rather than the whole bone
have been studied (Fig. 9.4 ). Marcus (31) reported excellent local control using tailored
fields, noting the ability to spare a component of the long bones in tumors less than 8 cm in
diameter, whereas full-bone irradiation is often needed to achieve a 4-cm margin around
larger tumors. Despite the higher overall rates of local failure in the St. Jude Children’s
Research Hospital study, Hay es et al. (55) also noted local control in 12 of 14 patients with
lesions less than 9 cm in diameter using smaller target volumes.
Figure 9.4 Changes in treatment volume for Ewing sarcoma. A: Field encompassing the
entire length of the medullary cavity for a tumor involving the proximal left humerus. B:
Tailored field encompassing only the proximal aspect of the leg for a limited tumor of the left
tibia; there is a 5-cm distal margin beyond known bone involvement as demonstrated by all
imaging procedures. In recent years, national protocols have called for a 2- to 3-cm margin.
An important study in the determination of the proper field size for the irradiation of
localized Ewing sarcoma was POG-8346. Between 1983 and 1988, 184 children were studied.
Of this group, 179 were truly eligible for the study ; 79% had localized disease, and 21% had
metastases. Induction treatment was cy clophosphamide and adriamy cin followed by local
treatment with either surgery or radiation therapy. This was followed by actinomy cin D and
vincristine. Patients treated to the local site with radiation therapy were randomized to receive
whole-bone irradiation to 39.6 Gy with a 16.2-Gy boost or involved-field irradiation to 55.8
Gy. For the 104 patients with localized disease who were irradiated, the 5-y ear event-free
survival was 42%, with no difference in event-free survival between those randomized to
receive large or small fields. The local control rate was only 45% for those not treated
according to the protocol-specified volume (80).
The current recommendations for treatment volume mandate the use of MRI whenever
possible to identify the tumor extent. The entire bony abnormality and soft tissue mass are
included, identified at diagnosis before either surgery or chemotherapy as the gross tumor
volume (GTV), with a 1-cm margin added to cover potential occult tumor. An additional
margin, generally determined by the institution, is then added. This results in the planning
target volume (PTV) to account for daily setup, patient movement, and an additional margin
for dosimetric considerations. The exception to this method is the case of a large soft tissue
mass that protrudes into a body cavity at diagnosis and is responding to chemotherapy and
allowing normal tissues to move back to their normal position. In this circumstance, the initial
GTV excludes the prechemotherapy volume if that volume previously extended into the
body cavity. The volume of infiltrative soft tissue disease is not modified. The entire original
bony abnormality is alway s treated.
Page 191In postoperative irradiation, the appropriate target volume has not been
adequately defined. Based on the data supporting local volume for primary radiation therapy,
one would recommend treatment to the preoperative tumor bed with adequate margins, later
reducing the treatment fields to documented sites of tumor residual in incompletely resected
lesions. In all cases with residual tumor in the operative specimen, encompassing the surgical
incision appears to be important.
Dosage
Early reports established the efficacy of radiation dosages of 50–60 Gy at 180–200 cGy per
fraction, describing better local control than is achieved with a total dosage of less than 45 Gy
(6,81). Dosage recommendations have included 40–45 Gy to the entire medullary cavity,
with a boost to the primary site to cumulative levels of 55–60 Gy (77).
The IESS-I results indicated no dose–response relationship between 40 and 68 Gy. Using
50 Gy in 25 fractions, the National Cancer Institute reported clinically apparent local
recurrence in 20% of cases (39). Whether the lower frequency of local recurrence in the
IESS and selected single-institution series using 60 Gy reflects a dose–response relationship is
uncertain based on available data (43,49).
Alterations in total dosage and the time–dose relationship were found in University of
Florida research using hy perfractionated irradiation (31,82,83). Patients were treated with
120 cGy twice daily to 36 Gy for initial target volumes encompassing the primary tumor in
4-cm margins. Subsequent reduced fields were used to cumulative levels of 50.4 Gy (with
total resolution of the soft tissue component by preirradiation chemotherapy ) and 55.2 Gy
(with no response to chemotherapy ). For patients with a lesion less than 8 cm in diameter,
local recurrence was documented in only 1 of 11 children (84). In a review of the University
of Florida series of patients treated between 1969 and 1987, those with tumors 8 cm or
smaller treated with twice-daily irradiation had a local control rate of 88%, compared with
92% for once-daily radiation. However, for those with tumors larger than 8 cm, the local
control rate for twice-daily radiation was 88%, compared with 58% for once-daily
irradiation. Evaluation of this data must be tempered by the previously cited randomized trial
of CESS, which did not show a benefit to multiple-daily -fraction irradiation (40,60). With
larger lesions, some have used more aggressive sy stemic therapy and total-body irradiation
(TBI; 400 cGy twice daily ) with reported improved local and overall disease control (21).
The current dosage recommendations are 55.8 Gy for gross residual disease and 50.4
Gy for microscopic disease. Lesions of the vertebral body are treated with 45 Gy. Standard,
once-per-day fractionation is generally used. No dosage modifications are recommended for
smaller tumors, although normal tissues should be protected whenever possible. The shielding
of critical structures must also be weighed against the possibility of underdosing known tumor-
bearing tissue.
Chemotherapy influences local control.
Aforementioned studies suggested a local control
benefit from the addition of adriamy cin, and
more recent reports address the prognostic
implications of the histologic response of the
primary tumor to chemotherapy. The recent
randomized trial CCG-7881 and POG-8850
showed a local control benefit of VACA with
ifosfamide and etoposide compared with VACA
alone (Table 9.4 ) (71). It is likely that along
with improved imaging (MRI and functional
MRI) for tumor identification, improvements in
chemotherapy will increase local control of the Table 9.4 Influence of Chemotherapy
primary tumor. on Local Control of Ewing Sarcoma in
CCG-7881 and POG-8850
Technique
Radiation delivery techniques have dramatically improved over the y ears. Currently, the
standard of care around the country is three-dimensional (3D) CT and MRI-aided radiation
planning. The improved imaging and its incorporation into the planning process for radiation
treatments have allowed increased sparing of normal tissues and better dose localization into
the tumor. The imaging studies of CT, MRI, and PET scanning can be used and often
registered to the planning CT scan to better delineate the gross target volume and clinical
target volumes. Currently, 3D conformal radiotherapy (3DCRT) and intensity -modulated
radiotherapy (IMRT) are widely available and considered the standard of care for these
tumors when they require radiation therapy. However, another major advance with
tremendous promise is proton radiation, which will be used more commonly as more
facilities open over the next decade.
Sophisticated radiation therapy techniques will achieve maximal local tumor control
while minimizing treatment-related complications. For extremity lesions, sparing a strip of
linear soft tissue is fundamental. Avoiding circumferential irradiation decreases the likelihood
of significant late fibrosis and edema (43,85). To achieve adequate coverage, treatment plans
incorporating oblique opposed fields or angled pairs with compensating wedges may be
necessary. Conventional opposed anterior-posterior or lateral field configurations may be
ideal if adequate soft tissue can be spared. Immobilizing casts or molds are important for
daily reproducibility and accuracy during treatment (see Chapter 22 ).
Page 192Large extremity lesions often necessitate irradiation of the adjacent joint. With
the same attention to normal tissue sparing, the major late problem associated with joint
irradiation appears to be greater growth alterations if both epiphy ses of the joint are included,
particularly at the knee (41,85).
Lesions of the distal extremities, including the ankle, feet, and hands, present
individualized problems regarding treatment planning. The use of tissue compensation,
immobilizing devices, and detailed attention to dosimetry are critical to achieving excellent
tumor control and functional integrity (23,81). The use of a water bath to achieve dosage
homogeneity has been suggested. Alternatively, a single-photon beam incident on the
contralateral surface of the hand or foot may be combined with an ipsilateral electron field.
For pelvic lesions, techniques to avoid full-dose irradiation of the bladder often are
possible with oblique or multifield configurations. Carefully including the soft tissue extent,
often more impressive on CT or MRI studies, will ensure maximal tumor control. For
vertebral Ewing sarcoma, uniform irradiation of the adjacent vertebrae will minimize late
effects. The use of weighted opposed anterior–posterior fields or a wedged-pair technique
generally ensures adequate coverage of the vertebrae, of necessity including the spinal canal.
Rib lesions (Askin tumor) are generally large tumors, often with extension to the pleural
surfaces. This site warrants special consideration because it is often associated with a large
soft tissue component (68). The surgeon must not attempt to remove the tumor initially before
chemotherapy. After biopsy, chemotherapy should be given for large lesions because it
induces tumor shrinkage (29,86). In thoracic rib and soft tissue primaries, the
postchemotherapy volume appears adequate to define the irradiation volume. If resection is
done first, margins may be positive and may necessitate a much larger volume of irradiation.
The radiation volume often is limited by organ toxicity such as the heart in left sided lesions.
Resection after chemotherapy may be adequate if operative margins are clearly negative
after nearly complete response to chemotherapy. If the resection margins are positive or the
tumor is incompletely resected, local irradiation is indicated to increase the likelihood of local
tumor control (22,26,28,55,86). Inclusion of the pleural cavity in patients with cy tologically
positive effusions has been recommended because the pattern of failure as described by
Askin et al. (27) included the pleura in a significant number of cases. There is also a risk of
pleural relapse in patients with Askin tumor and no initial pleural effusion. Some clinicians
attempt to treat the pleural surface but spare the lung by using external beam electrons. An
alternative technique is intrapleural radioisotope application. A small amount of dy e is placed
in the pleural cavity with saline and the patient is rotated. Free flow is confirmed by
fluoroscopy. As an alternative, a tracer amount of radioactivity may be used to confirm free
flow in the pleural space with a gamma camera. After free flow is confirmed, a therapeutic
dose of 32P is instilled to irradiate the pleural surface. The patient is turned periodically to
distribute the isotope (86). The treatment of the entire pleural surface in the absence of a
positive pleural effusion is controversial.
There is a limited experience with brachy therapy for Ewing sarcoma. Potter et al. (87)
described six patients treated with chemotherapy, external beam irradiation, and
intraoperative high-dose rate brachy therapy for close surgical resection margins. All six
children are alive and well.
Improvements in imaging modalities, particularly the routine use of MRI scans to assess
tumor extent, provide more accurate target definition. Technologic advances in radiation
therapy treatment delivery will also allow greater sparing of normal tissue without
compromising tumor treatment. Such technologic advances may include the use of intensity -
modulated radiation therapy and the use of protons.
Proton radiation is similar in quality as photon radiation, which means that it causes
ionizing events in cells and causes DNA damage that is believed to be the lethal event in tumor
cells. However, it has the advantage over photon radiotherapy (IMRT or 3DCRT) in that it
better localizes the dose to the tumor with better sparing of the normal surrounding tissues.
Dose to normal tissues is decreased by a factor of 2 or more in many cases. Protons deliver
maximum dose at a finite range, in contrast to photons that have infinite range with dose
decreasing exponentially with depth. When treating a tumor at some depth in tissue, protons
enter the tissue with a decreased entrance dose compared with photons, and then deposit a
higher dose in the tumor. Protons have no exit dose bey ond the tumor being targeted (88).
Photons entail both an entrance dose and an exit dose to normal tissues in the process of
targeting a tumor. The result is similar dose distribution to the tumor itself but decreased dose
to normal tissue (89,90). This technique therefore should result in reduced acute and long-
term side effects including a reduction in second malignancy risk. Protocols are open at some
proton centers in the United States and these centers use protons instead of photons to treat the
patients with the endpoints of morbidity and side effects (Fig. 9.5A, B ).
Figure 9.5 A, B: Example of a teenage boy with a pelvic Ewing sarcoma planned with
proton radiotherapy. Note sparing of even low dose to most of the bladder, rectum, small
bowel, and contralateral hip.
Radiation Therapy for Metastatic Disease

The efficacy of low-dose irradiation in controlling pulmonary micrometastases is
documented in the IESS-I study. The frequency of pulmonary relapse was lower and survival
rates were higher with prophy lactic pulmonary irradiation in comparison to triple-drug
chemotherapy alone (17,49,58,91).
For patients with metastatic Ewing sarcoma of the lung, local irradiation to the lungs and
primary site are valuable in overall disease control (30,67). An interesting review addressed
the role of lung irradiation for Ewing sarcoma with pulmonary metastases at diagnoses (67).
Of patients accessioned to CESS studies from 1981 to 1992, 42 presented with pulmonary
metastases. One died of progressive disease before irradiation. The other patients either had a
complete radiographic remission after chemotherapy (n = 25) or chemotherapy with
resection of the lung metastases (n = 4). Twenty -two patients received bilateral lung
irradiation at doses of 12–21 Gy. Six had no additional treatment after chemotherapy or
surgery, and one underwent bone marrow transplantation. Of the 10 patients in complete
remission, 9 had received lung irradiation and 1 had undergone complete resection of lung
metastases. Overall, one of six patients was in complete remission without lung irradiation,
compared with 4 of 10 who received 12–16 Gy and 5 out of 6 who received 18–21 Gy. These
data suggest the value of lung irradiation for a patient with pulmonary metastases at diagnosis
of Ewing sarcoma, and they appear consistent with the suggestion from IESS-I that
pulmonary irradiation may sterilize micrometastatic disease in the well-oxy genated lungs. A
currently open prospective randomized international trial is comparing bilateral whole-lung
irradiation to high-dose chemotherapy -based regimen using busulfan and melphalan in
patients with pulmonary metastases. The results of this important multi-institutional trial will
help to determine the best management for patients with pulmonary metastases.
Page 193The treatment strategy for patients presenting with bone metastases is under
investigation. Treatment of the primary site using a tailored field is recommended. Although
irradiation of bony metastatic sites is generally recommended, this treatment remains
unproven and one must be cautioned to limit the irradiation to less than 50% of total bone
marrow volume (92).
Total-Body Irradiation and Stem Cell Transplantation

TBI has been used in advanced Ewing sarcoma since the late 1960s (44). Improvement in
survival using TBI led the Princess Margaret Hospital group to studies incorporating sequential
hemibody irradiation with an attenuated three-drug chemotherapy regimen (93). The use of
low-dose, fractionated TBI (15 cGy twice weekly to cumulative levels of 150 cGy ) at the
National Cancer Institute (NCI) has been followed by studies using “intensification TBI” (400
cGy twice daily ), both at NCI and the University of Florida (21,39). These initial reports have
y ielded different results, with a positive impact in the University of Florida series and little or
no impact in the NCI series. The NCI series has been updated, and the long-term results
continue to demonstrate no benefit to this approach (94).
Burdach et al. (95) reported using TBI (12 Gy, 1.5 Gy twice daily ) and simultaneous
high-dose melphalan, followed by etoposide and stem cell rescue. Their results (17 patients)
are encouraging, with 7 of 17 patients disease-free, 45% ± 12% at 6 y ears, compared with
2% ± 2% for the historic control group. Reports using a non-TBI regimen appeared to y ield
similar results (19,91). Overall, reports of improvements in overall survival for patients with
advanced local or metastatic disease have been mixed (96,97).
Figure: National Cancer Institute Protocol
INT-0091 (Children’s Cancer Group Study
7881 and Pediatric Oncology Group Study
8850)
Figure:
Changes in treatment volume for Ewing sarcoma. A: Field encompassing the entire length of
the medullary cavity for a tumor involving the proximal left humerus. B: Tailored field
encompassing only the proximal aspect of the leg for a limited tumor of the left tibia; there
is a 5-cm distal margin beyond known bone involvement as demonstrated by all imaging
procedures. In recent years, national protocols have called for a 2- to 3-cm margin.
Figure: Influence of Chemotherapy on Local
Control of Ewing Sarcoma in CCG-7881 and
POG-8850
Figure:
A, B: Example of a teenage boy with a pelvic Ewing sarcoma planned with proton
radiotherapy. Note sparing of even low dose to most of the bladder, rectum, small bowel,
and contralateral hip.
CURE RATES AND SIDE EFFECTS OF TREATMENT
Current experience with Ewing sarcoma indicates 5-y ear disease-free survival in 50–75% of
patients with localized disease at diagnosis (17,25,54,66). There have been late relapses, and
the 10-y ear survival is decidedly worse than the 5-y ear survival. A limited number of single-
institution reports indicate higher disease-free survival (21,40,50). Survival clearly parallels
initial disease extent (38). Disease-free survival greater than 75% has been documented for
limited volume Ewing sarcoma involving the distal extremities. Survival rates of only 25–35%
are achieved with large central lesions (22,38,40,54).
Overall functional results after treatment of Ewing sarcoma have correlated closely with
the degree of attention to detailed local management. Selection of primary surgery for
lesions permitting function-preserving resection with negative or microscopically positive
margins may decrease late effects of high-dose irradiation, particularly in prepubertal
y oungsters (25,53,54).
With appropriate radiation therapy, patients treated for Ewing sarcoma of the extremities
had excellent functional results in more than 60% of cases. The NCI late effects review noted
minor alterations in leg length or minimal sy mptoms of soft tissue change in another 20% of
cases (83). Significant treatment-related morbidity occurred in 20% of the NCI cases and
was related primarily to larger primary lesions. Significantly higher morbidities have been
reported in series combining sy stemic chemotherapy with dosages greater than 60 Gy
(22,54,85). In a limited number of patients treated with 70 Gy to the primary site, severe
functional deterioration was reported in 26% of patients (50).
Page 194The risk of fracture after treatment has also been related to total dosage.
Fracture appears to correlate more directly with the extent of cortical disruption at the time of
biopsy, in addition to tumor size and y ounger age at presentation (17,20,53,57).
Limited changes have been reported after primary irradiation of tumors of the upper
extremities. Some degree of hip dy sfunction and potential growth disturbances are
documented in long-term follow-up of patients with pelvic Ewing sarcoma. Combined
cy clophosphamide-irradiation cy stopathy has also been noted in such cases (22,41). One of
the primary concerns regarding irradiation is the impact on bone growth. Morphologic
changes of the irradiated epiphy sis have been reviewed in the NCI series (85). Quantitatively,
reduction and subsequent growth relates to the sites of epiphy seal irradiation and the age at
treatment. Overall functional results are less favorable in very y oung children (41,85) (see
Chapter 19 ).
The high incidence of secondary tumors in Ewing sarcoma was originally suggested in
the combined reporting of the Late Effect Study Group (LESG), assessing the frequency of
secondary bone sarcomas in 9170 children surviving more than 2 y ears after treatment for
cancer. The rate of carcinogenesis in patients with Ewing sarcoma was second only to that in
patients with retinoblastoma in this study. There was a sharp dose–response relationship after
dosages to the bone of more than 60 Gy. With the current standard in Ewing sarcoma of 45–
55 Gy, this risk of second tumors appears to be less than in the original reports. In contrast to
the 22% actuarial risk of second tumors reported by LESG (96), more recent data
demonstrate a cumulative incidence of 9.2% for any second malignancy and 6.5% for
secondary sarcoma (46). Here again, a dose–response relationship was demonstrated, with
no secondary sarcomas seen with a dosage of less than 48 Gy. The risk of secondary
leukemia may be greater with high-dose regimens as well (98).
In an overall review of second
malignancies after treatment for Ewing sarcoma
in CESS-81 and CESS-86, the addition of
radiotherapy to surgery or treatment with
radiotherapy alone was associated with a higher
cumulative risk of second malignancies (Table
9.5 ) (99). The Childhood Cancer Survivor
Study, a retrospective study of 13,581 children
diagnosed with cancer before age 21 and
surviving at least 5 y ears, reported a 5%
cumulative incidence of secondary
malignancies at 25 y ears for the entire cohort
(42). The incidence continued to increase over
the follow-up period. Survivors of Ewing
sarcoma were at higher risk of developing Table 9.5 Second Malignancies in
second malignant tumors than others in the Patients Treated in the German
cohort. Other factors in addition to radiotherapy Cooperative Ewing Sarcoma Studies
were found to play a role in the development of CESS-81 and CESS-86
a second malignant tumor. The use of
anthracy cline increased the risk of soft tissue sarcoma, and the use of alky lators increased the
risk of secondary bone tumors. Although children treated for Ewing sarcoma and PNET must
be followed up over the long term, the success in treatment should not be overshadowed by
these adverse sequelae.
Figure: Second Malignancies in Patients
Treated in the German Cooperative Ewing
Sarcoma Studies CESS-81 and CESS-86
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CH A P TER 10
Osteosarcoma, Chordoma, and
Chondrosarcoma
Anita Mahajan and Edward C. Halperin
Page 197Osteosarcoma is the most common primary malignant bone tumor in children. The
tumor derives from bone forming mesenchy me (1,2,3,4,5,6,7,8,9,10,11) (Fig. 10.1A &
B ). The incidence is one to three new cases per million per y ear (6). The majority of
cases occur in the second decade of life with a male predominance. There is a bimodal
distribution with a second smaller peak of incidence at age >60 y ears (Fig. 10.2 ) (6,12).
Figure 10.1 A & B: Histopathology of osteosarcoma: low power (A) and high power (B).
Figure 10.2 Osteosarcoma incidence per million people per year by age based on SEER
data. The peak for older people is associated with Paget disease. (Reproduced from Mirabello
L, Troisi R, Savage S. Osteosarcoma incidence and survival rates from 1973 to 2004: data
from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009;115:1533, with
permission.)
Inactivation of the retinoblastoma (Rb) and P53 pathway s appears to be a central event
in the genesis of osteosarcoma. Rb is a tumor suppressor gene that is discussed in detail in
Chapter 5 . Abnormalities (70–80% allelic loss, 10–20% rearrangements, 20–30% point
mutations) in the p53 locus on the short arm of chromosome 17 have been noted in up to 50%
of cases (13). Patients with a germline mutation of p53 are at very high risk of osteosarcoma
(14). Genetic studies on human, canine, and murine osteosarcomas have revealed mutation
of c-kit (15) and TP53 (16) genes, overexpression of urokinase plasminogen activator/uPA
receptor (17), CRM1 (18), Ezrin (19), alpha V integrin and vascular endothelial growth factor
(20), runt-related transcription factor Runx2 (21) and URG4 gene (associated with cell
proliferation) (22), increased phosphory lation of cJun, JNK, and ERK1/2 (23), and expression
of cy clooxy genase (COX-2) (24) and somatostatin receptors (25). Some of these genetic
alterations may have oncogenic or prognostic significance and may also be potential
therapeutic targets. High-resolution array comparative genomic hy bridization in combination
with interphase fluorescence in-situ hy bridization has been shown to detect chromosomal
instability and genomic imbalance that have been correlated to response to chemotherapy
(26).
Second malignant neoplasms can occur in patients with osteosarcoma treated with
surgery alone or with surgery and chemotherapy, perhaps as a result of these genetic
abnormalities (27,28,29). Osteosarcoma may develop in long-term survivors of heritable Rb.
These secondary osteosarcomas may arise in or outside the irradiated field and in children
treated without radiotherapy (see Chapters 5 and 20 ).
Figure:
A & B: Histopathology of osteosarcoma: low power (A) and high power (B).
Figure:
Osteosarcoma incidence per million people per year by age based on SEER data. The peak for
older people is associated with Paget disease.
(Reproduced from Mirabello L, Troisi R, Savage S. Osteosarcoma incidence and survival rates
from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program.
Cancer. 2009;115:1533, with permission.)
SIGNS, SYMPTOMS, EVALUATION, AND STAGING
Page 198Osteosarcoma usually occurs in the metaphy ses of the long bones, especially
around the knee joint. The bones most commonly involved are the femur (approximately
40% of cases), tibia (15%), and humerus (15%) (Fig. 10.3 ) (1,3,6,7,30). The usual clinical
presentation is swelling or pain. A few patients present with a pathologic fracture and may be
associated with a poorer overall survival and disease-free interval (31).
On conventional radiographs, the tumor has a ty pical appearance. There are poorly
defined margins, interrupted periosteal new bone, and soft tissue invasion. Where the bony
cortex is penetrated at the edge of a tumor, there may be a periosteal elevation and vertical
spicule formation (Codman triangle) (3,7,30). Computed tomography (CT) and magnetic
resonance imaging (MRI) help delineate the intramedullary extent of tumor as it tracks along
the marrow cavity and the soft tissue extent of tumor (7,32) (Fig. 10.4 ). The bone scan has
nearly 100% sensitivity for the presence of malignant bone tumor, although the specificity is
less. On the bone scan, one may observe osteoblastic activity in the shaft of the long bone
proximal to the primary tumor. This may represent reactive change and not indicate the
presence of malignancy (7). Thallium scintigraphy has been used for tumor localization;
however, whole-body fluorine-18-flurordeoxy glucose positron emission tomography (FDG-
PET) in combination with CT scans has been shown to have a role in tumor assessment,
staging, and restaging for patients with osteosarcoma (33,34). A surgeon may order an
angiogram to determine tumor vascularity, detect vascular displacement, determine the
relationship between vessels and the tumor, and identify vascular anomalies. The most
common sites of distant metastases are the lungs and bones (3,4,30,32, 35,36,37). To evaluate
pulmonary metastases, a plain chest radiograph is used to identify chest nodules or
cannonball lesions. A chest CT can be used to assess the presence or absence of small nodules
(33,37).
Page 199If we are to improve the treatment of osteosarcoma, it will be important to
adapt therapy to the individual patient’s prognostic factors (38). The conventional means of
doing this is a staging sy stem. The presence or absence of metastases and the use of histologic
subty ping do help predict prognosis (Table
10.1 , Fig. 10.5 ). A variety of factors have
been investigated as potential prognostic factors.
As will be discussed later in this chapter,
histologic response to neoadjuvant
chemotherapy is useful in predicting outcome.
However, information of this ty pe is available
only after chemotherapy and surgery. Clinical
features with predictive value in determining
outcome include the duration of presenting
sy mptoms (shorter is worse), tumor size (larger
is worse), location of the primary tumor (head,
spine, rib, and pelvic sites are worse), and weight
loss of >10 lb. The primary tumor size seems
strongly predictive of outcome and may be Figure 10.3 Skeletal distribution of
calculated as either absolute tumor length (>10 primary osteosarcomas in patients
cm), relative tumor length given as the treated on the Neoadjuvant Cooperative
proportion of tumor length to the overall length Osteosarcoma Study Group protocols of
of the involved bone (more than one-third of the the Cooperative German–Austrian–Swiss
involved bone), or absolute tumor volume (>70 Osteosarcoma Study Group. (Modified
or 150 cm 3) (40,44). from Bielack S, Kempf-Bielack B, Delling
G, et al. Prognostic factors in high-grade
osteosarcoma of the extremities or
trunk: an analysis of 1702 patients
treated on Neoadjuvant Cooperative
Osteosarcoma Study Group protocols. J
Clin Oncol. 2002;20:776–790, with
permission.)
Figure 10.4 An 18-year-old right-
handed high-school senior presented to
medical attention when his tennis game
and weight-lifting activities were
inhibited by pain in his left shoulder.
Diagnostic images showed a mixed
sclerotic and lytic mass in the proximal
left humerus. Incisional biopsy made the
diagnosis of osteosarcoma. The patient
was treated with induction
chemotherapy in the hope of producing a
substantial tumor response eventually
leading to limb-sparing surgery.
Unfortunately, within 2 years of the initial
diagnosis, widespread pulmonary
metastases developed, refractory to
chemotherapy, which led to the patient’s
death.
Table 10.1 A System for Osteosarcoma Subclassification by Histology and Origin

Figure 10.5 Diagram summarizing osteogenic tumor developmental lineages. From Atlas
of Genetics and Cytogenetics in Oncology and Haematology.
http://atlasgeneticsoncology.org/ , with permission.
There is no widely used staging sy stem for osteosarcoma. Some clinicians simply
separate patients into two groups: those with localized disease and those with metastatic
disease. The sy stem developed by Enneking and adopted by the Musculoskeletal Tumor
Society is used by some orthopedic oncologists. In general, there are few low-grade
osteosarcomas; therefore, in this sy stem, most tumors are stage II or III (Table 10.2 ). One
study from the European Osteosarcoma
Intergroup (EOI) suggested that patients with
chondroblastic tumors had a slightly superior
survival to those with other histologies; however,
the SEER data suggest that the conventional
osteosarcoma subty pes have similar 5-y ear
overall survival rates (12,45).
Page 201The Cooperative German–
Austrian–Swiss Osteosarcoma Study Group
(COSS) has provided an extensive evaluation of
prognostic factors in high-grade osteosarcoma of
the extremities or trunk. In an evaluation of 1702
patients treated on neoadjuvant osteosarcoma Table 10.2 The Enneking Staging
protocols, the investigators found that the long- System for Osteosarcoma
term survival of patients with limb primaries was
superior to that of those with axial primaries, patients who presented without metastases had
higher survival rates than those who presented with metastases, patients with extremity
sarcomas occupy ing less than one-third of the bone had higher survival rates than those with
sarcomas occupy ing more than one-third of the bone, and distal extremity tumors had a
superior outcome to proximal tumors. The response to chemotherapy (i.e., the amount of
tumor necrosis at the time of resection in a setting of neoadjuvant chemotherapy ) also was a
highly important predictor of outcome along with the extent of surgical resection (Table
10.3 ) (46,48).
Table 10.3 Influence of the Histologic Response to Neoadjuvant Chemotherapy on

Survival in Osteosarcoma
Figure:
Skeletal distribution of primary osteosarcomas in patients treated on the Neoadjuvant
Cooperative Osteosarcoma Study Group protocols of the Cooperative German–Austrian–
Swiss Osteosarcoma Study Group.
(Modified from Bielack S, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade

osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on
Neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol. 2002;20:776–
790, with permission.)
Figure:
An 18-year-old right-handed high-school senior presented to medical attention when his
tennis game and weight-lifting activities were inhibited by pain in his left shoulder.
Diagnostic images showed a mixed sclerotic and lytic mass in the proximal left humerus.
Incisional biopsy made the diagnosis of osteosarcoma. The patient was treated with
induction chemotherapy in the hope of producing a substantial tumor response eventually
leading to limb-sparing surgery. Unfortunately, within 2 years of the initial diagnosis,
widespread pulmonary metastases developed, refractory to chemotherapy, which led to the
patient’s death.
Figure: A System for Osteosarcoma
Subclassification by Histology and Origin
Figure:
Diagram summarizing osteogenic tumor developmental lineages.
From Atlas of Genetics and Cytogenetics in Oncology and Haematology.

http://atlasgeneticsoncology.org/, with permission.
Figure: The Enneking Staging System for
Osteosarcoma
Figure: Influence of the Histologic Response
to Neoadjuvant Chemotherapy on Survival
in Osteosarcoma
Surgery
Local Disease
The biopsy site should be selected to allow access to the infiltrating edge of the tumor. In
general, either minimal or no cortical bone should be removed in order to reduce the risk of
pathologic fracture (41,49,50,51,52).
The classical definitive operative procedure is an amputation above the region of the
affected bone or a disarticulation at the joint above the lesion. Traditional teaching is that if
one resects the bone bey ond the site defined by all radiographs as the most proximal extent of
disease and if the margins are pathologically negative, the chance of stump recurrence is
negligible (50,51). In recent y ears, surgical treatment for local osteosarcoma has changed.
New limb salvage procedures have been performed with gratify ing results (53,54).
Limb-sparing operations may be selected if there is no evidence of neurologic or
vascular compromise by the local tumor, if the surgeon believes that he or she can obtain an
adequate margin around the primary osteosarcoma, and if there is a plan for reconstruction
that will provide better function than amputation. Relative contraindications to limb sparing
include the presence of a pathologic fracture, a poor response to neoadjuvant chemotherapy,
or skeletal immaturity that will lead to significant limb growth discrepancies (55,56).
What is an adequate surgical margin for local management of osteosarcoma? A radical
margin entails removal of the entire bone of origin with accompany ing soft tissue
involvement, as is achieved by a hip disarticulation for a distal femoral tumor. A wide margin
is defined as excision of the tumor with a cuff of surrounding normal tissue, and a marginal
margin entails excision of the tumor and its surrounding reactive pseudocapsule. Local control
is improved by the adequacy of the surgical margin and a good response to neoadjuvant
chemotherapy (57). It is generally accepted that limb-sparing surgery has a slightly greater
risk of local tumor recurrence than does amputation. Amputation has a slightly greater risk of
local recurrence than does disarticulation (Table 10.4 ). A good chemotherapeutic response
may allow the surgeon to have a tighter margin on the primary tumor and exclude more
normal tissue from the resection. However, to know before surgery whether a marginal
excision is reasonable, one must have an idea of what tumor response was achieved by
chemotherapy. Unfortunately, no single imaging study can reliably provide this information,
although plain radiographs, CT, bone scan, MRI, and FDG-PET scan can be used (55,59).
By un et al. (60) report that the incorporation of serial dual phase 18F-FDG-PET (at 60 and
150 minutes) after one cy cle of neoadjuvant chemotherapy can predict histologic response
with an accuracy of >70%.
Page 202The reconstruction technique
elected after limb-sparing procedures depends
on the location of the osteosarcoma, whether
there is joint involvement, the extent of bone and
soft tissue resection, the patient’s age, the
functional demands of the patient and the family,
and the prospects for rehabilitation. When the
excision is intra-articular (within or involving a
joint), reconstruction options include custom
segmental total joint replacement, whole
segment osteoarticular allograft (i.e., from a
cadaveric donor), allograft–prosthetic composite Table 10.4 Local Recurrence Rates
reconstruction, arthrodesis (surgical fixation of a for Osteosarcoma as a Function of the
joint; artificial anky losis) with autologous or Extent of Surgery
allogeneic bone, or arthrodesis with a porous
prosthesis allowing host bone ingrowth and bone graft. If a joint is not involved, one can
reconstruct with autologous or allogeneic bone, a prosthesis, or a segmental prosthetic spacer.
Rotation-plasty is also an option in certain situations (2,61,62,63).
It is gratify ing that, in modern pediatric oncology practice, the child with osteosarcoma
may be offered limb-sparing options for local treatment bey ond the traditional amputation or
hip disarticulation. The previous discussion has cited indications and relative contraindications
to limb-sparing surgery, the risk of local recurrence after various forms of surgery, options
for reconstruction after tumor resection, and the need for adequate surgical margins.
Although limb function after limb-sparing surgery is generally good in many patients, limb-
sparing surgery is not for every one faced with osteosarcoma. Case selection by a skilled
orthopedic oncologist, invocation of sound oncologic principles, and adequate rehabilitative
services postoperatively are necessary to achieve the best possible function and cancer
control.
Metastatic Disease
Surgery also play s a role in treating
osteosarcoma metastatic to the lung. Some
patients present with a primary tumor along with
limited pulmonary involvement. Aggressive
multiagent chemotherapy, surgical management
of the primary tumor, and thoracotomy for
resection of pulmonary metastases appear to
have significantly increased survival in cases
that seemed hopeless (Table 10.5 ) (44,64).
The most common sites of metastases in the
relapse of initially localized osteosarcoma are
lung and bone (Fig. 10.6 ). When tumor
relapses in the lung, surgical resection of
pulmonary nodules may result in a prolonged
disease-free interval and, together with
aggressive chemotherapy, a small potential for
cure (4,28,35,36,50,65,66). In some patients,
repeated thoracotomies appear to have
prolonged survival in the face of multiple
episodes of pulmonary metastases (41). By
diagnosing pulmonary recurrences earlier and
with limited tumor bulk, thoracic CT may either
Table 10.5 Factors Predicting Event-
open the possibility for a beneficial effect of
Free Survival in Patients with Primary
surgery, create a lead-time bias but still requires
Metastatic Osteosarcoma in the
improved specificity and sensitivity (67,68).
German–Swiss–Austrian Cooperative
Osteosarcoma Study Group Clinical
Trials
Page 203
Figure 10.6 John Hunter (1728–1793) was an extraordinary surgeon, anatomist, teacher,
and collector. His magnificent collection of scientific specimens was purchased by
Parliament and placed in the custody of the Company of Surgeons, renamed the Royal
College of Surgeons in 1800. These illustrations of osteosarcoma, taken from the Hunterian
Museum, Lincoln’s Inn Fields, London, appear by permission of the president and council of
the Royal College of Surgeons of England. In November 1786, Hunter encountered a patient
with “a hard swelling of the lower part of the thigh, as it were beginning from the knee …
the part began evidently to enlarge … and was attended with more pain as it enlarged …
and the pain was now exhausting him much.” An amputation was done. Hunter described an
“osteoid sarcoma” of the distal femur (A) and also noted the intramedullary spread of the
tumor: “A short distance below the site of amputation there is a second hemispherical tumor
in the medullary canal … above the main growth, the disease having extended within the
canal, in this case, for an unusual distance beyond the limits of the external swelling.” Four
weeks after the amputation, the patient “began to complain of a difficulty in breathing, but
not attended with the least pain … he began to lose his flesh and sink gradually, his breathing
being more and more difficult … he died; living only 7 weeks after the operation.” On
autopsy, “bony tumors were found in the cellular membrane of the lungs, upon the
pericardium, and some very large ones of the pleura, adhering to the ribs, and upon the
anterior surface of the vertebrae of the back” (B & C). Hunter noted that “when the leg was
amputated he had not the least symptom of any disease in the chest” but deduced that the
lung metastases “had taken place a considerable time before the symptoms took place.” As
for the osteoid appearance of the tumor, Hunter wrote that “one can figure to themselves a
reason why the tumor which formed on the outer surface of the thigh-bone might become
bony, because it might acquire that disposition from the bone it surrounded but, from these
tumours formed in the chest becoming bone, shows it was the nature of the tumours
themselves.” The remaining figure (D) is “the osseous part of an osteosarcomatous tumor”
from “the rib of a Horse” from Hunter’s collection. (Descriptions of this material are found in
Descriptive catalog of the pathological series in the Hunterian Museum of the Royal College
of Surgeons of England. Edinburgh and London: E. & S. Livingstone, 1972; Part I:133–138; Part
II:75–77. Biographical material is from Allen E. Hunterian Museum [pamphlet], Royal College
of Surgeons, 1974.)
Several variables must be considered when one uses metastasectomy for pulmonary
metastases. These include the aggressiveness of the proposed operation, whether they are
unilateral or bilateral, the interval between the development of the metastases and the
treatment of the primary, the extent of vascular invasion, the presence or absence of hilar
ly mph node involvement, and whether additional salvage chemotherapy is available after
surgery (44,55,69). Thoracoscopic assisted procedures may be hampered by limited ability
to palpate the tissues for complete assessment of the lung tissues (70).
Bielack et al. (44) reviewed the outcomes of 249 consecutive patients with second and
subsequent recurrences of osteosarcoma. With mainly chemotherapy and surgery, the 5-
y ear overall and event-free survival rates were 32% and 18% for second, 26% and 0% for
third, 28% and 13% for fourth, and 53% and 0% for fifth recurrences, respectively. The role
of the bony metastasectomy is not well defined, undoubtedly because the occurrence of
bony metastases in the setting of potentially salvageable osteosarcoma is far less common
than that of pulmonary metastases (55).

Prebiopsy
Sweetnam (50) administered low-dose irradiation before the initial biopsy (approximately 10
Gy ) to 29 patients in the hope of reducing the viability of cells that might be disseminated into
the bloodstream by the biopsy. The 20% overall survival rate, no different from that of
historic controls, discouraged additional investigation. Only 2 of 19 patients survived when
treated with amputation without prior biopsy.
Primary and Preoperative Treatment

The Cade Technique
In the era before adjuvant chemotherapy, phy sicians were distressed by the practice of
treating the primary lesion with amputation or disarticulation, only to have the y oung patient
die within 6 months of pulmonary metastases. Because the survival rate with surgical ablation
alone was only 20%, many limbs were sacrificed in vain. Surgeons and radiotherapists
reasoned that if high-dose local irradiation could obtain at least temporary control of the
primary tumor, time would pass and allow the selection of cases suitable for a radical
surgery. Patients who develop pulmonary metastasis in a 4- to 6-month waiting period after
irradiation would be spared an unnecessary amputation. Those who did not develop
pulmonary metastasis after the waiting period would undergo extirpation of the primary
tumor. This philosophy was promulgated by English phy sician Sir Stanford Cade (1895–1973)
and is called the Cade technique. The 5-y ear survival rates of 15–20% were equivalent to
those achieved in the preadjuvant therapy era with immediate surgical ablation. The delay in
surgery appears to have cost no lives (6,71,72,73,74,75,76,77,78). There generally was a
reduction in pain and swelling at the tumor site after the first 20 Gy. This response tended to
continue for several weeks after completion of radiotherapy. In patients who underwent limb
ablation after radiotherapy, a histologic analy sis could be performed to assess the presence or
absence of viable tumor. The majority of patients had a good or excellent local response
(Table 10.6 ). There were also some long-term survivors after aggressive treatment with
radiation therapy alone (4,77).
Table 10.6 The Cade Technique: Management of Osteosarcoma with Primary Irradiation
or Primary Irradiation and Selected Delayed Amputation (Excluding Parosteal Tumors)
Modern Series of Primary Photon Radiation Therapy

In modern radiotherapy practice, it is rare to be asked to use radiotherapy as the primary
local treatment for osteosarcoma except for lesions in surgically inaccessible sites. However,
the data acquired with the Cade technique make it reasonable to consider the use of radiation
in certain situations. Preoperative radiotherapy has been given in research protocols to reduce
tumor viability before surgery, increase the probability of performing limb-sparing surgery
instead of amputation, or reduce the risk of local recurrence (66,78). In patients with
nonresectable primary tumors, such as difficult pelvic bone sites, vertebral column, frontal
bones, or base of skull, and in patients who refuse definitive surgery, consideration should be
given to precision high-dose irradiation. Modern photon techniques use three-dimensional
computerized treatment planning and intensity -modulated radiation therapy. Neutron or
proton beams can improve local control in certain circumstances and are discussed later in
this chapter. There is also precedent for high-dose preoperative irradiation and rapid surgery,
preoperative radiotherapy with local hy perthermic perfusion (81), intraoperative electron
beam therapy (82), and radiotherapy with intra-arterial infusion of a radiosensitizer (83).
Page 205Data on photon irradiation as primary treatment for osteosarcoma, in lieu of
surgery and in conjunction with aggressive chemotherapy, are available from Albrecht et al.
from Berlin (84). They described 13 patients with osteosarcoma who were treated from 1977
to 2004 according to contemporary protocols (Table 10.7 ). Eleven patients refused the
appropriate amputation or rotation plasty. Two had inoperable primary tumors. One patient
had a solitary lung metastasis and one patient was diagnosed with osteosarcoma after
treatment for leukemia. Each patient received 50–70 Gy of conventionally fractionated
photon irradiation. Two of the three patients who had local recurrence after 40–46 months
were salvaged and survived. Three patients had died at a median follow-up of 13.5 y ears.
Death was attributed to pulmonary metastasis, disseminated disease after local recurrence
and my elody splastic sy ndrome. A pathologic fracture occurred in five patients within 3 y ears
of radiation therapy. This small clinical series suggests that photon radiotherapy in
conjunction with chemotherapy may be used to manage osteosarcoma if appropriate
surgery is impossible or refused. Whether such patients are best treated with photons,
neutrons, or protons is a matter for debate.
Table 10.7 Significant Recent Cooperative Group Trials Addressing the Management of
Localized Osteosarcoma
Page 207Some patients with unresectable osteosarcomas are treated with conventional
external beam irradiation. The COSS described a series of patients with osteosarcoma of the
spine who were treated with intralesional or marginal resections and also received photon
irradiation, neutron beam treatment, or samarium. In the analy sis of patients who underwent
either incomplete surgery or no surgery, 7 received postoperative irradiation and 10 did not.
The seven patients who received irradiation had a slightly higher long-term survival than
those who did not, 50% versus 10%, respectively (p = 0.059) (95).
In 2003, COSS investigators described a group of patients with pelvic osteosarcomas
treated between 1979 and 1998. Of 30 patients with intralesional surgery or no primary
surgery, 11 received radiotherapy (65–68 Gy with photons, two were treated with neutrons,
and one also received 153Sm). The 5-y ear overall survival of the irradiated patients (16%)
was superior to that of those not irradiated (0%, p = 0.0033) (58).
Machak et al. (96) reported a retrospective review of 31 patients with limb osteosarcoma
who refused definitive surgery and were treated with cis-platinum, doxorubicin (IV or IA), or
both. All patients received 40–68 Gy at 2.5–3 Gy per fraction, one fraction per day, or 1.25–
1.5 Gy twice daily. With a median follow-up of 39 months, the predicted 5-y ear overall
survival was 61%. Local progression-free survival was 56% (40% for 50 Gy or less, 77% for
more than 50 Gy ). There were five fractures, one skin necrosis, and one osteomy elitis. It is
conceivable that use of neoadjuvant radiotherapy with chemotherapy increased the
proportion of good responders of the time of surgery.
Hirano et al. (61) from Nagasaki University sandwiched 30 Gy (2–3 Gy per fraction) in
the midst of preoperative chemotherapy in 15 patients with osteosarcoma. Histology of the
resected specimens showed a tumoricidal effect in nine patients and a lesser effect in three.
Wagner et al. (78) used a combination of short-course preoperative irradiation (19.8
Gy ), surgical resection, intraoperative 90Y plaque brachy therapy to at-risk areas of the dura
when applicable, and postoperative irradiation with sequential cone-downs to 50.4–58.2 Gy
(total 70.2–77.4 Gy ) to treat bone tumors mainly involving the spine and pelvis. For patients
with osteosarcoma, the 5-y ear local control, disease-free survival and overall survival were,
respectively, 75%, 50%, and 67%.
Dincbas et al. (97) showed that preoperative radiation therapy (usually 35 Gy in 10
fractions) and preoperative chemotherapy (three courses) allowed successful limb-sparing
surgery in 44 out of 46 patients. Tumor necrosis rate was >90% in 87% of patients, and 5-
y ear local control rate was 97.5%. The overall 5-y ear survival rate was 44%.
Maxilla and Mandible
Some surgeons believe that a wide surgical excision of osteosarcoma of the maxilla or
mandible is risky because of the functional consequences. Local recurrence and death after
intralesional resection or resection with a positive margin are ty pical (98,99). Chambers and
Mahoney reported 33 patients treated with preoperative brachy therapy. Implantation was
accomplished by drilling holes in the mandible and placing radium needles. The dosage was
100–160 Gy. Wide surgical excision of the involved hemimandible and adjacent soft tissue
was performed 2–4 weeks after irradiation. Out of 11 children, 10 were long-term survivors
with follow-up from 4 to 15 y ears (100). Suit reported additional three cases (two of the
mandible and one of the maxilla) locally controlled with a similar technique (49,101). Heroic
brachy therapy is rarely necessary in modern practice. With radical surgical resection of the
tumor, followed by reconstruction, local control of facial bone osteosarcoma is to be
expected (102).
Lung
Historically, the propensity of osteosarcoma to metastasize to the lungs stimulated interest in
the use of prophy lactic lung irradiation (Table 10.8 ). The fundamental problem with
thoracic irradiation is that pulmonary tolerance may be exceeded before necessary
tumoricidal dosages are achieved (108). Abbatucci et al. (109), working from radiobiologic
principles, showed that the exponential kill of clonogenic cells produced by fractionated
radiotherapy, in principle, could eradicate subclinical metastases in a highly oxy genated lung.
Visible tumor deposits, detectable on chest radiograph, measure 6–10 mm in diameter and
contain 108–109 cells. If one assumes that the dosage needed to reduce the number of viable
clonogenic cells in a tumor to 10% (D10) is 4 Gy for osteosarcoma, then 20 Gy of
fractionated irradiation should be able to prevent the growth of metastases containing 104 or
105 cells. However, more recent experiments on canine osteosarcoma cell lines showed that
the cells were relatively radio-resistant with a survival fraction at 2 Gy to be 0.62 and a mean
alpha–beta ratio of 3.5 (105). Breur (110,111) analy zed 13 patients with microscopic
pulmonary metastasis and extrapolated backward in time, showed that about 1 in 4 patients
with subclinical metastasis had tumors containing about 105 cells. In principle, these small
metastatic deposits would be curable by adjuvant pulmonary irradiation. This argument has
been criticized by Baeza et al. (112).
Table 10.8 Prophylactic Lung Irradiation in the Treatment of Osteogenic Sarcoma
The technique of prophy lactic pulmonary irradiation is ty pically parallel-opposed

anterior and posterior fields encompassing both the apices and posterior costophrenic angles
of the lungs. Some phy sicians use a customized anterior cardiac shield, particularly if
concurrent cardiotoxic chemotherapy is used. The dosimetry conventions at many institutions
do not make corrections for the increased transmission of radiation through healthy lung
tissue. Uncorrected prescriptions, based on the inaccurate assumption that the lungs have the
same density as normal tissue, underestimate the actual dosage given to the center of the
lungs by about 14% (108). Advanced techniques have been explored using intensity -
modulated radiation therapy (IMRT) for whole-lung irradiation in a series of patients to
explore feasibility and benefit. A significant component of the heart, mediastinal and
infradiaphragmatic structures can be spared with a more precise and homogeneous dose
delivery to the target tissues (113).
Page 208The Role of Adjuvant Whole-Lung Irradiation (WLI) in

Osteosarcoma in Nonrandomized Studies
Lougheed et al. (104) thought that elective prophy lactic WLI irradiation of clinically normal
lungs might delay the development of pulmonary metastases in osteosarcoma. They treated
only one of the lungs, giving 15 Gy in combination with actinomy cin D. Four of eight patients
developed metastases in the untreated lung, but only one patient progressed in the irradiated
lung.
Newton reported that fewer patients developed pulmonary metastases in the early
follow-up after elective pulmonary irradiation than unirradiated patients. Only 4 of 13
irradiated patients progressed after prophy lactic irradiation, although the effect was short
lived (105). Caldwell performed sequential elective bilateral WLI in 38 patients with a variety
of tumors, including 7 with osteosarcoma. Seventeen had no detectable metastases. Twenty -
one, who had pulmonary nodules, received WLI followed by surgical resection or a local
boost radiation field to a higher dosage. Three of the four patients with osteosarcoma had no
detectable metastases at presentation and were alive and well with no active disease at 2- to
4-y ear follow-up (114).
Caceres et al. (115) treated seven evaluable patients with 20 Gy of prophy lactic WLI.
Ten patients received adjuvant doxorubicin. After 13 months of follow-up, 3 of 7 irradiated
patients were free of disease, compared with 6 of 10 on the chemotherapy arm.
Page 209Evaluating 62 patients with osteosarcoma in Toronto, Jenkin et al. (75) included
six patients who received 15 Gy of prophy lactic WLI and actinomy cin. All six developed
diffuse pulmonary metastases in 2–6 months. The French Bone Tumor Study Group
published studies on a nonrandomized series of 41 evaluable cases of extremity osteosarcoma
treated with chemotherapy and 20 Gy of prophy lactic WLI (116). The 5-y ear disease-free
survival was 58%, and the overall survival was 66%. This compared well with historic control,
but there was marked lung toxicity including restrictive ventilatory effects, five life-
threatening infections, and one death from Pneumocystis carinii pneumonia. A study by
Gilchrist et al. (117) from the May o Clinic showed no benefit of prophy lactic WLI in
osteosarcoma.
Evidence from Randomized Studies

In 1976, Rab et al. (106) described a randomized trial of WLI (uncorrected) while receiving
100% oxy gen with intravenous actinomy cin D. The control group did not undergo
prophy lactic WLI. The median survival time was 42 months in the irradiated arm and 25
months in the unirradiated arm. However, there was no significant difference in overall
survival or disease-free survival. The European Organization for Research and Treatment of
Cancer (EORTC) conducted the two most important initial trials of WLI. The first study, Study
O2, enrolled six patients. The use of local therapy plus 17.5 Gy of WLI achieved a superior
but not statistically significant improvement in 5-y ear survival over local therapy alone. The
subsequent trial permitted patients to undergo definitive surgery, delay ed technique, or
radiotherapy. Among the 205 patients, 19% underwent radiotherapy as treatment for the
primary tumor, 52% underwent amputation, and 29% underwent disarticulation. In the first
arm of the study, adjuvant chemotherapy consisting of doxorubicin, vincristine, and
methotrexate was given every 2 weeks for the first 12 weeks. This was followed by a
consolidation phase in which these drugs were alternated with cy clophosphamide every 4
weeks for 6 months. The total adjuvant chemotherapy period was 41 weeks. The second
treatment arm was identical to that of Study O2 with no chemotherapy but with WLI to a total
dosage of 20 Gy after air correction. In the third treatment arm, the chemotherapy of Arm 1
was used, followed after 12 weeks by WLI. The 5-y ear overall survival for this study was
43%, with no significant difference between the three treatment arms. The disease-free
survival at 5 y ears was 24%. An unpublished analy sis cited by Burgers asserts “the
localization of pulmonary metastases was mainly behind the dome of the diagram behind the
heart and mediastinum in those patients who were irradiated. These areas had received a
smaller dose, as the irradiation passes partly through nonaerated tissue” (103). No other
assertions similar to this appear in the literature. Subgroup analy sis showed that the 5-y ear
disease-free survival in patients y ounger than 17 y ears was 50% in the irradiated patients and
31% in the unirradiated patients (p = 0.074) (35).
As chemotherapy became more popular for osteosarcoma, the EORTC and the
International Society for Pediatric Oncology (SIOP) jointly launched the O3 trial in 1978.
Two hundred and forty patients y ounger than 30 y ears were randomized to receive treatment
with adjuvant chemotherapy, prophy lactic WLI to 20 Gy, or chemotherapy with
prophy lactic irradiation. The ty pe of adjuvant treatment did not significantly alter the overall
survival, disease-free survival, or metastasis-free survival. The patterns of relapse were no
different in the three groups. Acute toxicity was greater with chemotherapy and resulted in
three deaths. The prophy lactic WLI was well tolerated, although more irradiated patients
developed a late but asy mptomatic deterioration in pulmonary function (103).
Between 1979 and 1984, approximately 57 patients with osteogenic sarcoma were
enrolled in a University of Florida protocol in which patients had definitive surgical treatment
of the primary tumors. Within 7 day s of the surgery, all patients received WLI to a total
dosage of 16 Gy in 10 fractions with parallel-opposed anterior and posterior fields with 8-MV
photons. An anterior heart block was used. After WLI, patients received five courses of
doxorubicin. Detailed results of the efficacy of this program have not been published. In
reports published 4 and 8 y ears after the study was closed to patient accrual, the crude
survival was approximately 67% and the crude metastasis-free survival was about 56%
(118).
In the “Standards, Options and Recommendations” (SOR) project conducted by the
Federation of French Cancer Centers, a thorough review of the literature from January 1992
to October 2003 was performed. One conclusion was that prophy lactic WLI is not indicated
in nonmetastatic osteosarcoma (119).
Cases of breast cancer developing in long-term survivors after elective WLI for
osteosarcoma have been reported (120,121). There may also be a higher risk of breast
cancer in women who have had osteosarcoma but never underwent WLI (122). In light of the
association of osteosarcoma with abnormalities of tumor suppressor genes, concern is
warranted about radiation-induced malignancy.
WLI for Advanced Osteosarcoma

Thoracotomy offers a chance of cure for some patients with pulmonary metastatic disease.
Patients more likely to be cured by thoracotomy include those with fewer than four lesions
completely removed at the first thoracotomy, unilateral disease, and a prior disease-free
interval of at least 18 months (36,123,124,125).
When WLI is used for overt pulmonary metastases, one would expect little effect (126).
Weichselbaum et al. (124) reported an aggressive program for treating metastatic
osteosarcoma with chemotherapy, WLI, and boost irradiation to individual metastases. Three
of 10 patients were alive without evidence of disease. Equivalent or better results have been
achieved with chemotherapy, thoracotomy, and no WLI (63). Individual lung lesions may
respond to high-dose radiation incorporating a stereotactic body radiotherapy (SBRT)
approach. Yu et al. (126) report an equivalent 2-y ear progression-free survival rate and
overall survival rate in 27 patients treated with SBRT (70 Gy in 10 fractions to the gross
tumor) in comparison to 31 patients who underwent surgery. The pneumonitis rate was
acceptable.
Giritsky et al. (127) failed to show a benefit of prethoracotomy or postthoracotomy
irradiation. However, the Study O3 suggested that successful metastasectomy was possible
more often after previous prophy lactic lung irradiation than after adjuvant chemotherapy
(103).
Page 210Extracorporeal Irradiation (ECI)
Among the more innovative uses of radiotherapy in osteosarcoma treatment has been ECI.
Limb conservation has been changed from being an exception to standard practice in the
primary management of osteosarcoma of the extremities. Bony defects created by limb-
sparing procedures may be treated with custom-made prostheses with mobile joints,
osteoarticular allografts, allograft–prosthesis composites, or intracalary segments filled with
autografts. The complication rates from some of these procedures can be high.
Reimplantation of a bone autograph after tumor-ablative ECI has several theoretical
advantages. A major advantage is the precise anatomic fit of the reimplanted bone segment.
This may increase the probability of joint mobility. In skeletally immature patients, limb-
sparing surgery must be performed carefully to avoid later limb length discrepancy. ECI can
avoid the growth discrepancy commonly seen in prosthetic replacements by avoiding
resection of the normal growth plate and appositional bone growth from surrounding healthy
bones. The reimplantation of irradiated bone avoids some of the other problems associated
with allografts such as dependence on a bone bank, graft rejection, and the risk of viral
transmission. It is also theoretically possible that dead tumor cells in the irradiated bone may
stimulate a desirable immunologic response (128,129,130).
Hong et al. (128,130) from New South Wales, Australia, report on 101 patients (37 of
whom had osteosarcoma) who received a single dose of 50 Gy of ECI using a linear
accelerator or blood product irradiator. The bone was wrapped in a sterile wrapping, taken for
irradiation, and then returned to the operating room. After reimplantation, it appears that the
reimplanted bone serves as the framework for appositional bone growth from surrounding
healthy bones. There is no evidence of local tumor recurrence at a median follow-up of 49
months. The 5-y ear overall survival rate for those with localized osteosarcoma was 85.7%.
For the most part, the functional outcome appears to have been good. Puri et al. (131)
describe 32 patients (16 with osteosarcoma) treated with 50 Gy ECI. Three of the 32 had
upper extremity tumors. At a mean follow-up of 34 months, three patients had local
recurrences, all in soft tissue away from the graft (129,132).
Chemotherapy
For many y ears, it was accepted that the long-term survival of patients with osteosarcoma
treated with radical surgical ablation alone was approximately 20%. A 1978 M. D. Anderson
Cancer Center trial used cy clophosphamide, vincristine, melphalan, and doxorubicin and
achieved a 2-y ear survival rate of 50% (133). Subsequent pediatric trials from M. D.
Anderson used the T7 protocol of preoperative intra-arterial cis-platinum, surgery, and
postoperative programs of doxorubicin, methotrexate, cis-platinum, and cy clophosphamide in
various combinations. Patients undergoing limb salvage had a 58% 110-month disease-free
survival. Patients undergoing amputation had a 54% disease-free survival (difference not
significant). Optimum survival (80%) was found in patients with more than 90% tumor
necrosis, induced by the preoperative chemotherapy, at the time of amputation. Survival was
also correlated with smaller primary tumor volumes (134). Patients with a poor histologic
response had a 33% disease-free survival rate (48,135).
In a separate report from the M. D. Anderson group covering the y ears 1979–1982,
reporting 37 patients of the age of 16 y ears or older with extremity lesions, preoperative
doxorubicin and intra-arterial cis-platinum were followed postoperatively by the same drugs.
Patients who suffered cis-platinum toxicity received dacarbazine as a substitute (136).
Based on these results, the T7 protocol was modified by the use of cis-platinum,
doxorubicin, bleomy cin, cy clophosphamide, and dactinomy cin in the postoperative period.
This was called the T10 protocol (135). Sixty additional patients, treated from 1983 to 1988,
received intensified preoperative intra-arterial cis-platinum. Postoperatively, complete
responders received doxorubicin and cis-platinum (or dacarbazine), and partial or poor
responders were changed to an alternating program of methotrexate, doxorubicin, or
dacarbazine, and bleomy cin, cy clophosphamide or actinomy cin. Patients treated from 1979
to 1982 had a 54% 5-y ear disease-free survival. Those treated from 1983 to 1988 had a 69%
3-y ear disease-free survival (134).
In an attempt to confirm the preliminary good results of the T10 protocol, the Children’s
Cancer Group (CCG) undertook a single-arm trial of neoadjuvant chemotherapy that based
the postoperative therapy on the histologic response of the preoperative chemotherapy. The
protocol, CCG-782, accrued 268 patients with nonmetastatic osteosarcoma of the extremity
between 1983 and 1986. Preoperative chemotherapy consisted of four courses of high-dose
methotrexate and one course of bleomy cin, cy clophosphamide, and dactinomy cin. Good
histologic responders (i.e., those with less than 5% residual viable tumor) were treated
postoperatively with methotrexate, bleomy cin, cy clophosphamide, dactinomy cin, and
doxorubicin. Poor histologic responders were treated with bleomy cin, cy clophosphamide,
dactinomy cin, doxorubicin, and cis-platinum. The 8-y ear event-free survival was 53%. The
overall survival rate was 60%. Good histologic responders had an 8-y ear postoperative event-
free survival rate of 81% and a survival rate of 87%, whereas those with a poor histologic
response had an 8-y ear postoperative event-free survival of 46% and a survival rate of 52%
(88).
Pratt et al. (137) from St. Jude Children’s Research Hospital, in studies open from 1973 to
1981, reported 76 patients who received doxorubicin, cy clophosphamide, and methotrexate at
two different dosage levels after amputation. The actuarial 10-y ear survival was 46% and
56% for two chemotherapy protocols, compared with 18–25% for historic controls who
received ineffective or no chemotherapy after amputation (p < 0.001).
Sequential chemotherapy trials were conducted at New York’s Memorial Sloan-Kettering
Cancer Center from 1976 to 1986. Patients received preoperative high-dose methotrexate
with leucovorin rescue (some patients were randomized to additionally receive vincristine)
and postoperative cy clophosphamide, bleomy cin, doxorubicin, and actinomy cin D. In recent
y ears, patients who had a poor response to methotrexate received doxorubicin and cis-
platinum. The 10-y ear survival of 279 patients was 73%. As in the M. D. Anderson studies
and other series, histologic response of the primary tumor to neoadjuvant chemotherapy was
an important predictor of survival (83,85,90,103,136,138,139,140,141,142).
Page 211The apparent successes of adjuvant chemotherapy trials were challenged by a
research team at the May o Clinic. This group suggested that there might be a change in the
natural history of osteosarcoma. Whereas the May o Clinic noted a 20% survival rate from
ablative surgery in patients treated from 1963 to 1965, a comparable group treated from 1972
to 1974 without chemotherapy had a 50% overall survival rate (38). A randomized
prospective trial reported by the May o Clinic Group showed that high-dose methotrexate as
adjuvant therapy, in comparison to no chemotherapy, offered no benefit: survival in both
groups was 52% (136,143,144,145).
Two randomized prospective trials attempted to resolve the argument over the value of
adjuvant chemotherapy. The University of California at Los Angeles (UCLA) trial
randomized 59 patients with nonmetastatic osteosarcoma. All patients received preoperative
doxorubicin. Thirty -two patients were randomized to receive adjuvant postoperative high-
dose methotrexate, doxorubicin, bleomy cin, cy clophosphamide, and actinomy cin D.
Twenty - seven patients received no adjuvant chemotherapy. Of the patients who received
adjuvant chemotherapy, 55% remained disease free at a median of 2 y ears after excision of
the primary tumor. Of the patients who received no adjuvant chemotherapy, only 20%
remained free of disease (p < 0.01). Of 18 control patients treated before the trial, the overall
disease-free survival was not significantly different from that of the 27 randomized control
patients treated without chemotherapy from 1981 to 1984. Overall survival for randomized
patients did not differ significantly between the two arms (140). When the larger group of
patients who chose their therapy was combined with the randomized group, there was a
significant overall survival benefit favoring chemotherapy at 6 y ears.
Link et al. (85,146,147,148) reported a randomized chemotherapy trial involving 36
patients. At 2 y ears, the actuarial relapse-free survival was 17% in the control group and 66%
in the group receiving adjuvant cy clophosphamide, bleomy cin, actinomy cin, methotrexate
with leucovorin rescue, doxorubicin, and cis-platinum (p < 0.001). A similar benefit to
chemotherapy was observed among 77 patients who declined to undergo randomization but
elected observation or chemotherapy.
The long-term results of the COSS-86 protocol included 171 eligible patients; 128 patients
were stratified into the high-risk group. “Low risk” was defined as a tumor length of less than
one-third of the involved bone, less than 20% chondroid brown substance in the biopsy
specimen, and more than 20% reduction of early - or late-phase activity in sequential bone
scans. Other patients were considered to be at high risk. Doxorubicin, high-dose methotrexate,
and cis-platinum were given to all patients. Patients who met one of the high-risk criteria
received early sy stemic treatment intensification with ifosfamide added as a fourth agent.
Postoperatively, the high-risk patients received cis-platinum intra-arterially or intravenously.
In the total group of 171 patients, which included the high- and low-risk patients, overall event-
free survival rates at 10 y ears were 72% and 66%, respectively. No benefit from intra-
arterial cis-platinum was seen (93).
A randomized trial of two chemotherapy regimens in operable osteosarcoma was
conducted by the European Osteosarcoma Intergroup and reported in the Lancet in 1997.
Patients with operable, nonmetastatic osteosarcoma were randomly assigned to receive
doxorubicin and cis-platinum preoperatively or alternatively vincristine, methotrexate, and
doxorubicin preoperatively and bleomy cin, cy clophosphamide, dactinomy cin, vincristine,
methotrexate, doxorubicin, and cis-platinum postoperatively. Of the 407 randomized patients,
391 were eligible and were followed up for at least 4 y ears. The proportion showing more
than 90% tumor necrosis in response to preoperative chemotherapy was about 29% in both
regimens and was a strong predictor for survival. Overall survival was 65% at 3 y ears and
55% at 5 y ears in both groups. Thus, there was no difference between the two-drug and
multidrug regimens. The two-drug regimen was shorter in duration and better tolerated (87).
A trial by the Children’s Oncology Group (COG) randomized patients to one of four
arms: a three-drug regimen (cis-platinum, doxorubicin, methotrexate), a four-drug regimen
(cis-platinum, doxorubicin, methotrexate, ifosfamide), the three-drug regimen plus muramy l
tripeptide (MTP), and the four-drug regimen plus MTP (94). The addition of ifosfamide did
not enhance event-free survival or overall survival. The addition of MTP significantly
improved 6-y ear overall survival (from 70% to 78%) and resulted in a trend toward better
event-free survival. COG, COSS, EORTC/the Medical Research Council (MRC), and
Scandinavian Sarcoma Group (SSG) have completed a Phase III trial to optimize treatment
strategies for resectable osteosarcoma based on histologic response to preoperative
chemotherapy. The induction chemotherapy was with methotrexate, doxorubicin, and cis-
platinum (MAP). Randomization occurs after surgery and assessment of histologic response.
Patients with good histologic response are randomized to receive either MAP or MAP +
ifosfamide (MAPifn) and etoposide. Patients with poor histologic response are randomized to
receive either MAP or MAP + pegy lated interferon alfa-2b (MAPIE). Results of this study
are not available y et. Additional completed efforts to evaluate trastuzumab or inhaled GM-
CSF in patients with metastatic osteosarcoma have not provided any survival benefit
(149,150).
In Table 10.7 , we summarize studies by several cooperative groups. The data
indicate that surgery plus modern chemotherapy should achieve a 60–70% 5-y ear event-free
survival (Figs. 10.7 and 10.8 ). It is not clear that neoadjuvant chemotherapy is superior
to postoperative chemotherapy.
Figure 10.7 A Kaplan–Meier survival curve for patients in two consecutive trials of the
European Osteosarcoma Intergroup shows improved survival for patients with at least 90%
necrosis after preoperative chemotherapy (p < 0.01 with one degree of freedom). (From
Hauben EI, Weeden S, Pringle J, et al. Does the histological subtype of high-grade central
osteosarcoma influence the response to treatment with chemotherapy and does it affect
overall survival? A study on 570 patients of two consecutive trials of the European
Osteosarcoma Intergroup. Eur J Cancer. 2002;38(9):1218–1225, with permission.)
Figure 10.8 Overall survival for patients with localized disease, compared with those with
metastases at diagnosis, in patients treated on Cooperative German–Austrian–Swiss
Osteosarcoma Group protocols. (From Bielack S, Kempf-Bielack B, Delling G, et al.
Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of
1702 patients treated on Neoadjuvant Cooperative Osteosarcoma Study Group protocols. J
Clin Oncol. 2002;20:776–790, with permission.)
Figure: Local Recurrence Rates for
Osteosarcoma as a Function of the Extent of
Surgery
Figure: Factors Predicting Event-Free
Survival in Patients with Primary Metastatic
Osteosarcoma in the German–Swiss–
Austrian Cooperative Osteosarcoma Study
Group Clinical Trials
Figure:
John Hunter (1728–1793) was an extraordinary surgeon, anatomist, teacher, and collector.
His magnificent collection of scientific specimens was purchased by Parliament and placed
in the custody of the Company of Surgeons, renamed the Royal College of Surgeons in 1800.
These illustrations of osteosarcoma, taken from the Hunterian Museum, Lincoln’s Inn Fields,
London, appear by permission of the president and council of the Royal College of Surgeons of
England. In November 1786, Hunter encountered a patient with “a hard swelling of the lower
part of the thigh, as it were beginning from the knee … the part began evidently to enlarge
… and was attended with more pain as it enlarged … and the pain was now exhausting him
much.” An amputation was done. Hunter described an “osteoid sarcoma” of the distal femur
(A) and also noted the intramedullary spread of the tumor: “A short distance below the site
of amputation there is a second hemispherical tumor in the medullary canal … above the
main growth, the disease having extended within the canal, in this case, for an unusual
distance beyond the limits of the external swelling.” Four weeks after the amputation, the
patient “began to complain of a difficulty in breathing, but not attended with the least pain
… he began to lose his flesh and sink gradually, his breathing being more and more difficult
… he died; living only 7 weeks after the operation.” On autopsy, “bony tumors were found in
the cellular membrane of the lungs, upon the pericardium, and some very large ones of the
pleura, adhering to the ribs, and upon the anterior surface of the vertebrae of the back” (B &
C). Hunter noted that “when the leg was amputated he had not the least symptom of any
disease in the chest” but deduced that the lung metastases “had taken place a considerable
time before the symptoms took place.” As for the osteoid appearance of the tumor, Hunter
wrote that “one can figure to themselves a reason why the tumor which formed on the outer
surface of the thigh-bone might become bony, because it might acquire that disposition from
the bone it surrounded but, from these tumours formed in the chest becoming bone, shows it
was the nature of the tumours themselves.” The remaining figure (D) is “the osseous part of
an osteosarcomatous tumor” from “the rib of a Horse” from Hunter’s collection.
(Descriptions of this material are found in Descriptive catalog of the pathological series in the
Hunterian Museum of the Royal College of Surgeons of England. Edinburgh and London: E. & S.
Livingstone, 1972; Part I:133–138; Part II:75–77. Biographical material is from Allen E.
Hunterian Museum [pamphlet], Royal College of Surgeons, 1974.)
Figure: The Cade Technique: Management
of Osteosarcoma with Primary Irradiation or
Primary Irradiation and Selected Delayed
Amputation (Excluding Parosteal Tumors)
Figure: Significant Recent Cooperative
Group Trials Addressing the Management of
Localized Osteosarcoma
Figure: Prophylactic Lung Irradiation in the
Treatment of Osteogenic Sarcoma
Figure:
A Kaplan–Meier survival curve for patients in two consecutive trials of the European
Osteosarcoma Intergroup shows improved survival for patients with at least 90% necrosis
after preoperative chemotherapy (p < 0.01 with one degree of freedom).
(From Hauben EI, Weeden S, Pringle J, et al. Does the histological subtype of high-grade
central osteosarcoma influence the response to treatment with chemotherapy and does it
affect overall survival? A study on 570 patients of two consecutive trials of the European
Osteosarcoma Intergroup. Eur J Cancer. 2002;38(9):1218–1225, with permission.)
Figure:
Overall survival for patients with localized disease, compared with those with metastases at
diagnosis, in patients treated on Cooperative German–Austrian–Swiss Osteosarcoma Group
protocols.
(From Bielack S, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade

osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on
Neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol. 2002;20:776–
RADIOTHERAPEUTIC TECHNIQUE
Dosage
Osteosarcoma has a reputation of being radio-resistant. This reputation is unjustified. Because
radiotherapy was formerly used to treat bulky tumors, it is no surprise that local failures were
common. The D0 values of human and rodent osteosarcoma cell lines are reported to be
similar to those of most other mammalian tumors, perhaps with a higher D0 (77,151).
Page 213Canine osteosarcoma has been treated with a variety of dosage and
fractionation schemes including 8 Gy three times at 0, 7, and 21 day s and 8 Gy four times at
0, 7, 14, and 21 day s. Radiotherapy is generally used to palliate the dog’s pain and
dy sfunction. High response rates are achieved, albeit with short follow-up, because most
animals are euthanized for metastatic disease (77).
In a dose–response study of patients treated with the Cade technique, Gaitan–Yanguas
produced uniform tumor sterilization with dosages of 80–100 Gy and alway s found persistent
tumor at 50 Gy or less (74). Phillips and Sheline (77) found viable tumor in 1 of 10 patients
receiving less than 100 Gy and in 2 of 7 patients receiving at least 100 Gy (77).
Lombardi et al. (152) administered 36 Gy at 6 Gy per fraction, with three fractions per
week for 2 weeks to 21 osteosarcoma sites irradiated for palliation in 14 patients. There was a
clinical response (disappearance of pain, decrease in tumor size, improvement in function) or
radiologic response at 18 of the 21 sites. Of eight primary sites irradiated because of
sy nchronous metastases, all showed a clinical or radiographic response. In five patients,
radiotherapy was given where preoperative chemotherapy had not rendered the patient
suitable for limb-sparing surgery. Surgery after radiotherapy revealed 95–100% tumor
necrosis in all cases. Limb-sparing surgery was performed in three of five cases, but because
of infectious complications related to soft tissue damage, all limbs were amputated
eventually.
Caceres et al. (138) from Peru gave 60 Gy in 6 weeks to 15 patients in conjunction with
chemotherapy. Post radiotherapy biopsy showed no evidence of active tumor in 12 of 15
(80%) patients. The whole specimen was studied, because of amputation or autopsy, in five
patients. No viable tumor was found. Complications were common, including pathologic
fracture, soft tissue fibrosis or necrosis, local infection, and moist desquamation. The degree
of tumor necrosis seen by Caceres et al. (72) is inconsistent with an earlier report from the
same group of less impressive tumor destruction after 80–120 Gy at 10–12 Gy per fraction
(Table 10.6 ). If radiotherapy is to be used alone as definitive treatment for a small (less
than 5 cm) osteosarcoma in an unresectable location such as the base of skull or vertebral
body, or if a patient refuses surgery, the dosage should be as high as normal tissue tolerance
allows, that is, 60–75 Gy at conventional fractionation with progressive shrinking-field
technique (153,154).
When radiotherapy is used for prophy lactic treatment of the lungs, the dosage is 13.5–
19.5 Gy at 1.5 Gy per fraction. These dosages generally have been reported without lung
correction factors being applied (35,106,107,155).
Volume
The treatment volume is determined by plain radiographs, bone scan, CT, MRI, and FDG-
PET scans if available. It is customary to define the tumor volume based on the largest
volume of these studies (the “worst-case volume”). A margin is then allowed.
Prophy lactic WLI is directed to the entire substance of the lung. Particular attention must
be paid to coverage of the apices of the lung and to the areas of the lung that curve over the
surfaces of the diaphragms, which can be identified with CT-based radiation planning.
Technique
An immobilization device is generally needed. The field should be contoured specifically to
the anatomic problem for the individual patient. In most cases, multiple fields are used. To
maintain a functional limb after irradiation, a strip of skin should be spared, and one should
avoid high-dose irradiation to the full width of the joint.
Some investigators have attempted to improve the local control rates of osteosarcoma by
altering tumor and normal tissue oxy genation. Of historical interest, the tourniquet technique
attempted to produce anoxia in both tumor and normal limb tissues to remove any advantage
the tumor might gain from hy poxic areas. Using this technique, patients received fractionated
irradiation up to total dosages of 75–160 Gy. In patients who were long-term survivors, the
functional result was poor (79,141). One group reported local response rates of
approximately 70% and reasonable limb function with tourniquet anoxia and high-dose-per-
fraction treatment (i.e., three doses of 25 Gy ). Radiation treatment under hy perbaric oxy gen
conditions was also investigated (79). A group of investigators from Stanford University
reported a series of patients who had unresectable osteosarcomas or who refused amputation,
treated with 42–48 Gy at 6 Gy per fraction, one fraction every 5 day s, and pulsed 5′ -
bromodeoxy uridine infused as a radiosensitizer (156). Local control was achieved in seven of
nine patients, four of whom were long-term survivors. Significant soft tissue injury occurred
in five patients (82).
Neutron Therapy
Neutrons are a form of high linear energy transfer radiation. They offer several advantages
over conventional photon or electron radiotherapy. First, neutrons are better able to kill
hy poxic cells than photons. The oxy gen enhancement ratio for neutrons is of the order of 1.6,
compared with 2.5–3.0 for photons. Second, repair of radiation-induced sub-lethal and
potentially lethal damage is less readily accomplished after neutron irradiation than after
conventional irradiation. Thirdly, neutrons are toxic throughout the phases of the cell cy cle
(M, G1, S, G2), whereas photons are more toxic in late G2/M (157,158).
Kubota et al. (151) compared the biologic effects of 13-MeV neutrons with those of
137Cs gamma ray s in MG-63 human osteosarcoma cells in plateau phase growth and in
multicellular spheroids. The relative biologic effectiveness varied slightly with the
measurement technique but was in the range of 1.9–2.29. If one accepts the assertion that
osteosarcomas are rapidly growing tumors with areas of necrosis and potentially hy poxic
areas, then one might conclude that these tumors would be more effectively irradiated by
neutrons.
There is a small clinical experience with the use of neutrons for local control of
osteosarcomas. Many of the patients treated had inoperable tumors or refused amputations
(159). The results of neutron treatment are shown in Table 10.9 . The 77 patients cited have
an overall local control rate of 44 of 77 (58%). Clearly, there are risks from combining the
results of 11 series to draw a conclusion. The local control rates of the individual series range
from 0% to 100%, and these series include patients with tumors at a variety of locations.
Dense fibrotic reactions can occur after neutron treatment, leading to severe complications
and, in some patients, to amputation (163,164). For a patient with osteosarcoma who refuses
definitive surgery or is medically or technically inoperable, it is reasonable to consider the
use of neutrons. However, part of the informed consent for such treatment must include a
discussion of the potential for serious late ill effects of such treatment.
Page 214
Table 10.9 Literature Review of the Local Control Rates for Osteosarcomas after
Neutron Therapy
Charged Particle Therapy

Osteosarcoma of the skull base and axial skeleton pose a particularly difficult problem for the
pediatric radiation oncologist. These tumors are more difficult to extirpate at surgery. An
initial gross and microscopic tumor resection is inhibited by the proximity of brainstem, spinal
cord, cranial nerves, nerve roots, or vessels. However, these normal tissue structures also
prevent the oncologist from using radiation as an alternative to surgery because tumoricidal
dosages for osteosarcoma exceed the tolerance of critical neural tissue (167). Although three-
dimensional or intensity -modulated treatment planning with multiple noncoplanar photon
beams may be used in an attempt to achieve an acceptable dosage distribution, the
penetrance and divergence of photons present significant limitations.
Protons and other charged particle beams (such as neon, helium, and carbon ions) have
a finite dosage range with steep dosage fall-off bey ond the Bragg peak. This property
engenders a treatment beam that has little exit dosage bey ond the deposition of energy in the
target volume, making these beams distinctly different from photons. The advantage of
protons resides solely in this phy sical difference because proton beams have no significant
biologic advantage over megavoltage photons (Fig. 10.9 ). Other charged particle beams
have both the advantage of rapid Bragg peak dosage fall-off and an increase in relative
biologic effectiveness (151). Charged particles can be used to shape a dosage distribution
around an osteosarcoma of the skull base or vertebral body with the possibility of maintaining
the dosage to the adjacent brain or spinal cord within acceptable limits.
Figure 10.9 Proton radiation dose distributions for a large pelvic osteosarcoma. Note the
sparing of most pelvic organs and the contralateral pelvic bones (bone marrow).
The Radiation Oncology Department at the Massachusetts General Hospital, in

collaboration with the Harvard Cy clotron Laboratory, treated 15 patients with osteosarcoma
with combined proton and photon irradiation (anatomic sites were base of skull, 7; cervical
spine, 3; lumbar spine, 2; sacrum, 3). Dosages of 61.1–80 cobalt Gray equivalent were
administered, and 14 of the 15 patients also received chemotherapy. At 5 y ears, the actuarial
local control rate was 59% and the overall survival rate was 44% (168). In a series that
includes skull base tumors of various histologies, Castro et al. (167) reported that 20% of
disease-free survivors after charged particle therapy had grade III, IV, or V complications
such as cranial nerve or vascular injuries. Investigators in China, Japan, after conducting an
initial Phase I/II trial with carbon ions (169), are treating patients with bone (including
osteosarcoma) and soft tissue sarcomas to 52.8–73.3 Gy E in 16 fractions with an overall 5-
y ear local control rate of 81% (172). A prospective study is underway in Heidelberg
exploring the utility of a carbon ion boost after proton therapy (170).
Intraoperative Radiation Therapy (IORT)

A combined specialty team at the Universidad de Navarra, Spain, treated 22 patients with
osteosarcoma with preoperative chemotherapy, surgical excision, a 15–20 Gy IORT using
electron beam to the tumor bed area, and postoperative chemotherapy (81). Five patients also
received preoperative and postoperative external beam radiotherapy. There was only one
local recurrence among the 22 patients, with a median follow-up of 18 months. Local
recurrence after definitive surgery for osteosarcoma is uncommon, and it is not clear that the
IORT was helpful.
Page 215An additional 32 patients with osteosarcoma were treated with IORT by
Yamamuro and Kotoura. Before 1984, treatment consisted solely of exposing the primary
tumor site and administering 50–60 Gy of IORT with 12–26 MeV electron beams. After 1984,
patients received cis-platinum and doxorubicin in combination with IORT. The clinical results
from this small series, spread out over many y ears (1978–1990), must be interpreted with
caution. Ten patients underwent limb amputation or prosthetic replacement 2–10 months after
IORT. Eight patients had complete necrosis of the tumor cells throughout the specimen except
for a “few scattered, markedly altered, presumably nonviable tumor cells in small clusters.”
Two patients showed local regional tumor recurrence in unirradiated areas, and one showed
recurrence in the radiation field (a juxtacortical osteosarcoma). Joint function was reported
as being satisfactory ; five patients had some evidence of moderate-to-severe skin necrosis,
but “among the patients who underwent neither limb amputation nor prosthetic replacement
and survived longer than 1 y ear after IORT, about 58% sustained pathologic fracture through
the lesions. All attempts of osteosy nthesis failed to fuse the fracture site” (162).
Oy a, Tsuboy ama, and colleagues from Ky oto University in Japan described 39 patients
with osteosarcoma of the extremities who were treated with definitive IORT. The tumor and a
margin were treated with 45–80 Gy of electrons or X-ray s in a single fraction while major
vessels and nerves were retracted out of the treatment field. Nine local recurrences
developed in these 39 patients. Eight were considered to be marginal recurrences or
occurrences from unirradiated surrounding normal tissue. Complications included associated
transient skin reaction attributable to radiation and two cases of mild peroneal palsy, possibly
caused by irradiation. Post-IORT fractures occurred in 13 patients. The problem seems to
have been solved by the use of preventive nailing in more recent patients (171,172).
These series must be interpreted cautiously. It is possible that IORT, in combination with
surgery and chemotherapy, may reduce the already low local recurrence rate for most
cases of osteosarcoma. This is a testable hy pothesis. The use of IORT as the definitive local
control measure, as described by Yamamuro and Kotoura (162), must be considered
investigational therapy with, apparently, a high risk of subsequent fracture.
Radioisotope Therapy
Bone-seeking radiopharmaceuticals are at an early stage of investigation in the treatment of
osteoblastic osteosarcoma. The uptake of radiopharmaceuticals in adult skeletal metastatic
lesions such as breast and prostate cancer results from an osteoblastic response in the normal
bones surrounding the metastases. However, osteosarcoma often produces bone matrix within
the target. A radioisotope that hones into bone and gives off radioactivity for a sufficiently
long period of time may produce a therapeutic benefit.
Samarium-153 ethy lene diamine tetramethy lene phosphonate is a bone-seeking
radiopharmaceutical. It is produced by neutron capture from 153Sm to y ield a radioisotope
of high purity that has both a medium-energy beta emission for therapeutic purposes and
gamma emission, which is useful for conventional gamma camera scintigraphic imaging.
Compared with technetium-99m methy lene diphosphonate preparations, which are used for
routine bone imaging, 153Sm has comparable or better bone–blood and bone–muscle ratios.
Because of these favorable bone-seeking characteristics, 153Sm has been used for palliative
treatment of bone metastases (173).
Page 216In pilot studies of the use of 153Sm to irradiate patients with osteosarcoma and
bone metastases, all patients receiving high-dose samarium experienced severe
pancy topenia: some requiring transfusions and even stem cell infusion. It appears that
samarium treatment can reduce bone pain in some patients, albeit with significant toxicity.
There also appears to be one long-term survivor, a patient with a large pelvic osteosarcoma
and multiple primary pulmonary metastases who was treated with external beam
radiotherapy to the pelvic lesion, multiagent chemotherapy, and samarium
(174,175,176,177).
Fourteen patients with metastatic, unresectable, progressive, and/or recurrent
osteosarcoma received high-dose 153Sm (30 mCi/kg) and gemcitabine chemotherapy and
peripheral stem cell rescue (178). Indicator lesions were improved on imaging in 8 of 14
patients, and alkaline phosphatase decreased in 6 of 8 patients. The investigators noted
temporary ly mphopenia but did not find significant nephrotoxicity or hemorrhagic cy stitis.
One patient with multiple lung metastases developed life-threatening pulmonary hemorrhage.
223Ra is a bone-seeking alpha particle emitting radioisotope that has been used for
osteoblastic lesions from prostate cancer and now is being evaluated metastatic osteosarcoma
and possesses characteristics similar to calcium (179,180).
Palliation
It is reasonable to consider radiotherapy to
palliate painful bony sites and treat spinal cord
compression (Fig. 10.10 ) (65,80,153,181).
Unfortunately, the literature documenting the
palliative efficacy of radiotherapy in
osteosarcoma is sparse. The 1964 report by Lee
and MacKenzie of the Westminster Hospital,
London, describes the results with the
administration of 7000–8000 R with a 2-MeV
Van de Graaff electrostatic generator. The
authors note “clinical response of the tumor was
very variable. Sometimes, there was apparent
worsening: there might be sudden increase in the
size of the tumor, with more pain. Such changes
might be the result of hemorrhage, or fracture,
or disintegration of bone. More often, there was
a gradual reduction of pain and swelling, starting
after some 2000 R (sometimes much later) and
continuing for several weeks after completion of
treatment” (80). In 1975, de Moor (182) from
Johannesburg described the use of radiation for
palliation and noted that “pain relief or reduction
in swelling was experienced generally, and often
within the first 2–3 weeks of treatment” (Fig.
10.10 ).
The series of Beck et al. (183) from the
University of California at San Francisco Figure 10.10 When osteosarcoma
included 44 patients with adequate information metastasizes to bone, radiotherapy may
“to assess whether the treatment represented be used for palliation. This 9-year-old boy
even a short-term subjective gain for the patient. presented with osteosarcoma of the left
In 19 patients (43%), there was definite
palliation. Twenty - five patients (57%) had either femur. Bone metastases were diagnosed
no change or worsening of sy mptoms. Those a year and a half after the primary tumor
who survived experienced relief only after was identified. When the child
surgery.” These authors used conventionally complained of pain in the spine, both MRI
fractionated radiation with total dosages ranging and bone scan identified metastatic
from 50 to 80 Gy. In contrast, Lombardi et al. disease in conjunction with pulmonary
(152) administered 6 Gy three times per week metastasis. For spinal cord compression,
for a total of 36 Gy in six fractions over 2 weeks. palliative radiation therapy was
In 14 patients with 21 evaluable sites, there was a administered.
clinical response in 18%.
Machak et al. (96) reported on 31 patients treated with curative intent with
chemotherapy ; they reported “a clinical response and limb function restoration” in 24 of the
31 (77%) patients but a good imaging and biochemical response in only 11. Of the 20
nonresponders, 15 (75%) improved after radiotherapy, supporting a palliative role for
radiotherapy.
Mahajan et al. (34) reported a series of 39 patients with metastatic and/or recurrent
osteosarcoma who were treated with radiation therapy (median dose 30 Gy in 10 fractions)
and concurrent chemotherapy (most commonly ifosfamide or methotrexate). Subjective
improvement occurred in 76% of painful sites. Sustained reduction of standard uptake vales in
positron emission tomography (PET)-CT scans or bone scans occurred in 72% of the patients.
In this report, the actuarial 4-y ear survival from the development of metastasis was 39%.
Thus, a substantial number of patients could have their painful bony sites palliated with a
combination of short-course radiation and concurrent chemotherapy.
Page 217Chordoma and Chondrosarcoma

Chordoma is a rare tumor originating from the embry onal notochord and usually arises from
the skull base, spine, and sacrum. Microscopically, the tumor is pseudoencapsulated and
comprised of uniform cells that contain eccentric nuclei with dense chromatin as well as
cy toplasmic vacuoles (phy saliferous cells). The cells are usually immunopositive for
cy tokeratin, epithelial membrane antigen, S-100, and vimentin (Fig. 10.11 ) The histologic
subty pes include conventional, chondroid, and dedifferentiated. Children have a higher
tendency than adults to present with aty pical or dedifferentiated chordomas.
Chondrosarcoma originates from primitive mesenchy mal cells or the embry onic rest of
cartilaginous matrix of the cranium, and usually involves the long bones, pelvis, and, less
commonly, head and neck including the base of skull (sometimes associated with Ollier
sy ndrome). The histologic subty pes include classical, mesenchy mal, and dedifferentiated.
Classical chondrosarcomas are divided into grade I, II, or III based on cellularity, nuclear
size, mitotic rates, and the amount of chondroid matrix. Immunochemical stains are negative
for cy tokeratin and epithelial membrane antigen but positive for S-100 and vimentin.
Constitutive activation of Hedgehog-mediated signaling has been implicated in the
pathogenesis (184).
Treatment
The primary treatment for chordomas is surgery. Postoperative radiation therapy is
generally necessary to reduce recurrence. In adults, the results of proton therapy appear
better than that of photon therapy, probably because of the higher radiation dose delivered. In
children, a small series reported 60% local
control after passive-scattered proton therapy to
doses ranging from 50.4 to 78.6 CGE (185).
Another small series using scanning proton
therapy to 74 CGE reported no recurrence after
a median follow-up time of 36 months (186).
Late side effects including neurologic deficits
and pituitary insufficiency have been reported in
up to 30% of the patients. A small series of
children and y oung adults with skull base
chordomas treated with carbon ion radiotherapy
has been reported (187). With a median follow-
up of 49 months, one out of seven patients with
chordomas recurred. Rombi et al. (188) reported
their experience on 26 children with skull base
tumors treated with proton therapy at the Paul
Scherrer Institute. Nineteen patients had
chordoma and 5-y ear local control and overall
survival rates were 81% and 89%, respectively,
after a mean dose of 74 Gy RBE. The value of
chemotherapy is unclear; however, some groups
have reported stability of disease with imatinib
and sorafenib (189,190,191). Brachy ury, a
nuclear transcription factor, is a strong mediator
of the epithelial to mesenchy mal transition and is
overexpressed in chordoma. A recombinant
vaccine encoding brachy ury activates human T
cells. This vaccine is being tested in a phase 1
study in patients with progressive chordoma with
encouraging preliminary results (192).
Page 218Surgery is also the primary Figure 10.11 Histopathology of
treatment for chondrosarcomas. Completely chordoma. Note the physaliferous cells
resected grade I chondrosarcomas do not need (A) and the triad of positive
adjuvant treatment. Postoperative radiation immunohistochemical stains for keratins,
therapy is usually offered to patient with higher- EMA (B), and S-100 (C) proteins.
grade or more malignant chondrosarcomas such
as mesenchy mal chondrosarcomas. For skull base chondrosarcomas treated with protons
(scattered or scanning), the local control rates were 70–100% (185,186), and with carbon ion
therapy the local control rate was reported as 100% (187). Mesenchy mal chondrosarcoma is
considered a malignant sarcoma in children. The Cooperative Soft Tissue Sarcoma (CWS)
and Osteosarcoma (COSS) Study Groups of the German Society of Pediatric Oncology and
Hematology (GPOH) reported the result on 50 children and adolescents (median age 16.6
y ears) (193). All tumors were resected; 13 patients received chemotherapy and 6 patients
received radiation therapy. The actuarial 10-y ear event-free and overall survival rates were,
respectively, 53% and 67%. Seven of eight patients whose tumors were completely resected
versus four of seven patients whose tumors were incompletely resected survived disease
free. One patient with local recurrence was salvaged after further surgery and radiation
therapy.
Figure: Literature Review of the Local
Control Rates for Osteosarcomas after
Neutron Therapy
Figure:
Proton radiation dose distributions for a large pelvic osteosarcoma. Note the sparing of most
pelvic organs and the contralateral pelvic bones (bone marrow).
Figure:
When osteosarcoma metastasizes to bone, radiotherapy may be used for palliation. This 9-
year-old boy presented with osteosarcoma of the left femur. Bone metastases were
diagnosed a year and a half after the primary tumor was identified. When the child
complained of pain in the spine, both MRI and bone scan identified metastatic disease in
conjunction with pulmonary metastasis. For spinal cord compression, palliative radiation
therapy was administered.
Figure:
Histopathology of chordoma. Note the physaliferous cells (A) and the triad of positive
immunohistochemical stains for keratins, EMA (B), and S-100 (C) proteins.
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CH A P TER 11
Rhabdomyosarcoma
Shannon M. MacDonald, Matthew Ladra, Alison M. Friedmann, Nancy J.
Tarbell, and Louis S. Constine
Page 223Rhabdomy osarcoma (RMS) is a highly malignant neoplasm that arises from
embry onal mesenchy me with the potential for differentiating into striated muscle. Although
the cells show differentiation along rhabdomy oblastic lines, RMS is not limited to cells with
recognizable muscle cross-striations (1,2). Weber initially described RMS in 1854, but
progress in our understanding of this complex neoplasm accelerated with Stout’s landmark
descriptive series in 1946 and the delineation by Horn and Enterline in 1958 of the four
classical forms of RMS (3,4,5). RMS can arise almost any where in the body, is locally
invasive, and rapidly disseminates early in its course. Near the beginning of the 20th century,
the only cures were accomplished with radical surgery in the few fortunate children without
metastases. Significant disfigurement and loss of function were common sequelae. High-dose
radiation therapy (RT) increased the potential for local control but caused a different set of
morbidities (6,7). As chemotherapy has become increasingly effective in eliminating
micrometastatic disease and assisting in local control, the need for aggressive surgery and
large-volume irradiation has diminished, although surgery and RT still play pivotal roles in the
curative treatment of RMS (8). Overall survival rates have concomitantly increased from 15–
25% to more than 70% (9,10,11,12).
RMS is a rare tumor with clinical and biologic heterogeneity. Consequently, multi-
institutional trials were necessary to develop and refine treatment approaches. North
American investigators of the Intergroup Rhabdomy osarcoma Study Group (IRSG) have
play ed an important role in this progress, now in its seventh generation of protocols. The
difficulty of this undertaking is clear in view of the my riad sites, stages, and histologies of
RMS which are associated with different natural histories and prognoses (13). Bey ond this,
advances in imaging, changes in end points, and the need for mature data all increased the
difficulty in conducting and comparing randomized, controlled clinical studies of patients with
RMS. With this view, the IRSG was established through the collaboration of three
multidisciplinary cancer treatment study groups (Cancer and Leukemia Group B, Children’s
Cancer Study Group, and the Pediatric Branch of the Southwest Oncology Group, which later
became the Pediatric Oncology Group). Intergroup Rhabdomy osarcoma Study I (IRS-I) was
open for patient entry from 1972 to 1978 (9). With an overall 5-y ear survival rate of 55% in
IRS-I, IRS-II was designed to improve survival for the patient subgroups with poor outcomes
and to refine treatment for the remaining patients (10). IRS-II ran from 1978 to 1984, IRS-III
from 1984 to 1991, IRS-IV from 1991 to 1997; and IRS-V from 1997 to 2005–2006. Although
the previous generations of IRS studies were based on a surgically oriented clinical grouping
sy stem dependent on the tumor that remained after initial surgery, IRS-IV and IRS-V were
based on a more biologically oriented staging sy stem, discussed later in this chapter. These
studies, each based on the results of its predecessor, have provided a database of over 4000
patients. The IRSG studies are now conducted through the Children’s Oncology Group (COG),
the United States-based cooperative research network that formed from the merger of the
Pediatric Oncology Group and the Children’s Cancer Study Group. The first generation of
studies, ARST0331 (low risk), ARST0531 (intermediate risk), and ARST0431 (high risk),
opened in 2005–2006, upon the completion of IRS-V. They were closed in 2012, 2014, and
2010, respectively. New studies are in development for intermediate- and high-risk patients
and patients with relapsed disease. Due to the excellent outcome seen on ARST0331 in low-
risk patients, there is currently not a plan to continue to perform clinical investigations in this
very favorable group of patients (14).
Other multi-institutional group studies have also provided important data (15,16,17,18).
Of particular note are the European-based International Society of Pediatric Oncology
(SIOP) and the United Kingdom-based Children’s Solid Tumor Group (CSTG) (16,17,18).
Finally, many single-institution studies have also been quite informative regarding RMS
(7,8,19,20). Progress in treating RMS is exemplified by the improvement in overall 5-y ear
survival in the IRS studies: 56% in IRS-I, 63% in IRS-II, 71% in IRS-III (Fig. 11.1 )
(9,10,11,12,21,22). Overall survival was 86% in IRS-IV, and in IRS-V, it was 97% for low-risk
patients and 79% for the intermediate-risk patients (23).
Page 224
Figure 11.1 Improvement in 5-year survival of children with RMS treated on the IRS
trials. (From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D,
eds. Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer;
2015.)
Figure:
Improvement in 5-year survival of children with RMS treated on the IRS trials.
(From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds.
Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer; 2015.)
EPIDEMIOLOGY
RMS accounts for about 3.5% of all malignant disease in children y ounger than 15 y ears of
age and 2% of cancer cases among adolescents and y oung adults 15–19 y ears old (24,25).
RMS is the most common soft tissue sarcoma of childhood, representing about half of this
otherwise very heterogeneous group of tumors. The annual incidence of RMS is 4.4 per
million in white children and 1.3 per million in black children. There is a slight male
predominance (1.4:1). Seventy percent of cases occur before the age of 10 y ears, with a
peak incidence at 2–5 y ears of age (Fig. 11.2 ). Congenital anomalies have been identified
in as many as one-third of children with RMS, most commonly involving the gastrointestinal,
genitourinary, cardiovascular, and central nervous sy stems (26).
Figure 11.2 Clinical features of RMS from IRS-I, IRS-II, and IRS-III pooled data. A: Age at
presentation; site of primary tumor (B); clinical group (C); histology (D). (Modified from
Wexler LH, Skapek, SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds.
Although the majority of cases of RMS occur sporadically, a proportion are associated
with genetic conditions, including the Li–Fraumeni sy ndrome (in which germline mutations of
p53 exist), neurofibromatosis ty pe 1, Costello sy ndrome, Noonan sy ndrome, and Beckwith–
Wiedemann sy ndrome (27,28,29,30). With greater recognition that rhabdomy osarcoma is a
cancer seen in patients with Li–Fraumeni sy ndrome and more frequent testing, this sy ndrome
is being increasingly recognized as an important cause of RMS, particularly embry onal RMS
(31). Some centers are now routinely referring children diagnosed with rhabdomy osarcoma
for genetic counseling and consideration of testing, as Li–Fraumeni sy ndrome has far-
reaching implications for both the child and other affected family members.
Figure:
Clinical features of RMS from IRS-I, IRS-II, and IRS-III pooled data. A: Age at presentation; site
of primary tumor (B); clinical group (C); histology (D).
(Modified from Wexler LH, Skapek, SX, Helman LJ. Rhabdomyosarcoma. In: Pizzo P, Poplack
D, eds. Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer;
2015.)
BIOLOGY
Although the origin and genetics of RMS remain unclear, clinical observations can provide
direction for additional understanding of this tumor. If we can determine the tumor
characteristics that predict radiochemotherapy responsiveness or, conversely, tumor
resistance to therapy and a propensity to disseminate, then we can select the patients in whom
more or less toxic therapy should be used. Moreover, we may devise novel biologic
maneuvers to treat such tumors that minimize normal tissue damage. Reducing the toxicity of
therapy becomes increasingly important as the cure rate continues to improve. Areas in
which progress has been made include the genetic control of my ogenesis, tumor suppressor
genes, and molecular diagnostics (32,33).
Cytogenetics
There are two major histologic subty pes of rhabdomy osarcoma, alveolar and embry onal.
Alveolar RMS is usually characterized by one of two translocations, both of which involve the
FKHR gene on chromosome 13 (32,33). The most common translocation, t(2;13)(p35;q14),
fuses the PAX3 gene, a transcription regulator, to the FKHR transcription factor. This
translocation is present in about 60% of children with alveolar RMS. The less common
translocation, t(1;13)(p36;q14), fuses the PAX7 transcription regulator to FKHR and is
involved in about 20% of cases. This latter translocation seems to occur in y ounger patients
and to be associated with a higher event-free survival rate than the PAX3 gene
rearrangement. Approximately 20% of alveolar RMS do not have either translocation, and
there is evidence that these fusion-negative tumors behave more like embry onal RMS
clinically, with a better outcome than fusion-positive alveolar tumors (34). The specific
translocations (or lack thereof) do not appear to correlate well with histologic features (35). In
the future, monitoring for these fusion products with sensitive techniques such as reverse
transcriptase poly merase chain reaction may be useful for detecting minimal residual
disease during or after treatment and for guiding therapy (36,37).
Page 225Embry onal RMS is often characterized by loss of heterozy gosity at 11p15.5,
suggesting the presence of a tumor suppressor gene (38).
Genomic amplification also differs in alveolar and embry onal RMS. It is rare in
embry onal RMS, whereas gains of whole chromosomes (particularly of chromosomes 2, 8,
12, and 13) and hy perdiploidy are common (39,40,41,42). In alveolar RMS, gene
amplification is common, as is near-tetraploidy.
Cell Cycle Control

My ogenesis involves differentiation of the mesenchy mal fibroblast into skeletal muscle and is
under the control of a series of gene products including the My oD protein family (my ogenin,
MYF5, and MYF6) (43). These gene products also halt cell cy cling. Expression of the My oD
proteins, which can be determined by an anti-My oD antibody, has demonstrated that
malignant cells have characteristics of skeletal muscle differentiation and therefore represent
RMS. It is possible that some tumor suppressor factor is present in the normal fibroblast that,
when combined with the RMS cell and the My oD gene product, can drive the cell toward
differentiation and halt cell proliferation.
Proto-oncogenes
The myc gene can contribute to uncontrolled cell proliferation via several pathway s including
insertion mutations, translocations, retroviral transductions, and amplification. Two reports
involving 20 patients showed that 50% of those with alveolar RMS had n-myc amplification, in
contrast to its uniform absence in patients with embry onal RMS (44,45). Impressively, among
the patients with alveolar RMS, n-myc amplification predicted a fatal outcome.
Tumor Suppressor Genes

Tumor protein p53 mutations can be demonstrated in a significant proportion of childhood
RMS (46). In the presence of damaged DNA, normal p53 produces G1 arrest and prevents
the cell with damaged DNA from undergoing any proliferation. In conjunction with myc, p53
drives such damaged cells toward apoptosis, potentially explaining why some forms of RMS,
which escape cure by radiochemotherapy, become progressively more virulent: they
generate resistant clones of tumor cells. Anaplastic histology has recently been linked to p53
germline mutations. In an analy sis of 11 patients with RMS and P53 germline mutations,
100% exhibited anaplastic nonalveolar histology, and had an average age at diagnosis of 40
months (47). The prognostic significance of the presence of anaplastic features is not clear; in
a retrospective review of over 500 patients, it was not an independent predictor of outcome in
multivariate analy ses (48).
Page 226RMS occurs in any anatomic location where there is skeletal muscle and in some
locations where skeletal muscle is not normally found (Fig. 11.2 ) (10). The most common
locations are the genitourinary sites and the head and neck. Genitourinary sites include the
bladder, prostate, vagina, uterus, urethra, and paratesticular region. Head and neck lesions are
divided into parameningeal sites (nasophary nx, nasal cavity, paranasal sinuses, middle ear
and mastoid region, infratemporal fossa, and ptery gopalatine and paraphary ngeal areas) and
other head and neck sites (parotid region, cheek, masseter muscle, oral cavity, orophary nx,
lary nx, hy pophary nx, scalp, face, and pinna) (49).
RMS commonly presents as a mass with poorly defined margins, but specific
presentations relate to the primary disease site. A mass in the genitourinary sy stem may
cause urinary tract or rectal obstruction. On occasion, the mass may protrude from the
cervix, vagina, or urethra. When the protruding tumor has the gross appearance of a cluster
of grapes, it is called botry oid (grapelike) sarcoma. Prostate and bladder RMS may also have
a botry oid appearance and protrude into the lumen of the bladder. Hematuria, urinary
frequency, or retention with subsequent renal failure may occur. Paratesticular RMS presents
with a mass and may be confused with a hy drocele, incarcerated hernia, or testicular torsion.
In the extremities, RMS often is palpable and causes pain or limits motion. Parameningeal
RMS may present with airway obstruction or a palpable mass. As the tumor grows, it can
erode the base of the skull and cause cranial nerve palsies. Penetration into the brain can
occur and mimic an intracranial mass, with headache, vomiting, and diplopia. RMS of the
cheek or lary nx causes obstruction of the aerodigestive track or a discernible mass; other
sy mptoms or signs referable to the head and neck include hoarseness, poly ps, decreased
hearing, persistent otitis, otorrhea, rhinorrhea, nasal congestion or obstruction, and headache.
Patients with orbital RMS usually present with proptosis, discoloration, or limitation of
extraocular motion. RMS of the trunk can present as a mass simulating a hernia or hematoma,
or causing a classical superior vena cava sy ndrome. In the retroperitoneum, RMS can cause
gastrointestinal discomfort or other mass-related sy mptoms.
Diagnostic Evaluation
The history and phy sical examination should focus on the extent of local disease and the
possible presence of metastases. RMS may extend locally and infiltrate along fascial planes
and into surrounding tissues. Tumor margins are often indistinct. Depending on the site, the
local tumor generally is imaged by some combination of computed tomography (CT) or
magnetic resonance imaging (MRI). Genitourinary RMS often is investigated initially by
ultrasound and barium enema, and voiding cy stourethrogram, cy stoscopy, or pelvic
examination under anesthesia occasionally is indicated. The draining ly mphatics, particularly
in genitourinary and extremity primary sites, are evaluated with CT and often surgery
(50,51). The most common sites of metastases are lung, bone, bone marrow, and locoregional
ly mph nodes (22). Chest CT is the optimal imaging method for lung metastases. A nuclear
medicine bone scan is performed to detect bony metastases but is not reliable in determining
skull base involvement in parameningeal tumors, which is evaluated with CT or MRI. Bone
marrow aspirate and biopsy are performed, and examination of cerebrospinal fluid (CSF)
cy tology is indicated if the tumor is in a parameningeal site (52). MRI is used to evaluate
spinal cord–related sy mptoms. Positron emission tomography (PET) scan is also being used
with increasing frequency and is effective at detecting regional ly mph node involvement and
identify ing distant metastases (53). A recent retrospective review of over 1600 children with
RMS enrolled in Intergroup studies from 1991 to 2004 suggests that about one-third of patients
(those with localized noninvasive embry onal tumors) do not need to undergo bone marrow
and bone scan examinations at diagnosis (54).
Prognostic Features
Histology
Most RMS are soft, fleshy tumors with variation in the extent of both invasion and necrosis.
Immunohistochemical stains, including antidesmin, antivimentin, and anti–muscle-specific
actin, are used routinely to help ascertain the muscle origin of the tumor cells, and the
detection of the muscle regulatory gene MyoD1 may be even more sensitive than desmin
(55).
Four histologic subty pes of RMS are classically described: embry onal, alveolar,
pleomorphic, and mixed (Fig. 11.2 ). However, the lack of agreement in classification
among pathologists and the need to develop a single sy stem that is prognostic prompted
formation of an international panel to devise a new sy stem, the International Classification of
Rhabdomy osarcoma (Table 11.1 ) (56,57,58). Classification on the basis of histologic
features remains a challenge and current COG clinical trials utilize central pathologic review
to ensure uniform pathologic diagnosis since stratification schema and guidelines vary by
histology (59).
Table 11.1 International Classification of Rhabdomyosarcoma
Favorable: Embryonal, Botryoid, and Spindle Cell Variants

Embry onal RMS is the most common histologic subty pe. Embry onal RMS accounts for 60–
70% of RMS in childhood and ty pically arises in the head and neck region and genitourinary
tract (56). This form is composed of blastemal mesenchy mal cells that tend to differentiate
into cross-striated muscle cells. Although it resembles normally developing skeletal muscle in
the 7- to 10-week fetus, great variation in the degree of differentiation can exist. Cellularity is
moderate, and the stroma is loose and my xoid in most cases. The cells are generally
fusiform or stellate, often admixed with primitive round cell forms. Cross- striations are
present in about one-third of cases (1). Periodic acid–Schiff staining, actin/desmin positive
reactivity, and Z band material usually are present. Loss of heterozy gosity at 11p15.5 may be
identifiable. The pathologic differential diagnosis often includes ly mphoma, Ewing sarcoma,
and neuroblastoma (other small, round, blue cell tumors of childhood that have in common
their light microscopic appearance and necessitate immunohistochemical evaluation for
further characterization).
Page 227The botry oid variant of embry onal RMS represents about 10% of all RMS
cases and occurs in mucosa-lined organs including the bladder, vagina, nasophary nx, nasal
cavity, middle ear, and biliary tree. The stroma is loose with a my xoid character and a
condensed tumor cell or cambial lay er must be identifiable. The tumor cells may be small or
large, with vary ing degrees of my ogenesis. These tumors are generally localized and
noninvasive (1,57,58).
The spindle cell variant is composed exclusively of spindle-shaped cells and has a low
cellularity. It can be collagen-rich or collagen-poor, with the former having a storiform
pattern. Its most common site is paratesticular.
Unfavorable: Alveolar
About 20% of children with RMS have the alveolar subty pe that is more common in
adolescents and in tumors involving the extremities, trunk, and perianal and perineal regions.
The alveolar form resembles developing skeletal muscle in the 10- to 20-week-old fetus. The
cells are round, with scanty eosinophilic cy toplasm that is occasionally vacuolated. Cross-
striations are quite rare. The name alveolar is derived from the pattern produced by the
tendency of cells to line connective tissue septa reminiscent of alveoli. Variable arrangement
of trabeculae may cause the tumor cells to be arranged in strands, clefts, sheets, or clusters
(1). The characteristic translocations are discussed in the “Biology ” section earlier in this
chapter. A “solid” variant has been identified, which grows as solid masses of closely
aggregated cells with little or no discernible alveolar arrangement.
Stage
RMS has been staged according to multiple sy stems developed in different institutions or
multi-institutional groups. With the advent of IRS-III, a pretreatment staging sy stem was
developed based on the tumor, node, and metastasis (TNM) sy stem used by the SIOP, which
reflected the disease characteristics at diagnosis (Table 11.2 ). IRS-IV, IRS-V, and the
current COG trials have used this TNM staging sy stem, which incorporates tumor size and
invasiveness (a or b, T1 or T2, respectively ), nodal status, presence of metastasis, and tumor
site. Essentially, stage 1 tumors are in favorable sites. Stage 2 tumors are in unfavorable sites
but are small (less than 5 cm) with negative ly mph nodes. Stage 3 tumors are in unfavorable
sites and are large or with positive ly mph nodes. Stage 4 tumors are at any site, with
hematogenous metastasis. This staging sy stem has been validated with respect to its
relationship to patient outcome (60).
Table 11.2 Tumor, Node, Metastasis Pretreatment Staging Classification
Page 228Group
Implicit in the discussion of the grouping and
staging sy stems is the importance of accurate
identification of prognostic variables. Most of
these variables are interrelated. A wealth of data
support the relevance of the clinical group of the
patient, which in essence is the postsurgical
disease extent at the time chemotherapy is
initiated. The clinicopathologic grouping sy stem
has been used since the first IRS studies (Table
11.3 , Fig. 11.2 ). The clinical group reflects
the absence of microscopic disease (group I,
13% of patients) or presence of microscopic Table 11.3 The IRS Grouping System
disease (group II, 20% of patients), gross disease
(group III, 48% of patients), or metastatic disease (group IV, 18% of patients) (11,21).
Clearly, the clinical group also reflects the disease site (ease of resection) and the biologic
invasiveness of the tumor. Because therapeutic decisions made before study entry affected
the assigned group, this sy stem did not accurately reflect the biology of RMS (60,61,62).
Moreover, the emphasis on surgical reduction of tumor bulk implicit in this sy stem led
surgeons to perform unnecessarily morbid surgeries at inappropriate times. In addition, the
surgical approach was not uniformly applied, which obfuscated interpretation of results (61).
However, data from all of the IRS studies support the utility of the grouping sy stem, and it
continues to be used in conjunction with stage and with careful surgical guidelines in the
current trials that are specific to site of disease (Fig. 11.3 ) (9,10,11,21).
Figure 11.3 Survival by clinical group for all patients treated in IRS-IV. Improved outcome
was seen in group II compared with group I and presumably due to undertreatment of select
patients with group I disease. (From Wexler L, Skapek SX, Helman LJ. Rhabdomyosarcoma.
In: Pizzo P, Poplack D, eds. Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia,
PA: Wolters Kluwer; 2015.)
Primary Site
The primary site is a strong determinant of outcome, as verified by data from IRS-II and
IRS-III (Fig. 11.4 ) (9,10,11,21). This relates, at least in part, to the association of site with
other tumor and treatment variables. The primary site generally determines the ability to
surgically remove the tumor, which in turn determines the IRS grouping (9). Surgical
removal also relates to tumor invasiveness and the morbidity that would attend resection.
Most orbital lesions are in group III (73.5% in IRS-I, IRS-II, and IRS-III); this is also true for
parameningeal lesions (which are never in group I) and genitourinary bladder or prostate
lesions (52,63). Conversely, most genitourinary nonbladder and nonprostate tumors are in
group I, and most extremity tumors are in group I or II or are metastatic (group IV) at
diagnosis. Other factors are also relevant to the association of primary site with prognosis. For
example, the tumor location determines the presenting signs and sy mptoms, which are often
related to the rapidity of diagnosis. Tumor size (up to 5 cm vs. more than 5 cm) is associated
with survival time (p < 0.001) by multivariate analy sis, and local failure in the group III
patients from D9803 was 25% for tumors ≥5cm and 10% for those <5cm (58,64). Size is also
related to tumor site through presenting sy mptoms and signs. Primary site influences the
propensity for ly mphatic spread (Table 11.4 ) (50,65). Whereas genitourinary, abdominal
or pelvic, and extremity tumors commonly involve regional ly mph nodes, tumors in the head
and neck, trunk, and female genital organs do so less commonly. However, the frequency of
ly mph node involvement is almost certainly underestimated by IRS data because the
assessment of nodal status has not been sy stematic. Data from Stanford and Memorial Sloan–
Kettering support the prognostic significance of ly mph node involvement. Pedrick et al. (20)
showed that 88% of patients presenting with involved nodes had primary tumors that were
invasive and extended bey ond the site or organ of origin. The more current IRS studies should
provide more consistent documentation of ly mph node status with improvements in imaging
techniques and careful surgical guidelines.
Page 229
Figure 11.4 Event-free survival of patients treated on Intergroup Rhabdomyosarcoma
Study IV by stage and site. A: For patients with nonmetastatic “favorable” site tumors (stage
1), the best outcome was seen for orbital primary tumors. B: For patients with
nonmetastatic unfavorable site tumors (stage 2 or 3), the best outcome was for those with
genitourinary (bladder–prostate) tumors, whereas those with extremity tumors had an
inferior outcome. GU B/P, genitourinary tract (bladder or prostate); GU non-B/P,
genitourinary tract (nonbladder, nonprostate). (From Wexler L, Skapek SX, Helman LJ.
Rhabdomyosarcoma. In: Pizzo P, Poplack D, eds. Principles and Practice of Pediatric Oncology.
7th ed. Philadelphia, PA: Wolters Kluwer; 2016.)
Table 11.4 Lymph Node Metastasis by Primary Site for 592 Patients with Visibly
Resected Diseasea from IRS-I and IRS-II aMicroscopic or no residual disease. -->
Other Factors
A variety of other factors have prognostic significance, some of which are general and others
specific to certain tumor subgroups. IRS data showed that ly mphocy te count, patient sex, and
age are prognostic (21). Although y ounger age is associated with a better outcome, the
specific subgroup of children y ounger than 1 y ear of age with alveolar histology has a
significantly poorer survival than do older children, a finding not seen for infants with the
embry onal subty pe (66,67,68). Some site-specific variables influence outcome. In the head
and neck, risk factors that predict tumor access to the cranial subarachnoid space (skull base
erosion, cranial nerve palsy, intracranial extension) decrease the likelihood of disease-free
survival (51% vs. 81% if no risk factors) (52,69,70). In extremity sites, the presence of ly mph
node involvement is strongly associated with a high incidence of relapse in metastatic sites
and inferior survival. In contrast to many other childhood cancers, early response to
chemotherapy has had a conflicting correlation with long-term disease-free control. Two
large analy ses of the most recent COG trials failed to show improved survival in patients with
a CR or PR after induction chemotherapy ; however, a correlation was seen in the German
cooperative group soft tissue sarcoma trials (15,71,72,73,74). Further, PET response after
induction chemotherapy in RMS has been shown to correlate with local control rates,
suggesting that chemotherapeutic response play s a role in local control (75,76). More
recently, two studies from the United States and Germany showed that for embry onal
parameningeal tumors, response to chemotherapy was linked to local control and event-free
survival, suggesting that response may only be prognostic for specific sites and/or histology
(15,71,73,74,77,78).
Figure: International Classification of
Rhabdomyosarcoma
Figure: Tumor, Node, Metastasis
Pretreatment Staging Classification
Figure: The IRS Grouping System
Figure:
Survival by clinical group for all patients treated in IRS-IV. Improved outcome was seen in
group II compared with group I and presumably due to undertreatment of select patients
with group I disease.
Figure:
Event-free survival of patients treated on Intergroup Rhabdomyosarcoma Study IV by stage
and site. A: For patients with nonmetastatic “favorable” site tumors (stage 1), the best
outcome was seen for orbital primary tumors. B: For patients with nonmetastatic
unfavorable site tumors (stage 2 or 3), the best outcome was for those with genitourinary
(bladder–prostate) tumors, whereas those with extremity tumors had an inferior outcome.
GU B/P, genitourinary tract (bladder or prostate); GU non-B/P, genitourinary tract
(nonbladder, nonprostate).
Figure: Lymph Node Metastasis by Primary
Site for 592 Patients with Visibly Resected
Diseasea from IRS-I and IRS-II
aMicroscopic or no residual disease.
GENERAL PRINCIPLES OF THERAPY
Page 230Currently, the COG studies stratify patients into three risk groups (low, intermediate,
and high) on the basis of known prognostic factors and historical outcome (13). The prognostic
features incorporated into the risk classification scheme include histology, stage (which in turn
incorporates site, tumor size, invasiveness, node status, and metastases), and clinical group.
General definitions of the risk groups are as follows:
Low risk: Patients with localized embry onal RMS occurring at favorable sites (stage 1)
and patients with embry onal RMS occurring at unfavorable sites with either completely
resected disease (group I) or microscopic residual disease (group II)
Page 231Intermediate risk: Patients with embry onal RMS occurring at unfavorable sites
with gross residual disease (group III) and patients with nonmetastatic alveolar RMS at
any site
High risk: Patients with metastatic RMS (group IV, stage 4)
Clearly, this scheme will continue to evolve as treatments improve and new data emerge
regarding particular subsets of patients and biologically based prognostic features. The overall
goals are to reduce long-term toxicities in patients with a high likelihood of cure and to
develop superior and innovative therapies for patients who continue to fare poorly with
modern treatment regimens.
The therapeutic struggle for clinicians managing children with RMS, to cure while
minimizing functional and cosmetic deficits, is heightened by the difficulty in eradicating both
local and sy stemic disease. The spectrum of locations and histologies complicates
determination of treatment strategies through differences in the propensity for local and
sy stemic control and treatment sequelae. It is clear that multidisciplinary therapy is
necessary. Aggressive surgery and RT alone have been curative in fewer than 25% of
children, with the exception of patients with orbital or genitourinary primary sites (18,79).
Conversely, chemotherapy alone is associated with high local failure rates, a lesson learned
by attempts to manage orbital or genitourinary tumors without radiation (18,80). The
judicious use of chemotherapy to eradicate micrometastatic disease and reduce the extent of
local disease and RT to increase the potential for local control has led to a decrease in
aggressive surgery except in selected situations (8). The current challenge is to develop
approaches to additionally enhance the complementary actions of all three treatment
modalities in terms of intensity and sequence.
Surgery
Before the advent of radiation therapy and chemotherapy, complete resection of RMS was
the clear goal of surgical treatment. This often involved radical surgeries such as pelvic
exenteration, radical prostatectomy, cy stectomy, amputations, and orbital exenteration. Even
so, less than 10% of children were amenable to complete resection and curable because of
the absence of metastatic disease. Bey ond this, most of these children had severely
compromised quality of life functionally, cosmetically, and psy chologically. Select sites that
were more often curable by aggressive surgery included the orbit and bladder. Combined
analy sis of patients with nonmetastatic disease from IRS-I, IRS-II, and IRS-III showed that
only 16% of children had disease amenable to complete resection (group I) and 20% had
tumors for which removal of gross disease (group II) was possible (Fig. 11.5 ). In general,
achievement of local control with organ preservation is the appropriate goal. This is
accomplished with appropriate combined modality therapy. Aggressive surgery remains
appropriate in certain situations, such as for salvage therapy.
Figure 11.5 Axial (A) and sagittal (B) images of a 10-month-old boy with a group III
rhabdomyosarcoma of the bladder/prostate. The tumor displaces the bowel and causes
urinary obstruction resulting in hydronephrosis.
Reoperation for microscopic residual disease after an initial excision, or when the first
operation was performed without knowledge of the ty pe of neoplasm involved, may be
indicated before additional management. Reoperation after chemotherapy as a second-look
procedure provides an attractive option for select cases. Many of these patients have had a
“pathologic” complete response and have survival similar to that of patients who had an initial
complete resection.
Page 232The role of ly mph node dissection as a component of surgical therapy
continues to evolve. Advances in imaging may improve radiographic detection of involved
ly mph nodes. Current guidelines are site specific because of the variability in the frequency
of ly mph node involvement and outcome data relating to its significance. Genitourinary and
extremity RMS have a high incidence of ly mph node metastases (Table 11.4 ) (50). The
high frequency of nodal spread for extremity tumors, often without clinical or radiographic
evidence of involvement, has both prognostic and therapeutic implications (81,82). Currently,
COG guidelines include surgical evaluation of ly mph nodes for RMS of the extremity and for
males who are older than 10 y ears of age with paratesticular tumors. Sentinel ly mph node
biopsy continues to be explored as an alternative to formal ly mph node dissection (83). This
topic is considered further in later sections because considerations are site specific.
Overall, the extent and timing of surgical excision depend on the site of tumor and
overall treatment strategy, balancing cure with functional outcome.
Chemotherapy
Before the 1960s, the role of chemotherapy in RMS was for the treatment of metastatic
disease. Several investigators reported responses to vincristine and actinomy cin used alone
(VA) or in combination with cy clophosphamide (VAC) (79). Various groups then began to
report that the adjuvant administration of chemotherapy for totally or subtotally resected
localized disease contributed to an increase in survival probability from 10–40% to 60–80%
(84). Hey n et al. (8) randomized 32 children with completely resected RMS to adjuvant
therapy with VA or no adjuvant therapy. There were eight deaths among the 15 children in
the control group and two deaths in the 17 treated children. All children with microscopic
residual disease received chemotherapy, and survival rates were excellent.
With the widespread adoption of chemotherapy as part of the therapy of RMS, several
trials were undertaken to establish the optimum drug combinations. IRS-I tested whether VAC
was superior to VA in group II disease and whether pulse VAC plus adriamy cin was superior
to pulse VAC alone in groups II and III (Table 11.5 ). The study found no benefit to
cy clophosphamide in group II disease, and no benefit to the addition of adriamy cin in groups
III and IV (9).
Table 11.5 Design and Results of IRS-I, 1972–1978 (686 Patients)
IRS-II built on the results of IRS-I (Table 11.6 ) (10). Patients in group I received VAC
or VA. Disease-free survival was similar. IRS-II showed no benefit to pulse VAC compared
with cy clic sequential VA for group II. In groups III and IV, pulse VAC was better than a VAC
and adriamy cin combination but not statistically significantly better.
Table 11.6 Design and Results of IRS-II, 1978–1984 (1003 Patients)
IRS-III (1984–1991) separated patients by histology into either a favorable (embry onal)
or unfavorable (alveolar, anaplastic, and monomorphous) histology. Results based on
subgroup are detailed in Table 11.7 . Several drug pairs (adriamy cin with imidazole
carboxamide [DTIC], actinomy cin D with VP-16, and actinomy cin D with DTIC) appear to
have been associated with gain in survival (11).
Table 11.7 Therapy and Outcomes According to Specific Patient Subgroups in IRS-III,
1984–1991 (1032 Patients)
IRS-IV (1991–1997) used the new staging sy stem to assign drug therapy. Patients with
group I paratesticular tumors and group I or II orbital tumors were treated with VA, and all
other nonmetastatic patients except those with preexisting renal abnormalities were
randomized to receive one of three chemotherapy regimens: VAC; vincristine, actinomy cin
D, and ifosfamide (VAI); or vincristine, ifosfamide, and etoposide (VIE) (12). Patients with
group III tumors were also randomized to receive conventional RT or hy perfractionated RT.
VAC, VAI, and VIE were equally effective, and overall the patients with embry onal tumors
who received three-drug therapy benefited in comparison to those in IRS-III, where just VA
was given. For patients with metastatic tumors, a pilot IRS study looked at the activity of
ifosfamide and doxorubicin in an up-front window and found a response rate of 63%
(complete and partial responses) (85). Subsequently, a full randomized IRS trial in 128
patients compared two up-front treatment windows, vincristine and melphalan (VM) and
ifosfamide and etoposide (IE), and later therapy consisted of VAC or VAC with the window
therapy included if the patient had an initial response (86). Initial response rates were
comparable (VM 74% vs. IE 79%), but 3-y ear failure-free survival (FFS) and overall
survival (OS) rates were superior in the patients who received the IE-containing regimen (FFS
33% vs. 19%, OS 55% vs. 27%).
Page 234IRS-V used a risk stratification schema very similar to the current sy stem
outlined above to assign patients to three risk groups (13). VA or VAC was used in a
nonrandomized fashion in the low-risk patients. VA was given to patients with tumors in
favorable sites with group I or group II disease, to patients with small, group I tumors in
unfavorable sites, and to all patients with orbital tumors (including group III). All other
patients meeting the low-risk criteria received VAC. All of the low-risk patients had
embry onal histology or one of its variants. For intermediate-risk patients, the gold standard
VAC therapy was compared in a randomized trial to VAC alternating with vincristine,
topotecan, and cy clophosphamide (VTC). This group included patients less than 10 y ears of
age with metastatic disease and embry onal histology. Previous studies in both untreated and
relapsed patients have shown topotecan to be a very active agent, particularly for patients
with alveolar histology. The results of this trial showed that there was no benefit to the addition
of topotecan (87). For high-risk patients with metastatic disease who have historically had
poor outcomes with standard VAC therapy, the combination of irinotecan and vincristine was
tested in an up-front window and then incorporated into subsequent therapy with VAC for
patients who responded (88). Irinotecan has demonstrated significant antitumor activity for
patients with both metastatic and relapsed RMS, though it is more active when given in
combination with vincristine than as a single agent (89,90,91).
The most recent clinical trial for intermediate-risk patients, ARST0531, compared
standard VAC with alternating cy cles of VAC and vincristine/irinotecan (VI) (92). The
preliminary report indicates that there is no difference in event-free survival between the two
arms. Given the significant reduction in cumulative alky lating exposure in the VAC/VI arm,
this has been recently adopted nationally as the best standard therapy for patients with
intermediate-risk disease.
The most recent low-risk trial (ARST0331) used VAC in a nonrandomized manner for all
patients (14). The cy clophosphamide dose was relatively low at 1.2 g/m 2 per cy cle. Four
cy cles were given initially with radiation administered at week 13 for patients with
microscopic, locoregional, or gross residual disease. Patients received an additional 4 or 12
courses of VA depending on which low-risk subset they were in. The goal was to increase
treatment efficacy by adding in a low cumulative dose of alky lating agent for the lowest-risk
patients while shortening the duration of treatment for these patients, and to decrease the risks
of both acute and long-term toxicities of treatment (in particular, infertility ) for the higher-risk
subset by decreasing the cumulative exposure to cy clophosphamide. This trial treated 271
low-risk patients. The 3-y ear FFS rate was 89% and the OS rate was 98%. Thus, shorter
duration of therapy did not appear to compromise outcome in these patients. Two recent high-
risk trials (ARST0431 and ARST08P1) have tested dose intensification of chemotherapy
delivered every 2 weeks instead of every 3 weeks in the small subset of patients with
metastatic disease, who continue to have a poor outcome despite the overall improvements in
survival made in nonmetastatic patients over the past few decades. ARST0431 used
alternating cy cles of vincristine, doxorubicin, cy clophosphamide with ifosfamide and
etoposide (93). This trial was based on intriguing results from the comparison of a single
institution trial to IRS-IV outcomes (94). The subsequent pilot study, ARST08P1, built on this,
using a similar intensive chemotherapy backbone, and then testing the addition of two newer
agents, temozolamide and cixutimumab, in separate arms. Final results from these trials are
not y et available.
The challenge remains to identify the drug combinations with the most favorable
therapeutic ratio when used in combination with the other modalities, and to develop
innovative therapies for the subset of patients who continue to fare poorly despite the
advances in therapy that have been made over the past few decades.
Radiation Therapy
The goal of RT today is to provide local and regional control, with or without surgery, in
conjunction with chemotherapy. The optimal multimodal strategy would coordinate RT with
these other therapies so as not to impair surgical healing or drug administration. Therefore,
major considerations would include the primary site of the tumor, the extent of surgery, the
interaction of RT with chemotherapeutic agents, and any emergent contingencies. An
analy sis of IRS-II data for group III patients underscores the difficulty that still exists in
obtaining local and regional control (95).
The responsiveness of RMS to RT was established in the 1940s and 1950s (96). Fifty to 65
Gy was thought to be necessary to achieve local control of the primary tumor regardless of
the nature of the surgical procedure. In the setting of postoperative microscopic residual
disease, these doses were demonstrated to achieve local control in 90% of cases
(84,97,98,99). Because RMS was known to extensively infiltrate tissues, large radiation
volumes initially were used, as was appropriate and standard for other soft tissue sarcomas.
As the efficacy of chemotherapy for micrometastatic disease became established and the
risk of normal tissue damage caused by combined-modality therapy was recognized,
investigators considered whether equivalent local control rates could be obtained with lower
radiation doses and volumes (98). Bey ond this, the need for any RT after wide local tumor
resection with negative margins was questioned. The IRS studies attempted to sy stematically
examine the issues of RT dosage and volume within the limits imposed by the many
chemotherapy questions that were also asked.
IRS-I patients in group I were randomized to receive postoperative RT or no RT, whereas
all other patients were irradiated (Table 11.5 ) (9). The dose was adjusted to the patient’s
age and ranged from 40 to 60 Gy. Daily fractions were 1.5–2 Gy, and RT was administered
immediately after surgery for group I patients and after 6 weeks of chemotherapy for groups
III and IV. At 5 y ears, approximately 80% of the patients in both group I study arms were
without evidence of disease. Overall survival for patients with group I RMS did not differ
significantly with RT. For this reason, RT was omitted for group I favorable histology cases for
IRS-II. In IRS-I, the dose given for local control was related to patient age and tumor size.
Dose response relationships were examined. A 32% local recurrence rate was seen after
doses less than 40 Gy and a 12% local recurrence rate was seen after doses greater than 40
Gy in the subgroup of children older than 6 y ears; however, this difference was not
statistically significant. IRS-I found no dose–response relationship when patients were
stratified solely by clinical group. The treatment volume was also analy zed for its impact on
local failure. Patients who received RT to less than the entire muscle bundle were compared
with those whose RT encompassed the entire bundle. In patients y ounger than 6 y ears, local
control rates were 84% versus 92%, respectively, and in older children rates were 91% versus
85%; however, these differences were not significant. RT to clinically uninvolved ly mph
nodes was not encouraged, whereas it was recommended for involved nodal regions. Local
control was better in genitourinary sites than in the extremity.
Page 235In IRS-II, the RT guidelines were modified based on IRS-I results (Table
11.6 ). Minimum tumor doses were 40 and 45 Gy for y ounger children (less than 6 y ears
of age) and older children, respectively, but tumors larger than 5 cm received 50–55 Gy
(100). Analy ses of local and regional failure have been performed for IRS-II, with local
failure defined as initial failure to achieve complete response or local relapse after an initial
response (10,95,100). Group I patients with an unfavorable alveolar histology had a
significantly higher frequency of locoregional recurrence than those with favorable histology.
Although the frequency of local failure was only 10% in group II, it was at 20% for group III
(excluding “special pelvic” sites) and 41% for group IV. When local relapse was analy zed as
a percentage of all relapses, it accounted for 46% of relapses in group I (despite “complete”
surgical removal of tumor) and 36%, 53%, and 20% of relapses in groups II, III, and IV,
respectively (10,95). Moreover, the local relapse rate was greater and survival rate inferior
for patients with unfavorable versus favorable histology (41% vs. 13%) and for lesions larger
than 5 cm versus smaller than 5 cm (34% vs. 23%). The predominant pattern of relapse for
group III tumors was locoregional (101). Those with ly mphatic involvement at diagnosis had
a significantly greater risk of relapse (101). The impact of radiation dose on local control was
suggested by an analy sis by Wharam et al. (49) for patients with nonparameningeal head and
neck tumors. An increased relapse rate occurred when a dose less than 40 Gy was delivered.
However, these data must be interpreted with caution, as this study was not randomized to
compare dose. Local control for all patients receiving more than 40 Gy was 93%.
In IRS-III, which accrued 1062 patients between 1984 and 1991, therapy was stratified
not only by clinical group but also by histology (with unfavorable ty pes comprising those with
alveolar, anaplastic, and monomorphous cells or patterns) and primary site (Table 11.7 )
(11). Postoperative RT was administered to all patients except those in group I with favorable
histology tumors and those in group III with special pelvic sites in complete pathologic
remission after primary chemotherapy. The RT dose for groups I and II patients was 41.4 Gy.
For patients with gross residual disease, the dose depended on patient age and tumor size: 41.4
Gy was given for children y ounger than 6 y ears with tumors smaller than 5 cm, 50.4 Gy was
given for children older than 6 y ears with tumors greater than or equal to 5 cm, and an
intermediate dose of 45 Gy was given for children who were either older or had larger
tumors, but not both. The overall survival at 5 y ears was 71%, superior to that in IRS-II (63%)
and IRS-I (55%) (11). An update of patients in group I with alveolar or undifferentiated
histology confirmed a benefit to the addition of RT for this cohort (102). For group III patients,
the rates were 73%, 65%, and 52%, respectively. Although local control rates of 90% were
achieved for patients in groups I and II, local recurrence in patients with group III disease
remained unacceptably high, as in IRS-II.
IRS-IV accrued 1011 patients between 1991 and 1997 and used the pretreatment TNM
staging sy stem to assign chemotherapy and the clinical grouping sy stem to assign
radiotherapy (12). Group II patients did especially well (Table 11.8 ). Because of the
unsatisfactory local control rates for patients with gross residual disease (group III) in IRS-II
and IRS-III and because of the normal tissue toxicities associated with radiation doses higher
than those used in the previous studies, hy perfractionated RT was tested in patients on IRS-IV
with group III disease (1.1 Gy twice daily to 59.4 Gy vs. 1.8 Gy daily to 50.4 Gy ) (103).
Although feasible, no advantage to hy perfractionation was demonstrated. There was no
difference in failure-free survival or overall survival between conventional RT and
hy perfractionated RT (by actual treatment received and when analy zed by age, gender,
tumor site, tumor invasiveness, ly mph node status, histologic features, stage, or tumor site
[Table 11.9] ).
Table 11.8 Outcome for Patient with Group II Tumors According to Histology, Primary
Site, and IRS Study
Table 11.9 Estimated Cumulative Incidence at 5 Years of Local, Regional, and Distant
Failure by Primary Site and Therapy for Patients Who Received Their Randomized
Therapy on IRS-IV
IRS-V looked prospectively at using lower doses of RT for patients with favorable
histology ; 36 Gy for patients with microscopic residual disease and no regional node
involvement, 45 Gy for patients with orbital tumors and gross residual disease, and 36–41.4
Gy for patients with superficial head and neck tumors, biliary tumors, and vulvar or uterine
tumors who undergo second-look surgery and have either negative margins or microscopic
residual tumor. All patients with alveolar group I tumors received 36 Gy to the primary site.
For intermediate-risk patients, IRS-V sought to determine the rate of local failure in patients
with gross residual tumor at diagnosis who, after second-look surgery, had response-adjusted
radiation dosage reduction (to 36 Gy for complete response and to 41.4 Gy for microscopic
residual). It also aimed to determine whether preoperative RT followed by second-look
surgery for patients with group III disease and poor response to induction chemotherapy was
feasible. Results of this study should be available soon.
The SIOP has taken a slightly different approach to the management of pediatric RMS.
They have investigated the omission or modification of local therapies based on response to
sy stemic therapy in attempt to decrease late toxicities (17,18,104). The SIOP MMT 89 trial
omitted RT or surgery for patients achieving a complete response to chemotherapy (104).
Overall survival and event-free survival were 71% and 57%, respectively. Local failure
represented the main cause of relapse. The salvage rate after local failure was high, but
prolonged follow-up is necessary to confirm durable disease control.
The most recent COG RMS trials, ARST0331 (closed in 2012) and ARST0531 (closed in
2014), enrolled patients with low-risk RMS and intermediate-risk RMS, respectively. These
trials required volume-based planning, but included the use of multiple radiation modalities
including photons, electrons, protons, and brachy therapy. Radiation was omitted only for
patients with group I favorable histology disease. Microscopic residual disease after surgery
was treated to a dose of 36 Gy and nodal disease was treated to 41.4 Gy. The dose for group
III orbital tumors was 45 Gy ; all other group III tumors receive 50.4 Gy. The gross tumor
volume (GTV) was defined as the prechemotherapy volume. A margin of 1 cm around the
GTV was recommended to define the clinical tumor volume (CTV). Nodal disease was also
included in the CTV. A volume reduction after 36 Gy was permitted for those patients
receiving 50.4 Gy who had had a substantial reduction in tumor size following sy stemic
treatment. The volume reduction was encouraged for noninvasive or “pushing” tumors, but
not for invasive tumors.
Page 237Three-y ear outcomes for ARST0331 were recently published showing a local
control rate of 92.4% for all patients (14). For patients with stage 1/2 group IIA tumors, the 3-
y ear local failure rate was 8.1% while those with group III orbital tumors had a local failure
rate of 11.5%. The isolated local failure rate was 6.7%. The 3-y ear outcomes for ARST0531
will be available in the near future. Enrollment of all patients on available protocols is
encouraged. Until the next-generation COG trials are open for enrollment, these parameters
will continue to provide the most useful guidelines for RT. However, recent reports indicating
higher than anticipated relapse rates for orbital RMS have prompted discussions regarding
higher doses for orbital RMS, particularly for patients that do not achieve a complete
response. In addition, tumor size greater than 5 cm predicts for increased local relapse and
dose higher than 50.4 Gy are being considered.
Figure:
Axial (A) and sagittal (B) images of a 10-month-old boy with a group III rhabdomyosarcoma
of the bladder/prostate. The tumor displaces the bowel and causes urinary obstruction
resulting in hydronephrosis.
Figure: Design and Results of IRS-I, 1972–
1978 (686 Patients)
Figure: Design and Results of IRS-II, 1978–
1984 (1003 Patients)
Figure: Therapy and Outcomes According to
Specific Patient Subgroups in IRS-III, 1984–
1991 (1032 Patients)
Figure: Outcome for Patient with Group II
Tumors According to Histology, Primary
Site, and IRS Study
Figure: Estimated Cumulative Incidence at 5
Years of Local, Regional, and Distant Failure
by Primary Site and Therapy for Patients
Who Received Their Randomized Therapy
on IRS-IV
SPECIFIC SITES
Bladder and Prostate Rhabdomyosarcoma

Bladder and prostate RMS combined represent approximately one half of genitourinary RMS
(10). The predilection of bladder RMS for males and the bladder trigone often make it
impossible to determine the origin of these tumors, and therefore these sites are generally
considered together (105,106). It is important to note that when the site of origin can be
determined, most data indicate a more favorable prognosis for bladder RMS (107,108). RMS
of this location tends to occur in very y oung children; most are under the age of 5 y ears at the
time of diagnosis. Urinary abnormalities, including dy suria, poly uria, incontinence, and in
particular urinary retention, are early signs. The first radiographic evaluation is ty pically
ultrasound. Thin cut CT scan and/or MRI of the abdomen and pelvis provide greater detail
allowing for evaluation of the primary mass and retroperitoneal ly mphatics while providing a
reliable study to assess response to chemotherapy and/or radiation. Figure 11.5 shows a
large RMS of the bladder or prostate (site of origin could not be determined radiographically )
in an infant. PET/CT may provide a useful diagnostic tool for evaluation of ly mphatics and is
being evaluated for its role in this disease (109). CT of the chest should also be performed as a
part of the metastatic workup. Endoscopic biopsy via cy stoscopy may allow for diagnosis. If
adequate tissue cannot be obtained by this method, open biopsy should be performed (110). If
urinary obstruction is present at diagnosis, initial management also includes urinary stent
placement or urinary diversion to protect renal function. Approximately 80% of tumors in
modern series have favorable histology, embry onal or botry oid ty pe. Regional ly mph node
involvement for this site is not uncommon, particularly when tumors arise from the prostate,
and documented in the range of 20–30% (50,65). The hy pogastric or external iliac nodes are
most commonly involved, although spread to lumboaortic nodes may occur, even in isolation.
Only 15% have demonstrable sy stemic metastases at diagnosis (111).
The therapeutic approach for RMS of the bladder and prostate has progressed over time
as documented in North American and European studies. High survival rates have been
achieved for decades but, sadly, these survivors have suffered considerable treatment-related
morbidity. Management has evolved from pelvic exenteration to less aggressive organ
preserving therapy while maintaining high survival rates. At present, the goal of
multimodality therapy for these children is a cure with preservation of bladder function.
Therefore, upfront radical surgical procedures are no longer performed. If the tumor cannot
be removed completely with preservation of bladder and urethral function, definitive surgery
is delay ed in attempt to achieve a response with chemotherapy +/− RT that will allow for an
organ preserving surgical procedure.
IRS-I (1972–1977) enrolled 64 patients with primary RMS of the bladder or prostate.
During the first y ears of this protocol, pelvic exenteration, most often anterior exenteration,
was the initial treatment for most patients followed by chemotherapy with or without
radiation (111). This treatment resulted in high rates of disease control and survival, but the
morbidity of surgery led to an effort to find a combination of therapy that might allow for
organ preservation. In the later y ears of this study, many participating institutions adopted
more limited surgery in attempt to preserve organ function. Partial cy stectomy, if complete,
resulted in excellent rates of disease control (112). Despite a high rate of complete responses,
primary chemotherapy and RT, without surgery, resulted in a higher rate of disease
recurrence. These patients did not undergo a second-look operation and chemotherapy was
less intense than delivered in other series of this time period that evaluated primary
chemoradiation for this disease (113). Pelvic exenteration provided salvage for many of
these patients. The bladder preservation rate for IRS-I was 23%. Ly mph node dissection and
adjuvant RT for patients with involved ly mph nodes did provide a benefit (65,114).
IRS-II (1978–1984) adopted a strategy using more vigorous primary chemotherapy with
the intention of using minimal surgery to remove residual tumor and avoiding the morbidity
of pelvic irradiation. RT was added in the setting of residual (postsurgical) disease or if an
exenterative procedure would be needed. Almost all patients eventually needed RT, surgery,
or both to achieve a complete remission. Although the 3-y ear survival for these patients
(71%) was similar to that in IRS-I (75%), the 3-y ear disease-free survival rate was
significantly lower (52% vs. 70%). Although the bladder preservation rate was initially high in
IRS-II (97%), the percentage of patients who retained their bladders and were alive at 3
y ears was disappointing at only 22%, comparable to 23% in IRS-I (112,115). Low doses of
radiation (2500 cGy ) utilized in certain cases prior to 1980 and delay of irradiation to week 16
may have decreased the likelihood of local control.
IRS-III (1984–1991) investigators approached the problem of prostate and bladder
tumors with a view of what appeared to limit successful bladder preservation in IRS-I and
IRS-II; therefore, RT was routinely administered to all patients at week 6 after induction
chemotherapy (intensified compared with IRS-I and IRS-II), except those in whom complete
tumor removal was possible without total cy stectomy. Surgery was then performed to
document a complete response or to excise residual tumor while attempting to maintain
bladder function. The results of IRS-III have been gratify ing: the bladder retention rate at 4
y ears was 60% and survival was 90% for patients presenting with local or regional disease.
An analy sis of the 28 group III patients by Hey n et al. showed that 15 (54%) ultimately
retained their bladders. Induction chemoradiotherapy induced a complete loss of tumor cells
in 46%; in cy stectomy specimens tumor cellularity was reduced, and tumor cell maturation
occurred. Of interest is that cellular maturation was greater in tumor specimens of patients
who retained their bladders and two patients with maturing cells did not experience
recurrence (116,117). Subsequent studies have also reported mature cells or rhabdomy oblasts
and suggest that this finding following therapy may represent a response (117). However, the
finding should be viewed with caution and reviewed by an expert pathologist. While radical
surgery is not indicated for this finding alone, close follow-up is prudent as recurrences have
been documented (117,118).
Page 238IRS-IV (1993–1997) enrolled 90 patients with nonmetastatic bladder/prostate
RMS (119). The recommended treatment regimen continued efforts to maintain bladder
function while achieving cure. All patients received alky lating based chemotherapy. Seventy -
four patients received RT. Fifty -three patients had at least one second-look procedure, most
after RT. At a mean follow-up of 6 y ears, overall survival was 82%, failure-free survival was
77%, and bladder preservation was close to 70%. IRS-IV attempted to formally evaluate
bladder function through patient questionnaires. Only 40% of all patients on IRS-IV had
normal bladder function. Although overall survival remained high with treatment on IRS-IV,
there is still room to improve functional outcome. In addition, urody namic studies can provide
a more accurate and objective way to evaluate bladder function and should be obtained for
patients with bladder/prostate RMS undergoing treatment with bladder preservation. IRS-IV
also evaluated hy perfractionated RT, but found no benefit (103).
Three-dimensional treatment planning is preferred for better visualization and
delineation of target volumes and normal structures. MRI may be of benefit for better
delineation of soft tissues while CT provides better visualization of growth plates. MRI–CT
fusion may be useful. For patients with large tumors displacing bowel, GTV is defined as the
preoperative tumor volume excluding the debulked portion of tumor and accounting for
shifting of structures. Critical structures in this region that should be considered include
bladder, rectum, bowel, pelvic and femoral head growth plates, penile bulb, and testes.
Although four-field techniques may be used, AP/PA or slightly oblique anterior or posterior
fields provide the benefit of shielding femoral head growth plates. IMRT may be of benefit
for some cases, but care should be taken in designing field arrangement to avoid exposure of
tissues that could be spared completely. Growth plates in these y oung children are sensitive to
low doses of radiation (10–20 Gy ) and second malignancies are a concern. Protons may
provide benefit for some cases (Fig. 11.6 ) and dosimetric comparisons show a consistent
ability of protons to reduce the dose to the gonads and bone growth plates in these cases (120).
Figure 11.6 Axial (A), sagittal (B), and coronal (C) images of a proton radiation plan for a
young child receiving radiation for microscopic disease following chemotherapy and surgical
resection. D: Bladder–prostate dose–volume histogram displaying growth plates and clinical
tumor volume. Additional structures contoured but not shown include bladder, bowel,
rectum, penile bulb, and penile shaft. Prescription dose 36 Gy (RBE) to CTV. Femoral head
growth plates receive a maximum dose of <3 Gy (RBE); pelvic growth plates receive dose in
a range of 6–20 Gy (RBE).
Paratesticular
Paratesticular RMS is less common than bladder/prostate RMS, accounting for approximately
one-third of GU RMS and 7% of all RMS (121,122). Intrascrotal paratesticular RMS usually
arises in the distal area of the spermatic cord and may invade the testis or surrounding tissues,
although primary RMS of the epididy mis or tunics can also occur (79,121). Patients generally
present with a painless scrotal mass. Scrotal ultrasound is generally the first diagnostic test that
confirms a mass in the scrotum that does not illuminate. Biopsy should not be performed and
the scrotum should not be violated. An orchiectomy is performed through an inguinal incision,
with a high ligation of the spermatic cord at the level of the inguinal ring. Paratesticular RMS
has a relatively high rate of spread to the ly mphatics, first to the para-aortic nodes, following
the course of the spermatic cord into the renal hilar retroperitoneal space. Histologically,
nearly all paratesticular RMS are of the embry onal subty pe (122). Thin slice CT scan of the
abdomen and pelvis is recommended to evaluate ly mphatics.
IRS-I and IRS-II (1973–1983) enrolled 150 patients with paratesticular RMS (122). The
majority had group I disease (n = 57) and only 14 had metastatic disease. Ninety -seven
percent had embry onal histologic subty pe. Patients with group I disease were significantly
y ounger. The 3-y ear overall survival rates by group were 98%, 90%, and 64% for group I,
group II, and group IV, respectively. There were only four group III patients. Considering the
relatively high risk of nodal involvement, surgical evaluation of ly mph nodes was performed
for most patients. Eighty -one percent of patients underwent exploratory laparotomy and
inspection and/or pathologic examination of retroperitoneal ly mph nodes; 67% of patients
underwent retroperitoneal ly mph node dissection (RPLND). Radiation therapy was delivered
to patients with group II and group III disease, while six group I patients received radiation.
Doses and volumes varied (hemiscrotum for scrotal violation, 19/20 patients with involved
RPLN received nodal RT). The results revealed the excellent prognosis for this subset of
patients, confirmed that unilateral RPLND was adequate and bilateral RPLND was not
necessary, and also indicated age as an important prognostic factor. In the most recent COG
ARST0331 study, EFS and OS for paratesticular RMS were 93% and 99%, respectively,
maintaining a similar strategy but with lower cy clophosphamide dosing to improve fertility
preservation (14).
One topic of substantial controversy over the past several y ears has been the necessity
of surgical evaluation of RPLN. IRS-III (1984–1991) required ipsilateral RPLND for all
patients, but IRS-IV (1991–1997) examined the use of CT scan of the abdomen and pelvis for
evaluation of ly mphatics in lieu of RPLND (123). The use of CT for staging led to a
significant change in the distribution of patients with group I and group II disease in these
trials. Sixty -eight percent of patients enrolled on IRS-III had group I disease versus 81% on
IRS-IV. This was a result of CT scan failing to detect ly mphatic involvement. As a result,
failure-free survival for patients with group I disease was inferior on IRS-IV, 81% at 3 y ears.
Failure-free survival was 96% on IRS-III. IRS-IV as well as the Italian and German
Cooperative Group discovered the high risk of nodal involvement for children over the age of
10 y ears (123,124). The IRS concluded that children over 10 y ears of age experienced a
superior failure-free survival (100%) on IRS-III compared to IRS-IV (68%) due to
recognized group II disease, likely as a result of receiving intensified chemotherapy and
RPLN radiation. In contrast, the Italian and German Cooperative Group performed RPLND
following negative CT scan and found only one patient to have positive ly mph nodes; 13 of
these patients were older than 10 y ears of age (124).
Page 239CT has been used to detect gross nodal involvement but may fail to
demonstrate microscopic infiltration in some patients. Consequently, it has been the practice
in the United States to perform a unilateral (trans-abdominal) nerve-sparing retroperitoneal
ly mph node dissection. Twenty -six percent of patients in IRS-I and IRS-II had retroperitoneal
ly mph node involvement at diagnosis, and 16% had positive ipsilateral inguinal nodes; contra-
lateral nodal involvement is rare (50,65). A similar percentage of patients in IRS-III had nodal
disease (125). Patients with group II disease on the basis of positive nodes receive RT to the
nodal areas in the IRS studies, in contrast to patients with negative ly mph node dissections.
Currently, on the open COG trials, ipsilateral RPLND is required for males diagnosed
with paratesticular RMS over the age of 10 y ears and any patient with suspicious ly mph
nodes by CT scan. Potential complications of RPLND include bowel, obstruction,
ly mphedema, and nerve damage (126). Nerve sparing techniques should be utilized for
RPLND. Laparoscopic RPLND has been explored as a minimally invasive technique to
evaluate ly mph nodes for paratesticular RMS and is the preferred surgical approach at some
institutions (127). If a trans-scrotal biopsy is performed instead of the inguinal approach, then
the patient is considered to have group II disease. Resection of the violated scrotal tissue is
recommended and radiation and/or hemiscrotectomy should be considered (51). The contra-
lateral testicle can be transposed laterally into the thigh before irradiation and later
reimplanted into the scrotum. The Italian and German Cooperative Group reported no local
relapses for 24 patients initially managed with trans-scrotal biopsy who were downstaged to
group I with re-excision (124). These patients received only chemotherapy, suggesting that
chemotherapy was sufficient to eradicate this microscopic disease.
Page 240The most common use of RT for paratesticular RMS is for nodal disease. All
patients with nodal disease should receive RT regardless of response. Currently on the COG
studies, gross nodal disease present after surgery receives a dose of 50.4 Gy. This may be
reduced to 41.4 Gy for microscopic disease if there is pathologic confirmation of tumor
response. Ly mph nodes follow the vessels and are generally present within 2 cm of the
vessels. Vessels and any involved ly mph nodes should be contoured. Anterior and posterior
opposed fields are generally used. Structures that are at risk in close proximity include bowel,
kidney s, bladder, and bony structures.
Vagina and Vulva

RMS of the vagina and vulva is rare accounting for 3% of pediatric RMS, the majority of
these occurring in the vagina (11,128). Vaginal RMS occurs in very y oung children (90%
y ounger than 5 y ears of age; mean age for vaginal primaries under 2 y ears (129). Presenting
sy mptoms include vaginal bleeding, vaginal discharge, and a protruding vaginal mass.
Vaginal tumors most commonly arise from the anterior wall, are often multicentric, and can
invade the vesicovaginal septum or bladder wall. Regional nodal involvement is uncommon.
Vaginal tumors are almost exclusively the embry onal (usually botry oid) subty pe (129).
Vulvar RMS is encountered even less frequently. Age range is more variable and the mean
age of girls with vulvar tumors is 8 y ears (129). Vulvar inflammation and genital bleeding are
the most common presenting signs. On clinical examination, vulvar RMS is most commonly
found as a firm nodule embedded in the labial folds or in a periclitoric location. Vulvar tumors
may be initially mistaken as an infected Bartholin gland. It is important that all members of
the pediatric oncology team examine the child at the time of diagnosis of a vaginal or vulvar
RMS. For the radiation oncologist, this evaluation is crucial for treatment planning as tumors
will likely respond rapidly to chemotherapy and imaging may not provide all details needed.
MRI and/or CT of the pelvis should be performed at diagnosis and during treatment to
evaluate local disease and response. Vulvar RMS may be of any histologic subty pe, and the
alveolar subty pe is often seen.
The classical surgical technique for treatment of vaginal tumors was an anterior
exenteration with urinary diversion. Surgeries considered less aggressive included
vaginectomy with or without hy sterectomy. Unfortunately, fewer than 20% of patients could
be cured with surgery alone (130). Survival rates improved to 60–80% when chemotherapy
was added to surgery, with or without RT. IRS-I (1972–1978) included nine patients with
vaginal primaries, eight without metastatic disease (9,131). Six underwent surgery upfront
(pelvic exenteration, vaginectomy, or hy sterectomy ) and two underwent delay ed
vaginectomy or hy sterectomy. All patients received chemotherapy and three patients
received radiation. There were high rates of disease-free and overall survival, but surgical
morbidity was great. The favorable outcome and chemosensitivity of these tumors was
recognized. The major goal of IRS-II (1978–1984) was to maintain outcomes while allowing
for organ preservation (115). This study adopted a strategy that included biopsy followed by
chemotherapy and organ preserving second-look surgery at week 8 or 16, depending on the
response. The use of RT depended on the completeness of the surgical procedure. Surgical
resection was performed with the goal of removing all residual disease with minimal
morbidity. Using this treatment approach, 18 of 21 (86%) patients survived at 3 y ears (115).
IRS-III (1984–1988) gave 20 weeks of chemotherapy and then RT to patients who had not
achieved a complete remission by that time. Patients with residual disease underwent surgical
resection, most with no pathologic evidence of tumor or only rhabdomy oblasts (131). IRS-IV
gave RT at week 9, and the cure rate remained high and only 13% of patients underwent
surgical resection more extensive than local excision or biopsy (131,132). For female genital
tract RMS, the rate of hy sterectomy decreased (48% in IRS-I/II to 22% in IRS-III/IV) and
the use of RT for unresectable tumors increased (23% IRS-II to 45% IRS-IV) (132). Survival
rates have remained with better preservation of organ function. For patients that do recur,
locoregional failure predominates. It is possible that introducing local therapy at an earlier
time point may be of benefit, but chemotherapy as the initial treatment modality has
provided superior functional outcomes and high tumor control rates and will remain standard
for unresectable disease (132). Salvage rates for patients who experience local failure is
higher for female GU sites than for other RMS locations (132). However, longer follow-up is
necessary as late relapses may occur. Current guidelines on COG trials are similar; limited
surgery is preferred, and radical surgery is inappropriate except in the setting of persistent or
recurrent disease. Surgery is currently performed if feasible as a second-look procedure at
week 13. Tumors that are not resectable receive radiation at this time. For those that can be
resected, radiation dose is based on margin status. Distal vaginal tumors may not require
hy sterectomy. Proximal lesions may require hy sterectomy with partial or total vaginectomy.
Irradiation with brachy therapy may also be considered for these patients. On ART0331 and
D9602, no radiation was given for patients who had a complete response to chemotherapy
and negative biopsies following chemotherapy. Walterhouse et al. (133) published a combined
analy sis of these trials showing unacceptably high local relapse rates for children with vaginal
primaries treated with reduced cy clophosphamide and no RT after a complete response to
chemotherapy (2-y ear-FFS 42% on ART0331 and 5-y ear-FFS 70% on D9602). Salvage rates
were high and OS still excellent, but ART0331 was amended to include RT for group II and
group III vaginal RMS. Vaginal and vulvar RMS represent a site that may benefit from
brachy therapy. The Institut Gustave Roussy has extensive experience with this technique and
they prefer brachy therapy to external beam radiation when feasible (134). Endocavitary
brachy therapy was used for vaginal primaries utilizing a customized mold, while interstitial
was preferred for vulvar RMS. Prescription dose was 60–65 Gy delivered in one to three
applications. They reported excellent local control for 39 females treated with excellent
sparing of surrounding critical structures and low rates of toxicity. Figure 11.7
demonstrates an endocavitary brachy therapy plan for a 3-y ear-old girl with a vaginal RMS.
Page 241
Figure 11.7 Depicts a brachytherapy plan for a vaginal rhabdomyosarcoma. This 3-year-
old girl relapsed after chemotherapy alone. Prescription dose delivered was 60 Gy. A: Axial
CT treatment planning image showing percent isodose prescription lines. This plan
demonstrates rapid fall off allowing for sparing of the pelvic growth and femoral growth
plates as well. B: A multiplanar view. C, D: Sagittal DRRs with and overlay of treatment
volumes, normal structures, isodose lines. (Courtesy of Christine Haie-Mader, MD.)
For treatment planning (external beam or brachy therapy ), CT planning should be

utilized. Critical structures to consider include uterus, ovaries, rectum, bladder, bowel, and
bony structures. Ovarian transposition may be necessary to avoid dose to the ovaries as they
can be affected by doses as low as 2 Gy (135). Vaginal stenosis and fistulas are other
potential side effects of treatment.
Uterus and Cervix

Uterine and cervical RMS is less common than vaginal RMS. They occur predominantly in
adolescent girls near puberty with a mean age of 13 (129). Patients may present with a
pedunculated poly p protruding from the cervix or with diffuse intramural involvement of the
uterus and/or cervix and even invasion of adjacent organs; bleeding is common
(129,136,137). When uterine tumors occur in y ounger children, distinction from a vaginal
tumor may be difficult. The predilection of uterine and cervix tumors for adolescents and of
vaginal tumors for the very y oung helps to predict the site of origin, but anatomical
determination is often possible only after regression of the tumor after chemotherapy.
Tumors of this location are generally of the embry onal histology, most often botry oid
subty pe.
In IRS-I and IRS-II, 10 patients had uterine or cervical primaries. In patients who
presented with localized poly poid tumors, poly pectomy and adjuvant chemotherapy was
highly curative (129). When hy sterectomy or vaginectomy successfully removed all gross
tumor, cure was also achieved. Conversely, all patients with infiltrative or metastatic RMS
died of disease within 11 months of diagnosis (129). Brand et al. (137) reviewed 21 cases of
botry oid sarcoma of the uterine cervix. Most patients received chemotherapy, and eight
underwent pelvic irradiation. Eighty percent of these patients survived.
Currently, treatment of uterine and cervical RMS is intended to preserve pelvic organs
when possible. Patients with initially resectable disease are placed in group I or II by surgery,
followed by chemotherapy, and then RT if microscopic residual disease is proven to persist,
or hy sterectomy with no RT. For those with group III disease, primary chemotherapy is
given, followed by a second-look laparotomy. If there is gross residual tumor that cannot be
completely resected with hy sterectomy, or if microscopic disease is found after resection,
the patient then receives RT and continues on chemotherapy. If the second-look exploration
shows no demonstrable tumor or tumor that is completely resected, then no radiotherapy is
given, and the patient continues on chemotherapy alone. Survival rates for nonmetastatic
uterine and cervix RMS should approximate those of patients with RMS of the vagina and
vulva, but response to chemotherapy may be less (132).
Page 242The SIOP approaches tumors of the female genital tract with initial
chemotherapy and local therapy only for those patients with tumors that do not completely
respond to chemotherapy, regardless of initial tumor characteristics (138). They reported 5-
y ear overall survival of 91% and event-free survival of 78% at 5 y ears for 38 females with
RMS of the vulva, vagina, and uterus treated in this manner (138).
Extremity
Extremity RMS comprises approximately 20% of pediatric RMS. Despite intensification of
therapy, tumors of this location continue to have a poor prognosis compared to other sites.
Overall survival rates have improved from 47% in IRS-I to just over 70% at 3 y ears in IRS-
III and IRS-IV, but relapses requiring salvage treatment remain high (FFS at 3 y ears in IRS-
IV was only 55%). The prognosis for patients with extremity RMS is compromised by the
high frequency of the alveolar subty pe, of ly mphatic metastasis at diagnosis, and of
metastasis to any site at diagnosis (27% vs. 18% in all patients with RMS) (139).
Approximately 50–70% of these lesions are alveolar RMS, an unfavorable histology (82).
Regional ly mph node involvement occurred in 17% and 12% of patients in IRS-I and IRS-II,
respectively (50,65).
Although there is no evidence that amputation is more often curative than wide local
excision, this procedure retains a role in patients where limited excision and high-dose
irradiation would produce unacceptable functional results, in patients with distal (alveolar)
extremity lesions where gross removal is otherwise impossible, and in patients with massive
local recurrences after conservative therapy (82,140). Outside of these situations, the
preferred operative procedure for primary management is wide excision with negative
margins. Another strategy in extremity tumors is delay ed primary excision (DPE). Surgical
biopsy is done initially and resection is delay ed until after induction chemotherapy with the
aim of avoiding amputation or functional deficits and potentially reducing the radiation dose
or avoiding it altogether. DPE was explored on the COG D9803 study and the local failure
rate for 31 patients undergoing DPE was 7% (64). It should be noted that 28 patients (90%)
still required radiation, though all received reduced doses of 36 Gy or 41 Gy rather than 50.4
Gy. Currently, radiation still remains a critical component in the treatment of extremity RMS
as a pooled analy sis of four international cooperative groups showed that local failure
occurred more often in patients who did not receive initial irradiation (31% vs. 22% in those
receiving RT as part of primary treatment, P = 0.02) (141).
Efforts to improve detection of involved ly mph nodes in hopes of appropriately
identify ing patients that will benefit from intensified chemotherapy and nodal radiation has
been a goal of recent research efforts. Clinical examination, MRI, and CT scan can identify
involved ly mphatics, but small amounts of nodal disease may go unnoticed with these
techniques. On IRS-IV, 76 of 139 patients underwent surgical evaluation of regional ly mph
nodes. Fifty percent of these patients were found to have ly mphatic involvement. Of those
patients that had clinically negative ly mph nodes, but underwent ly mph node sampling, 17%
had microscopic ly mph node involvement. PET and PET/CT have been explored in small
studies for its use in RMS and specifically extremity RMS (142). The recent COG RMS
studies are try ing to evaluate its utility on a larger scale. Sentinel ly mph node biopsy is now
routinely used for breast cancer and melanoma. Although the experience for pediatric RMS
is limited, its use should be explored further as it may prove an accurate method of
identify ing microscopic nodal involvement with less morbidity than ly mph node sampling or
full dissection (143). Current COG guidelines require sy stematic ly mph node sampling for
extremity tumors.
Chemotherapy is alway s given a
component of therapy for extremity RMS. RT is
omitted only for patients with completely
resected favorable histology tumors with
negative nodes. The tumor was treated with a
1.5-cm margin on the recent COG protocols (but
discretion should be used to avoid
circumferential irradiation and irradiation of the
joint space). Regional ly mph nodes are treated
only when involved. A strip of soft tissue along
the extremity should be spared to avoid Figure 11.8 Axial image of a 3D-
ly mphedema. Three-dimensional conformal RT conformal photon plan for a lower
using opposed fields (AP/PA or obliques) extremity sarcoma. Note that a strip of
generally results in optimal dose distribution. soft tissue is completely spared in an
Figure 11.8 demonstrates a three-dimensional effort to avoid lymphedema. (Courtesy of
conformal radiation plan for an extremity RMS Karen Marcus, MD.)
using opposed oblique fields.
Parameningeal
Parameningeal (PM) RMS accounts for approximately 15% of pediatric RMS and 40–50% of
head and neck RMS (11). They arise in sites adjacent to the meninges, as the name implies,
and have the potential to extend into the brain and spread through the CSF. The four main
subsites of PM RMS include the middle ear, nasal cavity /paranasal sinuses, nasophary nx, and
infratemporal fossa/ptery gopalatine fossa/paraphary ngeal area. Middle ear tumors originate
medially to the ty mpanic membrane. They may extend anteriorly and laterally and present
as a palpable mass in the region of the parotid, break through the ty mpanic membrane into
the external ear canal, or spread through the posterior mastoid to the posterior cranial fossa.
The three paranasal sinuses include the ethmoid, maxillary, and sphenoid sinuses. They
surround the nasal cavity and the true site of origin is often difficult to determine. These
tumors can invade the orbit or extend through the basal of skull in the region of the cavernous
sinus to the temporal lobes or through the cribiform plate to the frontal lobes. The
nasophary nx is located superiorly to the phary nx and is bounded by the nasal septum/nasal
cavity, sphenoid sinus, phary ngeal walls, and soft palate. Invasion of the base of the skull is not
infrequent and may involve the cavernous sinus causing cranial nerve palsies. Although
ly mph node involvement can occur, modern series report fewer than 20% of PM RMS as
having positive ly mph nodes (50,144). Approximately 80% of these tumors are of embry onal
histology ; the remaining 20% are alveolar. Meningeal penetration and leptomeningeal tumor
cell seeding should be assessed in patients diagnosed with PM RMS. Because PM RMS can
invade locations such as the orbit and parotid gland, it is sometime unclear if the site of origin
is truly PM. When this distinction is not clear, the tumor should be considered PM as this
dictates more aggressive therapy and invasion from more favorable sites into the sinuses,
middle ear, or paraphary ngeal space is less likely.
Page 243Complete surgical resection of the primary with a satisfactory cosmetic and
functional outcome is rarely possible; the vast majority of patients with PM RMS have group
III or group IV disease. The role of surgery is generally confined to establishing a diagnosis
with a biopsy or a subtotal excision. Cervical ly mph node dissection (radical neck dissection)
is rarely appropriate because of the associated morbidity and the low frequency of
subclinical nodal involvement; conversely, suspicious nodes should be surgically evaluated.
Before the use of chemotherapy, fewer than 20% of patients survived despite aggressive
surgery and radiation (84). For patients with PM RMS, the volume and timing of RT are
critical. The radiation volumes for PM tumors have been modified over the y ears as a result
of the lessons learned through the IRS studies (145).
IRS-I (1972–1977) enrolled 57 patients with PM RMS (146). Thirty -five percent had
evidence of meningeal involvement within 12 months of diagnosis. This was almost
universally fatal, as 90% of these patients died of their disease. RT on this protocol was
delivered to the tumor plus a 2-cm margin at week 6. Poor outcomes led to a revision of the
IRS-I protocol in 1977 near its conclusion and helped form guidelines for IRS-II. Patients
considered at high risk of meningeal dissemination defined as those with intracranial
extension, cranial nerve palsy, skull base erosion, or positive CSF received whole brain or
craniospinal radiation (69). Intrathecal chemotherapy with three agents was also advised.
Additionally, the timing of RT was changed with whole brain RT delivered week 0 and spinal
RT at week 6. After the conclusion of IRS-II, patients treated with intensive chemotherapy
and craniospinal radiation were compared to those treated with less intensive therapy and
without spinal irradiation (145). The risk of meningeal dissemination did not differ and
radiation to the spine was not advised on IRS-III (69).
In IRS-III, if there was no evidence of intracranial extension, CSF cy tology was
negative, and bone erosion or cranial nerve palsies were absent, then the primary lesion was
irradiated with a 5-cm margin, including treatment of the adjacent meninges. Patients not
meeting these criteria received intrathecal chemotherapy. If the CT or MRI demonstrated in-
continuity intracranial extension of the primary tumor, but the CSF cy tology was negative,
prophy lactic whole brain RT without spinal RT was given along with treatment to the primary
tumor. Finally, for positive CSF cy tology, craniospinal irradiation was given. Results are as
follows: 69% 5-y ear progression-free survival, 15% local failure for group III patients, and a
4.7% incidence of contiguous CNS relapse (52,147). IRS-IV reduced the radiation margin to 2
cm, and only patients with diffuse intracranial meningeal extension or multiple sites of brain
parenchy mal disease were treated to the entire cranial cavity (147). RT was given at the
beginning of the treatment course when there was clear evidence of intracranial extension,
defined as positive CSF cy tology results or any imaging evidence (by MRI) that tumor
touches, displaces, invades, distorts, or otherwise causes a signal abnormality of the dura.
Otherwise, chemotherapy was given first, with RT given at week 12. RT was omitted only for
patients with completely resected, favorable histology tumors with negative nodes.
Intrathecal chemotherapy and craniospinal irradiation were no longer used. The extent of
surgery was determined by the potential cosmetic and functional outcome, and second-look
procedures were allowed (148). IRS-V adopted the same guidelines for radiation. A review of
radiation timing for high-risk parameningeal patients with intracranial extension was carried
out comparing children from IRS-IV where intracranial extension mandated radiation at day
0 with children from IRS-V where radiation was given at week 12 (excluding those with
cranial nerve palsy or cranial base bony erosion) (149). Local control for all parameningeal
patients was 19% in both studies. Timing of RT did not affect outcomes for those with
intracranial extension (LF 21% vs. 15% p = 0.27) and therefore early irradiation is no longer
recommended for these patients.
For all of the above IRS studies, the prechemotherapy volume has been used to define
the GTV. There has been interest in evaluating a lower dose of radiation to the
prechemotherapy volume and then coning down to the postchemotherapy volume in attempt
to decrease toxicity. The underly ing principle supporting this theory is that areas of disease no
longer seen radiographically represents microscopic disease and thus should be controlled
with a dose of radiation for microscopic disease (36 Gy ). At the University of Pennsy lvania,
it has been their practice since 1992 to cone down to the postchemotherapy volume. They
reported favorable results for patients treated in this manner (150). ARST0531 defined the
CTV as the GTV plus 1 cm and continued to define the tumor volume as the
prechemotherapy volume, but allowed for a cone down to the postchemotherapy volume
after 36 Gy. All radiation started at week 4 to allow time for more complex planning and CT
planning is required. Figure 11.9 demonstrates target volume decrease following 36 Gy
for a patient with a parameningeal tumor and a good response to chemotherapy.
Figure 11.9 High-definition volume rendering. Treatment volumes for parameningeal
rhabdomyosarcoma. Recommendations on the current COG protocols are for treatment of
the prechemotherapy tumor volume (GTV) plus 1 cm to form the CTV. A: Although all IRS and
the current COG studies recommend the use of the prechemotherapy volume,
postchemotherapy volumes with a margin of 1 cm may be used for a cone down (although
not encouraged for invasive tumors) and have been explored in institutional studies as well as
European studies. B: The postchemotherapy volume plus 1 cm (after 4 weeks of
chemotherapy). Red, CTV; dark blue, parotid glands; cyan, optic nerves; green, cochlea;
yellow, hypothalamus and pituitary. (Courtesy of Fovia, Inc., and Justin Lee.)
There is often reluctance to adhere to radiation guidelines for very y oung children. The
SIOP demonstrated the significant value of RT for these patients (144). RT should not be
omitted, and the COG encourages adherence to RT guidelines even for patients less than 24
months of age (120). In all cases, the radiation oncologist should be involved at diagnosis to
allow for evaluation of tumor prior to chemotherapy and to allow adequate time for
treatment planning. Advanced techniques including IMRT and proton radiation can provide
improved sparing of normal tissues in this complex site (151). The Massachusetts General
Hospital has recently published its results for 57 pediatric rhabdomy osarcoma patients, the
most common site was parameningeal (n = 27), treated with proton therapy on a prospective
trial control (5-y ear OS and LC of 78% and 81%, respectively ) was found to be comparable
to the literature and very low rates of toxicity (120). Figure 11.10 shows a proton plan for
a 5-y ear-old boy with a PM RMS of the left infratemporal fossa.
Figure 11.10 Coronal (A) and axial (B) images for a proton plan for treatment for a
parameningeal rhabdomyosarcoma. C: Dose–volume histogram for proton plan for
parameningeal rhabdomyosarcoma. Advanced planning techniques are particularly useful for
sparing normal tissues in this region.
Page 244Orbit
Orbital RMS comprises approximately 10% of pediatric RMS (21). Because of the
accessibility of the orbit to examination and the sensitivity of ocular function to mass effect,
orbital RMS often is diagnosed early. Ey elid swelling and globe displacement are common
presenting signs. Orbital exenteration was the standard treatment until the mid-1960s, but local
disease control was rarely achieved. In the late 1960s, Cassady and coworkers observed that
RT afforded local control in five of five patients after a biopsy (7,152). RT has now assumed a
major role in the treatment of orbital RMS. Approximately two-thirds of orbital RMS are
group III. Treatment generally consists of biopsy, chemotherapy, and RT. The volume need
not include the entire orbit if the tumor is small. In the IRS study, local control has been 94%
with RT and is increased to 98% with surgical salvage (99). Of note, orbital RMS can also
invade meninges via erosion of the superior orbital fissure. An analy sis of IRS data suggested
a relationship of histology to outcome. For the 84% with embry onal histology, the 5-y ear
survival was 94%. However, for the 10% of children with alveolar RMS, this rate was 74%,
and all five infants with alveolar disease died (63). The most recent COG protocols dictated a
prescription dose of 45 Gy for both embry onal and alveolar RMS. However, patients with
alveolar orbital RMS (group III) were considered to be at intermediate risk and received
more intensified chemotherapy on ARST0531, while patients with embry onal orbital RMS
were treated on the favorable-risk protocol ARST0331. Because of the favorable outcome of
patients with orbital RMS and substantial late toxicity, the SIOP attempted to use
chemotherapy alone (153). Local control was compromised by this strategy. An international
workshop evaluating a total of 306 patients from four large cooperative groups found no
difference in overall survival based on delivery of RT at diagnosis, but a significant difference
in local control rates (82% with RT vs. 53% without RT) (154).
In a similar effort to reduce toxicity, the COG has varied the radiation and
cy clophosphamide dosing, to varied effect. Local control in IRS-III was 84% at 5 y ears with
VA chemotherapy and 45–50.4 Gy of radiation. This increased to 96% in IRS-IV with the
addition of cy clophosphamide and increased radiation doses to 50.4–59.4 Gy. In an effort to
reduce toxicity, the subsequent Intergroup D9602 trial reduced the radiation dose to 45 Gy
and omitted cy clophosphamide, but local control dropped to 86%. The most recent COG
ARST0331 trial kept the 45 Gy radiation dose, but added back cy clophosphamide at a lower
dose, achieving a 5-y ear local control rate of 89% (155). In ARST0331, the local control rate
for those 15 patients with a CR at week 12 was 100%, compared with 81% for those with a PR
or SD. Therefore, the optimum combination of chemotherapy and radiation dose is y et to be
determined, but dose escalation above 45 Gy should be considered for patients with a poor
response to chemotherapy and/or gross residual disease in the orbit following chemotherapy.
Page 245The functional and cosmetic late adverse effects of orbital irradiation are
considerable because of the close proximity of several critical structures. Three-dimensional
planning should alway s be utilized. The RT plan should be designed to deliver 45 Gy to the
tumor volume while taking into consideration the doses delivered to the lens, lacrimal gland,
cornea, retina, optic nerve, bony structures, and brain (156). Treatment with the ey e open to
avoid the bolus effect of the lids, unless the lids are involved, may be preferred. Advance
photon techniques should be considered. Proton therapy allows for substantial sparing of
normal tissues for patients with this disease and may help decrease late effects in the orbit
(Fig. 11.11 ) (120,157,158).
Figure 11.11 Proton treatment for an orbital rhabdomyosarcoma. A: A multiplanar view
of a large orbital rhabdomyosarcoma involving the superior orbit and invading lacrimal
gland. B: Axial view of proton plan. C: Dose–volume histogram.
Other Head and Neck Sites

Parotid region, oral cavity, orophary nx, scalp, and lary nx RMS comprise the head and neck
sites outside of the parameningeal region and orbit. They make up approximately 10% of
RMS and have a favorable prognosis. They are generally of embry onal histology ; however,
cheek and scalp lesions have a higher frequency of alveolar histology (99). Superficial lesions
may be marginally or, at times, widely resected with satisfactory cosmesis and function, a
situation that less often pertains for deeper tumors. Narrower resection margins (less than 1
mm) are acceptable because of anatomic restrictions. Optimal cosmesis with excellent
disease control may best be obtained with a marginal resection and subsequent RT. For the
deeper tumors (oral cavity, buccal mucosa, lary nx, paraphary ngeal, or parotid region), RT is
generally necessary. Because of the favorable outlook for patients with nonparameningeal
head and neck tumors, most patients have been classified as stage 1 or 2 in IRS-IV and IRS-V
and are now eligible for ARST 0331 and therefore receive less intense chemotherapy than do
those with PM head and neck tumors (159).
Page 246Although the early experience with head and neck RMS suggested that ly mph
node involvement was uncommon (8% in IRS-I and IRS-II), this may have resulted from less
than thorough assessments. In fact, ly mph nodes were positive in 20% of patients in whom
ly mph node status was reported (99). Donaldson et al. (84) reported a similar incidence. A CT
scan of the neck with thin slices should be performed for all patients with head and neck RMS.
Even with this study, detection of ly mphatic involvement can be difficult. PET/CT may
improve detection of ly mph nodes for this group of patients and is encouraged on the current
COG trials (109). Involved ly mph node groups may be treated with surgery and radiation.
Similar to PM RMS and orbital RMS, tumors are in close proximity to critical structures and
advanced radiation techniques may be of benefit in avoiding normal tissues (120,160,161).
Trunk
Truncal sites include the chest wall, paraspinal area, and abdominal wall, and diaphragm in
decreasing order of frequency. Scapular and buttock lesions are considered to be extensions
of the extremity, and retroperitoneal and perineal tumors are considered separately. An early
IRS report focused on 30 children with soft tissue sarcoma of the trunk (162). Ten of the 14
children with chest wall primaries had group I or group III disease, and five were long-term
survivors. None of the four children with metastases at diagnosis survived. Improvements in
outcomes were seen in IRS-IV. Five-y ear failure-free and overall survival was 68% and
78%, respectively (compared with 30% and 40%, respectively, for IRS-I) (163). A recent
report from the Children’s Oncology Group reported overall outcomes on the impact of
surgical excision for chest wall cases. They found no difference in failure-free or overall
survival based on the degree of resection.
Page 247Paraspinal tumors were rare (3.3%) in IRS-I and IRS-II. They tended to be
greater than 5 cm in diameter, often invaded the spinal extradural space, and were
commonly of an undifferentiated or extraosseous Ewing subty pe. Survival at 5 y ears was
approximately 50% in both studies (164). Local and distant relapses were common, and
patients with embry onal subty pes fared no better than others.
RMS of the diaphragm is ty pically unresectable and/or metastatic at diagnosis. A total of
only 15 patients were enrolled on IRS studies I–IV (165). Although complete remission was
achieved in 10 patients (67%), only 5 (33%) were alive without disease at a median follow-up
of 9 y ears.
Current guidelines include as wide a surgical resection as is feasible, either at diagnosis
or after chemoradiotherapy as a second look. For patients with an initial excision that was less
aggressive than feasible or of an uncertain nature, a re-excision should be considered. RT is
given to all patients except those with completely excised small, favorable histology tumors
and uninvolved ly mph nodes. RT fields encompass the original disease extent, and
chemotherapy is alway s used (162,164).
Retroperitoneal
Retroperitoneal tumors comprise 11% of RMS. Children usually present with abdominal pain,
back or lower extremity pain, and/or an abdominal mass (166). Median age at diagnosis is
approximately 6 y ears. The majority of patients have embry onal subty pe, but alveolar
histologic subty pe is seen (167). Retroperitoneal tumors are larger and have a higher rate of
distant metastases at diagnosis compared to tumors of other sites likely due to the ability of
tumors to grow in the abdominal or pelvic cavity without causing sy mptoms. They often
compress or invade abdominal or pelvic organs and/or major vessels and are usually not
amenable to up-front resection. In addition, ly mph node involvement is common (23% in
IRS-I and IRS-II; 28% in IRS-IV) (50). Delivery of RT is also problematic due to the size and
proximity of normal organs. In the IRS-I and IRS-II, advised RT was not delivered in 39%
(166). This very high number of RT protocol violations was attributed to the difficulty in
delivering the prescribed dose while respecting normal tissue tolerance. IRS-IV, similarly, had
a high number of protocol violations for this subsite (167). All these factors combine to render
the prognosis for retroperitoneal RMS worse than for most other sites. Five-y ear survival was
approximately 40% in IRS-II and 4-y ear survival was 60% in IRS-III (168). IRS-IV
demonstrated improved outcomes reporting estimated failure-free and overall survival at 5
y ears of 70% and 75%, respectively, for tumors of the retroperitoneum and non-GU pelvis
tumors (167). Locoregional recurrence continues to be problematic in this disease.
Embry onal subty pe and age less than 10 y ears were found to predict improved prognosis in
IRS-IV (167). Debulking of more than 50% of tumor may improve outcomes, but it is also
possible that debulking merely appears to improve outcome due to selection bias (smaller
tumors are amenable to debulking) (168). A debulking procedure should be strongly
considered if feasible (167). In addition, gastrointestinal toxicity is frequently encountered in
long-term survivors (169). Guidelines are essentially the same as those noted previously for
truncal tumors. Because of normal tissue tolerance, RT usually involves multiple reductions in
field size. CT planning should be used. IMRT may be of benefit. Proton radiation using fields
entering from posterior may be useful for sparing structures anterior to the tumor volume for
selected cases.
Perineal
Perineal tumors are rare (2% of RMS) and carry a poor prognosis (170,171). These tumors
include non–genitourinary tumors of the perineal and perianal tissue located outside of the
pelvis and between the pubic sy mphy sis and coccy x. Tumors of this region are more often of
alveolar histology than embry onal and ly mph node metastases are common (170,171). The
3-y ear survival reported for IRS-I and IRS-II combined was 59%, which was somewhat
inferior to that of patients with disease in other sites (64% for other sites) (21,170). The 5-y ear
failure-free and overall survival rates for IRS-I to IRS-IV reported collectively was only 45%
and 49%, respectively (172). When extent of disease was controlled for, only age less than 10
y ears predicted for an improved outcome. Based on the high incidence of ly mph node
involvement, the authors recommended surgical evaluation of both the iliac and inguinal
ly mphatics for accurate staging and to determine radiation fields. A recent analy sis of 29
patients from Japan and 14 patients from the United States also reported poor outcomes for
these patients (75,171). The approach to these patients also entails a resection as complete as
functionally acceptable, followed by chemotherapy and RT as appropriate. Figure 11.12
demonstrates an IMRT plan for a child with perineal RMS involving regional ly mph nodes.
Figure 11.12 Axial (A) and coronal (B) images of an intensity-modulated photon therapy
plan for a child with a perineal rhabdomyosarcoma with nodal involvement. (Courtesy of
Arthur Liu, MD.)
Hepatobiliary Tree
Hepatobiliary RMS is rare, often of botry oid subty pe, and generally occurs in very y oung
children. The common bile duct, the common, right, or left hepatic duct, and the ampulla of
Vater may be sites for RMS. A recent IRS report reviewed the experience of the 25 patients in
IRS-I to IRS-IV with RMS of the biliary tract (173). The majority of patients presented with
intermittent obstructive jaundice with or without abdominal distention, fever, pain, and loss of
appetite. Imaging was inadequate for the identification of regional metastases. Despite
aggressive surgery, gross total resection at diagnosis was possible in only six cases, two of
which had negative surgical margins. However, the 5-y ear survival rate was 78%, and much
of the mortality was related to infectious complications associated with external biliary
drains. The biliary tract is considered a favorable site, and current recommendations include
conservative surgery (without bile drainage) to establish an accurate diagnosis and determine
the extent of regional disease, followed by chemotherapy and RT. Delivery of RT may be
challenging given y oung age and volume and dose tolerances of the liver and kidney s. Proton
therapy may be of benefit, particularly for large tumors and when constraints cannot be met
with other RT modalities (Fig. 11.13 ).
Page 248
Figure 11.13 Axial images for a proton (A) versus an intensity-modulated photon plan (B)
for a 3-year-old child with biliary rhabdomyosarcoma. The properties of proton radiation
allow for increased sparing of liver and kidneys as seen in images and dose–volume
histograms (C, D).
Page 249Metastatic Disease

Approximately 15% of patients with RMS present with metastatic disease (15). Failure-free
survival at 3 y ears for this group of patients is only 25%. An analy sis of IRS-IV patients with
metastatic RMS showed a favorable subgroup of patients with embry onal histology and two
or fewer metastatic sites with a 3-y ear failure-free survival of 40% and overall survival of
47% (32). Patients with metastatic disease that does not involve the bone marrow are also
more likely to survive (25–30%) (15,20,32). A separate report examined outcomes for patient
with pulmonary metastases only (174). The majority of these patients had multiple lung
nodules, but most patients did not have biopsy to confirm metastatic disease. Thirty -five
percent of patients did not receive radiation to the lungs. Fewer lung recurrences were seen in
patients who did receive lung RT, but there was no significant impact on survival. Overall
survival for patients with disease metastatic to the lung did not differ from those with other
single-site metastases.
Chemotherapy is the mainstay of treatment for children with metastatic RMS. Surgery
and/or radiation are used for local control of both primary and metastatic disease. Although
long-term survival is poor, data suggest that the use of local therapy can improve outcome
(175).
Figure:
Axial (A), sagittal (B), and coronal (C) images of a proton radiation plan for a young child
receiving radiation for microscopic disease following chemotherapy and surgical resection.
D: Bladder–prostate dose–volume histogram displaying growth plates and clinical tumor
volume. Additional structures contoured but not shown include bladder, bowel, rectum,
penile bulb, and penile shaft. Prescription dose 36 Gy (RBE) to CTV. Femoral head growth
plates receive a maximum dose of <3 Gy (RBE); pelvic growth plates receive dose in a range
of 6–20 Gy (RBE).
Figure:
Depicts a brachytherapy plan for a vaginal rhabdomyosarcoma. This 3-year-old girl relapsed
after chemotherapy alone. Prescription dose delivered was 60 Gy. A: Axial CT treatment
planning image showing percent isodose prescription lines. This plan demonstrates rapid fall
off allowing for sparing of the pelvic growth and femoral growth plates as well. B: A
multiplanar view. C, D: Sagittal DRRs with and overlay of treatment volumes, normal
structures, isodose lines.
(Courtesy of Christine Haie-Mader, MD.)

Figure:
Axial image of a 3D-conformal photon plan for a lower extremity sarcoma. Note that a strip
of soft tissue is completely spared in an effort to avoid lymphedema.
(Courtesy of Karen Marcus, MD.)

Figure:
High-definition volume rendering. Treatment volumes for parameningeal
rhabdomyosarcoma. Recommendations on the current COG protocols are for treatment of
the prechemotherapy tumor volume (GTV) plus 1 cm to form the CTV. A: Although all IRS and
the current COG studies recommend the use of the prechemotherapy volume,
postchemotherapy volumes with a margin of 1 cm may be used for a cone down (although
not encouraged for invasive tumors) and have been explored in institutional studies as well as
European studies. B: The postchemotherapy volume plus 1 cm (after 4 weeks of
chemotherapy). Red, CTV; dark blue, parotid glands; cyan, optic nerves; green, cochlea;
yellow, hypothalamus and pituitary.
(Courtesy of Fovia, Inc., and Justin Lee.)

Figure:
Coronal (A) and axial (B) images for a proton plan for treatment for a parameningeal
rhabdomyosarcoma. C: Dose–volume histogram for proton plan for parameningeal
rhabdomyosarcoma. Advanced planning techniques are particularly useful for sparing normal
tissues in this region.
Figure:
Proton treatment for an orbital rhabdomyosarcoma. A: A multiplanar view of a large orbital
rhabdomyosarcoma involving the superior orbit and invading lacrimal gland. B: Axial view of
proton plan. C: Dose–volume histogram.
Figure:
Axial (A) and coronal (B) images of an intensity-modulated photon therapy plan for a child
with a perineal rhabdomyosarcoma with nodal involvement.
(Courtesy of Arthur Liu, MD.)

Figure:
Axial images for a proton (A) versus an intensity-modulated photon plan (B) for a 3-year-old
child with biliary rhabdomyosarcoma. The properties of proton radiation allow for increased
sparing of liver and kidneys as seen in images and dose–volume histograms (C, D).
RECURRENT DISEASE
Unfortunately, the prognosis for most patients with recurrent RMS is poor, although there is a
subset of patients with favorable salvage rates (176). These patients are those with favorable
histology who initially presented with stage 1 or group I disease and whose recurrence is local
or regional. The 5-y ear survival rates are 50–70% for this group, whereas most other children
have an extremely poor prognosis. Despite the poor long-term outlook for patients with
recurrent disease, many can still achieve a durable second remission with salvage therapy,
and there are several active chemotherapy regimens, including ifosfamide with etoposide
and cy clophosphamide with topotecan (177,178). The COG recently investigated a risk-based
approach to salvage treatment in which favorable-risk patients were treated with doxorubicin
and cy clophosphamide alternating with ifosfamide and etoposide, ARST0121 (179).
Unfavorable-risk patients with measurable disease received vincristine and irinotecan (with a
randomization to two different drug administration schedules), followed by the alternating
schedule, or the aforementioned regimen with the addition of a new agent, tirapazamine, for
patients without measurable disease. This trial found no difference in efficacy between the
two irinotecan schedules. A more recent trial, ARST0921, studied the addition of temsirolimus
and bevacizumab (in two separate arms), to the active chemotherapy combination of
vinorelbine and cy clophosphamide. The final results of this trial have not y et been published.
RT is often used for local control or palliative treatment, and aggressive surgery may
improve outcomes in the setting of recurrent disease, particularly for patients with orbital and
genitourinary tumors. Unfortunately, high-dose cy totoxic therapy with bone marrow rescue
has not proven to be effective for patients with metastatic or recurrent disease (180).
FUTURE DIRECTIONS
While it is clear that there has been tremendous progress over the last several decades,
largely attributable to the efforts and dedication of cooperative groups, phy sicians, patients,
and families, we must continue to improve outcomes for children diagnosed with RMS.
Advances in radiology and technical advances in radiation oncology should allow for better
detection of involved areas of disease and avoidance of healthy tissues while assuring
adequate delivery of radiation. Molecular profiles will indicate which patients may have
more biologically aggressive disease and are likely to play a larger role in determining what
patients may benefit from intensified treatment and/or new targeted agents. Continued
improvements in sy stemic therapy may allow us to avoid RT in some patients, while adding
to the benefit for others in whom local control comes to be of increased importance due to
eradication of sy stemic metastatic disease. We are optimistic that developments in radiation
oncology along with advances in the cancer disciplines of surgery and medicine will allow
for increased survival as well as an improvement in the quality of life for our pediatric
cancer survivors.
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CH A P TER 12
Soft Tissue Sarcomas Other Than
Rhabdomyosarcoma; Desmoid Tumor
Brandon R. Mancini, Kenneth B. Roberts, and Edward C. Halperin
Page 255The word sarcoma is derived from the Attic Greek word σàρκωμα or sarkoma
meaning a fleshy excrescence (1). The term was used by Galan with particular reference to
a nasal growth (2). An early English language dictionary from 1657 continued this definition
of sarcoma as a “flesh growing in the nostrils like the proud flesh in a sore” (3). In modern
usage, however, soft tissue sarcomas are defined as all malignant tumors of nonepithelial,
extraskeletal tissues including the peripheral and autonomic nervous sy stem, but excluding the
hematopoietic sy stem, glia, and supporting tissues of specific organs and viscera.
Soft tissue sarcomas constitute approximately 6.5–7% of childhood cancer. Of these,
40% are rhabdomy osarcoma and 60% are other ty pes of soft tissue sarcomas (4,5,6).
Because the distribution of the ty pes of soft tissue sarcomas in children is frequently different
from that in adults, Spunt and Pappo (7) have advocated the term nonrhabdomyosarcoma soft
tissue sarcoma (NRSTS). The United States’ Surveillance, Epidemiology, and End Results
(SEER) program provide some of the most comprehensive cancer epidemiologic data
available (8). Of the European Tumor Registries, only data published from Germany have
sufficient detail to distinguish rhabdomy osarcoma from NRSTS (9). Overall, NRSTS
comprise approximately 3–3.5% of all pediatric cancers with 550–600 new cases diagnosed
each y ear in the United States. The incidence rate over time has remained steady in the
range of 6–8 cases per million population. In Germany, the incidence rate is slightly less at
five cases per million persons. Data from SEER based on the time period 1975–1995 suggest
that NRSTS has had a propensity to dominate in older pediatric age groups (10–14 y ears and
15–19 y ears, specifically ) as part of the incidence curves for soft tissue sarcoma (STS)
leading into adulthood. There are certainly some NRSTSs that are characterized by a
pediatric predominance. But, for many of the soft tissue sarcomas, clinical features are
similar between children and adults, except that survival rates diminish for patients over age
50 y ears (10).
While the annual National Cancer Institute (NCI) report on Cancer statistics based on the
SEER database does readily distinguish among rhabdomy osarcomas and NRSTSs, pediatric
soft tissue sarcomas in the United States have been associated with improving survival over
time. For patients less than 16 y ears of age diagnosed with a soft tissue sarcoma in 1975–
1977, the adjusted 5-y ear survival was 61%. For those diagnosed in 2004–2010, there was a
statistically significant improvement in 5-y ear survival at 81% (11). But to what degree this
simply reflects an improvement in rhabdomy osarcoma management is difficult to discern.
Moreover, very few patients with NRSTSs have been enrolled in cooperative group clinical
trials. For instance, in the United States, prior to the 2006 Children’s Oncology Group (COG)
ARST0332 trial, less than 200 patients had been enrolled in only three prospective clinical
trials (12,13,14). The ARST0332 trial was open from 2007 to 2012 and accrued just 551
eligible patients over 5 y ears (15).
For most children with NRSTS, the origin or cause of the tumor is unknown. Some cases
may be traced to prior radiation exposure (see Chapter 20 ), chemical exposure,
iatrogenic or disease-caused immunosuppression, or a genetic predisposition. For example,
patients with neurofibromatosis—a set of autosomal dominant disorders of dy splastic growths
involving neural tissues often with skin manifestations—have a 7–10% lifetime risk of
developing a malignant peripheral nerve sheath tumor (MPNST). With changes in pathologic
definitions, MPNST has historically been called a neurofibrosarcoma or malignant
schwannoma. The association of sarcomas with neurofibromatosis indicates that some
sarcomas are associated with chromosomal deletions and translocations and the presence of
abnormalities of tumor suppressor genes. Homozy gous gene deletions occur in both the long
and short arms of chromosome 17 in neurofibromatosis ty pe 1. Candidate tumor suppressor
genes include 17q11 (the NF tumor suppressor gene) and p53 (17p13) (4).
Rhabdomy osarcoma and NRSTS also occur as part of the familial Li–Fraumeni sy ndrome.
More generally, in adult and pediatric soft tissue sarcomas, cy togenetic abnormalities are
common with a mixture of simple translocations or point mutations giving rise to fusion genes
or oncogenes and more complex genetic instability with a multiplicity of chromosome
aberrations (16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35) (Table 12.1 ).
Gastrointestinal stromal tumors are of particular interest, albeit rare in children, since its
associated c-kit oncogene is a successful therapeutic target with imatinib, a prototy pe ty rosine
kinase inhibitor (36). While not y et tested in pediatric NRSTS, there are a variety of other
molecular targets and associated agents under investigation in adult soft tissue sarcomas,
including platelet-derived growth factor receptor-A (sunitinib), Raf kinase (sorafenib), mTOR
(rapamy cin), vascular endothelial growth factor (bevacizumab), heat shock proteins,
hedgehog, histone deacety lase, and nucleotide excision repair (30). Within the COG, there
has been an effort to screen for actionable mutations by exon genomic transcriptional
analy sis. From a sample of 10% of the cases from the ARST0332 study using archived
formalin-fixed paraffin-embedded specimens, 33 potential mutations were found in 15
NRSTS subty pes, most involving mutations involved in Ras signaling, overlapping with
mutations in EGFR and TP53 (37). A variety of large chromosomal gains or losses were also
observed. These efforts will hopefully serve as the basis for future sy stemic therapeutics.
Page 256
Table 12.1 Common Cytogenetic Changes in Nonrhabdomyosarcoma Soft Tissue

Sarcomas
Figure: Common Cytogenetic Changes in
Nonrhabdomyosarcoma Soft Tissue
Sarcomas
PATHOLOGY
Page 257The frequency of the different histologic subgroups of NRSTS of childhood varies
between reporting institutions (Table 12.2 ). These differences may be attributable to
variations in referral patterns and to the small numbers in each series. SEER represents the
best population-based description of STS subty pe distribution, location of disease, and staging
across the age spectrum despite the problem of coding errors by tumor registries. Figure
12.1 display s the results of a 2011 SEER analy sis of soft tissue sarcomas by 10-y ear-age
intervals (10). Recapitulating the distribution of NRSTS is the experience from the recent
experience from the COG ARTS 0332 trial, which includes some y oung adults; the most
common subty pes were sy novial sarcoma (27%), MPNST (11%), and undifferentiated
sarcoma (9%) (15).
Table 12.2 The Most Common Types of Childhood Nonrhabdomyosarcoma Soft Tissue
Sarcoma in Recent Clinical Seriesa aIn each series, the most common histologic types are
indicated by bold type.
Figure 12.1 A: Distribution of histologic subtypes by 10-year age groups. B: Distribution of
primary tumor sites by 10-year age groups. C: Distribution of tumor stage by 10-year age
groups. RMS, rhabdomyosarcomas; fibroblastic, fibroblastic and myofibroblastic tumors;
Fibrohistiocytic, fibrohistiocytic tumors; NST, malignant peripheral nerve sheath tumors;
Kaposi, Kaposi sarcoma; pPNET, Ewing family tumors; rhabdoid, extraneral rhabdoid tumor;
liposarcoma, liposarcomas; synovial, synovial sarcomas; blood vessel, blood vessel tumors;
ASPS, alveolar soft parts sarcoma; miscellaneous, miscellaneous/unspecified soft tissue
sarcomas including other fibromatous neoplasms. From Ferrari A, Sultan I, Huang TT, et al.,
Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance
Epidemiology and End Results Database. Pediatr Blood Cancer. 2011;57:943–949.
In addition, NRSTSs often are difficult for

pathologists to classify, and there is wide
intraobserver variation (51). In an M. D.
Anderson Hospital series of sarcomas of the
head and neck in children and adolescents,
histologic diagnoses were changed in 22% of
patients (43). Several other studies have assessed
discrepancy rates between the original diagnosis
of soft tissue tumors and the diagnosis made by
expert reviewers when patients are referred to
specialty centers for entry in therapeutic trials. Figure 12.2 The histologic appearance
About 5–10% of cases having the original of a malignant fibrous histiocytoma on
diagnosis of sarcoma are revised to nonsarcoma, hematoxylin and eosin staining, original
and for 16–32% of patients with a sarcoma, the magnification 40×. Many pathologists
histologic subty pe is revised. Where grade was now categorize this lesion as a
analy zed, there was disagreement in up to 40% pleomorphic sarcoma. Note the spindle-
of the cases (52). For example, malignant cell proliferation (long, narrow, rod-like
fibrous histiocy toma (MFH) was first described cells) with frequent mitoses, enlarged
as a separate entity in the 1960s and by the hyperchromatic and pleomorphic nuclei,
1970s was widely accepted by pathologists, and a storiform pattern of growth
identify ing this entity as the most common soft (fascicles of cells radiating from a central
tissue sarcoma subty pe. Therefore, during this point). There is also some tendency
time decades ago, the reported incidence of toward a herringbone pattern in this
MFH in adults sharply increased while that of example, characteristic of a
fibrosarcoma fell (53). Historically, MFH has fibrosarcoma.
been unusual in childhood. But with general
advances in pathologic categorization based on immunohistochemistry, ultrastructural studies,
and cy togenetics, the diagnosis of MFH has been questioned as a distinct entity (54). At least
in adults, this is no longer a common diagnosis, and when undifferentiated it is generally
classified as a high-grade pleomorphic sarcoma. Figure 12.2 shows the histologic
appearance of an MFH or pleomorphic sarcoma.
Many of the childhood NRSTSs have
characteristic cell ty pes (Table 12.3 ). The
World Health Organization (WHO) classification
uses lines of differentiation to categorize tumors
into adipocy tic, fibroblastic/my ofibroblastic,
“so-called” fibrohistiocy tic, smooth muscle,
pericy tic (perivascular), and vascular ty pes, as
well as tumors of uncertain differentiation (55).
Of course, other sarcomas include the skeletal
muscle tumors/rhabdomy osarcomas and
bone/cartilaginous tumors discussed elsewhere in
this textbook.
MPNST has also been known as
neurofibrosarcoma, neurogenic sarcoma,
malignant schwannoma, or malignant
neurilemmoma. It is a malignant neoplasm that Table 12.3 Cells of Origin of
arises in a peripheral nerve sheath. In children, Nonrhabdomyosarcoma Soft Tissue
from one-fifth to two-thirds of cases of MPNST Sarcoma of Childhood
are associated with neurofibromatosis ty pe 1
(NF1). The morphology is characterized by fascicles of spindle cells with a herringbone or
storiform pattern. One may observe evidence of schwannian differentiation (56). There can
be areas of significant nuclear hy perchromatism and abundant mitotic figures (57). These
tumors usually are positive for S-100, vimentin, and neuron-specific enolase. In about 2–16%
of patients with NF1, nodular and plexiform neurofibromas transform to MPNSTs. NF1 is
transmitted as an autosomal dominant with variable penetrance. However, almost 50% of
cases are sporadic mutations (1). People with NF1 are 1.2 times more likely to have a
malignant neoplasm listed on their death certificates than those who do not have the disease.
These include MPNST, optic gliomas, and pheochromocy tomas (58). NF1 is also called the
von Recklinghausen disease. Biphasic synovial sarcoma, the more common ty pe, also has
spindle-shaped cells. These are mixed with oval and keratin-positive epithelial cells.
Pseudoglandular spaces or slits and clefts mimic sy novium (59). About one-third of sy novial
sarcomas in children are the monophasic ty pe (60). About two-thirds of cases involve the
lower extremity and one-third the upper. Sy novial sarcomas differ from other NRSTSs in that
they have a significant risk of ly mph node metastases (60,61). The monophasic ty pe may
have a better prognosis, but this is debatable (48,60). Sy novial sarcomas commonly have a
t(x;18)(p11.2;q11.2) translocation that may result in two different fusion genes (SYT-SSX1 and
SYT-SSX2). Controversy exists as to the prognostic importance of these fusion genes. Initial
reports suggested that SYT-SSX1 fusion was associated with improved survival and less
potential for metastasis (62,63). But in a contradictory small series, the SYT-SSX1 fusion was
associated with a 42% 5-y ear metastasis-free survival, compared with 89% for the SYT-SSX2.
The SYT-SSX1 fusion is also associated with a higher cell proliferation rate as assessed by Ki-
67 staining (64). Yet another recent report suggests tumor grade, rather than fusion gene
subty pe, in sy novial sarcoma is the more important prognostic factor (65).
F RI E D RI CH V ON RE CKL I N G HAUS E N
Friedrich Daniel von Recklinghausen (1833–

1910) was born in Guterslah, Westphalia,
Germany, and studied medicine at the
Universities of Bonn, Würzburg, and Berlin.
He was a professor in Konigsberg, Wurzburg,
and Strasbourg. Also known for coining the
term hemochromatosis, he published a
monograph in 1882 that first described
neurofibromatosis type 1 and the
accompanying benign neurofibromas having
a histologic appearance of disordered
peripheral nerves and fibrosis.
Page 260Liposarcomas originate from primitive mesenchy mal cells rather than from
mature adipose tissue. Some have a my xoid appearance, whereas others resemble benign
lipomas. The pleomorphic ty pe may resemble fibroblastic, my oblastic, or sy novial sarcoma.
Angiosarcoma should alway s be considered high grade with an aggressive behavior, a high
rate of local recurrence, a propensity to metastasize, and a poor prognosis (66).
Leiomyosarcoma originates from smooth muscle. The well-differentiated lesions usually have
a centrally located blunt-ended nucleus (“cigar-shaped”).
Fibrosarcoma is an infiltrative, fibrous
neoplasm composed of interlocking bundles of
spindle cells (67,68). The tumor usually stains
positive for vimentin. There are two clinically
different forms of fibrosarcoma in children. One
is a lesion appearing in the first 5 y ears of life,
with a low rate of distant spread. This ty pe of
fibrosarcoma, called the congenital ty pe, is
generally treated by excision (4,40,69). In
children less than 5 y ears of age, this tumor may
also be called infantile fibrosarcoma (Fig. Figure 12.3 Example of microscopic
12.3 ). The other occurs in children older than pathology of an infantile fibrosarcoma,
5 y ears and has a more ominous prognosis with original magnification × 20. This is
behavior similar to that of adult forms (68). This another fibrous spindle-cell proliferation
classical or adult-ty pe fibrosarcoma is treated as in the example of an MFH. While
according to the principles outlined for other histologically aggressive in appearance,
NRSTSs. Infantile fibrosarcoma has a rapid when this fibrosarcoma occurs in the first
initial growth, but generally indolent behavior. several years of life, there tends to be a
Local recurrence is common, metastases are benign biologic behavior with little
rare, spontaneous regressions have been potential for metastatic spread. Local
reported, and RT is rarely used. Infantile and excision is the primary management. In
adult fibrosarcomas are histologically identical. unresectable cases, chemotherapy can
There is no routine microscopic, be used to promote regression and
immunohistochemical, or ultrastructural way of subsequent surgery.
distinguishing the two clinical ty pes (67).
Page 261Low-grade fibromyxoid sarcoma is an indolent tumor that rarely occurs in
children or y oung adults. It consists of spindle and stellate cells with uniform nuclei arranged
in a whorled pattern with alternating areas of fibrous and my xoid stroma (70). In adults
across the age spectrum, these my xofibrosarcomas may be higher grade, multifocal
involving an extremity with late recurrences outside radiation treatment fields and without
any obvious ly mphatic mode of spread (71). True MFH are pleomorphic sarcomas as noted
above, often characterized by a whorled growth pattern. They are thought to arise from
histiocy tic cells acting as facultative fibroblasts. Hemangiopericytomas arise from pericy tes,
the modified smooth muscle cell with contractile function located on the internal surface of
venous capillaries and postcapillary venules (72). The malignant mesenchymoma has two or
more cell ty pes, any of which, taken by itself, might be considered a malignant neoplasm
(73,74); however, the term is losing favor as a clinicopathologic entity, as such sarcomas can
usually be classified in other way s (75). Ectomesenchymomas are felt to be of neural crest
origin with multidirectional differentiation exhibiting combinations of neuroblastoma,
ganglioglioma, schwannoma, emby ronal rhabdomy osarcoma, benign melanocy tic
proliferation, and bone or cartilage elements. These rare tumors may have a dominant
rhabdomy osarcomatous element with clinically similar response to chemotherapy and RT
(76) (Fig. 12.4 ).
Figure 12.4 This 10-month-old boy developed a 2.5-cm superficial mass in the right
supraclavicular fossa. After ultrasound showed this to be a solid lesion, a marginal excision
was performed in February 2003. An ectomesenchymoma was diagnosed having immature
cartilage separated by bands of collagen in a myxoid background with cellular areas having
primitive ovid and spindle cells. The dominant cellular pattern had features of an embryonal
rhabdomyosarcoma. Surgical margins were positive. There was no evidence of metastasis in
an adjacent lymph node or on CT imaging. As a wider excision was not possible due to tumor
abutting clavicle, lung apex, and carotid artery, postoperative radiotherapy was indicated.
Along with VAC chemotherapy as per rhabdomyosarcoma management, the patient
received 3060 cGy in 17 fractions using a four-field technique (AP, PA, RAO, LAO fields)
facilitated by daily general anesthesia with IV propofol. Shown is the radiation treatment
plan and digital reconstructed radiographs of three of the fields. The treatment plan
minimized the volume of distal clavicle, spine, and shoulder girdle being treated to full dose.
In last follow-up at age 7 years without evidence of disease, there is negligible boney
asymmetry seen on chest X-rays correlating with normal physical examination. A: Radiation
treatment plan. B: RAO Digital Reconstructed Radiograph (DRR). C: AP DRR. D: LAO DRR. E:
Follow-up CXRs in 2003, 2006, 2009, and 2011 show relatively normal bony development
although there is some minor clavicular shortening on exam in 2015.
There are several childhood NRSTSs that have a characteristic microscopic picture, but
the cell of origin is uncertain. The epithelioid sarcoma is a tumor of the subcutaneous tissue,
tendons, and fascia, usually of the upper extremity, including the hand. There is a nodular
arrangement of plump, poly gonal to round, epithelioid cells interspersed with spindle-shaped
cells (5,77). Central degeneration or necrosis is often present. The tumor tends to spread
within fascial planes or aponeuroses and may grow along the neurovascular bundle and
encroach on large vessels or nerves. Regional ly mph node metastasis may occur in
association with high-grade tumors and tumors larger than 5 cm (78). The tumor generally
stains positive for keratin.
Alveolar soft part sarcomas have a characteristic cry stalline material seen with periodic
acid–Schiff (PAS) stain (79,80). The tumor tests positive for vimentin on
immunohistochemistry. The tumor cells ty pically have an organoid or nest-like arrangement.
Vascular invasion is alway s seen. Of 11 children with alveolar soft part sarcoma seen at St.
Jude Children’s Research Hospital (SJCRH) in a 32-y ear period, 6 had localized disease and 5
had unresectable or metastatic disease. Cy togenetic studies indicate that 17q25 abnormalities
are common (80). In 19 patients seen in Italy, 4 had metastatic disease at presentation. The 5-
y ear survival for all 19 patients was 80% (81). A slow doubling time of the tumor may
explain its very late occurrences (sometimes more than 10 y ears) (47).
P A G E 2 6 2J A M E S S . E W I N G
Ewing sarcoma is named in honor of James
S. Ewing (1866–1943), an eminent
pathologist at Cornell Medical School and
the Memorial Hospital in New York City who
described this radiosensitve small round blue
cell tumor of bone. Ewing was a major force
in the early development of radiotherapy.
Securing a major donation of radium from a
mining industry philanthropist, Ewing set the
future Memorial Sloan Kettering Cancer
Center on a firm foundation in large part
from Ewing’s efforts in cancer treatment,
pathology insights, and administrative roles.
One hypothesis of his that proved incorrect,
however, was the assertion that sarcomas
were etiologically linked to trauma.
Nevertheless, Time Magazine honored him
on its cover page in 1931 entitled “Cancer
Man Ewing” (84).
Extraskeletal (or extraosseous) Ewing sarcoma (EOES) and peripheral primitive

neuroectodermal tumor (PNET) are characterized by cohesive, uniform, small
hy perchromatic cells in a fibrous background. Dense clumping of chromatin, mitotic figures,
and rosette formation are ty pical of PNET. On immunohistochemistry analy sis, EOESs are
generally positive for vimentin and HBA-17. PNET is generally positive for neuron-specific
enolase and other neuron-related markers such as S-100 protein, neurofilament, or HNK-1.
Both PNET and EOES are associated with a particular chromosome translocation t(11;22)
(q24;q12). The progenitor cell for these two small, round, blue cell NRSTSs is not established.
They may arise from neural crest, primordial germ cells, or perhaps mesenchy mal stem
cells (4,82). When a PNET or EOES arises in the thoracic cavity, it is called the Askin tumor
(83).
Page 263
F RE D E RI C B. AS KI N
Askin tumor is named in honor of Frederic B.

Askin, MD, professor of pathology at Johns
Hopkins University who continues in
academic practice. The tumor was
described in 1979 in Askin FB, Rosai J, Sibley
RK, et al. Malignant small cell tumor of the
thoracopulmonary region in childhood: a
distinctive clinicopathologic entity of
uncertain histogenesis. Cancer.
1979;43:2438–2451.
Desmoplastic small, round, blue cell tumor is a rare intraperitoneal malignancy occurring
predominantly in adolescent boy s. It is characterized by a reciprocal translocation t(11;12)
(p13;q12) associated with the EWS-WT1 gene fusion transcript. Cells often stain positive for
desmin, keratin, and neuron-specific enolase. The predominant pattern of relapse is
intraperitoneal (85). Generally, patients are treated with surgical debulking, alky lator
chemotherapy, and whole-abdomen irradiation or intra-abdominal P-32. The relapse-free
survival rate is approximately 20% (57,86,87,88). Positron emission tomography (PET)
scanning may be useful in follow-up for early diagnosis of recurrence (89). Figure 12.5
depicts a rare instance of this disease occurring outside the peritoneum.
Figure 12.5 This 12-year-old female presented with a subcutaneous mass over the left
shoulder that was marginally excised. Pathology showed a desmoplastic small, round-cell
tumor with a classical t(11;12) translocation on cytogenetics. This case represents an unusual
extra-abdominal presentation of this rare sarcoma. MRI scan showed contrast enhancement
in the surgical bed (upper panel). Reexcision, axillary node dissection, bone marrow biopsy,
and CT scans were negative for other sites of disease. The patient was treated with an Ewing
sarcoma type chemotherapy protocol with involved-field RT to 45 Gy in 25 fractions (middle
panel of axial, coronal, and sagittal CT images with superimposed radiation dose
distribution). Despite local control of the primary tumor, the patient unfortunately developed
progressive pulmonary metastases shortly after completing
vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide
chemotherapy (See bottom panel of four serial CT images showing progression of lung
metastasis over 6 months). Despite surgical excisions of lung nodules and salvage
chemotherapy, the patient ultimately succumbed to her disease.
Clear cell sarcoma is characterized by ovoid or poly gonal cells with abundant clear
cy toplasm, indistinct borders, large nucleoli, and abundant intracy toplasmic gly cogen.
Immunocy tochemistry often is positive for S-100 protein, neuron-specific enolase, and
melanocy te-associated antigen HMB-45. A specific chromosomal translocation t(12;22)
(q13;q12) involving the DNA transcription factors ATF-1 on chromosome 12 and the EWS
gene on chromosome 22 has been described in 60–75% of clear cell sarcoma cases (90,91).
A fair proportion of NRSTSs show no cellular differentiation. These are called undifferentiated
sarcomas or sarcomas not otherwise specified.
Figure: The Most Common Types of
Childhood Nonrhabdomyosarcoma Soft
Tissue Sarcoma in Recent Clinical Seriesa
aIn each series, the most common histologic types are indicated by bold type.
Figure:
A: Distribution of histologic subtypes by 10-year age groups. B: Distribution of primary tumor
sites by 10-year age groups. C: Distribution of tumor stage by 10-year age groups. RMS,
rhabdomyosarcomas; fibroblastic, fibroblastic and myofibroblastic tumors; Fibrohistiocytic,
fibrohistiocytic tumors; NST, malignant peripheral nerve sheath tumors; Kaposi, Kaposi
sarcoma; pPNET, Ewing family tumors; rhabdoid, extraneral rhabdoid tumor; liposarcoma,
liposarcomas; synovial, synovial sarcomas; blood vessel, blood vessel tumors; ASPS, alveolar
soft parts sarcoma; miscellaneous, miscellaneous/unspecified soft tissue sarcomas including
other fibromatous neoplasms.
From Ferrari A, Sultan I, Huang TT, et al., Soft tissue sarcoma across the age spectrum: a
population-based study from the Surveillance Epidemiology and End Results Database.
Figure:
The histologic appearance of a malignant fibrous histiocytoma on hematoxylin and eosin
staining, original magnification 40×. Many pathologists now categorize this lesion as a
pleomorphic sarcoma. Note the spindle-cell proliferation (long, narrow, rod-like cells) with
frequent mitoses, enlarged hyperchromatic and pleomorphic nuclei, and a storiform pattern
of growth (fascicles of cells radiating from a central point). There is also some tendency
toward a herringbone pattern in this example, characteristic of a fibrosarcoma.
Figure: Cells of Origin of
Sarcoma of Childhood
Figure:
Figure:
Example of microscopic pathology of an infantile fibrosarcoma, original magnification × 20.
This is another fibrous spindle-cell proliferation as in the example of an MFH. While
histologically aggressive in appearance, when this fibrosarcoma occurs in the first several
years of life, there tends to be a benign biologic behavior with little potential for metastatic
spread. Local excision is the primary management. In unresectable cases, chemotherapy
can be used to promote regression and subsequent surgery.
Figure:
This 10-month-old boy developed a 2.5-cm superficial mass in the right supraclavicular fossa.
After ultrasound showed this to be a solid lesion, a marginal excision was performed in
February 2003. An ectomesenchymoma was diagnosed having immature cartilage separated
by bands of collagen in a myxoid background with cellular areas having primitive ovid and
spindle cells. The dominant cellular pattern had features of an embryonal
rhabdomyosarcoma. Surgical margins were positive. There was no evidence of metastasis in
an adjacent lymph node or on CT imaging. As a wider excision was not possible due to tumor
abutting clavicle, lung apex, and carotid artery, postoperative radiotherapy was indicated.
Along with VAC chemotherapy as per rhabdomyosarcoma management, the patient
received 3060 cGy in 17 fractions using a four-field technique (AP, PA, RAO, LAO fields)
facilitated by daily general anesthesia with IV propofol. Shown is the radiation treatment
plan and digital reconstructed radiographs of three of the fields. The treatment plan
minimized the volume of distal clavicle, spine, and shoulder girdle being treated to full dose.
In last follow-up at age 7 years without evidence of disease, there is negligible boney
asymmetry seen on chest X-rays correlating with normal physical examination. A: Radiation
treatment plan. B: RAO Digital Reconstructed Radiograph (DRR). C: AP DRR. D: LAO DRR. E:
Follow-up CXRs in 2003, 2006, 2009, and 2011 show relatively normal bony development
although there is some minor clavicular shortening on exam in 2015.
Figure:
Figure:
Figure:
This 12-year-old female presented with a subcutaneous mass over the left shoulder that was
marginally excised. Pathology showed a desmoplastic small, round-cell tumor with a
classical t(11;12) translocation on cytogenetics. This case represents an unusual extra-
abdominal presentation of this rare sarcoma. MRI scan showed contrast enhancement in the
surgical bed (upper panel). Reexcision, axillary node dissection, bone marrow biopsy, and CT
scans were negative for other sites of disease. The patient was treated with an Ewing
sarcoma type chemotherapy protocol with involved-field RT to 45 Gy in 25 fractions (middle
panel of axial, coronal, and sagittal CT images with superimposed radiation dose
distribution). Despite local control of the primary tumor, the patient unfortunately developed
progressive pulmonary metastases shortly after completing
vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide
chemotherapy (See bottom panel of four serial CT images showing progression of lung
metastasis over 6 months). Despite surgical excisions of lung nodules and salvage
chemotherapy, the patient ultimately succumbed to her disease.
PRESENTATION, WORKUP, AND STAGING
Page 264Most NRSTSs present as a painless swelling, but may also present with signs and
sy mptoms of vascular compression, neurologic impairment from nerve compression, or
bowel dy sfunction when tumors arise from the retroperitoneum. Furthermore, the time
interval from first sy mptom to diagnosis appears to be inversely correlated with survival for
pediatric sarcomas (92).
The radiographic workup begins with a plain radiograph. One looks for evidence of soft
tissue mass, calcification, and destruction of adjacent bone. Radionuclide bone scanning is
used to assess metastatic bone involvement, activity in bone adjacent to the tumor, and active
vascular activity in the tumor itself. Arteriography is advocated for delineation of the tumor’s
blood supply, a matter of concern to the surgeon or to the direct infusional chemotherapist.
Computed tomography (CT) and magnetic resonance imaging (MRI) are the essential studies
for clear definition of tumor extent, patterns of infiltration, evaluation of adjacent bone, and
planning surgical and radiotherapeutic approaches. MRI often shows a larger area of
involvement than does CT. The evaluation for distant metastasis focuses on the most common
site, the lungs, with chest radiograph and thoracic CT scanning (59,88,93,94,95,96). Metabolic
scanning techniques, such as thallium scans and PET, are being used with increasing
frequency. PET measures glucose utilization rate in sarcomas and may be used to assess
lesion grade and to monitor neoadjuvant therapeutic response (97,98).
Page 265NRSTS in childhood may be staged by one of two sy stems. A few investigators
still use the rhabdomy osarcoma grouping sy stem, although their number is shrinking (see
Table 11.2 ). This sy stem is convenient and relies on surgical resectability as an important
prognostic factor. There is no doubt that tumor size and resectability are important in
predicting outcome in pediatric NRSTS. In fact, a retrospective analy sis of NRSTS from the
SJCRH has crudely identified three distinct risk groups: (1) grossly resected nonmetastatic
disease (89% 5-y ear survival); (2) initially unresectable, nonmetastatic disease (56% 5-y ear
survival); and (3) metastatic disease (15% 5-y ear survival) (38,99,100) (Fig. 12.6 ).
Adverse risk factors include metastatic disease, tumor size 5 cm, high-grade, positive surgical
margins, intra-abdominal primary tumor site, and omission of postoperative RT in localized
disease. Regarding tumor size as a prognostic factor in sarcoma patients (including
rhabdomy osarcoma and NRSTS), a recent report suggests that there should be an adjustment
for overall patient size (101). The authors noted, for example, that the mortality risk
associated with a patient with a body surface area of 1.75 m 2 and a 5-cm tumor was the
same as for a 0.6 m 2 child with a 2.8-cm tumor. A variation of this prognostic risk grouping
has been continued in the recently closed COG ARST0332 trial as noted below and validated
in a SEER based study (44).
Figure 12.6 Risk stratification of nonrhabdomyosarcoma soft tissue sarcomas. (From

Spunt SL, Hill DA, Motosue AM, et al. Clinical features and outcome of initially unresected
nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol.
2002;20:3225–3235, with permission.)
Histologic tumor grade, however, is of considerable importance and is not directly

considered in the rhabdomy osarcoma grouping sy stem (69,102,103,104). Sarcoma grade
assessment incorporates pleomorphism, spontaneous necrosis, and number of ty pical and
aty pical mitoses per 10 high-power fields. Building on the first tumor grading sy stem
(squamous cell carcinoma of the lip) in 1920, Broders and colleagues at the May o Clinic
published a grading sy stem for sarcomas in 1939
based on the degree of mitosis, tumor giant cells,
and fibrous stroma (105,106). In 1969, the
American Joint Commission (AJC) on Cancer
Staging described a staging sy stem for soft tissue
sarcoma that uses grade, tumor size, nodal
involvement, and presence of metastases as the
determinants of stage (Table 12.4 ). First
validated by Russell et al. (107) in 1977, the AJC
sy stem incorporates in the sarcoma staging
sy stem both TNM and tumor grade components.
Grade is determined by evaluation of the degree
of cellularity, cellular anaplasia or
pleomorphism, mitotic activity, expansive or
infiltrative growth, and necrosis (77). Frequency
of distant metastases increases and the survival
probability decreases with increasing size of the
primary tumor (103). About 15% of patients
have metastatic disease at presentation (4).
Histologic grading is an important way to
predict the outcome of NRSTS. Moreover, as
treatment decisions may often hinge on grading,
the clinician should be aware of the criteria and
uncertainties inherent in pathologic
interpretation. There are various strategies for
grading. One sy stem, developed by the Pediatric
Oncology Group (POG), labeled grade 1 as a
tumor that has little propensity for malignancy.
Grade 2 tumors are those with fewer than 5
mitoses per 10 high-powered fields or less than
15% geographic necrosis, and grade 3 tumors
are those known to be clinically aggressive by
virtue of histologic diagnosis and with more than
4 mitoses per 10 high-powered fields or more
than 15% geographic necrosis (108) (Table
12.5 ). One review of this POG grading
sy stem found 73% mortality in grade 3 lesions
and 15% mortality in grade 1 and 2 tumors
(109). Table 12.4 The 2012 American Joint
The more common sarcoma grading Committee on Cancer Staging System
sy stems that one is more likely to encounter in for Sarcoma of Soft Tissuea aThis staging
clinical usage are the NCI sy stem and the system does not apply to Kaposi
French Federation of Cancer Centres (FNCLCC) sarcoma, fibromatosis (desmoids tumor),
sy stem, despite being largely based on adult infantile fibrosarcoma, or sarcomas
cases (110). Both are a three-tiered grading arising in dura mater or brain,
sy stem. The aforementioned POG sy stem is a parenchymal organs, and hollow viscera.
variation of the NCI classification scheme. In the Staging system now includes
NCI sy stem (111), certain ty pes of sarcomas gastrointestinal stromal tumors,
are deemed low or high grade based on the dermatofibrosarcoma protuberans,
histologic subty pe. For instance, a ty pical angiosarcoma, and extraskeletal Ewing
liposarcoma is low grade, while epithelial or sarcoma.From Compton CC, Byrd DR,
sy novial sarcomas are alway s high grade. For Garcia-Aguilar J, et al., eds. AJCC Cancer
those subty pes that are not automatically Staging Manual.7th ed. New York, NY:
allocated to a grade, the degree of necrosis is the Springer; 2012, with permission from
most important factor distinguishing intermediate AJCC.
versus high grade. Minor pathologic factors
include the degree of mitosis, pleomorphism, cellularity, and stromal matrix. Necrosis as a
prognostic marker is categorized as being minimal (0–15%), moderate (15–30%), or marked
(>30%). Thus, when degree of necrosis is key to determining grade, the significant cutoff
value is 15%. A grade 2 soft tissue sarcoma (e.g., a fibrosarcoma or a pleomorphic sarcoma)
has up to 15% necrosis, while grade 3 disease is simply determined by greater than 15%
necrosis.
Page 266The FNCLCC has similarities to the NCI sy stem, but has a point scoring sy stem
based on tumor histology, necrosis, and mitosis that has a certain clinical appeal in its
reproducibility and simplicity (112). The main criticism, however, is that some histologic
subty pes (e.g., pleomorphic sarcoma, alveolar soft parts sarcoma) do not have attributes that
recapitulate normal tissues and cannot be easily scored in terms of differentiation (Tables
12.6 and 12.7 ). Worldwide, the French sy stem predominates.
Table 12.5 POG Grading System for
Pediatric Nonrhabdomyosarcoma Soft
Tissue Sarcomas
Table 12.6 Tumor Differentiation Scores of Sarcoma in the French Federation of Cancer
Centers System of Grading Soft Tissue Sarcomas
Table 12.7 French Federation of Cancer Centres System of Grading Soft Tissue
Sarcomas
Comparisons between the NCI and FNCLCC sy stem show that up to one-third of cases
have grading discrepancies, but the latter sy stem may be a slightly better determinant of
prognosis, albeit not for every NRSTS subty pe (110,113). The recent COG protocol on
NRSTS has central pathology review; one of its aims will be to directly compare the POG
and the FNCLCC grading sy stems for pediatric sarcomas. Recently, Khoury et al. (114)
directly compared the POG and FNCLCC grading sy stems for pediatric NRSTSs. In this
study, 130 tumors were graded using both the POG and FNCLCC grading sy stems and it was
determined that both grading sy stems were equally effective in predicting event-free survival
(EFS). Interestingly, the POG sy stem appeared to upgrade tumors compared with the
FNCLCC sy stem and conclusion was made that the FNCLCC sy stem was superior to the POG
sy stem for tumors of intermediate grade. Furthermore, the mitotic index cutoff was noted to
be a highly relevant grading parameter needing further study in a prospective trial. To date,
the WHO or other pathology associations have not endorsed any particular grading schema.
Page 267While the clinician may rely on sarcoma grading to make treatment decisions,
one must be aware of the degree of uncertainty in pathologic diagnosis. This problem has a
bigger dimension as the pathologist is increasingly forced to evaluate smaller biopsy
specimens rather than the whole tumor, as newer treatment algorithms involve preoperative
RT or chemotherapy. With smaller specimens, there is an increasing danger of sampling
errors as necrosis, mitotic activity, differentiation, pleomorphism, and other grading aspects
have geographical variability within a particular tumor. Despite advances in molecular
biology, identification of cy togenetic or particular DNA or RNA lesions has not y et supplanted
tumor grading to aid clinical decisions for NRSTS.
Figure:
Risk stratification of nonrhabdomyosarcoma soft tissue sarcomas.
(From Spunt SL, Hill DA, Motosue AM, et al. Clinical features and outcome of initially
unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin
Oncol. 2002;20:3225–3235, with permission.)
Figure: The 2012 American Joint Committee
on Cancer Staging System for Sarcoma of
Soft Tissuea
aThis staging system does not apply to Kaposi sarcoma, fibromatosis (desmoids tumor),
infantile fibrosarcoma, or sarcomas arising in dura mater or brain, parenchymal organs, and
hollow viscera. Staging system now includes gastrointestinal stromal tumors,
dermatofibrosarcoma protuberans, angiosarcoma, and extraskeletal Ewing sarcoma.From
Compton CC, Byrd DR, Garcia-Aguilar J, et al., eds. AJCC Cancer Staging Manual.7th ed. New
York, NY: Springer; 2012, with permission from AJCC.
Figure: POG Grading System for Pediatric
Sarcomas
Figure: Tumor Differentiation Scores of
Sarcoma in the French Federation of Cancer
Centers System of Grading Soft Tissue
Sarcomas
Figure: French Federation of Cancer Centres
System of Grading Soft Tissue Sarcomas
Page 268Surgery
Every biopsy should be planned to be consistent with the treatment plan. The two techniques
for biopsy are either via needle or open incisional. Needle biopsy techniques include fine-
needle aspiration (of variable accuracy and dependent on the experience of the
cy topathologist) or core needle biopsy (4). The incision for an open incisional biopsy should
be the minimum that is technically feasible and homeostasis should be secure. Incisions on
the extremity should be along the long axis (96). Muscle compartments should not be crossed;
one does not want to contaminate adjacent areas with tumor. The biopsy should be placed so
that the entire surgical tract will be removed at the time of the definitive operation.
Complete surgical excision is the mainstay of therapy. NRSTS may infiltrate widely.
Sarcomas tend to expand and infiltrate adjoining tissue spaces, producing a pseudocapsule
made up of compressed normal tissue intermingled with microscopic extensions of the tumor.
A sy stem for assessing the adequacy of surgical margins in sarcoma surgery was described
by Enneking et al. (115). An intralesional surgical margin is through tumor, with gross or
microscopic contamination. A marginal resection is through the reactive or inflammatory
zone. A wide excision is through normal tissue outside the inflammatory zone. A radical
excision is outside the anatomic compartment containing the tumor. A wide excision or
amputation often is needed to obtain the microscopic-free margin needed for control. Clinical
experience, primarily in adults, has shown that the local failure rate for simple excision of
malignant soft tissue sarcomas is 60–90% (59,88,116). This failure rate falls to 18–30% when
simple excision is replaced by radical resection, radical compartmental resection, or
amputation above the proximal joint (6,69,96,117,118,119,120). In a pediatric series, the 5-
y ear survival rate was higher for complete tumor excision than for partial excision (47). For
low-grade lesions, wide excision with negative margins may be curative as the sole treatment
(42,118). Surgical margins of at least 1.0 cm around gross tumor are preferred for optimal
local control (121). In cases of positive margin or unanticipated finding of NRSTS on
marginal excision, a re-excision should be strongly considered (122).
There are many patients for whom limb-sparing treatments may be considered and
preferred (119,120,123,124,125). Limb-sparing surgery removes a soft tissue sarcoma, while
preserving the extremity with a satisfactory functional and cosmetic result. To achieve results
comparable to those of radical procedures, most limb-sparing procedures involve the planned
use of preoperative or postoperative external beam irradiation, brachy therapy, or intra-
arterial or sy stemic chemotherapy. But regardless of adjuvant RT or chemotherapy, resection
with negative surgical margins is critical for optimal local control (126). In the presence of
planned RT, resection margins may be relatively tight within millimeters, but if surgery alone
is planned, margins greater than 1.0 cm are likely required along with an en bloc resection
bey ond any tumor pseudocapsule (127). For tumors abutting bone, stripping off the
periosteum en bloc is usually sufficient in the absence of any direct bone invasion; however,
the addition of RT in thigh sarcomas may entail a higher risk for later development of femoral
bone fractures (128). Other investigators have observed an increased risk of bone fractures as
simply a function of high radiation dose delivery and not necessarily related to periosteal
resection (129,130). Sarcomas that involve neurovascular bundles are challenging clinical
problems, in which surgical and adjuvant radiotherapeutic management must be
individualized regarding the sacrifice of blood supply or nerves.
Limb-sparing surgery is clearly not appropriate for some patients. These patients include
y oung children who may deal better with an amputation than with the limb-length
discrepancy that may occur with limb-sparing procedures, those with extremity lesions
where it is not possible to acquire adequate surgical margins and where RT may produce
major long-term complications, those with lesions that involve major vessels or nerves where
resection will severely compromise function, and those in whom a fracture has resulted from
tumor and the limb is useless and painful (117,123). Simply put, in the skeletally immature
patient, due consideration must be given to the possibility that inappropriate or incorrectly
administered RT may produce a stiff, painful, shortened, or disfigured extremity and
engender a risk of secondary malignancy. Therefore, in some situations amputation may be
preferred.
The role of regional ly mph node dissection in NRSTS is evolving. Overall, the incidence
of nodal involvement is about 4%, ranging from close to 0% for grade 1–12% for grade 3
(6,61). It is reasonable to biopsy enlarged regional nodes in high-grade primary tumors.
Certain histologic subty pes are more prone to ly mphatic spread, including epithelial and
sy novial sarcomas, while others are not. Kay ton et al. (131) has published a small series using
sentinel node biopsies in pediatric tumors suggesting its utility in NRSTSs that are at risk for
ly mphatic spread.
Surgery also play s a role in managing NRSTS in the treatment of pulmonary metastases
(132,133). With proper patient selection, long-term survival is possible for those undergoing
removal of pulmonary metastases. Preoperative evaluation with chest radiograph and
thoracic CT scanning is performed to determine the number and location of the metastases.
Tumor may be resected via a median sternotomy or lateral thoracotomy. Two studies in the
literature, both of which included adult and pediatric patients, evaluated the important
prognostic factors predicting survival after pulmonary metastasectomy. Higher survival rates
appear to be associated with complete resection of all metastases, the presence of few lesions
(i.e., 1–3), and a long disease-free interval before the development of metastases. Patients
rendered free of disease in the series of Jablons et al. (134) had a median survival of 26.8
months. A similar group in the series of Casson et al. (135) had a median survival of 28
months. It is only fair to note that there are no randomized series in the literature comparing
surgery with observation or with chemotherapy without resection. Therefore, it cannot be
proven that the apparent prolongation of survival after surgery is attributable to the surgical
therapy as opposed to good tumor biology (134). As an alternative to surgical resection of
oligometastatic disease, there is an evolving experience with high-dose ablative and
hy pofractionated stereotactic body radiosurgery (136,137,138). With some of these
radiosurgical techniques, the surgeon may be asked to assist with the placement of radio-
opaque fiducial markers into the tumor mass to facilitate precise radiation dose delivery with
minimal normal tissue exposures.
Page 269Radiotherapy
We have previously noted that the local control rate for NRSTS increases as the extent of
surgical resection increases. This is undoubtedly because more radical surgery extirpates
microscopic extension of tumor. It is well known that radiation can also sterilize microscopic
extensions of tumor (139). We may infer that radiation can be used to accomplish that which
is achieved by increasing the extent of surgery (96). The judicious combination of limited
surgery and RT should be able to achieve local control rates equivalent to those of radical
surgery, with a superior functional result in many cases. Most of the available data support
this line of reasoning (96,125,139,140,141).
POG protocol 8653 was designed to study the role of adjuvant chemotherapy in children
with resectable NRSTS (142). Local therapy was standardized to include surgery only for
patients with wide or radical margins and surgery with postoperative irradiation for marginal
excisions. Protocol guidelines were imperfectly followed. The results indicate higher local
control rates with RT for marginal excisions in high-grade tumors (143) (Table 12.8 ).
There will be situations in which radical surgery is not recommended for children or is
recommended and declined because of unacceptable functional, cosmetic, emotional, or
psy chological consequences. RT may play a crucial role for these patients by allowing more
conservative surgery with equivalent rates of local control.
Table 12.8 POG Protocol 8653: Local Control by Surgical Margins and Radiotherapy
In retrospective reviews of adult patients with NRSTS, treatment with conservative

surgery and postoperative irradiation for microscopic extension of tumor y ields local failure
rates of 10–20%, comparable to those of radical surgery (96,119,120). In an analy sis of 132
patients, largely adults, treated with preoperative radiation and conservative resection at the
Massachusetts General Hospital (MGH), the local control results were 97% for patients with
negative surgical margins and 82% for those with positive margins (144). In a series confined
to children, the local control rate for patients who had no or microscopic residual disease after
surgery and who were treated with postoperative irradiation was 79% (40). Tumor grade and
size are the most important predictors of local failure in these series. The randomized
prospective NCI trial, including adults and children, compared limb-sparing surgery and
postoperative irradiation with amputation. The 5-y ear disease-free survival rate for the limb-
spared group was 69% and was 72% for the amputated group (p = 0.7). The local failure rate
was higher in the limb conservation group, and several patients had to undergo salvage
surgery (120,145). Psy chological tests indicate that the amputees fared as well as those
having limb-sparing surgery (146).
In addition to survival as an endpoint, one should also consider the functional outcome of
limb-sparing surgery with RT for NRSTS. A retrospective review of a large number of NCI
patients who underwent limb-sparing surgery with RT for extremity NRSTS indicates that the
most common long-term complications are contracture, limb edema, decreased range of
motion, and decreased muscle strength. Certain RT technical factors were associated with a
higher risk of complications: inclusion of more than 50% of a joint in the portal, dosages over
the equivalent of 63 Gy at 1.8 Gy per fraction, and large portals that encompassed more than
75% of the extremity diameter (147). Bertucio et al. (148) analy zed 30 patients with
extremity sarcomas who were y ounger than 21 y ears at diagnosis and received RT as part of
a limb-sparing treatment. Of the 30 patients, 11 had NRSTS, 8 had rhabdomy osarcoma, and
11 had Ewing sarcoma. On follow-up, 50% of the patients had no limitation of limb function
and 40% had full function but had a mild limp or needed a shoe lift, compression device, or
pins or rods.
Four retrospective reviews of the SJCRH clinical experience with NRSTS, published in
1999–2002, considered the role of adjuvant RT (6,99,100,121). In completely resected
disease (clinical group I), postoperative irradiation appeared to reduce local recurrences only
in high-grade disease. In patients with positive surgical margins (clinical group II), RT
reduced local recurrences (p = 0.001) (Table 12.9 ). Several retrospective reviews,
confined to children, have suggested a role for postoperative irradiation of NRSTS. RT has
been used, in accordance with the standards of the Intergroup Rhabdomy osarcoma Study, in
patients with group II (grossly complete tumor resection with microscopic residual disease or
involved but completely resected regional nodes) and group III (incomplete resection with
gross residual disease) NRSTS (5,40,59,88,104,116,149). In a series of 40 patients with
generally high-risk, initially unresectable (group III) tumors, there was a trend that combined
chemotherapy, RT, and surgical resection improved outcomes in a subset of 27 patients, with a
33% long-term EFS (100).
Page 270
Table 12.9 Factors Affecting Local Relapse in NRSTS in the St. Jude Children’s Research
Hospital Retrospective Reviews
While there are considerable concerns with delivering high-dose RT to children with
NRSTS due to developmental defects and an increased risk for secondary cancers, the role of
RT for high-grade, incompletely resected, or recurrent soft tissue sarcomas in adults is well
established. There is one randomized trial of surgery alone versus surgery and postoperative
RT for extremity soft tissue sarcomas. In this small study from the NCI, 91 patients with high-
grade lesions were randomly assigned to surgery plus postoperative chemotherapy with or
without postoperative adjuvant RT. Another 50 patients with low-grade lesions were
randomized to surgery plus adjuvant RT or surgery alone (150). RT to 45 Gy in 25 fractions
was delivered to a wide field followed by a boost for an additional 18 Gy to the tumor bed.
Among the patients with high-grade lesions, there were no local recurrences in the patients
who received RT, while for patients receiving only adjuvant chemotherapy, the actuarial local
failure rate was 22% at 10 y ears of follow-up. For patients with low-grade sarcomas, the
local relapse rates were 4% versus 33% for those receiving postoperative RT and resection
alone, respectively. As half of the “low-grade” patients had my xoid liposarcoma (possibly
undergraded) or desmoid tumors (known to respond to RT), this small randomized trial is not
definitive. Indeed, other retrospective studies of low-grade soft tissue sarcomas with a wide
resection generally have very low local recurrence rates, especially for superficial tumors.
Regardless, within this NCI trial, there was no influence of postoperative RT on overall
survival for either high- or low-grade tumors.
A common conundrum occurs when anticipating that there will be positive or close
margins at the time of surgery. For patients undergoing preoperative radiotherapy who are
found to have close or positive surgical margins when they ultimately undergo surgery,
postoperative radiotherapy has historically been a consideration. Such microscopic tumor
residua in the surgical bed may still be destined to die from the prior effects of radiotherapy,
however. Recent data from the several investigators suggest that there is little benefit to this
practice of delivering a postoperative boost in fact (151,152). Another consideration when
balancing potential toxicities and local control benefit from radiotherapy is to plan on the
integration of either brachy therapy or intraoperative radiotherapy directed at the surgical
bed. Placement of afterloading hollow catheters in conjunction with surgical resection helps
to better localize radiation dose where it is needed most. This is discussed below including
later in this chapter under radiotherapy techniques.
One such adult randomized RT trial from the Memorial Sloan–Kettering Cancer Center
(MSKCC) shows a benefit for high-grade extremity sarcomas managed with surgery and
brachy therapy (153). After complete resection of either extremity or superficial trunk soft
tissue sarcoma (45 low grade, 119 high grade), patients were randomized to surgery alone
versus low-dose-rate brachy therapy using afterloaded Ir-192 to deliver a dose of 45 Gy to
the tumor bed. In patients with high-grade sarcomas, the 5-y ear local control rates were 91%
with brachy therapy compared with 70% with surgery alone. There was no benefit to
brachy therapy for the low-grade tumors. Moreover, there was no difference among the
patient groups from brachy therapy in terms of distant metastasis or disease-specific survival.
The other major phase III study in adult sarcoma patients compared preoperative versus
postoperative RT (154). The theoretical advantage of preoperative RT is a smaller volume as
well as a lower dose of RT that must be employ ed. The RT need only be directed at the gross
tumor with a several centimeter margin, rather than having to encompass the larger surgical
resection bed. In the postoperative setting, higher radiation doses are generally employ ed to
counter any potential incremental tumor hy poxia or clonogenic repopulation during the
healing phase after surgery. Thus, preoperative RT in this setting tends to employ a radiation
prescription of 50 Gy compared with 64–70 Gy in the postoperative setting. The major
disadvantage of preoperative RT is a relative impairment of wound healing with a higher risk
of dehiscence and infection. Nevertheless, the concept of preoperative RT for NRSTS has not
been extensively studied. Certainly, there could be an improvement in function and lower risk
of secondary cancers with this approach.
More specifically, this Canadian trial comparing preoperative and postoperative RT
enrolled 190 patients, most more than 50 y ears old. The trial was open from 1994 to 1997 and
included patients with limb MFH, liposarcoma, leiomy osarcoma, and other spindle-cell
sarcoma histologies. Half received 50 Gy of preoperative RT and a 16–20 Gy postoperative
boost for a positive margin. Patients in the postoperative group received 50 Gy and a 16–20
Gy boost. In a planned interim analy sis, the study was terminated early due to higher wound
complications (defined as secondary wound surgery, hospital admission for wound care, or
the need for deep packing or prolonged wound dressings within 120 day s of tumor resection)
with the preoperative as opposed to postoperative RT (35% vs. 17%) (154). In subsequent
publications, the local recurrence rate, regional or distant failure rate, progression-free
survival, and functional outcome did not differ between the groups, with local control rates of
over 90% in both treatment groups at 7 y ears of follow-up (155,156). Of interest, the
postoperative RT patients have experienced greater late toxicity, particularly with greater
functional problems due to fibrosis within the irradiated volume. There were also trends
toward more ly mphedema and joint stiffness in this group contributing to adverse functional
outcomes (157).
Page 271Investigators from the University of Florida have reported on 95 NRSTS
patients, including those who were y oung adults who had resectable disease that was
managed with either preoperative RT to a median dose of 50.4 Gy or postoperative RT to a
median dose of 61 Gy (158). Overall local control was 12% at 5 y ears. Patients with close,
defined as less than 1 cm, or positive margins had inferior local recurrences in 8 out of 30
patients (27%) compared with 4 out of 64 patients (6%) with negative margins. There were
no associations based on grade, but as this was not a randomized trial, low-grade tumors
tended to not be irradiated in comparison to high-grade tumors. Finally, all local recurrences
led to ultimate death of the patient. The COG ARST0332 trial is described in more detail
below in conjunction with chemotherapy indications, but suffice it to say that low-grade,
localized NRSTS patients were divided into two separate schema of surgery alone versus
surgery and postoperative RT based on tumor size, grade, and surgical margins.
In conclusion, acceptable indications for RT in childhood NRSTS are localized,
incompletely resected tumor with gross residual disease; palliation of metastasis (palliation of
pain or compressive sy ndromes requires 35–50 Gy ; however, conventional RT is rarely
effective for gross lung metastases) (6,117); as part of a planned limb-sparing procedure; and
after an attempt at gross total tumor removal when there is microscopic residual tumor or
positive regional ly mph nodes. More attention to preoperative RT in pediatric NRSTS is likely
to become an active area of further investigation with encouraging recent cooperative group
studies mature, as also based on the evolving experience in adult soft tissue sarcomas. For
oligometastatic disease, there is recent enthusiasm for stereotactic body radiosurgery or high-
dose, hy pofractionated conformal RT as an alternative to surgery resection (136).
Chemotherapy
The use of adjuvant chemotherapy in childhood NRSTS initially was defended on the basis of
the significant risk of metastatic disease and local recurrence in high-grade lesions,
retrospective comparisons, and the success of chemotherapy in rhabdomy osarcoma. The
most active single agents are adriamy cin and ifosfamide (159). Other active agents are
dacarbazine, actinomy cin D, vincristine, etoposide, and cy clophosphamide
(6,59,69,88,94,104,118,145, 160,161). In this section of the chapter, we will review the most
pertinent larger-scale studies.
Cooperative Group Studies of Chemotherapy and NRSTS Exclusive of

PNET, EOES, and Askin Tumor
POG protocols 8653 and 8654 were open to patients y ounger than 21 y ears at diagnosis with
any biopsy -proven soft tissue sarcoma other than rhabdomy osarcoma, EOES, or
undifferentiated round-cell sarcoma. Children who were treated with surgical resection with
complete extirpation of tumor; surgical excision of the tumor with postoperative irradiation; or
biopsy, preoperative irradiation, and secondary surgery obtaining complete resection were
randomized to receive postoperative adjuvant vincristine, adriamy cin, and
cy clophosphamide (VAdrC) or observation. This randomization, constituting protocol 8653,
would be analogous, were one to use the rhabdomy osarcoma grouping sy stem for NRSTS, to
randomizing patients in groups I–III, including those rendered resectable by radiation (142).
Protocol 8654 was for patients who were judged to have inoperable tumors or for those
with metastatic disease. These patients were randomized to receive either VAdrC or VAdrC
plus dacarbazine. Involved-field radiation was administered to the primary tumor site (13).
Study 8653 was open from June 1986 to May 1992. Study 8654 was open from June 1986
through April 1994. However, there was approximately a 1-y ear period in which all patients
in Study 8654 were treated with vincristine, actinomy cin, and cy clophosphamide because of
a shortage of dacarbazine. There were 81 eligible patients for protocol 8653. Only 30 patients
accepted randomization: 15 received chemotherapy, and 15 were observed. Of the remaining
51 patients, 19 elected adjuvant chemotherapy and 32 elected observation. For the total group
of 81 patients, the 5-y ear overall survival was 85%, and the EFS was 72%. The 5-y ear EFS
for randomized patients was 69% for the chemotherapy arm and 87% for the observation
arm (Fig. 12.7 ). A grade 3 tumor conferred a significant disadvantage with respect to EFS.
The 3-y ear EFS was 75% for grade 3 and 91% for grades 1 and 2 (p = 0.018). Therefore,
there was no discernible benefit to the use of chemotherapy. For study 8654, 75 patients were
enrolled in this trial; the 4-y ear EFS for patients receiving vincristine, actinomy cin D,
cy clophosphamide, and adriamy cin (VACA) was no different from that for patients
receiving the four drugs plus dacarbazine. The 4-y ear overall survival and EFS were 31% and
18%, respectively (6,14,162). Not surprisingly, nonmetastatic and low-grade disease had
better outcomes relative to metastatic and high-grade disease.
Figure 12.7 Pediatric Oncology Group protocol 8653 randomized children with intergroup
rhabdomyosarcoma study groups I–III nonrhabdomyosarcoma soft tissue sarcoma to
observation or vincristine, cyclophosphamide, adriamycin, and actinomycin D. Of the 81
eligible patients, 15 were randomized to observation, 15 were randomized to chemotherapy,
19 elected chemotherapy, and 32 elected observation. The four survival curves show no
benefit to chemotherapy. (From Pratt CB, Pappo AS, Gieser P, et al. Role of adjuvant
chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous
soft tissue sarcomas: a Pediatric Oncology Group study. J Clin Oncol. 1999;17:1219–1226,
with permission.)
POG 9553 was a phase II trial of vincristine, ifosfamide, and doxorubicin in unresected
or metastatic NRSTS (12). Surgery was considered at week 7 with RT thereafter. Radiation
doses were age dependent: 54 Gy if under the age of 6 y ears and 64 Gy for those older.
Pulmonary metastasis management included low-dose whole-lung RT, although this is
currently a controversial practice. Doxorubicin was withheld during RT. Results were reported
for 39 patients. The 3-y ear overall survival and progression-free survival rates (± standard
deviation) for eligible patients were 59% ± 8% and 44% ± 7%, respectively. There was
suggestion that sy novial cell sarcomas responded better to chemotherapy compared with
other histologies.
Page 272The German soft tissue sarcoma study, CWS-81, was initiated in 1981 under the
auspices of the German Society of Pediatric Oncology. This study was open to children with
rhabdomy osarcoma, undifferentiated sarcoma, EOES, sy novial sarcoma, leiomy osarcoma,
peripheral PNET, fibrosarcoma, hemangiosarcoma, neurofibrosarcoma, and liposarcoma.
For the purposes of this chapter, we will confine our discussion to the results concerning
NRSTS, exclusive of EOES and PNET. Patients with localized, completely resected disease
received vincristine, actinomy cin D, cy clophosphamide, and adriamy cin. Patients with
grossly resected tumor, microscopic residual disease, and no evidence of regional node
involvement received the same chemotherapy, but also had involved-field irradiation. These
patients were then treated with vincristine, actinomy cin D, and cy clophosphamide. Patients
with grossly resected tumor with microscopic residual disease and regional nodal
involvement, or those with incomplete resection or biopsy with gross residual disease, initially
received four-drug chemotherapy. Those who were good responders continued on this
chemotherapy and received involved-field irradiation; ultimately, the adriamy cin was
discontinued. Those who were poor initial responders received involved-field irradiation, but
ifosfamide was substituted for cy clophosphamide. Patients who had stage IV disease
received vincristine, actinomy cin D, ifosfamide, and adriamy cin. In 1984, ifosfamide was
also added for patients with stage III disease who did not respond to preoperative
chemotherapy. Detailed information is available concerning the 30 children and adolescents
with sy novial sarcomas treated on this study (163). A survival rate of 70% was observed, with
a median observation time of 34 months. Patients with sy novial sarcoma of the extremities
had a disease-free survival rate of 88%. Six of eight patients who had their tumors resected
with no residual disease are disease-free survivors, seven out of nine patients who had their
tumor resected with microscopic residual disease are disease-free survivors, six of eight
patients who have had their tumor resected with gross residual disease are disease-free
survivors, and three of five patients with metastatic disease at presentation (stage IV) are
disease-free survivors. Obviously, the German study was not a head-to-head comparison of
chemotherapy and observation, and it is not clear what the survival would have been if
patients were treated with local therapy alone.
The International Society of Pediatric Oncology (SIOP) has conducted two protocols for
NRSTS. The treatment program consisted of primary complete tumor excision, if feasible
without mutilation. For patients who were not resectable initially, neoadjuvant chemotherapy
was administered. Initial chemotherapy was ifosfamide, vincristine, and actinomy cin D.
Second-line chemotherapy on study MMT84 was cy clophosphamide and doxorubicin, and in
study MMT89 it was epirubicin, doxorubicin, carboplatin, and VM26. Patients were then taken
to surgery, if possible. RT was used for macroscopic residual tumor after surgery. For patients
who had initial primary excision, adjuvant chemotherapy was given with ifosfamide,
vincristine, and actinomy cin D. In nonmetastatic patients an initial complete excision was
obtained in 24% of patients, complete response was obtained in 30% of patients by initial
partial excision followed by chemotherapy, and a complete response was obtained in 30% of
patients by an initial biopsy, neoadjuvant chemotherapy, and second surgery. In 8% of
patients, a complete tumor response was obtained by surgery, chemotherapy, and RT, and in
another 8% of patients complete response was obtained by surgery, chemotherapy, second
surgery, and RT. Therefore, 16% of patients received RT. The overall survival rate in study
MMT84 was 73% at 5 y ears for nonmetastatic patients, and in MMT89 it was 84%. Survival
was only 15% for metastatic patients. The 5-y ear survival rate was 60% for fibrosarcoma,
leiomy osarcoma, sy novial sarcoma, and other classified sarcomas and 50% for PNET and
EOES (45,164). Very y oung patients represent a considerable challenge in which surgery is
performed with very tight margins, chemotherapy has to be attenuated due to altered
metabolism of drugs, and RT is generally avoided. A report from SIOP that included 38
patients with NRSTS treated on the MMT84 and MMT89 protocols suggested that patients less
than 1 y ear of age at diagnosis had similar survivals to older patients (75% in infants and 71%
in older children, p = 0.61) (165). Data were not specified for the subset of nonmetastatic
tumors.
Page 273Large-Scale Studies of Adjuvant Chemotherapy in Adults with

NRSTS
There are at least 18 randomized prospective trials of mostly adult patients evaluating
adjuvant chemotherapy for NRSTS. These studies include comparisons of observation with
doxorubicin as a single agent; with doxorubicin, cy clophosphamide, dacarbazine, and
vincristine; with adriamy cin, vincristine, cy clophosphamide, dactinomy cin, and dacarbazine;
with doxorubicin, cy clophosphamide, and methotrexate; with doxorubicin,
cy clophosphamide, vincristine, and dacarbazine; and with doxorubicin and ifosfamide. The
majority of these studies are equivocal as to the benefit of adjuvant chemotherapy. We will
briefly summarize some of the larger published trials.
The NCI trial was conducted for patients with stages IIA–IIIB extremity soft tissue
sarcoma. Patients underwent either amputation or limb-sparing surgery followed by RT.
They were then randomized to observation or adriamy cin and cy clophosphamide. After a
maximum cumulative dosage of adriamy cin, chemotherapy was switched to methotrexate
with leucovorin rescue. At a median follow-up of 7.1 y ears, the 5-y ear relapse-free survival
was better for patients who received chemotherapy (p = 0.04); however, the difference in
overall survival was not significant (118,123,145).
The Scandinavian Sarcoma Group randomized 240 patients with high-grade sarcomas to
receive either adriamy cin or no sy stemic treatment. No significant difference was seen
between the adriamy cin and control groups with respect to local recurrence, relapse-free
survival, or overall survival for the 181 evaluable or the 240 randomized patients (166).
The European Organization for the Research and Treatment of Cancer’s (EORTC) Soft
Tissue and Bone Sarcoma Group conducted a phase III trial of chemotherapy after local
therapy of histologically proven soft tissue sarcoma in adults with either surgery or RT.
Randomization was to treatment with cy clophosphamide, vincristine, adriamy cin, and
dacarbazine or to observation. Between 1997 and 1998, 468 patients entered the study ; 151
patients were considered ineligible. The mean follow-up duration was 80 months. Relapse-
free survival with chemotherapy was 56%, compared with 43% for control subjects (p =
0.006); local recurrence was lower in the chemotherapy arm (17% vs. 31%, p = 0.0041), but
overall survival did not differ significantly between the two arms (66% for chemotherapy vs.
55% for observation, p = 0.64). In patients with extremity tumors, no significant improvement
was seen with chemotherapy in terms of local recurrence, metastases, or survival. In
contrast, local recurrence was lower with chemotherapy for head, neck, and trunk sarcomas
(167).
An Italian cooperative group compared adjuvant epirubicin, ifosfamide, sodium
mercaptoethane sulfonate (MESNA), and granulocy te colony -stimulating factor (G-CSF)
with a control group (168). There was a median disease-free survival of 16 months in the
control group, compared with 48 months in the adjuvant group (p = 0.04), and an
improvement in median survival from 46 to 75 months (p = 0.03). There was thought to be an
improvement in survival at 4 y ears in the adjuvant arm on a planned interim analy sis of the
data. However, a closer analy sis of the data showed that the adjuvant chemotherapy group
experienced fewer metastatic events at 2 y ears (28% vs. 45%, p = 0.08). By 4 y ears, this
difference had disappeared, with 44% of the control group having metastatic disease and 45%
in the group treated adjuvantly (p = 0.94). The difference in disease-free survival in the
groups at 4 y ears was related to a significantly greater frequency of local failure in the
patients in the control group (17% vs. 6% in those receiving chemotherapy ).
Several meta-analy ses have been published. A widely quoted 1997 analy sis included 14
earlier trials of 1568 patients—fewer than 1% of the patients were y ounger than 15 y ears—
showing an improvement in local control and disease-free survival, but not overall survival
(169). About two-thirds of the analy zed patients had high-grade tumors, and one-half
received RT (169,170,171). With several more recent trials emphasizing the addition of
ifosfamide to doxorubicin, an updated 2008 meta-analy sis of 1953 patients shows an overall
survival advantage in a subset analy sis (172). More specifically, the odds ratio for local
recurrence and overall recurrence were 0.73 and 0.67, respectively, in favor of
chemotherapy. These statistically significant values were similar to the earlier meta-analy sis,
but in this update the odds ratio for overall survival was 0.56 (0.36–0.85, 95% confidence
interval [CI]) in favor of doxorubicin and ifosfamide combination chemotherapy.
Doxorubicin alone (OR 0.84, 0.68–1.03, 95% CI) was not associated with a statistically
significant overall survival benefit. The absolute risk reduction for ifosfamide/doxorubicin was
11% (30% vs. 41% risk of death). The major caveat to these findings is that two large EORTC
trials of adjuvant ifosfamide/doxorubicin chemotherapy in 819 patients were not included in
this updated meta-analy sis; the preliminary analy sis of these additional trials does not show a
survival advantage (173). The meta-analy ses have demonstrated a trend that the most benefit
to chemotherapy is seen in patients with bulky and high-grade tumors. Particular histologic
subty pes were not found to be more chemosensitive, although a variety of individual reports
suggest otherwise. For instance, there is a school of thought that sy novial cell sarcomas and
round-cell/mesenchy mal liposarcomas may be more responsive to chemotherapy.
Page 274Patients with metastatic disease are infrequently cured. A recent study of adults
with NRSTS from institutions participating in the Scandinavian Sarcoma Group described a
highly select group of 38 patients with metastatic NRSTS or locally advanced disease and
who had achieved a complete response with chemotherapy alone or chemotherapy followed
by surgery. The drug programs used were vincristine, ifosfamide, MESNA, and G-CSF
(VIG), VIG with doxorubicin, or ifosfamide, vincristine, doxorubicin, dacarbazine, and
MESNA. The 2-y ear disease-free survival, even in this select group, was only 34%. In
general, the complete response rate to chemotherapy in advanced NRSTS is less than 10%,
and the combined complete and partial response rate is less than 50% (174).
The drugs used for the adjuvant treatment of NRSTS, particularly doxorubicin, have
significant toxicities. With the data currently available, chemotherapy probably is not the
appropriate adjuvant therapy for low-grade NRSTS treated with appropriate local therapy. As
already noted, for high-grade lesions, trials are ongoing to evaluate drug combinations such as
doxorubicin and ifosfamide. It has been argued that improved staging and better local control
techniques have been the major contributing factors to improved survival in NRSTS, as
opposed to any benefits of chemotherapy. Adjuvant therapy for NRSTS is best given in the
context of a clinical trial. However, chemotherapy often is given as a component of the
treatment of metastatic disease.
Modern USA and European Pediatric Cooperative Group Trials for

NRSTS with Selective Use of Adjuvant Therapies Based on Risk
The COG ARST 0332 represents the best effort to date to treat patients in a unified risk-
adapted schema in a cooperative group setting that tries to minimize the use of RT relative to
adult management given the concerns for late toxicities. As such, 30% of the eligible patients
did not receive RT (15). Figure 12.8 outlines the treatment scheme in which 551 patients
were allocated into four treatment strata and correspondingly into three risk-group categories.
The grossly resectable NRSTS patients were divided into four separate clinical treatment
groups. Clinical Group A underwent definitive surgical resection without radiotherapy for any
low-grade tumors less than 5 cm in diameter, irrespective of surgical margins, including the
complete resection of any metastases. Clinical Group B underwent definitive surgical
resection followed by postoperative radiotherapy to a total dose of 55.8 Gy for patients with
high-grade tumors less than 5 cm with positive surgical margins. The surgical concept was to
manage patients without RT if resection avoiding interrupting a fascial plane. Notably, there is
some precedence for managing well-selected adult patients with small, high-grade,
superficial sarcomas with surgery alone in several published series (175,176,177,178). The
use of adjuvant ifosfamide and doxorubicin chemotherapy after definitive surgical resection
preceded RT for Clinical Group C patients in setting of tumors at least 5 cm and high histologic
grade as well as a select group of patients with high-grade metastatic disease completely
resected. Note is made that this trial avoided postoperative RT for small, high-grade tumors
with positive margins and used a lower radiation dose than in adult practice in which
retrospective reviews show that postoperative radiation doses in the 60–66 Gy range is
optimal (179). For patients whose disease was not resectable upfront, Group D patients
received preoperative chemotherapy and radiotherapy, with the later employ ing 45 Gy.
Postoperative boosts were mandated if eventual surgery resulted in positive pathologic
margins.
Figure 12.8 Treatment schema in COG ASRT0332 trial.
Page 275Nonmetastatic Group A and B were deemed low-risk (LR) strata.

Nonmetastatic group C and D were intermediate risk (IR) strata. And those with metastatic
disease including only ly mphatic spread were high risk (HR). The preliminary results of COG
ARST 0331 by risk group with a median follow-up of 2.6 y ears have been presented. The 3-
y ear EFS and overall survival rates by risk group are: LR 83% and 97%; IR 79% and 93%;
and HR 16% and 29%, respectively (15). Moreover, this categorization of patients into these
three risk groupings has been validated in a population cohort from the SEER database (44).
We await further analy sis and follow-up data from this recently closed trial to see if any
subsets of patients who in adult practice would have been managed differently with respect to
use avoidance of RT or use of lower doses have excessive local recurrence rates. But for the
moment, this complex trial supports a new standard of care in the United States for pediatric
soft tissue sarcomas.
In summary, relatively few pediatric patients with NRSTS have been studied in
cooperative groups, but treatment guidelines based on a relatively large COG ARST 0332
now exist. The small POG study that randomized patients with NRSTS to chemotherapy or
observation showed no benefit to chemotherapy. But for patients with more locally advanced
tumors, preoperative sequential chemotherapy and radiotherapy may be beneficial.
Nevertheless, the two major international cooperative groups have adapted similar treatment
strategies with their current investigational protocols. The COG represents most centers in the
United States. In Europe, the German and Italian cooperative groups have combined their
efforts with a series of reports on pediatric soft tissue sarcomas (66,67,90,180,181); however,
more recently since 2000, a European-wide consortium called the European Paediatric Soft
Tissue Sarcoma Study Group (EPSSG) is sponsoring an NRSTS trial open since 2005. The
essential strategy in both the United States and Europe is to risk stratify patients based on
tumor size, grade, localized versus metastatic, and resectability. Intermediate- and high-risk
patients receive ifosfamide and doxorubicin chemotherapy (159). Surgery is emphasized for
local management, but with adjuvant or preoperative RT or chemoradiotherapy in a risk-
adapted treatment schema. In metastatic NRSTS, the EPSSG has shown some activity from
the combination of ifosfamide, doxorubicin, vincristine, and actinomy cin D (182). Of the
more common subty pes of NRSTS, there are now suggestive data that nonmetastatic sy novial
cell sarcoma patients reap the most benefit from trimodality therapy (44,160,183). MPNSTs,
on the other hand, do worse and seem less responsive to chemotherapy and radiotherapy as
adjuncts to surgery (44,160).
Figure: POG Protocol 8653: Local Control by
Surgical Margins and Radiotherapy
Figure: Factors Affecting Local Relapse in
NRSTS in the St. Jude Children’s Research
Hospital Retrospective Reviews
Figure:
Pediatric Oncology Group protocol 8653 randomized children with intergroup
rhabdomyosarcoma study groups I–III nonrhabdomyosarcoma soft tissue sarcoma to
observation or vincristine, cyclophosphamide, adriamycin, and actinomycin D. Of the 81
eligible patients, 15 were randomized to observation, 15 were randomized to chemotherapy,
19 elected chemotherapy, and 32 elected observation. The four survival curves show no
benefit to chemotherapy.
(From Pratt CB, Pappo AS, Gieser P, et al. Role of adjuvant chemotherapy in the treatment
of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric
Oncology Group study. J Clin Oncol. 1999;17:1219–1226, with permission.)
Figure:
Treatment schema in COG ASRT0332 trial.
RT for childhood NRSTS may be administered after biopsy but before definitive surgery
(preoperatively ), postoperatively, or intraoperatively. The arguments for preoperative
irradiation include the following. First, preoperative treatment will produce partial regression
of the tumor, and the resection may be less extensive than if the surgery had been done
initially. Second, preoperative treatment may decrease the risk of autotransplantation of the
tumor in the surgical bed and may also decrease the risk of intravascular seeding. Third, in
preoperative treatment, the clinically and radiographically demonstrable areas of risk are
treated, while other tissues are shielded (184,185). In addition, because postoperative
treatment must cover all surgically manipulated areas, the irradiated volume often is larger.
Finally, the postoperative surgical bed may be poorly vascularized. The concern regarding
tumor cell hy poxia in this setting has led to higher radiation doses being required. Results of
the Canadian randomized trial suggest an equivalence of 50 Gy preoperatively to 66–70 Gy
postoperatively (154,156).
Some of the results of preoperative RT in combined adult and pediatric series of NRSTS
from single institutions are also promising. Suit and coworkers (96,119) achieved an 88% 5-
y ear actuarial local control rate and a 66% survival with limited surgery and RT in 258
patients with extremity and head and neck primaries. These results have been echoed in other
studies (102,186). Eilber et al. (125,127) administered preoperative external beam irradiation
and intra-arterial doxorubicin (30 mg/day for 3 day s) followed by limb-sparing surgery for
extremity sarcomas. The local control rate was 96% for patients who received 35 Gy, 90–
95% for those who received 28 Gy, and 82% for those who received 17.5 Gy.
The disadvantages of preoperative therapy include a delay in the start of definitive
surgery, loss of ability to examine the whole tumor specimen for stage and grade, and loss of
the ability to surgically assess the extent of the disease. Therefore, many radiotherapists and
surgeons favor postoperative treatment. Postoperative RT must be delay ed until adequate
wound healing has occurred (96,119). A retrospective review comparing preoperative and
postoperative external beam irradiation from the University of Minnesota for adults with
NRSTS found no significant difference in overall or relapse-free survival or local control.
However, wound complications were more common in preoperative RT patients (31% vs.
8%, p = 0.0014) (184). Several other centers have performed retrospective comparisons of
preoperative and postoperative irradiation in series of largely adult patients. Some studies
favor preoperative treatment (96,187); others do not (117,188). The aforementioned
randomized trial of preoperative versus postoperative RT conducted at the Princess Margaret
Hospital for adult patients with soft tissue sarcomas presents the best data supporting
preoperative RT (154,155,156,157). While there were more problems with wound healing
after RT as compared with postoperative RT (35% vs. 17%, p = 0.01), proper selection of
patients and surgical attention to avoiding tension on the surgical wound may help mitigate this
problem. Preoperative RT uses lower radiation doses (50 Gy vs. 66–70 Gy ) and smaller
treatment volumes. This translates into lower late complications with fibrosis, ly mphedema,
and joint stiffness. And importantly, the local and distant control of disease is equivalent with
the two approaches of preoperative versus postoperative RT.
Page 276Most agree that wound complications are higher with preoperative treatment
(187,188). When the therapeutic plan includes external beam radiotherapy (EBRT) and
surgery for the local treatment of NRSTS, it is generally preferable to completely excise
small lesions and treat with postoperative irradiation when indicated. Small, low-grade lesions
resected with good surgical margins may be observed. Resected tumors with high-risk
features, including large-size, high-grade, or positive surgical margins should be considered
for postoperative RT. High-grade tumors that have been cleanly resected have controversial
indications for postoperative RT due to the concerns about late effects. As noted above, the
COG ARST 0332 trial allocated small, high-grade, negative-margin tumors to surgery alone,
while in adult practice some of these patients might be treated with adjuvant radiotherapy.
Positive surgical margins (group II disease) are a clear indication for postoperative RT.
Paulino published a series of 83 NRSTS patients managed at the University of Iowa (50).
Overall local control rate at both 5 and 10 y ears was 66%. On multivariate analy sis, the size
of the tumor and postoperative RT were prognostic factors for local control. Twenty -five
patients had positive surgical margins. Five-y ear local control rates were significantly
improved with the use of RT, 82% versus 43%, p = 0.04. In a subset of 13 group I patients with
low-grade, small tumors, surgery alone resulted in no local recurrences. On the other end of
the spectrum of localized NRSTS, most large lesions, particularly of high grade, are better
treated with biopsy, preoperative irradiation or chemoradiation, and then excision. While the
actual evidence for postoperative radiotherapy in the pediatric setting after surgical resection
in NRSTS is sparse, there is support as nicely reviewed by Million and Donaldson (189).
Volume
Extremity NRSTSs tend to grow in a longitudinal fashion by following muscle groups.
Historically, generous proximal and distal margins bey ond the tumor volume (5–10 cm) have
been used. Because the lesions usually do not cross muscle compartments, the
circumferential margins may be more modest (120). Krasin and colleagues have reported on
a small series of 32 high-grade NRSTS cases in which 2-cm margins around gross tumor
volumes were chosen (190). Median doses for preoperative and postoperative radiotherapy
were 45 Gy and 60 Gy, respectively. The 3-y ear local recurrence rate was 4%. Local
recurrences were in the high-dose radiation volume and correlated with those patients who
had marginal resections.
A limb MRI scan, followed by a computerized treatment plan, is extremely helpful.
Peritumoral edema within a muscle compartment seen on MRI scanning has a high likelihood
of harboring microscopic tumor and should be targeted (191). The treatment of sarcomas
often is a venue for the demonstration of the benefits of intensity -modulated radiation therapy
(IMRT), three-dimensional (3D) treatment planning techniques, tissue compensators, wedges,
customized blocking, and rigid immobilization for reproducible treatments. The use of
intensity -modulated radiotherapy to better conform the high-dose radiation distribution to the
tumor region may well reduce developmental toxicities, but comes with the theoretical
problem of increased integral dose which may increase the later risk for secondary cancers
(192,193). One should avoid high-dose irradiation of the entire width of a limb in order to
avoid severe ly mphedema (radiation-induced elephantiasis) (117). Blocking should be used to
avoid the anky losis attendant to the high-dose irradiation of the full width of a joint (139).
Growth plates should be shielded when possible (although it is usually better to fully treat a
growth plate and shorten a limb rather than asy mmetrically irradiate a growth plate and
angulate a limb). There is also an evolving understanding that fractures may be minimized by
reducing the volume of bone, especially weight-bearing bones such as the femur, being
treated to high doses (129,130). The use of IMRT and proton RT is under investigation in this
regard. In nonextremity lesions, the tumor volume must be covered with as generous a
margin as is feasible. In children with NRSTS, there may be a more compelling reason to use
IMRT or protons to reduce the exposure of normal tissues. In fact, particle therapy, such as
protons, is enthusiastically under investigation and has shown preliminary benefit in Ewing
sarcoma and rhabdomy osarcomas (194,195,196). Limiting the high-dose regions to the
affected muscle compartment, while reducing dose to adjacent bone, growth plates, joints,
other muscle groups, skin, and uninvolved neurovascular bundles, may result in better
functional outcomes and less developmental toxicities. IMRT also facilitates differential
dosing or a dose gradient between gross tumor and adjacent normal tissues, which can be
important in limiting toxicities or escalating radiation dose in cases of unresectable disease.
For instance, with retroperitoneal sarcomas, investigations are underway in adults to deliver
higher preoperative doses within the target volume where a tight surgical margin is
anticipated, while potentially lowering dose to the intestines and kidney. Similar concepts are
adaptable to childhood NRSTS. The rational reduction in radial margins with these techniques
requires the technical advances of cross-sectional imaging with 3D treatment planning, an
anatomic understanding of tissues at risk, and precise immobilization and field verification.
Epithelioid sarcoma and sy novial sarcoma may metastasize to ly mph nodes in 10–20%
of cases (5,59,197,198,199,200). Some phy sicians use elective ly mph node irradiation for
these lesions, particularly high-grade tumors. Its efficacy is unknown.
Page 277Dosage
Modern radiobiologic evidence gives little credence to the assertion that NRSTSs are
inherently radioresistant. The available retrospective reviews suggest that a minimum of 40
Gy is necessary for the postoperative control of microscopic NRSTS in children (88,116). At
these dosages, however, there is a substantial chance of local failure. More aggressive
treatment is generally warranted. Several investigators favor a dosage of 50–60 Gy using a
shrinking field technique (96,117,201). In a University of Florida series for excised pediatric
NRSTS tumors, 54 Gy appeared to be an adequate total dose (143,202). Although
hy perfractionation is out of favor after a negative randomized trial in rhabdomy osarcoma
(203), some clinicians have suggested the use of twice-a-day irradiation (i.e., 1.1–1.2 Gy
twice daily to 66–72 Gy ) (67,117). In adults, however, a retrospective analy sis from the M.
D. Anderson Cancer Center suggests that cumulative doses of at least 64 Gy are optimal
(204). Another analy sis from the University of Chicago suggests 60 Gy is adequate with no
benefit to higher postoperative doses when there are negative surgical margins, but poor
lower control with lower doses (179). As previously noted, the COG ARST 0332 trial
employ ed 55.8 Gy in 31 fractions as a standard postoperative RT dose (15).
For preoperative treatment, lower radiation doses may be used on the order of 50 Gy.
The COG ARST 0322 trial used 45 Gy for a preoperative radiotherapy dose (15). The
administration of additional radiation given postoperatively if there are positive surgical
margins is now considered controversial (151). Historical experience in the POG used
different radiation dose levels depending on age, which has become a less favored concept.
POG protocol 8653 intended that unresectable (i.e., group III) tumors receive preoperative
RT to 55 Gy for children less than 6 y ears of age and 65 Gy for older children. At least six
patients—out of an unclear number of group III patients—had an insufficient response and
could not undergo planned resection (14). POG 9553 used either 54 or 64 Gy (depending on
the age of the child), following initial chemotherapy, in a prospective series of 25 children
with group III NRSTS. This preoperative management resulted in a 3-y ear overall survival
rate of 80% and progression-free survival of 60% (12). A retrospective series from St. Jude
Children’s Research Hospital of 27 patients with localized unresected NRSTS and a 33% 5-
y ear EFS included 15 patients who received preoperative RT, most often with chemotherapy ;
the RT doses ranged from 35 to 65 Gy, but these dose tallies included some component of
postoperative RT (100). As one of the larger of such series, there is no clarification of optimal
radiation doses for group III NRSTS patients such that the adult experience gives the best
guidance for the present. But as previously noted, COG ARST 0332 employ ed a preoperative
RT dose of 45 Gy, modestly less than the 50 Gy standard used for adults.
When intraoperative boosts with brachy therapy or electrons are given as part of a
combined approach, the dosage usually is 10–20 Gy. Gross residual sarcoma requires 65–72
Gy by external beam and implant (40,119,120). Some adult patients with unresectable lesions
have been treated with external beam and intravenous radiosensitizers, external beam plus
hy perthermia, combined brachy therapy and interstitial hy perthermia, or neutron beam
therapy (42,205).
Brachytherapy and Intraoperative Radiation Therapy

Brachy therapy may play an important role in limb-sparing surgery for NRSTS (206).
Brachy therapy is often, but not alway s, given in combination with preoperative or
postoperative external beam treatment. Brachy therapy has the following potential
advantages: Its radiobiologic effectiveness is increased by the administration of a high dosage
of irradiation over a few day s rather than several weeks; an intense dose is given deep in the
tumor bed; surrounding normal tissue and overly ing skin are spared through the rapid falloff
of the dosage; and the short treatment time is more convenient, avoiding the problems of
travel and housing for protracted external beam therapy (140,207,208).
Conventional afterloading brachy therapy is suitable for children capable of doing self-
care. It is more complex, from a nursing standpoint, in y ounger children. Several techniques
are available for brachy therapy for NRSTS in children. The most commonly used ty pe is a
manually loaded low-dose rate sy stem. Plastic catheters are inserted into the target volume
with the aid of hollow needles. These catheters are subsequently loaded with the radioactive
sources. Needles may be placed freehand or with the assistance of a custom-built or
standardized template. Intracavitary applicators have been developed for use in treating
vaginal sarcomas and lesions of the upper aerodigestive track. Most commonly, iridium-192
or cesium-137 is used. When there is particular concern about radiation exposure to nursing
personnel or parents, and if the anatomy of the tumor allows, one should consider using a
low-energy radioisotope such as iodine-125 or palladium-103. When these isotopes are used,
thin sheets of lead applied over the treatment area or a standard lead apron provides a
measure of protection for visitors.
In a conventional low-dose rate afterloading procedure, the afterloading catheters are
placed at the time of surgical excision. After tumor excision, the radiation oncologist and
surgeon inspect the operative bed and plan the implant. Parallel plastic catheters are placed
approximately 1 cm apart throughout the entire tumor bed, usually with a 1-to-2-cm margins.
For extremity lesions, some radiation oncologists place the catheters parallel to the axis of the
limb (i.e., parallel to the incision), whereas others place catheters perpendicular to the axis of
the incision and limb. Postoperative radiographs are taken with dummy sources to calculate
the dose distribution and rate. Initial wound healing is allowed to begin, and the catheters are
afterloaded with iridium-192 (the most commonly used isotope in this situation) around the
sixth postoperative day. Earlier loading is associated with a significant risk of wound
complications, up to a 44% incidence (209,210). When the situation warrants it, catheters
may be placed adjacent to bone or neurovascular bundles. In general, little irradiation is
given via the implant to the superficial incision. Figures 12.9 and 12.10 are two
illustrative examples of afterloading brachy therapy used as a boost for hand sarcomas
(although the second case was ultimately associated with a local recurrence).
Page 278
Figure 12.9 A: Orthogonal films of brachytherapy catheters and Ir-192 sources. B:

Brachytherapy dose distribution in axial projection. C: Simulator film of external beam field.
Figure 12.10 A: CT scout film showing the brachytherapy catheters. B: The
brachytherapy volume of the 45 cGy/hour isodose relative to the boney anatomy. C: The
brachytherapy dose distribution in the axial projection. D: Simulator film of the external
beam field.
The second general technique of pediatric brachy therapy for NRSTS involves
permanent interstitial implant. Low-activity iodine-125, gold-198, or palladium-103 seeds are
used. They may be placed with the use of a seed gun (a device used for their implantation),
through individual needles, or embedded in Vicry l suture material and then sewn into the
tumor bed. Although the low energy of these radioactive sources lowers the risk to visitors,
these implants often are extremely difficult to perform.
The third form of brachy therapy for pediatric NRSTS is remote afterloading. This may
be done at a low-dose rate, high-dose rate, or pulsed-dose rate (intermittent use of a high-dose
rate machine). The catheters or applicators are inserted into, or placed on, the tumor site.
They are then connected to the afterloader for remotely controlled radioactive loading. The
radioactive sources are retracted into the high-dose rate applicator’s vault during planned
interruptions. The procedure may be done in an outpatient clinic or operating room. Some
departments have specially designated rooms for this purpose. Intraoperative high-dose rate
brachy therapy is a modification of this general technique (209,210,211,212,213,214).
In the treatment of NRSTS, brachy therapy may be used as a boost after or before EBRT,
or as a form of irradiation monotherapy (100). In general, the planning volume for
brachy therapy for NRSTS is smaller than for EBRT. In brachy therapy, the volume treated
closely approximates the clinical target volume. There is no need to allow for internal organ
movement, patient movement, or setup errors. Because the dosage from the radioisotope falls
off rapidly, the volume of normal tissue irradiated outside the planning target volume is
minimized.
Page 279When brachy therapy is the sole form of irradiation to be given, surgical drain
sites usually are not implanted. In adult practice, if 45–50 Gy of external irradiation is given
as part of a course of treatment, the brachy therapy boost generally is 10–20 Gy at about 50
cGy per hour. If brachy therapy is the sole form of irradiation used in combination with
surgery, then 40–50 Gy in 4 or 5 day s is given. The role of brachy therapy in adult NRSTS has
been evaluated in several retrospective reviews, but some randomized prospective trials are
particularly noteworthy. Between 1982 and 1987, 126 patients, mostly adults, with soft tissue
sarcoma were entered into the aforementioned prospective randomized trial at MSKCC
(153,215). Patients underwent a grossly complete resection with a limb-sparing operation for
NRSTS of the extremity or superficial trunk. Intraoperatively, after the resection was
complete, patients were randomized to receive either adjuvant brachy therapy or no adjuvant
therapy. Patients who received the implant had a dosage of 42–45 Gy administered with
iridium-192 over a 4- to 6-day period. The median follow-up of this trial was 76 months. The
5-y ear actuarial local control rate for high-grade tumors was 89% for brachy therapy -treated
patients and 66% for control subjects (p = 0.0025). There was no local control benefit in the
low-grade tumor group.
The improved local control with brachy therapy in high-grade tumors did not translate
into an overall decrease in distant metastasis. Even in the high-grade tumor, freedom from
distant metastases was approximately 70% at 5 y ears in both the brachy therapy and control
arms (215,216). This trial is of interest not only because it demonstrated a benefit to adjuvant
brachy therapy but also because it showed a benefit to a form of therapy that, in contrast to
adjuvant external beam irradiation, generally does not irradiate the full surgical scar, does not
irradiate the drain site, is shorter in duration (10–14 day s of hospitalization vs. 6–7 weeks of
outpatient treatment), and is slightly less costly.
Page 280The team from MSKCC elected to explore the use of brachy therapy in low-
grade tumors in more detail because their initial randomized trial did not include a large
number of patients with low-grade NRSTS. From 1982 to 1992, they randomized 45 patients
with low-grade tumors to brachy therapy or observation. There was no benefit to
brachy therapy in terms of local recurrence (about 76% local control in each arm, p = 0.60)
or overall survival (p = 0.38). In two studies, patients with high-grade NRSTS with a negative
margin had 89% and 94% local control rates, respectively, when treated with brachy therapy,
compared with 59% and 77% in those with a positive margin. In patients with high-grade
tumors and positive margins treated with brachy therapy and external beam irradiation, the
local control rate was 90% (209,215,217). In the view of the investigators, these two
randomized trials argue in favor of adjuvant brachy therapy for resected high-grade tumors,
for surgery alone as the treatment for resected low-grade tumors smaller than 5 cm, and for
consideration of external beam for resected low-grade tumors larger than 5 cm because of
the remaining high risk of local recurrence in these tumors (i.e., 20–25%). In the early y ears
of the MSKCC trials, there was a substantially higher rate of wound complications in the
brachy therapy -treated patients than those in control subjects (44% vs. 14%, p = 0.0006). The
higher rate of complications has been alleviated by a policy of not loading patients with
radioactivity until the fifth postoperative day (216). Burmeister et al. (210), in Australia,
obtained slightly less satisfactory results with brachy therapy and external beam therapy in
patients with large high-grade sarcomas with close or positive margins. When brachy therapy
is used as the only form of RT, some of the local failures result from marginal misses
(140,208,215,218). In the Institut Gustave–Roussy series, 14 of 16 local failures were
marginal or distant from the high-dose brachy therapy region (218).
Data from approximately 100–150 children given brachy therapy for the treatment of
rhabdomy osarcoma and NRSTS have been reported. The techniques have included low-dose
rate applications, high-dose rate applications, and pulse applications. Although the local
control rate is excellent, it is clear from the retrospective reviews that careful patient selection
is essential for successful outcomes. In general, brachy therapy seems to be most appropriate
for patients who have NRSTS, microscopic small-volume residual disease at an accessible
site and for those who have responded well to chemotherapy, external beam RT, and surgery.
The American Brachy therapy Society ’s recommendations for brachy therapy for soft tissue
sarcomas offer general guidelines as to the appropriate dosage. When brachy therapy alone is
used, 45–50 Gy is administered over 4–6 day s. For patients in whom low-dose-rate
brachy therapy is used in combination with EBRT (generally 40–50 Gy ), a 15- to 25-Gy boost
is given. There are few clinical data to invoke in selecting dosages for fractionated high-dose-
rate brachy therapy. When high-dose-rate therapy is used as the sole local control modality, a
dosage of 2.5–3 Gy twice daily, to a total dosage of 30–36 Gy, may be considered (213,214).
If high-dose-rate brachy therapy is used as a boost to EBRT, then the linear quadratic model
can be used to devise a fractionated scheme that generates the equivalent to a low-dose-rate
brachy therapy dosage of 15–25 Gy (212,213).
What are we to conclude, on the basis of
these NRSTS studies, concerning the role of
brachy therapy in pediatric patients?
Brachy therapy should be considered as an
option in treating children. It has the ability to
deliver a highly localized dose while sparing
normal tissue (Fig. 12.11 ). However, in
children, brachy therapy poses problems of
inpatient management: can the child provide his
or her own feeding, bodily care, and immediate
needs while radioactive? If not, will there be an
unacceptable exposure to nursing personnel or to
the parents during the implant? Several solutions
have been proposed. One is to use a remote
afterloading brachy therapy machine. If a high-
dose-rate remote afterloader is used, the
duration of the radiation exposure is short and
personnel exposure is minimized. The drawback
is that the dose rate is so high that some of the
normal tissue-sparing benefits of brachy therapy Figure 12.11 The volume selection for
may be lost. To address this latter concern, some pediatric brachytherapy for NRSTS is
phy sicians pulse or fractionate the highly nuanced. In many cases, the
brachy therapy (i.e., use multiple exposures). As patient has been treated with induction
an alternative, one can use a remote afterloader chemotherapy or EBRT. Often one cannot
with conventional activity sources. In this way, be sure whether a partial response of
the duration of the implant is no different than gross tumor implies a complete response
with conventional afterloading. However, the of all or part of the initial occult disease
sources can be withdrawn whenever nursing volume. Consider the following
personnel or a parent enters the room for a hypothetical example: I: An NRSTS is
planned feeding, wound care, bathing the child, shown near an epithelial surface. The
and so on. A third way to deal with the particular bulky tumor’s left-to-right dimension is
problems of brachy therapy in a child is to use noted by line AB. Let us assume that the
iodine-125 instead of iridium-192. The treatment tumor is treated with induction cytotoxic
energy for iodine-125 is 28 keV, compared with therapy and that it regresses. II: The left-
380 keV for iridium-192. The lower energy of to-right dimension, demarcated in
iodine-125 reduces exposure to clinical staff and relation to line AB, has shrunk. If the
family, allows more efficacious shielding with brachytherapy volume is denoted by the
lead drapes, and reduces exposure to normal bracketed area, then the irradiated
tissue at a distance from the implant. The iodine- volume will be adequate. III: On the other
125 may be embedded in suture material or hand, assume that the tumor regressed
absorbable mesh (216). significantly but that the total left-to-
Page 281Intraoperative radiation therapy right dimension did not change. If the
(IORT) has been described for the treatment of brachytherapy volume is addressed only
NRSTS (219). There are two general forms: to the readily palpable or visible tumor,
intraoperative electron beam therapy (IO-ERT) as shown by the bracketed area, then a
and intraoperative high-dose rate brachy therapy large portion of the tumor will be missed.
(IO-HDRBT). There are three techniques for
administering IO-ERT. Historically, patients underwent surgery in the operating room and
then were transported, using specialized sterile techniques, from the operating room to the
radiation oncology department. The linear accelerator suite was draped and prepared as a
temporary operating room.
The accelerator was “docked” to a cone used to demarcate the area that the phy sicians
wanted to irradiate. A single large fraction of electrons was administered. Normal tissue was
spared by retraction and shielding. A second technique involved placing a linear accelerator
in the operating room as a dedicated IO-ERT device. Of course, this necessitated reinforcing
the weight-bearing capacity of the floor of the operating room, particularly if it was located
in an upper floor of the hospital. The accelerator was only used for its electron-generating
capabilities, so the purchase of a conventional linear accelerator with photon and electron
capabilities wasted the photon capabilities of the machine. This problem was addressed by the
third technique for IO-ERT: the development of an electron-only dedicated linear accelerator
for placement in the operating room. Such devices are now available and can be moved from
operating room to operating room. Because they generate only electrons, shielding needs for
the walls, floor, and ceiling of the operating room are minimal.
Some authorities view IO-HDRBT as an alternative to IO-ERT or an adjunct to it.
Intraoperative electrons often cannot treat inaccessible or highly contoured sites such as the
base of the skull, the pelvic sidewall, the deep pelvic area, or angled areas in the abdomen or
thorax. The IO-HDRBT device uses flexible applicators and catheters to treat almost any
surface. Retraction and shielding are used to spare critical normal structures. A single high-
activity iridium-192 source is used, and one can customize the dose distribution. However,
one is constrained by the penetration attendant to iridium-192. There is very limited clinical
experience with the use of IORT to treat childhood NRSTS. In small series of highly selected
patients, excellent local control rates have been achieved. The generally recommended
dosage, if 40–50 Gy of EBRT is used, is an IORT boost of 10–15 Gy (211,212,213,214,219).
High–Linear Energy Transfer Radiotherapy (e.g., Neutrons)

Radiobiologists and clinical radiotherapists have been intrigued by the therapeutic uses of
neutrons (220). High–linear energy transfer (LET) neutrons, by virtue of a low-oxy gen-
enhancement ratio and lack of cell-cy cle cy totoxicity preference, are toxic and have been
used to treat bulky tumors of various histologies and sites. Data are available from the United
States, Europe, and Japan concerning the use of neutrons to treat bulky sarcomas of adults and
children. Although definitions of local tumor control vary between reports, the local control
rate for neutron treatment of inoperable or residual soft tissue sarcomas is about 50% (221).
In a retrospective comparison, Laramore et al. (222) found a higher local control rate of
bulky sarcomas with neutrons than with photons and electrons (53% vs. 38%). Between
November 1980 and June 1981, 14 patients, presumably adults, were entered in a prospective
trial comparing postoperative photons and fast neutrons (15.6 Gy ) for NRSTS. Two of the nine
patients treated with photons (63 Gy ) relapsed locally, as did two of the five patients treated
with neutrons. The trial was halted because of unacceptable late tissue damage in the neutron-
treated patients. Schwarz has summarized the prior European experience with neutron
therapy at 11 centers to treat 1171 sarcoma patients (223). For patients with resectable
tumors, no advantage to neutron therapy was evident. For unresectable sarcomas or following
a debulking surgery, neutron therapy resulted in a local control rate of 47%. Complications at
various centers ranged from 7% to 29%, roughly correlating with treatment volume effects
and perhaps with the experience of the particular center. There has been little published
experience on neutron therapy for soft tissue sarcomas since the mid-1990s; however, with
the theoretical advantages of proton RT and its evolving clinical experience related to the
Bragg peak depth-dose characteristic, there is a growing investigation of heavy charged
particle radiations such as carbon ions that have the combined elements of high LET, Bragg
peak, and elimination of an exit beam bey ond the targeted tumor.
Figure:
A: Orthogonal films of brachytherapy catheters and Ir-192 sources. B: Brachytherapy dose
distribution in axial projection. C: Simulator film of external beam field.
Figure:
A: CT scout film showing the brachytherapy catheters. B: The brachytherapy volume of the
45 cGy/hour isodose relative to the boney anatomy. C: The brachytherapy dose distribution
in the axial projection. D: Simulator film of the external beam field.
Figure:
The volume selection for pediatric brachytherapy for NRSTS is highly nuanced. In many
cases, the patient has been treated with induction chemotherapy or EBRT. Often one cannot
be sure whether a partial response of gross tumor implies a complete response of all or part
of the initial occult disease volume. Consider the following hypothetical example: I: An
NRSTS is shown near an epithelial surface. The bulky tumor’s left-to-right dimension is noted
by line AB. Let us assume that the tumor is treated with induction cytotoxic therapy and
that it regresses. II: The left-to-right dimension, demarcated in relation to line AB, has shrunk.
If the brachytherapy volume is denoted by the bracketed area, then the irradiated volume
will be adequate. III: On the other hand, assume that the tumor regressed significantly but
that the total left-to-right dimension did not change. If the brachytherapy volume is
addressed only to the readily palpable or visible tumor, as shown by the bracketed area, then
a large portion of the tumor will be missed.
RESULTS
When NRSTS in children is localized and amenable to definitive surgical excision or limited
excision plus RT, the survival probability is 60–90%. The 5-y ear EFSs in the retrospective
reviews from St. Jude Children’s Research Hospital are group I, 83% group II, 65% group IV,
approximately 9% groups I and II and less than 5 cm, 92% groups I and II and more than 5
cm, 55% (6,38). In the May o Clinic series, the 10-y ear EFS was 76%. A worse prognosis is
associated with high stage, high grade, and tumor size greater than 5 cm (48). The 5-y ear
disease-free survival for children with NRSTS of the head and neck in the M.D. Anderson
Hospital series was 75% (43). For patients with stages I–III NRSTS treated on SIOP trial
MMT84, the 5-y ear survival rate was 73% and it was 80% for trial MMT89 (45,164). A
multivariate analy sis of predictive factors for local tumor recurrence in the Roy al Marsden
series of NRSTS (adults and children) showed significant worsening of the risk for local
recurrence with retroperitoneal versus lower limb tumors, high grade versus low grade, and
inadequate surgical margins. Metastases were predicted by tumor size more than 5 cm, high
grade, local recurrence, or the presence of involved ly mph nodes (117). In POG Study
8653/8654, the 5-y ear overall survival for IRS groups I–II NRSTS was 82% and EFS was
71%, while for IRS groups III–IV disease the overall survival was 26% and EFS was 19%
(14). A retrospective review from the Rambam Medical Center, which includes desmoid
tumors in the series, showed 5-y ear overall survival of 72% for IRS group I, 75% for group
II, 90% for group III, and 40% for group IV (47). A retrospective review of sy novial
sarcoma treatment in children and adolescents treated with surgery, chemotherapy, and RT
found that progression-free survival was associated with IRS group (I, 79% II, 82% III, 38%
IV, 0%), maximum tumor diameter (less than 5 cm, 82% more than 5 cm, 56%), and
histology (monophasic, 86% biphasic, 54%) (60). A small series of childhood angiosarcomas
had a characteristically poor event-free (29%) and overall (22%) survival (66). For
fibrosarcomas, because of the difference in behavior between the congenital or infantile and
adult ty pes, survival is a function of age (y ounger than 2 y ears, 79% older than 2 y ears, 51%)
(67,224).
Page 282Locally advanced (group III) NRSTSs continue to be a challenging problem.
Preoperative chemotherapy and RT may convert a subset of these patients to having
resectable tumors, which improves local control and has some prospects for cure. The small
series from SJCRH showed a 33% 5-y ear disease-free survival with this strategy (100). More
encouragingly, within the POG 9553 protocol of ifosfamide and doxorubicin followed by
EBRT to 54 or 64 Gy, depending on age, 25 patients with group III tumors had a 60% 3-y ear
disease-free survival (12). Fifteen of these patients had sy novial cell sarcoma, thought by
some investigators to be more sensitive to chemotherapy. Similar results in a larger cohort of
200 patients were seen in the COG ARST 0332 trial, where those patients with bulky, high-
grade tumors receiving sequential preoperative chemotherapy and radiotherapy followed by
surgery where feasible had a 52% 3 y ear disease-free survival (15).
Ferrari et al. (160) published a retrospective pooled analy sis from the United States and
Europe investigating prognostic variables and treatment modalities in 304 patients with
initially unresectable, but nonmetastatic NRSTS (akin to rhabdomy osarcoma clinical group
III). This study noted that there was similar negative prognostic implication of particular
tumor characteristics compared with adult soft tissue sarcoma, with those poor prognostic
features including large tumor size, MPNST histology, older patient, and axial location of
tumor. When examining response rate to chemotherapy, a 41% response rate was recorded
(in terms of complete response and major partial response). This was 57% if minor responses
were included. In addition, it was reported that final outcome was directly correlated with
response to initial chemotherapy. Particular importance of local therapy was also emphasized
in this study, as local progression and relapse was the major cause of treatment failure and
patients able to undergo complete delay ed resection had the best outcome. From a
radiotherapy perspective, the use of radiotherapy also was directly correlated with a better
survival on multivariate analy sis. It was noted that radiotherapy improved survival after
incomplete resection, but had little or no benefit after complete surgery. However, the authors
do describe a selection bias for those patients who received radiotherapy, as these patients
were a selected subset with unfavorable features. Furthermore, the use of radiotherapy was
not homogeneous and was highly variable over time between centers included in the study.
Radiotherapy was the only local modality in 72 patients. An additional 72 patients underwent
surgery and radiotherapy with the vast majority undergoing radiotherapy postoperatively.
The median total radiation dose was 54 Gy for patients receiving RT alone or postoperative
RT for positive margins. Patients who had a complete surgical resection and who received RT
had a median radiation dose of 50 Gy. Overall, this study concluded that aggressive
multimodal treatment strategies should be pursued with effort to get patient to a complete
surgical resection. This study has also pointed out that there are histology specific predictors
of chemotherapy response seen in other studies, which in turn impact on prognosis.
Specifically, sy novial cell sarcoma is a relatively chemosensitive tumor while MPNST
tended to be more chemoresistant. Investigators at COG in designing future NRSTS studies
are contemplating using preoperative chemoradiation for locally advanced tumors in which
lower radiation doses will be justified if there is a good response to chemotherapy or in the
case of chemosensitive histologies.
Unresectable or metastatic disease carries a dismal prognosis. Unresectable NRSTSs are
rarely cured by RT with chemotherapy, and the local control rate is also poor (143). The 5-
y ear survival rate for children with stage IV NRSTS treated on SIOP trials MMT84 and
MMT89 was 15% (45,164). In an SJRCH review of metastatic NRSTS, the 2-y ear
progression-free survival was 15% (4,6,90,99).
Another University of Florida study focused on unresectable, nonmetastatic NRSTS
patients documented relatively poor results associated with radiotherapy and chemotherapy
(225). Of the 19 patients in this small study, the median radiation dose was 55.2 Gy, 12
patients received chemotherapy, and 13 patients had high-grade tumors. The 5-y ear local
control rate was only 40%. Nine of the thirteen recurrences were local only, but all
recurrences ultimately resulted in patient death, half of which never developed metastatic
disease. This study highlighted the need for more intensive therapies aimed at improving local
control for unresectable NRSTS.
COG ARST0032 approached metastatic disease based on initial tumor grade. For high-
grade tumors, patients were then divided into two groups, grossly resected versus unresected,
where they received adjuvant chemotherapy plus radiotherapy versus neoadjuvant
chemoradiotherapy, respectively. For low-grade tumors, if all disease was resected,
independent of microscopic margin status, these patients went on to observation alone. If all
disease was not resected, they entered in the high-grade arm of the algorithm where further
therapy was assigned. Results of this strategy for metastatic disease have not y et been
reported.
DESMOID TUMORS
Page 283There are a variety of childhood mesenchy mal tumors of fibroblastic and
my ofibroblastic derivation that are generally regarded as benign in the sense that these
tumors have no potential for metastasis. The group includes infantile my ofibromatosis, digital
fibromatosis, fibromatosis colli, and desmoid tumors (226). The term desmoid derives from
the Attic Greek word δέσμη or desmē meaning “package, bundle,” and in medicine has come
to refer to ligamentous or tendenous (3). In addition to the term desmoid tumor (which dates
back to an 1847 surgical treatise), these lesions are called extra-abdominal desmoid, well-
differentiated nonmetastasizing fibrosarcoma, aggressive fibromatosis, and grade 1
fibrosarcoma (desmoid) (227,228). The usual presenting complaint is a deep-seated, firm
mass arising in muscles or soft tissues (226,227,228,229). These lesions tend to extend along
fascial planes. Histologically, spindle cells with an abundant collagenous background form
interlacing bundles and infiltrate surrounding tissue. Mitoses are rare (Fig. 12.12 )
(226,229,230,231,232). Immunohistochemical staining for beta-catenin is important in the
diagnosis (233).
Figure 12.12 Desmoid tumor in a child. Note both H&E (A) and immunostaining (B) for
beta-catenin, in which nuclear staining is characteristic for this disease.
Occurring with an estimated incidence of two to four cases per million persons per y ear,
desmoid tumors have relative peaks in incidence between 6 and 15 y ears of age and between
puberty and 40 y ears of age in women. Risk factors include high-estrogen states (like
pregnancy ) and prior surgical trauma (20). A small fraction of desmoid tumors are
associated with Gardner sy ndrome. As such, there is an associated, inherited mutation in the
adenomatous polyposis coli (APC) tumor suppressor gene (20).
Desmoid tumors almost never metastasize. The goal of treatment is to obtain local
control. Desmoid tumors can occur in a wide variety of locations. For this reason, the degree
of resectability is quite variable. Tumors in an accessible site, not adjacent to vital structures,
are more amenable to gross total excision than those adjacent to major nerves or vessels. In
general, about two-thirds of desmoids can undergo gross total excision. Moreover, there is
some suggestion in the medical literature that pediatric as opposed to adult desmoid tumors
may be more aggressive (234,235). And a recent series from SJCRH suggests that the margin
of surgical resection does not predict well for ultimate local control such that the initial
surgical approach should attempt to remove all gross tumor when feasible but with primary
attention to preserving function (236). The problem of the extent of excision leads us to the
first of several controversies in the management of pediatric desmoid tumors.
What is to be done in the child who has undergone an excision but in whom there are
positive margins of resection? Several papers from the MGH argue that such patients ought to
be closely observed. In a 2001 review, Suit and Spiro (237) wrote:
Patients with primary desmoid tumors who have had grossly complete
resection, but whose surgical margins are positive on pathological examination
are exposed to a risk of no local regrowth of at least some 30–40%. This high
local control results in margin-positive patients and the fact that salvage
treatment of patients who failed locally is usually successful warrant a policy
of placing such patients on observation. This policy has been followed at the
MGH for approximately 25 years. To date, there have been no regrets and a
worthwhile number of patients have not been exposed to the risk of radiation-
induced damage to normal tissues, including tumor induction. In contrast,
margin-positive resection of recurrent desmoid tumors is an unequivocal
indication for additional treatment.
In contrast to this argument, one can turn to

a 2000 review by Nuy ttens (232) of 22 series of
mostly adult patients concerning the treatment of
desmoid tumors. Table 12.10 , derived from
this review article, shows that the local control
rate for patients with positive margins treated
with surgery alone is approximately half that of
patients treated with surgery and radiation
therapy. Data of this sort may be used to argue
for more routine use of postoperative irradiation
in patients with positive margins, albeit balancing
any toxicity concerns. Further supporting this
position is the finding from the SJCRH seeing a Table 12.10 Local Control of Desmoid
trend toward better local control with the addition Tumors with Three Forms of Therapy
of RT to surgery. Noting that only 18% of
patients had surgically negative margins of resection, the use of postoperative radiotherapy
RT was associated with a longer 10-y ear relapse-free survival of 79.6% versus 48.6% for
surgery alone, although this was not statistically significant in view of the small number of
patients (236). But overall survival was not changed by upfront radiotherapy.
Page 284If one weighs the conflicting data on this point, several issues ought to be
considered:
The long-term ill effects of radiation therapy in children with desmoid tumors can be
considerable. Therefore, it would be best to minimize the use of radiation wherever
possible.
Although postoperative irradiation in patients with positive margins reduces the risk of
local relapse, most patients with local relapse after surgery alone can be cured by
additional surgery and radiation therapy.
Therefore, it would be reasonable to adopt a policy of watchful waiting in accessible
sites, amenable to close follow-up. A significant number of these patients might be
locally controlled with surgery alone, even with positive margins. For those who relapse,
one could use surgery and radiation therapy to obtain local control.
The probability of local control with surgery alone is unpredictable a priori, and a wide range
of local control rates are reported (226,227,228,238,239). A consensus view is that local
control in patients with free margins is obtained in about 70% of cases. Several ty pes of
patients are at particularly high risk for local recurrence and progression. These include those
with unresectable lesions, those who have undergone resection and gross tumor has been left
behind, those who have undergone resection with large areas of clearly positive histologic
tumor margins, and those who have already suffered one or more local recurrences after
primary surgical therapy. With the exception of patients with microscopic positive margins,
the remainder should be considered for RT (Fig. 12.13 ).
Several retrospective series, combining pediatric and adult patients, have demonstrated
that fractionated external beam irradiation or external beam plus brachy therapy can locally
control approximately 75% of desmoid tumors (Tables 12.10 and 12.11 ). Complete or
partial resolution may take 2–3 y ears after completion of a course of treatment (227,256).
For some patients, “local control” means cessation of growth rather than tumor regression.
The long-term ill effects of radiation therapy for the treatment of desmoid tumors can
include fibrosis in the treated area, paresthesias that are most often associated with growth of
tumor into a nerve, limb edema, fracture associated with surgical stripping of the ostium or
curettage, skin ulcers, cellulitis, and the induction of second malignant neoplasms (Fig.
12.13 ) (232,235,248).
Figure 12.13 A right buttock desmoid
tumor was diagnosed in a 6-year-old boy.
The lesion was excised in 1979, 1980,
1982, and 1983 and recurred each time.
Postoperative irradiation (49.6 Gy) was
given after a reexcision of gross disease.
Angled photon fields were used to
minimize rectal dosage. The tumor
slowly regressed, and local control has
been maintained up to the time of this
writing (2009). There is partial atrophy of
the right buttock musculature, the bones
of the right hemipelvis are smaller than
those of the left hemipelvis, and the
patient walks with a marked limp.
Diabetes mellitus was diagnosed in 1994.
In 2002, 19 years after RT, the thin,
atrophied tissues gave way and a deep,
infected ulcer developed in the right
buttock. Plastic surgery with rotation of
vascularized flaps was needed for wound
closure.
Table 12.11 Local Control Rates in Combined Pediatric and Adult Series of
Radiotherapy with or without Surgery for the Management of Desmoid Tumors
This risk of late effects raises the question of whether one should be particularly cautious
in using radiation therapy in children with desmoid tumors. A report by Merchant et al. (235)
from SJCRH argued that desmoid tumors in pediatric patients are particularly locally
aggressive and often occur after radiation therapy. This adverse biologic behavior, in
conjunction with the associated ill effects of radiation, argues against the use of radiation
therapy in desmoid tumors. The study by Merchant et al. contains data from only 13 patients
collected over a 36-y ear period. The desmoid tumors arose from a particularly unusual set of
locations, such as the paraspinal region in five cases and the nasophary nx and ptery goid fossa
in two cases. A wide variety of treatments were used, including surgery and chemotherapy,
in addition to radiation therapy. Enzinger and Shiraki (228) and Walther et al. (260) also
reported a high risk of failure in adolescents.
Page 286On the other hand, as shown in Table 12.11 , a large number of patients have
been treated successfully with radiation therapy. Most series are a mixture of adults and
children. However, they do not report that desmoid tumors in children are more aggressive.
Therefore, it seems reasonable to use radiation therapy to treat desmoid tumors in children,
albeit with the cautions about positive margins raised earlier in this section.
Desmoids can widely infiltrate. When external beam is used, treatment portals should be
generous. Marginal relapses account for a very large number of the relapses after external
beam radiation therapy (232,248,243,249,251). MRI studies of desmoids often show an
infiltrative margin. At surgery, microscopic tumor has been found to extend bey ond the
volume defined by MRI. All available evidence from the phy sical examination, surgical
report, CT, and MRI should be integrated to determine the tumor volume. Generous margins
(about 5 cm) should then be used around this volume. Daily fractions of 1.8–2 Gy are used.
There may be a higher local recurrence rate when dosages less than 50 Gy are used. In
1984, Kiel and Suit (226) suggested that dosages greater than 60 Gy may be associated with a
greater incidence of local control and had treated some patients with 70 Gy, often using
photons and protons. Schulz–Ertner et al. (251) found no benefit of administering more than
50 Gy rather than less than 50 Gy on univariate analy sis. Zlotecki et al. (248) found no benefit
of hy perfractionated irradiation over standard fractionation. Almost all patients received 50–
56 Gy. However, Ballo et al. (257) reported a significant difference in local control between
dosages less than 50 Gy and dosages more than 50 Gy. They also found greater irradiation-
associated morbidity in patients who received dosages more than 56 Gy. Evidence indicates
that a total dosage of 50–55 Gy is appropriate and that higher dosages may increase the risk
of complications without commensurate gain in local tumor control (227,237,256).
Brachy therapy has been reported as a treatment for desmoids, either alone or with external
beam therapy, by one institution (243). The recent SJCRH series reported that seven of 16
patients receiving postoperative radiotherapy involved brachy therapy (236). However,
because of concerns about the assessment of tumor margins and their coverage, we believe
that the role of brachy therapy is limited in children with desmoids.
In y oung children with desmoids, radiation’s effects on growing bone, the risk for
subsequent soft tissue fibrosis, and the potential for secondary malignancy may prompt
consideration of alternative therapies. A large range of drugs are available for managing
desmoid tumor. There have been some efforts to use cy totoxic chemotherapy, mostly
employ ed to treat recurrent tumor after surgery and radiation. For instance, a series of six
children with fibromatosis were treated with VAC (vincristine, actinomy cin D, and
cy clophosphamide) with five having long-term control, although three subjects also received
high-dose RT (41). The POG published a prospective phase II trial of vinblastine and
methotrexate showing a response rate of 31% (261). Of a total of 27 patients, 16 had
recurrent desmoid tumor and 11 had untreated disease not amenable to either surgery or
irradiation. There have been other anecdotal reports of the use of gemcitabine, liposome-
encapsulated doxorubicin, and temozolomide.
Page 287Other medical treatments are evolving. Several reports on the pathophy siology
of desmoid tumors show expression of platelet-derived growth factor receptor (262,263),
estrogen receptor (264,265), somatostatin receptors (266), and cy clooxy genase-2 (267). In
turn, this has provided a rationale for the reported use of various “targeted therapies” either
alone or in combination. This has included imatinib mesy late (262,263), tamoxifen, or other
estrogen antagonists (264,265,268), octreotide radiolabeled with Y-90 (266), and nonsteroidal
anti-inflammatory drugs (268,269,270). A COG study formally evaluated high-dose
tamoxifen and sulindac in pediatric patients with recurrent or untreated fibromatosis (271).
Fifty -nine eligible patients were enrolled of which six (16%) had prior radiation. While no
life-threatening toxicity was reported, 12 of 30 females developed ovarian cy sts, which were
asy mptomatic in 11 of the cases and did not require stopping treatment. Response rates were
low, included four partial and one complete response (5/59 = 8%). The estimated 2-y ear
progression-free and overall survival rates were 36% and 96%, respectively. Of note, there
were three deaths due to progressive desmoid tumor which tended to be late events. Finally,
there have been anecdotal reports of responses to other agents including colchicine and
interferons.
Figure:
Desmoid tumor in a child. Note both H&E (A) and immunostaining (B) for beta-catenin, in
which nuclear staining is characteristic for this disease.
Figure: Local Control of Desmoid Tumors
with Three Forms of Therapy
Figure:
A right buttock desmoid tumor was diagnosed in a 6-year-old boy. The lesion was excised in
1979, 1980, 1982, and 1983 and recurred each time. Postoperative irradiation (49.6 Gy) was
given after a reexcision of gross disease. Angled photon fields were used to minimize rectal
dosage. The tumor slowly regressed, and local control has been maintained up to the time of
this writing (2009). There is partial atrophy of the right buttock musculature, the bones of the
right hemipelvis are smaller than those of the left hemipelvis, and the patient walks with a
marked limp. Diabetes mellitus was diagnosed in 1994. In 2002, 19 years after RT, the thin,
atrophied tissues gave way and a deep, infected ulcer developed in the right buttock. Plastic
surgery with rotation of vascularized flaps was needed for wound closure.
Figure: Local Control Rates in Combined
Pediatric and Adult Series of Radiotherapy
with or without Surgery for the Management
of Desmoid Tumors
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CH A P TER 13
Wilms Tumor
John A. Kalapurakal and Edward C. Halperin
PAGE 294HISTORY
It is thought that the first description of a Wilms tumor was by Thomas F. Rance (1) in his
1814 report “Case of Fungus Haematodes in Kidnies.” In 1828, Dr Ebenezer Gairdner (2),
Fellow of the Roy al College of Phy sicians, Edinburgh, published a second case. The patient
was a 3-y ear-old girl named Agnes B. Agnes B died of a left renal tumor that weighed 5
pounds, 3 ounces. In 1879, renowned phy sician William Osler (3) described two cases of
“my osarcoma of the kidney,” one of which had tumor extension into the right heart and
pulmonary artery. Max Wilms (1867–1918), who was trained in pathology, internal medicine,
and surgery, thoroughly reviewed the pertinent literature and added seven new patients in his
1899 monograph Die Mischgeschwuelste. In addition to renal tumors, Wilms described the
histologically “mixed tumors,” of the ovary, testicle, head and neck, bladder, and other organs
(4). It was because of Wilms exceptional monograph that his name became connected with
this childhood tumor (Fig. 13.1 ) (5).
Figure 13.1 A & B: In his monograph, Die Mischgeschwulste der Niere (the mixed tumor of
the kidney), published in Leipzig in 1899, Max Wilms described, as his first illustrative case,
“Niven Tumor von einem 3 jahrien Mädchen” (“renal tumor of a 3-year-old girl”). C: Wilms
described the blastemal, epithelial (tubules), and stromal elements seen on microscopic
examination of “mixed” renal tumor.
By the mid-20th century, radiation oncologists had developed a large body of clinical
experience with Wilms tumor and began formulating opinions about the role of radiotherapy.
Ralston Paterson (6), distinguished radiation oncologist of the Christie Hospital and Holt
Radium Institute of Manchester, England, wrote in his 1948 textbook:
We feel that the most promising policy is to start treatment by radiotherapy
and not by surgery. X-ray therapy is used and consists of abdominal x-ray
baths to cover the entire tumor and any possible intra-abdominal extension.
An interval of 6 weeks to 3 months is then allowed in which the tumor mass
entirely disappears.… Two opposing fields, anterior and posterior… cover the
whole abdomen including the liver.… The essential point in the treatment of
Wilms tumor is to remember that even enormous tumors can be made operable
and that radiation followed by nephrectomy can undoubtedly obtain cure in
some cases.
Dean and Guttmann (7) expressed the predominant viewpoint of US radiation oncologists
when they wrote in their 1950 textbook:
The successful treatment of a Wilms tumor depends upon the complete

removal or complete devitalization of the primary growth before metastasis
occurs. No type of treatment given singly or combined with other forms of
treatment has proved successful after metastasis have become established.
Ladd, working at the Children’s Hospital of Boston, has obtained by far the best
end results by operating on these infants as soon as possible. We also
recommend prompt removal… [When preoperative therapy is necessary]… to
shrink a Wilms tumor and thereby facilitate its operable removal, external
roentgen therapy is the treatment of choice. Usually, however, after five or six
exposures, the tumors become significantly smaller and sometimes at the end
of 2 weeks it is no longer palpable.… Following radiation infarction seems to be
more widespread.
Dean and Guttmann’s views were reinforced by Jacox and Cahill’s (8) 1850 review of
the management of Wilms tumor. They wrote:
At present we believe that nephrectomy should be performed as soon as the
diagnosis of Wilms tumor is made, irrespective of the size of the mass. In
general, preoperative irradiation is not favored, because we believe that
waiting needlessly jeopardizes the patient’s chances of survival. Ladd and
White and their confreres at the Boston Children’s Hospital have made a
serious study of the removal of these tumors by the transperitoneal route, with
a minimum of handling either for diagnosis or on the operating table, with
ligation of the renal vessels and pedicle before displacement of the tumor. The
result has been a much higher proportion free from recurrence that has
formerly been reported.
Page 295What we can see, in this brief historical review of the origins of radiotherapy
for Wilms tumor, is the divide between US radiation oncologists and their European
colleagues. The European literature favored preoperative treatment, and the US literature
favored postoperative radiation therapy. We also see the acknowledgment that wide treatment
volumes to cover the entire tumor bed are necessary. We will address these themes later in
this chapter.
Figure:
A & B: In his monograph, Die Mischgeschwulste der Niere (the mixed tumor of the kidney),
published in Leipzig in 1899, Max Wilms described, as his first illustrative case, “Niven Tumor
von einem 3 jahrien Mädchen” (“renal tumor of a 3-year-old girl”). C: Wilms described the
blastemal, epithelial (tubules), and stromal elements seen on microscopic examination of
“mixed” renal tumor.
EPIDEMIOLOGY
Wilms tumor (nephroblastoma) is an embry onic kidney tumor. It is the most common
abdominal tumor in children and represents 6% of childhood cancer. The incidence rate in
white children y ounger than 15 y ears is 8.1 new cases per million population (9). There are
approximately 470–500 new cases in the United States per y ear (10,11). Wilms tumor is
bilateral at presentation in 4–8% of cases (12,13,14).
For unilateral tumors, the median age at diagnosis is 41.5 months for boy s and 46.9
months for girls. For bilateral tumors, the median age at presentation is 29.5 months for boy s
and 32.6 months for girls (11). More than 75% of patients present before 5 y ears of age. The
male-to-female ratio is 0.92 for unilateral tumors and 0.6 for bilateral tumors (11). The
incidence rate is approximately three times higher for blacks in the United States and Africa
than for East Asians. Rates for the white populations in Europe and North America are
intermediate between those of blacks and East Asians. Children tend to present with more
advanced disease in less developed nations (11,12,13,14).
MOLECULAR BIOLOGY
In Chapter 5 , we discussed the Knudson “two-hit” hy pothesis of the origins of

retinoblastoma. After vetting his hy pothesis for retinoblastoma, Knudson proposed a similar
model for Wilms tumor in 1972 (15,16). Like retinoblastoma, Wilms tumor may be unilateral
or bilateral. The 4–8% occurrence of bilateral disease, appearing at an earlier age than
unilateral disease and associated with a greater frequency of other hereditary anomalies,
supports the concept of a specific predisposing constitutional chromosomal deletion. It should
be noted that fewer familial and bilateral cases of Wilms tumor than retinoblastoma were
available for analy sis because of the lower incidence of familial Wilms tumor and the poor
disease survival at that time (15,16,17).
Wilms tumor is associated with congenital anomalies in 10–13% of cases (16,17,18,19).
Aniridia is present in 1% of children with Wilms tumor; hemihy pertrophy is noted in 2–3%
(19,20,21). Other genitourinary (GU) malformations are identified in 5% of cases, primarily
cry ptorchidism, hy pospadias, double collecting sy stem, or fused kidney (21,22). It seemed
reasonable to look for candidate Wilms tumor genes in association with these congenital
anomalies.
Page 296The next major clue to the molecular genetics of Wilms tumor was found from
the sy ndrome of Wilms tumor with aniridia, GU malformations, and mental retardation
(WAGR sy ndrome). Kary oty pic analy sis of children with WAGR sy ndrome showed a
deletion on the short arm of chromosome 11, band 13 (11p13). This deletion encompasses the
aniridia gene PAX6 and the Wilms tumor suppressor gene WT1. WT1 is a developmentally
regulated transcription factor of the zinc finger family. However, analy sis of sporadic Wilms
tumors shows evidence of WT1 mutation in only 5–10% of cases. Therefore, although WT1
appears to be a tumor suppressor gene, it accounts for a minority of Wilms tumors
(19,20,21,22,23,24).
Wilms tumor also occurs with greater frequency in the Beckwith–Wiedemann
sy ndrome (BWS) (25,26). This familial condition variably includes macrosomia or
hemihy pertrophy, macroglossia, omphalocele, abdominal organomegaly, and ear pits or
creases. The genetic locus of this sy ndrome is also on the short arm of chromosome 11
(11p15). The putative second Wilms tumor suppressor gene, located at this site, is called WT2.
WT2 (LP15) has effects on IGF2, the H19 tumor suppressor gene, and the P57 cell cy cle
regulator (25,26,27,28).
In addition to the tumor suppressor genes associated with Wilms tumor, there is evidence
of genetic loci that may be related to more malignant or aggressive Wilms tumors. In a study
of patients from National Wilms Tumor Studies (NWTS) 3 and 4, loss of chromosomal
material (called loss of heterozy gosity [LOH]) on the long arm of chromosome 16 (16q) and
short arm of chromosome 1p was associated with inferior outcomes (27,28). In NWTS-5,
2021 children were prospectively evaluated for the poor prognostic significance of tumor
specific LOH for chromosomes 1p or 16q. In clear cell sarcoma of the kidney (CCSK) and
rhabdoid tumor (RTK), LOH for 1p and 16q were rarely observed. The results for favorable
histology (FH) Wilms tumor are shown in Table 13.1 . The incidence of LOH at 1p and
16q was 11.3% and 17.4%, respectively. LOH at either 1p or 16q was only associated with
higher risk of relapse for low-stage (stage I/II) patients in comparison to stage III/IV. It was
postulated that two-drug chemotherapy was insufficient to overcome the effect of loss of the
putative tumor suppressor genes located within these chromosomal regions. Conversely, the
more intensive treatment with three drugs did overcome the effect of this loss in stage III/IV
patients. The relative risk of relapse and death in low- and high-stage patients was
significantly elevated in those patients with LOH at both loci (29). The Children’s Oncology
Group (COG) is presently using LOH status at 1p and 16q in addition to tumor stage and
histology in stratify ing patients according to risk of relapse. Children with low- and high-stage
tumors with LOH at both 1p and 16q will have more intensified therapy compared with
NWTS-5.
Table 13.1 Analysis for the Joint Effect of LOH at 1p and 16q for (A) Stage I/II and (B)
Stage III/IV Favorable Histology Patients (29)
In 2007, a previously unknown gene on the X chromosome WTX was found to be

inactivated in approximately one-third of Wilms tumors. Tumors with mutations in WTX lack
WT1 mutations and both genes share a restricted temporal and spatial expression pattern in
normal renal precursors. The data suggest that WTX is a Wilms tumor suppressor gene with
an important role in normal kidney development. WTX is frequently altered in sporadic
tumors by a single somatic event that affects both sexes equally. The one-hit inactivation of a
tumor suppressor gene is a departure from the biallelic Knudson model (30). Other known
abnormalities in Wilms tumor include activating mutations in the beta-catenin gene (CTNNB1)
on chromosome 3p22, which often coincide with WT1 mutations (31).
Another interesting study showed constitutional 11p15 abnormalities in genomic
ly mphocy te DNA from 3% of patients with nonsy ndromic sporadic Wilms tumors, including
12% of bilateral cases. No such abnormalities were detected in control subjects. Such findings
may be helpful in assessing the risk of contralateral Wilms tumor development and for
targeted surveillance of at-risk family members (32).
Page 297In an effort to identify specific biologic markers associated with relapse in FH
Wilms tumor, the COG conducted a study to determine the feasibility and potential clinical
utility of classifiers of relapse based on global gene expression analy sis. There were no
significant genetic markers for relapse in stages I and II tumors. However, for stage III
tumors, the sy stem that was developed using 50 genes was associated with relapse with a
sensitivity of 47% and specificity of 70%. This compares with a sensitivity of 8% and
specificity of 96% for LOH of both 1p and 16q in stages III and IV FH Wilms tumor.
Analy sis of specific genes revealed apoptosis, IGF-1 signaling, Wnt/β-catenin pathway, 1q
gain, and epigenetic modification to be mechanisms important in relapse. Two additional
potential therapeutic targets identified in this study were FRAP/MTOR and CD40. All these
pathway s are potential targets for future therapies (33).
The NWTS has defined very low-risk Wilms tumors (VLRWT) based on age, stage, and
tumor weight (Table 13.2 ). Recent gene expression studies have shown that VLRWT is
comprised of at least two biologically distinct clusters of tumors. Cluster 1 that is comprised of
epithelial differentiated tubular histology tumors without nephrogenic rests and lack of LOH
for 1p, 16q, and 11p. These tumors have a unique gene expression profile consistent with
renal developmental arrest following mesenchy mal to epithelial transition. None of these
tumors relapsed. Cluster 2 comprised of mixed histology tumors with nephrogenic rests and a
heterogenous gene expression pattern including down regulation of WT1. WT1 mutation and
11p15LOH were significant predictors of relapse in VLRWTs. Prospective validation of these
novel biomarkers will enable refinement of the current arbitrary definition of VLRWT based
on age and tumor weight (34,35).
Table 13.2 COG Risk-Stratification Schema for Renal Tumor Protocols
Another recent COG study has demonstrated that gain of 1q is a promising biomarker for
patients with FH Wilms tumor. In a report from the NWTS that studied 212 patients from
NWTS-4, 27% of patients display ed 1q gain. The 8-y ear event-free and overall survival rates
were 76% and 93% (p = 0.002) for patients with 1q gain and 89% and 98% (p = 0.008) for
those lacking 1q gain. Gain of 1q did not correlate with tumor stage. After stratification for
tumor stage, 1q gain was associated with significantly increased risk of disease recurrence
(risk ratio 2.72, p = 0.009) (36).
Figure: Analysis for the Joint Effect of LOH
at 1p and 16q for (A) Stage I/II and (B) Stage
III/IV Favorable Histology Patients (29)
29 Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity for chromosomes 1p and 16q is
an adverse prognostic factor in favorable histology Wilms tumor: a report from the National
Wilms Tumor Study Group. J Clin Oncol. 2005;29:7312–7321.
Figure: COG Risk-Stratification Schema for
Renal Tumor Protocols
PATHOLOGY
The childhood kidney tumor pathology classification sy stems are those of the NWTS (Table
13.3 ), the International Society of Pediatric Oncology (SIOP) study (Table 13.4 ), and
COG (Table 13.5 ).
Table 13.3 Classification of Pediatric Renal Tumors

Table 13.4 International Society of Pediatric Oncology National Wilms Tumor Study
Table 13.5 Children’s Oncology Group Classification of Renal Tumors
Mesoblastic Nephroma
Mesoblastic nephroma is the most common renal tumor encountered in the first month of life.
Its median age at presentation is 3 months. It is distinguished from Wilms tumor by its usually
benign behavior, a preponderance of mesenchy mal derivatives, and a lack of the malignant
epithelial components seen in Wilms. The tumor consists of spindle-shaped cells in interlacing
bundles adjacent to renal parenchy ma where there are foci of cy stic or dy splastic tubules.
The treatment of choice is nephrectomy. Local recurrence is unusual. Nonetheless, adequate
margins of resection should be obtained, although recurrence even after operative rupture or
positive margins at resection is rare. Distant metastases are also rare. The actuarial 2-y ear
survival rate is 98% (37,38,39,40).
Page 298Nodular Renal Blastemas and Nephrogenic Rests
A spectrum of “pre–Wilms tumor” entities has been described. Nodular renal blastemas are
small but visible sub-capsular nodules composed of benign embry onic rests. Nephrogenic
rests may be limited to the periphery of the renal cortex (perilobar) or randomly distributed
throughout the renal lobe (intralobar). Multifocal or diffuse nephrogenic rests are called
nephroblastomatosis.
Wilms Tumor
Wilms tumor is a triphasic embry onal neoplasm, which includes blastemal, epithelial
(tubules), and stromal elements. Each element may exhibit a variety of patterns of
aggregation or lines of differentiation (Fig. 13.2A–C ) (38,39,40). The proportion of the
three components varies from tumor to tumor. If one of the components comprises more than
two-thirds of the tumor sample, the pattern is designated according to the predominant
component. The mixed ty pe is most common (41% of Wilms tumor), followed closely by
the clinically more aggressive blastemal predominant (39%), the more indolent epithelial
predominant (18%), and the stromal predominant (1%), which behaves like the mixed ty pe
(38,39,40).
Figure 13.2 A & B: James B. Ewing, renowned for the four editions of his book Pathology
of Neoplasia (Philadelphia, PA: WB Saunders; 1942) and his identification for the tumor now
called Ewing sarcoma, also provided excellent histologic descriptions of Wilms tumor. These
slides, from Ewing’s book, show the topography of Wilms embryonal tumor of the kidney with
(A) epithelial tubules lining in masses of spindle and polyhedral cells and (B) the small round
cells of the embryonal tumor infiltrating adjacent tissue. C: Favorable histology triphasic
Wilms tumor with predominantly epithelial (tubular) differentiation (arrow).
The gross pathologic features of Wilms tumor include its general occurrence as a single
unilateral tumor, although multicentric growth and bilateral disease can occur. The tumor is
ty pically solid, lobulated, and not calcified. However, soft and cy stic areas may be
encountered.
Histopathologic studies in the NWTS identified factors that correlate with prognosis. In
the first NWTS, 88% of cases were categorized as FH, defined as having ty pical histologic
features of Wilms tumor without anaplastic or sarcomatous components (41). The frequency
of this pattern was upheld in the third NWTS, with 89% of cases categorized as FH on central
pathology review (42).
Page 299Three entities traditionally have been grouped under the general term
unfavorable histology (UH) in the NWTS: anaplastic Wilms tumor, CCSK, and RTK (39). The
latter two are no longer considered to be variants of Wilms tumor but are distinct entities (38).
Anaplasia is defined as the significant enlargement of nuclei in the stromal, epithelial, or
blastemal cell lines to at least three times the diameter of adjacent nuclei of the same cell
ty pe; hy perchromatism of these enlarged nuclei; and multiple mitotic figures. DNA indices
greater than 1.5 are associated with anaplastic histology (Fig. 13.3A & B ) (38,40,43,44).
Anaplasia was noted in 4% of all NWTS-3 entries and in 5% of patients in the SIOP studies
(38,40,43,44). Anaplastic tumors are extremely rare in infants, are uncommon before 2
y ears of age, and make up about 10% of Wilms tumors diagnosed after 5 y ears of age (40).
Anaplasia appears to be associated with greater resistance to chemotherapy rather than
greater aggressiveness of Wilms tumor. The 4-y ear survival rate in NWTS-3 for patients with
anaplastic histology was 82% but was lower in earlier studies (41,42,43,44).
Figure 13.3 Anaplastic Wilms tumor with a large dark hyperchromatic nucleus (arrow)
(A) and multipolar mitosis (arrow) (B).
Anaplastic Wilms tumor may be focal or diffuse. When this distinction was originally
drawn, the term diffuse anaplasia was applied to tumors with anaplastic nuclear changes in
more than 10% of 400 microscopic fields. Focal anaplasia was applied to the remainder of
anaplastic tumors. Using this distinction, focal anaplasia was associated with a more favorable
outcome than diffuse anaplasia in the first NWTS, but this difference did not obtain statistical
significance and was not confirmed in the second and third NWTS trials (45).
The original distinction between focal and diffuse anaplasia did not consider distribution
of tumor throughout the kidney, which might affect the likelihood of complete resection. In a
recently revised definition, focal anaplasia refers to anaplasia that is sharply localized in the
primary tumor, without significant nuclear or mitotic aty pia in the remainder of the lesion.
Diffuse anaplasia is either nonlocalized anaplasia, localized anaplasia with severe nuclear
unrest elsewhere in the tumor, anaplasia outside the tumor capsule or in metastases, or
anaplasia found in a random biopsy taken from the tumor.
Using the new criteria, and on review of patients in NWTS-3 and NWTS-4, patients with
focal anaplasia had a 4-y ear survival rate statistically significantly higher than that of patients
with diffuse anaplasia (97% vs. 50%). This difference did not exist for stage I tumors (100%
survival for focal or diffuse) but did exist for stages II (90% vs. 55%), III (100% vs. 45%),
and IV (100% vs. 4%) (40,45).
Page 300Patients with anaplastic histology Wilms tumor were treated in prospective
single-arm studies in NWTS-5. Patients with stage I anaplastic tumors were treated with
vincristine and dactinomy cin for 18 weeks without radiation therapy. Patients with stages II–
IV diffuse anaplastic histology were treated with regimen “I” chemotherapy that consisted of
vincristine, doxorubicin, cy clophosphamide, and etoposide for 24 weeks plus flank/abdominal
radiation therapy. Among 2596 patients with Wilms tumor enrolled onto NWTS-5, 281
(10.8%) had anaplastic histology. The 4-y ear event-free and overall survival rates for stage I
anaplastic histology tumors were 70% and 83%, respectively. The 4-y ear event-free and
overall survival rates in stages II, III, and IV diffuse anaplastic tumors after immediate
nephrectomy were 83% and 82%, 65% and 67%, and 33% and 33%, respectively. These
results form the basis for the COG study with augmentation of therapy for stages I, III, and
IV anaplastic tumors (46).
Rhabdoid Tumor of the Kidney

Rhabdoid tumor of the kidney (RTK) is a highly malignant tumor characterized by uniform
cellular infiltrates initially interpreted as rhabdomy oblastic or sarcomatous elements. The
tumor is unrelated to rhabdomy osarcoma or Wilms tumor and may be of neural crest origin
(38,39,40). Rhabdoid cells are characterized by eosinophilic cy toplasm that contains hy aline
globular inclusions. On electron microscopy, these inclusions are found to be intermediate
filaments; most contain vimentin and cy tokeratin. The nuclei are large, round, and vesicular,
often containing a centrally placed eosinophilic nucleolus (Fig. 13.4 ) (40).
Most RTK of the kidney are diagnosed in the first 2 y ears of life. RTK have also been
reported as primary extrarenal lesions; there is a known association between RTK and
primary central nervous sy stem neoplasms (40). Children with RTK have responded poorly
to the therapies of the NWTS. The 4-y ear relapse-free survival rate for patients treated with
vincristine, actinomy cin D, and adriamy cin on NWTS-3 was 23%, and the 4-y ear overall
survival rate was 25% (42,47).
Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney (CCSK) is a primitive mesenchy mal neoplasm that makes
up 4% of childhood renal tumors. The cell of origin is unknown. The lesion is distinguished by
cells with poorly stained cy toplasm. The cell
boundaries are indistinct, and cy toplasmic
vacuolation may be prominent. The classic
histologic pattern has a characteristic arborizing
network of thin-walled capillary blood vessels
that separates groups of cells (Fig. 13.5 )
(40,48). In NWTS-3, 23% of children with CCSK
developed bone metastases, compared with
0.3% of all other children entered in the study.
Response of CCSK to therapy was poor until
adriamy cin and local irradiation were added to
the treatment program. The 4-y ear relapse-free Figure 13.4 Rhabdoid tumor (RTK)
survival rate for patients with stages I–IV CCSK with tumor cells with large eccentric
treated with vincristine, adriamy cin, and vesicular nuclei, prominent nucleoli, and
actinomy cin D on NWTS-3 was 71% (42). cytoplasmic inclusions (arrow).
A total of 86 patients with CCSK were
registered in NWTS-4. This study was designed to compare the efficacy and toxicity of a
new schedule of administration of dactinomy cin and doxorubicin. There was no significant
difference between those patients initially randomized to standard and pulse-intensive (PI)
chemotherapy with vincristine, dactinomy cin, and doxorubicin. The 8-y ear relapse-free and
overall survival rates were 72% and 87% for PI and 70% and 84% for standard
chemotherapy, respectively. The second randomization was to short-duration (no further
chemotherapy ) and long-duration (additional 9 months) chemotherapy. Again, there was no
significant difference in survival between the two arms. The 8-y ear relapse-free and overall
survival rates were 61% and 86% for the short-duration chemotherapy and 88% and 88% for
the long-duration chemotherapy, respectively. Even though the relapse-free survival rates
were not significantly different (p = 0.08), the long-duration arm resulted in a higher relapse-
free survival rate. The overall survival rate in NWTS-4 (83%) was significantly higher than in
NWTS-3 (67%) (49).
Figure 13.5 Clear cell sarcoma (CCSK)

with tumor cells composed of uniform
clear cytoplasm surrounding entrapped
renal tubules: low power (A), high power
(B) showing prominent vacuolated
cytoplasm (arrow).
Figure: Classification of Pediatric Renal
Tumors
Figure: International Society of Pediatric
Oncology National Wilms Tumor Study
Figure: Children’s Oncology Group
Classification of Renal Tumors
Figure:
A & B: James B. Ewing, renowned for the four editions of his book Pathology of Neoplasia
(Philadelphia, PA: WB Saunders; 1942) and his identification for the tumor now called Ewing
sarcoma, also provided excellent histologic descriptions of Wilms tumor. These slides, from
Ewing’s book, show the topography of Wilms embryonal tumor of the kidney with (A)
epithelial tubules lining in masses of spindle and polyhedral cells and (B) the small round cells
of the embryonal tumor infiltrating adjacent tissue. C: Favorable histology triphasic Wilms
tumor with predominantly epithelial (tubular) differentiation (arrow).
Figure:
Anaplastic Wilms tumor with a large dark hyperchromatic nucleus (arrow) (A) and
multipolar mitosis (arrow) (B).
Figure:
Rhabdoid tumor (RTK) with tumor cells with large eccentric vesicular nuclei, prominent
nucleoli, and cytoplasmic inclusions (arrow).
Figure:
Clear cell sarcoma (CCSK) with tumor cells composed of uniform clear cytoplasm
surrounding entrapped renal tubules: low power (A), high power (B) showing prominent
vacuolated cytoplasm (arrow).
CLINICAL PRESENTATION AND WORKUP
As we have already noted, several clinical sy ndromes are risk factors for the development of
Wilms tumor. These include aniridia, BWS (exomphalos, macroglossia, and gigantism), and
hemihy pertropia. If somatic changes of these kinds are known to exist, then routine screening
in an attempt to make the early diagnosis of Wilms tumor is appropriate (50). A phy sical
examination and periodic ultrasound are indicated. It is interesting to note that in Germany,
10% of patients with Wilms tumor are diagnosed at infant and childhood screening
examinations, conducted for known predisposing sy ndromes, and at routine well-baby
examinations (50).
Page 301The majority of children with Wilms tumor are diagnosed in response to a
medical complaint causing a visit to the doctor. The clinical presentation usually is an
abdominal mass (83%), fever (23%), or hematuria (21%). Abdominal pain (37%) may be
the result of local distention, spontaneous intralesional hemorrhage, or peritoneal rupture. In
one major series, abdominal pain correlated with poorer 5-y ear survival (51). Less common
presenting signs and sy mptoms include hy pertension, varicocele, hernia, enlarged testicle,
congestive heart failure, hy pogly cemia, Cushing sy ndrome, hy drocephalus, pleural effusion,
and an acute abdomen (52).
The presence and character of the abdominal pain, the previous medical history, and the
family history are important aspects of the medical interview. Phy sical examination is of
value in assessing abdominal status and identify ing associated congenital anomalies.
The optimum diagnostic imaging workup for Wilms tumor is a matter of controversy.
Evaluation of disease extent classically included intravenous py elogram (IVP) and chest
radiograph. Current imaging protocols largely replace the IVP with abdominal ultrasound.
Ultrasound usually allows determination of the origin of a childhood abdominal mass,
identifies a contralateral kidney, and demonstrates the presence or absence of tumor
extension into the renal vein or inferior vena cava (53).
When an abdominal mass is identified or suspected, abdominal computed tomography
(CT) is used to assess the volume of tumor
involvement in one or both kidney s, renal
function, retroperitoneal ly mph nodes, and
invasion of the collecting sy stem or renal vein;
evaluate the margin between tumor, kidney, and
surrounding structures; assess hepatic metastasis
(although many children thought to have
invasion of the liver from a right-sided Wilms
tumor are found at surgery to have hepatic
compression rather than invasion); and
demonstrate lesions in the opposite kidney, which Figure 13.6 A 5-year-old girl presented
may represent either bilateral Wilms tumor
with intermittent sharp abdominal pain,
(BWT) or nephrogenic rests (Fig. 13.6 ) (53).
nausea, vomiting, weight loss, and
The evaluation of the contralateral kidney has
hematuria. Abdominal computed
become a matter of discussion in the surgical tomography showed a 7.9- to 12.5-cm
literature. Some authorities believe that mass at the left renal region, beginning
preoperative CT and magnetic resonance immediately sub-diaphragmatically and
imaging (MRI) can be used to rule in or rule out extending to just below the aortic
BWT. Others believe that imaging is useful but bifurcation. There was a calcified rim
not definitive and that a surgical exploration of superiorly and a heterogeneous
the contralateral kidney remains essential during parenchymal enhancement. Left renal
the surgical approach to the primary tumor vein invasion and inferior vena cava
(17,50).
thrombosis were observed. On
Plain chest radiographs should be obtained exploratory laparotomy, tumor was
to determine whether pulmonary metastases are palpated in the inferior vena cava. The
present. Some centers recommend thoracic CT tumor was resected, with some tumor
to detect pulmonary metastasis that might be spillage from a weak point on Gerota
missed on chest radiograph. CT-positive, chest fascia. Tumor thrombus was removed
radiograph–negative lung metastases do occur from the inferior vena cava. Pathology
(53). There has been much uncertainty showed a favorable histology Wilms
regarding appropriate therapy for pulmonary tumor, 13.5 cm in greatest diameter,
disease documented only by CT in the presence invading through the renal capsule to the
of normal plain chest films (54). Radionuclide inked surgical margin. Rupture of the
bone scan is indicated in CCSK and renal RTK. renal capsule was identified. Tumor was
Bone scan and skeletal survey are present at the renal vein margin of the
complementary in CCSK. If only one technique tumor thrombosis with focal invasion of
is used, metastases may be missed (41,55). the vein wall. No lymph nodes were
Brain MRI is of value in RTK and, perhaps, in
Wilms tumor with overt pulmonary involvement involved. For pathologic stage III Wilms
at diagnosis. tumor, favorable histology, the child was
treated with chemotherapy and flank
irradiation. There was no evidence of
persistent or recurrent tumor 3 years
after diagnosis.
Figure:
A 5-year-old girl presented with intermittent sharp abdominal pain, nausea, vomiting, weight
loss, and hematuria. Abdominal computed tomography showed a 7.9- to 12.5-cm mass at the
left renal region, beginning immediately sub-diaphragmatically and extending to just below
the aortic bifurcation. There was a calcified rim superiorly and a heterogeneous
parenchymal enhancement. Left renal vein invasion and inferior vena cava thrombosis were
observed. On exploratory laparotomy, tumor was palpated in the inferior vena cava. The
tumor was resected, with some tumor spillage from a weak point on Gerota fascia. Tumor
thrombus was removed from the inferior vena cava. Pathology showed a favorable histology
Wilms tumor, 13.5 cm in greatest diameter, invading through the renal capsule to the inked
surgical margin. Rupture of the renal capsule was identified. Tumor was present at the renal
vein margin of the tumor thrombosis with focal invasion of the vein wall. No lymph nodes
were involved. For pathologic stage III Wilms tumor, favorable histology, the child was
treated with chemotherapy and flank irradiation. There was no evidence of persistent or
recurrent tumor 3 years after diagnosis.
STAGING
Page 302A staging sy stem for Wilms tumor was first published by Cassady et al. (56,57) in
1973, building on prognostic factors identified in a review from Garcia et al. (58). The
Cassady sy stem remains useful for determining whether y oung children with early stage
disease may be appropriate for therapy with surgery alone. For tumor confined to the kidney
and completely excised in children y ounger than 2 y ears of age at diagnosis and with tumors
that weigh less than 550 g, the prognosis is excellent. Such patients may be treated
appropriately with surgery alone and are considered to have stage I disease (57,58,59). The
absence of an inflammatory pseudocapsule, renal sinus invasion, capsular invasion, and
intrarenal vessel invasion in such patients are additional factors that mitigate against the risk of
relapse when treated with nephrectomy alone (53).
The NWTS proposed initial staging criteria to prospectively address tumor-related
factors. The first two NWTS studies were based on a sy stem of surgically identified groups
(41).
Beginning with the third NWTS trial in 1979, a new staging sy stem was adopted. Specific
disease-related parameters noted to be prognostically significant in analy ses of NWTS-1 and
NWTS-2 led to modifications of the sy stem and the change from groups to stages. A closed or
open biopsy permitted categorization as stage II (rather than group III), assuming subsequent
total tumor removal. Local spill of tumor during surgery was downstaged from group III to
stage II, reflecting data indicating that such cases had excellent tumor control even with
limited irradiation and chemotherapy in NWTS-1 and NWTS-2 (60). Also, the NWTS-3
staging sy stem upstages all previous group II cases with ly mph node metastasis to stage III,
even when all visible disease has been completely resected. The adverse impact of ly mph
node involvement, both on abdominal recurrence and on ultimate relapse-free survival, has
been documented (13,22,41,61).
For NWTS-5, the most significant change was the distinction between stages I and II.
Criteria for stage I was refined to accommodate an important subset of patients who were
being managed by nephrectomy alone. Before NWTS-5, the distinction between stages I and
II in the renal sinus was established by the hilar plane, which was an imaginary plane
connecting the most medial aspects of the upper and lower poles of the kidney. This criterion
was difficult to apply because of tumor distortion, and thus the hilar plane criterion has been
replaced with renal sinus vascular or ly mphatic invasion. This definition includes not only the
involvement of vessels within the hilar soft tissue, but of vessels located in the radial
extensions of the renal sinus into the renal parenchy ma (62,63).
The COG staging guidelines for Wilms tumor are shown in Table 13.6 . These
guidelines are essentially similar to NWTS-5 except for the fact that children with tumor
spillage are upstaged from stage II to stage III because of the higher risk for relapse with two-
drug chemotherapy alone (64).
Table 13.6 Children’s Oncology Group Staging of Wilms Tumor
In the SIOP Wilms tumor trial 1, investigators compared preoperative radiotherapy with
primary surgery. The staging sy stem used in this trial is shown in Table 13.7 . SIOP
subsequently began using NWTS grouping and staging, with the proviso that the NWTS
sy stems were not specifically designed for the
preoperative therapy often used by SIOP
(65,66,67,68,69,70,71). For this reason, outcomes
between NWTS and SIOP studies should not be
compared stage-for-stage. In addition, SIOP
uses a “stage II, node-negative” and “stage II,
node-positive” distinction and therefore includes
some NWTS stage III tumors in the stage II
infradiaphragmatic SIOP stage.
Table 13.7 Staging System Used in
SIOP Wilms Tumor Trial 1
Figure: Children’s Oncology Group Staging
of Wilms Tumor
Figure: Staging System Used in SIOP Wilms
Tumor Trial 1
NWTS, SIOP, AND THE MANAGEMENT OF WILMS TUMOR
The NWTS, SIOP, and the United Kingdom Children’s Cancer Study Group (UKCCSG) have
compiled a large body of information concerning the clinical management of Wilms tumor.
The most widely quoted studies are those of NWTS and SIOP.
The NWTS and SIOP Strategies

The SIOP studies began with the presumption that treatment with radiation therapy or
chemotherapy before surgery would render a Wilms tumor less vulnerable to intraoperative
rupture and surgery -related tumor seeding. Downstaging the tumor was also hoped to reduce
treatment-related morbidity by reducing the total amount of treatment (65,66,67). In
accordance with this philosophy, the initial strategy of SIOP was to evaluate the roles of
radiotherapy and chemotherapy before definitive surgery based on clinical diagnosis.
Subsequently, treatment was assigned according to the extent of disease found at surgery. One
disadvantage is the risk of misdiagnosis and mistreatment (i.e., treating a tumor other than
Wilms tumor or treating benign disease). In SIOP 9, the error rate (i.e., the proportion of
patients who were found not to have Wilms tumor) was 6%. In addition, the SIOP approach
runs the risk of obscuring important prognostic clues in individual patients (67). Ly mph node
involvement and histologic subty pe may be affected by preoperative therapy. A particular
drawback of preoperative therapy is that one may miss diffuse anaplasia. Because prognosis
and subsequent therapy are influenced by histology and ly mph node involvement, the SIOP
approach may render therapy less precise by interfering with histology obtained at the time
of definitive surgery. Supporting this contention was a review of data from two SIOP studies
indicating that necrotic changes were more frequently seen in patients pretreated with
radiotherapy than in those pretreated with chemotherapy. However, an analy sis of post
treatment histology in these two SIOP studies and in 83 patients who underwent
prenephrectomy chemotherapy in NWTS-3 showed no evidence that prenephrectomy
therapy altered the detection of anaplastic histology (65,66,67). It appears that the SIOP
presurgical therapy approach does not influence histology.
Page 303The NWTS strategy is to forgo preoperative therapy in order to obtain the
maximum amount of information concerning prognostic factors and tailor therapy
accordingly. Therefore, the local extent of the primary tumor, degree of anaplasia, presence
of unusual histology, and presence or absence of ly mph node involvement are assessed in the
absence of the confounding influence of preoperative chemotherapy or radiotherapy in order
to select therapy. The benefits of the NWTS approach are the generation of a large body of
information about prognostic clues, the avoidance of misdiagnosis, and the customization of
therapy.
Page 304The National Wilms Tumor Studies

NWTS-1 (1969–1974) asked several important treatment questions: Is postoperative
radiotherapy necessary in group I disease? Is single-agent chemotherapy with either
vincristine or actinomy cin D equivalent to combining these drugs for group II and III disease?
Is preoperative vincristine of value in group IV disease? The study is shown schematically in
Figure 13.7 , and the results are summarized in Table 13.8 (41). Radiotherapy dosages
were age adjusted (birth to 18 months of age, 18–24 Gy ; 18–30 months, 24–30 Gy ; 31–40
months, 30–35 Gy ; 41 months or older, 35–40 Gy ). Radiotherapy appeared to be
unnecessary in group I babies; combined drug therapy was superior in groups II and III; and
preoperative vincristine was not helpful in group IV. Patients older than 2 y ears with group I
tumors showed an advantage with irradiation. However, patients with group II tumors
receiving actinomy cin D with vincristine seemed to do as well as those with group I disease.
It was postulated that postoperative vincristine with actinomy cin D could substitute for
postoperative radiotherapy with actinomy cin D (41,73). This study demonstrated the
significance of the UH versus FH distinction, with a 2-y ear relapse-free survival rate of 29%
for UH and 89% for FH (73,74). Large tumor size, ly mph node involvement, and age older
than 2 y ears were confirmed as poor prognostic factors. No radiation dose–response
relationship was discerned in the 10–40 Gy range, delay s of up to 10 day s in initiating
postoperative irradiation appeared acceptable, and whole-abdomen irradiation (WAI) was not
found to be necessary for tumor spills confined to the flank or for prior tumor biopsy
(17,43,60). In these patients, limited radiotherapy fields sufficed.
Figure 13.7 The design of NWTS-1. (From D’Angio GJ. National Wilms’ Tumor Study.
Seattle, WA: NWTS Data and Statistical Center; 1991[Informational Bulletin #19], with
permission.)
Table 13.8 NWTS-1 Results
Page 305NWTS-2 (1974–1979) explored three major questions: Can vincristine and
actinomy cin D substitute for radiotherapy in older children with group I disease? Are
adjuvant vincristine and actinomy cin D for protracted periods helpful in group I? Is the
addition of adriamy cin to actinomy cin D and vincristine of value in groups II to IV? The
study is shown schematically in Figure 13.8 (75). Flank irradiation was given in groups II–
IV disease according to the same age-dependent scale as NWTS-1. WAI was reserved for
diffuse peritoneal seeding. Lung metastases were initially treated with 14 Gy of whole-lung
irradiation (WLI), but when a 10% incidence of pneumonitis occurred, the dosage was scaled
back to 12 Gy. Study results are summarized in Table 13.9 . About 85% of the patients
were FH and 15% UH. Two-y ear survival rates were 54% for UH, 90% for FH, 54% for
ly mph node positive, and 82% for ly mph node negative. Excellent survival rates appeared to
be achievable without irradiation in group I, and adriamy cin added considerable benefit in
groups II–III FH and some benefit in groups II–III UH and group IV. The 2-y ear relapse-
free survival rate for all NWTS-2 patients was 88% for group I, 78% for group II, 70% for
group III, and 49% for group IV (17,75,77,78,79).
Figure 13.8 The design of NWTS-2. (From D’Angio GJ, Tefft M, Breslow N, et al. Radiation
therapy of Wilms’ tumor: results according to dose, field, post-operative timing and histology.
Int J Radiat Oncol Biol Phys. 1978;4:769–780, with permission.)
NWTS-3 (1979–1985) incorporated two major changes in treatment planning: Patients

were stratified by stages rather than by groups and the distinction between FH and UH was
incorporated into the treatment algorithm (Fig. 13.9 ). Although data from NWTS-1 and
NWTS-2 were analy zed by histology, histology was not used to stratify treatment (41,53,75).
Figure 13.9 The design of NWTS-3. (From D’Angio GJ, Evans A, Breslow N, et al. The
treatment of Wilms’ tumor: results of the Second National Wilms’ Tumor Study. Cancer.
1981;47:2302–2311, with permission.)
NWTS-3 considered five major questions: Can the duration of chemotherapy be

shortened for stage I FH? Can radiotherapy be eliminated for stage II FH? What is the
minimum effective radiotherapy dosage for stage III FH? Is cardiotoxic adriamy cin clearly
beneficial and therefore necessary in stages II and III FH? Will the addition of
cy clophosphamide improve survival in stages I–III UH and in stage IV FH and UH?
NWTS-3 results are summarized in Tables 13.10 and 13.11 . Short-course therapy
appeared equivalent to long course therapy in stage I FH. Patients in this group can be treated
successfully with a 10-week program of vincristine and actinomy cin D without irradiation
and can achieve a 4-y ear relapse-free survival rate of 89% and overall survival rate of 96%.
Elimination of radiotherapy was acceptable in stage II FH. The 4-y ear relapse-free and
overall survival rates for the patients not receiving irradiation were 87% and 91%,
respectively. In stage III FH, 10 Gy was equivalent to 20 Gy. There was no statistically
significant difference in frequency of intra-abdominal relapse between 10 and 20 Gy,
although the trend favored the use of adriamy cin or irradiation (intra-abdominal relapse for
vincristine, actinomy cin D, and 10 Gy, 7 out of 61, or 11%; vincristine, actinomy cin D, and
20 Gy, 3 out of 68, or 4%; vincristine, actinomy cin D, adriamy cin, and 10 Gy, 3 out of 70, or
4%). In an analy sis of patients with stage III, local relapse with doxorubicin occurred in 4 out
of 134 patients, whereas without doxorubicin, it occurred in 11 out of 141 patients, suggesting
that chemotherapy play ed a role in establishing local control. The addition of adriamy cin was
not clearly beneficial in stage II but seemed to be of benefit in stage III FH.
Cy clophosphamide did not benefit stage IV FH. The 4-y ear survival rate for stage IV FH
treated with vincristine, actinomy cin D, adriamy cin, and abdominal and lung irradiation was
81% (78). The use of cy clophosphamide seemed to help patients with focal anaplasia.
Patients with CCSK did well, whereas those with RTK continued to do poorly (17,22,42,53).
Table 13.11 NWTS-3 Relapse Rates
Page 306NWTS-4 (1986–1994) addressed issues of minimization of therapy (and,

presumably, therapy -related toxicity ) and customization of therapy by stage and histology.
The trial was the first study of a pediatric population to evaluate the economic impact of two
different treatment approaches, one of which entailed fewer clinic visits. By the end of
NWTS-3 it had been shown that 62% of patients with Wilms tumor (stages I–II, FH) needed
neither irradiation nor adriamy cin. The study was designed to compare the relapse-free and
overall survival rates of patients with stages I and II FH and stage I anaplastic tumors treated
with conventional actinomy cin D and vincristine and with pulsed, intensive actinomy cin D
and vincristine. Stages III and IV FH and stages I–IV CCSK were treated with conventional
actinomy cin D, vincristine, and adriamy cin, compared with pulsed, intensive actinomy cin D,
vincristine, and adriamy cin; all patients received radiotherapy (for FH, 10.8 Gy to the
abdomen; 12 Gy WLI where appropriate; for stages II–IV anaplastic tumors, a sliding scale
of radiation dosage was used, as in NWTS-1). Stages II–IV anaplastic Wilms tumors were
treated with appropriate irradiation followed by actinomy cin D, vincristine, and adriamy cin,
compared with these three drugs plus cy clophosphamide. Stages II–IV FH and stages I–IV
CCSK were treated with 26 or 54 weeks of chemotherapy (Fig. 13.10 ) (79).
Figure 13.10 NWTS-4 simplified schema. Stage IV anaplastic tumors continued the
randomization of NWTS-3. (From Thomas PRM. Wilms’ tumor: changing role of radiation
therapy. Semin Radiat Oncol. 1997;7: 204–211, with permission.)
The results of NWTS-4 are shown in Table 13.12 . There was no difference in the
low-risk or high-risk patients for standard or PI therapy. When one breaks down the results
based on histology, stage, standard or PI therapy, and, for the more advanced patients, short
or long course of therapy, there are, once again, no significant differences between the
various treatment groups (79). Comparing the results from NWTS-4 with those of the
UKCCSG Wilms Tumor Study 2, reported contemporaneously, we see surprisingly similar
results (Table 13.13 ) (80). The risk of local recurrence of patients enrolled in NWTS-4 is
shown in Table 13.14 .
The NWTS evaluated the frequency with which spilled tumor cells of FH produce intra-
abdominal disease recurrence. Flank irradiation but not doxorubicin reduced abdominal
relapse rates. The odds ratio for the risk of recurrence relative to no radiation was 0.35 for 10
Gy and 0.08 for 20 Gy. Tumor spillage resulted in higher relapse and significantly lower
survival among stage II patients. For stage II patients (NWTS-4), the 8-y ear event rates, with
and without spillage, respectively, were 79% and 87% for relapse-free survival (p = 0.07),
and 90% and 95% for overall survival (p = 0.04) (64).
The evidence from NWTS-4 is that PI initial chemotherapy is as effective as a longer
program. Shorter-course subsequent chemotherapy appears as effective as a longer
program. Overall survival rates are excellent, and few patients are irradiated (79).
The long-term data from NWTS-3 and NWTS-4 show no significant effects for
doxorubicin in stage II FH patients; however, for stage III patients, the relapse-free and
overall survival rates were 84% and 89% with and 74% and 83% without doxorubicin,
respectively. For stage III patients, the use of doxorubicin results in a significant reduction in
local and general recurrence without any improvement in overall survival (81).
NWTS-5 (1995–2001) treated stage I
favorable and anaplastic histology and stage II
FH with 18 weeks of actinomy cin D and
vincristine. Stage I FH in children y ounger than
24 months of age and with tumor weight less
than 550 g was treated with surgery alone.
Stages III–IV FH and stages II–IV focal
anaplastic tumors were treated with 24 weeks of
actinomy cin D, vincristine, adriamy cin, and
local irradiation and WLI as appropriate. Stages
II–IV diffuse anaplastic sarcoma and stages I–
IV CCSK were treated with cy clophosphamide,
vincristine, adriamy cin, and etoposide along with
local irradiation and WLI as appropriate. Stages
I–IV RTK was treated with carboplatin,
etoposide, cy clophosphamide, and radiotherapy.
The radiotherapy guidelines in NWTS-5 were
similar to those used in NWTS-4 except for
anaplastic tumors where a dose of 10.8 Gy was
recommended as compared with an age-
adjusted schedule used in NWTS 1-4. As a
major objective, NWTS-5 sought to evaluate the
importance of LOH for chromosome 1p and 16q Table 13.12 NWTS-4 Results
markers for prognosis. These results have been
detailed earlier in the chapter (Table 13.1 ) (29).
The outcome of 57 patients with FH tumors and peritoneal implants at the time of
nephrectomy in NWTS-4 and NWTS-5 were analy zed. Stage III tumors were seen in 74%,
and 26% had stage IV tumors. All children received multimodality therapy with three-drug
chemotherapy and irradiation. Forty -seven
patients (82%) received WAI and the radiation
dose was 10.5 Gy in 50 patients. The overall
abdominal and sy stemic tumor control rates
were 97% and 93%, respectively. The detection
of peritoneal implants was not associated with
inferior survival after this therapy. The 5-y ear
relapse-free survival rates with and without
peritoneal implants were 90% and 83%,
respectively (82).
Page 308Children’s Oncology Table 13.13 Comparing Results:

Group Studies NWTS-4 and UK Children’s Cancer Study
Group Wilms Tumor Study 2
The COG is the successor of the NWTS. The
COG risk-group classification for treatment
assignment in the new generation of Wilms tumor protocols is shown in Table 13.2 . This
classification, will in addition to tumor stage, also consider patient’s age, tumor weight,
presence or absence of LOH at 1p and 16q, and response to chemotherapy in children with
FH tumors and lung metastases. The main objectives of the first generation of COG protocols
are listed below. The COG radiation therapy (Table 13.15 ) and chemotherapy regimens
are outlined in Table 13.16 . All these studies have completed accrual and are currently
closed. While final results of these studies are awaited, some of these studies have
preliminary outcome data that are shown below.
Table 13.14 Risk of Local Recurrence
in NWTS-4
Table 13.15 COG Radiation Therapy Guidelines
Table 13.16 COG Chemotherapy Regimens
AREN03B2
This is a renal tumors classification, biology, and banking study. The objectives are:
1. To classify patients with renal tumors by histologic categorization, surgicopathologic

stage, presence of metastases, age at diagnosis, tumor weight, and LOH for
chromosomes 1p and 16q, to thereby define eligibility for a series of therapeutic studies.
2. To maintain a biologic samples bank to make specimens available to scientists to evaluate
additional potential biologic prognostic variables and for the conduct of other research by
scientists.
3. Page 309To monitor outcome for those patients who are not eligible for a subsequent
therapeutic study including patients initially classified as low risk, defined as those with
FH Wilms tumor stage I (>2 y ears old or tumor weight >550 g) or stage II whose final
risk classification is low risk and whose tumors do not have LOH at 1p and 16q.
4. To describe the sensitivity and specificity of abdominal CT by comparison with surgical
and pathologic findings for identification of local tumor spread bey ond the renal capsule
to adjacent muscle and organs, ly mph node involvement at the renal hilum and in the
retroperitoneum, preoperative tumor rupture, and metastases to the liver.
5. To compare the sensitivity and specificity of preoperative abdominal CT and MRI for
the identification and differentiation of nephrogenic rests and Wilms tumor in children
with multiple renal lesions.
6. Page 310To correlate the method of conception (natural vs. assisted reproductive
technology ) with the development of Wilms tumor.
7. To evaluate the frequency of INI1 mutations in renal and extrarenal malignant RTK.
AREN0321
This was a study for the treatment of children with high-risk renal tumors. The primary
objectives were as follows:
1. To evaluate whether a regimen of cy clophosphamide/carboplatin/etoposide alternating

with vincristine/doxorubicin/cy clophosphamide improves the event-free and overall
survival of patients with diffuse anaplastic Wilms tumor.
2. To evaluate in a phase 2 “window” study, the antitumor activity of a combination of
vincristine and irinotecan against metastatic diffuse anaplastic Wilms tumor.
3. To evaluate whether a regimen of cy clophosphamide/carboplatin/etoposide alternating
with vincristine/doxorubicin/cy clophosphamide improves the event-free and overall
survival of patients with malignant RTK.
4. To evaluate in a phase 2 “window” study, the antitumor activity of a combination of
vincristine and protracted schedule irinotecan against metastatic or unresectable RTK.
5. To maintain the excellent event-free survival of patients with stage I CCSK without the
use of abdominal irradiation.
Preliminary Results: A higher than expected severe toxicity rate was encountered in these
y oung children with UH tumors after treatment with these intensive multimodality treatment
regimens. Despite reductions in chemotherapy dosages and large-field RT doses in y oung
infants, severe toxicities continued to be observed and thus the study was permanently closed
in 2013. Final results are awaited. The indications and dosages of flank and WAI were
modified as shown in Table 13.15 . In a preliminary report of AREN0321, a total of 24
patients with stage IV diffuse anaplastic Wilms tumor were enrolled on the phase 2 window
with vincristine and irinotecan. The partial response rate was 79% indicating that this regimen
has high response rate in patients with diffuse anaplasia (83).
AREN0532
This was a study for the treatment of children with very low and standard risk FH Wilms
tumor. The objectives were as follows:
1. To demonstrate that very low-risk patients treated by nephrectomy and observation

alone will have a 4-y ear event-free survival rate of ≥85% and 4-y ear overall survival
rate of ≥95%.
2. To document continued excellent outcome (4-y ear event-free and overall survival rates
of ≥85% and ≥95%) for patients with stage III FH Wilms tumor without LOH of 1p and
16q treated with vincristine, dactinomy cin, doxorubicin, and radiotherapy (regimen
DD4A).
3. To improve the current 4-y ear event-free survival for patients with FH Wilms tumor
with LOH of 1p and 16q by adding doxorubicin but not radiotherapy to the standard
dactinomy cin and vincristine regimen.
4. To determine whether omission of adjuvant therapy increases the incidence of renal
failure in the very low-risk patients that have metachronous relapse.
5. To monitor the outcomes for very low and standard risk subsets of FH Wilms tumors for
correlation with biologic data generated from the study of the tissues collected from
these cases.
Preliminary Results: A total of 116 children with very low-risk Wilms tumors were treated
with nephrectomy alone on this study and their 4-y ear event-free and overall survival rates
were 90% and 100%, respectively. Tumor 11p15 methy lation status was highly predictive of
relapse (84). Among patients with stage I/II tumors with LOH at 1p and 16q, the 4-y ear
event-free survival after augmentation of therapy with DD4A was 84% compared with 75%
with regimen EE4A (85).
Page 311AREN0533
This is a study for the treatment of newly diagnosed higher risk FH Wilms tumors. The
objectives are as follows:
1. To demonstrate that patients with stage IV FH Wilms tumor with pulmonary metastases
only, who have complete resolution of the pulmonary lesions after 6 weeks of regimen
DD4A chemotherapy (vincristine, dactinomy cin, and doxorubicin) and are called rapid
complete responders (RCR), will have at least an 85% 4-y ear event-free survival after
therapy with additional chemotherapy (regimen DD4A) and without WLI.
2. To demonstrate that stage IV FH patients who do not have resolution of pulmonary
metastases by week 6, called slow incomplete responders (SIR), will have a 4-y ear
event-free survival rate of 85% with the addition of cy clophosphamide and etoposide to
a modified regimen DD4A (regimen M) and WLI.
3. To improve the 4-y ear event-free survival rate to 75% for patients with stage III or IV
FH Wilms tumor with LOH for chromosomes 1p and 16q.
4. To determine the relationship between the burden of pulmonary metastatic disease and
outcome in stage IV FH patients.
Preliminary Results: Among patients with stage III/IV tumors with LOH at 1p and 16q, the 4-
y ear event-free survival after augmentation of therapy with regimen M was 92% compared
with 66% with regimen DD4A (86). Among 296 patients with lung metastasis, 105 (39%) had
a complete response at week 6. Their 4-y ear event-free and overall survival rates were 78%
and 95%, respectively, without WLI. While these results were inferior to the event-free
survival of 85% with WLI and DD4A, the difference was not statistically significant (87).
Among patients who had a slow incomplete response at week 6, the augmentation of therapy
with regimen M and WLI resulted in a 3-y ear event-free and overall survival of 88% and
92%, respectively. These outcomes were significantly superior to the estimated event-free
survival of 75% with regimen DD4A and WLI (88).
Page 312AREN0534
This is a study for the treatment for patients with bilateral, multicentric, or bilaterally
predisposed unilateral Wilms tumor. The objectives are as follows:
1. To improve the 4-y ear event-free survival rate to 73% for patients with BWT.
2. To prevent complete removal of at least one kidney in 50% of patients with BWT by
using prenephrectomy three-drug chemotherapy induction with vincristine,
dactinomy cin, and doxorubicin.
3. To evaluate the efficacy of chemotherapy in preserving renal units in children with
diffuse hy perplastic perilobar nephrogenic rests (DHPLNR) and preventing Wilms
tumor development.
4. To facilitate partial nephrectomy in lieu of nephrectomy in 25% of children with
unilateral tumors and aniridia, BWS, hemihy pertrophy, or other overgrowth sy ndromes
by using prenephrectomy two-drug chemotherapy induction with vincristine and
dactinomy cin.
5. To have 75% of children with BWT undergo definitive surgical treatment by 12 weeks
after initiation of chemotherapy.
SIOP Wilms Tumor Studies

A classical study by Schweisguth and Bamberger (89), published in 1963, suggested that about
one-third of patients with Wilms tumor could be cured by preoperative radiotherapy and
nephrectomy (Table 13.17 ). The SIOP studies built on this experience.
SIOP Study 1 (1971–1974) (Tables 13.18 and 13.19 ) registered 397 patients from
42 participating centers. In patients older than 1 y ear and y ounger than 15 y ears at diagnosis,
the randomized trial was designed to ascertain whether preoperative plus postoperative
primary tumor site irradiation is superior to postoperative irradiation only and whether a
single postoperative course of actinomy cin D is equal to multiple courses. To answer the first
question, 73 children were randomized to receive 20 Gy before surgery, and 64 children
underwent immediate surgery. SIOP stage I patients randomized to undergo preoperative
irradiation received no additional irradiation, and stages II and III patients were given an
additional 15 Gy. Children who were randomized to the postoperative irradiation arm
received 20 Gy for stage I and were given 30 Gy for stages II and III, with provision for
additional boosts for bulky stage III. Three of 72 evaluable patients who received
preoperative radiotherapy had tumor rupture during surgery (4%), whereas 20 of 60 patients
who received no preoperative irradiation suffered from tumor rupture (33%, p = 0.001). The
5-y ear recurrence-free survival rate was 51% for those without tumor rupture and 27% for
those with rupture (p = 0.01), with no difference in 8-y ear overall survival rate (66% vs.
61%) between the two groups (65,66,67,68). In the randomization between one and seven
courses and actinomy cin D (15 mg/kg/day 5 day s), there was no survival difference
(65,66,67,68).
Table 13.17 Results of the Treatment

of New Cases of Historically Confirmed
Wilms Tumor, with More Than 2 Years of
Follow-Up, As Reported by Schweisguth
and Bamberger of the Institut Gustave
Roussy in 1963
Table 13.18 SIOP 1 Wilms Tumor Treatment Protocol
Table 13.19 SIOP 1 Results
SIOP trial 2 (1974–1976) (Tables 13.20 and 13.21 ) was a nonrandomized study
comparing patients receiving 20 Gy of irradiation and 5 day s of actinomy cin D before
surgery with children treated with primary surgery. Tumor rupture occurred in 5% of the
preoperatively treated patients and in 20% of the other patients (p = 0.0025) (65,66,67). The
main reason for not giving preoperative therapy was small tumor size. Survival rate was only
61% in patients with larger tumors who received preoperative and postoperative irradiation.
SIOP trials 1 and 2 demonstrated that presurgical treatment with radiotherapy reduced the
number of tumor ruptures. This, in turn, reduced the need for WAI and its attendant ill effects
in y oung children (65,66,67).
Page 313SIOP trial 5 (1977–1980) was designed to ascertain whether preoperative

actinomy cin D (two 3-day courses, 15 mg/kg) and vincristine (four weekly injections, 1.5
mg/m 2) were equally effective preoperative therapy when compared with the previously
used program of 20 Gy plus actinomy cin D (Table 13.22 ). After surgery, the
preoperatively irradiated patients were given an additional 15 Gy for NWTS group II or III
disease, whereas those treated preoperatively only with chemotherapy received 30 Gy for
group II or III disease. All patients received postoperative maintenance vincristine and
actinomy cin (Table 13.23 ). An analy sis of the 172 randomized patients showed no
significant difference in the reduction in tumor size, incidence of tumor rupture, stage
distribution, mean weight of the tumor specimen, or 3-y ear recurrence-free survival (89%
for preoperative chemotherapy alone vs. 83% for chemotherapy plus radiotherapy ). Major
histologic changes such as necrosis were significantly less common after preoperative
chemotherapy than after preoperative chemoradiotherapy (Tables 13.23 and 13.24 )
(65,66,67,68,90).

Table 13.24 Effect of Preoperative Treatment: SIOP Trial 5
SIOP trial 6 (1980–1987) adopted the prenephrectomy chemotherapy used in SIOP trial
5. All patients received actinomy cin D and vincristine. Patients who had stage I disease at the
time of surgery were randomized to receive postoperative vincristine and actinomy cin D for
17 or 38 weeks. All ly mph node-negative stage II patients received 38 weeks of vincristine
and actinomy cin D and were randomized to receive or not receive 20 Gy of involved-field
irradiation. Stage II node-positive patients and stage III patients were randomized to receive
vincristine, actinomy cin D with intensified vincristine, or the two drugs with doxorubicin
(Table 13.25 ). The stage distribution for the 396 SIOP trial 6 patients was stage I (56%),
stage II node negative (27%), and stage II node positive and stage III (17%). Tumor rupture
was found in 6% of cases (65,66,67,68,69,90).
Page 314In the radiotherapy randomization

for stage II node-negative patients in SIOP trial
6, there were eight relapses among 50
nonirradiated patients. Of these eight, seven had
subdiaphragmatic regrowth of tumor, and in six
the tumor bed was the site of first relapse. This
was in contrast to only one local recurrence of
the 58 patients given postoperative irradiation.
However, 12 of the 58 children developed lung
metastases. Three of the 50 nonirradiated
patients died, and 5 of the 58 irradiated patients
died of disseminated Wilms tumor. The overall
survival rate of the two groups at 4 y ears was not
different: 90% of the nonirradiated patients and
85% of the irradiated patients (Table 13.26 )
(65,66,67,68,69,90).
SIOP trial 9 (1987–1993) had, as its
primary question, the appropriate duration of Table 13.26 SIOP 6 Results
prenephrectomy chemotherapy. One-half of the
patients with disease confined to the abdomen received 4 weeks of actinomy cin D and
vincristine, and one-half received 8 weeks. After nephrectomy, patients with multicy stic,
tubular, and nephroblastoma with fibroadenomatous-like structures received no additional
therapy. Patients with UH received actinomy cin D, epidoxorubicin, vincristine, ifosfamide,
and generally, irradiation. Patients with FH tumors received the following postoperative
treatments along with local irradiation (15 Gy to the tumor bed with an optional boost to
residual disease up to 30 Gy ): stage I, actinomy cin D and vincristine; stage II node negative,
actinomy cin D, vincristine, and epidoxorubicin; and stage II node positive and stage III,
actinomy cin D, vincristine, and epidoxorubicin. Infants y ounger than 6 months underwent
upfront nephrectomy. Children with a preoperative diagnosis of stage IV disease received
actinomy cin D, vincristine, and epidoxorubicin. This was followed by nephrectomy and
possible metastasectomy. Those rendered free of disease continued on actinomy cin D,
vincristine, and epidoxorubicin. Those with persistent metastatic disease received ifosfamide,
vincristine, and actinomy cin D and irradiation (Tables 13.27 –13.29 ). The study ’s results
show that the duration of prenephrectomy chemotherapy did not influence the stage
distribution at the time of surgery. There was also no difference in toxicity between the 4-
week and 8-week chemotherapy arms (65,66,67,68,69,70). Among patients receiving 4 weeks
compared with 8 weeks of preoperative chemotherapy, there was no difference in the
frequency of stage I tumors (64% vs. 62%), tumor rupture (1% vs. 3%), and 5-y ear overall
survival (92% vs. 87%). Thus, 4 weeks of preoperative chemotherapy was established as the
standard duration of induction chemotherapy in SIOP protocols (70).
Page 315

Table 13.28 SIOP 9: Stage IV Protocol
Page 316In SIOP 9, approximately 10% of patients had completely necrotic tumors with
no viable tumor after induction chemotherapy. The 5-y ear event-free survival rate among
these patients was 98% and the only death was due to veno-occlusive disease. It was proposed
that such patients be considered for reduction in therapy after nephrectomy (71).
SIOP trial 93-01 (1993–2000): Patients were classified into three histologic groups as
shown in Table 13.4 . Because the available results show no difference between 4-week
and 8-week preoperative chemotherapy, 4 weeks has been adopted as the standard. Patients
with stage I low-grade histology received no additional therapy. Patients with stage I
intermediate- or high-grade tumors were randomized to a 4-week postoperative program of
vincristine and actinomy cin D or a 6-week program. All stage II and III patients with
intermediate-grade tumors received therapy as in SIOP trial 9. Stage II and III high-grade
tumors were treated with ifosfamide, etoposide, and carboplatin (Tables 13.30 and
13.31 ). The survival results are excellent (Tables 13.32 and 13.33 )
(65,66,67,68,69,72). In SIOP 93-01, 410 patients with stage I intermediate-risk and anaplastic
Wilms tumor after 4 weeks of chemotherapy were randomized postoperatively to no further
therapy or two additional cy cles of chemotherapy. There was no difference in 2-y ear event-
free survival between the no further therapy group (91%) compared with those who received
additional chemotherapy (89%) (72). Among 1090 patients in SIOP 93-01, 5% had tumor
progression during preoperative chemotherapy
in SIOP 93-01. These tumors were generally
smaller at diagnosis, more often stage III after
surgery and associated with higher grade
histology. They had significantly poorer event-
free and overall survival compared with those
who responded to chemotherapy (91). A
pathologic review of stage II tumors in SIOP 93-
01 revealed that there was a significantly higher
survival among patients who were stage II due to
nonviable tumor in the renal sinus or perirenal
fat compared with those with viable tumor in
these sites (100% vs. 91%). It was proposed that
the definition of stage II be revised (76).
Table 13.30 SIOP 93-01 Wilms Tumor
Treatment: Postoperative Treatment
Strategies for Unilateral Wilms Tumor
Table 13.31 SIOP 93-01 Stage IV Protocol
Table 13.32 SIOP 93-01 Results

Table 13.33 SIOP 93-01 Results
Page 317A summary of SIOP trials 1, 2, 5, 6, 9, and 93-01 shows that 4 weeks of
prenephrectomy chemotherapy, without irradiation, results in 56% of patients having stage I
disease at surgery. In most cases, these patients go on to receive postoperative chemotherapy
and have a survival rate of more than 90%. Stage II node-positive and stage III patients have
approximately a 61% relapse-free survival and a 75% overall survival (65,66,67,68). A
diminishing number of patients have received radiotherapy in the sequential SIOP trials. The
estimated percentages of patients who received irradiation are as follows: SIOP 1, 90%; SIOP
2, 90%; SIOP 5, 72%; SIOP 6, 34%; SIOP 9, 24% (68). If one excludes patients with
metastases, then only about 16% of SIOP patients receive irradiation (90,92).
The latest SIOP protocol 2001 treatment and radiation therapy guidelines are
summarized in Tables 13.34 , 13.35 , 13.36 , and 13.37 .
Table 13.34 SIOP 2001 Postoperative Treatment Strategies for Localized Tumors
Table 13.35 SIOP 2001 Stage IV Postoperative Treatment

Table 13.36 SIOP 2001 Indications for Radiotherapy
Table 13.37 SIOP 2001 Radiation Therapy Dosage (Total Dose/Dose per Fraction)
A recent report from the SIOP 2001 protocol showed that intensification of
chemotherapy for blastemal ty pe Wilms tumors resulted in improved 5-y ear event-free
survival of 80% compared with 67% seen in SIOP93-01. There was no difference in overall
survival. The benefit of augmented therapy for improved overall survival was only seen in
stage I tumors by the addition of doxorubicin (93). In another report from SIOP 2001, the
omission of doxorubicin for children with stage II–III intermediate-risk Wilms tumors without
blastemal subty pe tumors did not result in inferior outcomes. Following treatments with and
without doxorubicin, the 2-y ear event-free survival was 93% and 88% and 5-y ear overall
survival was 97% and 96%, respectively (94).
Figure: NWTS-1 Results
Figure:
The design of NWTS-1.
(From D’Angio GJ. National Wilms’ Tumor Study. Seattle, WA: NWTS Data and Statistical
Center; 1991[Informational Bulletin #19], with permission.)
Figure:
(From D’Angio GJ, Tefft M, Breslow N, et al. Radiation therapy of Wilms’ tumor: results
according to dose, field, post-operative timing and histology. Int J Radiat Oncol Biol Phys.
Figure:
(From D’Angio GJ, Evans A, Breslow N, et al. The treatment of Wilms’ tumor: results of the
Second National Wilms’ Tumor Study. Cancer. 1981;47:2302–2311, with permission.)
Figure: NWTS-3 Relapse Rates
Figure:
NWTS-4 simplified schema. Stage IV anaplastic tumors continued the randomization of NWTS-
3.
(From Thomas PRM. Wilms’ tumor: changing role of radiation therapy. Semin Radiat Oncol.
1997;7: 204–211, with permission.)
Figure: Comparing Results: NWTS-4 and UK
Children’s Cancer Study Group Wilms
Tumor Study 2
Figure: Risk of Local Recurrence in NWTS-4
Figure: COG Radiation Therapy Guidelines
Figure: COG Chemotherapy Regimens
Figure: Results of the Treatment of New
Cases of Historically Confirmed Wilms
Tumor, with More Than 2 Years of Follow-
Up, As Reported by Schweisguth and
Bamberger of the Institut Gustave Roussy in
1963
Figure: SIOP 1 Wilms Tumor Treatment
Protocol
Figure: SIOP 1 Results
Protocol
Protocol
Figure: Effect of Preoperative Treatment:
SIOP Trial 5
Protocol
Protocol
Figure: SIOP 9: Stage IV Protocol
Figure: SIOP 93-01 Wilms Tumor
Treatment: Postoperative Treatment
Strategies for Unilateral Wilms Tumor
Figure: SIOP 93-01 Stage IV Protocol
Figure: SIOP 93-01 Results
Figure: SIOP 93-01 Results
Figure: SIOP 2001 Postoperative Treatment
Strategies for Localized Tumors
Figure: SIOP 2001 Stage IV Postoperative
Treatment
Figure: SIOP 2001 Indications for
Radiotherapy
Figure: SIOP 2001 Radiation Therapy Dosage
(Total Dose/Dose per Fraction)
Page 318Surgery
If one follows the NWTS philosophy, 90–95% of intra-abdominal tumors are resectable at
diagnosis, and surgery is the initial definitive treatment. Operative approaches have included
a vertical incision or a thoracoabdominal exposure. The current preferred approach is a wide
transverse abdominal incision and total resection generally is achievable with a
transperitoneal approach (95). The surgeon should try and accomplish the safe and complete
removal of the tumor. A thorough exploration of the abdominal cavity should be performed
and the liver and regional ly mph nodes should be examined for evidence of tumor spread.
The presence or absence of ly mph node metastases is of major importance in determining
treatment and relapse-free survival. Ly mph node sampling is necessary for accurate staging.
After the abdominal exploration is completed, radical nephrectomy is performed. The tumor
should be handled carefully throughout the procedure in order to avoid tumor spillage, as this
complication results in a significant increase in local abdominal relapse. The incidence of
operative rupture or spill ranges from 15% to 30% (41,61,64,65,66,67,68,69,70). Most cases
of operative spill are focal (limited to the operative site) rather than diffuse (contamination of
the peritoneal cavity ) (64). The risk of abdominal relapse and mortality has been significantly
greater after surgical spill (41,64,65,96,97). In cases with marginally operable tumors or with
large areas of central necrosis, preoperative radiotherapy or chemotherapy may be
preferable to attempted resection with spill. As noted earlier in this chapter, the SIOP
philosophy, using preoperative chemotherapy, has significantly reduced the risk of operative
spill and tumor rupture.
Page 319Surgical staging is important in determining treatment and prognosis. Palpation
and visual assessment of the opposite kidney and liver are routine, although, as noted earlier in
this chapter, some surgeons believe that preoperative imaging studies, particularly MRI, can
exclude contralateral kidney involvement with tumor. The prognostic importance of ly mph
node involvement has been established (Table 13.9 ) (74,98,99).
A review of NWTS-4 patients undergoing primary nephrectomy found an 11%
incidence of surgical complications (100). The most common complications of nephrectomy
are hemorrhage and small bowel obstruction. The risk factors associated with increased
surgical complications were higher local tumor stage, incorrect preoperative diagnosis,
intravascular extension, and en bloc resection of other visceral organs. Heroic attempts to
excise en bloc all or parts of adjacent organs to which the tumor appears to be adherent are
not warranted, because such procedures are associated with an increased risk of surgical
complications (100,101). Wilms tumors are generally very large and their gross appearance
at the time of surgery can be misleading in interpreting tumor extent or operability. These
tumors often compress and adhere to adjacent structures and in the majority of cases,
pathologic evidence of organ invasion is not present (101).
Page 320In NWTS-3, surgeons encountered renal vein involvement in 10% of patients.
Extension into the inferior vena cava and atrium occurs in up to 5% or more. En bloc removal
of the kidney and renal vein tumor thrombus is possible in most children, and separate
removal is possible in others. In some cases, the thrombus is “milked” from the inferior vena
cava to the renal vein before removal. With meticulous surgery, renal vein involvement does
not adversely affect prognosis (102).
Inoperability results primarily from large tumor size with direct involvement of the liver
or retroperitoneal structures. Some surgeons recommend preoperative chemotherapy to
improve the chance of resectability. Those who subscribe to the viewpoints of the SIOP
studies will be predisposed to using preoperative chemotherapy without a biopsy. For those
who feel uncomfortable with a diagnosis made by phy sical findings and diagnostic imaging,
percutaneous biopsy is indicated, and tumor resection is planned after response to
preoperative chemotherapy (100). A needle biopsy may entail general anesthesia or heavy
sedation with local anesthesia. Ultrasound or contrast-enhanced CT scans may be used to
localize the biopsy site. A proper biopsy must provide an adequate, representative specimen
(39,77). Tumor subcapsular bleeding is a possible biopsy -related complication. For this
reason, some clinicians prefer a posterior approach for the biopsy so that bleeding is more
locally confined and less likely to spill into the abdominal cavity.
In the 1930s, nephrectomy alone achieved cure in 15–30% of children (95). Recent
experience with the management of highly selected small intrarenal primary Wilms tumor
suggests that one can identify a group of patients at extremely low risk of sy stemic
micrometastasis potentially treatable with surgery alone. In a pilot study at Children’s Hospital
in Boston, eight patients y ounger than 2 y ears with unilateral, nonmetastatic, small (< 550 g
total tumor and kidney specimen weight) FH tumors (stage I) underwent nephrectomy with
no additional therapy. With mean follow-up of 5 y ears, all eight children are alive. Seven are
continuously disease-free; one developed a metachronous bilateral tumor and was treated
successfully (56,57). In NWTS-5, 75 children y ounger than 2 y ears and with stage I FH
tumors weighing < 550 g were enrolled in a prospective study and treated with nephrectomy
only. Eleven patients relapsed, among them five had recurrent disease in lung, three in the
operative bed, and three in the contralateral kidney. The 2-y ear disease-free and overall
survival rates were 87% and 100%, respectively (103). Long-term results of this study
revealed a 5-y ear relapse-free and overall survival of 84% and 98%, respectively (104).
Surgical techniques in children with Wilms tumor can impact both the tumor stage and
risk of local recurrence. In a surgical quality assessment (QA) review from the NWTS-5,
among 1305 patients who underwent nephrectomy, 117 (9%) did not have ly mph node
sampling and tumor spillage occurred in 253 patients (19%). A total of 30 patients were
deemed to have had unnecessary biopsies either preoperatively or intraoperatively leading to
local tumor spillage. This report and an earlier one from NWTS-4 have clearly demonstrated
that the absence of a ly mph node biopsy and tumor spillage were both associated with a
higher rate of abdominal relapse (97,105). A surgical QA program is presently in place in the
COG to educate surgeons regarding the value of ly mph node sampling and avoidance of
procedures that result in tumor spillage.
Radiation Therapy
In 1950, Gross and Neuhauser of Boston Children’s Hospital reported that 10 of 31 (32%)
patients treated for Wilms tumor from 1931 to 1939 appeared to be cured of their tumors,
compared with 18 of 38 (47%) cured when treated between 1940 and 1947. The authors
suspected that the difference resulted from the radiotherapy administered to 36 of the 38
patients in the later period. It was customary to irradiate children in the immediate
postoperative period (i.e., shortly after they left the operating room). Dosages of 200 R/day
were given to a total dosage of 4000–5000 R (106).
At present, approximately 70–75% of children with Wilms tumor are treated without
radiation therapy. The number rises to 80–85% if metastatic disease is excluded. The NWTS
and SIOP trials that have led to this restricted use of radiation therapy are described earlier in
this chapter. When irradiation is used, it is successful in limiting the frequency of abdominal
relapse to 0–4% of children with FH tumors (78).
Chemotherapy
In 1966, Sidney Farber reported improved results in the treatment of recurrent and metastatic
Wilms tumor. His series included 16 patients with recurrent disease and 15 with metastatic
disease at diagnosis. Patients were treated primarily with actinomy cin D and, to a limited
degree, vincristine. The 2-y ear survival rate was 58% (107).
The addition of effective chemotherapy has substantially improved the overall results in
Wilms tumor in the past two decades. The NWTS and SIOP studies that have substantially
established the indications for chemotherapy are discussed earlier in this chapter.
The current guidelines for external beam radiation therapy in COG protocols are summarized
in Table 13.15 . Indications for radiation therapy in the current SIOP 2001 trial are
summarized in Tables 13.34–13.37 .
The timing of postoperative irradiation is important. Delay ed initiation of treatment
bey ond 10 day s after surgery has been related to higher risk of abdominal recurrence in
several, but not all, studies (41,42,60,75,77,78). Most relapses related to delay ed start of
therapy have been in patients with UH. A recent analy sis (NWTS-3 and NWTS-4) looked at
the influence of delay of radiation therapy on outcome in Wilms tumor in patients with stages
II–IV FH tumors. The mean delay in radiotherapy was 10.9 day s from surgery, and the
median was 9 day s; 59% of children were treated 8–12 day s postoperatively. For children
who were treated 0–9 day s postoperatively and those treated at least 10 day s postoperatively,
there was no difference in the rate of flank or abdominal recurrence. In NWTS-1 and
NWTS-2, 80% of children were treated with radiotherapy during week 1, whereas in NWTS-
3 and NWTS-4, 24% of children were treated in week 1 but 66% were treated with
radiotherapy in week 2 (108). NWTS-5 recommended that postoperative irradiation begins no
later than the ninth postoperative day. In the COG protocols, it is recommended that radiation
therapy be initiated by day 9 if possible, but no later than day 14 after nephrectomy.
Page 321Volume
The irradiation volumes for the flank, WAI, and WLI are identical in NWTS, SIOP, and COG
protocols.
Local–regional irradiation treatment fields include the tumor bed, importantly
differentiated from the renal bed to include the entire preoperative tumor extent in the
abdomen. The tumor bed is defined as the outline of the kidney and any associated tumor.
The tumor volume is established by careful review of the surgical findings, IVP, CT,
ultrasound, or MRI. The superior margin of the field is placed at the upper pole of the
kidney /tumor with an additional 1-cm margin and the inferior portal margin encompasses the
lower margin of the kidney /tumor with a 1-cm margin. The field should extend to the dome
of the diaphragm only in patients in whom the tumor is known to have extended that far
superiorly. A variable proportion of the liver is necessarily included to adequately encompass
the initial tumor extent for right-sided lesions. Medially, the target volume should encompass
the entire width of the vertebral bodies, with
adequate contralateral extension to include the
entire para-aortic ly mph node chain but exclude
the remaining kidney. The choice of the medial
margin reflects the importance of ly mph node
radiation therapy. In addition, homogeneous
irradiation of the vertebral bodies avoids one
mechanism of late scoliosis by equally affecting
growth on each side of the vertebral body.
Laterally, the treatment field tangentially
includes the abdominal wall. Parallel-opposed
anterior and posterior fields are used (Fig.
13.11 ).
For patients with preoperative
intraperitoneal tumor rupture, intraoperative
rupture with diffuse dissemination of tumor,
diffuse peritoneal implants, or massive Figure 13.11 Flank radiation therapy
abdominal disease, irradiation must address the field for a left-sided Wilms tumor. The
entire abdominal cavity. The target volume gross tumor volume (GTV) based on
includes all of the peritoneal surfaces, defined preoperative CT scan is shown in green.
superiorly by the diaphragms and inferiorly The right kidney (blue) and the diaphragm
through the lower pelvic region, generally at the (yellow) are also shown.
bottom of the obturator foramen. The
acetabulum and femoral heads are blocked (Fig. 13.12 ). Attempts to limit irradiation by
blocking the contralateral pelvic region of the peritoneal cavity have been associated with
abdominal recurrence when abdominal irradiation was appropriate (109).
WLI must be administered carefully to encompass both apices and the posterior inferior
extent of the lungs. The average field extends above the clavicles and approximately down to
T12-L1. The shoulders are excluded from the field by blocks. Care should be taken not to
irradiate the uninvolved kidney in the whole-lung field (Fig. 13.13 ).
When clinical situations call for WLI plus flank irradiation as in abdominal stage III
patients with lung metastases, it is preferred that patients be treated with one large field,
reducing off the flank at 10.5 Gy and then continue with WLI to 12 Gy. If these fields are
treated separately, field matching with appropriate gaps and feathering are important in
avoiding excessive liver irradiation in right-sided disease and avoiding irradiation of the
remaining kidney in left-sided tumors.
Figure 13.12 Whole-abdomen

radiation therapy field for a left-sided
Wilms tumor (green). The field
encompasses the entire peritoneal cavity
extending from the dome of the
diaphragm to the pelvic floor. The right
kidney (blue) and diaphragm (yellow) are
also shown.
Figure 13.13 Whole-lung radiation
therapy field for stage IV Wilms tumor
after left radical nephrectomy. The total
lung volumes (yellow) and right kidney
(blue) are shown.
Figure:
Flank radiation therapy field for a left-sided Wilms tumor. The gross tumor volume (GTV)
based on preoperative CT scan is shown in green. The right kidney (blue) and the diaphragm
(yellow) are also shown.
Figure:
Whole-abdomen radiation therapy field for a left-sided Wilms tumor (green). The field
encompasses the entire peritoneal cavity extending from the dome of the diaphragm to the
pelvic floor. The right kidney (blue) and diaphragm (yellow) are also shown.
Figure:
Whole-lung radiation therapy field for stage IV Wilms tumor after left radical nephrectomy.
The total lung volumes (yellow) and right kidney (blue) are shown.
DOSAGE FOR ABDOMINAL DISEASE
As stated earlier, the first two NWTS trials incorporated an age-dependent scale of dosages
ranging from 18 to 40 Gy and the results showed no apparent dose–response relationship, with
equal frequency of abdominal recurrence at dosage levels of 18–20 Gy, 20–24 Gy, and 24–
40 Gy (41,75). The NWTS-3 trial has established that doses of 10 Gy are adequate with
three-drug chemotherapy and this has been adopted in subsequent NWTS and COG protocols
(42). In patients with residual disease (>3 cm), a booster (10.8 Gy ) dose may be given for a
cumulative tumor dose of 21.6 Gy. In recent SIOP trials, local–regional radiation therapy is
given to patients who, after preoperative chemotherapy and nephrectomy, are found to have
stage II high-risk tumors or stage III. These categories comprise approximately no more than
25% of patients. The dosage to the tumor bed is 14.4–25.2 Gy, with an optional boost to
localized areas of tumor as needed (Tables 13.34 –13.37 ) (69).
Page 322Intensity-Modulated Radiation Therapy in Wilms Tumor

The application of intensity -modulated radiation therapy (IMRT) in the management of
Wilms tumor has been reported in dosimetry and clinical studies. Dosimetry studies have
shown that compared with standard AP-PA techniques, the use of IMRT for WLI and whole-
liver irradiation can significantly reduce the radiation dose to the whole heart and cardiac
chambers including the ventricles (for WLI) and the only remaining kidney (whole-liver
irradiation) (110,111). A prospective multicenter clinical trial of cardiac sparing IMRT for
WLI was recently completed and preliminary results have confirmed the dosimetric
advantages of superior cardiac protection with IMRT. This study has also demonstrated the
feasibility and safety of cardiac sparing whole-lung IMRT in children with pulmonary
metastases (112). These IMRT techniques will be utilized in future COG protocols.
Bilateral Wilms Tumor

Stage V or BWT is found in 4–8% of patients (10,11,43). The 2-, 5-, and 10-y ear survival
rates are 83%, 73%, and 70%, respectively (10,43,113). The majority of bilateral cases
present with simultaneous or sy nchronous involvement in both kidney s. UH is found in 10%,
and discordant histology (i.e., UH on one side and FH on the other) is found in some patients
(10). UH, older age at diagnosis, and the most advanced stage of the individual tumors are the
most important prognostic factors (10,43,113).
The goal of therapy is cure with preservation of renal function. Radical nephrectomy
should almost never be performed as part of the initial surgical procedure. Rather, the initial
operation defines the extent of tumor in each kidney, obtains bilateral biopsies to histologically
confirm the diagnosis, and biopsies suspicious ly mph nodes. Subsequently, the child should be
treated with chemotherapy tailored to the worst histology (favorable or unfavorable) and the
stage of the primary tumors (i.e., more aggressive chemotherapy if one of the tumors is
intra-abdominal stage III, less aggressive if both tumors are stage I). After this initial
chemotherapy, the child is returned to the operating room for second-look surgery. If the
tumor can be removed with preservation of renal function, it should. If surgery successfully
removes the tumors and there is no gross or pathologic evidence of persistent or residual
disease, chemotherapy is continued appropriate to the surgical stage. If there is gross or
microscopic residual intra-abdominal tumor after second-look surgery, the patient is switched
to alternative chemotherapy. If abnormalities persist in the kidney s on repeat imaging, a third
operation may be attempted to finally excise the tumors (10,43,113,114,115,116). In NWTS-
2 and NWTS-3, complete excision of all gross disease was possible in only 38% of patients
following one or more operations. Among them, the 34 patients who received only
dactinomy cin and vincristine had a 100% 3-y ear survival. They found no statistical
difference in outcome between patients undergoing an initial definitive surgery (complete or
partial nephrectomy ) or biopsy alone at diagnosis (10). In NWTS-4, complete removal of all
gross tumor was successful in 118 of 134 (88%) kidney s following renal parenchy mal sparing
surgery (either partial nephrectomy or enucleation), but local recurrence of tumor occurred
in 8% of the remaining kidney s (113,114,115). Despite these results, the outcomes of children
with BWT are not as good as for children with unilateral tumors at diagnosis. In the SIOP
protocols, the 10-y ear overall survival for sy nchronous BWTs treated with preoperative
chemotherapy /radiation was 69% (116). Unpublished NWTS-3 and -4 data showed a 10-y ear
relapse-free and overall survival rates of only 65% and 78%, respectively. This was
significantly inferior to outcomes for stages I–IV unilateral FH tumors with a relapse-free
survival and overall survival rates of 86% and 92%, respectively. Among 158 patients in
NWTS-5 with bilateral disease, the 4-y ear relapse-free and overall survival rates were only
61% and 80%, respectively. The factors that could have contributed to the poor outcomes
were: under staging and/or under treatment, delay in local disease control with definitive
surgical resection, and increased incidence of anaplasia. The size of these tumors often
precludes access to the hilar area and great vessels to examine ly mph nodes. Failure to
sample ly mph nodes can lead to under staging and an increased risk for abdominal
recurrence, presumably due to undertreatment (97). Delay ed definitive surgical resection of
the tumor is an important cause of poor outcomes in these patients. In NWTS-4, 38 had
clinically progressive or nonresponsive disease. Ten of these lacked pathology review. Of the
remaining 28 patients, 15 had rhabdomy omatous differentiation, complete necrosis, or
stromal differentiation. These patients would not have required prolonged/intensive courses of
chemotherapy with delay s in definitive surgery. These 38 patients actually received a
median of 7 months of chemotherapy prior to definitive surgery with a range of 2–29 months
(117). Anaplastic Wilms tumors are present in about 10% of BWTs and carry the same
adverse prognosis as in unilateral tumors. Although there are several advantages to the initial
use of percutaneous needle core biopsies, it was inadequate for identify ing anaplasia. In a
report from the NWTS, anaplasia was identified in zero of seven tumors by core needle
biopsy, three of nine tumors by open biopsy, and in seven of nine patients by partial or
complete nephrectomy. The mean duration of first chemotherapy in each of these three
groups, respectively, was 20, 39, and 36 weeks. Early incisional biopsy or tumor resection no
later than 6–12 weeks after initiation of chemotherapy was recommended in order to identify
anaplastic histology and limit the duration of ineffective chemotherapy (118). Future COG
protocols like AREN0534 are aiming for earlier biopsies or resection of tumors that are not
responding to therapy in the hope of avoiding prolonged ineffective therapies for patients with
diffuse anaplasia. The study aims to intensify chemotherapy upfront (three drugs), require
second-look surgery at 6 weeks, definitive surgery at 12 weeks, and recommend
chemotherapy based on histologic response after definitive surgery.
Page 323Some centers have advocated parenchy mal sparing procedures in unilateral
Wilms tumors to reduce the risk of renal insufficiency. However, the overall incidence of
renal failure following treatment in unilateral tumors is only 0.25% (119). There are certain
groups of children at higher risk for renal failure. Breslow et al. (120) reported a 38% risk of
renal failure at a median of 14 y ears after diagnosis among certain subgroups like patients
with WAGR and Deny s–Drash sy ndromes. Other groups of children that could benefit from
renal parenchy mal sparing surgery are those at increased risk for development of
metachronous Wilms tumor such as those with aniridia, and a number of overgrowth
sy ndromes, for example, BWS and idiopathic hemihy pertrophy (121,122).
Radiation therapy in stage V Wilms tumor is indicated when definitive surgery has been
accomplished and one or both of the primary tumors are found to be stage III FH, stages I–
III anaplastic tumors, CCSK, or RTK or when preoperative chemotherapy and one or two
surgeries have not achieved successful extirpation of tumor with negative resection margins.
Metastatic Disease
The ability to control overt pulmonary metastasis was the major advance consequent to the
addition of actinomy cin D to irradiation in the management of Wilms tumor (50,52,53,107).
In stage IV patients with pulmonary metastasis at diagnosis, conventional NWTS
management begins with nephrectomy, postoperative chemotherapy, abdominal irradiation if
appropriate, and WLI. The indications for infradiaphragmatic irradiation are dictated by the
degree of abdominal disease. For patients with pulmonary metastasis by chest radiograph at
diagnosis, the addition of lung radiation therapy is standard (13,41,42,75). Although earlier
reports documented excellent control at dosage levels of 16–18 Gy, the impressive results in
recent series using dosages limited to 12 Gy at 1.5 Gy per fraction approach the control rates
for abdominal disease with attenuated dosage levels (13,41,42,75). A boost to local sites of
residual pulmonary nodules to cumulative levels of up to 20 Gy is appropriate if permitted by
the lung volumes. Stage IV FH with lung metastases had an 80% 4-y ear survival rate on
NWTS-3, whereas survival rate for those with stage IV UH was about 55% (42).
Page 324In the new SIOP protocol, stage IV disease is treated with preoperative
chemotherapy. Nephrectomy is then performed. Radiation therapy is administered according
to SIOP guidelines for intra-abdominal disease (discussed earlier in this chapter). WLI is
reserved for those who do not have a complete pulmonary tumor response and are not
rendered free of disease by metastasectomy.
Is WLI necessary in stage IV (pulmonary ) Wilms tumor? In a UKCCSG study, patients
with stage IV FH were spared WLI if they had complete resolution of pulmonary metastases
after chemotherapy. Thirty -five of 39 patients were treated without WLI. The 6-y ear
disease-free and overall survival rates were 50% and 65%, respectively (123). These results
appear to be somewhat worse than the 4-y ear survival rate of 82% on NWTS-3, probably
because of the inclusion of routine lung irradiation in the NWTS-3 (42). In the second
UKCCSG Wilms tumor study (UKW2), the 4-y ear survival rate in these patients improved to
75%, probably owing to the greater use of WLI (80). In a SIOP study, 36 patients with stage
IV FH received chemotherapy, with abdominal irradiation given for stage III or node-positive
stage II. Chemotherapy eradicated lung disease in 27 of 36 patients. Six additional patients
were cleared of lung metastases with surgery. Only seven children ultimately received WLI:
seven for recurrent tumor, one immediately after nephrectomy for inoperable multiple
metastases, and two after complete tumor clearance by chemotherapy. Five-y ear actuarial
disease-free survival rates were 83% (66,92,124). A UKCCSG report revealed that children
with stage IV lung metastases on chest X-ray had a significantly worse outcome when
treated with three drugs alone (doxorubicin dose of 360 mg/m 2) without lung irradiation
compared with those who received lung irradiation and lower dose of doxorubicin (300
mg/m 2). The event-free survival rate was 53% versus 79%. However, there was no
significant difference in overall survival (73% vs. 84%) (125).
The value of WLI in CT-only but not chest X-ray lesions has also not been resolved. A
report from St. Jude Children’s Research Hospital suggested that patients with pulmonary
metastases detectable only by CT scan have an increased risk of pulmonary recurrence
following treatment with chemotherapy only (54). However, a retrospective review of the
experience with similar patients treated on NWTS-3 and NWTS-4 did not demonstrate a clear
benefit of WLI. The 4-y ear event-free survival rate was 89% for patients treated with
chemotherapy only and 80% for those who received irradiation (126, 127). A recent report
has suggested that children with FH Wilms tumor and CT-only lung metastases registered on
NWTS-4 and NWTS-5 have an inferior relapse-free survival when treated with one-drug or
two-drug chemotherapy with or without lung irradiation compared with those who received
doxorubicin. There were no additional benefits to lung irradiation when doxorubicin was
added to two-drug chemotherapy (128). A report from the UKCCSG in patients with stage I
tumors and CT-only pulmonary metastases showed a significantly higher pulmonary relapse
rate (43%) after single-agent vincristine alone. The pulmonary relapse rate in similarly
treated patients without CT lung lesions was 10% (129).
The value of a lung biopsy in patients with lung metastasis is not well established. Among
2498 patients registered on NWTS-5, 252 (10%) had pulmonary metastasis detected by chest
X-ray (5%) and CT only in 5%. Among patients with CT-only lesions, 33% underwent a lung
biopsy. The positive biopsy rate in patients with isolated and multiple lung lesions was 82%
and 69%, respectively. Although this report did not conclusively address the issue regarding
value of lung biopsies, it does point out that not all lung lesions on detected by CT only were
metastasis. The authors recommended that in suspicious lesions on CT scans, a negative lung
biopsy may obviate the need for unnecessary intensification of therapy with doxorubicin
and/or WLI (130).
In COG protocol, AREN0533 chemotherapy response at week 6 will be used to
determine whether WLI is delivered or not. Patients who achieve a complete radiologic
response to three-drug chemotherapy at week 6 will not receive lung irradiation. All patients
with UH tumors will receive WLI regardless of whether they are detected by chest X-ray or
CT scan (Table 13.15 ).
Liver metastases may be treated by hepatic irradiation in addition to chemotherapy.
Whole-liver irradiation is sometimes given for diffuse disease, with supplementary boosts to
gross disease (41,42,47). When possible, however, more limited radiotherapy fields are used
if the disease is more localized in the liver. In a report from NWTS-4 and -5, the relapse-free
survival rate for 96 patients with FH tumors and liver metastases was 76%. Their survival
rates were similar to that of patients with lung metastases (76%), liver and lung metastases
(70%), and metastases to other sites (64%). Twenty -two patients had a primary liver
resection and 13 underwent resection after chemotherapy /irradiation. Eighty -two patients
received abdominal radiation (131).
Recurrent Wilms Tumor

A large body of evidence from the NWTS, UKCCSG, and SIOP trials has been gathered
concerning the important prognostic factors after relapse of Wilms tumor (132,133,134,135).
The major prognostic factors are: site of recurrence, initial stage of disease, tumor histology,
time to relapse from initial therapy, and nature of prior therapy (two drugs vs. three drugs ±
RT). In NWTS-2 and NWTS-3, the 3-y ear postrelapse survival rate was 57% for initial stage
I, 36% for initial stage II and III, and 17% for initial stage IV (133). The survival after relapse
of patients with FH is two to four times greater than that of patients with UH
(132,133,134,135). The 3-y ear postrelapse survival for patients in NWTS-2 and NWTS-3 who
relapsed 0–5 months after diagnosis was 18%, 6–11 months after diagnosis was 30%, and 12
months or more after diagnosis was 41% (133). Patients who relapse after initial therapy that
included adriamy cin or abdominal irradiation fare worse than those who did not receive such
therapy. Presumably this is because the use of adriamy cin or radiotherapy is a surrogate
marker for initially more advanced disease and because tumor that recurs after such therapy
may represent more resistant disease (132,133,134,135). In NWTS-3, the 3-y ear postrelapse
survival for patients with recurrent Wilms tumor after initial therapy that included radiation
therapy was 15%. Among those treated initially with surgery and chemotherapy only, the 3-
y ear postrelapse survival rate is 77% after retreatment (133). The lung is a common site of
recurrence of Wilms tumor. Relapse confined to the lung has a 44% 3-y ear postrelapse
survival. Relapse in the liver portends a worse prognosis with a 4-y ear survival rate of 14%
(133). There are some survivors of solitary metastases to brain or liver
(132,133,134,135,136). Patients who had relapsed or progressive disease after initial
chemotherapy with vincristine and actinomy cin D and no radiation therapy were treated on
stratum “B” of the NWTS-5 relapse protocol. The relapse treatment included chemotherapy
with regimen “I” with alternating courses of vincristine, doxorubicin, cy clophosphamide and
etoposide/cy clophosphamide, surgery, and radiation therapy. The 4-y ear event-free and
overall survival rates were 71% and 81% for all patients, 68% and 81% for those who
relapsed in the lung only, and 78% and 83% for those who relapsed in the operative bed with
or without lung metastasis (137). Patients who had relapsed or progressive disease after initial
chemotherapy including vincristine, actinomy cin, and doxorubicin and radiation therapy
were treated on stratum “C” of the NWTS-5 relapse protocol. The relapse treatment included
alternating courses of drug pairs: cy clophosphamide/etoposide and carboplatin/etoposide,
surgery, and radiation therapy. The 4-y ear event-free and overall survival rates were 42%
and 48% for all patients and 49% and 53% for those who relapsed in the lung only (138).
Page 325See Table 13.15 for COG radiation therapy guidelines for relapsed Wilms
tumor patients.
Renal Tumors in Very Young Children

Renal tumors diagnosed in the first 7 months of life generally have an excellent prognosis
though histology is an important factor. A collaborative study by the North American and
European Wilms tumor study groups revealed that 7% of 10,430 registered patients were
diagnosed with a renal tumor before 213 day s of age. The tumor ty pes were Wilms tumor
(58%), congenital mesoblastic nephroma (18%), malignant RTK (8%), CCSK (2%), non-
Wilms tumor (6%), and unknown histology (9%). Although Wilms tumor is the most common
renal tumor in these children, congenital mesoblastic nephroma is also a common entity
especially in the first 2 months of life. For all patients, the 5-y ear event-free and overall
survival rates were 80% and 86%, respectively. The 5-y ear overall survival rates for Wilms
tumor, CMN, CCSK, and RTK were 93%, 96%, 51%, and 16%, respectively (139).
TOXICITIES
The late effects of treatment of childhood cancer and the causes and frequency of treatment-
induced second malignant neoplasms (SMNs) are considered in detail in Chapters 19 and
20 . In this section, we will review the late ill effects, including induced neoplasms,
particularly associated with the treatment of Wilms tumor.
Hematologic Toxicity
Review of the data from NWTS-3 indicates clinically significant acute hematologic toxicities.
Fatal toxicities occur in a small proportion of patients. Depending on the drugs given, severe
hematologic toxicity occurs in 6–64% of patients over a 6-week course of treatment. Toxicity
and infections account for 15% of the deaths of NWTS children, producing a 1% treatment-
related mortality rate (79).
Hepatic Effects
Hepatotoxicity from Wilms tumor therapy may be indicated by an increase in transaminases
or by hy perbilirubinemia. Veno-occlusive disease consists of the clinical triad of
hepatomegaly, ascites, and icterus. In unirradiated NWTS-4 patients, the frequency of
hepatic toxicity related to actinomy cin D (serum glutamic–oxaloacetic transaminase, serum
glutamic–py ruvic transaminase elevations) rose from 2.8% in patients receiving 15 mg/kg of
standard divided-dose therapy to 3.7% in those receiving pulse intense (PI) 45 mg/kg and
14.3% in those receiving 60 mg/kg PI therapy. These data prompted replacement of the 60-
mg/kg treatment with the 45-mg/kg dosage (140). A review of cases accrued via the German
Pediatric Oncology Hematology Group to SIOP trial 9 studied 58 patients who received
chemotherapy and abdominal irradiation. Eleven of these 58 patients developed signs of
hepatotoxicity, four of them with veno-occlusive disease. There was a predominance of
children with right-sided tumors in the group with hepatic injury (9 out of 33, 27%, vs. 2 out of
24, 8%) (141). In a report from the NWTS-1 to NWTS-4, a case–control study was
conducted to determine relationships among doxorubicin, liver radiation dose, patient gender,
and the development of portal hy pertension. The 6-y ear cumulative risk for portal
hy pertension was 0.7% for right-sided tumors versus 0.1% for those with left-sided tumors (p
= 0.002). There was a significant association between minimum and maximum liver dose
(>15 Gy ) and portal hy pertension. Doxorubicin and gender were not significant (142).
Orthopedic Effects
In long-term follow-up studies of Wilms tumor survivors, scoliosis and musculoskeletal
abnormalities are more common in irradiated patients than in those not irradiated. This may
result from asy mmetric irradiation of the vertebral bodies or the paraspinal musculature.
Rate et al. (143) identified 31 children with Wilms tumor who received abdominal irradiation
between 1970 and 1984 and were followed past skeletal maturity. Ten of the children were
irradiated with orthovoltage and 21 with megavoltage. Of the children irradiated with
megavoltage, the most common orthopedic abnormalities were lower rib hy poplasia (57%)
and mild scoliosis (10–20 degrees) (48%). In the patients irradiated with orthovoltage, lower
rib hy poplasia occurred in 50%, mild scoliosis in 40%, severe scoliosis (more than 20
degrees) in 40%, and limb length inequality in 20% (143,144). Scoliosis as a late ill effect of
abdominal irradiation for Wilms tumor was confirmed by a report from the University of
Helsinki in which 21 of 24 patients (88%) had some degree of scoliosis. Most patients had
been irradiated with cobalt-60 (144,145).
Renal Effects
After unilateral nephrectomy in childhood, the
remaining kidney generally adjusts its function
and size; this is called compensatory
hy pertrophy of the kidney. One y ear after
nephrectomy for Wilms tumor, the glomerular
filtration rate (GFR) and effective renal plasma
flow are approximately 90% of normal values
for age-matched children with two normal
Table 13.38 Long-Term
kidney s. Children treated with surgery and
chemotherapy also have close to normal values. Complications of Renal Function
The addition of radiation to chemotherapy
results in a diminished renal function to approximately 73% of normal GFR (Table 13.38 )
(141,146). In a report from the NWTS, the 20-y ear cumulative risk of renal failure for
children with unilateral tumors without congenital abnormalities, BWT, male GU anomalies,
Deny s–Drash sy ndrome, and WAGR sy ndrome was <1%, 5.5%, 10.9%, 62%, and 38%,
respectively. It was recommended that patients with aniridia and GU abnormalities be
carefully monitored throughout life for signs of nephropathy or renal failure (120).
Page 326Cardiac Effects

Cardiac injury in long-term survivors is
associated with the use of doxorubicin or the
cardiac irradiation that occurs during WLI. The
20-y ear cumulative frequency of congestive
heart failure among patients treated on NWTS-1
to NWTS-4 was 4.4% for patients treated
initially with doxorubicin and 17.4% for those Table 13.39 Long-Term
treated with doxorubicin for relapse. The relative Complications of Cardiac Function (99)
risk of congestive heart failure was significantly
increased in females, cumulative doxorubicin dose, lung irradiation, and left-sided abdominal
irradiation (Table 13.39 ) (147).
Pulmonary Effects
In a report from the NWTS, among 6500 patients from NWTS1-4 with a median follow-up of
18 y ears, the 15-y ear cumulative incidence of pulmonary disease (abnormal pulmonary
function tests or clinical sy mptoms and signs of restrictive pulmonary disease) was <0.5%
without lung RT and 4–5.5% after lung RT was delivered for primary stage IV tumors or at
relapse. There was no correlation between the incidence of pulmonary disease and WLI dose
as the majority of patients received between 12 and 14 Gy (148).
Pregnancy Outcome
There is now long-term follow-up on pregnancy outcome in irradiated women who were
treated, as children, for Wilms tumor. As Table 13.40 indicates, the risk of early or
threatened labor, malposition of the fetus, short gestation, or low birth weight appears directly
correlated with the irradiation dosage. The outcome also appears worse for those treated with
abdominal–pelvic fields and those treated with higher irradiation dosages (149,150).
Table 13.40 Pregnancy Outcome
Treatment-Induced Neoplasms
Initial reports concerning the risk of SMNs after treatment of Wilms tumor indicated that the
cumulative incidence 10 y ears after diagnosis was 1% (151,152). In an NWTS report, the 15-
y ear cumulative risk of SMN was 1.6% since Wilms tumor diagnosis. The risk of developing a
ly mphoma or leukemia was 0.4% at 8 y ears after which no cases occurred. However, the
risk of developing a solid tumor continued to rise sharply with time. Approximately 73% of
solid tumors arose within a previous irradiated field. Higher abdominal radiation dose,
doxorubicin use, and treatment for relapse were the significant factors correlated with the
development of second tumors (153). Long-term follow-up indicates that there is a risk of
acute my elocy tic leukemia in long-term survivors of Wilms tumor. This may be related to
the administration of alky lating agents and abdominal irradiation (154). In another NWTS
report on the rates and causes of mortality in Wilms tumor patients, the standardized
mortality ratio (SMR) was 24.3 within 5 y ears of diagnosis, 12.6 for the next 5 y ears, and
>3.0 thereafter. The main cause of mortality within the first 5 y ears was original disease
(91%). However, bey ond 5 y ears, the two important causes of mortality were original
disease (40%) and late effects of treatment (39%). The three common treatment-related late
effects that contributed to mortality were SMNs, congestive heart failure, and end-stage renal
disease. The risk of death particularly from treatment-related late effects remained elevated
even 20 y ears after diagnosis (155). In the British Cancer Survivor Study, the cumulative
incidence of a second primary neoplasm at 30, 40, and 50 y ears of age was 2%, 7%, and
12%, respectively. Thirty -five of 39 solid neoplasms that developed in the thoracic,
abdominal, or pelvic regions occurred within irradiated tissue. Higher doses of radiation
therapy delivered to the abdomen and pelvis was an important reason for the development of
secondary tumors (156). In another recent NWTS report, female survivors who received
WLI had nearly a 15% risk of developing invasive breast cancer by age 40 y ears. This report
highlighted the need for reevaluating current COG guidelines that recommend breast cancer
screening only for those who received >20 Gy to the chest (157).
Growth Abnormalities
Abdominal irradiation can also produce
significant reduction in sitting height and a more
modest decrease in standing height. These
effects are more pronounced the y ounger the
patient is at the time of radiotherapy (143,158).
Long-term analy sis of predicted height deficits
in children who receive flank radiation for
Wilms tumor indicates, as shown in Table
13.41 , that the y ounger a child is at the time
of flank irradiation, the greater the predicted
height deficit. Furthermore, the higher the Table 13.41 Predicted Deficit in
dosage of irradiation administered, the greater Height at Age 18 Years after Flank
the predicted height deficit. These effects are Irradiation at Selected Ages and Dosages
related to irradiation of the thoracolumbar
vertebral bodies. Abnormalities can also ensue from asy mmetric irradiation of the
paravertebral musculature, which may, over time, lead to a risk of scoliosis.
Figure: Long-Term Complications of Renal
Function
Figure: Long-Term Complications of
Cardiac Function (99)
99 Breslow N, Sharples K, Beckwith JB, et al. Prognostic factors in non-metastatic favorable
histology Wilms’ tumor—results of the Third National Wilms’ Tumor Study. Cancer.
1991;68:2345–2353.
Figure: Pregnancy Outcome
Figure: Predicted Deficit in Height at Age 18
Years after Flank Irradiation at Selected
Ages and Dosages
FUTURE DEVELOPMENTS
Page 327In spite of the tremendous progress that has been made in the management of
Wilms tumor, a significant amount of clinical and basic research is being conducted by the
NWTS and SIOP investigators to further optimize therapy in this disease. The future risk
stratification of Wilms tumors for the next generation of COG protocols will likely include two
promising biomarkers (11p15 LOH for VLRWT and 1q gain for FH tumors) in addition to the
other currently used prognostic factors including tumor histology, age, tumor weight, tumor
stage, LOH status, and tumor response to chemotherapy. Treatment strategies for the various
risk groups are currently being developed. Based on the preliminary findings of current COG
protocols, chemotherapy response at week 6 will determine the need for WLI in children with
FH tumors and lung metastasis. Regimen ‘M’ will be used for patients with higher risk tumors
including those with LOH and slow responders to chemotherapy at week 6. Vincristine and
Irinotecan will be included in the chemotherapy regimen for children with diffuse anaplastic
Wilms tumors. Safer multimodality treatment regimens are being considered for UH tumors.
The indications for and dosages of radiation therapy will likely remain the same. As discussed
above, IMRT will be recommended for WLI and whole-liver irradiation. The COG radiation
oncologists will continue research to answer some of the remaining clinical radiotherapy
questions including: RT dose response in relapsed Wilms tumor and diffuse anaplasia; RT
quality assurance review data for patients enrolled on COG protocols; RT effects on flank
relapse in stage III patients with tumor rupture; correlation of RT dose with late effects among
NWTS survivors such as infertility, SMNs, etc.; and the possible role of proton therapy to
reduce late effects in children with Wilms tumor.
Finally, it is very important for all phy sicians involved in the care of children to promote
the recruitment of childhood cancer survivors into long-term follow-up programs that are
designed to provide education and specific surveillance guidelines for the early detection and
prompt management of any potential treatment-induced sequelae. Such measures will go a
long way in preventing or ameliorating the negative impacts of such sequelae on their quality
of life. The COG long-term follow-up guidelines for survivors of childhood, adolescent, and
y oung adult cancers are updated annually and are available on the COG website
(http://www.survivorshipguidelines.org ) (159).
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CH A P TER 14
Liver Tumors in Children
Bow-Wen Chen, Eric Yi-Liang Shen, Skye H. Cheng, and Andrew T. Huang
Page 331Childhood primary tumors of the liver

are rare. Approximately two-thirds of all liver
tumors in children are malignant. The incidence
varies from geographic region to region.
According to the Surveillance, Epidemiology,
and End Results (SEER) data, between 1973 and
1977 and between 1993 and 1997,
hepatoblastoma rates increased (from 0.6 to
1.2/1,000,000), while hepatocellular carcinoma
rates decreased (from 0.45 to 0.29/1,000,000)
(1). The most common liver tumors in children
according to histopathology are hepatoblastoma Table 14.1 Incidence of Primary
(HBL 43%), hepatocellular carcinoma (HCC Hepatic Tumors in Childhood
23%), benign vascular tumor (13%),
mesenchy mal hamartoma (6%), and sarcoma (6%) (Table 14.1 ). Benign tumors are
usually found incidentally as an asy mptomatic abdominal mass. Malignant tumors usually
present with abdominal distension with or without a palpable abdominal mass. Children with
both HBL and HCC may also present with weight loss, fever, and anorexia. Anemia,
thrombocy topenia, and leukocy tosis are sometimes associated findings.
Complete surgical resection is the standard curative treatment for malignant liver
tumors. However, most malignant liver tumors are large and initial resection may not be
attainable without prior therapy. Chemotherapy, radiotherapy, and local ablation are
adjunctive to surgery or palliative treatment for patients with incurable diseases.
Computed tomography (CT) and magnetic resonance imaging (MRI) are the most
definitive diagnostic tests and can often help to differentiate benign from malignant tumors
preoperatively.
Figure: Incidence of Primary Hepatic
Tumors in Childhood
BENIGN TUMORS
Vascular Tumors
The most common benign lesions in children are hemangiomas and hemangioendotheliomas.
Hemangiomas are the more common and usually occur within the first 6 months of life (2).
Most hemangiomas are incidentally discovered on imaging studies. Infantile
hemangioendothelioma is a subty pe of hemangioma that is ty pically found in infants. A
female predilection is noted, with a female-to-male ratio of 4.3:1 to 2:1. Afflicted infants
generally present with abdominal distension and cutaneous hemangiomas (10% of cases) that
suggest the diagnosis. More than 50% of these infants have high-output cardiac failure at
initial presentation (2). The classical triad of hepatomegaly, anemia, and congestive heart
failure leads to the suspicion of infantile hemangioendothelioma. Kasabach–Merrit sy ndrome
with consumptive coagulopathy, thrombocy topenia, and hemorrhage is the leading cause of
morbidity and mortality seen in infantile hemangioendothelioma (3).
The natural history for hemangiomas is spontaneous regression in the first 2 y ears of
life; however, treatment is required if cardiac failure or platelet consumption occurs. Several
treatment options are available, including high-dose corticosteroids (3–5 mg/kg/day ),
interferon-alfa (3 MU/m 2/kg/day SC), aminocaproic acid, vincristine, and
cy clophosphamide; all are associated with potential severe side effects and poor outcome (4).
Focal lesions can be treated with complete surgical excision. Selective hepatic artery
embolization may not be as successful for multifocal as it is for focal lesions. Operative
ligation of the hepatic artery can be used to decrease shunting through the lesion, with
subsequent improvement in cardiac output (5). Radiation therapy is usually avoided because
angiosarcomatous degeneration may follow radiation. Rarely, liver transplantation may be
indicated for diffuse disease that is unresponsive to steroid and interferon therapy.
Mesenchymal Hamartoma
Infantile mesenchy mal hamartomas are rare benign tumors, comprising 6% of liver tumors
in children (Table 14.1 ), and can be considered more of a malformation than true tumors.
They tend to be diagnosed before the age of 2 y ears and are more common in the right lobe
of the liver. They usually present as an asy mptomatic abdominal mass after a period of rapid
growth during the first few months of life and cause compression of adjacent tissue but are
curable by resection (6). Alpha fetoprotein (AFP) levels may be variably elevated. CT scan
reveals a well-circumscribed, multilocular, heterogeneous, cy stic mass with solid septa and
stroma. Biopsy is recommended if cy sts are small or appear more solid rather than septated.
Complete surgical excision, with a rim of normal tissue (if possible), is the treatment of
choice (7).
Page 332Focal Nodular Hyperplasia and Hepatic Adenomas

Focal nodular hy perplasia (FNH) and hepatic adenomas are rarely seen in children. Both of
these benign lesions have an association with a high-estrogen environment and frequently
occur in adolescent girls. Hepatic adenomas are associated with oral contraceptive use. Signs
and sy mptoms may be absent or are nonspecific and include abdominal pain and mass
sy mptoms. A characteristic central stellate scar on CT scan is pathognomonic for FNH. A
triphasic helical CT scan is the optimal method to make the diagnosis of FNH. Differentiating
FNH from adenomas may require a technetium sulfur colloid scan, which reveals uniform
uptake by FNH lesions. Patients suspected of FNH should be managed conservatively. If a
diagnosis remains unclear, a liver biopsy may be helpful. If the lesion becomes sy mptomatic
or rapidly enlarging, complete surgical resection may be necessary to differentiate FNH
from malignant tumors (7).
PRIMARY MALIGNANT LIVER TUMORS
Children with primary malignant liver tumors (PMLTs) often present with an abdominal mass
or generalized abdominal enlargement. The child may have pain localized to the right upper
quadrant, fever, anorexia, weight loss, jaundice, or vomiting. The first presentation may, on
occasion, be an acute abdominal crisis caused by tumor rupture and hemoperitoneum.
Paraneoplastic sy ndrome, such as precocious sexual development, has been associated with
PMLTs (8). Anemia and thrombocy tosis often occur. This is probably related to the ability of
HBL cells to secrete gonadotropin and interleukin-1B, which induces IL-6 production in
fibroblasts of endothelial cells (9).
Hepatoblastoma
HBL is the most common PMLT occurring in the first 20 y ears of life and accounts for 1% of
all pediatric malignancies and about 60% of PMLTs in the pediatric age group (8). Median
age at diagnosis is 16–19 months. Only 5% of the cases occur in children older than 4 y ears.
As with all PMLTs, there is a male predominance with a reported male-to-female ratio of
1.4–2.0:1. HBL has been reported to be associated with a host of conditions, including
Beckwith–Wiedemann sy ndrome, Wilms tumor, adrenal cortical tumors, fetal alcohol
sy ndrome, familial adenomatous poly posis (FAP), prematurity, low birth weight, parental
cigarette smoking, and paternal excess exposure to metals or petroleum products. The cell of
origin is thought to be a pluripotent hepatic stem cell.
HBL may be histologically classified into six patterns (Table 14.2 ). Conventional
HBLs contain fetal hepatoblasts, embry onal hepatoblasts, or a mixture of the two cell ty pes
(Figs. 14.1 and 14.2 ). Fetal-ty pe hepatoblasts recapitulate the cy toarchitecture of the
normal human fetal liver. Cells of the early fetal liver and the cells of fetal HBL are of
similar size and configuration. Both proliferate as cuboidal cells with trabeculae one- to two-
cell thick. Both display strong positivity for AFP. Both tissues also display sinusoidal
hematopoiesis and a lack of intrahepatic bile ducts. Fetal cells are slightly smaller than normal
hepatocy tes and have a low nucleocy toplasmic ratio. In contrast, embry onal hepatoblasts
have a higher nucleocy toplasm ratio than do fetal cells, and they also have a compact
basophilic cy toplasm (Fig. 14.3 ). This gives a light-microscopic impression of a higher
cell density. Small-cell undifferentiated or anaplastic HBL contains sheets and nests of
medium-sized cells, with little or no evidence of hepatoblastic differentiation. There is scant
cy toplasm and a high mitotic index. Mixed epithelial and mesenchy mal HBL is composed of
ty pical areas of fetal epithelial and embry onal ty pe cells mixed with primitive mesenchy me
and various mesenchy mally derived tissues.
It is unclear whether the recognized
histologic subty pes are related to prognosis. The
subty pes can occur together within the same
tumor in vary ing composition. Some
investigators report that in long-term survivors of
HBL, the most common histology is the
conventional ty pe, with a predominantly fetal
cell pattern (10). However, there is no uniformly
accepted definition of “predominantly ” or
“pure” fetal histology. Although conventional Table 14.2 Histologic Classification of
epithelial tumors constitute 60% of all HBLs, Hepatoblastoma
they represent 85% of HBLs in children who
have undergone complete tumor resection and
are long-term survivors. Almost no children with
anaplastic HBL survive the disease. A Pediatric
Oncology Group (POG)–Children’s Cancer
Study Group (CCSG) trial showed the distinction
between fetal HBL and other histologic subty pes
to be of prognostic importance in stage I disease
(3-y ear progression-free survival of 79% vs.
56%, p = 0.11) (11). However, not all
investigators have confirmed the prognostic
importance of histologic subty pes in all stages. Figure 14.1 Hepatoblastoma, ×20
For example, a large analy sis, the Japanese magnification. (Courtesy Dr. John
Study Group for Pediatric Liver Tumor (JPLT), Buchino.)
found no significant influence of HBL histologic
classification on outcome (12).
Page 333Hepatocellular Carcinoma

HCC, the second most common PMLT in children, accounts for about 20% of all pediatric
hepatic malignancies (8). HCC is uncommon in children y ounger than 5 y ears, and is the
most common hepatic malignancy of adolescence. The median age of presentation for
pediatric HCC is 10–12 y ears (8,10).
Approximately 25% of cases in children are
associated with cirrhosis (10). Causes that lead to
cirrhosis include biliary atresia, Fanconi anemia,
glucose-6-phosphatase deficiency, and
hereditary ty rosinemia. HCC has also been
reported in association with hemihy pertrophy,
anomalies of the abdominal venous drainage
sy stem, and the use of oral contraceptives. HCC
occurs in areas with a higher prevalence of
hepatitis B viral infection (13). There are strong
associations of mother-to-infant HBV Figure 14.2 Hepatoblastoma, ×40
transmission in children with HCC (13). magnification. (Courtesy Dr. John
Beginning in 1984, Taiwan has implemented a Buchino.)
universal hepatitis B vaccination program for
newborns, which has led to a threefold decreasing incidence of HCC in children from 0.54 in
1981–1984 to 0.19 per 100,000 in 1990–1996, indicating the value of hepatitis B immunization
as an effective means of controlling HCC (14,15).
Page 334Fibrolamellar (FL) HCC constitutes a distinct histologic variant that occurs more
in children older than 10 y ears. This variant is characterized by large poly gonal neoplastic
hepatocy tes and lamellar bundles of collagen. Although patient numbers are small, this tumor
variant is associated with a higher frequency of resectability and a better 5-y ear survival
(55%). However, others have failed to demonstrate a favorable outcome of the FL variant in
children (7,8,16).
Undifferentiated Embryonal Sarcoma of the Liver

Undifferentiated embry onal sarcoma of the liver is the third most common liver malignancy
in children and adolescents, comprising 9–13% of liver tumors. Most are diagnosed at the age
of 5–10 y ears. It may be solid or cy stic on imaging, frequently with central necrosis.
Distinctive features are characteristic intracellular hy aline globules and marked anaplasia in a
mesenchy mal background.
Embry onal rhabdomy osarcoma arises from bile ducts and usually occurs in children
y ounger than 5 y ears. It may share some common clinical and pathologic features with
undifferentiated embry onal sarcoma of the liver.
Clinically, undifferentiated embry onal sarcoma
of the liver tends to occur in older children, often
arises in the right lobe of the liver, and does not
present with jaundice or biliary obstruction,
while bile duct rhabdomy osarcoma occurs more
frequently in y ounger age (median 3.4 y ears),
arises in hilar area, and presents with more
jaundice than the former. Surgery alone may
achieve local control for undifferentiated
embry onal sarcoma of the liver, while surgery
and radiotherapy are required for bile duct
rhabdomy osarcoma. Chemotherapy regimens
used to treat the former differ from those used to
treat bile duct rhabdomy osarcoma (17).
Figure 14.3 Hepatoblastoma. A: Fairly

well-defined tumor cells arranged in a
trabecular pattern and composed
predominantly of cells with fetal
hepatocyte differentiation pattern. There
are trabeculae of cuboidal cells that
contain small round nucleus with fine
nuclear chromatin and an indistinct
nucleolus. The cytoplasm varies from
eosinophilic to clear and contains many
pigment deposits (hematoxylin and eosin
×100). B: A second population of small
ovoid cells is arranged in clusters. These
cells are of embryonal origin (arrow)
(hematoxylin and eosin ×400).
Figure: Histologic Classification of
Hepatoblastoma
Figure:
Hepatoblastoma, ×20 magnification.
(Courtesy Dr. John Buchino.)

Figure:
Hepatoblastoma, ×40 magnification.
(Courtesy Dr. John Buchino.)

Figure:
Hepatoblastoma. A: Fairly well-defined tumor cells arranged in a trabecular pattern and
composed predominantly of cells with fetal hepatocyte differentiation pattern. There are
trabeculae of cuboidal cells that contain small round nucleus with fine nuclear chromatin
and an indistinct nucleolus. The cytoplasm varies from eosinophilic to clear and contains
many pigment deposits (hematoxylin and eosin ×100). B: A second population of small ovoid
cells is arranged in clusters. These cells are of embryonal origin (arrow) (hematoxylin and
eosin ×400).
DIAGNOSIS
Liver enzy mes and bilirubin are usually normal or mildly elevated. Abdominal ultrasound
helps to establish the presence of a hepatic mass and differentiates cy stic from solid lesions.
Color Doppler ultrasound may be performed to assess tumor vascularity and evaluate
inferior vena cava for tumor thrombus (18). The technetium-90m sulfur colloid scan is of
some value in localizing the tumor to the liver and defining its boundaries. It is a sensitive test,
but not specific. CT and MRI provide superior delineation of the mass and show evidence of
multifocality (19). On nonenhanced CT, epithelial HBL is a homogeneous low-attenuation
mass. The mixed ty pe is inhomogeneous. Calcifications can be present. Contrast
enhancement of the periphery or septa may be seen. On MRI, the epithelial ty pe is
homogeneous and hy pointense on T1 and hy perintense on T2. The mixed ty pe may be more
inhomogeneous and hy pointense on T1 and T2, and hemorrhage will show high signal
intensity on T1 and T2 (Fig. 14.4 ). On CT, HCC will show solitary or multiple masses.
Calcification can occur. The tumor rim may show enhancement with contrast. On MRI, the
T1 images may be isointense or hy perintense. On T2 images, a mosaic pattern (caused by
necrosis, hemorrhage, septa, and fatty metaplasia) is common (20). The operating surgeon
may request an angiogram to obtain information about the origin and distribution of the right
and left hepatic arteries to provide additional information on the vascular supply of the tumor
(8). Routine chest radiographs and thoracic CT scans are necessary because 10–20% of
patients with HBL and 30% of patients with HCC have lung metastasis at the time of diagnosis
(9,21,22). Positron emission tomography CT with 18F-Fluorodeoxy glucose has proved to
more sensitive than MRI or CT in detecting recurrent or metastatic diseases (23,24).
Metastases to brain and bones are not uncommonly seen, especially in advanced HCC.
Figure 14.4 A–D: Hepatoblastoma is best visualized on cross-sectional imaging. It is
homogeneous and hypointense on T1 and hyperintense on T2 on magnetic resonance images.
Page 335Approximately two-thirds of children with HBL and HCC have an elevated
AFP. The clinician should note that AFP, sy nthesized by the fetal liver, is high in the normal
newborn infant but drops rapidly throughout the first several months of life. By age 1 y ear,
the serum AFP is <10 ng/mL. The clinician should be cautious as well that AFP is not alway s
elevated in HBL and HCC, and AFP may be elevated mildly in benign hamartomas, infantile
rhabdoid tumor, and fibrolamellar HCC. Absence of AFP elevation may be a poor prognostic
sign in HBL, which is often associated with small-cell (anaplastic) histology and responds
poorly to therapy. It is also elevated in germ cell tumors with y olk sac components, and some
arise in the liver. For patients with elevated AFP, it may be of value in monitoring the course
of therapy (18). Complete resection of HBL or HCC should result in a normal AFP by 2
months postoperatively. No change in an elevated AFP after surgery indicates either residual
tumor or regenerating normal liver. The diagnosis of growing tumor depends on confirmatory
imaging studies. An elevation in the AFP level during the follow-up period generally heralds a
local tumor recurrence or distant metastasis. A diagnostic tumor biopsy for all patients should
be performed before chemotherapy, regardless of their age and serum AFP level (25).
Adequate tumor samples can be obtained via percutaneous core needle biopsy, laparoscopic
core needle or wedge biopsy, and/or open core needle or wedge biopsy, depending upon
patient characteristics, the size and location of the tumor, and the team available at the
institution. Fine-needle aspiration should be avoided for diagnosis, as the material obtained is
usually insufficient to evaluate tumors in this age group.
Genomic Abnormality
Hepatoblastoma mutation frequency, as determined by whole-exome sequencing, was very
low (three variants per tumor) in children y ounger than 5 y ears (26,27). Hepatoblastoma is
primarily a disease of WNT pathway activation. The primary mechanism for WNT
pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1
mutations have been reported to be present in 70% of cases. Rare causes of WNT pathway
activation include mutations in AXIN1, AXIN2, and APC (APC seen only in cases associated
with familial adenomatosis poly posis coli) (28). The frequency of NFE2L2 mutations in
hepatoblastoma specimens was reported to be 7% in one study and 10% in another study
(26,27). These mutations render NFE2L2 insensitive to KEAP1-mediated degradation,
leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative
stress and is believed to confer resistance to chemotherapy.
A first case of pediatric hepatocellular carcinoma has been analy zed by whole-exome
sequencing showing a higher mutation rate (53 variants per tumor) and the coexistence of
CTNNB1 and NFE2L2 mutations (29). Fibrolamellar hepatocellular carcinoma, a rare
subty pe of hepatocellular carcinoma observed in older children, is characterized by an
approximately 400 kB deletion on chromosome 19 that results in production of a chimeric
RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of
the molecular chaperone DNAJ, fused in frame with PRKACA, the cataly tic domain of
protein kinase A (30).
Figure:
A–D: Hepatoblastoma is best visualized on cross-sectional imaging. It is homogeneous and
hypointense on T1 and hyperintense on T2 on magnetic resonance images.
STAGING
There are two major staging sy stems for

PMLTs. Histologically, the US Children’s
Oncology Group (COG) has staged liver tumors
similar to other solid tumors, based on surgical
respectability, presence of residuals, and
metastasis (Table 14.3 ). In stage I, the tumor
was removed by surgery. Stage II refers to
resected with microscopic residual disease.
Stage III means unresectable disease or
presence of gross residual tumor, including local
ly mph node involvement. Stage IV are those
with distant metastasis. The drawback of this Table 14.3 Staging System of
sy stem is that it applied to initial diagnosis only. Hepatoblastoma by the Children’s
If upfront chemotherapy is given and if this Oncology Group
produces a substantive tumor response before
surgery, then the initial stage may no longer be pertinent. Second, histology is changed after
preceding chemotherapy. The European staging sy stem developed by the International
Society of Pediatric Oncology Liver Tumor Study Group (SIOPEL) is based on the number
of liver segments involved (Fig. 14.5 ), This pretreatment extent of disease (PRETEXT)
staging sy stem divides the liver into four sections. Staging is assigned according to tumor
extent within the liver and involvement of hepatic/portal veins, regional ly mph nodes, and
distant metastasis.
Page 336
Figure 14.5 PRETEXT is distinct from Couinaud 8-segment (I–VIII) anatomic division of the
liver. PRETEXT defines four “Sections.” Boundaries of each section are defined by the right
and middle hepatic veins, and umbilical fissure (From López-Terrada D, Alaggio R, de Dávila
MT, et al. Towards an international pediatric liver tumor consensus classification: proceeding
of the Los Angeles COG liver tumors symposium. Mod Pathol. 2014;27:472–491).
In the German HBL Study HB94, the following six factors predicted poor prognosis (31):
Metastatic disease
Initial AFP greater than 1 × 106 ng/mL
Extrahepatic and intrahepatic vascular invasion
Multifocal disease and involvement of both liver lobes
Stage (tumor, node, metastasis [TNM])
Poor epithelial differentiation
In the SIOPEL-1 study, only metastatic disease and involvement of all four sectors of the
liver predicted poor outcome (32,33).
Figure: Staging System of Hepatoblastoma
by the Children’s Oncology Group
Figure:
PRETEXT is distinct from Couinaud 8-segment (I–VIII) anatomic division of the liver. PRETEXT
defines four “Sections.” Boundaries of each section are defined by the right and middle
hepatic veins, and umbilical fissure (From López-Terrada D, Alaggio R, de Dávila MT, et al.
Towards an international pediatric liver tumor consensus classification: proceeding of the Los
Angeles COG liver tumors symposium. Mod Pathol. 2014;27:472–491).
Surgery
The key to successful treatment of malignant liver tumors is surgical removal, either by
tumor resection/partial hepatectomy or liver transplantation. It is also possible to achieve a
cure with a near-complete excision in conjunction with adjuvant therapy that is able to
further eliminate residual tumor. Tumor resectability is determined by tumor size, the
existence of bilobar involvement necessitating resection of more than three liver segments,
vascular invasion, or distant metastases (34).
Less than 25–50% of all HBLs are resectable at time of diagnosis. After neoadjuvant
cisplatin-based chemotherapy, the probability of resection rises to about 90% and renders
tumor free through tumor resection after initial chemotherapy (35). Tumors that are
unresectable but without overt metastasis have EFS of 60–70%, while those with metastasis
disease do poorly with approximately 20–30% EFS (36). Only 30–50% of the cases of HCC
are amenable to complete resection at presentation because of multilobar involvement or
massive tumor size (37). HCC does not respond well to chemotherapy or radiotherapy.
The timing of surgical approach is crucial. Surgeons with experience in pediatric liver
resection and transplantation should be involved early in the decision-making process. There
are three way s a surgeon is used to treating a primary liver cancer, including initial surgical
resection, delay ed surgical resection (following chemotherapy ), and orthotopic liver
transplantation. Controversy exists between COG and SIOPEL approaches to the role of
preoperative chemotherapy (initial biopsy only ) versus primary resection. In the SIOPEL-1
study, primary surgery was performed only for patients with PRETEXT group 1, and
resection was attempted for all others after four to six cy cles of cisplatin-based
chemotherapy (25). When chemotherapy is initiated without a histologic diagnosis, there is
about a 4% risk that the patient may not have HBL or HCC. Errors in diagnosis include
hemangioendothelioma, angiosarcoma, neuroblastoma, and germ cell tumor. COG favors
primary surgery and adjuvant chemotherapy, except for clearly unresectable tumors.
Preoperative chemotherapy reduces the tumor burden in the majority of HBL cases, and
children with initially unresectable HBL may be rendered resectable by preoperative
chemotherapy (38). However, 3–4% of stage 1 HBL do not require chemotherapy (well-
differentiated, pure fetal histology with low-mitotic rate) and a small subgroup of small
undifferentiated cells does not respond to current chemotherapy, thus making upfront
chemotherapy undesirable (39). It is difficult to compare the COG and European approaches,
as the 5-y ear survival of PRETEXT stage I and II patients is 90–100% on the European
studies and seems to be similar to the US studies where surgery was performed before
chemotherapy (40). The current COG trial, AHEP-0731, has now assigned patients to risk-
based and surgical guidelines and recommends up-front resection only for PRETEXT I and
II tumors (41) (Table 14.4 ).
Page 337
Table 14.4 Hepatoblastoma Staging and Risk Stratification
When the patient comes to definitive surgery, a bilateral subcostal incision allowing a
large area of exposure is often performed (35). A simple tumorectomy with adequate
margins is rarely possible. Rather, hepatic lobectomy or extended lobectomy is needed.
Intraoperative ultrasonography has been widely applied to determine the exact location of the
tumor relative to the vessels. Perioperative mortality was reported to be as high as 18–33% in
the past but is now in the order of 5–10% in specialized centers (37). Surgical complications
include severe bleeding, bile duct injury, pleural effusion, rupture of the inferior vena cava,
cardiac arrest, convulsions, and subhepatic abscess (42). Improved surgical techniques such
as vascular reconstruction, ultrasonic aspiration, and dissection under vascular exclusion and
improvements in anesthesia, blood product replacement, and postoperative intensive care
have produced the significant reduction in operative and perioperative mortality. In stage IV
disease, surgical resection of pulmonary metastases can be considered if they persist after
preoperative chemotherapy and if the primary tumor has been rendered resectable by drug
treatment (37). In patients with stage I disease at initial diagnosis that recurs with isolated
pulmonary disease, surgical resection is recommended and often result in extended or even
long-term survival (32,43).
Liver transplantation has had an increasing role in children with nonresectable tumors or
in those who show chemotherapy resistance. Otte reported the result of SIOPEL-1
(International Society of Pediatric Oncology ), which showed overall survival (OS) at 10
y ears after liver transplantation to be 85% for the seven children who received a “primary
liver transplantation” and 40% for the five children who underwent “rescue liver
transplantation” after previous partial hepatectomy (44). They reviewed the world
experience (147 cases), and the overall survival rate at 6 y ears after liver transplantation was
82% for 106 patients who received a “primary liver transplantation” and 30% for 41 patients
who underwent “rescue liver transplantation.” There is a trend for a better patient survival
after living related liver transplantation (45,46,47). D’Antiga and Czauderna recommended
early referral to a transplantation center for patients who had the following characteristics:
older patients who had multifocal tumors, high PRETEXT scores, involvement of major liver
vessels, and AFP levels <100 ng/mL (33,48). Because of rarity of this disease and to optimize
result, children with extensive primary liver cancer should be managed and treated in centers
experienced in liver transplantation. In both the nationwide survey of the outcomes of living
donor liver transplantation for hepatoblastoma in Japan and the United States, the actuarial 5-
y ear survival rates exceeded 75% (49,50). Cases with multifocal or large solitary lesions,
tumors involving all four sectors of the liver, and unifocal, centrally located tumors that
involve the main hilar structures or main hepatic veins should be referred to a transplant
surgeon (51). Increasing evidence suggests that transarterial chemoembolization is feasible in
patients with unresectable hepatoblastoma, in patients who are not candidates for liver
transplant, or both.
Chemotherapy
The most important advance in the care of children with HBL has been the discovery of
effective adjuvant chemotherapy in improving surgical and overall outcomes. Cisplatin-
based chemotherapy has been successful in the treatment of HBL with a survival rate >90%
for children with stage I and II disease (22,52,53,54,55). Chemotherapy in some cases is able
to eradicate pulmonary metastases completely and eliminate multinodular tumor foci in the
liver (56). Initial reports showed the efficacy of vincristine, cy clophosphamide, doxorubicin,
and 5-fluorouracil. Cisplatin is the most active single agent used to treat hepatoblastoma.
Doxorubicin is active as well. Carboplatin has been replaced to reduce ototoxicity ; however,
the effect and efficacy have not been compared in randomized control studies to date.
Irinotecan and etoposide, paclitaxel, gemcitabine, and bevacizumab show promising activity
but need to be studied further (57,58). Bevacizumab is associated with side effects such as
hy pertension, leukoencephalopathy, and wound healing complications that must be taken into
consideration. Chemotherapy is usually started approximately 4 weeks after surgery to allow
liver regeneration. A minimum of 2 weeks should be elapsed before administration of
cy totoxic agents. Treatment usually consisted of six cy cles of chemotherapy in 2–4 weeks
interval.
Page 338Only four international groups—the Intergroup (USA/Canada), JPLT (Japan),
GPOH (Germany /Austria), and the SIOPEL—were sufficiently large to set up independent
studies (Table 14.5 ).
Table 14.5 Multicenter Studies in Hepatoblastoma—Comparison of Results
In 1976, CCG trial 881 added doxorubicin and 5-fluorouracil to the three drugs used in
trial 831. Adjuvant chemotherapy was given to 24 patients who did not have measurable
disease after surgery. Of these, 83% were disease-free survivors with a median follow-up of
30 months, whereas only 12 (44%) of 27 different patients with measurable disease achieved
a response with a median duration of 18 months (61).
CCG trial 823F used cisplatin and continuous-infusion doxorubicin in an attempt to reduce
tumor size in children with unresectable or incompletely resected HBL or HCC to allow for
subsequent surgery. Thirty -three children with HBL and 14 with HCC were entered in the
study. Twenty -six HBL patients completed the initial four courses of chemotherapy, 25
achieved either complete or partial response, and 22 of them had second-look surgery. Of the
22, 16 had complete resections and 15 of them are alive without evidence of disease. In nine
of the resected specimens, no viable tumor was identified. Of the 25 children who had a
response to chemotherapy, 19 (78%) are alive and disease free. The estimated 2-y ear
survival for the initial 33 patients with HBL is 67%. Children with HCC did not fare as well as
those with HBL; however, of the 14 patients with HCC, 12 died of progressive disease and 2
remained free of disease. Only 14% of the HCC patients had complete tumor removal at
second-look laparotomy (61).
The Pediatric Intergroup Hepatoma Study INT-0098 (CCG-8881/POG-8945)
demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and
cisplatin/doxorubicin in the treatment of HBL. Although equally effective in terms of overall
and event-free survival (EFS; p = 0.219) (Table 14.6 ), the combination of
cisplatin/vincristine/fluorouracil is significantly less toxic than that of cisplatin/doxorubicin.
Five-y ear EFS rates for patients with stage I, II, and resectable III, and IV HBL were 91%,
100%, and 83%, respectively. Patients with unresectable or metastatic disease had EFS of
50% and 10%, respectively (55,62,63). For patients with HCC, no differences were found
between the two programs for either EFS (p = 0.78) or OS (p = 0.80). All seven stage I
patients were event-free survivors (64,65), compared with 88%, 8%, and 0% for patients with
stage I, III, and IV HCC (65).
Table 14.6 Results of the Pediatric Intergroup Hepatoma Study for Hepatoblastoma
(CCG-8881 and POG-8945)
Page 339The German Cooperative Pediatric Liver Tumor Studies HB-89 and HB-94
treated 141 patients with HBL (Table 14.7 ). Forty -eight patients were primarily resected,
and 14/48 (30%) had micro- or macroscopic residual tumor in the liver. Most (81/141)
children were operated after an initial therapy with ifosfamide, cisplatin, and adriamy cin.
Only 15/78 (19%) cases were recognized as “incomplete resection” (p < 0.044). In cases of
insufficient tumor response, high-dose cisplatin and adriamy cin were added. With a median
follow-up of 6 y ears, disease-free survival (DFS) is 98% for stage I, 55% for stage II, 63%
for stage III, and 78% for stage IV. These results underline the necessity for preoperative
chemotherapy in all HBL (32,42,59).
Table 14.7 Summary of Recent Hepatoblastoma Multicenter Trials
(12,25,31,36,53,54,55,59,60,66,67,68)
In POG-8697 (Table 14.7 ), 19 of 21 patients with stage I or II disease survived

disease free at 5 y ears after five postoperative courses of cisplatin, vincristine, and 5-
fluorouracil. Twenty -four of 31 patients with stage III disease achieved a Complete Response
(CR) after chemotherapy and surgical excision; actuarial DFS at 4 y ears is 67% (Fig.
14.6 ). Those who remained unresectable received 33–39 Gy of local irradiation plus
additional chemotherapy. Of the five irradiated patients, three became resectable, achieved a
complete resection, and remained alive (53,69).
Figure 14.6 PRETEXT (Pretreatment Extent of Disease) and POSTTEXT (Posttreatment

Extent of Disease) extent of liver involvement system. (From López-Terrada D, Alaggio R, de
Dávila MT, et al. Towards an international pediatric liver tumor consensus classification
proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol. 2014;27:472–491.)
JPLT Protocol-1 enrolled 145 patients with HBL from 1991 to 1999 (Table 14.5 ).
Preoperative and postoperative cisplatin and tetrahy drapy rany l-adriamy cin were
administered, and 134 patients were evaluable. The complete resection rates by stage were
89% for stage I, 100% for stage II, 84% for stage IIIA, 40% for stage IIIB, and 58% for stage
IV. The 6-y ear survival rate was 100% for stage I, 96% for stage II, 74% for stage IIIA, 50%
for stage IIIB, and 39% for stage IV (12).
In the SIOPEL-1 trial (Table 14.5 ), 138 patients with HBL received four to six
courses of preoperative chemotherapy using platinum and continuous infusion doxorubicin
(PLADO), followed by surgery. Tumor response, defined as “any tumor shrinkage
associated with a serial decrease in serum AFP,” occurred in 82%. Five-y ear EFS in
PRETEXT I, II, III, IV and metastatic disease was 100%, 83%, 56%, and 46% and 28%,
respectively (52). SIOPEL-2 use PLADO for six cy cles in standard-risk HBL (PRETEXT I-
III without metastasis, vascular invasion, extrahepatic disease, portal vein invasion), and
cisplatin alternating with carboplatin/doxorubicin for high-risk HBL (PRETEXT IV or positive
M, V, E, P). Three-y ear EFS was 73% for patient with standard-risk HBL, and 48% for high-
risk disease, and 36% for HR metastatic disease (70). In SIOPEL-3, high-risk patients
received cisplatin alternating with carbo/doxorubicin for a total of 10 cy cles (58). Three-y ear
EFS was 65% for those with high-risk HBL, and 56% for metastatic disease. SIOPEL-6 now
assess feasibility of six courses cisplatin in the standard-risk, and 8 weekly cisplatin plus three
courses of doxorubicin in high-risk HBL. Surgery applied after four courses in standard-risk,
and after three courses in high-risk HBL.
The German Cooperative Pediatric Liver Tumor study HB94 used a complex treatment
algorithm to assess the efficiency of preoperative chemotherapy (IFO/CDDP/DOXO) and
determined prognostic significance of pretreatment factors. A new treatment arm with
additional etoposide and carboplatin (VP16/CARBO) was evaluated in patients with advanced
or recurrent HBL. OS was 77% after a median follow-up of 56 months. DFS and EFS are
shown in Table 14.7 (31,32).
POG-9345 was confined to advanced stage III and IV HBL. Patients were treated with
carboplatin, vincristine, fluorouracil, and cisplatin/etoposide (71). A total of 33 patients were
entered and were eligible for analy sis. Twenty -two (67%) had stage III and 11 (33%) had
stage IV. The 5-y ear OS was 73% in stage III, with EFS of 59%. In stage IV, the 5-y ear OS
was 27% and EFS was also 27%. Complete tumor resection was achieved in 19 (58%) of 33
patients, including 15 (68%) of 22 stage III patients and 4 (36%) of 11 stage IV patients. Five-
y ear EFS for this group was 79% (64).
The Pediatric Intergroup Hepatoblastoma Study POG 9645 was designed to compare the
risk of treatment failure for patients with stage III/IV HBL randomized to either C5V
(cisplatin + 5-fluorouracil + vincristine) or CC (alternating cisplatin and carboplatin). The 1-
y ear EFS was 37% for CC arm and 57% for C5V (p = 0.017). Patients assigned to CC
required more blood product support. Random assignment was discontinued early because of
ineffectiveness in improving in long-term outcome associated with CC (60).
High-dose chemotherapy (HDC) with autologous stem cell rescue has been attempted.
The Pediatric Blood and Marrow Transplant Consortium review experience showed that EFS
and OS are consistent with current data using multimodal therapy without HDC, suggesting
that HDC for hepatoblastoma may not be beneficial (72).
The current COG trial, AHEP-0731, has now assigned patients to risk-based method.
Surgical guidelines recommend up-front resection only for PRETEXT I and II tumors (21),
assess the feasibility and toxicity of adding doxorubicin to C5V (C5V-D) for intermediate-risk,
and estimate the response rate to up-front window of vincristine, irinotecan, and temsirolimus
in high-risk, metastatic HBL (Table 14.8 ). Novel strategies have been investigated by
JPLT. In JPLT 2, the use of high-dose chemotherapy with autologous stem cell rescue in the
highest risk patients was not found to improve survival (68).
Table 14.8 Current Chemotherapy Recommendations of the Different Study Groups

(66,68,73,74,75)
HCC has epidemiologic and pathologic characteristics different from those of HBL. It
usually presented at an older age, involved the liver multifocally, and is more related to
vertical transmission of maternal hepatitis B virus. HCC is so infrequent in children that these
patients have often been treated according to HBL regimens. Surgical resection remains the
foundation of curative therapy. Unresected HCC are far less responsive to chemotherapy and
carry very poor prognosis. Unfortunately, complete surgical resection of HCC is possible in
fewer than 30% of children at diagnosis. HCC is only partially chemosensitive; thus,
chemotherapy and radiation have limited efficacy as adjuvant or neoadjuvant therapy,
although one or both are often used to temporarily control disease. In patients who are
chemosensitive, chemotherapy may allow a meaningful reduction in tumor size before
surgical control, and in some cases rendering unresectable tumors resectable. Commonly
used regimens in children are C5V or doxorubicin and cisplatin (PLADO). The 5-y ear
survival rates for patients undergoing multiagent therapy and surgical resection in Group I
disease is approximately 85–90%, 55–60% in group II, and less than 20% in groups III and
IV.
Page 341Thirty -nine children with HCC were registered on the SIOPEL-1 trial and
treated with preoperative chemotherapy (cisplatin and doxorubicin). EFS at 2 y ears was 23%,
and 17% at 5 y ears. Five-y ear OS, by PRETEXT group, was 44% for stages I and II, 22%
for III, and 8% for IV (22). In INT-0098 (CCG-8881/POG-8945) Pediatric Intergroup
Hepatoma Study, there were 46 patients with HCC, randomized postoperatively to cisplatin,
vincristine, and fluorouracil or cisplatin and doxorubicin. The 5-y ear EFS rates were 88%,
8%, and 0% for stages I, III, and IV, respectively. There was no difference with either
regimen (64). In meta-analy ses in adults, a clear benefit of adjuvant chemotherapy in HCC
cannot be shown (65).
Page 342Meta-analy sis of randomized controlled trials in adults with unresectable HCC
treated with transarterial chemoembolization (TACE) significantly reduced the overall 2-y ear
mortality rate (odds ratio, 0.54; 95% CI: 0.33, 0.89; p = 0.015) compared with best supportive
treatment (76). Experience with chemoembolization in children is limited but feasible and
effective in inducing surgical resectability of primary hepatic tumors in children (77,78).
Selected cases may benefit from chemoembolization as a “bridge” through the
pretransplantation waiting (79). Patients whose primary tumor remains unresectable after
chemotherapy should be considered for orthotopic liver transplantation. Liver transplantation
has been a successful therapy for children with unresectable HCC; survival is about 60%, with
most deaths resulting from tumor recurrence. If the primary tumor is not resectable after
chemotherapy and the patient is not a transplant candidate, alternative treatment approaches
used in adults include: Sorafenib, Cry osurgery, Radiation therapy.
Recently, sorafenib, an oral multikinase inhibitor, which suppresses tumor cell
proliferation and angiogenesis, was approved by the US FDA for the first-line treatment of
HCC after the completion of a phase III trial, Sorafenib versus Placebo in Advanced
Hepatocellular Carcinoma (SHARP) for adult patients (80,81). Nevertheless, there are no
data on the safety and dosing in children.
Bevacizumab, a monoclonal antibody that exclusively targets vascular endothelial
growth factor (VEGF), was evaluated in several phase II trials alone and in combination with
chemotherapy in HCC. A survival benefit supports phase III trial of bevacizumab in HCC
(82).
Radiation Therapy
Radiation therapy has been used preoperatively and postoperatively as an aid to the curative
treatment of HBL and HCC. Its preoperative use has been intended to reduce the tumor
burden and increase the probability of resection. Contemporary treatment for HBL favors
using chemotherapy alone preoperatively (83), and in children who have unresectable
tumors after initial chemotherapy, radiotherapy can also be considered (84,85). POG-8697,
included five patients in whom radiotherapy was added to chemotherapy when their disease
remained unresectable after initial chemotherapy. Three of them ultimately became
resectable (69,86).
Some evidence also exists that postoperative radiotherapy is valuable in children who
have residual disease after an attempt at resection. A combined CCSG–POG protocol studied
177 children with HBL or HCC. Patients with microscopic residual disease (stage II) received
postoperative chemotherapy and 45 Gy of radiation to the tumor bed. The 3-y ear
progression-free survival was 60% for stage II and 22% for stage III (11). The Institute
Gustave Roussy administered preoperative chemotherapy, performed surgical resection, and
then gave radiotherapy and additional chemotherapy if there was microscopic or
macroscopic persistent tumor at surgery. A dosage of 25–45 Gy was given, targeted to the
area of postoperative disease only. Seven of nine children were disease free at 22–98 months
of follow-up, two patients died, one from local failure and another from both local and distant
failure (84). The evidence in favor of the use of irradiation for residual disease is not
unequivocal, and we cannot y et determine that chemotherapy by itself would not have
ultimately controlled the persistent microscopic disease. No clear treatment policy can be
developed and adopted on the basis of the current limited evidence.
When radiotherapy is to be considered preoperatively to improve resectability or
postoperatively for residual disease, the defining of tumor volume is crucial. It is essential to
spare as much normal liver tissue as possible. Therefore, the radiation oncologist must
carefully examine the diagnostic imaging studies and any available operative and
histopathologic reports.
The tumor volume should be delineated and covered by portals with a 1- to 2-cm
margin. Extra margin (0.5–2.5 cm) is added in the cephalocaudal direction to cover
diaphragmatic respiratory excursion. This should be confirmed fluoroscopically. Techniques
to control breath including respiratory gating, deep inspiration breath hold, and abdominal
compression for external beam radiotherapy may enable a margin reduction on tumor
volume. This, in turn, may allow dosage escalation without increasing toxicity (87). In the
majority of cases, three dimensionally planned or intensity modulated fields from a linear
accelerator are used. On occasion, the best treatment plan is anterior and posterior fields. If a
fair portion of the liver can be spared, then a total dosage of 50–60 Gy would be appropriate.
As we described in the previous section concerning POG-8697, preoperative irradiation of an
unresectable HBL may convert it to resectability (53).
Comparing to the photons used in current radiotherapy, proton beam radiotherapy has
lower entrance dose, sharper penumbra, and no dose deposits deep to the target. Because of
the superior dose distribution, proton therapy can achieve higher prescription dose with
adequate sparing of normal tissue and lower integral dose in avoidance of second
malignancies. Evidences for proton beam in treating HBL are scarce and limited to case
report and dosimetric studies (88,89). However, proton therapy has more potentials than
photon in bridging unresectable tumors to resectable tumors. The study for the role of proton
beam therapy as a definitive treatment in unresectable tumors is needed. Meanwhile, the
published treatment results of proton beam for adult HCC increase promptly. In general,
outcomes from proton therapy are better than those from conformal radiotherapy (90). One
study from University of Tsukuba recruited 318 patients, including 24% Child-Pugh B and 2%
Child-Pugh C. The 1-y ear and 5-y ear survival were 90% and 45%, respectively (91).
When postoperative irradiation is given for residual disease after a resection, 45 Gy to a
limited area is appropriate for microscopic disease, and 50–60 Gy is appropriate for bulkier
residual disease. Full attention must be given to respecting hepatic tissue tolerance to radiation.
In adults with unresectable HCC, available retrospective reviews suggest a dosage of 30 Gy
as the upper limit for normal liver tissue (92). If radiotherapy is to be administered to the
whole liver for advanced tumor, then parallel-opposed anterior and posterior fields are almost
alway s used. The dosage generally is prescribed to the mid-portion of the liver, and the
accepted parameters of liver tolerance to irradiation should not be exceeded. Therefore, with
palliative intent for advanced HBL or HCC, 20–25 Gy in 2–2.5 weeks is reasonable. The
treatment of metastatic lesions from HBL or HCC can have a palliative effect, and the usual
palliative dosages of irradiation (based on the surrounding normal tissue tolerance) may be
applied.
Page 343Investigational techniques that may have some promise include intraoperative
irradiation, regional hy perthermia in conjunction with intra-arterial y ttrium-90 microspheres,
intra-arterial iodine-131 lipiodol, and iodine-131 antiferritin administered along with
chemotherapy (93,94,95). For patients with more advanced disease, transarterial
chemoembolization (TACE) into isolated branches of the hepatic artery, which may benefit
patients with nonmetastatic but unresectable or recurrent tumor, has been used with promising
results. This is the more commonly used approach in adults, in whom sy stemic
chemotherapy has had essentially no impact on disease-free survival. The optimal scheduling
of radiotherapy and TACE is unknown.
Radiation-induced liver disease (RILD), previously called radiation hepatitis, can be a
serious complication of radiation therapy for HBL or HCC. Reactivation of viral hepatitis and
precipitation of underly ing liver disease also can occur after radiotherapy for HCC (96).
RILD is characterized by central liver lobular congestion, sinusoidal congestion, atrophy of
the liver plates, and focal necrosis. RILD can occur weeks to months after radiotherapy. One
should be particularly concerned about the risk of RILD in patients already compromised by
prior hepatic surgery, chronic viral hepatitis, or liver cirrhosis. The laboratory signs of RILD
include elevation of alkaline phosphatase and transaminases (96).
The mean liver dose associated with a 5% risk of RILD for patients with HCC is 28 Gy in
2-Gy fractions (97). As the majority of patients in the analy sis by Lawrence of the
University of Michigan were having Child A liver function, their results cannot be used to
describe the risk of toxicity in patients with Child B or C liver function. Intensity Modulated
Radiation Therapy (IMRT), compared to three-dimensional conformal radiotherapy, can
reduce the incidental dosages to the spinal cord, kidney s, and stomach. The application of
IMRT, which uses multiple fields with the mean dosage to the liver being higher than with
three-dimensional planning (29.2 Gy vs. 25.0 Gy, p = 0.009), should be done cautiously,
especially in patients with compromised liver function.
Is whole-lung irradiation (WLI) appropriate in HBL metastatic to the lung? Data on the
subject are sparse. Metastatic disease to the lung should be treated with surgical resection of
the metastatic deposits plus chemotherapy. However, there is alway s a risk of subsequent
pulmonary relapse (43). This understanding may be used as an argument in favor of WLI to
treat presumed small deposits of well-oxy genated metastatic disease. Based on the
experiences from Wilms, Ewing tumor, or osteosarcoma, for example, a total dosage of 12–
13 Gy would be considered appropriate for childhood HBL and HCC.
Figure: Hepatoblastoma Staging and Risk
Stratification
Figure: Multicenter Studies in
Hepatoblastoma—Comparison of Results
Figure: Results of the Pediatric Intergroup
Hepatoma Study for Hepatoblastoma (CCG-
8881 and POG-8945)
Figure: Summary of Recent Hepatoblastoma
Multicenter Trials
(12,25,31,36,53,54,55,59,60,66,67,68)
12 Sasaki F, Matsunaga T, Iwafuchi M, et al. Outcome of hepatoblastoma treated with the
JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: a report from the
Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg. 2002;37(6):851–856.
25 Aronson DC, Schnater JM, Staalman CR, et al. Predictive value of the pretreatment
extent of disease system in hepatoblastoma: results from the International Society of
Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol. 2005;23(6):1245–
1252.
31 Fuchs J, Rydzynski J, von Schweinitz D, et al. Pretreatment prognostic factors and
treatment results in children with hepatoblastoma: a report from the German Cooperative
Pediatric Liver Tumor Study HB 94. Cancer. 2002;95(1):172–182.
36 Zsíros J, Maibach R, Shafford E, et al. Successful treatment of childhood high-risk
hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final result of
the SIOPEL-3HR study. J Clin Oncol. 2010;28:2584–2590.
53 Douglass EC, Reynolds M, Finegold M, et al. Cisplatin, vincristine, and fluorouracil therapy
for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1993;11(1):96–99.
54 Perilongo G, Shafford E, Maibach R, et al. Risk-adapted treatment for childhood
hepatoblastoma—final report of the second study of the International Society of Paediatric
Oncology—SIOPEL 2. Eur J Cancer. 2004;40(3):411–421.
55 Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of
cisplatin/vincristine/fluorouracil and cisplatin/continuous-infusion doxorubicin for treatment
of pediatric hepatoblastoma: a report from the Children’s Cancer Group and the Pediatric
59 von Schweinitz D, Byrd DJ, Hecker H, et al. Efficiency and toxicity of ifosfamide, cisplatin
and doxorubicin in the treatment of childhood hepatoblastoma. Study Committee of the
Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric
Oncology and Haematology. Eur J Cancer. 1997;33(8):1243–1249.
60 Malogolowkin MH, Katzenstein H, Krailo MD, et al. Intensified platinum therapy is an
ineffective strategy for improving outcome in pediatric patients with advanced
hepatoblastoma. J Clin Oncol. 2006;24(18):2879–2884.
66 Haeberle B, von Schweinitz D. Treatment of hepatoblastoma in German cooperative
pediatric liver tumor studies. Front Biosci. 2012;4:493–498.
67 Perilongo G, Maibach R, Shafford E, et al Cisplatin versus cisplatin plus doxorubicin for
standard risk hepatoblastoma. N Engl J Med. 2009;361:1662–1670.
68 Hishiki T, Matsunaga T, Sasaki F, et al. Outcome of hepatoblastoma treated using the
Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the JPLT.
Pediatr Surg Int. 2011;27:1–8.
Figure:
PRETEXT (Pretreatment Extent of Disease) and POSTTEXT (Posttreatment Extent of Disease)
extent of liver involvement system.
(From López-Terrada D, Alaggio R, de Dávila MT, et al. Towards an international pediatric

liver tumor consensus classification proceedings of the Los Angeles COG liver tumors
symposium. Mod Pathol. 2014;27:472–491.)
Figure: Current Chemotherapy
Recommendations of the Different Study
Groups (66,68,73,74,75)
66 Lemerle J, Voute PA, Tournade MF, et al. Effectiveness of preoperative chemotherapy in
Wilms’ tumor: results of an International Society of Pediatric Oncology (SIOP) clinical trial. J
Clin Oncol. 1983;1:604–610.
68 Jereb B, Burgers JMV, Tournade MF, et al. Radiotherapy in the SIOP (International Society
of Pediatric Oncology) nephroblastoma studies: a review. Med Pediatr Oncol. 1994;22:221–
227.
73 D’Angio GJ, Tefft M, Breslow N, et al. Radiation therapy of Wilms’ tumor: results according
to dose, field, post-operative timing and histology. Int J Radiat Oncol Biol Phys. 1978;4:769–
780.
74 Breslow NE, Palmer NF, Hill LR, et al. Wilms’ tumor: prognostic factors for patients
1978;41:1577–1589.
75 -D’Angio GJ, Evans A, Breslow N, et al. The treatment of Wilms’ tumor: results of the
RESULTS AND FUTURE DIRECTIONS
Recent cooperative studies with multimodality treatments have improved OS and EFS for
pediatric patients with HBL and HCC in the past two decades. The 5-y ear survival rates for
stages I, II, III, and IV were 95%, 100%, 65–70%, and 36–45%, respectively (Table
14.7 ). The choices of chemotherapy regimens include C5V, and PLADO (55).
Doxorubicin is used widely throughout Europe (52). Toxicity in previous North American
trials has limited its use (55); however, there are ongoing discussions regarding the
reintroduction of doxorubicin in North American clinical trials (62).
Surgery remains the cornerstone of curative treatment for HBL and HCC; preoperative
chemotherapy with or without radiotherapy increases the possibility of complete resection.
Radiotherapy is recommended in patients who have residual tumor after surgery. As surgical
technique advances and better immunosuppressive agents with fewer long-term side effects
become more available, a steady improvement in the success of liver transplant patients will
likely be observed. In addition, living donor transplantation has also become a promising
option (98). Early referral to liver transplant centers is encouraged for nonresectable tumors
or those that show chemotherapy resistance. Ongoing questions are to search for new
chemotherapeutic agents with less toxicity and to properly time and prioritize liver
transplantation for unresectable cases (44).
As more is understood of the molecular and genomic pathway s in HBL and HCC, the
development of newer targeted therapies may raise new hopes for better control of these
dreadful diseases. Newer targeted agents that “selectively ” interfere with pathway targets
involved in tumor growth, progression and vascular development such as insulin-like growth
factor (IGF-1), phosphatidy linositol 3-kinase (PI3K), mammalian target of rapamy cin
(mTOR) sirolimus, sorafenib as antiangiogenics, and vascular endothelial growth factor
(VEGF) are currently under development. Gene-directed treatment approaches and
immunotherapy have high potential as future treatment options (99). Both therapy options
have display ed promising results in preclinical models so far but are clearly only in the
infancy of their scientific evaluation.
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CH A P TER 15
Germ and Stromal Cell Tumors of the
Gonads and Extragonadal Germ Cell Tumors
Christian Carrie and Edward C. Halperin
Page 347Gonadal or extragonadal germ cell tumors (GCTs) represent less than 2% of
pediatric malignant tumors. They have three important features:
The origin is related to abnormal migration of primordial germ cells, and tumor can
occur along this migration path;
Serum tumor markers allow diagnostic and treatment evaluation; and
The cure rate is high if the clinician respects treatment guidelines.
GCTs result from malignant transformation of a primordial germ cell (Fig. 15.1 ).
FIGURE 15.1 Classification of germ cell tumors.
In the human embry o, the primordial germ cells are found in the vicinity of the allantoic
stalk. From this position, the germ cells migrate into the adjoining mesenchy me at 4–5 weeks
of gestation. The cells then assume positions in the germinal ridges and migrate along these
structures.
GCTs may occur in the ovary, testes, sacrococcy geal region, vagina, retroperitoneum,
pelvis, omentum, and mediastinal areas. Extragonadal and testicular sites predominate in
children less than 3 y ears of age. Gonadal sites are most common during and after puberty
(1). The main histologic ty pes are germinoma, embry onal carcinoma, y olk sac tumor (also
known as endodermal sinus tumor or Teilum tumor), chorioepithelioma malignant mixed
GCTs, and malignant teratomas (sometimes called immature teratomas) (Table 15.1 )
(2,3,4,5). Mature and immature teratomas have a benign behavior but can relapse with a
malignant part (6). Endodermal sinus tumor ty pically shows microcy tic areas, Shiller–Duval
bodies, and periodic acid–Schiff–positive extracellular hy aline droplets. The tumor is often
positive, on immunohistochemistry, for alpha-fetoprotein (AFP) and cy tokeratin (7).
Structural abnormalities of chromosome 1 are frequent (1).
TABLE 15.1 Biologic Characteristics of Pediatric Germ Cell Tumors
Teratomas (from Greek teratos, “monster,”

and onkoma, “swelling”) are the most common
pediatric GCTs. Malignant teratomas may
develop any where along the pathway of
germinal tissue migration. By definition,
teratomas are composed of tissues derived from
two or three germinal lay ers (tridermal
ancestry ): ectoderm, mesoderm, and endoderm.
Malignant teratomas are so named because of
foci of endodermal sinus tumor, embry onal
TABLE 15.2 Grading of Immature
carcinoma, germinoma, or choriocarcinoma.
Teratomas
There may also be foci of neuroblastoma,
nephroblastoma, or hepatoblastoma and, in this
case, are called teratoma with malignant somatic component (TMSC) (8). In general, frank
malignancy is identified in about 20% of teratomas (5). The distinction must be made
between immature teratomas with distinct malignant elements, which warrant aggressive
adjuvant therapy, and immature teratomas with primitive neuroepithelium, which can be
cured with surgery alone. Immature teratomas are graded by the sy stem of Norris, which
also predicts relapse (Table 15.2 ).
Figure:
Classification of germ cell tumors.
Figure: Biologic Characteristics of Pediatric
Germ Cell Tumors
Figure: Grading of Immature Teratomas
GENERAL ASPECTS OF CLINICAL PRESENTATION, STAGING, AND
WORKUP
Page 348There is a bimodal age distribution for GCTs, with a peak in children y ounger than 3
y ears and a second peak in children older than 12 y ears. The male:female ratio is 2:1 (11).
Girls predominate in the patient population during the first 3 y ears of life because of a female
predominance in sacrococcy geal tumors. There is an association with intersex disorders
(1,12,13). The association between undescended testes and the development of testicular
cancer has been established. Currarino sy ndrome and Down sy ndrome could be associated
with mature or immature teratomas (6).
The staging workup should include assay s for AFP and human chorionic gonadotropin
(hCG). AFP is elevated in almost all cases of endodermal sinus tumor and in many other
patients with GCTs (14,15). Successful treatment, whether by surgery, chemotherapy, or
radiotherapy, is regularly associated with AFP decline, consistent with its half-life of 5 day s in
children 2 months or y ounger, 33 day s in 2- to 4-month-olds, and 5 day s in children 8 months
or older (1,15,16). AFP falling too slowly, failing to normalize after treatment, or rising
generally signifies inadequate tumor response and precedes clinical or radiographic evidence
of treatment failure. hCG activity is present in some tumors, particularly choriocarcinoma.
The half-time of beta-hCG is 24–36 hours.
Diagnostic imaging of the pelvis and presacral space is best performed with computed
tomography (CT), magnetic resonance imaging (MRI), and ultrasound (5). The role of a PET
scan is not well established, probably not necessary for nonseminomatous tumor and more
useful to identify viable tumor in case of residual lesion after chemotherapy (17). CT is
useful to assess the presence of pathologic retroperitoneal ly mph nodes and extension of
tumor into bone. Imaging may show GCTs to be cy stic, solid, or a combination of both.
Sacrococcy geal and ovarian lesions that are predominantly cy stic are less likely to be
malignant, whereas solid lesions are more likely to be malignant. However, the correlation is
far from perfect. This is particularly important because it argues strongly against using the
term solid teratoma as the equivalent of malignant or immature teratoma (4,5,18,19).
Data from seven COG and CCLG group trials were compiled by the MaGIC (Malignant
Germ Cell Tumor International Collaborative) in order to define new risk classification: from
this series of 519 patients with extracranial germ cell tumors, it appears that age >11 y ears,
ovarian stage IV, and extragonadal stage III to IV have the worst outcome (20).
Page 349Ovary
Of primary ovarian tumors of childhood, about
71% are GCTs, 17% are epithelial, and 12% are
sex cord stromal tumors (1,18,21). The histologic
distribution is approximately : mature teratoma,
47%; immature teratoma, 12%; dy sgerminoma,
5%; y olk sac tumor (endodermal sinus), 10%;
mixed GCTs, 0–24%; and choriocarcinoma,
<1% (1,9,22,23) (Fig. 15.2 ). In the series of
Taskinen, two cases had a predisposition
condition, that is, Turner sy ndrome (23).
The risk of germ cell malignancy in girls
more than 3 y ears old is 20%. All pediatric
ovarian tumors must be considered as malignant.
In the series by Germa, (22) 46% of girls
presented with pain. In the POG/CCG intergroup FIGURE 15.2 Ovarian dysgerminoma.
study, 11% of girls presented with an acute
abdomen due to rupture or torsion (24). The long infundibular pedicle in the child explains this
risk (14,22). Other presenting signs and sy mptoms included an asy mptomatic palpable mass
(19%), abdominal distention (36%), and, less commonly, menstrual irregularities, malaise,
nausea, vomiting, or vaginal bleeding (11,22,25,26,27,28,29,30,31,32,33,34). The stromal
Sertoli–Ley dig cell tumors may present with defeminization or virilization. Ovarian
dy sgerminomas are rarely hormonally active or productive of tumor markers. If a patient
with an ovarian dy sgerminoma is found to have an elevated AFP or signs of hormonal
imbalance, there should be a meticulous search of the pathology specimen for elements of
other tumors. Preoperative assessment is crucial for the postoperative management. Sample
AFP HGG and beta-hCG must be obtained in all solid ovarian tumors.
Both primary and second-look surgery are used to treat ovarian GCT. The initial surgical
procedure should remove as much tumor as possible with a reasonable possibility of retention
of fertility. At the time of laparotomy, the entire peritoneal surface should be examined for
the presence of metastasis. Particular attention should be paid to the surfaces of the liver and
to the inferior surface of the diaphragm (14). The involved ovary should be removed.
Dy sgerminoma has a 5–10% incidence of bilaterality (21). For childhood ovarian GCT other
than dy sgerminoma, the probability of bilateral involvement ranges from 0% to 14% (27).
Therefore, the contralateral ovary should be biopsied and, if there is no evidence of
malignancy, preserved (33). Palpation and biopsy of all suspicious ly mph nodes in the pelvic
and para-aortic regions should be done. Peritoneal biopsies and washings (or collection of
ascites) for cy tology are important to complete the surgical staging (34). When frontline
definitive surgery is not possible or appropriate, chemotherapy can be given followed by
second-look surgery (35).
In the POG study, positive ascetic cy tology was found among 100 girls despite negative
random biopsy samples:
Due to this finding, the Children’s Oncology
Group published new guidelines including
peritoneal washing (Tables 15.3 and 15.4 ).
Ovarian GCTs are lethal malignancies that
can kill by early metastasis and rapid invasion of
abdominal and pelvic structures. The prognosis
of girls with these tumors was poor when they
were treated with surgery only or surgery in
combination with either radiotherapy or single-
agent chemotherapy, except in some cases of
dy sgerminoma (18). An increasing body of
evidence indicates that postoperative
chemotherapy has increased the probability of Table 15.3 Children’s Oncology Group
survival (1,4,9,15,18,22,25,26,30,31,32,33). Surgical Guidelines for Ovarian Germ
Active drugs include cisplatin (P), vinblastine Cell Tumor in Pediatric Patients
(V), bleomy cin (B), adriamy cin (Ad),
actinomy cin (A), cy clophosphamide (C), etoposide (E), methotrexate (M), and vincristine
(O) (11,37,38,39). Combinations used include VAC, POMB-ACE-PAV, PVB-ACAd, and PEB
(5,12,18). PEB or PVB is most commonly used (9,40,41). A six-drug regimen (VAC, JEB, or
PEB) or JEB therapy have both achieved 5-y ear survival rates as high as 90% for all stages
(42,43). The report of MaGIC, including UK and COG studies, found no differences between
the different treatment regimens for GCT, and all could be considered as equivalent (20).
The generally accepted standard of care for pediatric ovarian GCT is summarized as
follows:
Page 350Benign mature teratomas and immature teratomas: surgery and observation
Stage I malignant GCT: surgery and observation
Stages II–IV malignant GCT: surgery and PEB or PVB (1)
AFP and hCG are valuable in patient follow-up.

Contemporary treatment programs do not use radiotherapy if initial surgery and, if used,
chemotherapy renders the child disease-free (44). Radiotherapy is reserved for residual
disease that cannot be resected at second operation and is not treated with alternative
chemotherapy. The persistent tumor volume, generally treated with progressive shrinking
fields, is irradiated to 40 Gy (12,15,22,44).
The two principal treatment options in patients with stage I dy sgerminoma in adults are
surgery followed by observation, or
chemotherapy with one cy cle of carboplatin
(45) or para-aortic radiation. To avoid irradiating
most girls with ovarian dy sgerminoma, the
following are the criteria for treatment with
unilateral salpingo-oophorectomy alone:
unilateral encapsulated tumor (stage I); greatest
tumor diameter <10 cm (although this is not
uniformly found to be a prognostic sign); no
ascites; no evidence of enlarged or abnormal
ly mph nodes by palpation, ly mphangiogram,
biopsy, or CT; well-differentiated pure
dy sgerminoma; and confidence that the patient
will attend regular follow-up appointments.
Under these criteria, selected patients may be
cured with preservation of fertility TABLE 15.4 Children’s Oncology
(28,29,34,40,46). Group Staging for Pediatric Ovarian
If ovarian dy sgerminoma is locally Germ Cell Tumors
extensive (bey ond stage I) or bilateral, then
chemotherapy should be administered (22,38,44). When chemotherapy is used, PEB, as for
other ovarian GCT histologies, is selected. Carboplatin alone is not y et a standard in pediatric
GCT. In a series from Germa (22), chemotherapy -induced amenorrhea was reversed in 14
of 15 patients after chemotherapy. Three patients attempted to become pregnant: two had
uneventful pregnancies and one had a spontaneous abortion. Whether ovarian failure will
ultimately develop in chemotherapy -treated patients remains to be seen, although Mann (15)
stated that “in ovarian dy sgerminoma, chemotherapy is preferable to radiotherapy to
preserve fertility.” Except in very specific cases, there is very little role for RT in ovarian
germinoma.
For all histologies of ovarian GCTs combined, the reported probability of survival is 60–
90%. For the most part, deaths appear to be in stage IV
(1,2,9,15,22,25,26,27,28,29,33,34,38,40,44,47,48). The survival of children with ovarian
dy sgerminoma is 95–100% when disease is confined to the pelvis or has limited abdominal
involvement (2,38,49). Tumor rupture or extensive metastasis reduces the probability of
survival (49).
Ovarian stromal and epithelial tumors are rare in children. Stromal tumors of the
childhood ovary, including juvenile granulosa cell tumors, often are cured by surgical
resection alone (50). These stromal tumors usually present with precocious pseudopuberty in
prepubertal girls because of estrogen production by the tumor. The roles of surgery and
chemotherapy for ovarian epithelial tumors in adolescents (mucinous or serous
cy stadenocarcinomas) follow the same guidelines as those for adults (12,31,51).
Inhibin can be used as marker for the follow-up of granulosa cell tumors (52). For
Ley dig cell tumor, conservative surgical therapy is possible (53).
Testis
Testicular GCTs generally present as a palpable
painless mass or with signs and sy mptoms that
simulate infection, torsion, or posttraumatic
hematoma (54). The diagnostic workup includes
testicular ultrasonography, CT of the abdomen
and chest, AFP, and hCG. The most common
GCT of the testes in pubertal children is y olk sac
tumor (endodermal sinus) (Fig. 15.3 )
(15,18,54). Oosterhuis classified the testicular
GCT in three groups according to their
pathogenesis and the overrepresentation of the
short arm of chromosome 12: ty pe I encompass
teratoma, y olk sac tumor without 12p
rearrangement, ty pe II seminoma and
nonseminomatous with 12p rearrangement, and Figure 15.3 Testicular yolk sac tumor.
ty pe III spermatocitic seminoma with gain of
chromosome 9 (55). Less common histologies include embry onal carcinoma, mature,
immature, and malignant teratoma, and mixed tumor. Prepubertal children more often have
non–germ-cell tumors such as Sertoli or Ley dig cell tumors or sarcomas. Testicular GCTs
usually are staged by the COG sy stem (Table 15.4 ) or the UICC 2009 (Table 15.5 ).
Most cases are stage I at diagnosis. Teenagers may hesitate to discuss the presence of
testicular mass and tend to have more advanced disease at diagnosis (11,14,54).
Page 351Most testicular tumors are
suspected before surgery. A radical orchiectomy
should be performed with high ligation of the
spermatic cord. Transscrotal procedures should
be avoided because they can spread tumor and
increase ly mphatic metastases. If a scrotal
biopsy has been done, some authorities advise a
hemiscrotectomy (54). Others cite data from
adults to argue that there is no increase in the
relapse rate in stage I tumors if
hemiscrotectomy is not done (56). Regarding
pure seminoma, clinical stage 1, the European
consensus for adults allows three strategies:
surveillance with salvage irradiation or
chemotherapy at relapse, adjuvant
chemotherapy with carboplatin, or adjuvant
radiation treatment (17). These options seem to TABLE 15.5 Children’s Oncology
be adaptable for childhood seminoma, but Group Staging for Pediatric Testicular
adjuvant radiotherapy is less and less used. Germ Cell Tumor
The debate concerning the role of
retroperitoneal ly mph node dissection in early -stage testicular GCT appears to be resolving in
favor of a limited role for the procedure. The older literature indicates that 0–33% of children
with GCT have involved retroperitoneal ly mph nodes (11,14,57,58,59). Proponents of
retroperitoneal ly mph node dissection suggested that it was important in staging and in the
removal of small foci of malignant cells and that it possibly improved the chance of cure.
Objections to dissection, based on loss of ejaculatory function, were obviated by the use of
the modified retroperitoneal dissection (50). With the widespread availability of serum tumor
marker studies and CT screening, however, it is now clear that the staging node dissection is
unnecessary in stage I disease. In children with tumor confined to the testes, where AFP
levels normalize within 1 month after orchiectomy and where the chest radiograph and
retroperitoneal imaging studies are normal, retroperitoneal ly mph node dissection is
unnecessary. In one study, 28 patients with stage I testicular y olk sac tumors were treated with
radical orchiectomy alone; 24 (86%) were cured. The remaining four (14%) relapsed and
were rendered free of disease by chemotherapy (58). Both the UK Children’s Cancer Study
Group and the St. Jude Children’s Research Hospital (SJCRH) series have almost uniform
survival for stage I patients treated with radical orchiectomy alone (16,54). There is no
difference in disease-free survival between children with stage I disease who undergo
retroperitoneal ly mph node dissection and those who do not (14,27,58). Retroperitoneal
ly mph node dissection may still be appropriate for children with no markers or unknown
markers at diagnosis to confirm staging, more aggressive histologies (i.e., embry onal cell),
demonstrable moderate-sized nodal metastasis at the time of presentation (i.e., SJCRH stage
II), or an elevated AFP after surgery (27,50,60). PET could be useful in this case (61).
The management strategy for testicular GCT is as follows:
Stage I, surgery alone

Stages II–IV, surgery followed by PEB
For stage I, chemotherapy is used for documented relapse. The survival for all stages is of the
order of 90–100%.
For more advanced disease, patients should be treated according to the International
Germ Cell Cancer Consensus Group (IGCCGG) recommendation (62).
For a small primary tumor or bilateral testicular tumors, one could consider organ-
preserving surgery ; but this option is still experimental and must be done within a clinical trial
(63).
Extragonadal
Extragonadal GCTs usually are found in the midline, consistent with embry onic patterns of
migration. The most common sites are the sacrococcy geal, presacral, and buttock region.
This is followed by the mediastinal, vaginal, uterine, and prostatic regions. Other reported
sites of origin include the neck and face, retroperitoneum, stomach, orbit, pancreas, heart, and
pericardium (1,9,64).
Sacrococcygeal Tumor (SCT)

Sacrococcy geal GCTs may develop early in fetal life (Fig. 15.4 ). Urinary tract
obstruction, compression of the umbilical vessels, chronic hemorrhage into the tumor and
amniotic sac, and arteriovenous shunting with cardiac failure (65) may occur. Prenatal
ultrasonography may demonstrate the mass, hy dronephrosis, fetal hy drops, or prominent
poly hy dramnios (5). More than one-half of patients with malignant and benign
sacrococcy geal teratomas present to medical attention on the first day of life. These children
often have other congenital anomalies such as abnormalities of the genitourinary tract or of
the lower vertebral bodies (66).
Page 352Approximately 60–70% of sacrococcy geal teratomas are unequivocally
benign by virtue of the exclusive presence of mature somatic tissue. These lesions in
newborns may be cured by surgery. Many are diagnosed by prenatal ultrasonography ;
ultrasound and echography must be used for the prenatal management: the tumor growth is
variable and the determination of growth rate is a prognostic indicator of adverse outcome
(67). Ten percent to 15% of teratomas are composed of a mixture of embry onic or fetal
elements in mature structures along with poorly
differentiated embry onic tissue. These lesions
constitute a category of indeterminate biologic
behavior and are called immature benign
teratomas. In the surgical treatment of benign
and intermediate-grade sacrococcy geal
teratomas in infants, every effort must be made
to remove the tumor mass. The early, safe, and
total extirpation of the tumor and coccy x is
necessary. The coccy x should alway s be
removed with the mass because failure to
remove the coccy x is associated with a local
recurrence rate of 37% (68). However, positive
surgical margins of mature or immature SCT
are not correlated with an increased risk of local FIGURE 15.4 Sacrococcygeal yolk sac
failure (69). Due to the high vascularity of such tumor.
tumors, surgery can follow a ligation of the
sacral artery (70). Only 2–10% of sacrococcy geal region tumors are malignant when
removed in infants less than 4 months old. After 4 months of age, the rate of malignancy rises
to 50–90% (5,31,68). Simply put, there are two basic ty pes of sacrococcy geal GCT: large,
predominantly benign masses in neonates, and pelvic, primarily malignant masses in older
children.
A useful classification sy stem for sacrococcy geal GCT has been developed by the
Surgical Section of the American Academy of Pediatrics. Ty pe I tumors are primarily
external; ty pe II tumors are dumbbell-shaped, with significant external and intrapelvic
components; ty pe III tumors have a small external component, with the majority of the
lesion extending into the pelvic and abdominal spaces; and ty pe IV tumors occupy the
presacral space and have no appreciable external component. As a general rule, the
prevalence of malignancy is lowest in ty pe I tumors and increases as one moves from ty pe
II through ty pe IV (66). Malignancy rates by ty pe are 8% for ty pe I, 21% for ty pe II, 34%
for ty pe III, and 38% for ty pe IV (1). The malignancy rate also rises with age (Tables
15.6 and 15.7 ).
Table 15.6 TNM Classification (UICC 2009)
TABLE 15.7 Children’s Oncology Group Staging for Pediatric Malignant Extragonadal
Germ Cell Tumors
Preoperative imaging studies help to determine the lesion’s ty pe, and they also evaluate
whether the lesion is invading adjacent structures rather than displacing them, a suggestion of
malignancy. Only a few malignant sacrococcy geal GCTs are resectable per primum and
16% of the patients reported by Garg had intraspinal extension (71). In general, the surgeon
obtains an initial biopsy, and chemotherapy is administered. There is evidence documenting
complete responses of both metastatic and primary disease to chemotherapy with long-term
survival. Unresectable tumors have been rendered resectable, with long-term survivorship
reported. If there is a satisfactory reduction of tumor volume, the tumor may be deemed
resectable at a later date. The POG (72) and a German protocol (73) MAKKEI did not show
any difference in survival rate between patients treated by preoperative or postoperative
chemotherapy. The 4-y ear overall survival was 90%. In summary, stage I extragonadal
mature and immature sacrococcy geal teratomas and completely resected malignant GCTs
are resected and observed. Stages II–IV malignant GCTs are treated with PEB or PVB plus
surgery even in the case of intraspinal extension survival rate reaching 90% (71).
Mediastinal GCT
Pediatric mediastinal GCTs account for <5% of all GCTs (9). They are generally in the
anterior mediastinum and can cause superior vena cava sy ndrome or acute respiratory
deficiency (74). Calcification in the tumor is one of the X-ray characteristics (Fig. 15.5 ).
As the tumor is generally unresectable at diagnosis, most patients undergo cisplatin-
based chemotherapy first, followed by surgery. The Indiana University reported 127
consecutive patients (adults and children): among them, 27 had a localized primary
mediastinal nonseminomatous germ cell tumor and 20 had a metastatic disease. All were
treated by upfront platinum-based
chemotherapy and thoracic surgery in all cases
even if the serum tumor marker was still
elevated after chemotherapy : 45 have still
residual germ cell tumor, but among the 27 with
localized disease 14 are free of disease with a
mean follow-up of 156 weeks (75). In a Belgium
report, mediastinal GCTs have the worst
prognosis of all GCTs with a mortality rate of
28% (76). In the last international analy sis done
Figure 15.5 Thoracic germinoma.
by Bokemey er (77), the 2-y ear survival rates
were, respectively, 34% and 84% for
nonseminomatous and seminomatous tumors.
In general, the survival rate for extragonadal GCT is not as high as for ovarian and
testicular lesions. The survival rate in the United States for mediastinum lesions is 40–60%. In
the recent International Society of Pediatric Oncology (SIOP) and German protocols, the 10-
y ear event-free results are as follows: ovarian, 89%; sacrococcy geal, 81%; testicular, 97%;
and all others (except brain), 88% (9,56).
Page 353The Role of Radiotherapy

Radiotherapy is not necessary for children who have a documented complete response to
surgery and chemotherapy (44). The local recurrence rate in this particular set of patients is
low. In a study by Flamant et al. (25), the majority of children with nonseminomatous
malignant GCT (stages III and IV) did not need radiotherapy when aggressive induction
chemotherapy was used as a complement to surgery. In 11 of Flamant’s cases failing initial
therapy, 9 had a local recurrence at the site of first failure. However, when only a partial
response to chemotherapy and surgery is achieved in localized disease, the chance of
irradiation achieving local control is only fair. Ablin (44) described 17 children with GCTs of
gonadal and extragonadal locations who were irradiated for persistent disease after
chemotherapy. Radiotherapy failed in the field of treatment in 10 of the 17 cases. The
primary site of failure in all seven sacrococcy geal GCTs was at the initial site of tumor. Mann
et al. (15) reported irradiating eight patients with GCT in a variety of locations. When obvious
disease was present, no sustained responses occurred. There were three survivors who had
normal AFP levels at the time of irradiation and who may have been already cured before
irradiation. Kersh et al. (28) reviewed the results of radiotherapy in adult and pediatric
patients with nonseminoma GCTs in the mediastinal, retroperitoneal, and sacrococcy geal
regions. Local control was obtained in two of eleven patients with mediastinal lesions, zero of
two patients with retroperitoneal tumors, and one of four patients with sacrococcy geal lesions.
In summary, the results of radiotherapy for patients with persistent disease after
chemotherapy are poor, and the radiotherapy literature is based upon older forms of
chemotherapy. However, it is also clear that with residual unresected disease after
chemotherapy, the risk of tumor regrowth at the primary site is almost certain (68).
Therefore, we conclude that radiotherapy is worth the effort, albeit with only modest claims
for success.
Page 354If radiotherapy is used for extragonadal GCT, dosages of 45–50 Gy are
recommended, as limited by the tolerance of surrounding normal tissue. The radiotherapy
portals are dictated by radiographic imaging studies and surgical exploration. Metastatic
lesions may necessitate palliative treatment with local field irradiation.
Figure:
Ovarian dysgerminoma.
Figure: Children’s Oncology Group Surgical
Guidelines for Ovarian Germ Cell Tumor in
Pediatric Patients
for Pediatric Ovarian Germ Cell Tumors
Figure:
Testicular yolk sac tumor.
for Pediatric Testicular Germ Cell Tumor
Figure:
Sacrococcygeal yolk sac tumor.
Figure: TNM Classification (UICC 2009)
for Pediatric Malignant Extragonadal Germ
Cell Tumors
Figure:
Thoracic germinoma.
RESULTS
Survival for stages I–II GCTs at gonadal sites approaches 100%. Survival for stages III–IV
GCTs at gonadal sites is about 95%. Extragonadal GCT survival is about 90% for stages I–II
and about 75% for stages III–IV (1).
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CH A P TER 16
Endocrine, Aerodigestive Tract, and Breast
Tumors
Line Claude, Xavier Druet, and Anne Laprie
PAGE 357ADRENOCORTICAL CARCINOMA

Histology
Adrenocortical carcinoma (ACC) is an aggressive cancer originating in the cortex of the
adrenal gland.
Epidemiology
ACC is rare around the world (0.2% of child cancer), except in Southern Brazil (3.5
cases/million children y ounger than 15 y ears) (1,2,3,4,5). The frequency is dependent on the
age: 0.4 per million before 4 y ears and decreases to 0.1–0.2 per million after 10 y ears (4,6).
Sex ratio is 1:5.3 before 4 y ears and 1:0.8 after 4 y ears (5).
Genetics
ACC occurs more frequently among individuals with the Li-Fraumeni sy ndrome, which
results primarily from germline mutations in the TP53 gene (7,8) (Table 16.1 ). Screening
and surveillance of heterozy gous carriers of TP53 mutation could be effective in detecting
adrenocortical tumors (9).
Clinical Aspects
Virilization (pubic hair, clitoromegaly or phallomegaly, acne, deep voice, and hirsutism) is the
most common sign of ACC. In the large Brazilian experience, more than 90% of the patients
had pubic hair, and more than 80% of girls had clitoris hy pertrophy. Other frequent signs are
abdominal pain in 50% and Cushing sy ndrome in
30% (hy pertension, centripetal fat distribution,
moon face, buffalo hump of the neck,
accelerated growth velocity, weight gain).
Biology
Because the tumor cells may secrete a number
of adrenal hormones either alone or in
combination (androgens, glucocorticoids,
mineralocorticoids, and estrogens), it is possible
to establish an endocrine profile of most
pediatric ACC. Urinary 17-ketosteroids (17-KS)
and 17-OH steroids are elevated in more than
90% of the cases (5). Table 16.1 Constitutional Genetic
Abnormalities Associated with Adrenal
Molecular Biology Cortical Tumors (ACT)
In adult series, Ki-67 marker proliferation, p53 mutation, mdm-2 mutation, and p21 mutation
have been identified as associated with ACC, but no specific pattern is known. While tumor
cell proliferation (Ki-67) correlates with mitotic activity and morphologic index, tumor
morphology remains a better predictor of metastatic risk (10).
Prognostic Factors
The distinction between benign and malignant ACC is made on cy tologic abnormality, tumor
weight, and presence of metastases (11). Some lesions are frankly malignant on microscopic
examination. For those of borderline histologic appearance, one should consider resectability,
the extent of capsular invasion, adherence to surrounding structures, the presence of aberrant
vessels on angiography, tumor size, and the presence or absence of metastases to distinguish
benign from malignant lesions. Well-encapsulated and easily excised tumors may be cured
by surgery alone. In the remaining resected but more locally advanced cases, there is a
substantial risk of local relapse and distant metastases (10,12).While stages are well defined in
adults (McFarlane classification (3), classification is less clear in childhood. Michalkiewicz et
al. (4) proposed a classification based on more than 250 patients. Factors independently
associated with good prognosis in terms of survival include Stage I tumor (tumor completely
excised, tumor weight <200 g, and absence of metastasis), virilization alone, age <4 y ears
(4). The proliferation marker Ki67 has been recently confirmed as an important prognostic
factor after resection (13).
Imaging
Imaging studies are of great importance for
surgical planning and disease staging. Magnetic
resonance imaging (MRI) and
tomodensitometry (TDM) are necessary to
determine the size of tumor and to detect
invasion of local structures, metastasis, and
vessels involvement (vena cava, for example).
Due to frequent liver and lung metastasis, TDM
is recommended. Brain and bone metastases are
rare but possible; technetium bone scan and/or
brain MRI should be performed in case of
observed sy mptoms. Positron emission
tomography (PET) scan has not been
extensively studied, but in a very small series in
adults, it can y ield additional information in
defining tumor metabolic activity and necrosis,
and in the earlier detection of metastases in
comparison with computed tomography (CT)
(14) (Fig. 16.1A and B ).
Figure 16.1 A & B: Young girl, 17 years
Page 358Treatment old, diagnosed with a left ACC. FDG PET
clearly shows the main mass but also a
Surgery
large vena cava involvement. Lung
As in adults, for localized disease, open and metastases were seen on CT as well as on
potentially laparoscopic adrenalectomy for FDG PET.
selected patients is the main treatment
(5,15).Tumor friability often justifies en bloc resection to avoid tumor spillage and rupture of
the capsule and to compromise prognosis. Therefore, transabdominal approach is necessary.
Chemotherapy
Patients with residual disease after surgery or with metastatic disease usually receive
chemotherapy using different regimens, including mitotane, cisplatin, etoposide, and
doxorubicin. Results are generally poor (16). The use of mitotane (1-(2-chloropheny l)-1-(4-
chloropheny l)-2,2-dichloroethane) in combination with etoposide, doxorubicin, and cisplatin
in the treatment of metastatic disease has been assessed in an international randomized trial
(FIRM-ACT trial) involving adult patients and is now the established first-line cy totoxic
therapy. Mitotane is an isomer of the insecticide DDD, which has adrenoly tic activity. It has
been used as a neoadjuvant to treat advanced metastatic ACC in cases of inoperable tumors,
in adjuvant situation for patients at high risk to relapse, and to control sy mptoms associated
with production of adrenal hormones (5). Administration of this drug is associated with toxic
effects such as nausea, vomiting, renal and hepatic dy sfunction, and neurologic alterations.
As in the adult series, response rates to mitotane are heterogeneous (0–56%) and highly
dependent on achieving a serum therapeutic level to 20 µg/mL (13).
Radiotherapy
Radiotherapy (RT) has often been considered ineffective. However, old clinical reports have
described tumor response rates up to 42% (17), which indicate that ACC is not resistant to RT.
The only series reported with children is Magee’s study (11). Fifteen patients including five
children were treated for ACC. Nine of them had postoperative irradiation. Three were girls
who presented under the age of 2 y ears with hormonally active tumors and who survived for
more than 10 y ears after gross total tumor resection, followed by 30 Gy in 4 weeks. Two of
these three patients died of second malignancies arising in the irradiated field. The high
frequency of second primary malignancies is observed in other studies, and it points out the
need for close surveillance after RT (18).
Page 359Recommendations of an international consensus conference were published in
2005 for adults without any data for children. Radiation therapy is recommended in the
treatment of bone, brain, and other metastases. It is also recommended in the treatment of
sy mptomatic local recurrences. Concerning adjuvant situations, it should be discussed in case
of incomplete local resection. There is no recommendation concerning adjuvant RT in cases
of complete resection, and no major evidence to support it (19). However, some
retrospective studies supported the efficiency of adjuvant RT of the tumor bed (± bilateral
para-aortic ly mph node in seven patients due to ly mph node involvement) in terms of local
control with no impact on survival (20,21,22). If there is a high risk for local recurrence (e.g.,
incomplete/R1 resection), a total dose of >40 Gy with 1.8–2 Gy fraction should be delivered,
including a boost volume to reach 50–60 Gy. The high frequency of Li-Fraumeni disease in
children with ACC makes one reluctant to use RT due to the high risk of radio-induced cancer.
Follow-Up
Hormonal monitoring every 2 months in the first y ear followed by monitoring every 4
months in the second y ear should be done, and from then on, monitoring every 6 months was
done (19). Imaging studies are indicated only in the presence of hormonal abnormalities for
functional ACC.
Results
In children, considering all the stages, 5-y ear overall survival (OS) ranges from 30% to 55%.
Event-free survival (EFS) and OS are very close (4). Stages (quality of resection, tumor
weight, and metastasis), age, virilization, and Ki67 rates are factors significantly associated
with survival. In patients with stage III or IV, OS is from 0% to 20% at 5 y ears; 5-y ear OS for
stages I and II is 80–100% and 30–50%, respectively (4).The Surveillance, Epidemiology,
and End Results (SEER) database was queried for the y ears 1973 through 2008 for 85 patients
with ACC less than 20 y ears of age (23). Overall 5-y ear OS was 57%; 5-y ear OS for patients
<4 y ears was 91% and that for patients ages 5–19 y ears was 30%.
Figure: Constitutional Genetic
Abnormalities Associated with Adrenal
Cortical Tumors (ACT)
Figure:
A & B: Young girl, 17 years old, diagnosed with a left ACC. FDG PET clearly shows the main
mass but also a large vena cava involvement. Lung metastases were seen on CT as well as
on FDG PET.
PHEOCHROMOCYTOMA AND PARAGANGLIOMA
Definition
These tumors arise from the chromaffin cells in the sy mpathetic adrenal sy stem (24,25,26).
Pheochromocy tomas (PHs) develop from medullary gland, whereas paragangliomas
(PGLs) come from extramedullary chromaffin cells (27). Adrenal medullary PHs produce
epinephrine and norepinephrine, whereas PGLs produce only norepinephrine. Some PGLs
are nonsecretant. PGLs are described to have larger size, a higher rate of open surgery, more
R2 resection, and more malignant histology than PHs (28).
Histology
As with many other neuroendocrine tumors, distinction between benign and malignant tumors
is difficult. The histologic scaling sy stem “Pheochromocy toma of the Adrenal Gland Scaled
Score” uses a range of histologic criteria (vascular and capsular invasion, necrosis, and
increased mitotic figures) to determine aggressive behavior, but it cannot predict malignancy.
Histologic markers (Ki67, p53) may be indicative of a malignant disease, but none has been
shown to be a prognostic marker (29). Malignancy is often defined retrospectively by
presence of metastases (27).
Epidemiology
PHs and PGLs in the pediatric population are rare, accounting for <1% of childhood cancer,
with an incidence of 2 per million (30,31,32). Two-thirds of pediatric cases occur in boy s. The
incidence of malignant PHs ranges from 3% to 36% (33).
Genetics
Classically, it was thought that 10% of PH/PGL cases were hereditary, the remaining 90%
being sporadic or nonsporadic. Familial PH/PGL was associated with three endocrine tumor
sy ndromes: multiple endocrine neoplasias 2 (mutation of RET gene, PH, medullary thy roid
cancer, and hy perparathy roidism), Von Hippel–Lindau, and neurofibromatosis (NF1)
diseases. In 2000, the identification of germline mutation in succinate dehy drogenase
complex changed our understanding of this tumor. A mutation in one of six susceptibility
genes VHL, RET, SDHB, SDHC, SDHD, and NF1 was identified in 24–27% of cases
(34,35,36); in a pediatric series, this proportion was 40% (32). Genetic counseling is
recommended after diagnosis of PGL/PH.
Clinical Aspect
The classical triad presentation is headache, sweating, and palpitations. Hormone secretion
can be associated with a wide variety of sy mptoms (fever, nausea, weight loss, fatigue, and
headache), although hy pertension is the most consistent clinical sign (29). Childhood
hy pertension can be explained by PH/PGL in 1% of cases. Convulsions and hy pertrophic
cardiomy opathy can also occur (31). Prevalence of asy mptomatic PH is estimated to be
21% more in sporadic tumors. Children with PH have a higher incidence of bilaterality than
adults (31,37).
Biology
Urinary 24-hour and plasma levels of normetanephrine and norepinephrine had a high
diagnostic sensitivity (31), 100% in pediatric series. Urinary and plasma levels of epinephrine
or its metabolites (vany l mandelic acid) had lower sensitivity (33–57%) (38).
Imaging
TDM and MRI are sensitive to localize the tumor; iodine 131-MIBG scan confirms the
functional aspect. 18-F-DOPA TEP is promising for more accurate diagnosis of PGL/PH,
particularly in patients with negative MIBG (39,40).
Treatment
En bloc resection is the major treatment for this condition. Appropriate preoperative
management is necessary to avoid perioperative complication due to catecholamine
secretion. Alpha blockers (i.e., prazosin) and calcium blockers (i.e., nicardipine) are used to
reduce hemody namic instability. Introduction of medical preoperative treatment in 1950
reduced perioperative mortality from 45% to less than 2% (29). Laparoscopic resection is
preferred to open procedure because it decreases the blood loss during surgery and
postoperative length of stay (38). Open procedures are reserved for very large tumors or
suspicion of malignancy with regional disease (29,32). Cortical-sparing adrenalectomy
avoids long-term corticosteroid dependence in the majority of patients with hereditary PH
with minimal risk of acute adrenal insufficiency. It can be considered in case of bilateral
lesions or in case of Von Hippel–Lindau sy ndrome (41). The risk of local relapse is low.
Chemotherapy was described in malignant disease in one pediatric series using cisplatin and
adriamy cin. Cy clophosphamide, vincristine, and dacarbazine were used in an adult series
(31,42). No randomized studies are available. Chemotherapy can provide tumor regression
and sy mptom improvement in up to 50% of patients. External beam irradiation (EBRT) is
effective for metastases. A recent retrospective study on 24 patients reported conformal
EBRT to a mean dose of 31.8 Gy to 3.3 Gy /fraction, or fractionated stereotactic radiosurgery,
delivered in 24 adult patients. Sy mptomatic control was achieved in 81% of lesions (43). Yu et
al. (44) reported efficacy of RT in nerve decompression. I-labeled MIBG therapy is the
single most valuable treatment after surgery in metastatic disease (33). Sy mptomatic
response was observed in 77–85% of cases in an adult series. A meta-analy sis on 17 studies
(243 patients) was published in 2014. It suggests that stable disease and a partial hormonal
response can be achieved in over 50% and 40% of patients, respectively. Better results are
obtained for PGLs than for PHs (45). There is no consensus regarding the doses. The major
adverse effect is bone marrow aplasia. No benefit was observed on 5-y ear survival
(46,47,48).
Page 360Results
OS and 5-y ear disease-free survival (DFS) depend on malignancy and genetic abnormalities.
Coutant et al. (49) described 30 cases of pediatric malignant PHs with 3-y ear survival rates
significantly lower in SDHB mutation than in other cases (36). A 100% OS and 5-y ear DFS
were found in a series with low malignant rates (38). The probability of late recurrence
justifies an indefinite clinical and biochemical follow-up (36).
THYROID CARCINOMA
Histology/Epidemiology
Thy roid cancers are divided into:
A. Carcinoma derived from the follicular epithelium:

Follicular carcinoma: no papillary nucleus is seen in these tumors; capsular and vascular
invasion is common
Papillary carcinoma: nucleus is ty pical, with cy toplasmic inclusions
Poorly differentiated carcinoma: includes insular and solid/trabecular carcinoma, with
morphology between well-differentiated and poorly differentiated tumors
Nondifferentiated carcinoma: loss of follicular architecture, with aggressive behavior
(necrosis, mitosis, vascular invasion)
B. Medullary carcinoma: this subty pe is derived from C-cells or neural crests—
parafollicular cells
C. Other tumors: ly mphomas and metastasis from other cancers
Thy roid carcinoma represents 1% of childhood cancer, 80% in females. Papillary

carcinoma represents 87–95% of pediatric cases (50), whereas follicular, poorly
differentiated, and medullary carcinomas are rare (<5%); anaplastic forms are practically
absent (51,52).
Only papillary and medullary carcinomas will be discussed.
Follicular, Papillary, and Poorly Differentiated Carcinomas

Risk Factors
Risk factors are female sex, postpubertal age, coexisting thy roid disease, family history of
thy roid disease, and previous irradiation of the neck (53).
Clinical Aspects
Clinical presentation of pediatric thy roid carcinoma differs significantly from that of adults
because of delay in diagnosis. The volume of the thy roid nodule was much larger and neck
node involvement and extra thy roidal extension or distant metastases were found more
frequently in childhood (51,52,54). Lung is the most frequent site of distant metastasis.
Children with distant metastatic disease are usually y ounger than those without (55). Most
children with thy roid carcinomas are euthy roid.
Imaging
Ultrasonography (US) is the better and less invasive examination to explore thy roid nodules
or neck adenopathy. US criteria used to identify malignant nodule in children are
controversial. As previously reported, a recent study on 184 children and adolescents with
thy roid nodules confirmed that microcalcifications, hy poechogenic pattern, intranodular
vascularization at Doppler US examination, ly mph node alterations, and thy roid stimulating
hormone concentration were independent predictors of malignant outcome (56). In a recent
meta-analy sis on 750 thy roid nodules, the presence of internal calcifications and enlarged
cervical ly mph nodes were the US features with the highest likelihood ratio for thy roid cancer
(50). Fine-needle aspiration and cy tology of thy roid are justified in nodules >1 cm diameter
or in US suspicious nodules. Accuracy of fine-needle aspiration and cy tology of thy roid
nodule are less well-known in childhood than in adults, but “follicular lesion” at cy tology
indicates the need for surgery to establish a diagnosis (57).
Prognostic Factor
In papillary thy roid cancer, mutations of RET, BRAF, or RAS, activating the MAP kinase
pathway, are found. Contradictory data are reported, but it seems that RET rearrangements
are more frequent in children and the BRAF mutation is absent (58). No correlation with a
genetic pattern and an aggressive behavior of thy roid carcinoma is established y et (59).
Treatment
Surgery
Before surgery, a whole-neck US is required to optimize the preoperative surgical plan. FNA
of suspicious lateral neck ly mph nodes is recommended. In addition, imaging by MRI or CT
with contrast should be performed in patients with large or fixed thy roid masses, vocal cord
paraly sis, or bulky metastatic ly mphadenopathy to optimize surgical planning. Total
thy roidectomy with en bloc dissection of the central compartment is the preferred operation
in T1 stage or higher followed by postoperative serum thy roglobulin (Tg) levels monitoring
and I-131 therapy (59,60,61). Lobectomy alone was discussed in the past, but this less-
aggressive strategy leads to higher recurrences due to the high rate of multifocal disease. The
extent of ly mph node removal is also debated; central compartment dissection is
recommended, while routine removal of jugular–carotid chains remains controversial. A
cy tologic confirmation of metastatic disease to ly mph nodes in the lateral neck prior to
surgery is desirable. Routine prophy lactic lateral neck dissection (levels III, IV, anterior V,
and II) is not recommended, except in patients with cy tologic evidence of metastases to the
lateral neck (60). A complication of surgery is permanent hy poparathy roidism. In a high-
volume tertiary endocrine surgical practice, the risk of permanent hy poparathy roidism
<2.5% (61,62,63). Other complications can rarely occur including spinal accessory nerve
injury or Horner sy ndrome.
Page 361Radioiodine Ablation

Postoperative staging is usually performed within 12 weeks after surgery for stratification of
patients who may or may not benefit from further therapy, to include additional surgery or
131I therapy. After total thy roidectomy, radioiodine ablation (RAI) is performed to destroy
thy roid residues and occult distant metastasis or cervical ly mph nodes. Chow et al. (64) in a
pediatric series showed that postoperative RAI significantly reduces the risk of relapse and
improves10-y ear locoregional failure-free survival. This data was confirmed by a
multivariate analy sis of a large pediatric series, independently of ty pe of surgery or ly mph
node resection (65).
The American Thy roid Association (ATA) task force recommended 131I for treatment
of iodine-avid persistent locoregional or nodal disease that cannot be resected as well as
known or presumed iodine-avid distant metastases. To maximize RAI uptake, TSH should be
>30 mIU/L after stimulation. Postoperative L-thy roxin supplementation is necessary.
There is no consensus regarding RAI doses in adult and in children and between 30 and
150 mCi is given, adapted dose to the body weight. In adults, most centers used 100 mCi, but
more data are required to determine the minimal effective doses for children on thy roid
remnant destruction, recurrence rate, and DFS (59,65). Due to the differences in body size
and iodine clearance in children compared with adults, ATA recommends that all activities of
131I should be calculated by experts with experience in dosing children. Consecutive serum
levels thy roglobulin measurement allow confirming the residual disease or metastatic
ablation (59). Unstimulated and stimulated Tg levels must be undetectable. Elevated Tg would
provide indirect evidence of presence of functional thy roid tumors. Pediatric differentiated
thy roid carcinomas appear to be more radioiodine sensitive than adult carcinomas. RAI can
be repeated every 6 months. Limits of cumulated doses are not established, but leukemia risks
increase between 18.5 and 37 GBq. Early side effects (nausea, vomiting) are more frequent
in children than in adults. Bone marrow or pulmonary fibrosis can appear after repeated
doses to treat bone or pulmonary metastases. Second cancers are rare but can occur (59,65).
Brown et al. (66) reported data from over 30,000 subjects and found a significant risk of
second malignancies among patients treated with 131I (relative risk 1.16, p < 0.05), especially
in y oung patients.
External Beam Radiotherapy

There is no place usually for this treatment in local differentiated thy roid carcinoma. Kim et
al. (67) have studied the benefit of EBRT in T4 stage. No significant difference in survival was
found. The 7-y ear survival rate was 98% for no-EBRT group and 90% for EBRT group, but
the locoregional control at 5 y ears was significantly higher after EBRT (95% vs. 68%) (67).
Bone or soft tissue metastases that are not suitable or do not respond to RAI may be treated
effectively with conventional EBRT.
Follow-Up
Follow-up is recommended by TSH, T3L, T4L, and Tg measurement at 3 months, with US of
the neck. Tg measurement after R-TSH is performed at 6 and 12 months. In cases of
persistent or relapsed disease, repeated ly mph node or metastasis removal is possible.
American Thy roid Association Guidelines have been recently published specifically for
children and should be followed (60).
Results
Survival rates for children diagnosed with a thy roid cancer are good, 97% in the EUROpean
CAncer REgistry –based study on survival and CARE of cancer patients (EUROCARE study )
(68), and similar data are reported in the United States (69). In a study on 227 patients (<20
y ears) treated between 1979 and 2012, the 10-, 20-, and 30 y ear-OS rates were 99, 99, and
97%, respectively. The 10-, 20-, and 30-DFS rates were 84, 71, and 64.0%, respectively.
Gender and preoperative ly mph node metastasis were identified as significant factors related
to DFS in the multivariate analy sis (70) (Table 16.2 ).
Table 16.2 Differentiated Thyroid Cancer in Children from 11 Pediatric Series
Figure: Differentiated Thyroid Cancer in
Children from 11 Pediatric Series
RADIATION-ASSOCIATED THYROID CANCER IN CHILDREN
Cancer Survivors
In the Childhood Cancer Survivor Study, including more than 20,000 survivors of leukemia,
central nervous sy stem (CNS) cancer, Hodgkin disease, non-Hodgkin ly mphoma, kidney
cancers, neuroblastoma, soft tissue sarcoma, and bone tumors, any radiation exposure to the
thy roid gland was associated with a 2.6-fold increased risk of thy roid cancer (95% IC 1,1–
7,1) (78,79). Histologic subty pe was papillary in 78% of cases. Sixty -six percent of thy roid
cancers were diagnosed 10–19 y ears after the first cancer (median 15–19 y ears). Risk of
thy roid cancer increased with radiation until 30 Gy and decreased after, consistent with a
cell-killing effect of radiation at high dose. The dose–response relation differed by age at first
cancer diagnosis, and the peak of relative risk was higher if the first cancer was diagnosed
after 10 y ears. Hodgkin ly mphoma seems to be a risk factor for thy roid malignancy,
independent of radiation dose and age at the time of first cancer diagnosis. Thy roid cancers
were usually diagnosed at lower tumor size after Hodgkin disease, due to sy stematic
surveillance of Hodgkin survivors. A recent publication concerning 2548 patients followed
after Hodgkin disease is available (80). Totally 147 cases of secondary malignant neoplasia
occurrence were diagnosed in 138 patients, including 47 second thy roid cancers; 41 of the 47
patients had a papillary carcinoma. The median time between thy roid cancer and first
treatment was 13 y ears. All patients had received RT to the neck and/or mediastinum. No
difference was seen between men and women, among different age groups at the time of the
treatment, or relates to different RT doses. Long-term follow-up guideline for survivors of
childhood cancer recommends a y early clinical examination of the thy roid gland. US
screening should be considered (81).
Page 363The Chernobyl Accident

After the Chernoby l accident, the incidence of thy roid cancer among children increased
more than 100-fold in children less than 5 y ears old. The risk of thy roid cancer related to
environmental contamination was linear over the dose range of up to 2.7 Gy, and the excess
relative risk was estimated as 1.65 per Gy (95% CI: 1,10-3,20) (79). About 5000 cases of
differentiated thy roid cancer have been diagnosed in the regions of Russia, Ukraine, and
Belarus in y oung people previously exposed to the Chernoby l radiation during childhood (82).
Pacini et al. (83) have compared post-Chernoby l thy roid carcinomas and naturally occurring
carcinoma in Italy and France. In Belarus, thy roid cancers affected y ounger subjects, were
less influenced by gender, were mostly papillary, and had a higher aggressiveness at
presentation. However, the prognosis remains good. With a follow-up period of about 10
y ears, the disease-specific mortality rate in these pediatric thy roid cancer cases that
developed after the Chernoby l accident is 1% or less (82).
Specific forms of DNA damages were see (84). Some of these cases were also
explained by chronic iodine deficiency in many of the contaminated areas before the
accident.
MEDULLARY THYROID CARCINOMA
Clinical Aspect
Medullary Thy roid Carcinoma (MTC) accounts for up to 8% of thy roid cancer in adults (85)
and 5% in children. It is a tumor derived from parafollicular or C-cells of the thy roid, which
can secrete calcitonin. As a consequence, clinical presentation is mainly thy roid nodes with
or without diarrhea, due to calcitonin secretion (85). The diagnosis of MTC in childhood is
based on serum calcitonin (Ct) levels and neck US. If a thy roid nodule is present, fine-needle
aspiration is recommended.
Genetics
One-fourth of the adult cases are associated with MEN 2A sy ndrome (MTC, PH, and
parathy roid gland hy perplasia), MEN 2B (MTC, PH, no hy perparathy roidism, and
marfanoid status), or familial non-MEN MTC (strong predisposition to develop MTC without
other clinical manifestation of MEN 2A), with different mutation of RET oncogene. Even if
these sy ndromes are rare, recognition is important to genetic counseling (86). Children with
clinically evident MTC are usually belonging to MEN2 families, particularly MEN2A and
MEN2B (87). A strong genoty pe–phenoty pe correlation was observed with aggressiveness,
time of onset MTC, and presence or absence of other endocrine tumors (86). Primary
surgery is curative in the majority of patients with early stages, but up to 80% of patients with
palpable disease have nodal involvement.
Treatment
Genoty pe–phenoty pe correlation and clinical presentation are the basis for a
recommendation for prophy lactic thy roidectomy in childhood (86). Three levels of risk were
defined in a codon-based genoty pe–phenoty pe correlation.
Transforming potential of level 3 (codon 918 and 883 in MEN 2B) and level 2 (e.g.,
codon 634 in MEN 2A) mutations are well established, and total thy roidectomy is
recommended, respectively, as early as possible, preferably before the first y ears of birth
and before the age of 5 y ears (86). For level 1 (FMTC, codon 804 or 891 MEN 2A), age at
prophy lactic surgery is discussed, when Ct level rises before 5 or 10 y ears of age (86). For
localized MTC in children, the standard treatment is total thy roidectomy and central neck
node dissection (88). The neck node dissection could be avoided in case of Ct <30 pg/mL.
Distant metastases are observed in up to 25% of cases. Reoperation is the best treatment, but
cy totoxic chemotherapy drugs such as cy clophosphamide and vincristine have been tested,
with a poor response rate (85). Interferon-γ or somatostatin analogs are used to improve
diarrheal sy mptoms. Thy roid kinase inhibitors, such as vandetanib, sorafenib, motesanib, or
sunitinib, have been studied in this indication based on the inhibition of RET protein. For
advanced metastatic cases, vandetanib has been demonstrated to be effective in adults and in
children. Local invasion can be eventually treated by external beam radiotherapy, with poor
results (85,89,90).
AERODIGESTIVE TRACT
Juvenile Nasopharyngeal Angiofibroma

Epidemiology
Juvenile nasophary ngeal angiofibroma (JNA) is a rare benign neoplasm. It represents 0.5%
of all head and neck tumors (91) with an incidence of 1 per 150,000. It predominantly affects
adolescent boy s and men between the ages of 14 and 25 y ears (92,93). Both male
predominance and time of occurrence (adolescence) suggest a link of JNA with hormonal
status (94). Hormonal disorders have been reported in patients with JNA. Moreover, androgen
and estrogen receptors have been identified in tumor tissue.
Histology
JNA is a benign but locally aggressive vascular tumor, developed from the posterolateral wall
of the nasal cavity. JNA may extend to the nasal cavity, the maxilla, involve the skull base,
and extend intracranially. JNA tends to extend along natural foramina and fissures, spreading
toward the paranasal sinus (ethmoid, sphenoid, and maxillary ) and through the
ptery gopalatine fossa laterally. This growth in soft tissue spaces is limited only by bone,
which can be eroded by pressure. The vascular structures of the basisphenoid region can be
involved, especially in the area of the sphenopalatine foramen (95). Intracranial extension
had been reported in 10–20% of all cases before the era of modern neuroimaging. JNA is
composed of a proliferating and irregular vascular component within a fibrous stroma (96).
Some angiogenic markers, growth factors, and proliferation markers have been found to be
associated with the pathogenesis of JNA, and some were also described in vascular anomalies
(97,98). In recent immunohistochemical studies, vascular endothelial growth factor (VEGF),
its transcriptional regulator hy poxia-inducible factor-1 (HIF-1), and other proangiogenic
factors have been localized in JNA stromal cells, suggesting that deregulated vessel growth is
driven by stromal derived growth factor (99,100).
Page 364Clinical Aspect
Patients with JNA usually present with recurrent painless spontaneous epistaxis, nasal
obstruction, facial deformation, and nasal discharge. Less frequently, a reduced sense of
smell, snoring, headache and facial swelling, and cranial nerve palsies can lead to JNA
diagnosis (101,102).
Imaging
The tumor mass is usually seen on CT as a well-delineated and high-density lesion that
display s a homogeneous enhancement in the posterior nasal cavity and ptery gopalatine fossa.
Erosion of bone behind the sphenopalatine foramen with extension to the upper medial
ptery goid plate must be assessed. Good bone imaging on CT is essential to show invasion of
the cancellous bone of the sphenoid. MRI scans are particularly useful in analy zing the
intracranial and intraorbital extension. The characteristic features on MRI are due to the high
vascularity of the tumor causing signal voids and strong postcontrast enhancement. The
vascular supply may come from the internal maxillary, accessory meningeal, ascending
phary ngeal or ascending palatine arteries. MRI shows the preoperative soft tissue extent of
angiofibroma optimally, but an equally important application is to provide postoperative
surveillance to show any residual or recurrent tumor, record tumor growth or natural
involution, and monitor the effects of RT (103,104). Due to the possibility of asy mptomatic
relapses, a CT or/and MRI is recommended about 4 months after surgery, to rule out
posterolateral or extranasophary ngeal recurrences (105).
Prognostic Factors
The reported rate of recurrences following treatment varies between 0% and 57%
(96,106,107). The main predictor of recurrence seems to be the invasion: the deeper the
extension, the larger the potential tumor remnant is likely to be left following surgery. In a
retrospective study on 55 males treated for JNA, size of tumor and ty pe of invasion were
predictive for relapse: invasion to anterior infratemporal fossae (ITF) and/or to
ptery gomaxillary fossae, to the posterior ITF, or intracranial extension were associated with
recurrences in 2 of 15, in 8 of 18, and in 8 of 12 cases, respectively. Tumors less than, greater
than, or equal to 6 cm were associated with zero and with 18 recurrences, respectively (p =
0.006) (108). Similarly, a retrospective review of 44 cases treated between 1985 and 1996
invasion of the skull base affected two-thirds of the patients, and the rate of recurrence was
27.5%. Extensions to the infratemporal fossa, sphenoid sinus, base of ptery goids and clivus,
cavernous sinus, foramen lacerum, and anterior fossa were correlated with more frequent
recurrence (104).
Classification
A wide variety of scales and staging sy stems have been described, but Radkowski’s
classification is the most often used in recent publications (109). More recently, Yi et al. (110)
proposed another classification based on a modern therapeutic approach. The management
and prognosis for the three ty pes of JNA were compared and evaluated and this classification
seems to be reliable. Ty pe I includes JNAs fundamentally localized to the nasal cavity,
paranasal sinus, nasophary nx, or ptery gopalatine fossa. Ty pe II includes JNA extending into
the infratemporal fossa, cheek region, or orbital cavity, with anterior and/or minimal middle
cranial fossa extension but intact dura mater. Ty pe III represents massive tumor lobe in the
middle cranial fossa.
Treatment
Surgical Approach
Endoscopic resection is nowaday s the main definitive treatment for JNA. Endoscopic
resection achieves similar local control rates than those obtained with open surgery, but with
less blood loss, hospital stay, and local sequelae. Open surgical management of JNA is
performed in case of massive intracranial extension or optic nerve or internal carotid artery
entrapment by the tumor. Surgery is challenging. In a sy stematic review reported in 2013 on
72 patients from 15 studies, the mean follow-up period was 47 months and the recurrence
rate was 18%. Facial paresthesia was reported in 16%, followed by ophthalmoplegia (12%)
and intranasal crusting (12%) (111). As a consequence, intracranial infiltration sometimes
leads clinicians to propose RT as an alternate to the risks of surgery (112). More recently,
radiosurgery after surgery in critical sites has been reported in few patients with encouraging
results. From 1999 to 2007, 10 advanced JNAs were treated by primary surgical resection
followed by Gamma Knife Radiosurgery of residual tumor. After a 3-y ear minimum follow-
up, all the patients are asy mptomatic and have stable disease or partial response (113).
Radical Surgery
There are several surgical approaches: transpalatal, lateral rhinectomy, and craniofacial
resection, with infratemporal approach. Preoperative hormone therapy such as flutamide
(114) and embolization before surgery are still discussed. With adequate operative exposure
and resection, 70–100% of the patients are cured without adjuvant treatment.
Endoscopic Resection
The use of an endoscopic approach to treat small JNA is supported by good results from a
number of operative series published since the beginning of the 2000s. A quite large study
identified 65 patients treated for JNA, mean age 15 y ears. Six consecutive patients underwent
successful resection of JNA by way of an endoscopic approach since 2001. Compared with
the conventional surgery group, the endoscopic group had less intraoperative blood loss (225
vs. 1250 mL), a lower occurrence of complications (1 patient vs. ≥30 patients), shorter length
of hospital stay (2 vs. 5 day s), and lower rate of recurrence (0% vs. 24%) (115). Most of the
studies confirm that endoscopic approach gives excellent results in small dimension tumors
(Radkowski’s stages I–IIb tumors and selective IIc-IIIb lesions), whereas open surgery
remains a more standard procedure for patients with larger tumors. In terms of long-term
results of the endoscopic approach, a sy stematic review was published in 2014 on 92 studies
(over 800 patients) (116). Recurrence occurred in 10%, 9.3% had complications, and 7.7%
had residual tumor (117).
Page 365Chemotherapy
Chemotherapy with doxorubicin and dacarbazine or vincristine, actinomy cin, and
cy clophosphamide has been used for recurrent lesions that are not amenable to additional
surgery or irradiation with some success (118,119). Flutamide has also been tested in
neoadjuvant JNA treatment, with poor results; the mean tumor reduction was 11% in a small
series of seven patients (120,121). It seems to give better results in postpubertal patients (121).
Radiotherapy
RT has been employ ed for advanced disease or for relapse after surgery. Doses ranging from
30 to 50 Gy at 1.8–2 Gy per day give excellent results (Table 16.3 ) considering the more
recent studies available (118,122,123,127). More recently, 24 patients treated with definitive
RT were reported. A dose response for tumor control was described: 77% with 30–32 Gy
versus 91% with 35–36 Gy leading to recommend a total dose of at least 36 Gy. All
recurrences were at the primary site and presented within 5 y ears of completing
radiotherapy (92).
Table 16.3 Radiotherapy for Juvenile Nasopharyngeal Angiofibroma: Most Recent
Studies
Patients are usually treated in conformal RT, or with intensity modulation, using a head
holder. Inadequate treatment fields are the major cause of local failure (128). Proper
mapping of the tumor volume is crucial, using CT and MRI (fusion) to establish the treatment
volume, including cranial extension if necessary. McAffee et al. (92) used approximately 2-
cm margins around the tumor for the treatment planning with excellent local control.
Late effects, especially the risk of malignant cancer, neuroendocrine dy sfunction, and
cataract, must alway s be considered; but these effects remain quite rare and should be
weighed against the risk of surgery in case of advanced disease. In a retrospective study on
130 patients treated over a 41-y ear period (1960–2000), 27 patients received radiation (30–55
Gy ) as first treatment (123). Fifteen percent of the irradiated patients developed relapse 2–5
y ears later. Fifteen percent of the patients developed significant late complication, including
growth retardation, pan-hy popituitarism, temporal lobe necrosis, cataracts, and radiation
keratopathy. Two of the patients developed in-field cutaneous basal cell carcinomas but were
at risk for skin tumors. Cummings et al. (128) reported one patient who developed thy roid
carcinoma after 35 Gy. The main visual complication after RT is cataract formation, while
optic neuropathy and retinopathy are uncommon at conventionally fractionated doses
between 30 and 36 Gy. Cummings et al. (128) reported cataract development in 2 of 55
patients (3.6%). Lee et al. (123) observed cataracts in 3 patients on 27 (11%). Cummings
examined the risk factors associated with surgery and RT and found that the relative risks of
significant complications were similar with both treatment modalities (128). Intracavitary RT
has been used rarely (126) due to major bleeding and often inadequate coverage of the
treatment volume (128). Conformal RT or IMRT can be used. IMRT offers a better sparing of
critical organs in complex volumes but also leads to deliver low doses to larger volumes
(129,130).
Nasopharyngeal Carcinoma (NPC)

Histology
The World Health Organization (WHO) has classified NPC into three subty pes in 2005: ty pe I
is keratinizing squamous cell carcinoma, ty pe II is nonkeratinizing epidermoid carcinoma, and
ty pe III is undifferentiated carcinoma. The malignant origin is epithelial, but in tumor ty pes II
and III, ly mphoid, plasmoid, and eosinophilic cell infiltration are common. The most
common histologic ty pe seen in children and adults is undifferentiated carcinoma, with a high
incidence of locoregionally advanced disease (131,132).
Page 366Epidemiology
NPC represents 1% of all childhood cancers, and one-third of all malignancies involving the
nasophary nx in children (133). The classical age incidence is bimodal, with a first peak of
incidence at 10–20 y ears and a second at 40–60 y ears. The incidence of NPC varies
according to racial and geographic factors. Undifferentiated NPC is an endemic tumor that is
common in southern parts of China, Southeast Asia, Alaska, and in the Mediterranean Basin
(incidence 20/100,000) (134). In children, the median age of NPC development is 13 y ears,
with a male predominance (sex ratio 1.8:1) (135).
Genetics
Individuals who have human leukocy te antigen A2 Bsin2 haploty pe, Aw19, Bw46, and B17
ty pes were found to have an increased risk of NPC (136,137).
Clinical Aspects
The tumor initially develops in the walls of the nasophary nx without any sy mptoms,
explaining the usually late diagnosis. The most common presenting sy mptom is a painless
mass in the upper neck; 421 cases (135,138). Local tumor effects can include nasal
obstruction, blood-tinged drainage, bleeding, and conductive hearing loss or serous otitis.
When the tumor invades the base of the skull through direct extension, the cranial nerves are
frequently involved leading to sy mptoms (drooping of the upper ey elid, ey e pain, loss of
vision, double vision, difficulty swallowing, spasms of masticatory muscles, disturbances of
taste and voice).
About 20% of patients have distant metastasis at diagnosis including the bones (60–70%),
liver (about 30%), lungs (about 20%), bone marrow (about 20%), and mediastinum.
Biology
An Epstein–Barr virus (EBV) infection association with NPC has been well described in
childhood (139,140). EBV has been identified as a causative agent in several patients. High
antibody titers of immunoglobulin G (IgG) and immunoglobulin A (IgA) against early antigen
or viral capsid antigen are commonly seen in patients with NPC, particularly those with the
undifferentiated form of the disease. Circulating EBV DNA load may be a useful prognostic
marker in endemic regions.
Imaging
Contrast-enhanced cranial CT and MRI are useful to assess the extent of local tumor growth
and base of skull involvement. A heterogeneous mass (primary tumors and ly mph nodes)
with necrosis has been reported as characteristic in adults (141). Thirteen patients, 30 y ears
old or less, with undifferentiated NPC were reviewed in terms of CT and MRI findings. The
signal intensity of tumors was slightly higher than that of muscles in six cases and isointense to
that of muscles in two cases on T1-weighted images. In all cases, the signal was higher than
that of muscle and lower than that of cerebellar gray matter on T2-weighted images. Internal
signals were homogeneous in both pre– and post–gadolinium-enhanced MR images in all
cases (142).
A large prospective study on adults (8) assessed the usefulness of fluorodeoxy glucose
(FDG)-PET in initial M staging of NPC. Three hundred patients with NPC were compared in
terms of staging. Conventional workup (CWU) included chest radiography, abdominal US,
and skeletal scintigraphy and was compared with FDG-PET staging. About 20% patients were
found to have distant metastases. FDG-PET was more effective than CWU (p < 0.001) to find
them, especially for detecting bone (p < 0.001) and chest metastases (p < 0.001). It was
equally effective for detecting hepatic metastases than abdominal ultrasound (143). A recent
study was performed on 18 pediatric patients, which concluded that FDG may underestimate
tumor extent and regional ly mphadenopathy compared with MRI at the time of diagnosis but
that it helped detect metastasis and clarify ambiguous findings. In the follow-up, it showed
disease clearance 3–6 months earlier than MRI without false positive or false negative
findings (144) (Fig. 16.2A and B ).
Page 367Prognostic Factors

TNM stage is the major prognostic factor for NPC. Locoregional invasion may extend to
cranial nerves and the base of the skull, which increases the risk of local failure after RT
(145). For example, between 1990 and 2000, 81 pediatric patients from Mumbai, median age
14 y ears, with a diagnosis of NPC were treated. Of the 81 patients, 32 (39%), 21 (26%), and
28 (35%) had T1–T2, T3, and T4, respectively. Ninety -one percent had nodal metastasis.
Thirty patients (37%) had ly mph nodes >6 cm, and 45 (56%) had bilateral nodes at
presentation. Nodal status had a significant impact on DFS (p = 0.021) and OS (p = 0.006)
(146).
Classification
Several classifications for NPC have been done, but the most popular in Western countries is
the AJCC staging sy stem (147). The fifth edition of this classification was designed to merge
the best predictive factors of the fourth edition. Another staging sy stem is most frequently
applied to Asian populations, described by Ho (148) (Table 16.4 ).
Treatment
Indications
Treatment depends on the stage. Stage I patients
usually receive RT alone, while stages II and III
patients are treated with chemotherapy and RT.
Stage IV patients usually receive CT. Except for
a diagnostic biopsy, surgery is not part of the
treatment of NPC.
Stage I
RT alone remains the standard treatment of stage
I patients, without node involvement, leading to a
98% 10-y ear overall survival rate (149).
Stages II–III
The place of chemotherapy remains
controversial in the initial management of
localized NPC. In adults, phase III trials and
meta-analy sis comparing induction
chemotherapy with RT alone (150,151,152) did
not show any improvement in OS, despite a Figure 16.2 A & B: Young boy, 15
significant reduction in local and distant failures years old, diagnosed with large bilateral
(150,151). In addition, excess treatment-related NPC. FDG confirms a bilateral cervical
deaths were observed in the induction nodes involvement without
chemotherapy trials (153). supraclavicular disease.
In contrast, recent trials and meta-analy ses
in adults have confirmed the role of concomitant
chemotherapy with RT in locoregionally
advanced NPC. The last meta-analy sis of
chemotherapy in nasophary nx carcinoma
(MAC-NPC) was performed by the
Collaborative Group. Eight randomized trials
compared chemotherapy plus RT versus RT
alone in locally advanced NPC. All trials used
conventional RT and cisplatin-based
chemotherapy. A total of 1753 patients were
included. A significant benefit was found for OS
(6% at 5 y ears) and EFS (10% at 5 y ears) with
the addition of chemotherapy. The benefit on
survival was observed when chemotherapy was
administered concomitantly with RT (153).
Concomitant (cisplatin-based) chemo-
radiotherapy now appears to be the standard
treatment for locally advanced (T2B and more)
and/or node positive (Np) patients in adults (154).
In children, some large studies tend to
demonstrate the same results (155). Fifty -two
pediatric patients with stages I–IVB NPC
received RT dose of 60–66 Gy in 2-Gy fractions
to the nasophary nx and cervical nodes. Among
them, 22 also received chemotherapy with
cisplatin and 5-FU. Three-y ear DFS with
concurrent chemotherapy was 82% compared
to 40% for patients treated with RT alone (p =
0.001) without impact on 3-y ear OS. Thirty - Table 16.4 Staging System for
three patients, median age 14 y ears, were also Carcinoma of the Nasopharynx
treated for stages I–IVB NPC. Thirteen patients
(39%) received RT alone and 20 patients (61%) had chemotherapy and RT. The addition of
chemotherapy had no significant effect on locoregional control but did reduce the
development of distant metastases (16% vs. 57%, p = 0.01). Combined modality therapy
improved 10-y ear DFS (84% vs. 35%, p < 0.01) and survival (78% vs. 33%, p < 0.05) over
radiation alone (156).
Page 368Of 165 patients reviewed between 1978 and 2003, median age 14 y ears, 12.7%
patients were treated with RT alone, while 87.3% received chemotherapy and RT. The
median follow-up time was 48 months. In multivariate analy sis, patients treated with RT alone
had poorer locoregional relapses-free survival (p = 0.0001) as well as DFS than patients
treated with chemotherapy and RT (p = 0.002) (157). Most chemotherapy is cisplatin-based
combination, used weekly or once every 3 weeks. The question to add induction
chemotherapy followed by concomitant chemoradiotherapy remains controversial. In adults,
several phase II studies (158,159,160) have shown good results on a poor prognostic
population (T2B, 3, 4, and/or N+) selected on good performance status, but further studies are
needed, especially in children.
The use of interferon beta has been evaluated in a phase II trial, as maintenance therapy
after combined therapy with neoadjuvant chemotherapy and radio-chemotherapy.
Treatment was well tolerated and resulted in a very good outcome that was superior to the
outcomes of published results from all other pediatric NPC study groups.
Stage IV
Treatment of metastatic disease is based on chemotherapy. Anthracy clines and bleomy cin
were the first agents used. Platinum-based regimens are now the standard chemotherapy for
metastatic NPC patients, and cisplatin–5-FU combination remains the most often used in first-
line treatment (159). In a retrospective review of 84 patients, mean age 13 y ears, with NPC
chemotherapeutic regimens involved cy clophosphamide from 1972 to 1982; vincristine,
cy clophosphamide, epirubicin, and actinomy cin-D protocol from 1982 to 1999; and cisplatin,
methotrexate, and 5-FU with leucovorine rescue after 1999. A total of 78.5% of the patients
were at advanced stage (stages III and IV). The survival rates (80%) were higher with the
cisplatin combination regimen (131,135,161,162).
Radiotherapy
Radiotherapy Dose
Before the beginning of RT, dental evaluation and prophy laxis are necessary. Baseline
neuroendocrine testing and audiograms are also useful for the assessment of late effects. The
optimum dose for local control NPC in children is not precisely known. Doses greater than 65
Gy have been shown to achieve better local control in some studies (131,132,161,162), but
others have not shown any correlation between the dose of radiation, rate of local relapse,
and survival time (163). Generally, doses ranging between 50 and 70 Gy are recommended
for patients older than 10 y ears, and a 5–10% reduction in this dose is recommended for
children y ounger than 10 y ears of age (161) Daily fractions of 1.8–2.0 Gy, 5 day s a week are
usually proposed in children. One of the ongoing questions in children is to reduce the RT dose
to ly mph nodes and/or to the nasophary nx area in case of good response to chemotherapy, to
limit the late effects of high-dose RT. For instance, in a French study, 34 children were treated
for AJJC-TNM stage IV NPC. After chemotherapy, cervical nodal irradiation was reduced
(<50 Gy ) in the 15 cases of a good response to chemotherapy (≥90% of initial tumor
volume). Median nasophary ngeal RT was 59.4 Gy, up to 66 Gy in some cases of partial
response to CT. The overall prognosis was not influenced by the dose of local RT delivered or
response to initial chemotherapy, but EFS was better in patients with a good response to
chemotherapy. The cervical local failure rate was low despite RT dose reduction in the case
of a good response to neoadjuvant chemotherapy (164).
Radiotherapy Volumes
CT and MRI are used in the delineation of clinical target volumes (CTVs) (165,166). The
CTV should include the nasophary nx, half (posterior) of nasal cavity, entire sphenoid sinus,
and posterior ethmoid sinuses. The posterior limit of the CTV is usually at the anterior part of
medullary canal. The inferior limit is represented by orophary ngeal wall to the midtonsillar
fossa, basioccipital bone, cavernous sinus, base of skull, ptery goid fossae, posterior one-third
of the maxillary sinus, retrophary ngeal nodes, bilateral cervical nodes, and supraclavicular
nodes (166). If the tumor has invaded the base of the skull, the superior border should be
raised to include all of the pituitary gland, the base of the brain in the suprasellar area, the
adjacent middle cranial fossa, and the posterior portion of the anterior cranial fossa. Sham et
al. (167) have shown that the protection of pituitary gland did not lead to increase local failure
if the skull base was not involved.
Radiotherapy Technique
In adults, intensity modulated radiotherapy (IMRT) substantially improves head and neck-
related sy mptoms and quality of life of patients with NPC without decreasing local control
(168,169,170). IMRT may provide improved local control in children with less late sequelae
(132). Thirty -six children, median age 14 y ears, with localized NPC, were included in Uzel’s
study. All of them were treated with a combination of chemotherapy and RT. Nineteen
underwent IMRT and 17 underwent conformal RT. They have shown that IMRT significantly
reduces and delay s the onset of acute toxicity (grade 3 toxicity of skin, mucous membrane,
and phary nx), resulting in improved tolerance and treatment compliance for children with
NPC. IMRT also permitted a superior target coverage and normal tissue sparing compared
with CRT (171), with decreased acute toxicity on skin, mucous membrane, and lary nx.
Nevertheless, acute toxicity may be severe even with IMRT and the use of a feeding tube
may sometimes become necessary.
The sparing of salivary glands and hearing structures made possible by IMRT decreases
late effects. In five pediatric patients with NPC treated by IMRT and concomitant platinum-
based chemotherapy, with a median follow-up of 6.3 y ears, all patients experienced three or
more long-term toxicities, including hy pothy roidism, xerostomia, hearing loss, and dental
disease (172). Interestingly the dose constraint to the cochlea was 25 Gy, but it has been
recently published that 10 Gy is the dose constraint with concomitant cisplatin (173). A larger
recent retrospective study on 95 pediatric and adolescent patients described late effects with a
rate of 48% xerostomia, 28% hearing impairment and 41% neck fibrosis (related to dose) but
all late effects were grade 1 or 2 (174). Endocrine late effects are frequent due to the
proximity of pituitary gland.
Hyperfractionation
Experiences with altered fraction schedules in NPC remain limited in adults, and are
infrequently described in children. In adults, hy perfractionation and accelerated fractionation
have not demonstrated an increase in survival efficacy (176), but local control is usually
better (177). The high rate of toxicity limits the use in children (178,179). For example, Teo et
al. (176) reported increased risk of temporal lobe injury in adults with NPC after altered
fractionated RT (176).
Page 369Results
Survival Outcomes are shown in Table 16.5 .
Table 16.5 Survival in Childhood Nasopharyngeal Carcinomas: Studies During the 1990s
and 2000s
Late Effects
Late effects of treatment in children include hy popituitarism, thy roid dy sfunction (73%), and
fertility defects. Other effects include xerostomia, chronic sinusitis, dental caries, hearing
loss, and neck fibrosis. Second malignancies, encephalopathy, osteoradionecrosis, cranial
nerve dy sfunction, hy poplasia, and fibrosis of facial bones occur less frequently
(132,147,162,184).
Esthesioneuroblastoma (or Olfactory Neuroblastoma)

Epidemiology
Esthesioneuroblastoma (EB) accounts for 3% of endonasal neoplasms with an incidence of
0.1–1/1,000,000 children less than 15 y ears per y ear (185). It is the most common cancer of
the nasal cavity, representing 28% in the SEER series (186). A bimodal distribution has been
described, with a first peak incidence at 10–20 y ears and a second one at 50–60 y ears. No sex
predominance is known.
Histology
EB is an aggressive malignant tumor derived from the olfactory specialized neuroepithelium
of the upper nasal cavity (187). Histologic features include small, round neuroepithelial cells
arranged in rosette or pseudorosette patterns, separated by fibrous elements. In cy tology,
fibrillary cy toplasm and smooth nuclear contours are usual; mitotic figures are generally
absent (188). The diagnosis needs a combination of parameters, including microscopic aspect
and immunohistochemical stains. The tumor may be positive for chromogranin,
sy naptophy sin, S-100 protein, and neuron-specific enolase (189). A histologic grading sy stem
is based on degree of differentiation, cellular anaplasia, and mitotic rate. This is a four-level
sy stem that is frequently simplified into low-grade (Hy ams grades I and II) and high-grade
(Hy ams grade III and IV) neoplasms (190). In a large recent report from SEER including
281 adults, patients with high-grade tumors had substantially worse survival rates than patients
with low-grade tumors. Surgery was an independent positive predictor of disease-specific
survival in patients with low-grade lesions. Kadish staging and radiotherapy were independent
positive predictors of disease-specific survival in patients with high-grade tumors (191).
Pathogenesis is not well known; however, nitroso derivatives (192) and viral induction (193)
have been discussed in the pathogenesis. EB has also been described as a member of Ewing
sarcoma and peripheral primitive neuroectodermal tumor (PNET) family, while the
EWS/FLI1 translocation has been shown in EB cell lines (194).
Page 370Clinical Aspect

Longstanding unilateral nasal obstruction, present for months, sometimes for y ears, is the
most common complaint (>50%). Less frequent complaints include recurrent epistaxis,
headache or sinus pain, nasal obstruction, loss of smell, facial mass, proptosis, diplopia,
excessive lacrimation, and inappropriate secretion of antidiuretic hormone (195,196,197).
Lacking specific early sy mptoms, patients are usually late diagnosed.
Imagery
Contrast-enhanced CT (<5-mm thick slices) is necessary, particularly to assess paranasal
cavities involvement. EBs are solid and aggressive nasal cavity tumors; erosion of osseous
structures can be seen. MRI is often necessary because it is more sensitive to explore
intracranial involvement (198).
Classification
The most commonly used classification is
Kadish staging sy stem (Table 16.6 ) (199).
About one-third of the patients are in group B,
half of them are in group C (197). Neck node
involvement has been reported in 10–50% of the
patients (195,200,201). Metastatic disease at
presentation occurs in 10–50% of patients, Table 16.6 Kadish Staging System
depending on the study reviewed (202,203). In
case of metastatic disease, the lesion area in 20–30% patients involves the subepithelial
endocrine cells (SNCs) that grow through the cribriform plate and invade the anterior basal
cranial base. It can then metastasize to brain parenchy ma or leptomeninges (197). Other
metastases are less frequently found in lung, liver, or bone (204).
Treatment
Due to low incidence of EB, even in adults, it is difficult to evaluate the efficiency of
treatment strategies. Options include surgery alone, RT alone, surgery and RT, chemotherapy,
and sometimes high-dose chemotherapy with autologous bone marrow transplantation. In
general, multimodality treatment offers the best survival rate, particularly with more
advanced disease.
Surgery
Outcomes improved significantly with the advent of craniofacial resection in the 1970s,
providing a more complete surgical resection (205). Surgical extirpation can usually be
accomplished, but obtaining standard oncologic negative margins in this area of critical
functional anatomy is not without great morbidity to the patient. Craniofacial resection allows
en bloc resection of tumor including the cribriform plate, with direct visualization of
intracranial extension and protection of the brain and optic nerves. DFS increased from 40%
to 80% when comparing extracranial resection with craniofacial resection in one published
study (205). Complications include infections, cerebrospinal fluid leak, and optic injury (205).
In a pediatric series, up to one-third of the patients had postoperative morbidities, including
complications involving the local wounds, the central nervous sy stem and the ocular orbit.
Postoperative mortality has also been reported in up to 5% of patients (206). If cervical
disease is present at diagnosis, complete neck dissection can be discussed (207). Due to
surgical morbidity and frequent indication for adjuvant therapies, other strategies have been
studied: treatment with smaller surgical margins followed by postoperative radiation, the use
of neoadjuvant chemotherapy followed by surgery and postoperative radiation, and the use
of chemoradiation without surgery (208,209). In particular, recent publications report
neoadjuvant chemotherapy in children. Less major surgical complications are thus reported
while delay ed surgery could be less aggressive (197). A meta-analy sis of adult data has been
published, concerning 361 patients treated between 1992 and 2008. A greater published
survival rate for endoscopic surgery compared to open surgery (p = 0.0019), even when
stratify ing for publication y ear (p = 0.0018), was found. Review of Kadish tumor staging for
each modality showed that larger tumors were more often treated with an open approach, but
open and endoscopic survival measures were comparable (210). In a large recent report
from SEER including 281 adults, surgery was the only independent positive predictor of
disease-specific survival in patients with low-grade lesions (191,211).
Radiotherapy
Multiple retrospective studies have demonstrated an improved outcome with the addition of
radiation before or after surgery (212). Delivering RT in preoperative situation offers several
theoretical advantages including an intact blood supply, leading potentially to a better radiation
efficacy. Definition of the tumor volume is also clearer before surgery. In small studies, RT
has been shown to provide a valuable complement to radical craniofacial resection, leading to
reduction in tumor burden in two-thirds of the patients. Patients experiencing reduction in
tumor volume by neoadjuvant therapy demonstrate an improved prognosis (213).
Postoperative radiation is generally accepted as important for treatment of advanced EB
(214,215,216). Broich et al. (212) reviewed the literature and reported 62.5% survival with
surgery alone and 72% survival with combined surgery and radiation at 5 y ears. It was
confirmed more recently in a large study on 70 adult patients (211). Patients who were
treated with surgery alone had a median disease-specific survival of 88 months versus 218
months for those who were treated with surgery and postoperative radiation. In a large recent
report from SEER including 281 adults, postoperative radiation therapy was a significant
independent factor in predicting disease-specific survival in only patients with high-grade
tumors (191). Even in pediatric series, despite the risk of late complications, the vast majority
of patients receive high-dose radiotherapy in adjuvant situation, leading to better local control
and the disease-free survival. In a recent study, all the 11 pediatric patients received
combined treatment including RT. It was performed in adjuvant situation in 10 of them and
with chemotherapy in one. The 5-y ear actuarial disease-free survival and overall survival
rate was 91% (217). Exclusive RT is not recommended as far as patients are eligible for
surgery and chemotherapy because the pattern of relapse is not only local. Benfari et al.
(218) reviewed 55 patients submitted only to radiotherapy alone. They had been selected
from publications between 1979 and 2006 according to the Kadish classification. With a
median follow-up period of 103.6 months, 6/6 stage A patients, 7/12 stage B patients (median
follow-up 120 months), and 7/37 stage C patients (median follow-up period of 77.3 months)
were free of disease.
Page 371RT technique is ty pically based on CT planning and simulation, with fusion of
MRIs to the treatment planning CT to more accurately define soft tissue and/or brain
parenchy mal extension. Ty pically, fields may include the entire nasal fossa, maxillary
sinuses with extension into the ethmoid, sphenoid sinuses, and the anterior cranial fossa.
Elective treatment of ipsilateral neck is controversial and likely not indicated without risk
factors for evidence of extension to the neck nodes; especially when chemotherapy is
delivered. In a recent study on 14 patients, no cervical nodal failure occurred in patients
treated with combined sy stemic chemotherapy regardless of elective nodal irradiation. In the
opposite neck, three cervical failures occurred in the four patients treated with ipsilateral neck
RT or neck dissection. These patients had not received sy stemic chemotherapy (219). Total
RT dose ranges from 50 Gy for microscopic disease to 55–60 Gy for gross disease
administered at 1.8/2.0 Gy per fraction. IMRT is often a good option due to the proximity of
organs at risk (220). Zabel et al. (221) reported that the IMRT plans gave equal dose coverage
and allowed more effective sparing of normal tissues in 13 cases. Proton beam RT has
allowed for dose intensification to the target volume with relative paring of adjacent normal
tissues, especially for bulky or unresectable diseases (222,223). Radiosurgery is another
treatment modality used for definitive treatment and for treatment of local relapse. It allows
the benefit of single fraction treatment. Small local relapses after previous RT may be treated
with this technique (224). In children, RT can cause significant late effects. A risk of second-
cancer, craniofacial growth impairment, damage to the permanent teeth, endocrine
dy sfunctions, and loss of the sense of smell represent the main late effects (225).
Chemotherapy
The role of chemotherapy is not well defined in the pediatric population. Chemotherapy has
been studied in the neoadjuvant and adjuvant situations in a small numbers of patients.
Cisplatin-based regimens, associated with cy clophosphamide, vincristine, or etoposide, have
been used (226,227,228). Some studies recommend chemotherapy in stage C disease. For
example, routine use of cy clophosphamide and vincristine in combination with RT and
surgery has demonstrated improved survival in a study at the University of Virginia (227). A
retrospective study on 19 patients <20 y ears of use has shown a benefit of multimodal
treatment regimens combining surgery and chemo- and RT for pediatric patients with Kadish
stage C. Chemotherapy appears to improve resectability, EFS, and OS (225). El Kababri et al.
(217) reported a 5-y ear actuarial disease-free survival and overall survival rate of 91% in 11
pediatric patients treated with neoadjuvant chemotherapy. High-dose chemotherapy with
stem cell rescue has been reported as primary and salvage therapy, with good results in small
series, after RT (229). A maintenance treatment by interferon has also been proposed (230).
Results
A meta-analy sis of data from 37 small
retrospective studies (386 patients) was published
in 2001, comparing outcomes by treatment
modality. Mean OS at 5 y ears was 45%. Survival
by treatment modality was 65% for surgery plus
RT, 51% for RT plus chemotherapy, 48% for
surgery alone, 47% for of all three modalities,
and 37% for RT alone. Higher histopathologic
grade and the presence of cervical ly mph node
metastases were poor prognostic factors (203)
(Table 16.7 ). Although recurrence can occur
with high frequency even after prolonged time
interval, long-time survival can be improved
after aggressive salvage therapy. Long-term
follow-up is mandatory (235). Recurrences have Table 16.7 Local Recurrence Rates in
been reported 15 y ears after treatment (236). Retrospective Series of the Treatment of
Esthesioneuroblastoma: Combined Adult
and Pediatric Series
Figure: Radiotherapy for Juvenile
Nasopharyngeal Angiofibroma: Most Recent
Studies
Figure:
A & B: Young boy, 15 years old, diagnosed with large bilateral NPC. FDG confirms a bilateral
cervical nodes involvement without supraclavicular disease.
Figure: Staging System for Carcinoma of the
Nasopharynx
Figure: Survival in Childhood
Nasopharyngeal Carcinomas: Studies During
the 1990s and 2000s
Figure: Kadish Staging System
Figure: Local Recurrence Rates in
Retrospective Series of the Treatment of
Esthesioneuroblastoma: Combined Adult
and Pediatric Series
MALIGNANCIES OF THE ORAL CAVITY, OROPHARYNX,
HYPOPHARYNX, AND LARYNX
Epidemiology
The German Childhood Cancer Registry has reported one of the largest studies, including 370
malignancies of the head and neck in children under the age of 15 between 1994 and 2003
(199 boy s and 171 girls). The overall incidence of malignancies of specific sites of the head
and neck in Germany is 4.48 per 100,000 children. The most frequently observed entities,
representing primary tumors, are soft tissue sarcomas (0.39/100,000), ly mphomas
(0.09/100,000), and thy roid carcinomas (0.07/100,000). The most commonly affected organs
are the thy roid (1.21/100,000), orbital region (0.91/100,000), nasophary nx (0.66/100,000),
tonsils (0.43/100,000), and paranasal sinuses (0.14/100,000) (237,238). A large American
study (SEER) confirmed the proportion of head and neck cancers to all cancers in the
pediatric population has remained stable between 1973 and 2010 in USA. The five most
prevalent head and neck cancers within the pediatric population were salivary gland tumors,
nasophary ngeal neoplasms, tumors of the nose, nasal cavity, and middle ear; gum and other
mouth tumors; and glossal tumors (239).
SALIVARY GLAND TUMORS
Page 372Epidemiology
Salivary gland tumors (benign or malignant) represent only 1% of head and neck tumors
(240,241). Only 5% of salivary gland cancers arise during childhood (242,243). Carcinomas
of the salivary glands represent 0.08% of cancer in the pediatric population (244).
Pathology
Fine-needle aspiration biopsy is generally used for the diagnosis of salivary gland mass
(245,246). Among epithelial tumors of the salivary glands, mucoepidermoid carcinoma
(MEC) and adenoid cy stic carcinoma (ACC) are the most frequent histologic ty pes in adults
and children. Histopathologic grades are usually defined as low, intermediate, or high. MECs
are more often low or intermediate grade in childhood than in adults. MECT1/MAML2 fusion
transcripts are also more common in children (247).
Mucoepidermoid Carcinoma As Second Tumors

Mucoepidermoid carcinoma (MEC) of the salivary glands represents 6% of the second
cancers and is also known to arise as a second malignant tumor in adulthood (248,249). In a
French retrospective study on 18 patients, 11 had a previous history of a nonsalivary
malignancy tumor (250). All except one had initially received chemotherapy with alky lating
agents, including cy clophosphamide in nine patients. External RT was also performed in
seven patients, with a dose range of 10–55 Gy. MEC occurred within or close to the original
radiation treatment field in all seven cases (250).
Clinical Aspects
The most frequent clinical presentation is an isolated, hardened, noninflammatory, painless,
and slow-growing tumefaction (251). Facial palsy is rare (250).
Treatment
MEC has a good prognosis in y oung patients. Differences in OS, specific survival, and DFS do
not seem statistically significant between the primary MEC tumors and the second cancers.
Definitive surgery is the treatment of choice and gives very good local control rates
(247,252). A neck node dissection is recommended in patients with advanced-stage disease,
and in high-grade tumors neck ly mph node metastasis is detected in 50% of cases (253,254).
A retrospective analy sis of clinical and histopathologic findings was published recently in 14
patients with MEC diagnosed at Texas Children’s Cancer Center between 2000 and 2014 (247).
They confirmed complete excision is the treatment of choice and is associated with excellent
outcome while no relapse occurred with a median follow-up of 24 months. The role of RT
after surgery remains unclear. A French study reported 38 pediatric patients, median age 14
y ears, treated for MEC: 37 patients had surgery, 29% received adjuvant RT, and 11%
received chemotherapy. With a median follow-up of 62 months, OS was 95%. One local
relapse (nodes) was reported. Low-/intermediate-grade lesions with early stage could be
treated by surgery alone. Neck dissection is recommended for high-grade lesion. They also
recommend adjuvant RT for high-grade or extensive MEC, and/or positive surgical margins
(255).
Surgery is the treatment of choice in adenoid cy stic carcinoma (ACC) for pediatric
patients, as for adults. The prognosis seems to be slightly better in childhood than in adults, and
for patients treated by surgery versus not, according to a large study (>3000 patients) from
the US National Cancer Institute’s SEER program (256). The overall 5-y ear, 10-y ear, and 15-
y ear survival outcomes for ACC patients were 90.3%, 79.9%, and 69.2%, respectively, for
the whole population (adults and children).
INFANTILE SUBGLOTTIC HEMANGIOMAS
Congenital subglottic hemangioma (SH) causes life-threatening airway obstruction during the
first few months of life. After an asy mptomatic neonatal period, the infant presents a
characteristic biphasic stridor as the lesion progressively obstructs the subglottic space. In 80–
90% of cases, these sy mptoms appear in the first 6 months of life. The involution process
generally begins at 12 months of age and continues until the SH regresses completely. The
mortality rate of recognized and untreated cases justifies active treatment. The aim of
therapy is to restore normal respiration, attempting to preserve the child’s voice and alter the
quality of life as little as possible.
Treatment
Sy stemic propranolol has demonstrated similar effectiveness to surgery and is now
considered as the standard of treatment (257,258). Twenty -seven patients, median age 2.3
y ears, were reported recently : 11 of 27 (41%) were managed with propranolol alone; the
remaining 16 of 27 (59%) also had a steroid injection. Propranolol dose was maintained at 2
mg/kg/d in all patients for a minimum of 7 months (range, 7–34 months; median, 15 months).
Stridor was eliminated within 24 hours or less of propranolol initiation in 23 of 27 (85%)
Before propranolol became widely used, endoscopic excision with carbon dioxide laser, used
alone or combined with other therapeutic techniques, was performed. A retrospective
comparative study of a previous cohort of 51 patients with SH was performed in which
patients were treated either by tracheostomy alone, tracheostomy and CO2 laser, sy stemic
steroids and CO2 laser with no tracheostomy and intralesional steroid injection, CO2 laser
therapy, or both, followed by intubation. Resolution of the SH was achieved in about 90% of
cases. However, a transitory tracheostomy was required in more than half of the cases. The
time to resolution of SH does not appear to be reduced by laser therapy compared with
treatment by tracheostomy alone. Intralesional steroid injection or laser therapy together
with intubation was associated with avoidance of a tracheostomy in 66% of cases (259).
Page 373Although RT is known to work, it carries a risk of inducing second thy roid
cancer later in life. In a series of 11 patients with SH, conventional RT was utilized in the first
7 patients. A radioactive gold grain directly was placed into the lesion in the last four patients,
leading to minimal thy roid gland irradiation compared to treatment by conventional RT. It
was successful in the four patients (260). When RT is used, a dose range between 3.5 and 5
Gy at 0.5–1.5 Gy per fraction is delivered. When dealing with a life-threatening situation, one
should be prepared to use irradiation if other treatment modalities are either inapplicable or
unsuccessful.
ESOPHAGEAL CANCERS
Esophageal carcinoma may develop in children; it may arise spontaneously, y ears after
chemical burns in the setting of Barrett esophagus (261), and, in one reported case, in
association with Cornelia de Lange sy ndrome (262). Both squamous cell carcinoma and
adenocarcinomas have been reported. They are managed similarly to adults (263) and have
usually poor prognosis. The rare case of esophageal sarcoma (leiomy osarcoma,
carcinosarcoma, and malignant schwannoma) may be treated with preoperative or
postoperative irradiation (264). Palliative RT is occasionally necessary for leukemia or
secondary or primary ly mphomatous infiltration of the esophagus (249,250). Other rare
esophageal neoplasms include leiomy oma, desmoid, and teratoma (265,266).
GASTROINTESTINAL MALIGNANCIES
Primary gastrointestinal (GI) malignancies are rare in childhood and adolescence. Non-
Hodgkin ly mphoma is the most common malignancy of the stomach in childhood (see
Chapter 8 ). As a group, leiomy osarcoma and leiomy oblastoma are the second most
common gastric malignancies in children (267,268). The average size of a gastric
leiomy osarcoma in childhood is 6–7 cm in diameter. Infiltration of tumor to adjacent
structures, including the liver or nodal metastasis, may occur (268). Therapy of gastric
leiomy osarcoma begins with surgery. The operative bed and the upper abdomen are
common sites of tumor recurrence. Postoperative RT is justifiable when there is a
particularly high risk of local recurrence created by positive surgical margins or posterior
penetration. However, the efficacy of adjuvant RT in this setting is not proven.
Gastric adenocarcinoma is rare in children, representing 0.05% of all gastrointestinal
malignancies (267,269). It may occur de novo or in association with Peutz–Jeghers
sy ndromes (270). Among the few pediatric cases reported in the literature, median survival
after diagnosis is poor, approximately 5 months (271). Initial chemotherapy is mainly
platinum-based. Large surgical resection offers the best option (271). There is epidemiologic
evidence that long-standing Helicobacter pylori infection and chronic gastritis are involved in
the development of a variety of gastric malignancies including adenocarcinomas,
ly mphomas, and mucosa-associated ly mphoid tissue ly mphomas. Acquisition of infection in
childhood appears to be a risk factor for development of neoplasia as an adult. However, the
impact of the treatment of all H. pylori–infected children on the risk of gastric malignancy
decades later is debated (272,273).
Gastrointestinal stromal tumors (GIST) have recently been identified by the
immunohistochemistry from other mesenchy mal tumors such as leiomy omas,
leiomy osarcomas, and plexosarcomas (274). The UK National Registry of Childhood
Tumours showed an annual incidence of 0.02 per million children below the age of 14 y ears
(275) representing about 1% of all GIST cases. GIST can occur sporadically or concurrently
with genetic sy ndromes, including familial GIST with germline KIT mutation,
neurofibromatosis ty pe 1, Carney triad and Carney –Stratakis sy ndrome. Multiple tumors are
frequently observed and regional recurrence rates are high in pediatric gastric GIST (276).
The most common sites of metastasis are liver, peritoneum and ly mph nodes.
Rhabdomy osarcoma, Hodgkin disease, malignant teratoma, GI stromal tumor, and nerve
sheath tumors also may occur in the stomach (277).
PULMONARY NEOPLASM
Epidemiology
Pulmonary neoplasms are unusual in the children and represent a wide spectrum of
pathology (278). An American study on patients 25 y ears of age has reported the relative
incidence of primary and metastatic lung tumors in children and adolescents through a single-
institution case series. A total of 204 pediatric lung tumors were diagnosed and analy zed.
About 83% were secondary lung lesions, 10% were benign lesions, and 7% were primary
malignant lesions.
Pathology
Adult lung cancers (adenocarcinoma, epidermoid carcinoma) are exceptional in childhood.
The most common primary lung malignancies in children are pleuropulmonary blastoma
(PPB) and carcinoid tumor and less frequent are peribronchial my ofibroblastic tumor and
other my ofibroblastic lesions, sarcomas (279), mesothelioma, and inflammatory
pseudotumor (plasma cell granuloma) of the bronchus. Metastatic lung tumors are relatively
common in children and also comprise a spectrum of cancers different from the adult
population (278,280).
Clinical Presentation
Sy mptoms are nonspecific: cough, fever, pulmonary infection, respiratory distress, weight
loss, pain, and hemopty sis (281).
Page 374Pleuropulmonary Blastoma (PPB)

PPB is the most frequent malignancy associated with lung cy sts, usually in early childhood
(282). PPB occurs almost exclusively in the first decade of life. This neoplasm is
histologically characterized by primitive blastema and a malignant mesenchy mal stroma that
often presents multidirectional differentiation. The early form of the disease, cy stic ty pe I
PPB, is a multilocular cy st form with variable numbers of primitive mesenchy mal cells
beneath a benign epithelial surface. Rhabdomy oblasts and cartilage nodules are seen in more
than 40% of the cases (283). Ty pe I PPB can have a resemblance to developmental lung
cy sts, making the diagnosis difficult. Ty pe II PPB is a solid-cy stic tumor, whereas ty pe III
PPB is solid tumor without epithelial-lined cy stic spaces.
Genetics
A constitutional genetic predisposition is suggested by the early age of diagnosis, the
association of PPB, and renal tumors (cy stic nephroma for instance), malignant germ cell
tumor, medulloblastoma, thy roid neoplasia together in patients and/or family members
(284,285). Recent data report a germline mutation in DICER1 is the genetic cause in the
majority of PPB cases (286).
Diagnosis
The median ages at diagnosis are 8–10, 34–35, and 41–44 months for ty pes I, II, and III,
respectively (International Pleuropulmonary Blastoma Registry, (286). The tumor equally
affects both genders. PPB in children aged <5 y ears is usually present as respiratory tract
infection or pneumothorax. PPB appears commonly as a solitary parenchy mal mass on
chest radiograph and CT (287). Large masses in the right hemithorax with heterogeneous low
attenuation, pleural effusion, contralateral mediastinal shift, lack of chest wall invasion (288),
and pneumothorax can be seen (289). Rarely, metastasis to central nervous sy stem, bones,
and liver can be seen in ty pe II and III PPB (290). A study on 39 patients showed that the
cumulative probability of cerebral metastasis by 5 y ears from diagnosis reached 11% for
ty pe II patients and 54% for ty pe III patients (291).
Treatment
Most cases are managed initially with surgery while total resection is associated with better
outcomes (292). However, the tumors often are large and locally extensive, making complete
surgical excision uncommon. Thoracic irradiation has been reported in case reports for the
postoperative treatment of patients with large tumors or positive margins (30–55 Gy ) with no
clear evidence of benefit (293). One should also consider RT for the treatment of local tumor
recurrence, where the situation is grim but not hopeless (294). Several reports describe the
need for combination chemotherapy for PPB without any consensus on the optimal regimen
(295,296). The agents that have been used are vincristine, actinomy cin D,
cy clophosphamide, doxorubicin, ifosfamide, etoposide, cisplatin, carboplatin, epirubicin,
methotrexate, and 5-fluorouracil. Recurrences after ty pe I PPB are usually advanced ty pes
II or III neoplasms with a poor prognosis. Salvage after ty pes II and III recurrence is poor
(about 40% in the best series).
Results
Despite the introduction of multimodal therapy (surgery, chemotherapy, and occasionally
RT), the prognosis for PPB patients remains poor. A report on 350 central pathology -
confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma
Registry showed the 5-y ear overall survival rate for ty pe I, II, and III patients were 91%,
71%, and 53%, respectively. All deaths in the group I were due to progression to ty pe II or III
(286). Almost all recurrences of this disease tend to occur within 24 months of diagnosis, and
with a few exceptions, within 36 months of diagnosis (297). Therefore, careful and strict
follow-up for 3 y ears is needed in patients with PPB. In terms of prognostic factors, the PPB
ty pe is the strongest predictor of outcome, as well as metastatic diseases (290,291). The
DICER1 germline mutation status does not seem to impact the outcome (286).
CARCINOID AND MUCOEPIDERMOID BRONCHIAL TUMORS
Endobronchial tumors are rare in children and often misdiagnosed. Although the true
incidence of this entity is unknown, bronchial adenomas alone may account for 5% of all
primary pulmonary neoplasms in children (298). The malignant lesions include bronchial
adenomas, carcinoids, MECs, and ACCs.
The most common endobronchial tumor in children and adolescents is carcinoid (281).
Carcinoid tumors can be divided into ty pical and aty pical forms with the latter exhibiting
histologically malignant features and aggressive clinical behavior. This histologic and clinical
distinction is not as clear in the pediatric age groups as it is in adults because of the limited
pediatric experience with this pathology (299). Because of the abundant vascularization,
endoscopic removal of these lesions can be hazardous and is not recommended. A
retrospective analy sis of all patients treated for a carcinoid or mucoepidermoid tumor in
France between 1984 and 2001 was performed to determine the characteristic features and
outcome of carcinoid or mucoepidermoid tumors in children (300). There were 11 cases of
carcinoid tumor and 6 cases of mucoepidermoid tumor. Twelve and six patients were
presented with evidence of bronchial obstruction and hemopty sis, respectively. Fiber-optic
bronchoscopy confirmed the presence of a bronchial tumor in all cases, and endobronchial
biopsies were diagnostic in 11 of 12 cases. Complete surgical resection (lobectomy in 15
patients and pneumonectomy in 2 patients) was performed in all cases without preoperative
chemotherapy or RT. With a mean follow-up of 4 y ears, no death was observed. In two
patients, auscultation asy mmetry and an episode of hemopty sis revealed the recurrence of a
mucoepidermoid tumor; a child was successfully cured by removal of the tumor and
chemotherapy and RT. The authors recommend a biopsy for diagnosis and a complete
surgical removal as treatment of choice. Long-term results are excellent in all the recent but
small series in childhood, but a long clinical follow-up is recommended (301,302).
NEOPLASMS OF THE PANCREAS
Primary neoplasms of the pancreas are rare in childhood. A retrospective review of the
Memorial Sloan Kettering Cancer center was undertaken of all patients less than 21 y ears of
age with malignant pancreatic tumors since 1967. Seventeen patients were identified mainly
with pancreatoblastoma (n = 5) and solid pseudopapillary tumor (n = 7), and more rarely
with acinar cell carcinoma, nonfunctioning pancreatic endocrine neoplasm, malignant
VIPoma, and PNET (303). Another more recent study has reported that malignant
pancreatic neoplasms were identified in 58 patients. They have reported an age- and
population-adjusted incidence of 0.021 (females) and 0.015 (males) per 100,000. Asians had
the highest incidence. Tumors were classified as exocrine in about half of the patients,
endocrine in one-third, or sarcomas in the rest (8%). Exocrine tumors included mainly
pancreatoblastoma and solid-cy stic tumor (SCT), less frequently ductal adenocarcinoma, and
acinar cell carcinoma. Ductal adenocarcinoma, SCT, acinar cell carcinoma, sarcomas, and
endocrine tumors were more common in children older than 10 y ears, whereas
pancreatoblastoma was more common in y ounger children. Almost half of the patients
presented with distant metastasis (304). Fourteen patients were also recently reported with
pediatric pancreatic tumors. Tumor ty pes were solid pseudopapillary neoplasm (n = 6),
insulinoma (n = 3), pancreatoblastoma (n = 1), congenital pancreatic cy st (n = 1), Burkitt
ly mphoma of the pancreas (n = 1) and metastatic lesions of other primary tumors (n = 2)
(305). In another study, 31 patients were identified with median age of 14.7 y ears (4–18
y ears). The most common histology was solid pseudopapillary tumor (71%), followed by
neuroendocrine tumors (13%), pancreatoblastoma (13%). %). On the whole, the prognosis is
good for pancreatic tumors in childhood. In the last described study, the overall 1- and 5-y ear
survival was 96% and 78%, respectively. Patients with pseudopapillary tumors have better
overall survival compared to patients with neuroendocrine tumors or pancreatoblastomas
(303,305,306).
PANCREATOBLASTOMA
Page 375Histology
Two components are seen: an epithelial component and a mesenchy matic component. It is
characterized by well-formed acinar areas along with squamoid corpuscles and zy mogen-
like granules. Because these organoid structures are similar to the pancreatic anlage,
pancreatoblastoma is thought to originate from pancreatic multipotential primordial cells
(307). Positive staining by periodic acid–Schiff, gamma-try psin, and gamma-keratin are
common (308). Elevated levels of alpha-fetoprotein (AFP) are seen in about two-thirds of
cases (309). AFP is also used in follow-up for the early diagnosis of relapse.
Diagnosis
The clinical sy mptomatology is often discrete, such as abdominal pain and/or intestinal transit
disturbances, and the revealing sign is usually the discovery of a voluminous abdominal mass
(310). Hy pogly cemia and jaundice can also be seen (309,311). Pancreatoblastoma is most
often located in the head or body of the pancreas but can be seen in any part of the pancreas.
It forms a full mass, rather well encapsulated, round and soft in consistency, often large in
size and that can develop bey ond the limits of the pancreatic gland. The most common
sy mptoms at presentation are abdominal pain, anorexia, and vomiting (305). Imaging
findings indicate usually a well-defined heterogeneous large mass in the pancreas or
mesentery. Pancreatoblastomas are heterogeneous and often multilocular with hy perechoic
and enhancing septa (312).
Treatment
Localized, nonmetastatic tumor that can be completely resected is generally cured by
surgery alone (311,313,314). An international study reported on 20 patients by the European
cooperative study group for pediatric rare tumors confirms the rarity of the disease, the
critical role of surgical resection both as therapy and as a prognostic parameter (315).
However, about 35% of patients present with metastases (mainly in the ly mph nodes, liver,
lungs and spleen) (310), and 50% die of tumor (303). A variety of chemotherapy programs
have been used to shrink unresectable tumors, to treat metastatic disease, or as adjuvant
therapy. There have been some notable successes in rendering unresectable tumors
resectable (303,307). The European cooperative study group for pediatric rare tumors
confirmed a response rate of 73% using chemotherapy before surgery (315). The
combination of cisplatin + adriamy cin seems to be the most effective neoadjuvant
chemotherapy regimen (310).
Local irradiation is indicated in case of incomplete resection or tumor spillage during
surgery since chemotherapy has not y et provided proven results in this context (310).
RT can also be discussed in case of relapse in patients naïve from previous RT. A dosage
of 40–50 Gy seems appropriate (309,307,313).
A variety of chemotherapy programs have been used to shrink unresectable tumors, to
treat metastatic disease, or as adjuvant therapy. There have been some notable successes in
rendering unresectable tumors resectable. Cy clophosphamide, vincristine, 5-FU, adriamy cin,
mitomy cin-C, cisplatin, etoposide, ifosfamide, actinomy cin D, bleomy cin, vinblastine, and
epirubicin have been used.
COLORECTAL MALIGNANCIES
Colorectal carcinoma (CRC) accounts for 2% of malignancies in adolescents and has been
reported in children as y oung as 9 months of age. In Japan, for example, one to three
pediatric colon carcinomas are identified annually (316). Based on the published reports,
which are small clinical trials or case reports, most CRC in children is sporadic (316,317).
Predisposing conditions include hereditary nonpoly posis colorectal cancer and familial
adenomatous poly posis (318). They also may occur as second malignant neoplasms after
treatment of childhood leukemia, rhabdomy osarcoma, Wilms tumor, or Hodgkin disease
(319). A sy stematic review was done recently on colorectal carcinoma diagnosed in the first
10 y ears of life (320). The mean age was 8.6 y ears and tumors were located in the rectum
and sigmoid in about 45% of the cases. More than 85% were adenocarcinomas.
Carcinomas of the colon and rectum in childhood present with pain, vomiting, anemia, a
palpable mass, hematochezia, diarrhea, or constipation (316,317). Because of the lack of
specificity of the sy mptoms and the rarity of the disease, the possibility of a child having
colorectal carcinoma is rarely considered, and the interval between clinical complaints and
diagnosis often is long (317,321). The median of latency of sy mptoms was 4–48 months in a
recent publication (71). As a consequence, involvement of regional ly mph nodes, distant
metastases, and inoperability are common in children (317).
Page 376The survival was poor in a recent review from Da Costa Vieira et al., about
15% at 5 y ears due to advanced stages at diagnosis (71,320). This is attributed to a delay in
diagnosis resulting in more advanced disease.
As a result of its rarity in children and the lack of prospective pediatric studies,
recommendations for therapy are primarily extrapolated from adult clinical trials. Complete
surgical resection with aggressive ly mph node dissection is essential for cure, and
neoadjuvant chemotherapy may be used in an effort to render unresectable lesions
resectable. In a study on 76 patients under 25 y ears with a CRC, overall survival significantly
increased in patients undergoing curative surgery. Other significant parameters on survival
were stage of disease, response to palliative chemotherapy in metastatic patients, and
postoperative adjuvant chemotherapy (72). Active agents in adults with CRC include FU,
folinic acid (leucovorin), oxaliplatin, and irinotecan. Furthermore, newer targeted therapeutic
agents, such as bevacizumab and cetuximab, have added additional efficacy to the standard
chemotherapy backbone but no trials have been done in pediatric population till now.
BREAST CANCER
Malignant lesions of the breast in children are rare and represent 0.08/100,000 cases. The
most common form of breast cancer occurring in y oung girls (or boy s rarely ) is juvenile
secretory carcinoma. Approximately 100 cases have been reported (73). The malignant cells
are characterized by abundant secretion of mucin and mucopoly saccharide-containing
materials (322,323). A unique pathologic feature is the presence of a thick-walled capsule that
is thought to be caused by a desmoplastic reaction around the tumor. This may be responsible
for its cy stic appearance on ultrasound (76). Surgery is the treatment of choice but there is
little consensus, however, about the extent of surgery. A sufficient number of case reports of
local recurrence suggest that local excision alone may not constitute adequate therapy, and
mastectomy has been advocated as standard treatment (324,325). Richard et al. reported a
literature review of 33 pediatric cases with a long follow-up. About 33% of the patients
treated by less than simple mastectomy demonstrated local recurrent disease (325). Sentinel
ly mph node biopsy seems to offer an interesting approach to explore the axillary ly mphatic
basin with a lower complication rate than formal dissection and is recommended by some
authors (326). For others, mastectomy with sentinel ly mph node biopsy or axillary ly mph
node dissection is recommended in any male case due to more relapses (316). The prognosis
is excellent in this benign tumor, and no RT or chemotherapy is generally necessary. There is
minimal experience with lumpectomy and RT.
Primary breast carcinoma is exceedingly rare in the pediatric age group. Less than 1%
occurs before the age of 30 y ears and less than 0.1/100,000 occurs before the age of 20
y ears. Infiltrating ductal, lobular, medullary, and inflammatory carcinomas have been
reported in y oung girls. Young women tend to have a more aggressive disease, hormonal
receptor negative and grade 3 lesions. Patients undergoing mastectomy have the same rate
for local recurrence as older women compared to a breast conservative surgery (317). With
almost no data available in children, we would be cautious about vary ing from the principles
of clinical management set by adult oncology (327). Seventy -five cases of teenage primary
breast carcinoma have been reviewed by Gutierrez et al. between 1973 and 2004: 55% were
carcinomas and 45% were sarcomas. In the carcinoma group, regionally advanced disease
was present in 11 patients (26.8%), whereas only 3 patients (7.3%) presented with metastatic
disease. All patients with sarcomatous tumors presented with localized disease. Ductal
carcinoma end phy llode sarcomas were the most frequent histology. Adjuvant RT was
administered in only 9.8% of carcinomas and 8.8% of sarcomas. About 85.4% of carcinoma
patients and 97.1% of sarcoma patients underwent surgical resection for their primary
disease. Subgroup analy sis revealed 5- and 10-y ear survival rates of 89.6% for patients with
sarcomatous tumors and 63.1% and 54.3% for carcinomas (318).
There have been case reports of primary non-Hodgkin ly mphoma, rhabdomy osarcoma,
ACC, radiation-induced spindle cell sarcoma, and cy stosarcoma phy llodes of the breast in
children (319,322,323,328). Reported breast metastases in children include hepatocarcinoma,
non-Hodgkin ly mphoma, rhabdomy osarcoma, Hodgkin disease, neuroblastoma, and
adenocarcinoma (181).
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CH A P TER 17
Langerhans Cell Histiocytosis
Edward C. Halperin
PAGE 384HISTORICAL BACKGROUND

Paul Wilhelm Heinrich Langerhans (Berlin,
Germany, July 25, 1847–Funchal, Madeira, July
20, 1888) (Fig. 17.1 ) was the son of a well-
known Berlin phy sician and the brother of two
others. Paul studied medicine at the Universities
of Jena and Berlin and was a student of Heckel
and Virchow. While a student, Langerhans used
Julius Cohnheim’s gold chloride staining to
identify a novel nonpigmentary epidermal
dendritic cell. When he was 21 y ears old, he
described this finding in an 1868 paper titled
“Uber die Nerven der menschlichen Haut” (on
the nerves of the human skin) (1). Langerhans
initially regarded these cells as intraepidermal
Figure 17.1 Paul Langerhans (1847–
receptors for extracutaneous signals of the
1888).
nervous sy stem. He later changed his mind and
in 1882 wrote that “my cells are in no way
essential for nerve endings” (2). Langerhans’ doctoral thesis was titled “Contributions to the
Microscopic Anatomy of the Pancreas.” In 1869, he identified small, poly gonal cells without
granules. These cells formed “zellhaufen,” literally cell heaps in the human pancreas, and
were called Langerhans islets by the French histologist G.E. Languesse. The insulin-secreting
function of these cells was established later. Langerhans graduated in 1869. After his thesis
defense, Langerhans demonstrated that cinnabar was taken up by white blood cells but not red
blood cells. This opened the door for Aschoff ’s concept of the reticuloendothelial sy stem.
In 1874, Langerhans became Professor Extraordinarius in Freiburg. Unfortunately, 1
week later, he was diagnosed with renal tuberculosis (TB). He was released from his duties at
the university and left for Madeira. He continued to do research on the flora and fauna of the
Canary Islands and Madeira including papers on the heart of amphibious animals and the
lamprey ’s ey e. His contributions were of such high quality that in 1909, a poly chaete worm
was named after him. He published two papers on TB, undoubtedly influenced by his own
condition and by the fact that his mother had died of TB and his half-brother had also
contracted the disease (3).
Langerhans practiced medicine whenever his health allowed. The majority of his
patients were German and British citizens who lived on the island for health reasons, usually
TB. Langerhans died of progressive renal degeneration caused by TB in 1888 (3,4,5).
In 1893, Dr. Alfred Hand Jr, a 25-y ear-old resident at the Children’s Hospital of
Philadelphia, reported the case of a 3-y ear-old boy with “a history of great thirst and
poly uria undersized and puny.”
At autopsy, a yellow spot about the size of a five-cent piece was noticed near
the right parietal eminence. When the skull-cap was removed, this spot was
seen on the inner side as well, and the entire thickness of the bone there was
soft and movable…. The lymphatic glands all through the body were greatly
enlarged…. The liver and spleen were enlarged and firm, and the former had
minute gray nodules in its substance…. Microscopial sections showed nodular
masses of small, round-celled infiltration in the liver, spleen, kidneys (6).
Hand suspected that he was dealing with a case of TB. In 1921, he noted the similarity of
his original case to ones subsequently reported by Schuller, Christian, and Kay. Eventually,
the term Hand–Schuller–Christian disease or triad was used to describe a disease occurring in
children more than 2 y ears old characterized by exophthalmos, lesions in the bones of the
skull, and diabetes insipidus (DI). The full triad was rarely seen, and the prognosis was good
(6,7).
Page 385In 1924 and 1933, Letterer and Siwe described what they perceived to be an
entity distinct from Hand–Schuller– Christian disease. Letterer–Siwe disease generally
occurred in children less than 2 y ears old. The diagnostic criteria included splenomegaly,
hepatomegaly, ly mphadenopathy, anemia, and a hemorrhagic diathesis. The prognosis was
poor (6,7).
In 1940, Otani and Ehrlich (8) described a granuloma of bone simulating a primary
neoplasm. Eventually, the solitary eosinophilic granuloma was described as occurring in
children more than 2 y ears old, characterized by a solitary, usually bony site of involvement,
and an excellent prognosis (7,9).
In 1953, Lichtenstein argued that eosinophilic granuloma of bone, Letterer–Siwe disease,
and Hand–Schuller–Christian disease were related manifestations of a single nosologic entity
(9). He used the name histiocytosis X to refer to a spectrum of diseases of the mononuclear
phagocy te (histiocy te). The X referred to the unknown etiology and pathogenesis of the
disease or diseases. The diseases formerly grouped under the heading “Histiocy tosis X” are
now called Langerhans cell histiocytosis (LCH).
Figure:
Paul Langerhans (1847–1888).
DEFINITION, PATHOGENESIS, AND PATHOLOGY
LCH is an accumulation or proliferation of a clonal population of cells bearing the phenotype of

a Langerhans cell that has been arrested in early stage of activation and is functionally
deficient. Langerhans cells along with lymphocytes, eosinophils, macrophages, normal
histiocytes, and, occasionally, multinucleated giant cells, form infiltrates typical for the disease,
which may be found to a varying extent in multiple or single organ(s). LCH can affect the skin,
bone, ly mph nodes, ear, gums, lungs, gastrointestinal tract including the liver, and the central
nervous sy stem (CNS) by causing DI.
The Langerhans cells are a family of related cells characterized by their dendritic
morphology and multiple thin membrane projections. Dendritic cells constitute 0.2% of white
blood cells in the blood and are present in even smaller proportions in tissues such as the skin.
Because of their rarity, their true function eluded scientists for nearly a century after
Langerhans first identified them in 1868. In 1973, Ralph M. Steinman of Rockefeller
University rediscovered the cells in mouse spleens and recognized that they are part of the
immune sy stem (10). The cells were unusually potent in stimulating immunity in
experimental animals. He renamed the cells dendritic because of their spiky arms, or
dendrites. The subset of dendritic cells that occur in the epidermis of the skin are commonly
still called Langerhans cells. In normal anatomy, Langerhans cells are found in the epidermis
and skin appendages, in squamous mucosal epithelium such as the buccal mucosa, vagina,
cervix, and esophagus, and in the spleen and ly mphatic sy stem. Dendritic cells attack
invading bacteria, digest them, and display their antigens on the surface. Antigen-bearing
dendritic cells travel to ly mph nodes or the spleen, where they interact with other cells of the
immune sy stem, including B cells, which make antibodies, and killer T cells, which attract
microbes and ingest them.
LCH cells cause tissue damage by infiltration and excessive production of cy tokines and
prostaglandins. Cells produce interleukin-1 (IL-1) and prostaglandin E2, which can cause bone
resorption through osteoclast activation. IL-1 may cause release of IL-2 and gamma
interferon from helper-inducer T ly mphocy tes, leading to the stimulation of other
ly mphocy tes and histiocy tes. Tissue injury results from the local immune response as the
collection of immune cells impairs normal tissue structure and function (11). On microscopic
evaluation, the lesions of LCH are found to be consistent with Hand’s original description: a
pleomorphic infiltrate of ly mphocy tes,
eosinophils, poly morphonuclear leukocy tes, and
Langerhans cells (Fig. 17.2 ). In the past, a
more definitive diagnosis was considered to be
made when electron microscopy shows Birbeck
granules. Birbeck granules are membranous
cy toplasmic structures, of unknown function,
200–400 mm wide and shaped like tennis rackets
(12,13,14) (Fig. 17.3 ). Now CD207
(Langerin) staining is used to prove the presence
of Birbeck granules. Light microscopy will show
that the Langerhans cells are ATPase positive; Figure 17.2 Langerhans cells
stain for S-100 protein, CD11, and CD14, anti- characterized by plump nuclei frequently
CD1 marker (also called the T6 surface marker), having longitudinal folds surrounded by
CD207, and alpha-D-mannosidase; and bind ample cytoplasm. Numerous eosinophils
peanut lectin (12,13,14,15,16,17) (Table are scattered throughout the tumor.
17.1 ).
Page 386Lesional cells of LCH may
represent Langerhans cells arrested in early
stage of activation. Immunohistochemical
expression of fascin, a protein that is a marker
for dendritic cells, is observed in many cases of
LCH. This immunoreactivity for fascin supports
LCH’s pathogenesis from cells of the dendritic
sy stem (14).
Until recently, the disease generally was not
thought to be monoclonal in origin. It was argued
Figure 17.3 Langerhans cells stain
that the individual cells do not show aty pia and
positive with CD1a antibody.
that the disease lacked the usual histologic
criteria for malignancy. Therefore, LCH was
generally considered to fall within the realm of reactive immunologic disorders or perhaps to
be of infectious origin. However, viral and immune causation theories generally have lacked
supporting evidence. In 1994, Willman et al. (18) provided evidence that LCH is a clonal
proliferative disorder. These investigators studied 10 lesions from patients with LCH and found
that they all contained clonal populations of cells. The proportion of clonal cells corresponded
to the proportion of lesional Langerhans-like cells, whether from solitary lesions or extensive
multisy stem disease (19). Yu et al. (20) reported similar findings by flow-sorting CD1a-
positive cells from three patients. About 50% of LCH cases exhibit somatic-activating
mutations of the proto-oncogene BRAF. For
these patients who test negative for BRAF, about
50% have mutations in MAP2K1. These findings
have implications for the pathophy siology and
therapy of LCH (12). There is also
circumstantial evidence of a genetic mutation or
mutations leading to LCH. On average, patients
with multiorgan LCH are y ounger than those
with single-bone disease. In the rare instances of
familial LCH, all the affected members have
multiorgan disease. These two observations,
reminiscent of the pattern of heritable versus
nonheritable retinoblastoma, suggested to Egeler Table 17.1 Immunophenotype of
the possibility that LCH’s behavior was Langerhans Cell Histiocytosis
explicable by Knudson’s two-hit hy pothesis and a
tumor suppressor gene (21). (The two-hit hy pothesis is discussed in detail in Chapter 5 .)
The distinction between calling LCH malignant and a reactive immunologic disorder is
important. Classification has significant consequences for how the clinician thinks about and
manages the disease. If one believes that LCH is primarily a malignancy, then radiation
therapy (RT), cy totoxic chemotherapy, and even bone marrow ablation and transplantation
seem to be acceptable primary therapies. However, if one thinks about LCH primarily as a
reactive disorder, then at least initially one would be likely to use more conservative and less
toxic therapies, including expectant observation. For the clinician, the truth lies between these
two classifications. Most cases of LCH are not life threatening and can be managed with
minimal therapy. There are a few instances of the disease running a fulminant and fatal
course, a situation that calls for an aggressive response.
Figure:
Langerhans cells characterized by plump nuclei frequently having longitudinal folds
surrounded by ample cytoplasm. Numerous eosinophils are scattered throughout the tumor.
Figure:
Langerhans cells stain positive with CD1a antibody.
Figure: Immunophenotype of Langerhans
Cell Histiocytosis
CLINICAL PRESENTATION, DIAGNOSTIC EVALUATION, AND
STAGING
The annual incidence of LCH is difficult to know. LCH goes by various names and as one of
many histiocy tic disorders is often lumped with them in incidence data. Our best estimate is
approximately 0.1–2.0 cases per 100,000 children per y ear. There is a slight male
predominance. Most cases are diagnosed between the ages of birth and 15 y ears
(12,14,16,22,23,24,25,26).
The form of clinical presentation is related to the child’s age
(22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37) (Tables 17.2 and 17.3 ). In children
less than 2 y ears old, there may be a widespread seborrheic rash (Fig. 17.4 ). The rash is
often most pronounced on the scalp and in the groin. Petechial hemorrhages in the involved
skin are characteristic. Erosive intertrigo in the groin, axilla, and perianal region is a common
feature. Ulceration and secondary skin infection may occur. Involvement of the mastoid and
middle ear may present as a chronic draining otitis (41). The infant may be irritable, with a
diminished appetite and failure to thrive. Palpable ly mphadenopathy may be seen secondary
to LCH infiltration. Liver involvement is common in disseminated LCH. Hepatomegaly,
elevation of liver enzy mes, increased conjugated bilirubin, ascites, edema, and failure to
thrive may be attributable to liver disease or involvement of the gastrointestinal tract.
Diarrhea may be the result of abnormal bile acid metabolism or malabsorption (17).
Splenomegaly may be accompanied by anemia, leukopenia, or thrombocy topenia (42).
Figure 17.4 Truncal rash and hepatosplenomegaly in an infant
with Langerhans cell histiocytosis. (From Berry CL, ed. Paediatric
Pathology. Berlin, Germany : Springer-Verlag; 1991, with
permission.)
Table 17.2 An Overview of the Clinical Presentation of Langerhans Cell Histiocytosis in

Several Recent Clinical Series
In children more than 2 y ears old, the most common presenting sy mptoms are related to
bone involvement (Table 17.3 ). There is localized pain, with or without an associated soft
tissue mass. Involvement of the orbital bones may cause exophthalmos. LCH may produce
premature eruption of the teeth or tooth loss because of gum and mandibular disease (42,43).
Back pain and loss of vertebral height may be seen. Spinal cord compression is rare.
DI is the most common complication of CNS involvement. The incidence varies, in
different reports, from 11% to 50%. Magnetic resonance imaging (MRI) may show lesions in
the posterior pituitary or the pituitary stalk (44,45). The mechanism of injury is thought to be
either infiltration of the meninges adjacent to the posterior hy pothalamic–pituitary axis or
direct involvement of the brain. DI often is associated with skull lesions, which may be seen
before the DI (27,39,41,45,46,47,48,49). Lung and oral mucous membrane involvement with
LCH often occurs in patients in whom DI develops (46). In a Dutch–German–Austrian study,
3 of the 93 patients (3%) with primary localized
disease and 16 of the 106 patients (15%) with
dissemination of LCH at diagnosis had DI (46).
In a series of patients from London’s Hospital for
Sick Children, DI was more common among
children with multisy stem disease (12 of 32)
than among those with disease apparently
confined to bone (3 of 20). Fourteen of the 15
children with DI had bone disease involving the
skull. The cumulative risk of developing DI
during the first 4 y ears after presentation with
LCH was 42% (47). In a series from San
Francisco, 25% of patients developed DI (29).
Page 387Pulmonary LCH has been
reported in infants and older adults. However, it
affects primarily adults in their twenties and
thirties. Chest CT demonstrates multiple nodules Table 17.3 Sites of Bone Involvement
with a predominance in the upper lobes. If in Langerhans Cell Histiocytosis: A
bronchioalveolar lavage y ields more than 5% Summary from the Published Literature
LCH cells, then the procedure is diagnostic. The
cells are CD1a positive. In adults, the natural history of pulmonary LCH is variable. It is often
associated with cigarette smoking, and patients who continue to smoke progress to end-stage
fibrotic disease or develop extrapulmonary complications. Smoking cessation is the most
effective therapy (50).
Page 388Skull lesions often are the first sign of LCH. Often very slow growing, they
may be single or multiple and can occur without other bony involvement. Although they have
a predilection for the temple area, they can be found any where on the skull. On plain
radiographs they will appear as punched-out lesions. With time they can develop a sclerotic
border (51). Calvarial lesions can have epidural extension. They may extend beneath the
dura into the brain parenchy ma.
A diagnostic radiograph skeletal survey should be performed to assess the extent of bony
involvement (Fig. 17.5 ). Bone scans are also often used (15,52). PET scanning may
identify active lesions and differentiate them
from healed lesions after treatment (15,53,54).
In skeletal radiographs, LCH produces a focal
area of rarefaction. The lucent area begins with
the medullary cavity and extends to involve the
inner table of the cortical bone. MRI may show
that the area of bone abnormality is larger than
suspected from other studies.
In disseminated LCH, cerebral involvement
may occur (55,56). There can be meningeal
involvement with formation of large plaques of
subdural tumor and/or intraparenchy mal lesions. Figure 17.5 Langerhans cell
The most common sites for intraparenchy mal histiocytosis (LCH) involving the left
disease are the hy pothalamus and cerebellum. second rib in a 5-year-old girl. The lesion
Less common locations are the frontal and was painful. The involved portion of the
temporal lobes (57,58). Occasionally, LCH can rib was subtotally resected and was
first present to medical attention as an isolated, diagnostic of LCH. This localized, unifocal
unifocal lesion of the CNS. The hy pothalamus is bone lesion was adequately treated with
the most common site for this rare situation. In surgery alone. There was no recurrence
such cases, the diagnosis is made after surgical of LCH.
exploration and biopsy (55,56,57,58,59).
LCH has a variable prognosis, and a sy stem of grouping patients by predicted outcome is
a valuable guide for the clinician (12,15,60,61,62). Patients with localized disease (skin, bone,
or ly mph node) have a good prognosis and often require minimal or no treatment. In contrast,
multiple organ involvement, which is particularly frequent in children <2 y ears of age, has
the risk of a poor prognosis (Table 17.4 ). Lahey and coworkers (33,34,73) found a striking
difference in survival between patients with and without organ dy sfunction. Of the 50 patients
without organ dy sfunction, 2 (4%) died. In 33 patients with dy sfunction of one or more of the
three organ sy stems, 22 (67%) died.
Table 17.4 Treatment of Localized Langerhans Cell Histiocytosis of Bone with
Intralesional Corticosteroid Injection
The stage distribution of LCH at presentation is almost certainly influenced by referral

patterns. A children’s hospital is likely to see a higher proportion of advanced disease than a
community hospital. In the Children’s Hospital of Philadelphia series, 33 of the 64 patients
(52%) had localized disease at presentation, 22 (34%) had multifocal disease without organ
dy sfunction, and 9 (14%) had multifocal disease with evidence of organ dy sfunction (24). In
a series by McLelland et al. (25) of 58 children, 14 (24%) had single-sy stem disease, 22
(38%) had multisy stem disease without organ dy sfunction, and 22 (38%) had multisy stem
disease with organ dy sfunction (22).
Figure: An Overview of the Clinical
Presentation of Langerhans Cell
Histiocytosis in Several Recent Clinical
Series
Figure: Sites of Bone Involvement in
Langerhans Cell Histiocytosis: A Summary
from the Published Literature
Figure:
Truncal rash and hepatosplenomegaly in an infant with Langerhans cell histiocytosis.
(From Berry CL, ed. Paediatric Pathology. Berlin, Germany : Springer-Verlag; 1991, with
permission.)
Figure:
Langerhans cell histiocytosis (LCH) involving the left second rib in a 5-year-old girl. The lesion
was painful. The involved portion of the rib was subtotally resected and was diagnostic of
LCH. This localized, unifocal bone lesion was adequately treated with surgery alone. There
was no recurrence of LCH.
Figure: Treatment of Localized Langerhans
Cell Histiocytosis of Bone with Intralesional
Corticosteroid Injection
In many cases LCH can take an indolent course or spontaneously remit. In some cases, it
may be possible to use minimal or no therapy. One should carefully balance the risks of
treatment against the apparent course of the disease. The potentially toxic effects of therapy
should not be engendered unless absolutely necessary (12,15,61,62,74,75,76,77,78,79,80,81).
In Table 17.5 , the authors outline a management strategy for LCH. A detailed discussion
of the particulars of the therapy follows.
Table 17.5 A Treatment Algorithm for Langerhans Cell Histiocytosis
Page 389Surgery
Regression of an isolated LCH bone lesion with no further treatment after the initial fine
needle aspiration biopsy has been reported. It is possible that a small amount of mechanical
perturbation of a LCH lesion is sufficient to initiate is regression without further treatment.
Pediatric Oncology Group (POG) Study 8047 evaluated the response rate of LCH bone
lesions to incisional or excisional biopsy. The study was open to patients less than 21 y ears old
with no more than two bone lesions and no sy stemic involvement by LCH. Open biopsy was
recommended, with curettage when possible. Needle biopsy was performed for vertebral
lesions, and excision was performed for expendable bone. Surgery proved highly effective:
20 of the 23 lesions (87%) were controlled without local LCH relapse (75).
Solitary bone lesions may be treated surgically. There is an equal probability of local
control with biopsy, curettage, or excision (75,81). In the past wide excision was considered in
an expendable bone such as the clavicle, ribs, or tip of the scapula. Now, more often, more
conservative surgery is done. In nonexpendable bone locations, a small, mill-like biopsy
instrument allows a tissue diagnosis and access to the medullary cavity for a curettage.
Relative contraindications to curettage are situations in which the procedure would result in
loss of function, severe orthopedic deformity, or poor cosmetic result. Gingival curettage
may be useful for gum disease.
Bone Sites Not Appropriate for Surgery

A curettage should not be performed at the axis, atlas, or femoral neck because of the risk of
bone instability. Indeed, in cases of isolated vertebra plana without a soft tissue component or
isolated involvement of the odontoid peg, close observation is thought preferable to biopsy
since spontaneous healing may occur and the risk of surgery avoided (15).
Direct Injection of Steroids

Methy lprednisolone (40–80 mg) or depomedrone may be injected into some bone lesions
under fluoroscopic guidance (67). Because the transient expansion of the medullary cavity
causes extreme pain, the procedure should be performed under general anesthesia (Table
17.6 ). One cannot be certain whether responses are obtained from the steroids or from the
disruption of the microenvironment caused by the needle (69,70,71,72,82,116,119).
Table 17.6 Results of External Beam Radiation Therapy for Langerhans Cell Histiocytosis
of Bone
Radiation Therapy
Through the span of time encompassed by the six editions of this book, the use of radiation
therapy (RT) to manage localized bone or soft tissue LCH has become very rare. This trend is
attributable to a better understanding of the prognostic factors predicting the behavior of LCH,
an appreciation of the frequency of disease remission after minimally toxic therapy, and
concern about the long-term ill effects of radiation, albeit at low dosages (17). The complete
response rate of solitary LCH in bone to curettage or excision is 70–90% (40,75,76,77,80,81).
There is no evidence that immediate postoperative irradiation improves these results.
Asy mptomatic bone lesions with sclerotic margins often resolve spontaneously and RT
usually is not necessary (75). If the clinician obtains follow-up radiographs of the child with
bony LCH, evidence of healing is common. Mey er et al. (44) described radiographic lesion
improvement in 14 out of 15 patients with multifocal LCH (93%) and 7 out of 8 patients with
unifocal LCH (88%). A change from a nontrabecular to a trabecular pattern, evolution of
sclerosis in a nonsclerotic lesion, and loss of distinct margins indicate healing (77). Minimum
time from diagnosis to evidence of mild healing was 3 months, although complete resolution
often takes longer (75).
Page 390Postoperative irradiation may be considered for patients who have no clinical
or radiographic signs of local healing. In addition, RT may be considered for local relapse
after surgery when the relapsed bone is the sole site of recurrent disease, where curettage is
not appropriate because of the risk of fracture (i.e., a ly tic lesion of the femoral neck;
mandibular involvement producing a loose, painful tooth, and reluctance to eat) or poor
cosmesis (i.e., the orbital bones) (40,43,62,73,120), when the potential compromise of critical
structures from expansile bone lesions (spinal cord compression, pressure on the globe or
optic nerve) demands a reliable and rapid response, or for pain relief. The success rate of RT
for bony LCH is extremely high (Table 17.5 ).
Vertebral lesions should be considered a special situation. Partial or complete collapse
(vertebra plana) of a vertebral body may be asy mptomatic (Fig. 17.6 ). These
asy mptomatic lesions generally do not warrant therapy because partial bone healing usually
occurs irrespective of treatment. However, if a vertebral lesion is painful, it may be treated
with chemotherapy or irradiated (120).
Figure 17.6 (A) Magnetic resonance imaging scan and (B) bone scan showing complete
vertebral collapse (vertebra plana) secondary to Langerhans cell histiocytosis (LCH) in 1992.
No therapy was given beyond a needle biopsy to establish the diagnosis. Pain resolved over a
month. Typically, healing includes fusion to adjacent vertebrae. The child remains without
evidence of recurrent LCH.
In patients with multifocal LCH or with organ dy sfunction, local RT may have a place.
Lesions that are painful despite chemotherapy should be considered for local RT (121).
Disfiguring bone or soft tissue lesions or bones at substantial immediate risk for fracture may
also be appropriate for local RT.
Recalcitrant skin lesions may be treated with electron beam or orthovoltage photon
therapy, but this should almost never be necessary in view of the other available agents
(49,122,123).
The value of RT for LCH-associated DI is very controversial. Greenberger et al. (123)
reported 21 patients irradiated for DI and noted a complete reversal of sy mptoms in four
patients with discontinuation of pitressin for 2, 5, 5, and 25 y ears. A complete response to RT
was observed in three of four patients treated within 1 week of the onset of sy mptoms. Only 1
of the 15 patients responded when the duration of sy mptoms before RT exceeded 2 weeks.
However, Smith et al. (124) reported no response in seven patients irradiated for DI.
Broadbent and Chu (125) reported six patients with DI who failed to respond to irradiation.
Selch and Parker (30) irradiated two patients with DI 3 months after the onset of sy mptoms.
Neither of these patients responded. There were no responses among seven patients treated
with chemotherapy with or without irradiation by Willis et al. (28). El-Say ed and Brewin
(108) reported successful radiotherapy of two patients with DI. Grois et al. (126) found that
none of the five patients treated with 10 Gy of radiotherapy to the pituitary within 1 month of
the occurrence of DI was able to decrease the desmopressin dosage. Some have discounted
the value of RT for DI without contributing additional supporting data to the literature
(21,39,124,127).
Page 392The largest series of DI in LCH has been reported by Minehan et al. (48) and
Kilpatrick et al. (31) from the May o Clinic. In 45 evaluable patients, the principal findings
were as follows: 10 of the 28 (36%) irradiated patients had a complete or partial
improvement in their DI, as opposed to none of the 17 nonirradiated patients; 6 patients were
complete responders, 5 of whom were irradiated within 14 day s of the diagnosis of DI; 77%
of all patients with LCH and DI had a non-CNS head and neck site involved with LCH;
computed tomography (CT) or MRI improvement in a pituitary –hy pothalamic mass did not
correlate well with improvement in DI; and in 12 of the 28 patients (43%) irradiated for DI,
growth hormone (GH) deficiency or parahy popituitarism developed. Minehan et al. (48) did
a literature review, to which we can add published patients they did not include, to generate an
overall response rate of less than 25% of DI to radiation (30,31,39,44,45,46,47,48,49,125). We
believe that RT is worth considering in DI if sy mptoms are of recent onset (approximately 1
week). Others recommend RT even for long-standing DI in the hope of preventing local
disease progression and additional neuroendocrine dy sfunction.
Focal LCH involving the brain can be treated successfully with radiotherapy (58). On
rare occasions, LCH may diffusely involve the parenchy ma of the brain (57). The true
incidence of this event is not known. Brain involvement of this sort occurs in the most
aggressive form of the disease. On MRI, cerebral LCH may demonstrate parenchy mal
masses that intensively enhance after gadolinium is administered. Other patients may show
diffuse infiltration of brain structures without tumor formation. A retrospective review by
Hund et al. (59) identified 36 histologically evaluated cases of cerebral LCH with an
extrahy pothalamic localization. Sixteen of the patients had cerebral involvement during the
course of the previously diagnosed LCH, whereas 20 patients had cerebral LCH without a
history or sy mptoms of sy stemic disease before the neurologic presentation. Solitary brain
lesions were treated by surgery in 13 patients. Six remained free of disease for up to 2 y ears
of follow-up. In another six, follow-up was not reported. One patient died 4 weeks after
resection of a posterior fossa mass. In an additional six patients, surgery was followed by RT
(10–41 Gy ) because of recurrence of a lesion or incomplete resection. In five of the six
patients, the lesions disappeared and did not recur for up to 2 y ears of follow-up. In three
patients with multiple lesions, the disease was controlled by radiation or chemotherapy for up
to 3 y ears. In others, regression, relapse, or new lesions occurred despite various treatments.
Eight of the 36 patients died; 4 had multiple intracranial lesions, and the remaining 4 had
localized lesions.
Page 393Chemotherapy
In the first three editions of this book, we stated that in multifocal LCH the indications for
sy stemic therapy are controversial. Because there was no agreement on the important
prognostic factors in LCH, the selection of patients needing chemotherapy was difficult
(128,129,130,131). The lack of a uniformly applied staging sy stem made comparison of
specific chemotherapy programs difficult. Many clinicians were reluctant to use
chemotherapy in multisy stem disease because of the study of McLelland et al. (25). Forty -
four children with multisy stem disease, including 22 with organ dy sfunction, were treated
conservatively. Five had no treatment, 1 received topical nitrogen mustard only, 2 received
radiotherapy alone, and 36 were treated with prednisone. Of these 36 children, 21 were given
cy totoxic drugs later when disease progressed despite prednisone. The 2-y ear mortality rate
(36% with organ dy sfunction, 0% without organ dy sfunction) was no different from that of
historical studies using aggressive upfront sy stemic cy totoxic chemotherapy. The rate of
development of DI in the group of McLelland et al. was 36%, which is higher than that in
some but not all other series of the era (25,124,125).
From the 1970s to the 1990s, the reported complete and partial response rates of
advanced LCH to prednisone and a wide variety of single-agent cy totoxic chemotherapeutic
agents (chlorambucil, cy clophosphamide, etoposide, vinblastine, and vincristine) were
between 50% and 100% (25,27,128,129,130,131,132,133). (These data are reviewed in Table
17.5 in the third edition of this book.) Relapse after initial therapy was common. By the
early 1990s, if sy stemic therapy was elected for LCH, then the consensus view was to begin
with high-dose steroids, usually prednisone. If that failed, then most clinicians opted for either
etoposide or vinblastine as a single agent.
There are now several large cooperative group studies that offer guidance in selecting
appropriate patients for chemotherapy.
AIEOP-CNR-HX*83
This prospective multicenter trial included 12 different Italian institutions (61,134). The
objectives were to determine the outcome of patients stratified according to the presence or
absence of organ dy sfunction, to test the efficacy of different single-agent chemotherapy
approaches in patients with a good prognosis, and to determine the incidence of disease-
related disabilities before and after treatment. In children with a single lesion, treatment was
variable and consisted of either incisional biopsy, curettage, total excision, RT, or
chemotherapy. This good-prognosis group was treated with immunotherapy with crude calf
thy mic extract and then sequential single-agent chemotherapy. First-line treatment was
vinblastine. Poor responders then received doxorubicin, and patients in whom doxorubicin
failed were placed on etoposide. The poor-prognosis group, consisting of patients with organ
dy sfunction, was treated with vincristine, cy clophosphamide, and prednisone. Of the 90
eligible patients, 84 were evaluable. The 16 patients with mono-ostotic LCH or a
paravertebral intradural mass survived. All had initial complete responses, and 15 were
recurrence free 3–6 months after diagnosis. Fifty -four patients with sy stemic disease but
without organ dy sfunction received good-prognosis chemotherapy. Thirty -four achieved a
complete response with vinblastine. The multiagent program for the poor prognosis group was
given to 11 patients. Only 2 achieved complete response and were recurrence free at 36 and
66 months, respectively. The overall survival for the 84 evaluable children was 93% at 48
months. Survival at 48 months was 100% for the 60 children more than 2 y ears old and 79%
for the 24 children less than 2 y ears old. All 73 children without organ dy sfunction were long-
term survivors, and the 11 patients with organ dy sfunction had a 46% survival rate at 12
months. Of the total 90 eligible patients, 18 developed DI. One patient developed acute
nonly mphocy tic leukemia (ANLL) 2 y ears after diagnosis and treatment with vinblastine and
etoposide.
DAL-HX83
This trial accrued 106 patients from institutions in Austria, Germany, and the Netherlands
from 1983 to 1989 (29,46,61,74,135). Disseminated disease was defined as the presence of
multiple LCH lesions of any ty pe or combination, with the exception of multiple skin lesions.
Group A patients were those with multifocal bone disease: lesions in multiple bones or more
than two lesions in one bone. Group B patients either had soft tissue involvement with or
without bone lesions and without signs of organ dy sfunction or patients with a single-bone
lesion and a biopsy -proven contiguous soft tissue mass, regional ly mph node involvement, or
endocrinologic disabilities. Group C patients had dy sfunction of liver, lung, or the
hematopoietic sy stem.
All patients with disseminated disease received chemotherapy immediately after
diagnosis with prednisone, vinblastine, and etoposide. Thereafter, all patients received
continuous oral 6-mercaptopurine (6 MP) for 46 weeks. Patients in group A received
prednisone and vinblastine. Patients in group B received continuation treatment with
prednisone, vinblastine, and etoposide. Patients in group C received continuation therapy with
those three agents plus methotrexate.
Complete resolution was achieved in 86% of all patients at 4 months. In group A, 25 of
the 28 patients (89%) achieved initial complete resolution of LCH. Recurrence occurred in
only three children (12%). In group B, 52 of the 57 patients (91%) achieved resolution of
disease. Twelve patients (23%) had recurrent disease. In group C, 14 of the 21 patients (67%)
achieved resolution of disease. Of these 14 patients, 6 (42%) developed a recurrence.
Disease-free survival was 88% in group A, 73% in group B, and 64% in group C (p < 0.05).
DI developed in 15% of patients.
Page 394DAL-HX90
DAL-HX90, a follow-up to DAL-HX83, made moderate changes including less aggressive
induction therapy utilizing fewer initial doses of etoposide for group C patients. Methotrexate
was eliminated from group C continuation. These changes produced no significant difference
in outcome.
LCH 1
In the Histiocy te Society ’s first LCH randomized trial, 447 patients were registered (61,133).
All patients with disseminated multisy stem LCH received high-dose methy lprednisolone. One
hundred and forty -three patients were then randomized to receive either etoposide (69
patients) or vinblastine (74 patients). Vinblastine and etoposide were equivalent in response at
week 6 of therapy, response at the last evaluation, toxicity, probability of survival, frequency
of disease reactivation, and risk of DI. After 6 weeks of treatment, 53% of patients were drug
responders. Reactivation of disease after a complete response occurred in 58% of these
patients after a median of 9 months. Overall, 4-y ear survival was 78%; 91% in responders to
initial therapy versus 34% in initial nonresponders. In general the results of the LCH trial 1
(LCH1) were compared unfavorably with those of the DAL-HX83/90 studies. The response
rate was lower, and the activation rate was higher. Poly chemotherapy given for 1 y ear
appeared superior to 6 months of monotherapy.
LCH2
The results of the LCH1 and the DAL-HX studies formed the basis of the Histiocy te Society ’s
LCH2 study, which opened in 1996. This randomized trial to compare the effect of oral
prednisone combined with vinblastine with or without the addition of etoposide in high-risk
patients defined as those with multisy stem disease with at least one of the organ sy stems
involved. Low-risk patients were more than 2 y ears old without involvement of the
hematopoietic sy stem, liver, lungs, or spleen (135). High-risk patients were randomized
between initial treatment with vinblastine and prednisone versus vinblastine, prednisone, and
etoposide. All high-risk patients received 6 MP in continuation. Low-risk patients were all
treated with vinblastine and prednisone and did not receive 6 MP.
LCH2 was an international randomized trial which randomized 193 patients to treatment
arm A which consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18
weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses versus these drugs plus
etoposide which was added in arm B. Considering all 193 randomized risk patients, there were
similar outcomes: rapid (6 weeks) response (arm A vs. arm B: 63%/71%), 5-y ear survival
probability (74%/79%), disease reactivation frequency (46%/46%), and permanent
consequences (43%/37%). Patients <2 y ears of age without risk organ involvement had 100%
survival and >80% rapid response. Risk organ involved patients not responding within 6 weeks
had highest mortality. The more intensive arm B reduced mortality in risk organ involved
patients. Comparison of risk organ involved patients in LCH1 and LCH2 confirmed that
increasing treatment intensity increased rapid responses (from 43% in arm A LCH1 to 68% in
arm B LCH2; p = 0.027) and reduced mortality (44% in arm A LCH1 to 27% in arm B LCH2;
p = 0.042) (15,136).
JLSG-96
The Japanese Langerhans Cell Histiocy tosis Study Group conducted a protocol that enrolled
patients with newly diagnosed multifocal LCH. There were 32 patients with single-organ
disease and 59 patients with multiorgan disease. All received induction therapy with
cy tarabine, vincristine, and prednisolone for 6 weeks followed by 6 months of maintenance
with cy tarabine, vincristine, and methotrexate. Patients found to be poor responders during
induction therapy were then switched to doxorubicin, cy clophosphamide, vincristine, and
prednisolone.
In the single-organ disease group, the 5-y ear overall survival was 100%. Seventy -six
percent of patients with multiorgan disease had some response with initial induction and 63%
achieved good response by the end of maintenance. Of the responders, 46% had a sustained
remission (61).
LCH3
LCH1 and LCH2 showed that “risk” organ involvement (hematopoietic sy stem, spleen, liver,
and lungs) and poor response to initial chemotherapy are the crucial prognostic factors for
LCH. Age <2 y ears at diagnosis was not of independent prognostic importance. LCH3 was
the treatment protocol of the third international study for LCH. It included a randomized trial
for clinical multisy stem LCH and a pilot study for patients with single sy stem multifocal bone
disease and localized special site disease. Prednisone and vinblastine were established in
LCH3 as first-line treatment for multisy stem disease and a total treatment duration of 12
months is superior to 6 months. Since VP-16 has not proven beneficial and is leukemogenic, it
was not been included in LCH3 (15,136,137). For single sy stem multifacial bone disease, 12
months of prednisone/vinblastine is appropriate.
Salvage Therapy
The LCH1S study was established to study salvage therapy for patients who did not respond to
initial chemotherapy (60,61,131). No superior strategy has been demonstrated for patients
who failed to respond to steroids and vinblastine or etoposide.
Some of the agents that have been used are:
2-Chlorodeoxy adenosine (2-CdA) is a purine analog resistant to the enzy me adenosine

deaminase (ADA) but not to the enzy me deoxy cy tidine kinase (DCK). ADA has an
essential role in the intracellular degradation of purine nucleosides derived from DNA
breakdown. Normal mature ly mphocy tes and monocy tes express high levels of DCK. In
vitro studies have shown that 2-CdA is a highly selective antimonocy te agent that causes
decreased monocy te function and viability and decreased IL-6 secretion. Because tissue
histiocy tes are derived from the same stem cells as circulating monocy tes, 2-CdA may
be a rational agent for treating patients with histiocy tic disorders. In a report by
Rodriguez–Galindo et al. (138), five out of six patients with multisy stem LCH achieved
remission with 2-CdA. Hampshire et al. reported a complete/partial response rate of
63% in 16 adults with LCH. Median response duration was 3 y ears (139). Although the
efficacy of 2-CdA in treating LCH probably results from its direct effects on histiocy tes,
the drug also may interfere with the immune abnormalities that are part of the
pathogenesis of LCH.
Page 395A multicenter pilot study of 2-CdA and cy tosine arabinoside for children with
refractory LCH and hematologic dy sfunction enrolled seven patients who received at
least two courses of therapy. Six responded but all patients suffered grade 4 hematologic
toxicity. Two other patients died of sepsis after the first course of therapy.
Skin Therapy
Skin involvement is a common component of multisy stem LCH in y ounger children. Skin
sy mptoms may include pruritus, ulceration, purulent exudation, odor, and painful defecation
caused by anogenetical involvement (23,68,72,85). Sheehan et al. (140) treated 16 patients
with sy mptomatic cutaneous LCH with a topical nitrogen mustard solution made by adding
tap water to nitrogen mustard powder and apply ing it daily to the skin with a watercolor brush.
A complete or partial response was obtained in all cases. In patients who do not respond to
topical nitrogen mustard or if cells are very sensitive to ultraviolet radiation, PUVA can be
effective in controlling skin disease. May ou et al. (141) successfully treated a case of
cutaneous LCH in an adult with oral etoposide (96). Concerned about the mutagenicity of
nitrogen mustard, these authors labeled the topical use of that compound for LCH as
“retrogressive.” Sy stematic corticosteroids have been advocated for the treatment of children
with persistent or recalcitrant skin disease (27).
Liver and Bone Marrow Transplantation

In some children, liver failure from LCH is the cause of death. There are a few case reports
of successful orthotopic liver transplantations. These patients did not appear to have active
LCH at the time of the transplant (27,142,143).
There have been a small number of children with refractory LCH, despite
chemotherapy, who have been successfully treated with autologous bone marrow rescue,
unrelated cord blood, stem cells, or other forms of allogeneic BMT. A variety of conditioning
programs have been used, including the treatment of many patients with programs that
include total body irradiation (TBI, e.g., 2–2.25 Gy per fraction daily or twice daily to 12–
15.75 Gy ) or combinations of cy clophosphamide, busulfan, carmustine, fludarabine,
melphalan, antithy mocy te globulin, and campath. However, because many of the children
who receive BMT for chemotherapy -resistant LCH are y oung at the time of transplantation,
TBI-containing conditioning programs should be used only with great caution. From the
available literature, about 60% of patients treated with BMT may be expected to be long-term
survivors (37,61,121,144,145,146,147,148,149,150).
Figure: A Treatment Algorithm for
Langerhans Cell Histiocytosis
Figure: Results of External Beam Radiation
Therapy for Langerhans Cell Histiocytosis of
Bone
Figure:
(A) Magnetic resonance imaging scan and (B) bone scan showing complete vertebral
collapse (vertebra plana) secondary to Langerhans cell histiocytosis (LCH) in 1992. No
therapy was given beyond a needle biopsy to establish the diagnosis. Pain resolved over a
month. Typically, healing includes fusion to adjacent vertebrae. The child remains without
evidence of recurrent LCH.
Dosage
There is no clear relationship between the dosage of irradiation and local control of LCH.
Childs and Kennedy (151) reported 12 patients treated with radiotherapy. Their series began
with an infant treated in 1927–1928 with a radium source. They thought that a dosage of
approximately 600 roentgens was necessary. Smith et al. (124) reported on 89 courses of
irradiation administered with 250-kV X-ray s or cobalt-60. Less than 1000 cGy was
administered in 92% of the cases, and the local success rate was 87%. Three of five sites
treated with less than 450 cGy had a local failure but were salvaged with additional
irradiation. Dosages greater than 1000 cGy did not appear to be more effective than dosages
of 450–1000 cGy.
Greenberger et al. (123) described 89 patients receiving RT to 380 fields for control of
bone lesions. Between 100 and 2000 cGy, local control was obtained in 75% of courses (Fig.
17.7 ). In a study of 56 irradiated sites, Selch and Parker (30) found no difference in
median dosage between controlled and relapsed bony sites (9 Gy vs. 10 Gy ) or soft tissue
sites (median dosage 15 Gy for either controlled or relapsed sites). Overall local control was
82% (Fig. 17.8 ). A review of radiotherapy for LCH from eight German centers described
80 patients treated to 74 bony sites and 28 nonbony sites with total doses of 3–50.4 Gy and a
median total dose of 15 Gy. Local control was no different with doses more or less than 10
Gy. There was a 77% complete remission rate, 12.5% partial remission, and 80% long term
local control rate (40). Reviews describe a very wide range of total dosages, with 5–10 Gy in
three to five fractions being the favored range (Fig. 17.9 ) (49). Cassady (152) advised
using a total dosage of 15–20 Gy in patients older than 18 y ears because of a perceived
higher risk of local failure and a lower risk of bone damage by radiation.
Figure 17.7 Local control of bone
lesions as a function of dosage delivered.
(From Greenberger JS, Cassady JR, Jaffe
N, et al. Radiation therapy in patients
with histiocytosis: management of
diabetes insipidus and bone lesions. Int J
Radiat Oncol Biol Phys. 1979;5:1749–1755,
with permission.)
Figure 17.8 A 4-month-old boy developed a seborrheic skin
rash with focal areas of ulceration. Skin biopsy showed
Langerhans cell histiocytosis (LCH). No other organ systems were
involved. At 6 months of age, proptosis was noted, and orbital
computed tomography scan demonstrated erosion of the lateral
wall of the right orbit by a destructive lesion. Surgery was felt to
be ill-advised because of concern over damage to the lateral
rectus muscle and an unacceptable cosmetic result. Vinblastine
and prednisone were administered. Proptosis improved but then
subsequently worsened. A total dosage of 6 Gy in four fractions
was administered with a right anterior oblique half-beam-
blocked 4-MV photon field with shielding of the lens and two-
thirds of the globe in 1984. Vinblastine was continued for 15
months after radiotherapy. The bone lesion healed within 2
months after irradiation. There is no evidence of LCH 32 years
after the initial diagnosis, the patient is a college graduate,
employed, married, and a father.
Figure 17.9 An 11-month-old boy presented to medical attention with protrusion of the
superior aspect of the left ear. Computed tomographic scan showed a left mastoid soft tissue
mass with erosion into the temporal bone. Open biopsy made the diagnosis of Langerhans
cell histiocytosis (LCH). In 1987, the child received local irradiation with 12-MeV electrons to
a total dosage of 6 Gy in three fractions. After irradiation, he was treated with vinblastine
and prednisone. He remains without evidence of persistent or recurrent LCH.
For DI, Smith et al. (124) reported no relief in seven patients treated with 500–1830 cGy.
Greenberger et al. (123) administered 345–1600 cGy to 21 patients and, as discussed
previously, observed a complete response in four patients and a partial response in another
four patients. Minehan et al. (48) reported three of the five patients (60%) with DI responding
when treated with more than 15 Gy, compared with 7 of 23 (30%) treated with less than 15
Gy. Saliba et al. (117) irradiated one of two DI patients with success.
Page 396Volume
Bone lesions should be treated with a field designed to cover the radiographic abnormality
with a small margin. In the treatment of skull lesions, we attempt to minimize the dosage to
the underly ing brain by treating with electrons or orthovoltage equipment. If electrons are
used, an adjustment for attenuation by compact bone infiltrated by LCH should be made.
This is best done by taking density measurements of the involved bone with a cranial CT scan.
To treat DI, one uses parallel opposed fields, arcs, a three-field technique, or
conformally planned fields to cover the hy pothalamic–pituitary axis.
Figure:
Local control of bone lesions as a function of dosage delivered.
(From Greenberger JS, Cassady JR, Jaffe N, et al. Radiation therapy in patients with
histiocytosis: management of diabetes insipidus and bone lesions. Int J Radiat Oncol Biol Phys.
Figure:
A 4-month-old boy developed a seborrheic skin rash with focal areas of ulceration. Skin biopsy
showed Langerhans cell histiocytosis (LCH). No other organ systems were involved. At 6
months of age, proptosis was noted, and orbital computed tomography scan demonstrated
erosion of the lateral wall of the right orbit by a destructive lesion. Surgery was felt to be ill-
advised because of concern over damage to the lateral rectus muscle and an unacceptable
cosmetic result. Vinblastine and prednisone were administered. Proptosis improved but then
subsequently worsened. A total dosage of 6 Gy in four fractions was administered with a right
anterior oblique half-beam-blocked 4-MV photon field with shielding of the lens and two-thirds
of the globe in 1984. Vinblastine was continued for 15 months after radiotherapy. The bone
lesion healed within 2 months after irradiation. There is no evidence of LCH 32 years after
the initial diagnosis, the patient is a college graduate, employed, married, and a father.
Figure:
An 11-month-old boy presented to medical attention with protrusion of the superior aspect of
the left ear. Computed tomographic scan showed a left mastoid soft tissue mass with erosion
into the temporal bone. Open biopsy made the diagnosis of Langerhans cell histiocytosis
(LCH). In 1987, the child received local irradiation with 12-MeV electrons to a total dosage of
6 Gy in three fractions. After irradiation, he was treated with vinblastine and prednisone. He
remains without evidence of persistent or recurrent LCH.
LONG-TERM SEQUELAE OF LCH AND ITS TREATMENT
Because of the low dosage of irradiation used, acute side effects of radiotherapy for LCH are
rare. However, it is common to see late sequelae of LCH, most of which may be attributable
to the disease and some of which may be attributable to the treatment (153,154).
The French LCH Group reported 320 living patients followed for a median of 39.5
months. The most common sequelae were DI (18%), GH deficiency and short stature (5%),
hy pothy roidism (2.5%), deafness (2.5%), and vertebra plana and orthopedic sequelae (2.5%)
(22). The most common sequelae in the University of California, San Francisco, series were
DI (26%), growth failure (20%), sex hormone deficiency (16%), and hearing loss (16%)
(28). The 90 children followed by the Italian Cooperative Group had an overall incidence of
disease-related disabilities of approximately 48%. These included DI, orthopedic
abnormalities, growth defects, tooth loss, chronic hepatitis, exophthalmus, and hearing loss
(134). McLelland et al. (25,155) described orthopedic abnormalities, endocrine dy sfunction,
and liver fibrosis as well as DI. The incidence of DI in conservatively treated patients with
multisy stem disease, for whom treatment was reserved only for exacerbations, was 36%
compared with a 15% incidence in the DAL series and 20% in the Italian trial, both of which
used intensive chemotherapy. However, the McLelland series is from a single institution, and
referral bias may be accounted for the difference. In a study of 15 long-term survivors of
LCH, Ransom et al. (154) found that 7 had an IQ < 89. In a large study of the Histiocy te
Society, DI (24%), orthopedic abnormalities (20%), hearing loss (13%), and neurologic
consequences (11%) were most frequent (155).
Page 397Growth and endocrine disorders are common in multisy stem LCH. A study of
144 patients with multisy stem LCH evaluated at the Great Ormond Street Hospital for Sick
Children in London showed that 50 had endocrinopathy, 49 of whom had DI. GH
insufficiency was present in 21 patients. GH therapy was able to significantly improve
growth in these patients. It was not clear that RT to the head increased the incidence of GH
insufficiency. It is clear that children with LCH should be investigated for hormone
insufficiency, especially those who have DI or growth failure. It appears that GH
insufficiency is secondary to direct hy pothalamic–pituitary involvement by the disease.
Thickening of the pituitary stalk on MRI scan provides additional evidence of GH
insufficiency (156).
The frequency of secondary malignancy after therapy for LCH is uncertain (7,60). In a
report describing the association between LCH and other malignancies (91 patients), 39 had
LCH and ly mphoma (Hodgkin or non-Hodgkin), 22 had LCH and leukemia, and 30 had LCH
and a solid tumor, most commonly lung cancer. Although the leukemias and nonlung solid
tumors most commonly occurred y ears after LCH, most of the ly mphomas and lung cancers
preceded LCH or were diagnosed concurrently, in an unexplained association (157). Affected
patients had initially received irradiation and chemotherapy, irradiation only, or chlorambucil
only (62,158). One case of leukemia was seen among 90 patients followed in the Italian
Cooperative Group Study (134). One case of leukemia was seen in 51 patients followed for
more than 3 y ears at the University of California, San Francisco (28). There were no second
malignancies in 106 patients with LCH treated in the Dutch–German–Austrian DAL-HX83
trial (29,74,135).
Haupt et al. (159) evaluated children with LCH enrolled in three protocols of the Italian
Association of Pediatric Hematology /Oncology. These patients received a variety of
chemotherapy programs including vinblastine, adriamy cin, etoposide, vincristine,
cy clophosphamide, and prednisone. The median follow-up after entry into the study cohort
was 5 y ears and 5 months. There were three cases of ANLL, all in children who had
received etoposide. Two had received etoposide alone, and one had received etoposide in
combination with alky lating agent chemotherapy and other chemotherapy or RT.
RESULTS
In patients presenting with solitary LCH of bone, close to 100% survival has been reported
(23,24,38,39,84). In the presence of organ dy sfunction with multisy stem disease, survival
ranges from 33% to 54%. In its absence, survival ranges from 82% to 96% (20,23,33,35,62).
In the 348 patients reported from 32 French centers treated from 1983 to 1993, the 6-y ear
actuarial survival according to the DAL-HX staging sy stem was as follows: localized disease,
isolated unifocal or bifocal bone involvement, 100%; soft tissue involvement with or without
bone involvement, no organ dy sfunction, 90%; liver, lung, or bone marrow dy sfunction, 49%
(19). In the DAL-HX83 trial, the probability of survival, using the DALHX83 staging sy stem
for disseminated disease described earlier in this chapter, was 100% for group A, 96% for
group B, and 62% for group C. The 15-y ear survival rates in the series of Willis et al., by ty pe
of initial presentation, were skin disease only, 83%; monostotic disease, 100%; poly ostotic
disease, 100%; and multisy stem disease, 76% (28,46,135).
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CH A P TER 18
Vascular Neoplasms and Skin Cancer
Natia Esiashvili and Ronica H. Nanda
PAGE 401VASCULAR NEOPLASMS

Classification of an individual vascular lesion as a malformation, reactive proliferative lesion,
or neoplasm may be problematic. The International Society for the Study of Vascular
Anomalies has stressed that designations ending in ‘‘oma’’ should only be applied to neoplasms
(1).
For example, lesions designated as ly mphangioma, venous hemangioma, and
arteriovenous hemangioma are in reality malformations and should be called ly mphatic,
venous, and arteriovenous malformations, respectively. The term ‘‘capillary hemangioma’’
was often applied to infantile hemangiomas in various stages of proliferation or regression,
vascular malformations of the small vessel ty pe, and other assorted lesions.
Differentiation between vascular neoplasms and vascular malformations is based on
clinical, radiographic, histologic, and immunohistochemical features. Vascular, or
vasoproliferative, neoplasms have increased endothelial cell turnover. Perhaps more simply
put, vascular neoplasms undergo mitosis. Conversely, vascular malformations (Table
18.1 ) do not exhibit mitosis or increased endothelial cell turnover. Instead, vascular
malformations are defined as structural abnormalities of the capillary, venous, ly mphatic,
and arterial sy stem that grow in proportion to the child (2). The fundamental role of
immunohistochemistry is to establish the endothelial phenoty pe of a suspected vascular
lesion. Vascular or vasoproliferative tumors are subdivided on the basis of presence or
absence of endothelial cell glucose transporter 1(GLUT1) isoform protein (3) (Table
18.2 ). Recently, WT-1 has been demonstrated to be useful as a marker to help
differentiate a vascular neoplasm from a malformation (4).
TABLE 18.1 Vascular Malformations

TABLE 18.2 Vascular Neoplasms
Figure: Vascular Malformations
Figure: Vascular Neoplasms
VASCULOPROLIFERATIVE TUMORS
Infantile hemangiomas, congenital hemangiomas, and kaposiform hemangioendotheliomas

constitute vasculoproliferative tumors. They are subdivided on the basis of presence or
absence of endothelial cell glucose transporter 1 (GLUT1) isoform protein. Infantile
hemangiomas and angiosarcomas express GLUT1 protein, whereas congenital hemangiomas
and kaposiform hemangioendotheliomas do not (3).
Infantile hemangioma is the most common benign vascular tumor in children and
affects approximately 40% of all infants. The skin, subcutaneous, and soft tissue of the head
and neck are the sites of origin in 60% of patients, followed by the trunk, extremities, and
viscera (e.g., liver, lung, gastrointestinal tract). Although infantile hemangioma is usually
solitary, up to 15% of patients have multiple cutaneous lesions, and visceral lesions are
ty pically associated with widespread cutaneous involvement (5,6).
The clinical course of infantile hemangiomas consistently progresses from rapid growth
(proliferative phase) in the first y ear of life to gradual regression (involution phase) from
ages 1 to 8 y ears, with nearly all lesions resolved by puberty. Most infantile hemangiomas
are easily diagnosed clinically. Color Doppler ultrasound is the imaging modality of choice
for infants with possible hemangiomas in any location. Extensive or complicated
hemangiomas require evaluation with MRI to better characterize and determine disease
extent; CT, although less often used today because of radiation concerns, has the advantage of
rapid imaging in urgent situations without requiring sedation. The final diagnosis of all
vascular anomalies rests with the pathologist, assuming use of the ISSVA classification
sy stem.
Treatment of infantile hemangiomas depends on the location and number of lesions as
well as associated sy mptoms. Laser therapy is available for skin ulceration, the most frequent
complication. For hemangiomas with sy mptoms, including thrombocy topenia or
hy pothy roidism, as well as heart failure caused by numerous hepatic hemangiomas,
treatment is ty pically started with antiangiogenic drugs (propranolol, steroids, and less often
vincristine) followed by gradually more aggressive treatments, such as embolization and
rarely surgery. External beam radiotherapy was used in the past for patients not responding to
steroids or interferon. The rise in platelet count was shown to predict tumor regression
following radiotherapy (7). Radiotherapy fields were guided by imaging findings (8). Total
doses of 300–750 cGy, and rarely exceeding 1000 cGy, at 10–20 cGy per fraction could
achieve good local control (7,9). Recently, radiotherapy fell out of favor because of concerns
for potential late effects, like scarring, bone growth abnormalities, dental and periodontal
problems (10,11), and secondary neoplasms (12,13,14,15,16,17,18).
Page 402The incidence of cancer after radiotherapy for skin hemangiomas has been
studied extensively in a series of articles from Sweden. These reports describe a total of
14,633 children below 18 months irradiated at the Radiumhemmet in Stockholm from 1909 to
1959 and 12,055 treated at Sahlrenska Hospital, Goteborg, from 1930 to 1965
(10,11,12,13,14,15). At the Radiumhemmet, treatment was most commonly by 226Ra
applicators (81%) or contact X-ray therapy (60 kVp or less, 16%). At Goteborg, 226Ra was
used for 99% of the treatments. The median age of treatment was 6 months at
Radiumhemmet and 5 months at Goteborg. There is a higher-than-expected incidence of
cancer in these irradiated children. Significantly higher levels of breast cancer were detected
in the pooled studies (hazard ratio 1.2, 95% confidence interval (CI): 1.06–1.36), and there
was an approximate twofold increase in the expected incidence thy roid cancer. Recalculation
of the dosages from the 226Ra applicators suggests a linear dose–response relationship.
Conceivably, the use of electron therapy in lieu of 226Ra might mitigate the long-term effects
of radiotherapy in these patients. Another large French report on 8307 patients treated for
4767 hemangiomas was included in an incidence study, among whom 3795 had received
radiotherapy (16). External radiotherapy, radium 226, strontium 90, y ttrium 90, and
phosphorus 32 were used. The mean estimated radiation dose received by the thy roid during
radiotherapy was 41 mGy. This study confirms that radiation treatment performed in the past
for hemangioma during infancy increased the risk of thy roid carcinoma and adenoma. A
significant dose–response relationship was found between the radiation dose received by
thy roid and the risk of thy roid cancer (excess relative risk per Gy, ERR/Gy : 14.7, 95% CI:
1.6–62.9). These studies strongly argue against the routine use of radiotherapy to treat
hemangiomas of infancy and indicate that irradiation of the thy roid, breast buds, and gonads
should be avoided (10,11,12,13,14,15,16). However, the response of cutaneous hemangiomas
of infancy to irradiation can be dramatic. In 1940, Kasabach and Merritt (17) originally
reported a combination of external irradiation with superficial X-ray s and interstitial
irradiation with radium needles as a successful primary treatment. Furst et al. (18) reported
good results in 88% of treated cases (12). In treating patients with Kasabach–Merritt
sy ndrome, the objectives are both regression of the hemangioma and control of the
thrombocy topenia and coagulopathy. Ogino et al. (7) demonstrated regression of the lesion
and an increase in platelet count to more than 105/mm 3 within 40 day s of radiotherapy.
Page 403Congenital hemangiomas can be distinguished from infantile hemangiomas on
a histopathologic and clinical basis. Congenital hemangiomas are GLUT1 negative. They are
already present at birth because they begin their proliferative phase in utero. Two ty pes of
congenital hemangiomas are included in the ISSVA classification sy stem: rapidly involuting
congenital hemangiomas (8) and noninvoluting congenital hemangiomas (9,19).
The natural history of the congenital hemangioma of infancy is rapid growth during the
first 6–9 months of life followed by a period of more slowly increasing size that parallels the
infant’s growth. Involution generally follows at a rate of about 10% per y ear, with complete
disappearance of 50% of the lesions by 4 or 5 y ears of age and 90% by 9 y ears (2,20,21).
Hemangiomas are most commonly seen on the face and neck (60% of cases), followed by
the trunk (25%) and extremities (15%) (22), and are in multiple locations in about 20% of
cases (23).
Observation of clinical course is ty pically sufficient to make a diagnosis, and biopsy is
rarely needed. Imaging findings for rapidly involuting congenital hemangiomas and
noninvoluting congenital hemangiomas are similar to infantile hemangiomas. Because
rapidly involuting congenital hemangiomas regress spontaneously, their treatment is the same
as that for infantile hemangiomas (24,25).
A prospective, randomized controlled trial on 121 infants aged 1–14 weeks with early
hemangiomas was recently published (26). The aim was to compare treatment with pulsed
dy e lasers with a wait-and-see policy. The number of children whose lesions showed
complete clearance or minimum residual signs at 1 y ear was not significantly different in the
treated and observation groups (42% vs. 44%; p = 0.92). Surgery is the treatment of choice
for noninvoluting congenital hemangiomas because of their lack of regression.
Kaposiform hemangioendothelioma is a rare GLUT1-negative vasoproliferative or
vascular tumor that presents at or shortly after birth. Histologically, it is formed of infiltrative
nodules composed of vascular and ly mphatic vessels. Most commonly, it arises in the trunk,
extremities, head, neck, and retroperitoneum, with extension into regional ly mph nodes and
adjacent soft tissues in many cases. Kaposiform hemangioendothelioma can present with
Kasabach–Merritt sy ndrome. In this sy ndrome, platelet sequestration and thrombocy topenia
lead to consumptive coagulopathy. Kasabach–Merritt sy ndrome has a poor prognosis, with a
30% mortality rate (27). Kasabach–Merritt phenomenon (KMP) is a rare thrombocy topenic
consumption coagulopathy associated with an enlarging cavernous hemangioma or
Kaposiform hemangioendothelioma (19). It may be complicated by a life-threatening
situation due to thrombocy topenia, hemoly tic anemia, and consumptive coagulopathy caused
by platelet sequestration and high shear stresses within the lesion (Kasabach–Merritt
sy ndrome) (19,28). In the absence of Kasabach–Merritt sy ndrome, treatment includes wide
local excision, embolization, or supportive care, depending on the clinical findings. However,
the large size and infiltrative nature of Kaposiform hemangioendothelioma make it difficult to
treat.
Angiosarcoma is another rare highly aggressive vascular tumor that is ty pically GLUT1
negative, with a very poor prognosis. By 2008, 38 pediatric cases had been reported, eight in
association with hemangiomas (29). Pediatric angiosarcomas tend to be more common in
girls, located in the liver, and have an average age of presentation of 3.7 y ears (30). On
imaging, angiosarcomas are heterogeneous lesions with a variable appearance with vigorous
enhancement with contrast. Multiple sy nchronous or metastatic lesions in the liver may be
present. The prognosis of angiosarcoma is very poor regardless of treatment.
VASCULAR MALFORMATIONS
Page 404In contrast, vascular malformations are essentially stable, demonstrating little or no
growth over time. These structural malformations include capillary (port-wine stain), venous,
ly mphatic, and arteriovenous malformations. Vascular malformations are subdivided into two
major groups: low- or slow-flow and high- or fast-flow.
Low-flow malformations involve a combination of capillary, venous, and ly mphatic
elements. High-flow malformations alway s have an arterial component along with variable
combinations of slow-flow elements. A variety of regional sy ndromes associated with low- or
fast-flow vascular malformations have been described.
Sturge–Weber sy ndrome, the most common of these, is thought to result from
nonhereditary defective regression and maturation of the primitive venous plexus. It presents
at birth with a facial capillary malformation (formerly port-wine stain), and seizures occur in
80% of children by 1 y ear (31). Mental retardation and glaucoma occur in 50% and 30% of
children, respectively. Sturge–Weber sy ndrome is progressive with no cure (32,33).
Klippel–Trenaunay sy ndrome is the second most common regional sy ndrome with low-
flow vascular malformations. It is thought to be caused by an anomaly of the ischial venous
sy stem leading to persistent malformed venous channels. Klippel–Trenaunay sy ndrome
presents with a regional capillary malformation, congenital varicose veins, and overgrowth
(34,35).
Parkes–Weber sy ndrome, although rare, is the most common regional sy ndrome with
high-flow vascular malformations. It may be confused with Klippel–Trenaunay sy ndrome
because of overlapping clinical manifestations, such as limb overgrowth.
Hereditary hemorrhagic telangiectasia, or Osler–Weber–Rendu sy ndrome, is the most
common diffuse sy ndrome with high-flow malformations. It is an autosomal dominant
disorder caused by abnormal growth factor (TGF)-β which controls mesenchy mal and soft-
tissue cell differentiation, proliferation, and cell death (36,37). Treatment depends on
sy mptoms but often requires multispecialty long-term planning. Catheter embolization of
feeder vessels has been successful; however, it comes with the risk of complications (38).
On rare occasions, the radiation oncologist is consulted on cases of vascular
malformations. Response of even large, sy mptomatic lesions to radiotherapy to a total dose
of 30–40 Gy can be substantial (39,40,41). Effective use of gamma knife radiosurgery has
been described for orbital hemangiomas, while increasing the possibility of visual function
preservation in selected cases in which the lesion is adjacent to the optic apparatus (42).
However, consideration of radiotherapy should be highly selective due to risk of late effects,
particularly secondary malignancy.
Rades et al. (43) analy zed the outcome after radiation therapy in the treatment of
sy mptomatic vertebral vascular malformations from University Hospital Eppendorf
(38,43,44,45,46,47). A total of 117 patients were evaluated, ranging in age from 12 to 78
y ears (median age 47 y ears). To identify a dose–effect relationship, patients were divided
into two groups based on the total radiation dose of 20 Gy (n = 62, median total dose 30 Gy )
or 36 Gy (n = 55, median dose 40 Gy ). Complete pain relief was achieved in 82% of the
higher dose group and 39% of the lower dose group (p = 0.003). Complete or partial pain
relief was obtained in 100% and 87% of the higher dose and lower dose patients, respectively.
This analy sis suggests that a total of 40 Gy delivered in 2 Gy per fraction can provide
effective palliation of sy mptomatic vertebral hemangiomas, likely mostly constituted of
vascular malformation based on the contemporary ISSVA classification sy stem (43).
Ly mphatic malformations usually are first noted in the neonate and can produce
sy mptoms at any age. They can occur throughout the body but predominate in the neck.
They may infiltrate the tongue or the floor of the mouth, causing deformity, pain associated
with frequent infections, and obstruction of the aerodigestive passages. Spontaneous
regression of these lesions is rare (48).
Four distinct forms have been described. These include capillary ly mphatic
malformations, an uncommon lesion that may have the appearance of an ordinary wart or
group of small vesicles. These lesions consist of a network of ly mphatic spaces formed by
small- and medium-sized vessels. Cavernous ly mphatic malformations occur in the skin and
subcutaneous tissue, salivary glands, and lips. These are diffuse spongy masses, often with
indistinct margins. They consist of multiple dilated ly mph channels that are lined with either
single or multiple lay ers of endothelial cells. Cy stic hy gromas are the most common
ly mphatic malformations. They are composed of cy sts ranging from a few millimeters to
several centimeters in diameter. The cy sts compress surrounding tissues, and small vessels
course over their walls.
Although surgical excision is the preferred therapy for ly mphatic malformations, this
may be difficult in certain situations and entail repeated operations (49,50,51). Various
sclerotherapy agents have been shown to have minimal effects and have been problematic
because of poor cosmetic outcome (52). Bleomy cin fat emulsions and, more recently, OK-
432 (Picibanil), an immunostimulant composed of group A Streptococcus pyogenes, have
been advocated for the treatment of unresectable malformations (49, 53,54,55). A sy stematic
review of the published literature regarding the efficacy of nonsurgical therapies in the
treatment of head and neck ly mphatic malformations in children was published in 2008 (56).
Random-effects modeling revealed that 43% of patients undergoing sclerotherapy with OK-
432 achieved a complete/excellent response, 23.5% achieved a good response, 16.9%
achieved a fair/poor response, and 15.4% observed no response. In the bleomy cin group, the
results were: 35.2% excellent, 37.1% good, 18.4% fair/poor, and 11.6% no response. Of note,
seven major complications were noted out of 289 patients in the series, including two
mortalities. The efficacy of this agent in treating large lesions in children has been questioned
elsewhere (57).
Radiation therapy is rarely used, although dramatic responses of neck, chest (58), vulva
(59), and mesenteric ly mphangiomas to external beam radiotherapy have been reported in
the literature (58,60,61,62). Fractionated radiotherapy to a total dosage of 15–30 Gy was
commonly used to treat the head and neck malformations. However, late toxicities, including
inhibition of bone growth and soft tissue development and the increased risk of cancer, should
be carefully considered in the decision to treat.
BASAL AND SQUAMOUS CELL CARCINOMAS
Page 405Nonmelanoma skin cancers like basal and squamous cell skin cancers are extremely
rare in childhood (63,64,65,66). Ty pically, they occur in predisposition sy ndromes, like in
basal cell nevus sy ndrome (BCNS) or xeroderma pigmentosa (XP). BCNS may provide a
unique example of the genetic–environmental interaction in the production of malignancies.
BCNS (also known as nevoid basal cell carcinoma sy ndrome or Gorlin sy ndrome) is
characterized by a positive family history for the sy ndrome, the occurrence of multiple basal
cell epitheliomas, keratocy sts of the jaw, epidermal cy st and hamartoma formation, palmar
and plantar pits, skeletal abnormalities, and oculoneurologic abnormalities (67). Intellectual
deficit is present in up to 5% of cases (67). Nevoid basal cell carcinoma sy ndrome is caused
by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with
complete penetrance and variable expressivity (68). XP is an autosomally dominant inherited
disease. The clinical manifestations occur primarily on sun-exposed skin that develops
abnormal pigmentation and multiple malignant tumors. Areflexia, mental retardation, and
other neurologic abnormalities are associated with XP. The biochemical defect appears to be
a poor ability to repair ultraviolet-induced DNA damage. Basal cell and squamous cell
carcinomas of the skin may develop in patients with XP.
There are several environmental exposures known to increase risk of nonmelanoma skin
cancers. They can arise in a nevus sebaceous (69), after thorium X treatment of a
hemangioma (70). Cranial irradiation for acute ly mphoblastic leukemia has significant
association with development of skin cancers (71). The Childhood Cancer Survivor Study
(CCSS) found that among the 13,132 five-y ear survivors of childhood and adolescent, 213
have reported nonmelanoma skin cancers (72). Radiotherapy was associated with a 6.3-fold
increase in risk. Ninety percent of patients had previously received radiation therapy ; 90% of
tumors occurred within the radiotherapy field. Another study evaluated 6306 patients who
received high-dose chemotherapy at ages 0–65 y ears after conditioning regimens with (n =
3870) or without (n = 2436) total-body irradiation (73). Patients were followed from 100 day s
to 36.2 y ears after receiving high-dose chemotherapy. The risk associated with radiation
exposure was higher for the y oung ones, with relative risks exceeding 20 for those
transplanted at ages below 10 y ears, and decreased with increasing age at exposure until age
40 y ears.
About 5–10% of BCNS develop in a setting of medulloblastoma therapy (74). Multiple
basal cell epitheliomas have been reported within 6 months to 3 y ears of craniospinal
irradiation. These skin cancers develop at an age distinctly earlier and in a distribution unlike
that of family members with BCNS. The distribution of basal cell epitheliomas corresponds to
the radiotherapy ports. The development of multiple cutaneous skin cancers has not been
generally reported in the long-term survivors in medulloblastoma outside BCNS setting (75).
Radiotherapy is relatively contraindicated in y oung children with BCNS. Because ionizing
radiation damage to XP cells is repaired normally, there is no theoretical objection to
radiotherapy treatment of tumors if indicated. However, situations in which radiotherapy is
appropriate are quite rare (76,77).
At St. Jude Children’s Research Hospital (SJCRH), eight children with skin carcinomas
were seen from 1962 to 1986. In four patients, basal cell epitheliomas developed in
previously irradiated fields (acute ly mphoblastic leukemia, Hodgkin disease, neuroblastoma).
There was a fifth patient with BCNS. The three patients treated for squamous cell carcinoma
had a prior diagnosis of XP (78). From 1971 to 1991, seven cases of basal cell carcinoma and
three cases of squamous cell carcinoma were encountered at the National Institute of
Pediatrics in Mexico City (63). Five of the seven children with basal cell carcinoma had XP,
one had BCNS, and one developed in a previous radiotherapy field. One of the three patients
with squamous cell carcinoma also had XP.
Patients with basal cell carcinoma of the skin may be treated with chemotherapy,
immunotherapy, electrodesiccation, cry otherapy, Mohs’ chemosurgery, or primary surgery
with reconstruction of the defect (68). Some children have been treated with radiotherapy,
although this treatment is generally reserved for adults.
MALIGNANT MELANOMA
Melanoma incidence is about 5–6 per million in children under age 20 y ears with only 300–
420 new cases diagnosed per y ear. As a result, there is sparse data regarding melanoma in
this age group compared to adults. Although melanoma in children and adolescents represents
less than 1% of cases of all cancers, melanoma is the second-most common adult-ty pe
cancer in this age group (after thy roid cancer). Incidence increases with age and varies by
sex, anatomic location of the lesion, and geographic residence across multiple age groups
(79,80). There is controversy about epidemiologic trends for pediatric melanoma. As in
adults, incidence has been linked with geographic residence. Childhood melanoma in
Australia is higher than that reported in other series, accounting for 3.3% of all pediatric
neoplasms. Melanoma is the most common cancer diagnosed in females between the ages of
25 and 29 y ears (81). This high incidence is attributed to excessive exposure to sunlight
(64,82). In the United States, the reported incidence of cutaneous melanoma rose
approximately twofold between 1974 and 1994, with the increase observed across all age
groups (83,84,85). Further reports also suggest its increase in the late 90s (86,87). However,
between 2000 and 2010, the incidence in the pediatric population started to decrease (88).
Regardless, melanoma should remain a prominent health concern in children and needs
further study.
Case–control studies in adults have identified multiple host and environmental factors
associated with increased risk of malignant melanoma. Host factors include fair skin, white
race, blond or red hair, light ey e color, tendency to burn with UV radiation exposure,
increased number of benign nevi, dy splastic nevi, family history of melanoma, and
xeroderma pigmentosum.
Environmental factors include sunburns, often in childhood, and increased exposure to
UV radiation. Proposed risk factors for pediatric melanoma include congenital, dy splastic, or
increased number of nevi; inability to tan; blue ey es; facial freckling; family history of
melanoma; disorders of DNA excision repair like xeroderma pigmentosum; acquired or
congenital immunosuppression; and a previous history of malignancy (89,90). Increased
exposure to UV radiation, measured by number of blistering sunburns (especially during
childhood), and reported time spent outdoors, confer a two- to fivefold increased risk of
melanoma in case–control studies of adults (91,92,93). Ethnic/racial predisposition or a lighter
skin color has previously been reported as a risk factor for the development of melanoma,
possibly related to a protective effect of (melanin) pigmentation (84). The risk of malignant
melanoma is also higher in congenital immunodeficiency sy ndromes and iatrogenic
immunosuppression, suggesting that immunoincompetence adversely influences melanoma
development. Sun exposure is a critical epidemiologic factor in the development of malignant
melanoma (87,94,95,96,97). Although there is a debate about the timing of sun exposure,
particularly severe sunburns, and the eventual development of malignant melanoma, the data
strongly support the concept that the lifetime total exposure to sunlight is directly related to the
incidence of malignant melanoma. Thus, medical practitioners, including radiation
oncologists, should counsel parents to protect children from excessive sun exposure.
Page 406Clinical and histopathologic features of pediatric melanoma are poorly
characterized. Melanoma can mimic benign lesions, like the Spitz nevus, and particularly in
children can delay diagnosis. Melanomas in children, especially prepubertal children, have
been observed to be more often amelanotic, nodular, and thicker at diagnosis than melanomas
in adults (79,98,99,100). Melanomas in children can also resemble other nonmelanocy tic
lesions such as py ogenic granulomas and warts (101,102,103). Previous publications have
specifically noted that prepubertal melanoma does not alway s follow the conventional ABCD
criteria (Asy mmetry, Border irregularity, Color variegation, and Diameter [6 mm])
(98,99,104,105).
To genetically characterize childhood melanoma, 21 pediatric patients were studied by
germline analy sis of CDKN2A, CDK4, and MC1R genes. Cutaneous melanoma in childhood
and adolescence shows frequent loss of INK4A and gain of KIT (56). Microscopically,
ambiguous melanocy tic proliferations with indeterminate malignant potential create
additional diagnostic dilemmas. Together with a low index of suspicion, features distinct from
those usually seen in adult melanoma may contribute to diagnostic delay s.
Pediatric melanoma is often classified by the mode of occurrence as well as the
histologic subty pe (98).
1. Transplacental melanoma, transmitted from the mother with melanoma to the fetus in
utero. There are rare reports of transplacental transmission of metastatic melanoma
from mother to child (106). The infant usually has disseminated disease at birth, and the
prognosis is poor.
2. Transformation from giant congenital melanocytic nevus. Large congenital nevocy tic nevi
(LCNN) are defined as congenital nevi 20 cm in diameter or larger. They may occur
any where on the body and include the so-called “bathing trunks” nevi. There is a
controversy in the literature regarding the relative risk of malignant melanoma arising in
LCNN, with lifetime risks ranging from 2% to 31% (98,106,107,108).
3. In association with congenital predisposing conditions such as xeroderma pigmentosum,
dysplastic nevus syndrome, and albinism. Familial dy splastic nevus sy ndrome is an
autosomal dominant trait characterized by unusual nevi at risk for developing melanoma.
Patients with XP are at significant risk for developing melanoma, as described earlier.
4. Development from healthy skin.
5. Development from a preexisting nevus. The total number of melanocy tic nevi strongly
influences the risk of developing melanoma later in life (82,83,84,85,98,106). In turn, the
number of melanocy tic nevi in children is closely associated with the degree of sun
exposure and the nevus counts in the parents (94).
Malignant melanoma is categorized histologically into four ty pes: lentigo maligna melanoma,
superficial spreading melanoma, acral lentiginous melanoma, and nodular melanoma.
Childhood melanoma may be staged with the following sy stem: stage I, localized disease;
stage II, regional ly mph node involvement; and stage III, distant metastatic disease (109).
Three important factors should be considered in evaluating stage I patients: the presence of
local ulceration, Clark’s level of invasion, and Breslow’s depth of invasion (Table 18.3 ). All
three have been shown to be important prognostic indicators in childhood melanoma (110). In
children, metastatic disease is rare in lesions less than 1.5 mm thick (109). In the SJCRH series
of 33 children treated from 1967 to 1988, there were no tumor-related deaths in children with
thin melanomas (Clark’s level I–II, Breslow thickness less than 1.5 mm). Twenty -four patients,
16 y ears of age or y ounger, with malignant melanoma were reviewed at St. Thomas’
Hospital, London, from 1981 to 1993. All the three patients with tumors 1.2 mm or smaller
were alive without tumor. In contrast, of the 19 children with tumors 1.6 mm or larger, 15
were disease-free, 3 were alive but suffered locoregional relapse, and 1 died of disease
(106). As in adult patients, brain metastases often occur and confer a poor prognosis (111).
Table 18.3 Classification of the Primary Lesion in Malignant Melanoma
It is important to distinguish malignant melanoma from juvenile melanoma or nevi of

large spindle or epithelioid cells or Spitz nevi. In 1948, Sophie Spitz (112), a pathologist at New
York’s Memorial Hospital, described 12 of 13 children who were long-term survivors of this
peculiar “benign” childhood melanoma. Spitz nevi usually are sy mmetric and small, exhibit
epithelial hy perplasia, contain clefts between nests of melanocy tes and epidermis, exhibit
mature melanocy tes, and contain dull, pink epidermal globules called Kamino bodies
(113,114,115). The histologic differentiation of Spitz nevi and malignant melanoma is
difficult, even among expert dermatopathologists (116).
The inclusion of benign Spitz nevi cases in pediatric malignant melanoma series results in
an overdiagnosis of malignant melanoma and an underestimate of mortality rate
(117,118,119). Analy sis of pediatric malignant melanoma series that exclude the benign Spitz
tumors indicates that survival rates in children are similar to those of adults. Among the 8635
patients registered with the Duke Melanoma Clinic, only 85 (less than 1%) were less than 18
y ears of age (106,120). Fifty -nine percent of the patients had the superficial spreading
histologic ty pe, and 20% of the remaining patients were Clark’s level III or IV.
Page 407Age-related disparities have been noted but are less well defined within the
pediatric population with melanoma. There are important differences in y oung children (age
< 10 y ears) with melanoma compared with adolescents and y oung adults that may reflect
distinct tumor biology and/or host characteristics. Younger patients are more likely to have
congenital nevi and, possibly, sy ndromes that predispose to cancer.
The standard treatment for localized malignant melanoma is wide local excision
(117,118,119,121,122,123). Once a diagnosis of melanoma has been made, the focus turns to
adequately staging the disease. Reexcision of the lesion is the first step in treatment, and
prospective, randomized trials have determined the necessary margin to minimize local
recurrence related to the lesion depth (124,125). In certain situations, a skin graft may be used
to close the resulting defect. The role of elective node dissection of clinically uninvolved
regional ly mph nodes has been a subject of debate. It is clear that not all patients are
candidates for elective ly mph node dissection. However, for patients with melanoma more
than 0.75 mm thick, the proper initial extent of surgery is debatable. The arguments in favor
of elective node dissection include staging, detecting microscopic disease, and treating occult
metastatic disease if present, thereby reducing tumor burden and removing a potential source
of future metastases (121,123).
Sentinel ly mph node biopsy is, however, emerging as the standard method of staging
metastasis to regional ly mph nodes. To identify the sentinel node (i.e., the first node draining
an anatomical site), a colloidal dy e or radioactive isotope, or both, is injected at the tumor
bed. During surgery, the sentinel node is identified by visual inspection or by a handheld
gamma probe, and the node is excised for sectioning and immunohistochemical staining. In
adults, this low-morbidity procedure offers an accurate and sensitive method of determining
nodal involvement (126). In turn, the regional ly mph node status has been found to be the
strongest prognostic factor in early stage melanoma (126,127,128,129). Although data on the
utility of sentinel ly mph node biopsy in malignant melanoma for the pediatric population are
limited because of the rarity of this disease, the similarities between malignant melanoma in
the adult and child suggest that sentinel ly mph node biopsy should be considered in staging
pediatric patients (130,131,132,133). It is quite well proven now that sentinel ly mph node
biopsy allows for an accurate biopsy in children. However, some y ounger patients may
require sedation, and it may be more challenging to isolate the sentinel node (134). Patients
with positive sentinel nodes usually undergo completion ly mphadenectomy and may be
candidates for clinical trials.
Metastatic and relapsed melanoma creates a significant clinical challenge. The evidence
for the role of sy stemic therapy comes largely from adult trials with very few pediatric
patients included; even fewer dedicated pediatric-specific reports exist in the literature.
Chemotherapy regimens usually have a poor activity against melanoma in adults. However,
St. Jude Children’s Research Hospital (SJCRH) has reported a complete or partial response in
8 of 18 (44%) pediatric patients receiving cy clophosphamide, vincristine, and dacarbazine
(135). Responses have also been observed with single-agent dacarbazine or melphalan with
hy perthermic isolated limb perfusion.
Immunotherapy and targeted therapy have recently gained increased recognition as an
effective anti-cancer therapy and their use in the treatment of melanoma helped to first
demonstrate their efficacy. Interferon (IFN)-alpha has anticancer effects both in the
preclinical models and in the clinical setting, although the mechanism of action is still unclear.
Adjuvant IFN has been evaluated in multiple phase III trials in an attempt to delay or prevent
subsequent metastasis and death. The results of Intergroup studies E-1684, E-1690, and E-
1694 established high-dose interferon (HDI) as the adjuvant therapy standard of care for
patients with high-risk or advanced melanoma, as there appears to be a recurrence-free
survival benefit and a modest overall survival benefit (136,137,138).
Page 408Given the favorable results with the use of IFN alpha-2b in adults, 15 patients
less than 18 y ears of age with stage III melanoma, defined as having a primary tumor
thickness >4 mm or having ly mph node or in-transit metastases, were included in a SJCRH
feasibility study (139). They concluded that IFN alpha-2b could be used in pediatric
melanoma patients with acceptable toxicity, without data on efficiency. Another recent report
from Toronto proposed the use of HDI in 6 children with metastatic disease on sentinel ly mph
node biopsy, and on 10 patients with melanoma (140). All patients in their series who had
positive sentinel ly mph nodes then underwent complete ly mph node dissection. Five of them
received HDI therapy, and one patient refused therapy. Most of the patients did complete
their therapy, and almost all required alterations in dosage due to toxicity. With a median
follow-up of 26 months, 10 out of 11 patients survived.
Interleukin-2 (IL-2) has been also identified as an effective treatment for patients with
stage IV melanoma (141).
By the late 1990s, meta-analy sis of patients with stage IV melanoma treated primarily
in phase II studies demonstrated the highest response rates and response durations for
biochemotherapy regimens in which chemotherapy (usually including cisplatin and
dacarbazine) was combined with IL-2 and IFN (142).
Intergroup Study of Cancer and Leukemia Group B, Children’s Oncology Group, Eastern
Cooperative Oncology Group, and Southwest Oncology Group (S0008) sought to determine
whether a shorter course of biochemotherapy would be more effective. This phase III trial
enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to
receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine,
interleukin-2, IFN alpha-2b (IFN-α-2b). Biochemotherapy for patients with high-risk
melanoma provided statistically significant improvement in RFS but no difference in OS and
more toxicity compared with HDI (143).
Targeted therapies, such as BRAF and MEK inhibitors that are approved for the
treatment of patients with advanced melanoma who harbor BRAF V600 mutation–positive
tumors, result in a high rate of initial tumor responses, with a significant survival advantage
over dacarbazine; however, the median duration of response is less than 1 y ear (144,145).
Recent approaches to the treatment of metastatic melanoma enhance antitumor
immunity by blocking immune checkpoints, such as cy totoxic T-ly mphocy te–associated
antigen 4 (146) and the programmed death 1 (PD-1) receptor. Ipilimumab, an anti–CTLA-4
antibody, is approved by the Food and Drug Administration (FDA) on the basis of
improvement in overall survival among patients with advanced melanoma, with objective
responses in approximately 11% of the patients (146,147). Nivolumab (a programmed death
1 [PD-1] checkpoint inhibitor) and ipilimumab (a cy totoxic T-ly mphocy te–associated antigen
4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in
metastatic melanoma. The trial randomized 945 treatment-naïve patients with advanced or
metastatic melanoma in a 1:1:1 fashion to 1 of 3 arms (56)—(1) nivolumab plus ipilimumab,
followed by nivolumab; (2) nivolumab plus placebo; or (3) ipilimumab plus placebo, until
disease progression or unacceptable toxicity (148). The objective-response rate and the
progression-free survival among patients with advanced melanoma who had not previously
received treatment were significantly greater with nivolumab combined with ipilimumab
than with ipilimumab monotherapy (Fig. 18.1 ).
Figure 18.1 Progression-free survival of patients treated with Nivolumab plus Ipilimumab
versus Ipilimumab alone (Adopted from 148. Postow MA, Chesney J, Pavlick AC, et al.
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med.
2015;372: 2006-2017).
Radiotherapy is reasonably effective for the sy mptomatic palliation of metastases.

Radiobiologic interest had been focused on the possibility that at a cellular level, malignant
melanoma is truly radioresistant (149). A survey of Dq values (width of the shoulder of the
cell survival curve in response to ionizing radiation) of various mammalian cell lines suggests
that a ty pical value for Dq is about 90 cGy. However, observations from several investigators
suggest that malignant melanoma in vitro has a particularly broad-shouldered survival curve,
with a Dq greater than 200 cGy. These data reinforced the belief that malignant melanoma,
though intrinsically radioresistant, might be more responsive to high dosages per fraction. A
review of several retrospective studies of the effect of fraction size on disease response in
malignant melanoma in adults suggested that the probability of a complete response was 34%
for dosages less than 400 cGy but 59% for dosages 400 cGy or greater (150). This analy sis
excluded bone metastases, which showed equal responses for small and large fractions (151).
Subsequently, a prospective clinical trial of patients at least 15 y ears old, with
measurable melanoma lesions, randomized 126 patients to either 4 weekly fractions of 8 Gy
per fraction or 20 fractions of 2.5 Gy per fraction 5 day s per week (152). In both the large
and conventional fractionation arms, equivalent complete and partial clinical responses were
observed. Stratification by tumor size (greater than or less than 5 cm) or tumor site (soft tissue
or skin, nodal, other) also failed to show any difference between the 8- and 2.5-Gy
fractionation schemes (121). Based on the retrospective results, it seems reasonable to use
high-dose-per-fraction radiotherapy for palliation of metastatic melanoma when late effects
are not an issue. The prospective trial suggests that conventional fraction is equally reasonable
when there is a significant probability of long-term survival.
There was no difference in the actuarial
survival rates between adult and juvenile stage I
patients (Fig. 18.2 ). Overall, on a stage-by -
stage basis, survival in children and adults
appears comparable (106). Conti et al. (117)
reported a series of 212 European children (age
less than 15 y ears) with melanoma identified
through the EUROCARE database over an 11-
y ear time period and attempted to evaluate the
population-based survival for this disease in
different national populations. The overall 5-
y ear survival for all children diagnosed with any Figure 18.2 Actual survival rates of
ty pe of melanoma was 79%, similar to 77% for the adult and juvenile stage I patients
the whole population. Five-y ear survival was registered at the Duke University
best for children diagnosed with cutaneous Melanoma Clinic. (Adapted from 106.
melanoma (87%) and worst for patients with Reintgen DS, Vollmer R, Seigler HF.
melanoma not of the skin or ey e (57%). Within Juvenile malignant melanoma. Surg
the cutaneous melanoma population, survival Gynecol Obstet. 1989;168(3):249–253,
was negatively impacted by having a primary with permission).
lesion on the trunk (76%) (117).
Page 409Younger patients were more likely to present with thicker primaries and ly mph
node metastases. Although survival and event-free survival did not statistically differ between
the two age groups, there was a trend toward improved survival in node-positive prepubescent
patients compared to node-positive adolescent patients (153). Selected studies did suggest
better survival outcome in y ounger adults with melanoma (154,155,156). Some series
reported 5-y ear survival rates in children with melanoma as high as 74–80% (89,117).
However, SEER data published by Strouse et al. (80) suggest that y oung children with
melanoma are more likely to have poor prognostic features (e.g., metastasis, thick primaries,
high-risk histology, history of cancer). The same group also demonstrated that melanoma-
specific survival in children has improved by approximately 4% per y ear during the last 3
decades. It is difficult to explain this dramatic improvement, aside from improved imaging,
surgery, and a modest effect of adjuvant therapies. Although earlier diagnosis could be
associated with improved survival, there has been no decrease in lesion thickness over the last
decade (80).
Survival of advanced stage and metastatic melanoma in children is more difficult to
evaluate. Pediatric patients were not included in most clinical trials of adjuvant therapy for
melanoma, with the exception of few studies (135,140,143). Therefore, treatment plans for
children are mainly extrapolated from adult studies.
Overall, better understanding of tumor biology and risk-tailored therapies are needed for
children and y oung adults diagnosed with melanoma in order to improve long-term
outcomes.
Figure: Classification of the Primary Lesion
in Malignant Melanoma
Figure:
Progression-free survival of patients treated with Nivolumab plus Ipilimumab versus
Ipilimumab alone
(Adopted from 148. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab
versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372: 2006-2017).
Figure:
Actual survival rates of the adult and juvenile stage I patients registered at the Duke
University Melanoma Clinic.
(Adapted from 106. Reintgen DS, Vollmer R, Seigler HF. Juvenile malignant melanoma. Surg
Gynecol Obstet. 1989;168(3):249–253, with permission).
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CH A P TER 19
Late Effects of Cancer Treatment
Sughosh Dhakal, James E. Bates, Debra L. Friedman, and Louis S. Constine
Page 413With advances in multimodality therapy and supportive care, the cure rate for
childhood cancer continues to improve and now approaches 80% (1). However, the therapies
associated with this improved survival, chemotherapy, radiotherapy (RT), and surgery, can
lead to adverse long-term health-related outcomes. These are commonly known as late
effects and can manifest months, y ears, or even decades after completion of cancer
treatment. Late effects include organ dy sfunction, subsequent malignant and benign
neoplasms, and adverse psy chosocial sequelae. They place survivors of childhood cancer at
risk for chronic health conditions as they enter their adolescent and adult y ears. Although
surgical procedures can independently cause late effects or compound those caused by
radiation and/or chemotherapy, this chapter will focus on the latter two treatment modalities.
Subsequent malignancies will be discussed in great detail in another chapter of this textbook.
In a report from the Childhood Cancer Survivor Study (CCSS), the 30-y ear cumulative
incidence for severe (grade 3) or disabling/life-threatening (grade 4) conditions, or death
(grade 5) due to a chronic condition was 42% (2). In another report from this same cohort
study, the 30-y ear cumulative mortality was 18% among survivors; RT increased the risk 2.2-
fold (3). From the CCSS, where survivors all now have over 20 y ears of follow-up since
childhood cancer diagnosis, Figure 19.1 shows the cumulative incidence of chronic health
conditions by organ sy stem, noting the incidence of debilitating problems. Figure 19.2
shows the cumulative incidence of grade 3–5 conditions by primary childhood cancer
diagnosis of survivors compared to their siblings, demonstrating the significant variability in
both incidence and latency period for manifestation of late effects by disease. Of particular
note is the lack of any meaningful plateau in the steady rise in incidence of late effects
throughout the lifespan. Figure 19.3 shows the cause-specific cumulative late mortality.
Risk of death remains highest for recurrence of original disease, but 14% of deaths from this
cohort are now from subsequent malignancies (4).
Figure 19.1 Cumulative incidence of chronic health conditions of adult survivors of
childhood cancer by primary childhood cancer diagnosis and severity of condition. (From
Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of
childhood cancer. N Engl J Med. 2006;355:1572–1582, with permission.)
Figure 19.2 Cumulative incidence of chronic health conditions for severe, disabling, life-
threatening or fatal health conditions, by primary childhood cancer diagnosis. Leukemia (A),
CNS tumors (B), Hodgkin lymphoma (C), non-Hodgkin lymphoma (D), kidney tumors (E),
neuroblastoma (F), soft-tissue sarcoma (G), and bone tumors (H). (From Armstrong GT,
Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling, life-threatening, and
fatal events in the Childhood Cancer Survivor Study. J Clin Oncol. 2014;32:1218–1227.)
To prevent or ameliorate late effects related

to RT exposure requires an understanding of
tissue tolerance to therapy. This is affected by
the total and fractional dosage of irradiation,
dosage rate, overall treatment time, machine
energy, treatment volume (5), and dosage
distribution. Radiation damage is produced by
some combination of parenchy mal cell loss and
injury to the underly ing vasculature. Initial tissue
recovery results mainly from parenchy mal cell
repopulation. The progressive component of
damage is related to arteriocapillary fibrosis,
Figure 19.3 Cumulative cause-specific
which predominates in the late irreparable
mortality. (From Armstrong GT, Liu Q,
injury and accentuates the cellular depletion of
Yasui Y, et al. Late mortality among 5-
the parenchy ma. It is the vascular changes that
year survivors of childhood cancer: a
follow irradiation, but not chemotherapy, that
summary from the Childhood Cancer
partially account for the differences in late
Survivor Study. J Clin Oncol.
effects of the two modes of treatment. The
2009;27:2328–2338, with permission.)
distribution of late radiation damage reflects
primarily vascular injury and cannot be
explained simply as an indirect effect of parenchy mal cell loss. Devastating late effects of
RT ± chemotherapy can occur in both rapidly and slowly proliferating normal tissues without
a clinically recognizable acute phase because of this vascular injury. Naturally, surgical
procedures that negatively affect either the macro- or microvasculature can accelerate this
process and thereby enhance injury.
Advances in molecular biophy siology have provided insights into the responses of
normal tissues to chemotherapeutic and radiation injury. The acute and late phases of adverse
effects are actually manifestations of an ongoing sequence of events caused by autocrine,
paracrine, and endocrine messages that occur immediately after injury to a variety of cells:
epithelial, endothelial, fibroblastic, and inflammatory. A variety of growth and inhibitory
factors are released, specific cell receptors are altered, and the resulting signals received by
these receptors are translated into postreceptor cy toplasmic, nuclear, and interstitial events. A
combination of cell death, the production of reactive oxy gen species, alterations in gene
expression, and the expression of both proinflammatory and profibrotic cy tokines are viewed
as integral in the pathogenesis of late effects.
Figure:
Cumulative incidence of chronic health conditions of adult survivors of childhood cancer by
primary childhood cancer diagnosis and severity of condition.
(From Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors
of childhood cancer. N Engl J Med. 2006;355:1572–1582, with permission.)
Figure:
Cumulative incidence of chronic health conditions for severe, disabling, life-threatening or
fatal health conditions, by primary childhood cancer diagnosis. Leukemia (A), CNS tumors
(B), Hodgkin lymphoma (C), non-Hodgkin lymphoma (D), kidney tumors (E), neuroblastoma
(F), soft-tissue sarcoma (G), and bone tumors (H).
(From Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling,
life-threatening, and fatal events in the Childhood Cancer Survivor Study. J Clin Oncol.
2014;32:1218–1227.)
Figure:
Cumulative cause-specific mortality.
(From Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood
cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27:2328–
EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY ON NORMAL
TISSUE
Page 414Late effects have been reported in patients who received dosages of chemotherapy
and RT below the generally accepted threshold levels for either of the two when used alone.
Therefore, one must be circumspect in accepting “tolerance dosages” for normal tissues and
organs in the combined treatment modality era. Untoward reactions can occur at unexpected
times and in unpredictable way s. In rapid renewal sy stems, the same stem cell population is
affected, and one can usually mitigate the increase in acute toxicity of concurrent treatment
by treating sequentially. In slow renewal tissues, the additive ill effects of drugs and radiation
often are related to entirely different target cell populations in the same organ sy stem. Late
effects may not be avoidable because chemotherapy, whenever applied, can result in
additional stem cell kill and lead to expression of subclinical radiation effects. Therefore, the
tolerance dosages of fractionated RT, listed in Table 19.1 , might be lower in the setting of
chemotherapy and in y ounger children, as well as if daily doses of greater than 2 Gy are
administered, which is increasingly common with advanced radiation techniques. Table
19.2 lists some of the common adverse effects of chemotherapy, which may act
sy nergistically with RT.
Table 19.1 Tolerance Dosages, TD5–TD50 (Fractionated Dosage, Whole or Partial Organ)
Table 19.2 Common Chemotherapy Late Effects
Figure: Tolerance Dosages, TD5–TD50
(Fractionated Dosage, Whole or Partial
Organ)
Figure: Common Chemotherapy Late Effects
INFLUENCE OF THE DEVELOPMENTAL STAGE OF THE TARGET
ORGAN ON ITS SENSITIVITY TO THERAPY
The potential for the development of debilitating effects in normal tissues is related to the
cellular activity and maturation in the tissue under consideration. In children, a mosaic of
different tissues is developing at different rates and in different temporal sequences. In many
(but not all) tissues, organ development goes hand-in-hand with cell growth, and cellular
proliferation starts during the prenatal period. During the developmental period of each tissue,
stem cells within the embry o will move bey ond the pluripotent stage and, under the influence
of intrinsic and extrinsic factors, will follow one of two paths: (a) toward self-renewal, that is,
generation of more stem cells (multipotency ), or (b) toward differentiation, thereby giving
rise to a more specialized cell ty pe or tissue (unipotency ). Achieving a delicate balance
between these two processes is critical for an organ to achieve homeostasis. Thus, both
pathway s are involved in growth as well as the repair and regeneration of tissues. It can be
simplistically assumed that the downstream consequences from an injury, such as radiation,
may be predicted from the response of the respective stem cell populations since stem cells
and their progeny proliferate to ensure both organ growth and regeneration of injured and
dy ing cells. However, as adulthood/full maturation is reached, each organ will be made up of
a mosaic of both dividing and nondividing cells, not just within the tissue as a whole, but also
within each of the representative cell populations. Nondividing cells exist in several
compartments: for example, some may be found resting in G0 phase, although not all of
these are fully quiescent since some populations appear to be capable of re-entering cell
cy cle if the tissue is challenged or stimulated (6). Clinically, it is clear that the greater
potential for growth in pediatric tissues will mirror many of the adverse effects of radiation
therapy since insult will absolutely compromise growth potential and manifest as impaired
development. In fact, the injury that can occur in a pediatric tissue may not become manifest
until that tissue rapidly develops. An example of this is the impairment of bone growth seen
during adolescence due to radiation many y ears prior.
Page 416Traditionally, radiation dosages in children are modified by age, but without
specific recognition of the periods of active proliferation, differentiation, and eventual
maturation of one organ or tissue as it differs from another. Since intrinsic radiation sensitivity
and vulnerability to radiation-induced normal tissue damage are related to cellular activity
and level of maturity, it is important to understand tissue development and consider differing
sensitivities to the same insult at any given time in a child’s development as this could
drastically change the potential for adverse late outcomes. When does a pediatric tissue or
organ become similar to an adult tissue or organ? This is a major question that must be
addressed in order to predict the sensitivity to late effects (6).
Page 418The growth of specific tissues from birth to adulthood was characterized by
Tanner over a half century ago by four classical patterns: (1) ly mphoid, with accelerated
growth followed by involution at the time of puberty ; (2) brain, with rapid postnatal growth
that slows and essentially completes by early adolescence; (3) gonadal, with little change
during early life but rapid development just before and coincident with puberty ; and (4) a
more general pattern, epitomized by the musculoskeletal sy stem, characterized by two major
periods of rapid growth during the postnatal period and puberty. Figure 19.4 shows the
growth relationships according to time and ty pe of organ in the neonatal period and childhood,
while Table 19.3 provides specific data for a broader number of organs and sy stems.
Figure 19.4 Growth curves of different tissues. (From Tanner JM. Growth at Adolescence.
Oxford, England: Blackwell Scientific; 1962, with permission.)
Table 19.3 Anatomy and Physiology: Relative Rate of Development
As noted above, identify ing the different rates and ages at which each tissue matures is
necessary for determining the relative radiosensitivity of any tissue at any particular time
(7). In addition, recognizing the mechanism of organ growth—that is, an increase in the size
of cells (hy pertrophy ) as opposed to the number of cells (proliferation)—allows better
identification of relative radiosensitivity because organs that only hy pertrophy are less
vulnerable to functional disturbance by irradiation.
Although the classical growth curves provide valuable information, these data are limited
in that they only describe growth in terms of phy sical size and more specifically weight.
However, it is important to note that changes in the mass of an organ do not necessarily
correlate with other phy sical parameters (such as volume) and moreover that organs grow
through a variable combination of parenchy mal cell hy perplasia and hy pertrophy, as well as
stromal development. In regard to the variable sensitivity to late radiation toxicity, growth and
phy siologic functional development as measured by these parameters may be more
important than simple increases in size.
For example, in regard to mass, the ovaries follow the gonadal growth pattern, with little
change during early life and rapid development just before and coincident with puberty.
However, the organ’s sensitivity to late effects from radiation therapy does not follow this
pattern, at least in regard to sterility, since the mass of the ovary as a whole rapidly increases
before and during puberty, presumably because of stromal proliferation. The pool of oocy tes
that are responsible for fertility is continuously decreasing until menopause without
replenishment after a maximum number at 5 months gestational age (8).
Page 419A classical study showed that the effective sterilizing dose to the ovary after
fractionated radiotherapy decreased at increasing age of irradiation: 20.3 Gy at birth, 18.4
Gy at 10 y ears, 16.5 Gy at 20 y ears, and 14.3 Gy at 30 y ears of age (9). This finding is also
supported by the Childhood Cancer Survivor Study, which showed that cy clophosphamide
exposure was a risk factor for sterility in older (13–20 y ears), but not y ounger (<13 y ears)
children (10). Finally, data exist showing that late ovarian dy sfunction may be reduced in
children receiving total body irradiation prior to menarche compared to postmenarchal
children (11). A more complete discussion of ovarian late effects will be provided later in this
chapter.
This example further highlights the complexity of human growth and development, even
at the level of individual tissues and organs, and the need to expand our knowledge of growth
patterns bey ond simple increases in mass. In addition to expanding our understanding to
include additional measures of phy sical growth, such as volume (Fig. 19.5 ), and various
phy siologic parameters, determining differential mechanisms of growth, such as
parenchy mal cell proliferation and hy pertrophy versus stromal development, will enhance
our ability to predict and minimize differential late effects from therapy.
Figure 19.5 Heart and lung volumes as function of age, as defined on CT scan from a single
institution. A: Heart volume (male); B: Lung volume (male); C: Heart volume (female); D:
Lung volume (male). (From Dhakal S, Paulino AC, Constine LS. Pediatric growth and
development: impact on vulnerability to normal tissue damage from cancer therapy. In:
Schwartz CL, Hobbie WL, Constine LS, et al., eds. Survivors of Child and Adolescent Cancer: A
Multi-Disciplinary Approach. New York, NY: Springer; 2015:33–41, with permission.)
Figure:
Growth curves of different tissues.
(From Tanner JM. Growth at Adolescence. Oxford, England: Blackwell Scientific; 1962, with
permission.)
Figure: Anatomy and Physiology: Relative
Rate of Development
Figure:
Heart and lung volumes as function of age, as defined on CT scan from a single institution. A:
Heart volume (male); B: Lung volume (male); C: Heart volume (female); D: Lung volume
(male).
(From Dhakal S, Paulino AC, Constine LS. Pediatric growth and development: impact on
vulnerability to normal tissue damage from cancer therapy. In: Schwartz CL, Hobbie WL,
Constine LS, et al., eds. Survivors of Child and Adolescent Cancer: A Multi-Disciplinary
Approach. New York, NY: Springer; 2015:33–41, with permission.)
LATE EFFECTS BY ORGAN SYSTEM
Central Nervous System

Pathophysiology
The brain, by mass, develops rapidly in the first 3 y ears of life and very little after age 6.
This growth is caused by an increase in the size but not the number of neurons. Axonal
growth, dendritic arborization, and sy naptogenesis are most active at this time. If maturation
is judged by the degree of my elinization, then most regions are well developed by the second
y ear but are not complete until puberty (12). Radiation injury would be expected to be
profound during the early y ears. The essential radiation insult in radiation injury to the central
nervous sy stem (CNS) is a demy elinating lesion with focal or diffuse areas of white matter
necrosis (13).
The basic mechanisms underly ing the pathologic changes are not precisely known for
any particular sy ndrome of radiation damage. There are three proposed mechanisms;
vascular, clonogenic death of glial cells, and the allergic mechanism. They may act alone or
in any combination. The vascular mechanism centers on the endothelial cells, which are
radiosensitive and vital for microcirculation patency. Damage is expressed as cell death or
endothelial hy perplasia. Because endothelial cell turnover is slow, injury based on these cells
occurs over a prolonged time interval. The evolution of hy alin degeneration and obliterating
sclerosis of the arterioles produces areas of complete and incomplete necrosis. The
clonogenic death of glial cells mechanism postulates a radiation-induced reproductive death
of the slowly reproducing oligodendrocy te that maintains my elin. These cells show a
decrease in numbers within weeks after irradiation. Damage in individual nerve fibers can be
demonstrated quantitatively by electron microscopy as early as 2 weeks after irradiation and
before vascular damage. Effects on my elin sy nthesis and maintenance may be especially
important in childhood because my elogenesis is most active in the first y ear of life. The
ultimate result is demy elination. The allergic mechanism argues that the lesions of delay ed
radiation necrosis sometimes consist of disseminated plaques of demy elination with central
necrosis and occasional petechial hemorrhage. In the patent blood vessels that remain, there
may be perivascular cuffing with ly mphocy tes and plasma cells. An antigen is produced by
the reaction of ionizing irradiation with the oligodendromy elin complex. This antigen would
stimulate the accumulation of inflammatory cells.
Page 420The classical findings of radiation-induced necrosis of the CNS are large areas
of confluent, coagulative necrosis of the white matter and deep lay ers of the cortex; the
vascular changes of fibrinoid necrosis or fibrin incontinence; aty pia or absence of endothelial
cells; vascular thickening; telangiectasis; and vascular proliferation.
Clinical Manifestations
Necrosis
The incidence of radiation necrosis after therapeutic dosages is uncertain. Quoted incidence
data range from 0.1% to 5% after dosages of 50–60 Gy fractionated over 5–6 weeks (13,14).
The variability in the data is the result of the uncertainty concerning the denominator, the long
time-delay until the occurrence of necrosis, the lack of histologic confirmation in many
surviving patients, and the absence of postmortem data in patients who succumb. The clinical
signs and sy mptoms of radiation necrosis are headache and mass effect. Surgical debulking is
performed when possible and is often therapeutic (14). Corticosteroids may offer transient
relief. There is limited evidence that anticoagulation or bevicizumab may also offer some
benefit (15).
Necrotizing Leukoencephalopathy and Mineralizing Microangiopathy

Leukoencephalopathy is a late complication of cranial irradiation and sy stemic methotrexate
(MTX). The histologic appearance is of multifocal white matter destruction, especially in the
centrum semiovale and periventricular regions, with loss of my elin and oligodendrocy tes.
Hy podense areas emerge in the white matter, and there is cerebral atrophy, an increase in
the sulcal width, and enlargement of the ventricles. Mineralizing microangiopathy can occur
and is visualized on computed tomography (CT) scanning as intracerebral calcification (16).
The clinical features include lethargy, seizures, spasticity, paresis, and ataxia. The
multifactorial origin and risk of leukoencephalopathy have been studied in acute
ly mphoblastic leukemia (ALL) survivors. Radiation and MTX appear to be contributing
factors (17). Of interest is a report from the German Late Effects Working Group, which
documented CT and magnetic resonance imaging (MRI) evidence of atrophy,
leukoencephalopathy, calcification, or gray matter changes in approximately 50% of children
treated for ALL (18). The frequency and severity of abnormalities were greater in children
treated with cranial RT and MTX than in those treated with MTX alone. It is worth
emphasizing that the situation is decidedly worse in children who have CNS involvement with
ALL. In these cases, the presence of leukemia can alter the cerebrospinal clearance of MTX
and increase the risk of injury.
Neuropsychologic and Intellectual Deficits

Cranial irradiation of children may have significant adverse effects on intelligence, learning,
and social and emotional adjustment (16,19,20,21,22). Neurocognitive late effects most
commonly follow treatment of malignancies that necessitate CNS-directed therapies, such as
cranial radiation and CNS-directed chemotherapy (including high-dose sy stemic
chemotherapy ). Thus, children with CNS tumors, head and neck sarcomas, and ALL are
most commonly affected. Studies of patients with brain tumors must account for the
confounding variables of CNS injury by the tumor, seizures and their therapy, elevated
intracranial pressure, and surgery. In patients with leukemia and brain tumors, the use of
chemotherapy and the impact of the illness on body image and school attendance may
complicate the issue.
Deficits occur in a variety of areas, which include general intelligence, age-appropriate
developmental progress, academic achievement (especially in reading, language, and
mathematics), visual and perceptual motor skills, nonverbal and verbal memory, receptive
and expressive language, and attention (16,19,20,21,22).
The effects of cranial RT on subsequent intellectual function have been studied in detail,
most comprehensively in survivors of CNS tumors and leukemia. However, the effects of
radiation on the brain are difficult to define, especially when cranial radiation is often
routinely a part of multimodality therapy that may also include surgery and sy stemic or
intrathecal (IT) chemotherapy. Moreover, tumor-related deficits caused by concomitant
direct invasion of the brain, seizures, and hy drocephalus must be recognized.
With detailed assessment of IQ, achievement tests, learning ability, and school
performance, it is clear that cranial RT can result in significant neurocognitive dy sfunction,
especially for y ounger children, as demonstrated in a widely cited report from St. Jude
Children’s Research Hospital (Fig. 19.6 ).
With changes in the dosage, fields, and volumes of cranial and craniospinal RT, changes
in the incidence and spectrum of these adverse effects of therapy are expected. More recent
studies using lower dosages and more targeted volumes have demonstrated improved results
(23,24,25). Radiation to specific regions of the brain such as the hippocampi and temporal
lobes may be particularly deleterious (26). Ris et al. (23) evaluated the intellectual outcome
of children treated for posterior fossa medulloblastoma or primitive neuroectodermal tumor
(PNET). The study used a reduced craniospinal RT regimen of 23.4 Gy to the neuraxis and
32.4-Gy boost to the posterior fossa with adjuvant chemotherapy. The estimated rate of
decline in the full scale intelligence quotient
(FSIQ) was 4.3 points/y ear, for verbal
intelligence quotient (VIQ) 4.2 points/y ear, and
for nonverbal IQ (NVIQ) 4.0 points/y ear. In
examining host-related factors, a more
significant decline was seen for girls for VIQ
and for children less than 7 y ears old for NVIQ.
This latter observation was noteworthy in that the
older children’s baseline was lower, with little Figure 19.6 Intelligence quotient (IQ)
decline over time, as compared with the scores after conformal radiotherapy in
y ounger children, who had a much higher children with low-grade glioma. (From
baseline followed by a steep decline. The effect Merchant TE, Conklin HM, Wu S, et al.
of baseline intelligence was examined for the Late effects of conformal radiation
whole group, and the same phenomenon was therapy for pediatric patients with low-
seen. Children who had a baseline IQ of 100 or grade glioma: prospective evaluation of
higher had a much steeper decline in FSIQ, VIQ, cognitive, endocrine, and hearing deficits.
and NVIQ than children who had a baseline J Clin Oncol. 2009;27:3691–3697.)
under 100. The effect on FSIQ is shown in Figure
19.7 .
Page 421Patients with medulloblastoma may demonstrate a decline in IQ values
because of an inability to acquire new skills and information at a rate comparable to that of
their healthy same-age peers rather than a loss of previously acquired information and skills
(20). A reduction in the volume of normal-appearing white matter has been observed in some
survivors of childhood brain tumors, and this was associated with decreased attentional
abilities, which led to an IQ deficit and impaired academic achievement (21).
For ALL, older studies again show significant neurocognitive impairment (27). Even
when combined with IT chemotherapy, reduction in the cranial radiation dosage has resulted
in less neurocognitive impairment (28,29,30). Studies regarding CNS prophy laxis for ALL
showed that children who received RT and IT chemotherapy had lower IQ scores than those
who received craniospinal RT alone. Meadows et al. (27) found a significant IQ deficit in
children treated with 24-Gy cranial RT combined with IT MTX, as compared with childhood
cancer survivors who received no CNS-directed therapy, with the effect greatest among those
less than 5 y ears old. A similar effect on cognition with the addition of IT MTX has been
found in children treated for medulloblastoma (31).
Controversy regarding the role of RT in impairing neurocognition will continue, largely
because of differences in the radiation dosages, radiation volumes, chemotherapeutic
regimens, and vary ing study endpoints. Prophy lactic cranial irradiation of 24 Gy at 2 Gy per
fraction in the treatment of ALL can lower IQ
and achievement test scores. IQ loss may be on
the order of 8–10 points (i.e., median of normals
of 100 down to 90–92). Some studies suggest that
the neurocognitive effects of 18 Gy are reduced
relative to 24 Gy, and that 12 Gy (commonly
used in current protocols) does not cause
identifiable deficits, but the evidence regarding
this is not definitive (27).
The deleterious effects of sy stemic MTX,
especially at dosages greater than 1 g/m 2, may
be no different from those of 18 Gy cranial RT Figure 19.7 Full-scale IQ change by
(32,33). At lower MTX dosages, there does not baseline intelligence. Blue, baseline IQ <
appear to be a consistent pattern of 100; Red, baseline IQ > 100. (From Ris
neurocognitive deficits (34). A long-term study MD, Packer R, Goldwein J, et al.
of infants who received high-dose sy stemic Intellectual outcome after reduced dose
MTX combined with IT cy tarabine and MTX radiation therapy plus adjuvant
for CNS leukemia prophy laxis showed that 3–9 chemotherapy for medulloblastoma: a
y ears after treatment, cognitive function was in Children’s Cancer Group study. J Clin
the average range (35). Oncol. 2001;19:3470–3476, with
Chemotherapy without RT for ALL may permission.)
result in cognitive dy sfunction, but study results
vary significantly. Some studies have demonstrated impairment in tasks of higher order
cognitive functioning, mathematics (32), and mild visual and verbal short-term memory
deficits (36) in leukemia survivors treated with IT chemotherapy alone. Yet, others have
demonstrated no significant problems (29,37,38). The substitution of dexamethasone for
prednisone in the treatment of ALL has been implicated in increasing cognitive dy sfunction
(30), but a recent study randomizing children with ALL to prednisone or dexamethasone
found no significant differences in neurocognitive performance (38).
Myelopathy
The spectrum of radiation injuries to the spinal cord includes both transient and irreversible
sy ndromes. Rarely, a rapidly evolving permanent paraly sis can occur, presumptively from
acute infarction of the cord. A more common form of radiation injury is manifested by the
Lhermitte sy mptom, which consists of an electric shock–like sensation that radiates down the
spine and often into the limbs (39). The location of the sensation can change with time. The
sy mptoms may be precipitated by flexion of the neck, walking/sitting on a hard surface, or
other forms of phy sical exertion. The sy ndrome generally occurs a few months after spinal
irradiation. The mechanism is thought to be transient demy elinization, although detailed
human pathologic studies are lacking. There are no known CT or MRI correlations. It is also
reported in association with cisplatin administration, where the results may be long-lasting
(40).
Page 422Chronic progressive radiation my elitis (CPRM) is rare. The initial sy mptoms,
generally subtle, are usually paresthesias and sensory changes (including diminished
temperature sensation or proprioception), which start 9–15 months after therapy and progress
over the subsequent y ear (41). Much longer intervals to initial sy mptoms are seen
occasionally. The neurologic lesion must be within the irradiated volume. Recurrent or
metastatic tumor must be ruled out. Cerebrospinal fluid (CSF) protein may be elevated, and
my elography can demonstrate cord swelling or atrophy. MRI and CT provide additional
supportive information.
The incidence of CPRM and the radiation dosage causing this event are poorly defined
because of the diagnostic difficulties and the variety of radiation techniques (with uncertain
dosimetries). A review by Wara et al. (42) suggests that 42 Gy in 25 fractions carries a 1%
risk, 45 Gy a 5% risk, and 61 Gy a 50% risk. Data from Marcus and William (43) suggest that
the cervical cord may be more tolerant to radiation than previously presumed when 1.8- to
1.9-Gy fractional doses are used; in 324 patients treated to dosages of 55 Gy or less, no cases
of my elitis were seen. A higher risk of my elopathy is associated with higher individual
fraction sizes, shorter overall treatment time, higher total dosages, and long lengths of the cord
treated (especially more than 10 cm). Children may be more susceptible to CPRM,
developing it after lower radiation dosages and with shorter latency periods (41).
Cerebrovascular Disease
The risk of stroke is also increased among survivors of childhood cancer. Data from the CCSS
suggests a RR of 29.0 for the occurrence of a stroke in survivors of brain tumors relative to
their siblings and a RR of 6.4 in survivors of leukemia. Cranial RT was associated with stroke
risk in a dose-dependent fashion with doses above 30 Gy portending some risk and doses
above 50 Gy with the highest risk (44). Both cranial and cervical RTs were associated with
increased stroke risk among survivors of HL (45).
Additional Manifestations
Irradiation of the brain of a child can result in the somnolence sy ndrome. This develops 4–8
weeks after irradiation and is characterized by drowsiness, nausea, irritability, anorexia,
apathy, and dizziness. It most frequently occurs after treatment for ALL but can occur after
treatment for brain tumors. The somnolence sy ndrome resolves spontaneously ;
corticosteroids hasten recovery.
Arterial vasculopathy is an uncommon occurrence, almost alway s described after
irradiation to the parasellar region, primarily in children. Single- or multiple-vessel narrowing
or obliteration results in ty pical stroke deficits (46).
Table 19.4 reviews several CNS late effects with respect to causative treatments,
signs and sy mptoms, screening and diagnostic tests, and management and intervention (47).
Table 19.4 Evaluation of Patients at Risk for Late Effects: Central Nervous System
Psychosocial
Psychological Effects
Due to the lack of sy stematic screening for patients with and without evident psy chosocial
difficulties, the prevalence of psy chological distress among survivors is poorly characterized
and likely significantly underappreciated.
Many childhood cancer survivors report reduced quality of life or other adverse
psy chosocial outcomes. Survivors with neurocognitive deficits are particularly vulnerable to
adverse psy chosocial outcomes that affect achievement of expected social competence
during adulthood.
Childhood cancer survivors are also at risk of developing sy mptoms of psy chological
distress. In a 16-y ear longitudinal study of more than 4500 survivors, subgroups of survivors
were found to be at risk of developing persistent and increasing sy mptoms of anxiety and
depression, with those reporting pain and worsening health status at the greatest risk of
developing sy mptoms of anxiety, depression, and somatization (48). Long-term survivors of
childhood cancer are also significantly more likely to experience late suicidal ideation (OR
51.9) or recurrent suicidal ideation (OR 52.6) relative to healthy siblings (49). This
psy chological distress can lead to phy sical health problems; social withdrawal in adolescent
survivors of childhood cancer was associated with adult obesity and phy sical inactivity, risk
factors for a my riad of other conditions (50).
Sy mptoms of somatic distress and depression among 1834 survivors of HL in the CCSS
cohort were compared to healthy siblings. Eighty -seven had scores on the brief sy mptom
index that were sy mptomatic for depression, and 237 for somatic distress. Risk factors
included female sex, low socioeconomic status, lack of a complete high school education, lack
of employ ment, intensive chemotherapy, and elapsed time since therapy (51). In a
subsequent analy sis of the entire CCSS cohort, Mulrooney et al. (52) evaluated risk factors for
fatigue or sleep impairment. In univariate analy sis, compared with other diagnostic groups, a
diagnosis of HL or sarcoma was associated with higher risks of fatigue, depression, and sleep
impairment. In multivariate analy sis of the fatigue risk factors, hy pothy roidism and
depression were independent risk factors, and radiation therapy had a marginal association.
It is clear that a meaningful minority of childhood cancer survivors and their parents
demonstrate sy mptoms of uncertainty, distress, and posttraumatic stress, with some meeting
full criteria for posttraumatic stress disorder (PTSD). In a study from the CCSS, the
prevalence of PTSD and posttraumatic stress sy mptoms in y oung adult survivors of childhood
cancer was estimated to be 15–20%, depending on criteria used to define these conditions.
Because avoidance of places and people associated with cancer is part of PTSD, the
sy ndrome may interfere with appropriate access to health care. Risk factors include
perception of threat to life and severity of treatment, poor family functioning and decreased
social support (53,54,55,56,57,58).
Neuroendocrine
Hy pothalamic–pituitary (HP) irradiation may produce a large spectrum of neuroendocrine
abnormalities. In the SJLIFE cohort, 56.4% of survivors treated with cranial RT doses of
greater than 18 Gy developed a HP axis disorder (59).
Growth Hormone
Cranial irradiation most commonly effects growth hormone (GH) production and release.
GH is secreted episodically by the anterior pituitary gland. Growth hormone–releasing
hormone (GHRH), produced in the hy pothalamus, stimulates GH production. Somatostatin,
also produced in the hy pothalamus, excretes an inhibitory effect. In the liver and other
tissues, circulating GH stimulates the production of insulin-like growth factor 1 (IGF-1, also
called somatomedin-C), which promotes cell proliferation and protein sy nthesis. The
anatomic site of the radiation injury that produces GH deficiency is most frequently the
hy pothalamus.
Page 424Clinical Manifestations

The potential for neuroendocrine damage is likely to decrease with modern RT techniques
including smaller field sizes and decreased dosages. Approximately 60–80% of irradiated
pediatric brain tumor patients who have received dosages greater than 30 Gy have impaired
serum GH response to provocative stimulation. This usually occurs within 5 y ears of
treatment. The dose–response relationship has a threshold of 18–20 Gy. The higher the
radiation dose, the earlier the GH deficiency will occur after treatment.
This was described in a report (60) (Fig. 19.8 ) featuring data from 118 patients with
conformal radiation therapy (CRT) to localized brain tumors, with peak GH modeled as an
exponential function of time after therapy and mean radiation dose to the hy pothalamus. The
average patient was predicted to develop GH dy sfunction with the following combinations of
time after CRT and mean dose to the hy pothalamus: 12 months and more than 60 Gy ; 36
months and 25–30 Gy ; and 60 months and 15–20 Gy. A cumulative dose of 16.1 Gy to the
hy pothalamus would be considered the mean radiation dose required to achieve a 50% risk of
GH dy sfunction at 5 y ears (TD50/5).
Children treated with CNS irradiation for leukemia are also at greater risk of GH
deficiency. Sklar et al. (61) evaluated children treated for ALL and showed a dose-response
relationship between increasing cranial RT dose and decreasing height. In the CCSS, Chow
demonstrated that risk for adult short stature is highest among patients treated with cranial or
craniospinal RT, but is also elevated among those treated with chemotherapy alone (62).
Figure 19.9 shows the height SDS for ALL survivors, treated pre- or postpubertally with
chemotherapy alone, cranial or craniospinal RT as compared with siblings.
Children who receive bone marrow
transplantation (BMT) with total body irradiation
(TBI) have a significant risk of GH deficiency.
Risk is higher with single-dose as opposed to
fractionated radiation, pretransplant cranial
irradiation, female sex, and posttreatment
complications such as graft-versus-host disease
(GVHD) (63,64). Regimens with busulfan and
cy clophosphamide also increase risk (64). Figure 19.8 Peak growth hormone
Hy perfractionation of the TBI dosage markedly (GH) according to hypothalamic mean
reduces risk in the absence of pretransplant dose and time after start of radiation.
cranial radiation (65). Among 181 children who According to equation 2, peak GH =
underwent stem cell transplantation before exp{2.5947 + time × [0.00079 × mean
puberty, an overall decrease in final height SDS dose]}. (From Merchant TE, Rose SR,
value was found compared with the height at Bosley C, et al. Growth hormone
transplant and genetic height. The ty pe of secretion after conformal radiation
transplantation, GVHD, GH, or steroid treatment therapy in pediatric patients with
did not influence final height. TBI (single greater localized brain tumors. J Clin Oncol.
than fractionated dosage), male sex, and y oung 2011;29:4776–4780.)
age at transplant were found to be major factors
for long-term height loss. The majority of patients (140 of 181) reached adult height within
the normal range of the general population.
GH deficiency should be treated with replacement therapy. There has been some
controversy surrounding this therapy, with a concern over increased risk of recurrence and
second malignant neoplasms (SMNs). However, most studies are limited by selection bias
and small sample size. Sklar et al. (66) studied 361 GH-treated cancer survivors enrolled in
the CCSS. The relative risk of disease recurrence was 0.83 (95% CI 0.37–1.86) for GH-
treated survivors. GH-treated subjects were diagnosed with 15 SMNs, all solid tumors, for an
overall relative risk of 3.21 (95% CI 1.88–5.46), mainly because of a small excess number of
SMNs observed in survivors of acute leukemia. Two other studies have shown no increased
risk of relapse or SMN (67,68). The data surrounding SMNs must be interpreted with caution
given the small number of events.
Page 425Non–Growth Hormone Tropins

Pubertal growth can also be adversely affected by cranial radiation. Dosages greater than 50
Gy may result in gonadotropin deficiency, and dosages of 18–47 Gy can result in precocious
puberty. Precocious puberty has occurred
mostly in girls who received dosages of at least
24 Gy. However, earlier puberty and earlier
peak height velocity are seen in girls treated with
18 Gy cranial radiation (69).
Shalet et al. (70) showed that the age of
pubertal onset is positively correlated with the
age at the time of cranial irradiation. The impact
of early puberty in a child with radiation-
associated GH deficiency is significant, and the
timing of GH is especially important for GH-
Figure 19.9 Height standard deviation
deficient girls also at risk of precocious puberty.
scores (SDS) for ALL survivors, treated
With higher dosages of cranial irradiation (more
pre- or postpubertally with
than 35 Gy ), deficiencies in the gonadotropins
chemotherapy alone, cranial or
can be seen, with a cumulative incidence of 10–
craniospinal RT. (From Chow EJ,
20% at 5–10 y ears (71).
Friedman DL, Yasui Y, et al. Decreased
Constine et al. (72) documented non-GH
adult height in survivors of childhood
abnormalities in 20 children treated with
acute lymphoblastic leukemia: a report
irradiation for brain tumors not involving the
from the Childhood Cancer Survivor
hy pothalamic–pituitary (HP) region including
Study. J Pediatr. 2007;150:370–375, with
low free T4 levels caused by hy pothalamic or
permission)
pituitary injury and low luteinizing hormone
(LH) and estradiol with oligomenorrhea. The
frequency of central hy pothy roidism after cranial irradiation relates to the dosage to the HP
axis, with a greater likelihood after dosages greater than 40 Gy. Although some reports
suggest that the incidence is as low as 6%, the radiation dosages to the HP axis in those reports
were not specifically determined (73,74). In Constine et al.’s series (75), 65% of patients
treated in the higher dosage range had evidence of subclinical or clinical hy pothy roidism. In
a report by Paulino (76) on children treated for medulloblastoma, and thus with somewhat
lower HP dosages, 19% of children developed central hy pothy roidism.
Adrenocorticotropin deficiencies and hy perprolactinemia are rare in children because
dosages greater than 50 Gy are needed for their development (72,77). Samaan et al. (78)
found deficiencies in 83% of patients treated for nasophary ngeal or paranasal sinus
carcinoma, in whom more than 60 Gy was ty pically administered. Twenty -seven percent
had thy roid abnormalities, attributed to hy pothalamic injury in one-third of the patients and
pituitary injury in the remainder. Cortisol deficiency attributable to hy pothalamic injury also
occurred in 27% of patients. Abnormalities of prolactin and LH were noted in 39% and 30%,
respectively. A summary of neuroendocrine complications of therapy, the relationship to
dosage, diagnostic studies, and interventions are provided in Table 19.5 (47).
Table 19.5 Evaluation of Patients at Risk for Late Effects: Neuroendocrine
Thyroid
Radiation-induced thy roid neoplasms are considered in Chapter 20 . The effects of
therapeutic irradiation on the endocrine function of the thy roid will be reviewed here. The
thy roid may be directly irradiated in the treatment of childhood head and neck cancers such
as rhabdomy osarcoma, nasophary ngeal ly mphoepithelioma, and squamous cell carcinoma,
a variety of other aerodigestive tract tumors, and HL. A photon spinal field used during
craniospinal irradiation for brain and spinal tumors and for leukemia will also deliver radiation
to the thy roid.
Pathophysiology
The thy roid gland consists of follicles filled with colloid and lined by follicular cells, which
trap iodide. The gly coprotein thy roglobulin is a major component of the colloid and
participates in the formation and storage of thy roid hormones. The primary, hormonally
active iodothy ronines, triiodothy ronine (T3) and thy roxine (T4), are largely bound to plasma
proteins when released by the gland. Thy roxine-binding globulin (TBG) is the major transport
protein, and only a small percentage of unbound T3 and T4 are available for activity. The
pituitary hormone thy roid-stimulating hormone (TSH) regulates sy nthesis and release of T3
and T4. TSH secretion is stimulated by the hy pothalamic hormone thy rotropin-releasing
hormone (TRH) and inhibited by the circulating free thy roid hormones.
The pathophy siology of radiation-induced thy roid dy sfunction is not precisely defined.
Direct radiation damage to the thy roid follicular cells, the thy roid vasculature, or the
supporting stroma may occur. Histopathologic changes in an irradiated thy roid gland include
progressive obliteration of the fine vasculature, degeneration of follicular cells and follicles,
atrophy of the stroma, and, less commonly, ly mphocy tic infiltration. Because radiation
damage depends on the degree of mitotic activity and the thy roid of a developing child grows
in parallel with body growth, this gland would be expected to show an age-related degree of
injury and repair.
Hypothyroidism
Of children treated with radiation therapy, most develop hy pothy roidism within the first 2–5
y ears posttreatment, though later dy sfunction is possible. Reports of thy roid dy sfunction
differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria
utilized to make the diagnosis. The most frequently reported abnormalities include elevated
TSH, depressed thy roxine (T4), or both (79,80,81,82). Compensated hy pothy roidism includes
an elevated TSH with a normal T4 and is asy mptomatic. Uncompensated hy pothy roidism
includes both an elevated TSH and a depressed T4.
The incidence of hy pothy roidism should
decrease with lower cumulative doses of
radiation therapy employ ed in newer protocols.
In a study of Hodgkin ly mphoma (HL) patients
treated between 1962 and 1979, hy pothy roidism
occurred in 4 of 24 patients who received mantle
doses less than 26 Gy but in 74 of 95 patients
who received greater than 26 Gy (75). Among a
cohort of CCSS patients treated for HL there was
a strong dose-response relationship between RT
dose and 20-y ear risk of hy pothy roidism (79).
The cumulative incidence of hy pothy roidism
among survivors 15 y ears following leukemia
diagnosis was found to be 1.6% in the CCSS
cohort. In multivariate analy sis, survivors who
Figure 19.10 Probability of developing
received ≥20 Gy cranial RT plus any spinal RT
an underactive thyroid after diagnosis of
had the highest risk of subsequent the Hodgkin disease. (From Diller L, Chow
hy pothy roidism (HR 8.3) compared with those EJ, Gurney JG, et al. Chronic disease in
treated with chemotherapy alone. In radiation
the Childhood Cancer Survivor Study
dosimetry analy sis, pituitary doses ≥20 Gy
Cohort: a review of published finding. J
combined with thy roid doses ≥10 Gy were Clin Oncol. 2009;27:2339–2355.)
associated with hy pothy roidism (83). Figure
19.10 shows the cumulative incidence of hy pothy roidism respectively after treatment for
HL.
Page 428Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at
increased risk of thy roid dy sfunction, with the risk being much lower (15–16%) after
fractionated TBI, as opposed to single-dose TBI (46–48%). While mildly elevated TSH is
common, it is usually accompanied by normal thy roxine concentration (84). Non–TBI-
containing regimens historically were not associated with an increased risk. However, in a
report from the Fred Hutchinson Cancer Research Center, the increased risk for thy roid
dy sfunction was not different between children receiving a TBI or busulfan-based regimen
compared with cy clophosphamide conditioning alone.
Central hy pothy roidism (low free T4 with low or inappropriately normal TSH) can also
occur. The threshold dose for development of central hy pothy roidism appears to be 42 Gy to
the hy pothalamus, with only 11% of those receiving less than 42 Gy developing the condition
and 44% receiving ≥42 Gy developing central hy pothy roidism (85).
Hyperthyroidism
Thy rotoxicosis may occur after mantle or cervical irradiation for HL. In Hancock et al.’s
report (86), approximately 2% of patients (n = 34) developed Graves’ disease. Almost all had
a diffuse goiter, high free T4, low TSH, and elevated thy roid uptake of radioiodine. One-half
of these patients developed infiltrative ophthalmopathy, as did an additional four patients who
did not have overt hy perthy roidism. The RR for Graves’ disease was 7.2–20.4. Six patients
developed silent thy roiditis characterized by transient mild sy mptoms of thy rotoxicosis,
elevated serum-free T4 and low TSH, no thy roid enlargement or tenderness, and low thy roid
uptake of radioiodine (87). All of these patients subsequently developed hy pothy roidism.
In the CCSS study of HL survivors by Sklar et al. (79), the relative risk for
hy perthy roidism compared with sibling control subjects was 8.0, with cases becoming
manifest 3–5 y ears after diagnosis. In the study of ALL survivors from the CCSS, the 15-y ear
cumulative incidence was 0.6%. Craniospinal RT was associated with an increased risk of
subsequent hy perthy roidism (HR 6.1) compared with chemotherapy alone. In radiation
dosimetry analy sis, pituitary doses ≥20 Gy combined with thy roid doses ≥15 Gy were
associated with hy perthy roidism (83).
Detection and Screening

Laboratory screening evaluations for asy mptomatic patients should include serum
concentrations of TSH and free thy roxine. Because the latent interval to the development of
abnormality can be prolonged, sy stematic clinical and laboratory evaluation should be
performed y early.
Management
Patients with uncompensated hy pothy roidism (low serum concentration of thy roxine) clearly
need thy roid replacement therapy. Patients with elevated serum concentrations of TSH but
normal thy roxine are treated with thy roid replacement therapy in most institutions. The
rationale for this approach is that subclinical hy pothy roidism may evolve into overt
hy pothy roidism, and prolonged TSH stimulation of an irradiated thy roid gland may increase
the risk of carcinoma (75,86).
Table 19.6 reviews several thy roid late effects with respect to causative treatments,
Table 19.6 Evaluation of Patients at Risk for Late Effects: Thyroid
Bone and Body Composition

Pathophysiology
It has long been established that bone growth can be impaired by radiation. The
pathophy siology of radiation injury to growing bone probably is attributable to damage to the
chondroblasts. Single doses of 2–20 Gy inhibit proliferation of cartilage cells, thereby
decreasing cellularity and causing disarray of the cellular columns within the growth plate.
The resulting diminished bone growth is attributed to this loss of proliferating cells in the
growth plate, the decreased ability of surviving cells to sy nthesize matrix, or the production of
an abnormal matrix that fails to calcify.
The effects of radiation on growing bone have been summarized by Rubin et al (6).
Epiphy seal irradiation, to a sufficient dosage, causes an arrest of chondrogenesis;
metaphy seal irradiation results in a failure of absorptive processes in calcified bone and
cartilage; and diaphy seal irradiation produces an alteration in periosteal activity, which causes
abnormal bone modeling. Therefore, the location of an RT field on a long bone can
significantly influence the nature and severity of the subsequent deformity.
Bone Growth Retardation
Clinically, radiation’s effects on growing bone may be most simply characterized as
shortening of long bones (i.e., femur, tibia, humerus) or hy poplasia of flat bones (i.e., ilium).
The crucial factors influencing the ultimate height of the patient may be inferred from the
data previously presented: the radiation total dose and dose per fraction; the energy, dose
distribution, and absorptive properties of the beams; the bones that are irradiated and the
epiphy seal plates that are encompassed; the age at the time of irradiation (imply ing that the
amount of growth already obtained is important in judging ultimate outcome); the influence
of other toxins on growth, such as exogenous steroids and cy totoxic chemotherapy ; and the
patient’s genetic constitution.
Page 430A large body of knowledge has been developed concerning loss of height after
childhood irradiation. Much of the data published in the 1970s and 1980s reflect treatment
with higher dosages of RT than those currently used. However, several recent reports indicate
that stature loss must still be considered in the late effects of RT. For children treated with
craniospinal RT, the cranial dosage can result in decreased growth by causing growth
hormone deficiency as previously discussed, and the spinal dosage can result in stature loss
through its effect on the vertebral bodies (62).
Patients who receive radiation therapy for the Wilms tumor are an ideal population for
study of the effect of RT and age at the time of treatment on stature. As a result of earlier
studies showing a higher risk of spinal curvature with asy mmetric radiation to the vertebral
bodies, standard flank radiation now includes the affected side and extends across the spinal
column but excludes the contralateral kidney. Hogeboom et al. (89) evaluated stature loss in
2778 children treated for Wilms tumors. For those under 12 months of age at diagnosis who
received more than 10 Gy, the estimated adult height deficit was 7.7 cm when contrasted with
the nonradiation group. For those who received 10 Gy the estimated trunk shortening was 2.8
cm or less. Among those whose height measurements in the teenage y ears were available,
patients who received more than 15 Gy of RT were 4–7 cm shorter on average than their
nonirradiated counterparts, with a dose–response relationship evident. Chemotherapy did not
confer additional risk.
Scoliosis and Kyphosis

Scoliosis and ky phosis are common consequences of spinal or flank irradiation. Asy mmetric
spinal growth has been seen most often after irradiation for Wilms tumor and neuroblastoma,
where there has also been flank surgery (e.g., nephrectomy ) (90). The ty pes of deformities
observed included a lateral flexion curve, concave to the side of the primary tumor, and a
rotary scoliosis. However, with current dosages and fields of RT used to treat the Wilms
tumor, scoliosis and ky phosis are less common. In a series by Paulino et al. (91), in a group of
42 children treated for Wilms tumor from 1968 to 1994, 7 developed muscular hy poplasia, 5
were found to have limb length inequality, 3 had ky phosis, and another 3 had iliac wing
hy poplasia. Scoliosis was seen in 18, with only 1 patient needing orthopedic intervention.
Median time to development of scoliosis was 102 months (range 16–146). A clear dose–
response relationship was seen, with children treated with lower dosages (less than 24 Gy )
having a significantly lower incidence of scoliosis than those who received more than 24 Gy.
There was also a suggestion that the incidence was lower in patients who received 10–12 Gy,
the dosages currently used for the Wilms tumor, although the sample size was small.
Asy mmetric irradiation of the vertebrae seemed to promote the development of rotary
scoliosis and lateral flexion curvature. Some clinicians believe that it is better to arrest a
growth plate than partially irradiate it and cause a curvature. It is for this reason that some
clinicians prefer true anteroposterior portals. Lateral and tangential ports may give sufficient
variation in intensity of radiation to the epiphy seal plates of the spine to produce scoliosis by
the irregular advance of the epiphy ses. This led to the change in RT fields now used to treat
unilateral intra-abdominal tumors of childhood. If therapy is limited to one-half of the
abdomen, it is advisable to bring the ports slightly bey ond the midline so that the entire
transverse diameter of the spine is included, receiving irradiation of fairly uniform intensity.
If the entire abdomen needs treatment and it must be subdivided into quadrants, caution
should be exercised in avoiding quadruple crossfiring of the spine, producing a “hot spot” in
the region of the first or second lumbar vertebrae.
Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphy sis (SCFE) is a clinically significant adverse effect observed in
patients after irradiation of the femoral head (92). There is a threshold dosage of 25 Gy for
this complication. It occurred in about 50% of children irradiated before 4 y ears of age (7 of
15), compared with only 4.8% of 5- to 15-y ear-olds (1 of 21). A similar age effect is seen
with TBI for HSCT. Fletcher et al. (93) found more significant metaphy seal and epiphy seal
abnormalities in those treated before 8 y ears of age than in those treated between 12 and 19
y ears of age. The mechanism of SCFE is postulated to be a radiation-induced delay in
maturation of the epiphy seal plate with disruption of normal calcification and bone matrix
deposition. This renders the plate weak and prone to slippage through shearing stress at the
tilted femoral line. When the femoral heads are shielded during irradiation, the frequency of
this complication is small.
Avascular Necrosis (Osteonecrosis)

Avascular necrosis (osteonecrosis [ON]) is reported now with increased frequency following
not only RT, but also following treatment with corticosteroid (Fig. 19.11 ). The self-reported
20-y ear cumulative incidence of ON in the CCSS cohort was 0.43% with a rate ratio (RR) of
6.2 (95% CI, 2.3–17.2) compared with siblings. A total of 44% developed ON in a previous
radiation field. Risk was greatest among survivors of stem-cell transplantation for leukemia.
Nontransplantation patients with leukemia and bone sarcoma were at higher risk for ON.
Older age at diagnosis, shorter elapsed time,
older treatment era, exposure to dexamethasone
(± prednisone), and gonadal and nongonadal
radiation were independently associated with
ON (94).
Even among patients treated with more
contemporary therapy for ALL or NHL without
RT, as many as 1 of 3 patients may be affected
by ON, likely reflecting the cumulative exposure
to glucocorticosteroid therapy. The pathogenesis
includes suppression of bone formation,
expansion of the intramedullary lipocy te Figure 19.11 Cumulative incidence
compartment, and a direct effect on nutrient (CI) of bony morbidity for 176 children
arteries. Children 10 y ears of age and older are treated for ALL between 1987 and 1991.
at particular risk and the disorder is substantially With 7.6 years of median follow-up, the
more prevalent in Caucasians than African overall 5-year CI (±SE) was 30% ± 4%.
Americans. The risk is also higher in newer The 5-year CI of fracture was 28% ± 3%,
protocols with higher cumulative dose and longer and of osteonecrosis, 7% ± 2%. (From
continuous duration dexamethasone therapy. Strauss AJ, Su JT, Dalton VM, et al. Bony
Genetic predisposition may play a role. In an morbidity in children treated for acute
analy sis from the Children’s Oncology Group, a lymphoblastic leukemia. J Clin Oncol.
PAI-1 poly morphism (rs6092) was associated 2001;19:3066–3072, with permission.)
with risk of osteonecrosis in univariate and
multivariate analy ses (adjusting for gender, age, and treatment arm) (95). Osteonecrosis is
often multiarticular and bilateral, affecting weight-bearing joints predominantly
(96,97,98,99).
Page 431Other Skeletal Abnormalities

A variety of other skeletal abnormalities can be seen after irradiation. These include sternal
deformity (hy poplasia, asy mmetry, pectus excavatum, pectus carinatum) (100); hy poplasia
of the iliac bones or lower ribs; cartilaginous exostoses (101); osteochondromata (102);
hy poplasia of the mandible; deformity of orbital, maxillary, nasal, or temporal bone
(102,103); and lower extremity abnormalities such as acetabular dy splasia, coxa vara, hip
dislocation, and leg shortening (104).
Table 19.7 reviews several musculoskeletal late effects with respect to causative
treatments, signs and sy mptoms, screening and diagnostic tests, and management and
intervention (47).
Table 19.7 Evaluation of Patients at Risk for Late Effects: Musculoskeletal
Osteopenia
Bone mineral density in childhood cancer survivors may be reduced, especially in children
treated for ALL, or with HSCT, where it has been best studied. Risk factors include increased
age at the time of exposure, estrogen deficiency, female sex, corticosteroid use and ty pe, GH
deficiency, and cranial radiation. Prevalence, chronicity, and severity are not consistent
across studies, so the risk remains poorly defined (105,106,107,108). Further research into the
pathophy siology, the contribution of the various risk factors, the ty pe and frequency of
screening, the populations at highest risk, and interventions are clearly indicated.
Metabolic Syndrome
An increased risk of metabolic sy ndrome (central obesity with hy pertension, dy slipidemia,
and abnormal glucose metabolism) or its components has been observed among cancer
survivors (109,110,111,112,113). The evidence for this outcome ranges from clinically
manifested conditions that are self-reported by survivors to retrospectively assessed data in
medical records and hospital registries to sy stematic clinical evaluations of clinically well-
characterized cohorts. Studies have been limited by cohort selection and participation bias,
heterogeneity in treatment approach, time since treatment, and method of evaluation, as well
as the evolving definition of the metabolic sy ndrome itself. Despite these limitations,
compelling evidence indicates that the metabolic sy ndrome is highly associated with
cardiovascular events and mortality (110,112,114), and therefore survivors are good
candidates for targeted screening and lifesty le counseling regarding risk-reduction measures
(115,116).
Cardiac
The functional and structural complexity of the heart places it at risk for a spectrum of RT and
chemotherapy injuries that can occur. The radiation-associated sequelae include acute
pericarditis during radiation (rare and associated with juxtapericardial cancer); delay ed
pericarditis, which can present abruptly or as chronic pericardial effusion (rarely progressing
to tamponade); pancarditis, which includes pericardial and my ocardial fibrosis with or
without endocardial fibroelastosis; my opathy in the absence of significant pericardial disease;
coronary artery disease (uncommon, usually involving the left anterior descending artery );
functional valvular injury ; and conduction defects (117,118,119). The hallmark of these
injuries histologically is fibrosis in the interstitium with normal-appearing my ocy tes and
capillary and arterial narrowing.
Several parameters must be considered in the evaluation of these radiation-associated
injuries, including the relative weighting of the radiation portals and, therefore, the amount of
radiation delivered to different depths of the heart; the presence of juxtapericardial tumor; the
volume and specific areas of the heart irradiated; the total and fractional irradiation dosage;
the presence of other cardiovascular risk factors in each patient such as age, weight, blood
pressure, family history, lipoprotein levels, and smoking status; and the use of specific
chemotherapeutic agents.
The effects of thoracic RT are difficult to separate from those of anthracy clines because
few children are exposed to thoracic RT in the absence of anthracy clines. Both individually
cause a significant increase in risk of late cardiac toxicity ; combined, their effects are likely
additive (120), if not multiplicative (Fig. 19.12 ).
Figure 19.12 A & B: Marginal (Kaplan–Meier) and cause-specific (C & E) (competing risk)
cumulative incidence of cardiac events (CEs) in childhood cancer survivors stratified
according to different treatment groups. A: Marginal cumulative incidence for all CEs,
stratified according to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank p <
0.001. B: Marginal cumulative incidence for all CEs, stratified according to different CTX
therapies, log-rank p < 0.001. C: Cause-specific cumulative incidence for congestive heart
failure, stratified according to different treatment groups, log-rank p < 0.001. D: Cause-
specific cumulative incidence for cardiac ischemia, stratified according to cardiac
irradiation (RTX) or no RTX, log-rank p < 0.01. E: Cause-specific cumulative incidence for
valvular disease, stratified according to RTX or no RTX, log-rank p < 0.001. The shaded
colorized background areas refer to the 95% CIs. Ant, anthracycline. (From van der Pal H,
van Dalen EC, van Delden E, et al. High risk of symptomatic cardiac events in childhood
cancer survivors. J Clin Oncol. 2012;30:1429–1437, with permission).
It is important to note that the pathogenesis of injury differs. Anthracy clines cause direct
damage to my ocy tes, which are a terminally differentiated cells and thus relatively resistant
to the cy totoxic effects of radiation (121). The incidence of cardiac disease is strongly
associated with the average dose to the heart, with doses greater than 15 Gy associated with
significantly increased incidence of CHF, MI, valvular disease, and pericardial disease,
especially 15–20 y ears after irradiation, as noted in another analy sis of the CCSS (120).
Echocardiographic evidence of sy stolic dy sfunction can be found at cumulative doses of 1–
19.9 Gy and diastolic dy sfunction can be seen at doses of 20–20.9 Gy (122) (Fig. 19.13 ).
Figure 19.13 Cumulative incidence of cardiac disorders among childhood cancer
survivors by average cardiac radiation dose. (From Mulrooney DA, Yeazel MW, Kawashima T,
et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer:
retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606.)
Page 433Among survivors of childhood cancer in Britain, cardiovascular disease was

associated with a 3.4% absolute excess risk of death (123). Review of data from the CCSS
shows significant cardiovascular morbidity across all survivors of childhood cancer, with the
caveat that the data are based on self-report. Cardiac disease is the most common severe,
disabling, life-threatening, or fatal chronic health condition found among long-term survivors
of childhood cancer with survivors having a 6.9-fold increase relative to healthy siblings
(124). Increased risk for CHF, MI, and pericardial disease was seen in survivors of childhood
leukemia, brain tumors, Hodgkin ly mphoma, non-Hodgkin ly mphoma, renal tumors,
neuroblastoma, sarcomas, and bone malignancies. Increased risk for valvular disease was
seen in all aforementioned tumor ty pes aside from brain tumors and sarcomas (125). Similar
efforts from Europe have replicated these findings in a cohort whose late effects were
verified via retrospective chart review rather than self-reporting (120). Among childhood
survivors of Hodgkin ly mphoma, there was a linear dose–response relationship between
mediastinal RT dose and risk of late cardiac toxicities; valvular disease was most common,
followed by CAD, cardiomy opathy, arrhy thmias, and pericardial disease (126). Finally,
cardiac complications after BMT may occur, with arrhy thmias, pericarditis, and my opathies
predominating. High-dose cy clophosphamide is clearly a causative agent. TBI is a secondary
contributing factor.
Page 434It is important to note that in regards to time after therapy there does not appear
to be a plateau in the excess cardiovascular risk for adult survivors of childhood cancers.
Although advances in radiation treatment planning and delivery (as well as decreases in
radiation prescription doses) have been made over the past few decades that greatly reduce
the radiation exposure of the heart, there exists a large cohort of adult patients, treated during
childhood, who were cured of their malignancy using older techniques and remain at
significant risk for the development of cardiovascular disease.
The risk of serious cardiac events appears to be potentiated bey ond what would be
expected by an additive model by the presence of concurrent conditions such as obesity,
dy slipidemia, diabetes, and, in particular, hy pertension. Hy pertension was independently
associated with all serious cardiac outcomes (RRs, 6-fold to 19-fold), even after adjustment
for anthracy cline use and chest irradiation (115). Survivorship care for patients treated with
cardiotoxic therapies should thus include screening, counseling, and optimal medical
management of modifiable risk factors for cardiovascular disease.
Pericarditis
Delay ed acute pericarditis can be sy mptomatically occult or present suddenly with fever,
dy spnea, pleuritic chest pain, friction rub, ST- and T-wave changes, and decreased QRS
voltage. Up to 30% of patients treated for HL with a mean midplane heart dosage of 46 Gy
are affected (127). With equally weighted AP:PA fields and the use of subcarinal blocking,
the frequency decreases to 2.5% (128). The onset of delay ed acute pericarditis averages 6
months, and 92% of effusions (usually exudative) occur within 12 months. Although the
effusion usually self-resolves within 10 months, it may persist for y ears. Pericardiectomy is
a high-risk procedure in this setting because of the coexistence of other ty pes of radiation-
induced damage and is thus reserved only for severe cases. Hancock et al. (129) noted a 4%
(at 17 y ears) actuarial risk of pericardiectomy (occurring only in children treated with higher
radiation dosages), and most patients improved after surgery. In an analy sis of the CCSS, the
30-y ear incidence of pericardial disease is 3.0% among all survivors of childhood cancer;
children receiving cardiac doses of 15–35 Gy were 2.2 times more likely than their siblings to
develop pericardial disease. This jumped to a hazard ratio of 4.8 among those receiving >35
Gy (125).
Cardiomyopathy
Cardiomy opathy is highly potentiated by doxorubicin and other anthracy clines (idarubicin,
epirubicin, daunomy cin) but can occur in its absence (128,129). Although an in-depth
discussion of the late cardiotoxic effects of anthracy cline administration will not be presented,
its importance and frequency must be emphasized. This is especially important because
more contemporary HL treatment protocols are using lower dosages of RT but continue to
use doxorubicin in the 200–300-mg/m 2 range. Doxorubicin has been the most extensively
studied of the anthracy clines, and its cardiotoxicity is often progressive and disabling.
Increased risk of doxorubicin-related cardiomy opathy is associated with female sex,
cumulative dosages greater than 200–300 mg/m 2, y ounger age at the time of exposure, and
increased time from exposure (130,131,132,133,134,135).
Page 435Prevention or amelioration of anthracy cline-induced cardiomy opathy is of
utmost importance due to the use of anthracy clines in cancer therapy (136). Dexrazoxane
(DZR) is a bis-dioxopiperazine compound that readily enters cells and is subsequently
hy droly zed to form a chelating agent. DZR has been shown to prevent cardiac toxicity in
adults and children treated with anthracy clines (136,137,138,139,140). An unexpected finding
of increased risk of SMN following DZR use has been reported in a single study of its use in
HL, where it was administered within hours of not only doxorubicin, but etoposide, another
topoisomerase II inhibitor (141). This has not been found to date in other studies where DZR is
used as a cardioprotectant (142).
Cardiomy opathy is additionally a significant effect seen following chest-directed RT
though it is of a different flavor than anthracy cline-induced cardiomy opathy. The traditional
measure of sy stolic function, left ventricular ejection fraction (LVEF) is markedly reduced in
long-term survivors of childhood cancer at cumulative anthracy cline doses greater than 100
mg/m 2. A decrease in LVEF is not seen until cumulative chest-directed RT doses reach 20 Gy.
However, an alternative measure of sy stolic function, global longitudinal strain, is depressed
in children receiving even 1–19 Gy of chest-directed RT. Additionally, chest-directed RT
doses of greater than 20 Gy place survivors at risk for diastolic dy sfunction; no cumulative
dose of anthracy cline was found to cause this (122). Long-term survivors are at a 2.2-fold
increased risk of CHF if they received 15–35 Gy of cardiac radiation and a 4.5-fold increase
if >35 Gy relative to their siblings.
Children who need HSCT are at especially high risk of cardiac toxicity. They may have
received anthracy clines or RT with the heart in the field as part of their initial cancer therapy,
and they are subsequently exposed to conditioning regimens that may include high-dose
cy clophosphamide and TBI (143,144). Assessment of the cardiovascular complications of
BMT will assume greater importance with the increasing number of children undergoing this
therapy. In a report from the University of Minnesota on 63 transplanted children, 74% of
children old enough to undergo treadmill exercise testing had a borderline or abnormal
response to exercise, and 12.7% of patients had sy mptomatic cardiovascular abnormalities
(143). The preparative regimen included TBI in slightly more than half of the patients, but this
was independently associated with outcome.
A model was developed that can estimate the risk for the development of heart failure in
childhood survivors of malignancy based on data from the CCSS and verified against the
SJLIFE, NWTS, and Emma Children’s Hospital cohorts. The input variables are sex, age at
diagnosis, anthracy cline dose, and chest RT dose, further emphasizing the role of treatment
modalities in the risk of development of late cardiac toxicities (145).
Valvular Disease
Fibrous valvular endocardial thickening occurs in 80% of autopsied patients treated with high
radiation dosages. The mitral, aortic, and tricuspid valves are most often affected (146).
Although such valvular lesions are common, they rarely evolve into sy mptomatic valvular
disease. Long-term survivors receiving less than 15 Gy mean cardiac dose had no increased
risk for valvular disease; those receiving 15–35 Gy had a 3.3-fold increased risk and those
receiving >35 Gy had a 5.5-fold increased risk relative to siblings (125). In some patients, the
radiation-induced cellular injury to the valvular endocardium, combined with chronic
pressure-related trauma, may eventually lead to valvular deformity, resulting in stenosis or
insufficiency. In a report by Hancock et al. (129) on 635 children treated for HL, 2 patients
died of valvular disease, and 3 others have undergone aortic (2 patients) or mitral (1 patient)
valve replacement. A contribution of mediastinal irradiation to significant or accelerated
valvular disease could not be clearly determined. Unfortunately, in another report, valve
replacement in such patients was infrequently successful and operative mortality was high
(66%) (147).
Arrhythmia
High-degree atrioventricular (AV) conduction abnormalities are rarely seen and have been
attributed to fibrosis of the AV node conducting branches (148). In one series, all patients with
radiation-associated AV block had received more than 40 Gy to the chest, with a median time
to development of the block of 14 y ears (149). Again, as with cardiomy opathy, the effect of
doxorubicin should be considered.
Coronary Artery Disease

As the population of cured childhood cancer patients ages and becomes exposed to the risk
factors for coronary artery disease (CAD) such as smoking, obesity, hy pertension, diabetes,
and elevated cholesterol, it is possible that excess morbidity and mortality from ischemic
heart disease may occur if RT or chemotherapy accelerates atherosclerosis. RT can lead to
ischemic heart disease via endothelial damage and obliteration of the microvasculature and
via accelerated atherosclerosis of large vessels.
The manner in which thoracic irradiation is
administered may significantly affect the
incidence of radiation-associated CAD. Modern
advances in radiation technique and field
construction have significantly reduced cardiac
dose. However, it is important to note that the
proximal coronary arteries, which are
commonly the site of obstruction, are not
shielded with routine cardiac blocking (Fig.
19.14 ) (118). Data from the University of
Rochester demonstrated that the site of coronary
artery stenosis in patients irradiated for HL was Figure 19.14 Location of the coronary
most commonly in the proximal coronary vessels (dark lines) on a standard mantle
arteries, no different than that which would be field is illustrated. The blocks are outlined
found in the general population. More in white. (From King V, Constine LS, Clark
specifically, the left main and the proximal D, et al. Symptomatic coronary artery
portions of the left anterior descending and right disease after mantle irradiation for
coronary arteries are most commonly involved Hodgkin’s disease. Int J Radiat Oncol Biol
(118). Phys.1996;36:881–889, with permission.)
Page 436The risk of my ocardial infarction
(MI), cardiac failure, and death are clearly related to RT dosage and field, although host
factors modify this risk. The Institut Gustave–Roussy reported 13 MIs in 499 mantle-
irradiated patients (10-y ear cumulative incidence of 30%) but observed no MIs in 138
patients who received no irradiation. Clearly modern techniques reduce this risk–Hancock et
al. (150) found that in patients with HL irradiated with more modern radiotherapeutic
techniques, there was no significant difference in MI mortality when compared with that in
age- and sex-matched control subjects. Data from the University of Rochester assessed the
risk of CAD in survivors of HL along with the prevalence of cardiac risk factors. Although the
risk of cardiac death was elevated at 2.8 (3.1 for males and 1.8 for females), other risk factors
were more common than in the general population; among patients with HL, 72% smoked,
72% were male, 78% had hy percholesterolemia, 61% were obese, 28% had a positive
family history, 33% had hy pertension, and 6% had diabetes (118). This suggests that RT is one
of several risk factors for CAD in patients treated for HL. Among a more mixed population of
childhood cancer survivors in the CCSS, there was a 2.4-fold increased risk of MI in patients
who received 15–35 Gy and 3.6-fold increased risk in patients who received >35 Gy of mean
cardiac radiation relative to their siblings. There was no increased risk seen in those receiving
less than 15 Gy. An increased risk was seen among survivors of leukemia, brain malignancies,
HL, neuroblastoma, sarcoma, and bone malignancies, but not among survivors of NHL and
renal tumors (125).
Table 19.8 reviews several cardiac late effects with respect to causative treatments,
Table 19.8 Evaluation of Patients at Risk for Late Effects: Cardiac
Lungs
The target cells for pulmonary injury are ty pe I and II pneumocy tes, fibrocy tes, endothelial
cells, and macrophages (6,151). Several pulmonary radiation sy ndromes occur in the child.
Acute pneumonitis and chronic fibrosis result from injury to the ty pe II pneumocy tes and
endothelial cells. Chronic respiratory limitations result from impairment in the development
of new alveoli or from growth impairment of the established ones. Limitations of a different
character result from a reduction in growth of the muscle, cartilage, and bone that form the
thoracic cage.
Pathophysiology
The acute reactions of radiation pulmonary injury, known as the exudative phase, can be
detected within 24 hours of irradiation. It is signified by intra-alveolar edema and exudation
of proteinaceous material into the alveoli, impairing gas exchange. Infiltration by
inflammatory cells and desquamation of epithelial cells from the alveolar walls occur. A
proliferative phase occurs between 2 and 6 months with accumulation of ty pe II alveolar
cells and protein leakage into the alveolar spaces. Interstitial edema organizes into collagen
fibrils, leading to the thickening of the alveolar septa and a clinical pneumonitis. Injury to the
ty pe II pneumocy te, with resultant changes in the surfactant sy stem (and thus alveolar
surface tension and compliance) and in the endothelial cell and capillary permeability, causes
these changes (152). After 6 months the fibrotic phase occurs. Alveolar septa become fibrotic
and thickened by bundles of elastic fibers, forming the basis for chronic respiratory injury.
Eventually, the alveoli collapse and are obliterated by connective tissue. Capillaries are lost,
replaced, and then recanalized. The target cells that trigger this process are less clearly
established but include the septal fibrocy te and endothelial cell.
Acute pneumonitis usually occurs 3–6 months after the start of radiation. The sy mptoms
include fever, congestion, a hacking but eventually productive cough, dy spnea, chest
tightness, and pleuritic pain. Signs are initially absent, but consolidation and pleural fluid or a
friction rub may be detected. If a large enough volume (greater than 75%) of lung is treated
at dosages greater than 45 Gy, then cor pulmonale and death can occur. Surviving patients
experience a protracted phase that slowly resolves. Lung function abnormalities are
generally not detected for 4–8 weeks after completion of irradiation. Restrictive changes with
volume loss occur, accompanied by a fall in diffusion capacity with mild arterial hy poxemia.
Hy poperfusion of the irradiated area and decreased lung compliance can be demonstrated.
The earliest radiographic changes (1–3 months after therapy ) are a diffuse infiltrate
corresponding to the radiation field with volume loss.
Chronic fibrosis is seen months to y ears after therapy, but most changes are apparent by
1–2 y ears. Most patients are asy mptomatic, but chronic respiratory impairment with
dy spnea, orthopnea, cy anosis, or cor pulmonale may occur. Maximum breathing capacity
and tidal volume decrease. Chest radiographs show linear streaking that may extend outside
the irradiated field. Regional contraction, pleural thickening, and tenting of the diaphragm
occur.
Radiation and Chemotherapy Effects on the Lung

In the modern management of pediatric malignancies, RT is often given in combination with
chemotherapy. It is important to recognize that many chemotherapeutic agents either induce
lung damage on their own or potentiate the damaging effects of radiation on the lung. In the
CCSS, both RT and chemotherapy increased risk of chronic lung problems. Statistically
significant associations were present between thoracic irradiation and lung fibrosis, need for
supplemental oxy gen, chronic cough, and pleurisy. Chemotherapy agents associated with the
same self-reported pulmonary problems included carmustine, lomustine, bleomy cin, and
cy clophosphamide. With ongoing follow-up of the cohort, the cumulative incidence continues
to increase for lung fibrosis up to 15–25 y ears after diagnosis for those who received chest RT
both with and without pulmonary -toxic chemotherapy (153,154). Figure 19.15 shows the
cumulative incidence of pulmonary toxicity with ongoing follow-up. Changes in lung function
in children treated to the whole lung for metastatic Wilms tumor have been reported. A
dosage of 12–14 Gy reduced total lung capacity and vital capacity to about 70% of predicted
values, and even lower if the patient had undergone thoracotomy. Fractionation of dosage
decreases this risk (155,156). Among a cohort of 122 long-term survivors at high-risk for
pulmonary dy sfunction per COG guidelines there was a 6.2-fold increase in restrictive
defects and 5.2-fold increase in diffusion defects relative to age and gender-matched healthy
controls. Age under 16 at diagnosis and chest RT >20 Gy were associated with restriction
defects; female gender and chest RT >20 Gy were associated with diffusion defects (157).
Chemotherapeutic agents such as doxorubicin, dactinomy cin, and busulfan are radiomimetic
agents and can reactivate latent radiation damage (155,158). The development of bleomy cin-
associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually
occurring at dosages greater than 200 U/m 2, higher than those used in pediatric malignancies
(158,159). While sy mptomatic pulmonary disease is uncommon with lower doses (15–25
Gy ) of RT in combination with bleomy cin therapy, pulmonary function tests may reveal
abnormal diffusing capacity (160,161).
Page 438
Figure 19.15 Cumulative incidence of chronic pulmonary conditions by type of therapy

(CRX, chest radiation; PTC, pulmonary toxic chemotherapy). (From Diller L, Chow EJ,
Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor Study cohort: a review of
published findings. J Clin Oncol. 2009;27:2339–2355, with permission.)
Patients who are treated with HSCT are at greater risk of pulmonary toxicity, related to
preexisting pulmonary dy sfunction, the preparative regimen (which may include
cy clophosphamide, busulfan, carmustine, and TBI), and to the presence of GVHD
(162,163,164,165). Although most transplant survivors are not clinically compromised,
restrictive lung disease may occur. Obstructive disease is less common, as is the recently
described late-onset pulmonary sy ndrome, which includes the spectrum of restrictive and
obstructive disease. Bronchiolitis obliterans, cry ptogenic organizing pneumonia, diffuse
alveolar damage, and interstitial pneumonia may occur as a component of this sy ndrome,
generally 6–12 months after transplant. Cough, dy spnea, or wheezing may occur with either
normal chest radiograph or diffuse or patchy infiltrates; however, most patients are sy mptom
free (163,165).
Cerveri et al. (162) evaluated pulmonary function tests in survivors of pediatric HSCT; of
note, 44% of patients had abnormal pulmonary function testing at baseline. At 3–6 months
posttransplant, 85% had abnormalities. At 24 months, these persisted in 62% of patients. A
restrictive abnormality was most common at 3–6 months after transplant.
The risk of acute pneumonitis increases from 5% after autologous transplantation to 20%
after allogeneic. The use of fractionated and low-dose rate regimens may decrease the risk.
Fry er et al. (152) and Keane et al. (163) analy zed the relationship between single doses
of irradiation to the whole lung and the resulting fatal pneumonitis. After correction for an
increased lung transmission of 15–20%, a dose–response relationship was generated. Lethal
pneumonitis was seen in 5% of patients after 8.2 Gy, 50% after 9.3 Gy, and 90% after 11 Gy.
Thus, a difference of 2 Gy could change mortality from 0% to 50%, which emphasizes the
importance of correcting for lung density. Increasing the dose rate from 0.1 to 0.5 Gy per
minute increased the frequency of injury from 50% to 90%.
Page 439The tolerance of the whole lung to fractionated doses of radiation is well
described, particularly in Wilms tumor patients (164,165,166). In the absence of
chemotherapy and with daily doses of 1.3–1.5 Gy, the TD5 is 26.5 Gy and the TD50 is 30.5
Gy. Young children experience more chronic toxicity at lower doses than older children and
adults because of interference with lung and chest wall development, in addition to fibrosis
and volume loss (167). After 20 Gy, mean total lung volumes and DLCO are reduced to 60%
of predicted values (166). Even within the dose range currently used for whole lung
irradiation (11–14 Gy ), restrictive changes occur (165).
Table 19.9 reviews several pulmonary late effects with respect to causative
intervention (47).
Table 19.9 Evaluation of Patients at Risk for Late Effects: Pulmonary
Ovary
Radiation and chemotherapy can cause transitory or permanent effects on reproductive
capacity, endocrine integrity, and sexual function. The complexity of defining these sequelae
stems from the dose-dependent effects caused by different chemotherapy agents, RT, and
their combination. Injury to the ovaries can cause both sterilization and suppressed hormone
production because of the relationship of the latter to the presence of ova and maturation of
the primary follicle. Therefore, affected patients can have impaired development of
secondary sexual characteristics, menstrual irregularities including amenorrhea, and
sy mptoms associated with menopause such as hot flashes, loss of libido, and osteoporosis.
Pathophysiology
The ovary produces oocy tes and secretes steroid hormones. Active mitosis of oogonia occurs
during fetal life. The cortices of the ovaries harbor the follicles within connective tissue. The
follicles arise from the germinal epithelium, which covers the free surface of the ovary.
Through involution, atresia, and, to a much lesser extent, ovulation, the follicles disappear
entirely at menopause. Hy pothalamic gonadotropin-releasing hormone (GnRH) surges in late
childhood to initiate puberty. GnRH stimulates release of the pituitary gonadotrophs, which
orchestrate follicular maturation (follicle-stimulating hormone, FSH) and ovarian luteinization
(LH). With sexual maturity comes the 28-day cy cle with an estrogen-dependent midcy cle
surge of FSH and LH. After ovulation, the corpus luteum forms and produces progesterone,
estradiol, and 17-hy droxy progesterone, and the resultant endometrial changes. Without
chorionic gonadotropin from a conceptus, the corpus luteum is exhausted and progesterone
and estrogen fall. As FSH increases, the endometrium sloughs (menstruation). Ovarian
hormones have critical phy siologic effects on other organs, including maturation and
maintenance of the breasts and vagina, bone mineralization, integrity of the cardiovascular
sy stem, and libido. With depletion of oocy tes by radiation, chemotherapy, or aging, the
ovaries undergo atresia, and menstruation and estrogen production cease.
Radiation causes a decrease in the number of small follicles, impaired follicular
maturation, cortical fibrosis and atrophy, generalized hy poplasia, and hy alinization of the
capsule. Alky lating chemotherapeutic agents affect the resting oocy te in a dose-dependent,
cell cy cle–independent manner. Thecal cells and ova are depleted, as are the primordial
follicles, resulting in arrest of follicular maturation and decreased estrogen secretion.
Primarily because girls treated before puberty have a greater complement of ova than do
older women, ovarian function is more resistant to the effects of chemotherapy RT in
y ounger girls.

Effect on ovarian function by RT depends not
only on dose and fraction, but also on the
patient’s age and sexual developmental stage.
Data from Ash (168) summarized the effect of
fractionated RT on ovarian function in women of
reproductive age (Table 19.10 ). Ovaries in
y ounger girls are more resistant to the effects of
RT than those of adolescents. When one
considers single-fraction doses to the ovary,
temporary sterility can occur with dosages of
1.7–6.4 Gy and permanent sterility after 3.2–10
Gy (169). Wallace et al. (170) reviewed data to
estimate an LD50 of 6 Gy for the oocy te. Whole
abdomen dosages of 20–30 Gy are associated
with primary or premature secondary ovarian
Table 19.10 Effect of Fractionated
failure. It is also possible that direct or scattered
Irradiation on Ovarian Function in
irradiation from the spinal component of
Women of Reproductive Age
craniospinal irradiation may produce ovarian
damage (170,171).
Historically, to shield the ovaries from direct irradiation during, for example, pelvic
irradiation from HL, an oophoropexy may be performed. During this, the ovaries are moved
to a midline position in front of or behind the uterus or laterally to the iliac wings. Central
pelvic blocking at the time of “inverted Y” fields prevented direct irradiation, although scatter
dose and transmitted dose will be inevitable. Medial or lateral transposition of the ovaries
results in ovarian dosages of 8–10% and 4–5%, respectively, of the pelvic dosage (172). This
is ty pically compatible with preservation of fertility. Fortunately, with modern CT-based,
three-dimensional treatment planning and highly conformal treatment delivery techniques
such as intensity modulated radiation therapy, ovarian function is often preserved without the
need for oophoropexy.
Because RT is no longer used as a single
modality to treat most forms of childhood
cancer, the effects of chemotherapy must also
be considered. Cy clophosphamide, nitrogen
mustard (mechlorethamine), busulfan,
procarbazine, and other alky lating agents and
nitrosoureas are all capable of causing ovarian
dy sfunction. In a study of 2498 survivors and
3509 siblings treated between 1945 and 1975,
there was a 7% fertility deficit among female
Figure 19.16 Cumulative incidence of
survivors as compared with their siblings. Forty -
nonsurgical premature menopause.
two percent of those with alky lating agent
(From Green DM, Sklar CA, Boice JD Jr,
exposure and abdominal radiation experienced
et al. Ovarian failure and reproductive
menopause by the age of 31 y ears (173).
outcomes after childhood cancer
Mechlorethamine and procarbazine together are
treatment: results from the Childhood
perhaps the most damaging of the agents.
Cancer Survivor Study. J Clin Oncol.
Substitution of cy clophosphamide for
2009;27:2374–2381, with permission.)
mechlorethamine appears to have significantly
reduced the risk of ovarian dy sfunction, which is
further lessened by reduction in total dosage of both agents. In the CCSS, acute ovarian failure
occurred in 8.3% of eligible survivors and premature nonsurgical menopause occurred in 8%
of survivors as compared with 0.8% of siblings. Strong positive dose–response relationships
were seen for both increasing ovarian RT doses and increasing alky lating agent score.
Attained age and a primary diagnosis of HL were also risk factors (174). Figure 19.16
shows the cumulative incidence of nonsurgical premature menopause (175).
In transplant recipients, TBI is associated with ovarian failure. Sklar et al. (176)
documented amenorrhea and the failure to develop secondary sexual characteristics in
prepubertal girls who received 10 Gy TBI and ovarian failure in all pubertal women, 50% of
whom had menopausal sy mptoms. Sanders et al. (177) evaluated gonadal function in HSCT
survivors 1–11 y ears after marrow transplantation. All 15 women less than 26 y ears old and 3
of 9 more than 26 y ears old who were treated with 200 mg/kg cy clophosphamide recovered
normal gonadotropin levels and menstruation. Of 38 women who were prepared with 120
mg/kg cy clophosphamide and 920–1200 cGy TBI, only 3 had normal gonadotropin levels and
menstruation.
Table 19.11 reviews several ovarian late effects with respect to causative treatments,
Page 441
Table 19.11 Evaluation of Patients at Risk for Late Effects: Ovarian
Breast
As would be expected, children and adults have different manifestations of late radiation
injury in the breast, with breast hy poplasia being the most common ty pe of late toxicity in
children. In 129 children less than 4 y ears of age receiving a mean dose of 2.3 Gy for
hemangioma, breast hy poplasia was observed in 53% (178). Others have also observed
breast hy poplasia after relatively low doses of radiation, such as for pulmonary metastases
from Wilms tumor where children receive bilateral lung irradiation to doses of 10–12 Gy
(179). The risk of development of secondary breast malignancies is strongly correlated with
age (children vs. adults). This is discussed in great detail in Chapter 20 .
Testes
Germ cell integrity, Ley dig and Sertoli cell functioning, and the neuromuscular control of
ejaculation are vulnerable to cancer therapy. Although fertility and hormone production are
closely related in the ovary because of their dependence on the ova and primary follicle,
these functions differ in the testes because of the differing sensitivity of the spermatogonia
and Ley dig cells to cy totoxic therapy. Therefore, the effects of surgery, radiation, and
chemotherapy must be considered in the context of various specific functions.
Pathophysiology
Spermatogenesis, or the formation of spermatozoa from immature germ cells, takes place in
the seminiferous epithelium in the tubules. The least differentiated germ cells, the
spermatogonia, divide to form spermatocy tes. Immediately after formation, these cells
undergo meiosis to form spermatids, which then metamorphose into motile spermatozoa. A
constant supply of germ cell precursors is essential to the continuous production of
spermatozoa, which are then transported through the lumen of the seminiferous tubules into
the epididy mis, where they are stored. Ley dig cells are the primary androgen-secreting cells
and account for at least 75% of the total testosterone produced by the normal man (180).
Normal secretion of LH by the pituitary gland is essential for Ley dig cell function; LH levels
rise if inadequate androgen is produced. The phy siologic role of FSH in spermatogenesis is to
trigger an event in the immature testis that is essential for the completion of spermiogenesis.
FSH levels rise if such spermatid differentiation is compromised. Once the process of
spermatogenesis is established, it proceeds continuously as long as the supply of testosterone
is available. Testosterone also stimulates the development of male secondary sex
characteristics and, through negative feedback, pituitary LH secretion. Measurement of
testosterone production by the testis, therefore, is of major significance in the evaluation of
testicular function.
There is no question that RT can cause infertility. The testes can be irradiated directly by
scattered irradiation, or by radiation transmitted through shielding blocks. Because the
spermatogonia are exquisitely sensitive to radiation, even small dosages can produce
measurable damage. Depression of sperm counts is discernible at dosages as low as 15 cGy.
This decrease in sperm counts may evolve 3–6 weeks after irradiation. Depending on the
dosage, recovery may take 1–3 y ears. The germinal epithelium is damaged by much lower
dosages (less than 1 Gy ) of RT than are Ley dig cells (20–30 Gy ) (181). Complete sterilization
may occur with fractionated irradiation to a dosage of 1–2 Gy. Spermatocy tes generally fail
to complete maturation division at dosages of 2–3 Gy and are visibly damaged after 4–6 Gy
with resulting azoospermia. Higher dosages are necessary to damage spermatids that will
damage the more sensitive spermatocy tes. At the highest dosages, permanent sterility is
common. At lower dosages, this reduced sperm count is seen 60–80 day s after exposure,
which is the time at which maturation would otherwise be complete (182).
Page 442A variety of studies have shown that multiple small fractions of radiation are
more toxic to spermatogenesis than a large, single fraction. This has been called the reverse
fractionation effect. It is the result of the extreme radiosensitivity of the testicular germinal
epithelium, the small number of stem cells, and rapid cell turnover (182). Table 19.12
summarizes the fractionated dose-related effect on spermatogenesis and Ley dig cell function
(168).
Table 19.12 Effect of Fractionated Testicular Irradiation on Spermatogenesis and
Leydig Cell Function
For abdominal RT, the effect of the testes results from scatter. Sklar et al. (183) evaluated
the effect of 12 Gy radiation to the abdomen on testicular function of long-term ALL
survivors and found 55% to have evidence of germ cell dy sfunction. Scatter from abdominal
radiation with dosages greater than 20 Gy for HL can cause transient elevation in FSH and
oligospermia, but there is no effect with lower dosages. When patients are treated for HL, the
scattered dosage to the testes from a mantle or para-aortic field is negligible. However, when
the pelvis is treated, the calculated dosage depends on the relative location of the testes to the
inguinal field, with dosages ranging from 3% to 10% without a specially designed testes shield
and less than 1% with such a shield. Therefore, the testis, with well-designed shielding,
receives less than 2 Gy, and this dosage can be reduced further with the use of multileaf
collimation. The available data on males treated for HL suggest that fertility is either
maintained or only transiently depressed.
The effects of RT are often combined with those of chemotherapy, particularly
alky lating agents. The germinal epithelium of prepubertal testes is susceptible to damage
produced by several chemotherapeutic agents including cy clophosphamide, nitrogen
mustard, and procarbazine. Testicular biopsies after chemotherapy have demonstrated
aplasia of the germinal epithelium. Spermatogenesis is highly sensitive to cy clophosphamide,
with a dose–response relationship and an effect exacerbated by coadministration of other
alky lating agents, such as procarbazine. This was illustrated in a study by Bokemey er et al.
(184) in which long-term gonadal toxicity was compared among survivors of HL and NHL.
Both groups had received comparable median cumulative dosages of cy clophosphamide, but
only the patients with HL received procarbazine. The incidence of gonadal toxicity was more
than three times higher in men in the HL group. The only men in the NHL group who had
FSH elevation had received far higher dosages of cy clophosphamide than the mean. There
has been a consensus that boy s who receive less than 4 g/m 2 of cy clophosphamide without
any other alky lating agents and without testicular or cranial radiation are likely to retain their
fertility. However, in a report from Hobbie et al. (185), even four cy cles of
cy clophosphamide, vincristine, procarbazine, prednisone (COPP)/ABV (doxorubicin,
bleomy cin, vinblastine), where procarbazine was given in addition to the cy clophosphamide,
without RT, can result in sterility in males.
Page 443More recently, ifosfamide has been used as part of multimodality therapy for a
variety of childhood cancers, often in combination with cy clophosphamide or
abdominopelvic RT. Little is known about its long-term gonadal toxicity. Several studies have
looked at small groups of male survivors and ifosfamide appears to be more sparing on
fertility and a cumulative dose of >60 g appears to be an important threshold (186,187).
In a study of 248 adult male long-term survivors of childhood cancer, gonadal function
was evaluated. Inhibin B was lower in survivors than controls and was the most sensitive
discriminator. Significantly decreased inhibin B levels and increased FSH levels were found in
men treated for HL and NHL, AML, neuroblastoma, and sarcoma as compared to other
malignancies. Cumulative dosages of procarbazine and cy clophosphamide were the only
independent chemotherapy -related predictors for the decrease of inhibin B levels and the
increase of FSH levels. Age at the time of treatment did not influence posttreatment inhibin B
or FSH levels (188). In a retrospective cohort study, proven fertility (ever fathered a
pregnancy ) was evaluated by self-report among 213 men treated for ALL before the age of
18 and compared with male siblings. Proven fertility of male survivors was not different
from that of controls (relative fertility (RF) = 0.95, 95% CI 0.63–1.43). However, married
men treated before the age of 10 with high-dose (24 Gy ) cranial RT, without spinal RT, had
only 9% of the fertility of controls. High-dose cranial RT at older ages was not associated with
a statistically significant fertility deficit (189).
The limited data available indicate that chemical changes in Ley dig cell function are
observable after direct testicular irradiation. Shalet et al. (190) studied 11 boy s irradiated with
24 Gy in 12–16 fractions for a testicular relapse of ALL. Abnormalities of gonadotropin
secretion consistent with testicular damage were seen in nine (82%) of the boy s. The
mechanism for the increase in FSH is not entirely clear, but it is inversely proportional to the
loss of germ cells in the seminiferous tubules. Brauner et al. (191) studied boy s treated with
24 Gy of testicular radiation with a mean follow-up of 3.8 y ears. Among 12 prepubertal
boy s, all had normal basal testosterone, 3 had elevated basal LH, and response to HCG was
diminished in 10. Among nine pubertal boy s, basal testosterone was diminished in six and
response to HCG was diminished in seven. A correlation exists between age and response to
HCG stimulation.
With the growing use of BMT to treat malignant and nonmalignant diseases, the effects
of the transplantation preoperative regimen on reproduction are of interest. High dosages of
alky lating agents often are used in the treatment program. After 200 mg/kg of
cy clophosphamide and marrow transplantation for aplastic anemia, 18 prepubertal boy s
were evaluated, on average, 9 y ears after transplant. All boy s over 13 y ears of age showed
normal progression through puberty and have demonstrated normal LH, FSH, and
testosterone levels. In eight patients who underwent semen analy sis, two are azoospermic and
six are normal. Another population of prepubertal boy s who received TBI or TBI plus
testicular irradiation was also studied. All boy s who received TBI plus additional testicular
irradiation of 18–24 Gy had delay ed development and elevated FSH and LH levels with
diminished testosterone levels. The majority of those who received TBI alone had normal LH
levels with elevated FSH (192). Table 19.13 reviews several testicular late effects with
respect to causative treatments, signs and sy mptoms, screening and diagnostic tests, and
management and intervention (47).
Table 19.13 Evaluation of Patients at Risk for Late Effects: Testicular
Reproduction and Offspring

Many survivors of childhood cancer previously treated with cy totoxic therapy remain fertile,
so pregnancy outcomes and the risk of cancer or genetic disease in offspring must be
addressed. Young women who have been exposed to RT below the diaphragm are at risk of
impaired uterine development, which can result in adverse pregnancy outcomes. The
magnitude of the risk is related to the radiation field, total dosage, and fractionation schedule.
This can lead to premature labor and low–birth weight infants. Female long-term survivors
treated with TBI and marrow transplantation are also at risk of ovarian follicular depletion,
impaired uterine growth and blood flow, early pregnancy loss, and premature labor if
pregnancy is achieved. Despite standard hormone replacement, the uterus of these y oung
girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at
which radiation was received (193).
With more childhood cancer survivors retaining their fertility, pregnancy outcome data
are now available. In the CCSS, 5149 female participants were compared with 1441 female
siblings and the RR for ever having been pregnant by survivors was 0.81. Risk factors included
hy pothalamic RT ≥ 30 Gy, ovarian/uterine RT dose of >5 Gy, high alky lating doses, treatment
with lomustine or cy clophosphamide (161). In the same cohort, Green et al. (194) evaluated
pregnancy outcomes of partners of male survivors. Among 4106 sexually active men, 1227
reported that they sired 2323 pregnancies, which resulted in 69% live births, 13%
miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analy sis.
Compared with partners of male siblings, there is a lower chance of live births (RR = 0.77)
but no significant differences of pregnancy outcome by treatment. The rate of miscarriage
was higher for the partners of male survivors treated with more than 5000 mg/m 2 of
procarbazine, which includes HL survivors treated with more than six cy cles of MOPP or
cy clophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapy.
In the NWTS, records were obtained for 427 pregnancies of more than 20 weeks’
duration. In this group, there were 409 single and 12 twin live births. Early /threatened labor,
malposition of the fetus, low birth weight (less than 2500 g), and premature delivery (less than
36 weeks) were more common among women who had received flank radiation, in a dose-
dependent manner (195). A large population-based study from Denmark, which included
1688 female survivors, found no differences between the survivors, their sisters or women in
the general population for any adverse pregnancy outcomes with the exception of a 23%
increased risk for spontaneous abortion related to RT (196). In the CCSS, offspring of female
survivors who received uterine RT doses of >5 Gy were more likely to be premature or small
for gestational age (175). However, there was no evidence for an increased risk of simple
malformations, cy togenetic sy ndromes, or single gene defects (174,197). Likewise, in a large
cohort of adult survivors of all childhood cancers, there were no differences in the proportion
of offspring with cy togenetic sy ndromes, single-gene defects, or simple malformations; ty pe
of malignancy, abdominal RT, nor alky lating agents effected this risk (198).
Page 445Preservation of fertility and successful pregnancies may occur after BMT,
although the conditioning regimens, which include TBI, cy clophosphamide, and busulfan, are
highly gonadally toxic. In a group of 21 female patients who had received a bone marrow
transplant in the prepubertal y ears, 12 (57%) were found to have ovarian failure when
examined between the age of 11 and 21 y ears, and the association with busulfan was
significant (199). Sanders et al. (200) evaluated pregnancy outcomes in a group of women
treated with bone marrow transplant. Of the 72 pregnancies in 41 women, 16 occurred in
those treated with TBI with 50% resulting in early termination, and 56 occurred in women
treated with cy clophosphamide without TBI or busulfan with 21% resulting in early
termination. There were no pregnancies among the 73 women treated with busulfan and
cy clophosphamide, and only 1 retained ovarian function.
Progress in reproductive endocrinology has resulted in the availability of several options
for preserving or permitting fertility in patients about to receive potentially toxic
chemotherapy or RT (201). For males, cry opreservation of spermatozoa before treatment is
an effective method to circumvent the sterilizing effect of therapy. Although pretreatment
semen quality in patients with cancer has been shown to be less than that noted in healthy
donors, the percentage decline in semen quality and the effect of cry odamage to
spermatozoa from patients with cancer are similar to that of normal donors (202,203,204).
For those unable to sperm bank, newer technologies such as testis sperm extraction may be an
option (205). Further micromanipulative technologic advances such as intracy toplasmic
sperm injection may be able to render sperm extracted surgically, or even poor-quality
cry opreserved spermatozoa from cancer patients, capable of successful fertilization
(205,206). In prepubertal and postpubertal females, cry opreservation of ovarian cortical
tissue or enzy matically -extracted follicles and the in vitro maturation of prenatal follicles are
of potential clinical use. Another option available to the postpubertal female is the stimulation
of ovaries with exogenous gonadotropins and retrieval of mature oocy tes for
cry opreservation. However, only a few oocy tes can be harvested after stimulation of the
ovaries (207). In vitro fertilization and subsequent embry o cry opreservation have also been
successful. These options may not be readily available to the pediatric and adolescent patient,
and the necessary delay in cancer therapy for ovarian stimulation or in vitro fertilization
cy cles often renders these interventions impractical (208). Furthermore, all these approaches
harbor the risk that malignant cells will be present in the specimen and reintroduced in the
patient at a later date. Those with hematologic or gonadal tumors would be at greatest risk for
this eventuality (207,208). With increased use of assisted fertility techniques in survivors of
childhood cancer, the risk of congenital anomalies must be followed closely due to reports of
increased anomalies in offspring born by in vitro fertilization or intracy toplasmic sperm
injection (209,210,211,212,213).
Risk of cancer in offspring remains a concern of childhood cancer survivors. In a study
of 5847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in
the absence of a hereditary cancer sy ndrome (such as hereditary retinoblastoma), there was
no increased risk of cancer (214). Preliminary data from the CCSS indicate that the risk of
cancer in offspring was not significantly elevated, but this was based on a small number of
offspring (n = 11). However, among survivors who themselves had second neoplasms or
SMNs, risk of cancer in offspring was significantly elevated (SIR = 15) and much higher than
for offspring of CCSS non-SMN cases (SIR = 1.0) (215). Further follow-up of offspring is
needed to see whether patterns of cancer in offspring change with elapsed time.
Urinary System
The radiosensitivity of the urinary sy stem varies widely, with the ureter being the most
resistant, the bladder having intermediate sensitivity, and the kidney the most sensitive.
Kidney
Pathophysiology
The progression of renal dy sfunction after irradiation is grouped into three periods. The acute
period (up to 6 months) is rarely sy mptomatic, though the glomerular filtration rate (GFR)
may be low. In the subacute period (6–12 months), the signs and sy mptoms include dy spnea
on exertion, headaches, ankle edema, lassitude, anemia, hy pertension, albuminuria,
papilledema, elevated blood urea, and urinary abnormalities (granular and hy alin casts, red
blood cells). Death might result from chronic uremia or left ventricular failure, pulmonary
edema, pleural effusion, and hepatic congestion. In the chronic period (generally after 18
months), either benign or malignant hy pertension is seen, depending on the severity of the
renal insult. Chronic radiation nephropathy in its mildest forms may not be diagnosed until
>10 y ears after therapy. Abnormalities may include only proteinuria and azotemia with
urinary casts and mild or no hy pertension.
The pathologic process is a progressive arteriolonephrosclerosis. The lesion involves the
microvasculature with injury to the intercellular connections between the renal capillary and
arterioles. There is degeneration and sclerosis of these arterioles with narrowing or occlusion
of the lumen and secondary degeneration of dependent structures (glomeruli, tubules).
Associated changes in connective tissue include a thickened basement membrane, increased
interstitial connective tissue, hy alinization, and fibrosis. Decreased perfusion of the kidney can
occur with capillary and venous thrombosis and, eventually, necrosis.

It is not clear whether renal injury is more severe in children than adults or if there are
periods of increased vulnerability during renal development, with the possible exception of
irradiation during neogenesis. This comparison is greatly confounded by the fact that much of
the data in regard to the effect of RT on the pediatric kidney has been collected from
survivors of pediatric Wilms tumor, who undergo resection and/or radiation therapy for their
primary renal malignancy (and also sometimes present with bilateral disease), as opposed to
adults whose kidney s are often only tangentially or incidentally irradiated during the
treatment of a range of abdominal/pelvic malignancies.
Nonetheless, it is clear that radiation nephropathy is dose-related. Dosages of >25 Gy to
both kidney s can cause renal failure at delay ed intervals of more than 6 months (216). The
effect of RT on the kidney has best been examined in survivors of pediatric Wilms tumor,
where unilateral nephrectomy is also common. Unilateral irradiation at dosages of 14–20 Gy
may reduce the ability of the contralateral (untreated) kidney to undergo compensatory
hy pertrophy. Long-term renal function was evaluated in 81 children with sy nchronous
bilateral Wilms tumor who received treatment. There was no dose–response relationship for
chemotherapy. Tumor recurrence necessitating additional surgery increased the risk of renal
dy sfunction. Those with less than one kidney remaining had more marked dy sfunction (217).
A comprehensive evaluation of end-stage renal disease (ESRD) was ascertained in 5910
patients enrolled in NWTSG during 1969–1994. Cumulative incidence of ESRD at 20 y ears
from diagnosis of unilateral Wilms tumor was 74% for patients with the Deny s–Drash
sy ndrome, 36% for patients with WAGR, 7% for male patients with hy pospadias or
cry ptorchidism, and 0.6% for patients with none of these conditions. The incidence of ESRD
after diagnosis of bilateral Wilms tumor was 50% for the Deny s–Drash sy ndrome, 90% for
WAGR, 25% for male genitourinary anomaly, and 12% for those without these conditions.
ESRD in patients with WAGR or GU anomalies tended to occur relatively late, often during or
after adolescence. This confirms an earlier study from this group showing higher risk for
patients with these predisposition sy ndromes. In that earlier study, presence of intralobar
nephrogenic rests in the unilateral disease group without a defined sy ndrome resulted in an
elevated cumulative risk of renal failure at 20 y ears of 3.3%, compared with 0.7% without
this pathologic finding (218).
Dose–volume histograms of renal radiation correlated with various renal function
endpoints will be necessary for accurate determination of functional tolerance levels. In a
review of several reports, Cassady (216) determined a threshold dosage of approximately 15
Gy delivered with conventional fractionation (in the absence of interactive drugs and
underly ing renal disease) as a reasonable estimate, and dosages of >25 Gy to the total renal
mass are likely to eliminate useful renal function in patients followed for sufficiently long
periods of time (Fig. 19.17 ).
Figure 19.17 Radiation dose–response curve for the occurrence of symptomatic radiation
nephropathy generated from data presented in several reports. An approximate threshold
dosage of 15 Gy (conventional fractionation) is seen, and a plateau is noted beyond dosages of
30 Gy. (Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol
Phys.1995;31:1249–1256, with permission.)
Late renal dy sfunction has been documented after TBI before BMT for childhood
malignancies. Tarbell et al. (219) reported a 35% incidence in children with ALL and a 71%
incidence in children with neuroblastoma who received fractionated TBI (12–14 Gy over 3–4
day s). Renal biopsies in two patients showed changes consistent with radiation nephropathy or
hemoly tic uremic sy ndrome. The onset of renal dy sfunction after TBI is 3–6 months, similar
to that of classically described radiation nephritis. Whereas Tarbell et al. (219) found that
renal injury occurs at a y oung age, Lonnerholm et al. (220) found an 18% incidence of renal
dy sfunction in autografted children without an apparent age effect. With more modern
techniques and longer interfraction intervals for TBI, less than 15% of children will develop
chronic renal insufficiency or hy pertension, and the risk is related to both the nephrotoxic
agents used and the TBI fractionation scheme and interfraction interval (221,222). Of interest
is that proximal tubular dy sfunction is more commonly abnormal than distal tubular function.
Chemotherapy can also adversely affect renal function. Cisplatin at dosages greater than
200 mg/m 2 can result in glomerular or tubular injury and renal insufficiency. Other
nephrotoxic agents such as aminogly cosides, amphotericin, and ifosfamide may further
increase risk. Effects can be seen acutely and may progress after completion of therapy
(223). A few small studies examining children treated with carboplatin have evaluated short-
and long-term nephrotoxicity related to carboplatin, finding none significant to date (224,225).
Page 447Ifosfamide can also cause glomerular and tubular (proximal greater than
distal) toxicity, with renal tubular acidosis, or the Fanconi sy ndrome. Dosages greater than 60
g/m 2, age less than 5 y ears at the time of treatment, and combination with cisplatin and
carboplatin increase risk. Abnormalities in glomerular filtration are less common and
generally not clinically significant. Further study of larger cohorts with longer follow-up is
needed (226,227,228). A study examining grades 3–4 ifosfamide-induced nephrotoxicity
among adult and pediatric patients found a prevalence of 17% in both, and neither age nor
cumulative ifosfamide dose was a risk factor (229). Table 19.14 reviews several renal late
effects with respect to causative treatments, signs and sy mptoms, screening and diagnostic
tests, and management and intervention (47).
Table 19.14 Evaluation of Patients at Risk for Late Effects: Genitourinary
Urinary Bladder
Pelvic or central nervous sy stem surgery, alky lator-containing chemotherapy including
cy clophosphamide or ifosfamide, pelvic radiation therapy, and certain spinal and
genitourinary surgical procedures have been associated with late effects involving the urinary
bladder.
Chemotherapy -associated hemorrhagic cy stitis presents as an acute toxicity and appears
to be a rare persistent effect among clinically well-characterized long-term survivor cohorts
(59). In a study of 6119 children treated between 1986 and 2010 (mean age, 12.2 y ears ± 6.3
SD), 1.6% (n = 97) developed hemorrhagic cy stitis, most of whom (75%) had severity scores
of II or III (scale, I–IV). Older age, previous bone marrow or peripheral stem cell
transplantation, and BK virus in the urine were risk factors for hemorrhagic cy stitis and were
associated with a higher severity score (230). Pelvic radiation therapy is also associated with
an increased risk of hemorrhagic cy stitis that may be either acute or chronic in presentation.
The risk of radiation-induced hemorrhagic cy stitis is greatest among survivors treated with
radiation doses of more than 30 Gy to the whole bladder or more than 60 Gy to a portion of
the bladder. Long-term bladder fibrosis and contracture may result as a sequelae of
hemorrhagic cy stitis or radiation therapy (231).
Naturally, surgical procedures involving the lower genitourinary tract have the potential
to impair normal function of the bladder and normal voiding mechanisms. Likewise, any
cancer therapy or tumor infiltration that disrupts innervation of the bladder can have
deleterious effects on bladder function that may manifest as impaired bladder storage,
inability to void and/or incontinence.
Digestive Tract
The esophagus, stomach, pancreas, and small and large intestines are irradiated in a variety
of pediatric malignancies. Although primary tumors of these organs are rare in childhood,
they may be incidentally irradiated in the treatment of HL and NHL, the Wilms tumor,
neuroblastoma, soft tissue sarcomas, and bone tumors.
The direct effect of digestive tract irradiation is loss of regenerating cells lining the gut.
Radiation damage of the fine vasculature of the digestive tract may progress to obliterative
vasculitis, with the ultimate development of ischemia (232). Acute radiation injury results
from the depletion of normally proliferating cell, mucosal sloughing, villus shortening, and
subsequent inflammatory infiltration and edema. The patient may suffer from ody nophagia,
dy sphagia, abdominal pain, or diarrhea, depending on the site affected. Late radiation injury
to the digestive tract is attributable to vascular injury. As the radiation vasculopathy
progresses to obliteration, necrosis, ulceration, stenosis, or perforation may result (232). Late
radiation enteropathy is characterized by malabsorption, pain, and recurrent episodes of
bowel obstruction, as well as perforation, infection, and death. The onset is generally 6–24
months after the conclusion of RT. Donaldson et al. (233) evaluated 44 children who received
abdominal irradiation for a variety of malignancies; 11% of the entire population and 36% of
the longterm survivors developed bowel obstruction. Contributing factors included prior
abdominal surgery, the use of concurrent actinomy cin D, and very y oung age. In general,
fractionated dosages of 20–30 Gy can be delivered to the small bowel without significant
long-term morbidity. Dosages greater than 40 Gy are needed to cause bowel obstruction or
chronic enterocolitis (234). Intestinal obstruction can be a particularly late effect, occurring at
a median of 12 y ears after diagnosis. The use of abdominal or pelvic RT increased this risk
(235). Sensitizing chemotherapeutic agents such as actinomy cin D and anthracy clines can
increase this risk. In a report of 42 survivors of the Wilms tumor treated from 1968 to 1994
with RT, actinomy cin D, and vincristine with or without doxorubicin, the actuarial incidence of
bowel obstruction at 5, 10, and 15 y ears was 9.5%, 13.0%, and 17.0%, respectively. Radiation
within 10 day s of surgery increased risk for obstruction (91).
The prevention and management of radiation digestive tract injury relies primarily on
the exclusion of normal tissues from the treatment beam whenever possible. For the
esophagus, stomach, and large bowel, this usually relies on beam direction planning and
patient positioning. For the mobile portions of the small bowel, the clinician also evaluates the
prone versus supine position; the use of compression, tilt tables, and false table tops; surgical
placement of omental slings and absorbable mesh; and other techniques. The patient with
acute radiation enteropathy may be helped by sy mptomatic interventions. Medical therapy
for late-onset radiation enteritis is unsatisfactory and has relied on intermittent steroids,
sulfasalazine, parenteral nutrition, and other supportive care. Surgical resection of damaged
or obstructed bowel may be used, but there is a high incidence of anastomotic dehiscence,
operative mortality, and reobstruction (232).
Pancreas
The pancreas has been thought to be relatively radioresistant because of a paucity of
information about late pancreatic-related effects. However, in the course of abdominal RT or
TBI, damage to the islet cells of the pancreas can occur manifesting with increased risk of
diabetes mellitus (DM) in long-term survivors of childhood cancer (236). This may be the
result of direct cy totoxicity to pancreatic cells from abdominal RT, but may also be related to
metabolic sy ndrome, discussed earlier in this chapter. In a study of 8599 survivors from the
CCSS, DM was reported in 2.5% of the survivors compared with 1.7% of the siblings. After
adjustment for body mass index, age, sex, race/ethnicity, household income, and insurance,
the survivors were 1.8 times more likely than the siblings to report DM. In adjusted models,
TBI was associated with a sevenfold increased risk, abdominal irradiation with a 2.7-fold
increased risk, alky lating agents with a 1.7-fold increased risk, and age 0–4 y ears at diagnosis
with a 2.4-fold increased risk (237).
Page 450Two studies have investigated dose/volume parameters associated with the
subsequent development of DM. In a retrospective cohort study, the risk of DM increased with
radiation therapy to the tail of the pancreas, where the islets of Langerhans are concentrated.
Risk increased up to 20–29 Gy and then plateaued. The estimated RR at 1 Gy was 1.61.
Radiation dose to other parts of the pancreas did not have a significant effect. Compared with
patients who did not receive radiation therapy, the RR of diabetes mellitus was 11.5 in patients
who received more than 10 Gy to the pancreas. Children y ounger than 2 y ears at the time of
radiation therapy were more sensitive than were older patients (RR at 1 Gy was 2.1 for the
y oung age group vs. 1.4 for older patients) (238). For the 511 patients who received more
than 10 Gy, the cumulative incidence of diabetes mellitus was 16% (238). Another study
evaluated the risk of diabetes mellitus in 2264 five-y ear survivors of Hodgkin ly mphoma
(42% y ounger than 25 y ears at diagnosis) After a median follow-up of 21.5 y ears, the
cumulative incidence of diabetes mellitus was 8.3% (95% CI, 6.9–9.8%) for the overall
cohort and 14.2% (95% CI, 10.7–18.3%) for those treated with more than 36 Gy para-aortic
radiation. Survivors treated with more than 36 Gy of radiation to the para-aortic ly mph nodes
and spleen had a 2.3-fold increased risk of diabetes mellitus compared with those who did not
receive radiation therapy. The risk of diabetes mellitus increased with higher doses to the
pancreatic tail (239).
Liver
The clinical signs and sy mptoms of radiation hepatitis include abdominal pain, increased
girth, ascites, weight gain, jaundice, and elevation of liver enzy mes. Severe
thrombocy topenia can be seen, most commonly in children who have also been treated with
actinomy cin D.
In the acute phase of radiation injury (less than 3 months after irradiation), the liver is
hy peremic and enlarged in the treated area (240). Dilatation and sinusoidal congestion
accompanied by atrophy around the central vein of the lobule may be seen. As the chronic
phase evolves (more than 3 months after treatment), characteristic central vein lesions
develop. The lumen narrows progressively with fibrotic changes involving the intima, leading
to increasing sinusoidal congestion and liver cell atrophy. Inflammatory exudate is uniformly
absent. After 6 months and up to 6 y ears after irradiation, the distance between the central
vein and portal space decreases, indicating the atrophy of hepatocy tes. Nodules of
regeneration are rare. Central veins become small and inconspicuous, and lobules are
distorted or collapsed. Concentric fibrosis in the portal spaces around the portal veins occurs.
This pathologic picture has been classified as veno-occlusive disease, a process that is
accelerated after BMT and can be seen with weeks of conditioning with TBI. With modern
chemotherapy and RT, it is the most critical hepatic toxicity. It is characterized by occlusion
and obliteration of the central veins of the hepatic lobules, with retrograde congestion and
secondary necrosis of hepatocy tes. Although there may be a dose effect of RT, this
complication is also reported after conditioning regimens with cy clophosphamide and
busulfan alone. Preexisting hepatic disease, including infection, and GVHD may increase the
risk (241). Escalation of cy clophosphamide dose is thought to be associated with increased risk
of veno-occlusive disease (242).
The cumulative dosage, volume of liver irradiated, and additional treatment with
chemotherapy are important risk factors for hepatic fibrosis. Radiation hepatopathy can
occur with dosages of 30–40 Gy to the entire liver, but significantly higher dosages to focal
volumes can be given with few clinical complications (243). Lower dosages can be
associated with hepatopathy if the child is also receiving sensitizing chemotherapy. This is
evident in a series of children treated for the Wilms tumor, neuroblastoma, or hepatoma with
RT to the liver and chemotherapy. Fractionated dosages to 12–25 Gy caused dy sfunction in
50% of patients, 25–35 Gy caused abnormalities in 63%, and more than 35 Gy was toxic in
86%. In the NWTSG, 16 out of 303 patients (5.3%) had liver toxicity with liver doses ranging
from less than 15 Gy to more than 30 Gy. Right-flank or whole-abdomen radiation increased
risk significantly more than isolated left-flank radiation. The injury was manifest as
thrombocy topenia, hepatomegaly, ascites, and, in four cases, hepatic failure. All patients
received chemotherapy, including vincristine, actinomy cin D, and, in some patients,
doxorubicin (244).
Table 19.15 reviews several gastrointestinal and hepatic effects with respect to
causative treatments, signs and sy mptoms, screening and diagnostic tests, and management
and intervention (47).
Table 19.15 Evaluation of Patients at Risk for Late Effects: Gastrointestinal
Eye
The ey e is composed of several tissues that vary greatly in their radiosensitivity. Acute
reactions include iridocy clitis, keratitis, conjunctivitis, and blepharitis. Delay ed reactions,
which generally occur after 6 months, include retinopathy, optic neuropathy, lacrimal gland
atrophy or duct stenosis, glaucoma resulting from iridocy clitis, cataract, corneal
vascularization and scarring, conjunctival telangiectasia, and ey elid atrophy with entropion or
ectropion.
Retina
Radiation retinopathy is characterized by a slowly progressive microangiopathy, which may
result in macular edema, capillary nonperfusion, retinal and disc neovascularization, vitreous
hemorrhage, and traction retinal detachment. The microangiopathic changes may appear 6
months to 3 y ears after therapy (245). Visual loss is painless unless neovascular glaucoma
develops. Using 1.8–2 Gy per fraction, the threshold for injury is 46 Gy, although the
frequency is rare below dosages of 60 Gy. As fraction size increases bey ond 2.5 Gy, the
frequency of injury increases (246). It is important to note that certain chemotherapeutic
agents can cause retinal toxicity, and the risk is higher in children with impaired renal function
who thereby accumulate renally cleared drugs (247).
Page 451Lacrimal Apparatus

Radiation may cause scarring of the canaliculi and puncta, ectropion of one punctum, failure
of the lacrimal pump secondary to decreased ey elid mobility, and reflex lacrimation
associated with ectropion, entropion, or conjunctival keratinization (245). Secondary
sy mptoms can develop within months and be fully developed by 1 y ear. The patient may
suffer from excess tearing, a foreign body sensation, and photophobia secondary to corneal
epithelial damage. When injury is severe, corneal ulceration, opacification, and
vascularization sufficient to cause visual loss occur. Injury is rare at dosages less than 45 Gy
and common above 60 Gy (248).
Lens
Whereas retinitis and lacrimal duct abnormalities are caused only by high RT dosages, low-
dose irradiation damages the germinal zone of the epithelium on the equator of the lens (249).
The radiation-induced cataract is a central, posterior subcapsular opacity that appears as a dot
at the posterior pole of the lens. As the cataract enlarges, small vacuoles and granules appear
around it. With continued enlargement, the opacity develops a clear center, giving it a
doughnut-shaped appearance (245). This progresses to the anterior pole, and the cortex then
becomes opaque. Merriam and Focht (250) reported an evaluation of the dose–response
relationship in 1958. After single doses of 200 cGy, abnormalities were detected but were not
clinically significant until dosages exceeded 400 cGy. With fractionated irradiation, a 60%
frequency (progressive in one-half) was seen after 750–950 cGy, whereas 100% was seen
after 1150 cGy (251). Reevaluation of atomic bomb survivor data suggests a 20–40%
incidence of radiation cataract after a single ey e dosage of 5 Gy mixed photons and neutrons
(252). The interval to abnormality in various studies is 2–3 y ears, but ranges from 6 months to
35 y ears depending on dosage.
Patients treated with TBI are also at greater risk of cataracts. Belkacemi et al. (253)
reported on cataracts after TBI in survivors of leukemia who underwent HSCT.
Hy perfractionation and lower dose rate were associated with decreased incidence of
cataracts. These data are shown in Figure 19.18 . Corticosteroids, GVHD, older age, and
allogeneic transplantation are also risk factors (253,254,255,256). In a French study of 271
children treated with TBI, 41.7% of patients treated with TBI developed a cataract with a
median follow-up of 10.3 y ears. Of note, only 8.1% required surgical intervention. The
cumulative incidence at 20 y ears was 78%; no plateau was seen in cataract incidence,
suggesting that with prolonged follow-up nearly all patients treated with TBI will develop
cataracts (257).
Page 452
Figure 19.18 Product-limit estimates for cataract incidence according to fractionation

and dose rate. FTBI, fractionated total body irradiation; HDR, high dose rate (>0.04
Gy/minute); LDR, low dose rate (≤0.04 Gy/minute); STBI, single-dose total-body irradiation.
(From Belkacemi Y, Labopin M, Vernant JP, et al. Cataracts after total body irradiation and
bone marrow transplantation in patients with acute leukemia in complete remission: a study
of the European Group for Blood and Marrow Transplantation. Int J Radiat Biol Oncol
Phys.1998;41(3):659–668, with permission.)
Radiation-induced cataracts are one of the reported complications of retinoblastoma

treatment. Contrary to first principles, an unblocked anterior beam and an angled lateral lens-
sparing setup have equivocal rates of cataract formation (258). This is almost certain because
variations in daily setup make complete lens sparing unlikely with most lateral approaches. If
a radiation-induced cataract causes visual impairment in the patient with retinoblastoma, it
may be removed. Persistent tumor is a contraindication to cataract removal. Final visual
acuity after cataract removal depends on the presence or absence of macular tumor, the
existence of radiation-induced keratopathy or retinopathy, severe ambly opia, a history of
rhegmatogenous retinal detachment, and tumor control. In the absence of negative factors,
visual acuity after cataract removal would be expected to be in the 20/20 to 20/50 range
(259).
Optic Nerve
Injury to the distal nerve end produces ischemic optic neuropathy, whereas more proximal
injury produces retrobulbar optic neuropathy. These are potentially blinding complications.
The peak onset is 1–2 y ears, manifested by visual field deficits or central scotoma (260).
Lid
Rounding of the lid margins is not seen below 40 Gy, and ectropion is uncommon below 60
Gy. The ey elash usually is spared by anterior beams so that it may remain partially intact
(245).
Orbit
For survivors of retinoblastoma, a small orbital volume may result after either enucleation or
RT. Age less than 1 y ear may increase risk, but this is not consistent across studies (261).
Better management of prosthetic implants and newer methods of delivering RT are likely to
reduce risk (261). Newer strategies for treating retinoblastoma use chemotherapy to reduce
tumor size, combined with local ophthalmic therapies that include thermotherapy,
cry otherapy, and plaque radiation. These strategies may be associated with local
complications that can affect vision; particularly tumors located near the macula and fovea
increase the risk of complications leading to visual loss (262,263,264,265).
One group of patients at risk for all of the aforementioned complications are survivors of
orbital rhabdomy osarcoma, who are at risk of dry ey e, cataract, orbital hy poplasia, ptosis,
retinopathy, optic neuropathy, lid epithelioma, and impairment of vision after RT dosages of
30–65 Gy. The higher dosages (more than 50 Gy ) are associated with lid epitheliomas,
keratoconjunctivitis, lacrimal duct atrophy, and severe dry ey e. Retinitis and optic neuropathy
may also occur after dosages of 50–65 Gy, and even at lower total dosages if the individual
fraction size is greater than 2 Gy (260). Cataracts are reported after lower dosages of 10–18
Gy (249,266).
Table 19.16 reviews several late effects involving the ey e with respect to causative
intervention (47).
Table 19.16 Evaluation of Patients at Risk for Late Effects: Eye
Hearing
The auditory apparatus may be irradiated during the treatment of brain tumors, aerodigestive
tract malignancies, soft tissue sarcomas, and ly mphoma. Fractionated dosages of more than
50 Gy can produce permanent changes in the temporal bone and adjacent soft tissues,
including empty lacunae in the bone, resorption, absent marrow, and replacement by fibrous
tissue. Temporal bone osteoradionecrosis is extremely rare with modern pediatric RT
technique. Radiation changes in the external auditory canal may include thickening of the
epithelium overly ing the ty mpanic membrane, atrophic ceruminous glands, and absent hair
follicles. On occasion, the combination of abnormal epithelium of the external auditory canal
and bacterial overgrowth can produce a persistent otitis externa necessitating the use of wicks,
otic antibiotics, and otic steroid preparations (267).
Cranial irradiation alone rarely has a
significant effect on hearing. RT can result in
cochlear damage, with sensorineural hearing
loss (SNHL) occurring in about 25% of patients
treated with dosages approaching 60 Gy, but
SNHL is considered rare at lower RT dosages in
the absence of cisplatin. Recent data suggest that
cochlear dosages of 30–50 Gy can cause
intermediate-frequency SNHL and that CSF
shunting procedures increase the risk (268). At
dosages as low as 270 mg/m 2, cisplatin can
result in hearing loss when combined with
cranial RT dosages of 40–50 Gy (269). The
sequence of chemoradiotherapy appears to Figure 19.19 Mean hearing thresholds
influence risk. Risk and severity of ototoxicity for three groups of patients with brain
are greater when cisplatin is administered after tumors. Group I (GRI; red) received
cranial radiation (Fig. 19.19 ) (270). cranial irradiation only, group II (GRII;
Page 455Hearing loss in the speech range blue) received cisplatin, and group III
(0.5–3 kHz), which may compromise language (GRIII, green) received cranial irradiation,
reception and expression, is reported with then cisplatin. (From McHaney V, Kavnar
cumulative cisplatin dosages of at least 360 E, Meyer W, et al. Effects of radiation
mg/m 2, and a 25% incidence of hearing loss is therapy and chemotherapy on hearing.
In: Green DM, D’Angio GJ, eds. Late
reported with dosages greater than 720 mg/m 2 in
Effects of Treatment for Childhood Cancer.
the absence of any RT. Fifty percent of children
New York, NY: Wiley-Liss; 1992:7–10, with
treated with cisplatin dosages greater than 450
permission.)
mg/m 2 have SNHL in the high-frequency range
(6–8 kHz). Younger age at the time of administration increases risk (270,271). Carboplatin
may be less ototoxic, but further follow-up in patients treated with high cumulative dosages is
necessary before a clear dose threshold can be established (271,272,273). In a series of
patients with neuroblastoma, the combined effects of cisplatin and carboplatin were
investigated. Severe (grade 3/4) deficits affected 25% of patients receiving cumulative doses
of cisplatin of 400 mg/m 2, 54% patients receiving cumulative doses of cisplatin of 600
mg/m 2, and 50% of patients receiving that dose of cisplatin, followed by my eloablative doses
of carboplatin. Patients <5 y ears at diagnosis had greater ototoxicity than adolescents or
y oung adults (274).
Hearing loss in the child with cancer merits detailed attention because it may lead to
additional difficulties with communication, speech and language acquisition, and development
of learning skills.
Table 19.17 reviews several late effects involving the ear with respect to causative
intervention (47).
Table 19.17 Evaluation of Patients at Risk for Late Effects: Ear
Teeth and Salivary Glands

Radiation-induced damage to developing teeth causes cosmetic and functional difficulties
throughout life. The age of the child at the time of therapy and the radiation dosage determine
the consequences. Teeth begin to develop from the dental lamina 6 weeks after conception.
The crowns of deciduous incisors are fully formed at birth. Calcification begins 3–5 months
after birth in the central incisors, canines, and first molars; by 1 y ear in the maxillary lateral
incisors; and by 2.5 y ears in premolars. By the end of the third y ear, the whole deciduous
dentition is developed (275).
Developing teeth are irradiated in the course of treating malignancies of the head and
neck. The defects that occur include destruction of the tooth germ causing tooth agenesis,
stunted growth of the whole tooth or its root, impaction, incomplete calcification, premature
closures of apices, premature eruption, tapering roots with apical constriction, delay ed
development, and caries (275). Maxillofacial abnormalities include trismus, abnormal
occlusal relationships, and facial deformities. Tooth defects are most severe before
histodifferentiation and incremental calcification of the tooth buds, and the extent of damage
is not apparent until the teeth erupt.
Dosages of 20–40 Gy can cause root shortening or abnormal curvature, dwarfism, and
hy pocalcification. More than 85% of survivors of head and neck rhabdomy osarcoma who
receive radiation dosages of more than 40 Gy may have significant dental abnormalities,
including mandibular or maxillary hy poplasia, increased caries, hy podontia, microdontia,
root stunting, and xerostomia (249). Children treated with 18–30 Gy for leukemia are less
frequently affected, with about 40% showing root or crown abnormalities of the maxillary
first molars (103). Children who undergo BMT are clearly at high risk for microdontia,
impaired tooth development, and compromised occlusion. These abnormalities are greater if
TBI is a component of the conditioning regimen, but they occur even without TBI (276,277).
Chemotherapy for the treatment of leukemia can cause shortening and thinning of the
premolar roots and enamel abnormalities (278). This could result from direct inhibiting
effects of chemotherapy, altered marrow milieu caused by leukemic involvement, or
sy stemic factors altering growth. Radiographic abnormalities are common after RT for
leukemia and sarcoma (278,279).
Salivary gland irradiation causes a qualitative and quantitative change in salivary flow.
When salivary glands are irradiated, acinar cells are destroy ed and replaced by ductal
remnants and loose connective tissue. Such damage is evident after 20 Gy of fractionated
irradiation. Salivary flow rate drops rapidly during a course of fractionated irradiation. Post-
RT xerostomia is irreversible if all major salivary glands are treated with dosages of 50–60
Gy. Stimulated and nonstimulated salivary flow comes primarily from the parotid and
submandibular glands. Among patients treated for HL with 40 Gy to regions including the
submandibular glands, flow rate reductions of about 55% have been documented (280). The
radiation dose–response relationship in the effect of radiation on parotid salivary flow is seen
in Figure 19.20 (281). In normal saliva, salivary antimicrobial substances diminish
cariogenesis. Radiation-induced changes in salivary pH and quantity produce a highly
cariogenic microflora along with a decrease in protective salivary electroly tes and
immunoproteins. These circumstances render the patient highly susceptible to radiation-
induced caries.
Figure 19.20 Proportion of unirradiated and irradiated parotid gland with measurable
salivary flow as a function of radiation dosage. (From Marks J, Davis C, Gottsman V, et al. The
effects of radiation on parotid salivary function. Int J Radiat Oncol Biol Phys.1981;7:1013–
Page 456Before radiation and chemotherapy, a dental evaluation is indicated. As

possible foci of infection, loose exfoliating primary teeth and orthodontic appliances should be
removed. The use of topical fluoride can dramatically reduce the frequency of caries, and
saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia (282). Data
support the efficacy of pilocarpine in improving saliva production and relieving sy mptoms of
xerostomia, with minor risks that are limited predominantly to sweating (283). Unfortunately,
it has been reported that the incidence of dental visits for childhood cancer survivors falls
below the American Dental Association’s recommendation that all adults visit the dentist
annually (284), and therefore, healthcare providers should screen for and encourage routine
dental care and dental hy giene evaluations for survivors of childhood treatment.
Table 19.18 reviews several dental and salivary late effects with respect to causative
intervention (47).
Table 19.18 Evaluation of Patients at Risk for Late Effects: Dental and Salivary
Bone Marrow
The hematopoietic progenitor cells and their offspring are cradled on a stroma of endothelial
cells, adventitial cells, fibroblasts, macrophages, and fat cells. Mechanisms of marrow-
induced failure include direct killing of hematopoietic progenitor cells, accessory cells (e.g.,
ly mphocy tes and monocy tes), damage to the stroma and microcirculation, and disturbance
of hematopoietic growth and regulatory factors (285).
The bone marrow is extremely sensitive to irradiation, to the degree that some injury is
produced by any fractional dosage. Irradiated bone marrow becomes hy pocellular. There is
destruction of fine vasculature followed by fatty marrow replacement of the normal
hematopoietic marrow (286). If the radiation dosage is sufficiently high, destruction of the
sinusoidal circulation precludes migration of hematopoietic cells from distant nonirradiated
sites. After 40 Gy fractionated irradiation, 85% of irradiated sites show a return of activity in
2 y ears; in 55% of those areas, recovery becomes complete. Conversely, single doses of 20
Gy to localized regions can produce permanent aplasia. Radiation-induced changes in bone
marrow may be detected by increased signal intensity on MRI because of the decreased T1
relaxation time of the increased fatty marrow content. Dosages greater than 50 Gy seem to
produce irreversible depletion of my eloid tissue (287).
Page 457The regenerative capacity of the bone marrow depends on the volume
irradiated 288). After irradiation to less than 25% of the bone marrow, the unexposed portion
is stimulated and successful in compensating for hematopoietic demands, and the treated
portion may never regenerate. When volumes in excess of 50% are irradiated, the unexposed
bone marrow is not adequate to meet the body ’s demands. Consequently, the paradoxical
phenomenon of in-field regeneration is seen 2–5 y ears later, and extension of bone marrow
activity into previously quiescent long bones is seen within 1–2 y ears.
Page 458Differences between children and adults in the response of the bone marrow to
irradiation relate primarily to the differing extent of active bone marrow at different ages
(289). In the immediate postnatal period, conversion from active red to fatty y ellow marrow
begins and is first evident in the extremities. This conversion progresses from peripheral
(appendicular) toward the central (axial) skeleton and from diaphy seal to metaphy seal in
individual long bones (Fig. 19.21 ).
Figure 19.21 The relative amount of red and yellow bone marrow in different anatomic
sites as a function of age. (From Kricun ME. Red–yellow marrow conversion: its effect on the
location of some solitary bone lesions. Skeletal Radiol. 1985;14:10–19, with permission.)
The acute and chronic effects of chemotherapeutic agents on the hematopoietic

compartment will not be detailed in this section. However, radiation oncologists must be
familiar with the acute my elosuppressive effects of various drugs, and they are summarized
in Table 19.19 .
Table 19.19 Antineoplastic Drug Category and Agent with Their Relative Degree and
Duration of Myelosuppression
Figure:
Intelligence quotient (IQ) scores after conformal radiotherapy in children with low-grade
glioma.
(From Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for
pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and
hearing deficits. J Clin Oncol. 2009;27:3691–3697.)
Figure:
Full-scale IQ change by baseline intelligence. Blue, baseline IQ < 100; Red, baseline IQ > 100.
(From Ris MD, Packer R, Goldwein J, et al. Intellectual outcome after reduced dose radiation
therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study.
J Clin Oncol. 2001;19:3470–3476, with permission.)
Figure: Evaluation of Patients at Risk for
Late Effects: Central Nervous System
Figure:
Peak growth hormone (GH) according to hypothalamic mean dose and time after start of
radiation. According to equation 2, peak GH = exp{2.5947 + time × [0.00079 × mean dose]}.
(From Merchant TE, Rose SR, Bosley C, et al. Growth hormone secretion after conformal
radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol.
2011;29:4776–4780.)
Figure:
Height standard deviation scores (SDS) for ALL survivors, treated pre- or postpubertally with
chemotherapy alone, cranial or craniospinal RT.
(From Chow EJ, Friedman DL, Yasui Y, et al. Decreased adult height in survivors of childhood
acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J
Pediatr. 2007;150:370–375, with permission)
Late Effects: Neuroendocrine
Figure:
Probability of developing an underactive thyroid after diagnosis of the Hodgkin disease.
(From Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor
Study Cohort: a review of published finding. J Clin Oncol. 2009;27:2339–2355.)
Late Effects: Thyroid
Figure:
Cumulative incidence (CI) of bony morbidity for 176 children treated for ALL between 1987
and 1991. With 7.6 years of median follow-up, the overall 5-year CI (±SE) was 30% ± 4%. The
5-year CI of fracture was 28% ± 3%, and of osteonecrosis, 7% ± 2%.
(From Strauss AJ, Su JT, Dalton VM, et al. Bony morbidity in children treated for acute
lymphoblastic leukemia. J Clin Oncol. 2001;19:3066–3072, with permission.)
Late Effects: Musculoskeletal
Figure:
A & B: Marginal (Kaplan–Meier) and cause-specific (C & E) (competing risk) cumulative
incidence of cardiac events (CEs) in childhood cancer survivors stratified according to
different treatment groups. A: Marginal cumulative incidence for all CEs, stratified according
to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank p < 0.001. B: Marginal
cumulative incidence for all CEs, stratified according to different CTX therapies, log-rank p <
0.001. C: Cause-specific cumulative incidence for congestive heart failure, stratified
according to different treatment groups, log-rank p < 0.001. D: Cause-specific cumulative
incidence for cardiac ischemia, stratified according to cardiac irradiation (RTX) or no RTX,
log-rank p < 0.01. E: Cause-specific cumulative incidence for valvular disease, stratified
according to RTX or no RTX, log-rank p < 0.001. The shaded colorized background areas refer
to the 95% CIs. Ant, anthracycline.
(From van der Pal H, van Dalen EC, van Delden E, et al. High risk of symptomatic cardiac
events in childhood cancer survivors. J Clin Oncol. 2012;30:1429–1437, with permission).
Figure:
Cumulative incidence of cardiac disorders among childhood cancer survivors by average
cardiac radiation dose.
(From Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult
survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer
Survivor Study cohort. BMJ. 2009;339:b4606.)
Figure:
Location of the coronary vessels (dark lines) on a standard mantle field is illustrated. The
blocks are outlined in white.
(From King V, Constine LS, Clark D, et al. Symptomatic coronary artery disease after mantle
irradiation for Hodgkin’s disease. Int J Radiat Oncol Biol Phys.1996;36:881–889, with
permission.)
Late Effects: Cardiac
Figure:
Cumulative incidence of chronic pulmonary conditions by type of therapy (CRX, chest
radiation; PTC, pulmonary toxic chemotherapy).
(From Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the Childhood Cancer Survivor
Study cohort: a review of published findings. J Clin Oncol. 2009;27:2339–2355, with
permission.)
Late Effects: Pulmonary
Figure: Effect of Fractionated Irradiation on
Ovarian Function in Women of
Reproductive Age
Figure:
Cumulative incidence of nonsurgical premature menopause.
(From Green DM, Sklar CA, Boice JD Jr, et al. Ovarian failure and reproductive outcomes
after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin
Oncol. 2009;27:2374–2381, with permission.)
Late Effects: Ovarian
Figure: Effect of Fractionated Testicular
Irradiation on Spermatogenesis and Leydig
Cell Function
Late Effects: Testicular
Figure:
Radiation dose–response curve for the occurrence of symptomatic radiation nephropathy
generated from data presented in several reports. An approximate threshold dosage of 15 Gy
(conventional fractionation) is seen, and a plateau is noted beyond dosages of 30 Gy.
(Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys.1995;31:1249–1256,
with permission.)
Late Effects: Genitourinary
Late Effects: Gastrointestinal
Figure:
Product-limit estimates for cataract incidence according to fractionation and dose rate.
FTBI, fractionated total body irradiation; HDR, high dose rate (>0.04 Gy/minute); LDR, low
dose rate (≤0.04 Gy/minute); STBI, single-dose total-body irradiation.
(From Belkacemi Y, Labopin M, Vernant JP, et al. Cataracts after total body irradiation and
bone marrow transplantation in patients with acute leukemia in complete remission: a study
of the European Group for Blood and Marrow Transplantation. Int J Radiat Biol Oncol
Phys.1998;41(3):659–668, with permission.)
Late Effects: Eye
Figure:
Mean hearing thresholds for three groups of patients with brain tumors. Group I (GRI; red)
received cranial irradiation only, group II (GRII; blue) received cisplatin, and group III (GRIII,
green) received cranial irradiation, then cisplatin.
(From McHaney V, Kavnar E, Meyer W, et al. Effects of radiation therapy and chemotherapy
on hearing. In: Green DM, D’Angio GJ, eds. Late Effects of Treatment for Childhood Cancer.
New York, NY: Wiley-Liss; 1992:7–10, with permission.)
Late Effects: Ear
Figure:
Proportion of unirradiated and irradiated parotid gland with measurable salivary flow as a
function of radiation dosage.
(From Marks J, Davis C, Gottsman V, et al. The effects of radiation on parotid salivary
function. Int J Radiat Oncol Biol Phys.1981;7:1013–1019, with permission.)
Late Effects: Dental and Salivary
Figure:
The relative amount of red and yellow bone marrow in different anatomic sites as a function
of age.
(From Kricun ME. Red–yellow marrow conversion: its effect on the location of some solitary
bone lesions. Skeletal Radiol. 1985;14:10–19, with permission.)
Figure: Antineoplastic Drug Category and
Agent with Their Relative Degree and
Duration of Myelosuppression
CONCLUSIONS AND FUTURE DIRECTIONS
RT and chemotherapy can result in adverse long-term phy siologic sequelae for survivors of
childhood cancer. However, these treatment modalities have resulted in a markedly increased
survival rate for almost all pediatric malignancies. Therefore, it is essential to balance the
benefits against risks. Both length of survival and the impact of phy siologic late effects on the
quality of that survival must be considered in therapy selection.
The pathophy siologic mechanisms of damage from RT and chemotherapy to normal
tissues are well described. However, what is unclear is the interindividual variation in
responses to the same therapeutic exposures. Although many children and adolescents are
treated with the same RT dosages, fields, and volumes, there is a significant degree of
variability in the proportion of those who develop radiation-related toxicities. For some, the
cy totoxicity of chemotherapy may enhance the RT effects. For others, effects related to
surgical intervention may augment the burden of late effects. However, little is known about
host-related factors, such as genetic susceptibility. This may include inherited differences in
radiation sensitivity to normal tissue or genes of xenobiotic metabolism, nucleotide provision,
or DNA repair. In addition, environmental and lifesty le factors such as diet, sun, tobacco, and
alcohol exposure that are etiologically related to the major problems in an aging population
are likely to influence the development of late effects for a given therapeutic exposure. New
patterns of late morbidity and mortality may emerge as survivors continue to age, and it is
only through continued study that such patterns will be identified and interventions for
treatment and prevention designed.
Page 459Furthermore, it is clear that the potential for the development of late effects in
normal tissues is related to cellular activity and maturation. As discussed, at any point in
development, a child’s body is a mosaic of different tissues developing at different rates and
in different temporal sequences. Since intrinsic radiation sensitivity and vulnerability to
radiation-induced normal tissue damage are related to cellular activity and level of maturity,
it is important to understand tissue development and consider differing sensitivities to the same
insult at any given time in a child’s development as this could drastically change the potential
for adverse late outcomes. Lastly, recognizing the mechanism of organ growth—that is, an
increase in the size of cells (hy pertrophy ) as opposed to the number of cells (proliferation)—
allows better identification of relative radiosensitivity because organs that only hy pertrophy
are less vulnerable to functional disturbance by irradiation.
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CH A P TER 20
Second Primary Cancers
Smita Bhatia and Louis S. Constine
Page 466Significant improvements in therapeutic options and supportive care strategies have
resulted in 5-y ear survival rates now approaching 70% for adult-onset cancers and 85%
childhood cancer (1). This improvement in survival has resulted in a growing population of
cancer survivors; currently in the United States, there are over 14.5 million cancer survivors.
However, this survival is associated with significant morbidity. In fact, 50% of y oung adult
survivors of childhood cancer will develop a life-threatening or fatal complication by age 50
y ears (2), and second primary cancers (SPCs) are the most devastating of these
complications.
SECOND PRIMARY CANCERS: THE SCOPE OF THE PROBLEM
SPCs are defined as histologically distinct

malignancies developing at least 2 months after
completion of the treatment for the primary
malignancy. Several large epidemiologic studies
have demonstrated that the SPC risk after adult-
onset cancers ranges from that observed in the
general population to a twofold greater risk (3,4).
The risk of SPCs after childhood cancer ranges
from 3.3-fold higher than that observed in the
general population to 11.2-fold (5,6,7,8). The 30-
y ear cumulative incidence in the CCSS cohort Figure 20.1 Cumulative incidence of
was 9.1% for NMSC, 7.9% for SMN (excluding any second neoplasm (SN), nonmelanoma
skin cancer (NMSC), second malignant
NMSC), and 3.1% for meningioma (Fig.
20.1 ) (7). Population-based registry data neoplasm (SMN), and meningioma.
from the ALiCCS y ielded an absolute excess risk (Friedman DL, Whitton J, Leisenring W, et
(AER) of 3–6/1000 person-y ears of follow-up al. Subsequent neoplasms in 5-year
(5). The BCCSS cohort demonstrated that 52% of survivors of childhood cancer: the
the excess cancers observed among those aged Childhood Cancer Survivor Study. J Natl
≥40 was attributable to digestive, genitourinary, Cancer Inst. 2010;102:1083–1095, with
permission.)
breast, or respiratory sites (6). Finally, the CCSS
cohort found that patients with SMNs remain at
considerable risk for additional SNs (9). These studies demonstrate that the relative risk of SPC
in survivors of adult-onset cancer is modest at best, and that the high relative risk of SPC after
a primary cancer in childhood does not translate into a high absolute excess risk.
Unique associations with specific therapeutic exposures have resulted in the classification
of SPCs into two distinct groups: chemotherapy -related my elody splasia and acute my eloid
leukemia (t-MDS/AML) and radiation-related solid tumors. Characteristics of t-MDS/AML
include a short latency (~3–5 y ears from primary cancer diagnosis) and association with
alky lating agents and/or topoisomerase II inhibitors (10). Solid tumors have a strong and well-
defined association with radiation and are characterized by a latency that exceeds 8–10 y ears
(10). SPCs are a leading cause of nonrelapse late mortality, both in childhood cancer
survivors (11), as well as in survivors of adult-onset cancer (12).
Figure:
Cumulative incidence of any second neoplasm (SN), nonmelanoma skin cancer (NMSC),
second malignant neoplasm (SMN), and meningioma.
(Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of

childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102:1083–
RISK FACTORS FOR SECOND PRIMARY CANCERS
Page 467Exposure to radiation or specific chemotherapeutic agents (alky lating agents,

etoposide, and anthracy clines) increases the risk of SPCs (13,14,15). In addition, the risk of
SPC is increased among female cancer survivors, among those diagnosed with specific
primary cancers (e.g., Hodgkin ly mphoma), and among those diagnosed with their primary
cancer at a y ounger age (7).
Primary Diagnosis
Hereditary retinoblastoma, Hodgkin ly mphoma, and soft tissue sarcomas are
overrepresented among patients who develop SPCs relative to their prevalence in the general
population (7,16). This could result from an interaction between genetic predisposition and
genotoxic insult (chemotherapy /radiation), as is clear in patients with hereditary
retinoblastoma and familial soft tissue sarcoma (16,17). In individuals with Hodgkin
ly mphoma, it is not clear whether the primary diagnosis is an independent risk factor for the
development of SPC or whether the specific therapies used to treat the primary cancer are
the major contributors to the development of SPCs. Associations between first and second
primary cancers are summarized in Table 20.1 .
Table 20.1 Second Primary Cancers and their Relationship with Primary Cancers
Host-Related Risk Factors

Age at Diagnosis of Primary Cancer
Younger age at diagnosis of the primary cancer has been reported to be associated with a
higher risk of radiation-associated SPCs (7,18,19). Conversely, for t-MDS/AML, which is
strongly linked with alky lating agents and topoisomerase II inhibitors, the risk increases with
age at therapeutic exposure (20).
Sex
Female sex is associated with a higher risk of SPCs, contributed to primarily by the excess
occurrence of secondary breast and thy roid cancers among female cancer survivors (7,21).
Moreover, some studies indicate a greater susceptibility of women to known carcinogens such
as cigarette smoke (22). Possible mechanisms that underlie this greater susceptibility include
higher activity of cy tochrome P450 (CYP) enzy mes, enhanced formation of DNA adducts,
and the effects of hormones such as estrogen on tumor promotion (22).
Page 468Therapy-Related Risk Factors

Radiation
Although ionizing radiation is capable of causing most ty pes of cancer, organs vary in their
susceptibility. The risk is highest when exposure occurs at a y ounger age and increases with
increasing radiation dose and with increasing follow-up from radiation (6,7,14,23). Radiation-
associated SPCs have a long latency period and ty pically develop in or at the edge of the
radiation field. Some well-established radiation-associated SPCs include breast cancer,
thy roid cancer, lung cancer, brain tumors, osteosarcoma, and nonmelanoma skin cancers
(Table 20.1 ).
Several principles characterize radiation-induced SPCs:
A variety of histologic ty pes of neoplasms can be induced by irradiation. These cancers

are indistinguishable morphologically from naturally occurring cancers. The
identification of a “radiation signature” in tumors would be important in evaluating SPC.
There is evidence that radiation produces a different spectrum of mutations than other
genotoxic agents. If these mutations could be discerned and characterized, then one
could clearly identify radiation-induced tumors and understand, more completely, the
radiation dose–response relationship for induced tumors. In this manner, molecular
forensics may affect our understanding of attributable risk (24). Of interest is data
showing that the risk of an SPC is proportional to the number of premalignant stem cells
created, and surviving RT. This is related to cell killing by RT, cellular repopulation
between RT fractions and after the last fraction, and the ratio of the proliferation rate of
premalignant cells to the proliferation rate of normal cells.
Low–linear energy transfer (low-LET) radiation (gamma ray, X-ray ) is generally less
efficient in inducing tumors than high-LET radiation. In a murine hepatocarcinogenesis
model, for example, neutron irradiation produced a greater incidence of hepatomas than
did gamma irradiation (25). Low-LET radiation appears to become less effective at
carcinogenesis per centigray as the dosage falls, whereas high-LET radiation (neutrons,
alpha particles) does not (26). With low-LET irradiation, there is less tumor induction
when the dosage is fractionated or administered at low dose rates, imply ing that repair of
carcinogenic damage is occurring. With high-LET irradiation, the radiobiologic effect is
higher at low dosages. The carcinogenic effectiveness of high-LET radiation is not
diminished and may be increased by dosage fractionation or protraction (27).
Orthovoltage therapy is more likely to be carcinogenic than megavoltage therapy
(28,29). This may be dose-related: By delivering a higher dosage to bone, orthovoltage
irradiation may increase the risk of an SPC of bone. The higher risk may also be related
to the long follow-up available for orthovoltage patients.
Although every tissue in the body is at risk for radiation-induced cancer, sensitivity
varies according to the tissue. For example, thy roid gland and breast are sensitive to
cancer induction after low radiation dosages; ly mphoid tissue, lung, and liver are
susceptible at moderate dosages, and bone at higher dosages. The relationship between
dosage and response may vary according to the induced tumor. For example, the
development of CNS tumors increases with increasing dose, whereas secondary thy roid
carcinomas have a peak incidence after doses of 20–29 Gy but then decrease (Fig.
20.2 ). Cancer risk from radiation may be given per unit dosage (gray, Gy ) or per unit
dosage equivalent (Sievert, Sv) where a “quality factor” (Q) is used to take account of
the vary ing biologic effectiveness of different radiations (e.g., for a gamma ray Q = 1,
and for a neutron Q = 20). Therefore, dosage in Sv = dosage in Gy × Q. Detailed
literature reviews indicate that the cancer mortality risk for the general population after
whole-body exposure is 1 × 10−4 to 4 × 10−4 per person-cGy. Pooled results of various
partial-body exposures give an estimated risk of 1 × 10−4 to 4 × 10−4 per person-cGy (4
× 102 Sv1). The risk based on incidence is about twice that for mortality (26,30).
Leukemia data can be fit by a curvilinear dose–response model, whereas skin cancer
appears to have a threshold dose–response function, and breast data fit a linear no-
threshold model.
Figure 20.2 A: Dose-risk for RT-induced CNS tumors from Childhood Cancer Survivor
Study. (From Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the
central nervous system in survivors of childhood cancer: a report from the Childhood
Cancer Survivor Study. J Natl Cancer Inst. 2006;98:1528–1537, with permission). B:
Dose-risk for RT-induced breast cancer from Childhood Cancer Survivor Study. (Inskip
PD, Robison LL, Stovall M, et al. Radiation dose and breast cancer risk in the childhood
cancer survivor study. J Clin Oncol. 2009;27:3901–3907 with permission.) C: Dose-risk for
RT-induced thyroid cancer from Childhood Cancer Survivor Study. (Bhatti P, Veiga LHS,
Ronckers CM, et al. Risk of second primary thyroid cancer after radiotherapy for a
childhood cancer in a large cohort study: an update from the Childhood Cancer Survivor
Study. Radiat Res. 2010;174:741–752.)
Radiation induces solid SMNs, within the radiation field and in a dose-dependent fashion.
A recent report assessed the relationship between the irradiated tissue volume (including
the tissue exposed to low doses adjacent to the target volume and thus the integral dose)
and the likelihood of developing a secondary malignancy. In a cohort of 4401 patients
who were 3-y ear survivors of all ty pes of childhood cancer, a dose–response
relationship was found between the overall risk of an SMN and the estimated integral
dose (Table 20.2 , Fig. 20.3 ) (38). As a corollary, data from Diallo et al. (39)
showed that a greater volume of tissues receives low or intermediate radiation doses in
regions bordering the irradiated volume with modern multiple beam radiation therapy
administrations, including intensity modulated radiation therapy (IMRT). However, in a
report that modeled risk for children treated with IMRT versus conventional therapy, an
increase was not seen (40). Additional data will be necessary to settle this issue.
Table 20.2 Characteristics of Therapy-Related Myelodysplasia or Acute Myeloid

Leukemia after Treatment with Alkylating Agents and Topoisomerase II Inhibitors
Figure 20.3 Integral dose and SMN risk in pediatric cancer survivors. (From Nguyen
F, Rubino C, Guerin S, et al. Risk of a second malignant neoplasm after cancer in
childhood treated with radiotherapy: correlation with the integral dose restricted to the
irradiated fields. Int J Radiat Oncol Biol Phys. 2008;70:908–915, with permission.)
SPCs may also be induced by agents other than radiation (chemotherapy, environmental
exposures, and genetic predisposition). The low-dose radiation dose–response curve
could be influenced by these confounding factors to produce a result that is the sum of
two independent rates or may be greater than simple addition would indicate. A variety
of chemotherapeutic agents, especially alky lators, are known to be carcinogenic, and
they may be additive or sy nergistic with radiation.
A large number of irradiated patients are necessary to calculate a radiation
carcinogenesis risk with reasonable accuracy.
Page 471Latent periods vary according to the induced tumor. At least two patterns of
latent periods for radiation-induced cancer have been described. The first, exemplified
by the risk of leukemia in atomic bomb survivors, consists of an early wavelike pulse of
increased risk followed by a gradual decline to baseline levels. The second, more ty pical
of solid tumors, is an increase in relative risk of SPCs over many y ears, which remains
constant over time thereafter. The latter pattern suggests that a multievent pattern of
carcinogenesis is involved: the initial event (radiation) is followed by promoting events
(i.e., smoking, alcohol, or environmental exposures) over many y ears (41). Long latent
periods complicate the study of radiation-induced cancer because the presence of other
carcinogens or disease processes may not be well documented.
The duration of follow-up for any study population influences the frequency of tumors
seen.
It is unclear whether the risk of tumor development after exposure is simply an absolute
increase that is proportional to the radiation dosage or a relative increase that builds on an
underly ing spontaneous risk (greater for some patients) of developing a malignancy.
Age is a critical factor in determining radiation risk. In children, the most common SPCs
occur in tissues undergoing rapid proliferation such as bone, thy roid, and breast. An
actively proliferating tissue may be more susceptible to malignant transformation in any
single cell because of the greater number of cell divisions. This might explain the higher
frequency of secondary bone tumors in children than in adults (42).
Chemotherapeutic Agents
Alky lating agents and topoisomerase II inhibitors are associated with t-MDS/AML (18,43,44).
Alky lating agents have also been linked with bone tumors (45,46) and bladder cancer (47). t-
MDS/AML has been reported in patients with HL, NHL, ALL, sarcomas, ovarian cancer,
testicular cancer, breast cancer, multiple my eloma (10), with the cumulative incidence
approaching 2% at 15 y ears after therapy (10). The incidence of t-MDS/AML ty pically
peaks at 4–6 y ears from diagnosis of the primary cancer and reaches a plateau after 15
y ears. The clinical observation that the risk of t-MDS/AML does not extend bey ond 15 y ears,
indicates that the at-risk population of cells is likely depleted (48). It may be that this period of
time allows early pluripotent hematopoietic progenitors to undergo clonal extinction and be
replaced from the compartment of resting stem cells by clonal succession. It is possible that
stem cells in the resting phase of the cell cy cle are relatively protected from the genotoxic
effects of chemotherapy and radiation and that the excess risk of t-MDS/AML would diminish
as undamaged cells were recruited into active hematopoiesis. t-MDS/AML is associated with
poor outcome, with an estimated 12-month survival of 10% (49). t-MDS/AML is a clonal
disorder characterized by distinct chromosomal changes (49,50,51). Two ty pes are
recognized by the WHO classification: alky lating agent–related ty pe and topoisomerase II
inhibitor-related ty pe (52).
Environmental and Lifestyle Factors

Environmental exposures and lifesty le factors such as tobacco, alcohol, diet, and hormonal
factors and their association with SPCs have been most commonly studied in survivors of
adult-onset cancers. Smoking increases the risk of radiation-related lung cancer in patients
with Hodgkin ly mphoma; the risk increases with radiation dose, suggesting a positive
interaction on a multiplicative scale (53). A recent study indicates that cigarette smoking
before first cancer diagnosis increases second cancer risk among cancer survivors of stage I
lung, bladder, kidney, and head/neck cancers, and elevated cancer risk in these survivors is
likely due to increased smoking prevalence (54). A sy stematic review and meta-analy sis
from published observational studies indicates that alcohol drinking in patients with upper
aerodigestive tract cancers is associated with an increased risk of SPCs (55). There are
several anatomic sites, such as colon, breast, ovary, uterus, and prostate, where nutritional and
hormonal factors play a role in carcinogenesis. Bidirectional associations across several
hy pothesized nutrition- and hormone-related cancers have been demonstrated across many
registries. However, these studies are generally lacking in specific exposure information, and
the support for a given etiologic hy pothesis usually is indirect because the correlations
between cancers hy pothesized to share a common risk factor are examined without direct
measurement of the putative common risk factors or potential confounders.
Characteristics of Second Primary Cancers

Certain radiation-related SPCs, such as breast,
brain, and thy roid cancers, and musculoskeletal
tumors, have been well characterized, especially
in survivors of childhood cancer (Fig. 20.4 ).
The next section is devoted to these SPCs,
focusing on the magnitude of risk and risk factors
associated with their development.
Alkylating Agent–Associated Acute

Myeloid Leukemia and
Figure 20.4 Standardized incidence
Myelodysplasia
ratio by type of second primary cancer.
Table 20.2 summarizes the incidence, risk (From Neglia JP, Friedman DL, Yutaka Y,
factors, and outcomes for patients with alky lating et al. Second malignant neoplasms in
agent-related t-MDS/AML (18,34,56). Alky lating five-year survivors of childhood cancer:
agents associated with t-MDS/AML include Childhood Cancer Survivor Study. J Natl
cy clophosphamide, ifosfamide, Cancer Inst. 2001;93: 618–629, with
mechlorethamine, melphalan, busulfan, permission.)
nitrosoureas, chlorambucil, dacarbazine, and
platinum compounds. Mutagenicity is related to the ability of alky lating agents to form
crosslinks and/or transfer alky l groups to form DNA monoadducts. Alky lation results in
inaccurate base pairing during replication and single- and double-strand breaks in the double
helix as the alky lated bases are repaired. The risk of alky lating agent-related t-MDS/AML is
dose-dependent, with a latency of 3–5 y ears after exposure (57). Alky lating-agent-related t-
MDS/AML is associated with abnormalities involving chromosomes 5 (−5/del [5q]) and 7
(−7/del [7q]), and a high frequency of multidrug-resistance phenoty pe (58). The 5q31–33
region of the long arm of chromosome 5 contains at least nine genes involved in
hematopoiesis. Defects in any of these genes could disrupt the balance between cell growth
and differentiation and play a role in initiation and progression of leukemia. Complete or
partial deletions of the long arm of chromosome 7 (7q− and −7) are nonrandom
abnormalities observed in therapy -related leukemia.
Page 472Topoisomerase II Inhibitor–Associated Acute Myeloid

Leukemia
Topoisomerase II cataly zes the relaxation of supercoiled DNA by covalently binding and
transiently cleaving and re-ligating both strands of the DNA helix. DNA topoisomerase II
inhibitors (epipodophy llotoxins and anthracy clines) stabilize the enzy me-DNA covalent
intermediate, decrease the re-ligation rate and cause chromosomal breakage. These events
initiate apoptosis, required for antineoplastic activity (59). Occasionally, repair of
chromosomal damage results in chromosomal translocations, leading to leukemogenesis
(60,61). Most of the translocations disrupt a breakpoint cluster region between exons 5 and 11
of the band 11q23 and fuse mixed lineage leukemia (MLL) with a partner gene (62). In vitro
studies provide evidence that epipodophy llotoxins can directly induce MLL rearrangements
in hematopoietic cells (63).
Table 20.2 summarizes the incidence, risk factors, and outcomes for patients with
topoisomerase II inhibitor-related t-MDS/AML Topoisomerase II inhibitor-related t-AML
presents as overt leukemia often with a high blast count, rather than an initial my elody splastic
presentation (58) with a predominance of monocy tic phenoty pes (M4 and M5), after a
latency of 6 months to 3 y ears; and is associated with balanced translocations involving
chromosome bands 11q23 or 21q22. Other translocations include inv(18) (p13q22) or t(17),
(19)(q22;q12) (58,64). Dosing schedule has been associated with epipodophy llotoxin-related
t-AML (35). Among patients who received epipodophy llotoxins twice weekly or weekly, the
cumulative risk of t-AML was 12.3% and 12.4%, respectively. On the other hand, among
patients who received epipodophy llotoxins every 2 weeks, did not receive
epipodophy llotoxins, or received them only during remission induction, the cumulative risk
was 1.6%. After adjustment for the frequency of treatment, cumulative dose was not
associated with t-AML risk (35). Another study demonstrated a dose-dependent relation
between epipodophy llotoxins/anthracy clines and risk of t-AML; patients who received 1.2–6.0
g/m 2 of epipodophy llotoxins or more than 170 mg/m 2 of anthracy clines were seven times
more likely to develop t-AML than patients who received lower dosages or none of these
drugs (65).
Musculoskeletal Tumors
The estimated risk of subsequent bone tumors among survivors of childhood cancer is
reported to be 133 times that of the general population (95% CI, 98–176) (45). The risk of
sarcoma was more than ninefold higher among childhood cancer survivors than among the
general population (SIR = 9.0, 95% CI, 7.4–10.9) (66). The excess absolute risk was 3.3 per
10,000 person-y ears. Higher risk was associated with primary sarcoma diagnosis (RR = 10.1,
95% CI, 4.7–21.8), radiation therapy (RR = 3.1, 95% CI, 1.5–6.2), with a history of other
SPCs (RR = 2.2, 95% CI, 1.1–4.5), and with treatment with higher doses of anthracy clines
(RR = 2.3, 95% CI, 1.2–4.3) or alky lating agents (RR = 2.2, 95% CI, 1.1–4.6). Radiation-
associated bone tumors and sarcomas demonstrate a clear association with radiation therapy
(66,67). The secondary bone tumors develop in the radiation field, ty pically after a latency
period of 10 y ears. As compared with matched controls who had survived cancer in
childhood but not developed bone cancer later, the risk (95% CI, 1.0–7.7) of developing a
bone tumor was 2.7 times higher in patients who received radiation therapy, with a sharp
dose–response gradient, reaching 40 times higher after dosages to the bone of more than 60
Gy. After adjustment for radiation therapy, treatment with alky lating agents was also linked to
bone cancer (RR = 4.7, 95% CI, 1.0–22.3), with the risk increasing with cumulative drug
exposure. Both bone tumors and sarcomas may be aggressive and respond poorly to therapy
(45,46).
Breast Cancer
Breast cancer is the most common solid SPC after Hodgkin ly mphoma, largely due to chest
radiation for treatment of Hodgkin ly mphoma (Table 20.3 ). The risk of radiation-related
breast cancer among female Hodgkin ly mphoma survivors ranges from 25- to 55-fold that of
the general population (7,13,72). The latency after chest radiation ranges from 7 to 10 y ears,
and the risk of breast cancer increases in a linear fashion with radiation dose with an
estimated relative risk of 6.4 at a dose of 20 Gy and 11.8 at a dose of 40 Gy (73). Moreover,
40% of identified cases were found to have developed contralateral disease. Among women
treated for childhood cancer with chest radiation therapy, those treated with whole-lung
irradiation have a greater risk of breast cancer than previously recognized, demonstrating the
importance of radiation volume (74). There appears to be a protective effect of early
menopause either because of alky lating agents or radiation dose above 5 Gy to the ovaries,
suggesting that ovarian hormones play an important role in promoting tumorigenesis once an
initiating event has been produced by radiation (69,73,75). The 25-y ear cumulative incidence
of breast cancer is reported to be 11% after allogeneic HCT (76). Allogeneic HCT survivors
are at a 2.2-fold increased risk for developing breast cancer, when compared with age- and
sex-matched general population. The median latency from HCT to diagnosis of breast cancer
is 12.5 y ears. The incidence is higher among those exposed to TBI (17%) than among those
who did not receive TBI (3%). The risk is increased among those exposed to TBI at a y ounger
age. The substantially increased relative risks of breast cancer observed at 10–20 y ears
postdiagnosis are not sustained into ages at which the risk of breast cancer in the general
population becomes substantial; among women who survived to an age of at least 50 y ears,
there is currently no evidence of an increased risk of breast cancer, as compared with the
general population (77). Importantly, mortality associated with breast cancer after childhood
cancer is substantial; breast cancer–specific mortality at 5 and 10 y ears was 12% and 19%,
respectively (74). Travis et al. (78) developed estimates of cumulative absolute risk for use in
counseling patients. For example, the cumulative absolute risks for an HL survivor who was
treated at age 25 y ears with a chest radiation dose of 40 Gy or more without alky lating agents
were estimated to be 1.4% after 10 y ears, 11% after 20 y ears, and 29% after 30 y ears.
Page 473
Table 20.3 Risk of Breast Cancer in Hodgkin Lymphoma Survivors by Age and Latency
Thyroid Cancer
Thy roid cancer is observed after neck radiation for Hodgkin ly mphoma, acute ly mphoblastic
leukemia, brain tumors and after TBI for hematopoietic cell transplantation (7,10). The risk of
thy roid cancer has been reported to be 18-fold that of the general population (79). Radiation
therapy at a y oung age is the major risk factor for the development of thy roid cancer. A
linear dose–response relationship between thy roid cancer and radiation is observed up to 20
Gy, with a decline in the odds ratio at higher doses, demonstrating evidence for a cell kill
effect (15,80,81) (Fig. 20.2 ). Female sex, y ounger age at exposure and longer time since
exposure are significant modifiers of the radiation-related risk of thy roid cancer (81).
Thy roid cancer develops after a latency of 8.5 y ears and is associated with an excellent
outcome.
Brain Tumor
Meningiomas and gliomas develop after cranial radiation for management of central nervous
sy stem disease among patients treated for acute ly mphoblastic leukemia or non-Hodgkin
ly mphoma, or after cranial radiation for histologically distinct brain tumors. Gliomas occur a
median of 9 y ears from the original diagnosis; for meningiomas, the latency is 17 y ears. For
gliomas, the excess relative risk per gray is highest among children exposed at less than 5
y ears of age. Childhood cancer survivors were 8.7-fold more likely to develop gliomas, and
the excess absolute risk (EAR) was 1.9 per 1000 person-y ears (7,14,82,83,84). The risk for
second brain tumors demonstrates a linear relation with radiation dose; the dose–response
appears weaker for gliomas than for meningiomas (Fig. 20.2 ) (14,84). Possible effects of
chemotherapy on the risk of second brain tumors have also been described by some (85,86).
Increased exposure to intrathecal methotrexate significantly increases risk of meningioma
(84).
Other Carcinomas
Bassal et al. (87) analy zed the risk of secondary carcinomas in 13,136 childhood cancer
survivors (>5 y ears) in the CCSS. Seventy -one carcinomas were diagnosed at a median age
of 27 y ears and a median elapsed time of 15 y ears, and included genitourinary sy stem
(35%), head and neck (32%), gastrointestinal (23%), and other sites (10%). Fifty -nine percent
developed the SPC in an irradiated field.
Lung Cancer
Lung cancer is reported after chest radiation for Hodgkin ly mphoma. Smoking is linked with
lung cancer developing after radiation for HL; the increase in risk of lung cancer with
increasing radiation dose is greater among the patients who smoke after exposure to radiation
than among those who refrain from smoking (53).
Page 474Skin Cancer

Nonmelanoma skin cancer (NMSC)
Among allogeneic HCT recipients, the incidence of basal cell carcinoma (BCC) was 6.5% at
20 y ears, whereas that for SCC is 3.4% (88,89). TBI increases the risk for BCC especially in
y ounger patients. Squamous cell carcinoma (SCC) risk is increased among patients with acute
graft versus host disease (GvHD), whereas chronic GvHD is associated with both BCC and
SCC. Immunologic alterations predispose patients to SCC of the buccal cavity particularly,
and hence the association with chronic GVHD (89). In patients with prolonged
immunosuppression, oncogenic viruses such as human papillomavirus contribute to SCC of
the skin and buccal mucosa. BCC is one of the most frequent SMNs in childhood cancer
survivors (90). Childhood cancer survivors are at a fivefold increased risk of nonmelanoma
skin cancer (90% BCC) compared with the general population. Ninety percent of patients
have previously received radiation therapy ; 90% of tumors occur within the radiation field.
Radiation is associated with a sixfold increase in risk.
Melanoma
Survivors of childhood cancer have a 2.5-fold increased risk of melanoma when compared
with the general population (91,92). Melanoma is reported in (HCT) recipients (93).
Radiotherapy may contribute to an increased risk of melanoma, but only at very high doses
of low linear energy transfer radiation (94). Previous studies have found that certain variants
of MC1R, CDKN2A, MTAP and PLAS2G6 genes are associated with an increased risk of
developing melanoma (95,96). Hereditary retinoblastoma survivors have are at a higher risk
of melanoma (97). The excess of melanoma following retinoblastoma is probably due to
common etiologic factors between these two tumor ty pes: the retinoblastoma protein (pRB) is
phosphory lated by CDK4 and CDK6, the two target kinases of CDKN2A.
Bladder
The risk of bladder cancer in childhood cancer survivors is increased 3- to 5-fold that of the
general population (87,98). Heritable retinoblastoma, exposure to cy clophosphamide and
pelvic radiation are associated with an increased risk (98,99).
Renal Cell Carcinoma
Childhood cancer survivors are at an eightfold increased risk of developing renal cell
carcinoma when compared with the general population (100). The highest risk is observed
among neuroblastoma survivors (101). Radiation to the renal bed at doses greater than 5 Gy
and platinum-based therapy increase the risk.
Salivary Gland Tumors

The incidence of salivary gland tumors is reported to be 39-fold higher in childhood cancer
survivors than in the general population (102). Exposure to ionizing radiation is a risk factor for
salivary gland carcinoma (SGC) (20,103,104). Risk increases linearly with radiation dose and
remained elevated after 20 y ears (102). Young children are more susceptible to radiation-
related salivary gland tumors than older individuals (102).
Molecular Underpinnings of Second Primary Cancers

Despite the unambiguous relation between therapeutic exposures and SPCs, there exists a
wide variation in individual susceptibility —a topic that has not been explored
comprehensively.
Mutations in high-penetrance genes (e.g., Li-Fraumeni sy ndrome, RB (retinoblastoma),
NF1 (neurofibromatosis), PTCH1 (Gorlin or nevoid basal cell carcinoma sy ndrome), WT1
(Wilms tumor), and ATM (ataxia telangiectasia) could possibly modify the association
between therapeutic exposures and SPCs. Many of the genes associated with familial cancer
sy ndromes are responsible for mediating cellular response to DNA damage (e.g., ATM,
BRCA) induced by genotoxic insults such as radiation and chemotherapy. Cancer survivors
who carry a deleterious high-penetrance mutation are likely to be at increased risk for
additional primary cancers (reviewed in Ref. 105). Cancer survivors carry ing these genetic
variants should be followed closely for the development of therapy -related SPCs.
However, the low frequency of these mutations in the general population (106) suggests
that the attributable risk to the development of SPCs is likely very small. The inter-individual
variability in risk of therapy -related SPCs is more likely related to common poly morphisms
in low-penetrance genes that regulate drug metabolism/disposition or, those responsible for
DNA repair. Between 20% and 95% of the variability in cy totoxic drug disposition can
possibly be explained by genetic variation (107), and poly morphisms in genes involved in
drug metabolism/disposition contribute to disease-free survival and drug toxicity (108).
Published literature demonstrates the role play ed by variation in DNA repair in susceptibility
to de novo cancer (109); using the same argument, variation in DNA repair could possibly
modify SMN risk among cancer patients exposed to DNA-damaging agents, such as radiation
and chemotherapy. Finally, it is conceivable that gene–environment (therapeutic exposure)
interactions could magnify functional impact of the poly morphisms.
Drug Metabolism and Disposition

Metabolism of genotoxic agents occurs in two phases. Phase I involves activation of substrates
into highly reactive electrophilic intermediates that can damage DNA—a reaction principally
performed by the cy tochrome p450 (CYP) family of enzy mes. The xenobiotic substrates of
CYP proteins include cy clophosphamide, ifosfamide, thiotepa, doxorubicin, and dacarbazine.
Phase II enzy mes function to inactivate genotoxic substrates. The more commonly examined
phase II proteins comprise the glutathione S-transferase (GST) and NAD(P)H:quinone
oxidoreductase-1 (NQO1). GSTs detoxify doxorubicin, lomustine, busulfan, chlorambucil,
cisplatin, cy clophosphamide, melphalan, etc. NQO1 uses the cofactors NADH and NADPH
to cataly ze the electron reduction of its substrates, produces less reactive hy droquinones, and
therefore prevents generation of reactive oxy gen species and free radicals which may
subsequently lead to oxidative damage of cellular components. The balance between the two
sets of enzy mes is critical to the cellular response to xenobiotics; e.g., high activity of phase I
enzy me and low activity of a phase II enzy me can result in DNA damage from the excess of
harmful substrates. Poly morphisms in drug metabolizing genes are very common in the
population; many are functionally significant, and may contribute to the risk of SPCs.
Page 475P-gly coprotein (encoded by MDR1) traps hy drophobic drugs in the plasma
membrane of cells and effluxes them using an ATP-dependent process; many
chemotherapeutic drugs are substrates of this protein. A number of functional poly morphisms
exist in the MDR1 gene and could play a role in the development of SPCs.
DNA Repair
DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and
oncogenes that can lead to cancer initiation and progression. Small differences in an
individual’s DNA repair capacity may be magnified in conjunction with exposure to
chemotherapy or radiotherapy. A number of DNA repair genes contain poly morphic
variants, resulting in large interindividual variations in DNA repair capacity. In fact, one-tenth
of the general population is known to have a reduced capacity to repair DNA damage (110).
Thus, individuals with altered DNA repair mechanisms are likely susceptible to the
development of genetic instability that drives the process of carcinogenesis as it relates to
SPCs.
Role of Genetic Susceptibility in Therapy-Related Leukemia
Table 20.4 summarizes the extant literature on the role of genetic susceptibility in t-
MDS/AML.
SL ID ESHOW
Table 20.4 Role of Genetic Susceptibility in the Development of Therapy-Related
Myelodysplasia/Acute Myeloid Leukemia
Drug Metabolism and Risk of t-MDS/AML

Studies found variant allele G of CYP3A4 1B(A290G) to be underrepresented in patients with
t-MDS/AML when compared with those with de novo AML or healthy individuals (111,112),
while two others found no association (113,114). A poly morphism of NQO1 gene that results
in an amino acid change (Pro to Ser), located in codon 187, produces the complete loss of
enzy me activity in homozy gous subjects (Ser/Ser) and has been associated with an increased
risk of alky lating agent-induced t-MDS/AML (115,116). Inheritance of the GSTP1 (GST pi)
valine allele in codon 105 was associated with an increased risk of t-MDS/AML, particularly
in those patients who have been treated with chemotherapeutic drugs that are substrates of
GSTP1 and not among t-MDS/AML patients with exposure to radiation alone (117) On the
other hand, GSTM1 or GSTT1 null genoty pes were found not be associated with t-MDS/AML
(118).
DNA Damage and Repair and t-MDS/AML

XRCC1, XRCC3, and XPD are poly morphic genes belonging to the major DNA repair
pathway s. XRCC1 is involved in base excision repair and repair of single-strand breaks. The
XRCC3 protein functions in the homologous DNA double-strand break repair pathway and
directly interacts with and stabilizes Rad51. The XPD protein is involved in the nucleotide
excision repair pathway, and functions to remove bulky damaged adducts from DNA. The
presence of at least one XRCC1 399Gln allele indicated a protective effect for the allele in
controls compared with patients with t-MDS/AML (124). RAD51 and XRCC3 are involved in
the repair of DNA by the HR pathway, and the two genes play a critical role in genomic
stability. Rad51 protein binds to DNA and promotes homologous pairing. Xrcc3 protein
stabilizes Rad51—and both are part of a complex consisting of Xrcc2, Xrcc3, Rad51B,
Rad51C, and Rad51D. Poly morphisms have been identified in both the RAD51 (RAD51-
G135C) and XRCC3 (XRCC3-Thr241Met) genes, and t-MDS/AML risk was found to be
significantly increased when both variant RAD51-135C and XRCC3-241Met alleles are
present (125). These results suggest that DNA double-strand breaks and their repair are
important in the pathogenesis of t-MDS/AML. Studies of radiation-induced t-MDS/AML in
mice suggest that the number of target stem cells is a risk factor, and the HLX1 homeobox
gene, which is important for hematopoietic development, could be a candidate gene. A
combined analy sis of RAD51 and HLX1 variant alleles demonstrated a sy nergistic 9.5-fold
increase in the risk of t-MDS/AML (122). ERCC2 encodes a DNA helicase integral to
nucleotide excision DNA repair, and a common functional variant at codon 751 (rs13181)
defines a low-penetrance risk allele for t-MDS/AML (123). An association between the
ERCC2 variant and t-MDS/AML (with alterations in chromosomes 5/7), possibly indicates that
the protein encoded by ERCC2 play s a role in the repair of alky lating agent-induced DNA
damage.
Genetic variation in the p53 pathway has been hy pothesized to affect t-MDS/AML risk,
and the association between t-MDS/AML and common functional p53-pathway variants
(MDM2 SNP309 and TP53 codon 72 poly morphism) has been examined (119). Although
neither poly morphism alone influenced the risk, MDM2 and TP53 variants interacted to
modulate responses to genotoxic therapy. This interactive effect was observed primarily
among patients previously treated with alky lating agents.
Methy lating agents such as procarbazine are commonly used to treat Hodgkin
ly mphoma and are associated with an increased risk of t-MDS/AML (129). Cy totoxicity of
methy lating agents is mediated primarily by the DNA mismatch repair sy stem. Loss of
MLH1, a major component of DNA mismatch repair, results in persistence of mutagenized
cells that are at high risk of malignant transformation. A common poly morphism at position
-93 (rs1800734) in the core promoter of MLH1 was overrepresented among patients who
developed t-MDS/AML after methy lating chemotherapy for Hodgkin ly mphoma, compared
to patients who did not receive methy lating therapy (121). Furthermore, the variant (C)
hMSH2 allele was found to be significantly overrepresented in t-MDS/AML cases that had
previously been treated with O6-guanine alky lating agents, including cy clophosphamide and
procarbazine, implicating this allele in conferring a nondisabling DNA mismatch repair defect
and predisposing the patients to the development of t-MDS/AML (120).
Impact of Antimetabolite Drugs and DNA Synthesis/Repair on t-

MDS/AML Risk
Methy lene tetrahy drofolate reductase (Mthfr) enzy me play s a role in DNA sy nthesis/repair
by directing 5,10-methy lene tetrahy drofolate toward methionine sy nthesis. The negative
effect on DNA sy nthesis/repair induces chromosomal aberrations in the hematopoietic
precursor cells. Poly morphisms of MTHFR (C677T and A1298C) are known to be associated
with decreased Mthfr activity (130). A sy nergistic effect between TP53 and MTHFR has been
reported (127). Expression of both TP53 and MTHFR was significantly lower in cases
compared to controls, supporting their role in t-MDS/AML development.
Page 479Using a case-control study design and a genome-wide association study
(GWAS) platform, 3 SNPs (rs1394384, rs1381392, and rs1199098) were found to be
associated with t-MDS/AML with chromosome 5/7 abnormalities (128). The findings were
confirmed in an independent replication cohort. rs1394384 is intronic to ACCN1, a gene
encoding an amiloride-sensitive cation channel that is a member of the degenerin/epithelial
sodium channel; rs1199098 is in LD with IPMK, which encodes a multikinase that positively
regulates the prosurvival AKT kinase and may modulate Wnt/beta-catenin signaling;
rs1381392 is not near any known genes, miRNAs, or regulatory elements, although it lies in a
region recurrently deleted in lung cancer.
Role of Genetic Susceptibility in Therapy-Related Solid SPCs

Table 20.5 summarizes the extant literature describing the role of genetic susceptibility in
the development of therapy -related solid SPCs. Variants comprise a risk locus associated with
decreased basal expression of PRDM1 and impaired induction of the PRDM1 protein after
radiation exposure. These data implicate PRDM1 in the etiology of radiation-induced SMNs.
The role of genomic variants in the risk of specific solid SMNs is described below.
Table 20.5 Role of Genetic Susceptibility in the Development of Therapy-Related Solid
Subsequent Malignant Neoplasms
Breast cancer
Ionizing radiation is an established breast carcinogen. The ATM gene is a key regulator of
cellular responses to the DNA damage induced by ionizing radiation. Women who carry rare
deleterious ATM missense variants and who are exposed to radiation may have an elevated
risk of developing contralateral breast cancer (133). However, the rarity of these deleterious
missense variants (<1%) implies that ATM mutations could account for only a small portion
of radiation-related breast cancers.
Meningioma
While ionizing radiation is an established risk factor for meningioma, a very small fraction of
irradiated individuals develop this tumor, suggesting the role for genetic susceptibility. The
SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility
gene 1–interacting protein 1, has been shown to be associated with an increased risk of
developing meningioma (137). Given that approximately 28% of the European population are
carriers of at-risk genoty pes for rs4968451, the variant is likely to make a substantial
contribution to the development of meningioma. Another study used the family -based
association test program, and showed that haploty pe associations were attained at 18q21.1,
18q21.31 and 10q21.3, providing support for a variation in PIAS2, KATNAL2, TCEB3C,
TCEB3CL, and CTNNA3 genes as risk factors for radiation-associated meningioma (135).
These findings suggest that genetic susceptibility to radiation-associated meningioma is likely
mediated through the co-inheritance of multiple risk alleles.
Thyroid cancer
The ATM G5557A and XRCC1 Arg399Gln poly morphisms (DNA damage response genes), is
shown to be associated with a decreased risk of papillary thy roid cancer. TP53 Arg72Pro is
associated with increased risk of radiogenic papillary thy roid cancer. In the analy ses of
ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC
genoty pe is associated with radiation-induced papillary thy roid cancer. The results indicate
that poly morphisms of DNA damage response genes may be potential risk modifiers of
ionizing radiation-induced papillary thy roid cancer (136). Significant associations have also
been reported for rs1801516 in ATM and rs1867277 in the promoter region of FOXE1,
suggesting that thy roid morphogenesis pathway, in addition to DNA double-strand break repair
pathway are involved in the etiology of papillary thy roid cancer risk (138). Telomere
shortening is observed in response to ionizing radiation exposure. An inverse relation between
telomere content and radiation-related thy roid cancer has been observed (139), suggesting
that shorter telomeres (resulting in genomic instability ) may contribute to thy roid cancer in
childhood cancer survivors.
In summary, radiation exposure to an un-involved organ (e.g., breast, thy roid, brain,
etc.) results in DNA damage, which in turn, initiates cellular responses to the DNA damage.
Aberrant DNA damage response results in an increase in mutational burden. Inability to
repair the DNA damage results in the development of specific genetic lesions. Finally, clonal
expansion of cells carry ing specific genetic lesions results in the development of solid SMNs.
Figure: Second Primary Cancers and their
Relationship with Primary Cancers
Figure:
A: Dose-risk for RT-induced CNS tumors from Childhood Cancer Survivor Study. (From Neglia
JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous system in
survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl
Cancer Inst. 2006;98:1528–1537, with permission). B: Dose-risk for RT-induced breast cancer
from Childhood Cancer Survivor Study. (Inskip PD, Robison LL, Stovall M, et al. Radiation
dose and breast cancer risk in the childhood cancer survivor study. J Clin Oncol.
2009;27:3901–3907 with permission.) C: Dose-risk for RT-induced thyroid cancer from
Childhood Cancer Survivor Study.
(Bhatti P, Veiga LHS, Ronckers CM, et al. Risk of second primary thyroid cancer after
radiotherapy for a childhood cancer in a large cohort study: an update from the Childhood
Cancer Survivor Study. Radiat Res. 2010;174:741–752.)
Figure:
Integral dose and SMN risk in pediatric cancer survivors.
(From Nguyen F, Rubino C, Guerin S, et al. Risk of a second malignant neoplasm after cancer
in childhood treated with radiotherapy: correlation with the integral dose restricted to the
irradiated fields. Int J Radiat Oncol Biol Phys. 2008;70:908–915, with permission.)
Figure: Characteristics of Therapy-Related
Myelodysplasia or Acute Myeloid Leukemia
after Treatment with Alkylating Agents and
Topoisomerase II Inhibitors
Figure:
Standardized incidence ratio by type of second primary cancer.
(From Neglia JP, Friedman DL, Yutaka Y, et al. Second malignant neoplasms in five-year
survivors of childhood cancer: Childhood Cancer Survivor Study. J Natl Cancer Inst. 2001;93:
618–629, with permission.)
Figure: Risk of Breast Cancer in Hodgkin
Lymphoma Survivors by Age and Latency
Slideshow: Table 20.4: Role of Genetic
Susceptibility in the Development of
Therapy-Related Myelodysplasia/Acute
Myeloid Leukemia
Figure: Role of Genetic Susceptibility in the
Development of Therapy-Related Solid
Subsequent Malignant Neoplasms
PRIMARY CANCERS ASSOCIATED WITH SECOND PRIMARY CANCERS
This section focuses on certain primary cancers that are associated with a significantly
greater risk of SPCs (e.g., retinoblastoma and Hodgkin ly mphoma). It also focuses on
primary cancers, with large, well-characterized cohorts of patients followed for sufficiently
long periods of time to develop SPCs (e.g., ALL and the Wilms tumor).
Retinoblastoma
Children with hereditary retinoblastoma are at exceptionally high risk of developing multiple
primary cancers, especially osteosarcoma and soft tissue sarcomas (16,140). On the other
hand, patients with nonhereditary retinoblastoma appear not to be at greater risk for SPCs.
The cumulative incidence of an SPC at 50 y ears after diagnosis was reported to be 51%
(±6.2%) for hereditary retinoblastoma and 5% (±3%) for nonhereditary retinoblastoma. The
high risk of multiple primary cancers in patients with hereditary retinoblastoma is attributable
primarily to germline mutations in the retinoblastoma tumor suppressor gene, RB1. For
second primary soft tissue sarcomas, the relative risks showed stepwise increase for all
dosage categories of radiation therapy at 10–29.9 Gy and 30–59.9 Gy. Third and additional
nonocular tumors (soft tissue sarcomas, bone tumors, and skin cancers) have been reported
among patients with retinoblastoma who had developed a radiation-related SPC (141), with
the 5- and 10-y ear incidence rates reported to be 11% and 22%, respectively. The cumulative
probability of death from an SPC has been reported to be 26% at 40 y ears after bilateral
retinoblastoma diagnosis (97). An extended (40+ y ears) follow-up of patients with bilateral
retinoblastoma reveals that these patients are at a 35-fold higher risk of developing SPCs
(sarcomas, melanomas, brain tumors, uterine malignancies, and lung cancer) (142).
Radiotherapy for retinoblastoma further increased the risk of mortality from second cancers
in this report. The risk for six subty pes of soft tissue sarcoma (fibrosarcoma, liposarcoma,
histiocy toma, leiomy osarcoma, rhabdomy osarcoma, and others) was evaluated in a cohort
of 963 one-y ear survivors of hereditary retinoblastoma (143). The study demonstrated
elevated risk for all sarcomas combined (standardized incidence ratio [SIR] = 184, 95% CI,
143–233), and for individual subty pes. The cumulative risk for any soft tissue sarcoma was
13.1% at 50 y ears (95% CI, 9.7–17%). Leiomy osarcoma was the most frequent subty pe (SIR
= 390, 95% CI, 247–585), with 78% of the leiomy osarcomas diagnosed 30 or more y ears
after the retinoblastoma diagnosis. Among patients treated with radiotherapy for
retinoblastoma, there was a statistically significantly increased risk of soft tissue sarcomas in
the field of radiation, as well as outside the field, indicating the role for genetic predisposition
independent of radiation. These studies indicate that genetic predisposition has a substantial
impact on risk of SPCs in patients with retinoblastoma; the risk is further increased by
radiation therapy. Moreover, patients with retinoblastoma are at a higher risk for developing
third and fourth tumors, although the location and other risk factors are similar to those
described for SPCs.
Page 481Hodgkin Lymphoma

Reports from large, well-characterized cohorts of patients reveal that in survivors of Hodgkin
ly mphoma the risk of developing SPCs is 7–18 times higher than in the general population
(7,13,18,31,32,144). Cancers of thy roid, female breast, bone and connective tissue, stomach,
and esophagus were observed, and were consistent with those associated with radiotherapy.
The risk of solid tumors remained elevated among 20-y ear survivors (RR = 6.6) (71). The
overall cumulative risk of SPCs was 1.9% at 10 y ears, 6.9% at 20 y ears, and 18% at 30 y ears
(32). High risks were observed for breast cancer (RR = 17, 95% CI, 9.9–28), thy roid cancer
(RR = 33, 95% CI, 15–62), secondary leukemia (RR = 17, 95% CI, 6.9–35), and the non-
Hodgkin ly mphoma (RR = 15, 95% CI, 4.9–35). The Late Effects Study Group followed a
cohort of 1380 children with Hodgkin ly mphoma diagnosed at a median age of 11 y ears
(range: 0.3–16) in North America and Europe between 1955 and 1986 to determine the
incidence of SPC and associated risk factors (18). The cohort was updated (13); the median
age at last follow-up was 27.8 y ears (3.5–52.7), and the median length of follow-up was 17.0
y ears (0.1–45). An additional 103 subsequent neoplasms were ascertained (total n = 212).
The cohort’s risk of developing SPCs was 18.5 times higher than that of the general population
(SIR = 18.5, 95% CI, 15.6–21.7). The cumulative incidence of any SPC was 10.6% (95% CI,
8.6–12.7) at 20 y ears, increasing to 26.3% at 30 y ears; and of the cumulative incidence of
solid SPCs was 7.3% (95% CI, 5.5–9.1) at 20 y ears, increasing to 23.5% at 30 y ears. Breast
cancer was the most common solid malignancy (SIR = 56.7, 95% CI, 40.5–77.3). Other
commonly occurring solid malignancies included thy roid (SIR = 36.4), bone (SIR = 37.1),
colorectal (SIR = 36.4), lung (SIR = 27.3), and gastric (SIR = 63.9) cancers. Risk factors for
solid tumors included y oung age at Hodgkin ly mphoma and radiation-based therapy. Thirty -
two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10
y ears from diagnosis of SPC.
Constine et al. (21) evaluated 930 children
with Hodgkin ly mphoma treated between 1960
and 1990. Treatment included radiation alone
(43%), chemotherapy alone (9%), or both
(48%). SPCs occurred in 102 (11%) patients,
with a 25-y ear actuarial rate of 19%. The
earliest solid tumors occurred at 8 y ears, and
continued to occur throughout the follow-up
interval. The survival for all patients, stratified
according to whether they developed an SPC, is
shown in Figure 20.5 . Notably, the SIR for Figure 20.5 Overall survival of
females, 19.9, was significantly greater than for patients according to whether they
males, 8.41 (p < 0.0001) (Fig. 20.6 ). After developed no secondary malignancy, a
excluding breast cancer, the SIR for females solid secondary malignancy, a
was 15.4, still significantly greater than for hematopoietic secondary malignancy, or
males (p = 0.0012) (Fig. 20.7 ), primarily due any secondary malignancy. (From
to secondary thy roid cancer. Increasing Constine LS, Tarbell N, Hudson MM, et al.
radiation dose was associated with an increasing Subsequent malignancies in children
SIR (p = 0.0085). Overall, an increased risk was treated for Hodgkin’s disease:
associated with female gender, increasing associations with gender and radiation
radiation dose, and age at treatment (12–16 dose. Int J Radiat Oncol Biol Phys.
y ears). 2008;72:24–33, with permission).
Figure 20.6 Cumulative proportion of second malignancies according to gender, with
standard errors. (From Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in
children treated for Hodgkin’s disease: associations with gender and radiation dose. Int J
Radiat Oncol Biol Phys. 2008;72:24–33, with permission).
Figure 20.7 Cumulative proportion of second malignancies according to gender, with
standard errors, after excluding breast cancer. (From Constine LS, Tarbell N, Hudson MM, et
al. Subsequent malignancies in children treated for Hodgkin’s disease: associations with
gender and radiation dose. Int J Radiat Oncol Biol Phys. 2008;72:24–33, with permission).
Prevention Strategies
The absolute excess risk of SPC is small, with fewer than two excess SPCs occurring per 1000
patient-y ears of follow-up (7). The ongoing efforts to improve survival after childhood
cancer must not be overshadowed by the risk of SPC. However, of all possible late sequelae,
SPC can be the most devastating. It is therefore imperative that patients and healthcare
providers are aware of the risk of SPC and the populations at greater risk for developing SPCs
so that surveillance is focused and early prevention strategies can be implemented.
Page 482Examples of primary prevention strategies include use of gender-specific
therapy for patients with Hodgkin ly mphoma to reduce the risk of radiation-associated breast
cancer among female survivors and elimination of the use of etoposide for stem cell
mobilization (shown to be associated with t-MDS/AML).
Page 483The elevated risk of breast cancer noted among survivors of childhood and
adolescent cancers supports the importance of evidence-based screening guidelines for this
high-risk group (72). Because outcome after breast cancer is closely linked to stage at
diagnosis, close surveillance resulting in early diagnosis should confer survival advantage.
Mammography, the most widely accepted screening tool for breast cancer in the general
population, may not be the ideal screening tool by itself, for radiation-related breast cancers
occurring in relatively y oung women with dense breasts; hence, the American Cancer
Society recommends including adjunct screening with MRI (145). Thus, the following are
recommendations for females who received radiation with potential impact to the breast (i.e.,
radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields):
monthly breast self-examination beginning at puberty ; annual clinical breast examinations
beginning at puberty until age 25 y ears; and a clinical breast examination every 6 months,
with annual mammograms and MRIs beginning 8 y ears after radiation or at age 25
(whichever occurs later). Females who received TBI or cumulative chest radiation doses of
10–19 Gy should be counseled regarding the benefits and risks/harms of screening; if a
decision is made to screen, the same recommendations apply as for those women who
received radiation doses of 20 Gy or higher (146). Screening of those at risk for early -onset
colorectal cancer (i.e., radiation doses of 30 Gy or higher to the abdomen, pelvis, or spine)
should include colonoscopy every 5 y ears beginning at age 35 y ears or 10 y ears following
radiation (whichever occurs last). Joint recommendations for monitoring long-term survivors
of HCT by the EBMT/CIBMTR/ASBMT suggest that all recipients of HCT should be advised
of risks for subsequent malignancies and encouraged to perform screening self-examinations,
such as breast and skin examinations. All patients should be advised to avoid high-risk
behaviors, including avoidance of tobacco or excessive unprotected exposure of skin to
ultraviolet light (147).
Future Directions
While the body of literature documenting the increased risk of SPCs is substantial, there still
remain many unknowns about the very long-term effects. Ongoing surveillance will, with
time, provide answers to these questions: (i) the magnitude of risk among survivors of adult-
onset cancer; (ii) clearly defined associations with therapeutic exposures in these survivors of
the adult-onset cancers; (iii) the nature and risk of SPCs in childhood cancer survivors
followed for an extended period of time; (iv) impact of the prevention strategies on the
reduction in risk of SPCs.
SPCs provide us with a unique opportunity to understand the etiology and pathogenesis of
cancer. The exact timing and magnitude of the primary exposure (i.e., cancer therapy ) are
known, and following the patients closely may lead to a better understanding of the
progression of events and perhaps the identification of biomarkers that would identify patients
who ultimately develop SPCs. Several such studies that involve prospective, longitudinal
follow-up of patients are being undertaken to elucidate the sequence of events that ultimately
lead to the development of SPC.
Figure:
Overall survival of patients according to whether they developed no secondary malignancy,
a solid secondary malignancy, a hematopoietic secondary malignancy, or any secondary
malignancy.
(From Constine LS, Tarbell N, Hudson MM, et al. Subsequent malignancies in children treated
Phys. 2008;72:24–33, with permission).
Figure:
Cumulative proportion of second malignancies according to gender, with standard errors.
Figure:
Cumulative proportion of second malignancies according to gender, with standard errors,
after excluding breast cancer.
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CH A P TER 21
Anesthesia for External Beam Radiotherapy
Scott R. Schulman, Marla B. Ferschl, Heather J. Frederick, and Edward C.
Halperin
Page 487Considering the awesome aspect of the therapy machines together

with the fact that no one may be with the patient during the period of
irradiation, it is surprising that the great majority submit to the complete
course of therapy with little or no restraint and no sedation … In a small
number of patients in the infant-to-toddler age group of 1½ to 5 years of age,
patient cooperation may be impossible to obtain … Complete immobility of the
patient is absolutely … essential for the accuracy and success of treatment …
Sedation of the patient becomes virtually a sine qua non.
Harrison and Bennet (1) made these observations more than 50 y ears ago. Their classic
article, “Radiotherapy Without Tears,” was the first published report describing anesthesia for
radiotherapy in children. The problem of inadequate sedation prompted the authors to
develop
the following simple method of anesthesia for radiotherapy of infants … The

method is applicable when the anesthetist remains outside the treatment
room and consists of the insufflation of nitrous oxide, oxygen, and halothane
through the sidearm of the oropharyngeal airway (1).
Forty y ears of progress in anesthesiology have validated not only Harrison and Bennet’s
observation but also their solution to the problem of providing anesthesia for radiotherapy.
This chapter reviews issues in the sedation of children with an emphasis on monitoring the
anesthetized child in the radiotherapy suite, develops a model of the ideal anesthetic for
pediatric radiotherapy, explores anesthetic options for radiotherapy, and discusses the
implications of the child’s underly ing disease that influence the anesthetic choice.
BEHAVIORAL TECHNIQUES TO AVOID ANESTHESIA
When possible, children should be irradiated without anesthesia. In some cases, a behavioral
program to teach children how to cooperate with radiation treatment without sedation and
anesthesia may be successful. Behavioral therapy techniques, called desensitization or
exposure therapy, were originally developed for treating severe anxiety, fears, and phobias.
The procedure involves inducing a relaxed state using music, cartoons, stories, or videos.
Subsequently, one introduces the staff, equipment, and routines needed for radiation
treatment.
A behavioral technique called differential positive reinforcement is used to strengthen
cooperation and coping. Incentives such as praise, stickers, toy s, and prizes are provided when
the child attempts to cooperate. These are used to shape the child’s ability to inhibit movement
when instructed to do so. Shaping is a behavioral psy chology technique whereby the criteria
for reinforcement are gradually altered as the child improves performance. At the beginning,
an approximation of the desired behavior is acceptable. After a while, more challenging and
rigid criteria are set for reinforcement.
Videos of cartoons or movies may be used to provide relaxation, distractions, and
ongoing positive reinforcement in training y oung children to cooperate with radiation therapy.
A small monitor or projection screen can be suspended near the treatment machine and
connected to an electronic device so that movies or cartoons may be play ed during
radiotherapy while the child is in the treatment position. Slifer et al. (2,3,4) demonstrated the
efficacy of this technique in children between the ages of 2½ and 7 y ears. Nine of 11
children were able to successfully undergo all of their radiation planning and treatment
sessions without sedation. Alternative strategies include play ing music to the child, or reading
them a book over a loudspeaker for the duration of the treatment.
The implementation of a psy choeducational intervention consisting of careful
preparation of the patient for radiotherapy through the use of picture books, medical play, and
reward sy stems reduced the need for anesthesia in a longitudinal study (5). After
implementing the intervention, the percentage of children requiring anesthesia decreased
from 21% to 9%. The authors concluded that the cost of implementation (median 6 hours of
time by a qualified nurse, plus materials) was offset by the reduced requirement for
anesthesia.
Page 488Many pediatric radiotherapy centers have thoughtful programs designed to
provide the services described above. Music therapists, psy chologists, child life specialists,
social workers, and radiation therapists throughout the world have created a variety of
culturally appropriate tools that they are almost alway s willing to share with colleagues,
including radiation therapy “comic books,” “coloring books,” video education tools, “make
y our own movie about radiotherapy with y ou as the star,” cheerful murals painted on the
walls of the radiotherapy waiting room, and decorating stabilization devices with child-
friendly themes. At meetings of professional societies, these heart-warming ideas are freely
shared with colleagues.
FREQUENCY OF ANESTHESIA FOR PEDIATRIC RADIOTHERAPY
When behavioral techniques to achieve patient cooperation and stability fail, anesthesia or
sedation must be used. The frequency of anesthesia use as a function of patient age at the
initiation of external beam radiation therapy in the Duke University Medical Center pediatric
radiotherapy population is shown in Table 21.1 . For very y oung children (≤3 y ears),
anesthesia is almost alway s needed. After approximately 5 y ears of age, however,
anesthesia is rarely needed. This has been further validated by a recent publication from
Indiana University, which demonstrated that almost all children age 3 y ears and under
required anesthesia for radiation therapy, but for those over age 3 y ears, anesthetic need
decreases in an age-dependent fashion (6).
Table 21.1 Need for Anesthesia in Children as a Function of Age at Initiation of

Irradiation
Figure: Need for Anesthesia in Children as a
Function of Age at Initiation of Irradiation
GOALS OF ANESTHESIA FOR RADIOTHERAPY
To accomplish the twin goals of irradiating the treatment volume while sparing healthy tissue,
control of patient movement must be precise and absolute. How are these goals achieved in
children? The approach varies depending on the institutional resources. Conscious or deep
sedation is used in some centers, whereas general anesthesia is used in others. Regardless of
the institutional practice, there is no substitute for vigilant monitoring and prompt intervention
by people skilled in detecting and managing complications associated with the administration
of sedative drugs to infants and children.
Anesthesiologists are increasingly asked to provide care outside the traditional operating
room setting, such as in the radiotherapy suite. This is appropriate because the specialty has
unique expertise in patient evaluation, selection, and monitoring and the ability to respond
immediately to any complication of therapy. Expertise in drug selection and a
comprehensive approach to the care of the child, which includes preanesthetic evaluation,
postanesthetic care, and the provision of up-to-date feeding guidelines, are hallmarks of the
anesthesiologist.
A prolonged fast before the induction of general anesthesia is no longer necessary. The
American Society of Anesthesiology recommendations on preanesthetic fasting apply to all
ages and are widely followed as standard of care (7). All patients can safely drink clear
liquids (e.g., apple juice, water, popsicles) until 2 hours before induction. Breast milk is
allowed up to 4 hours, and milk or formula until 6 hours before induction. A light breakfast, for
example toast and milk, may be allowed up to 6 hours prior to anesthesia for afternoon cases,
but ty pically solid foods are withheld after midnight, especially in older children.
The goals of anesthesia for pediatric radiotherapy are listed in Table 21.2 . There are
several options that, to vary ing degrees, accomplish the listed goals. There are no prospective,
randomized studies in the setting of pediatric radiotherapy that demonstrate the superiority of
one technique of general anesthesia over another.
Several routes of drug administration are available for sedation of children. Each drug
and drug combination has its own set of side effects and contraindications. Several general
guidelines may be considered. First, the route of administration of the drug should be the least
traumatic for the particular child. Oral or inhalational administration, avoiding intramuscular
or intravenous administration, should be considered when feasible. Second, it should be kept in
mind that some children will develop a tolerance to certain drugs used for sedation. Over
time, the amount of drug and time needed to achieve sedation may both increase.
Table 21.2 Goals for Ideal Anesthesia

for Outpatient Pediatric Radiation
Therapy
Figure: Goals for Ideal Anesthesia for
Outpatient Pediatric Radiation Therapy
INHALED ANESTHETICS
Page 489Several general anesthetic options exist for radiotherapy. The anesthesiologist
individualizes therapy based on data obtained from the patient’s history, phy sical and
laboratory examination, and discussions with the child, parents, and radiation oncologist. The
phy sical limitations of the radiotherapy suite (such as the presence of an air exhaust sy stem
so that volatile anesthetic agents can be used) are also important in devising the anesthetic
plan.
General anesthesia is accomplished with
either inhaled agents (Table 21.3 ) or
intravenous agents (e.g., barbiturates, ketamine,
propofol). The use of inhalational agents requires
an anesthesia machine, gas source and, ideally, a
waste scavenging sy stem. The first report of
anesthesia for pediatric radiotherapy used
halothane. Halothane is a halogenated Table 21.3 Inhalation Anesthetic
hy drocarbon volatile anesthetic first introduced Agents Commonly Used in Pediatric
for clinical use in 1956. Halothane has a long Radiation Therapy
history of safe, effective use in pediatric
patients. It rapidly produces an anesthetic state when inhaled, with minimal airway
complications such as coughing and lary ngospasm. Due to its tendency to depress
cardiovascular function in a dose-dependent fashion and its arrhy thmogenic potential, it has
generally been replaced by sevoflurane for mask induction in children (8). Sevoflurane has
minimal pungency compared with halothane and may be more readily tolerated by children.
It has less cardiovascular side effects than halothane, and its lower solubility permits a more
precise control over the delivery of anesthesia as well as a more rapid induction of and
recovery from anesthesia. Sevoflurane also seems to have a lower respiratory irritant
capacity than halothane and produces less coughing and breath holding than some other
inhaled agents (9,10,11,12) (Fig. 21.1 ).
A risk of inhalation anesthesia is upper
airway obstruction, which is often exacerbated
in radiation therapy by the position of the patient.
Positioning often entails immobilization of the
child’s head in a stabilization device (Fig.
21.2 ), which can impede airway patency
(Fig. 21.3 ) when an insufflation technique is
used. This obstruction is relieved with an
orophary ngeal or nasophary ngeal airway or a
lary ngeal mask airway (LMA). Although
endotracheal intubation may be necessary in a
Figure 21.1 Anesthesia for radiation
small proportion of patients presenting for
therapy may be initiated with an
radiotherapy, it is preferable to avoid this
intravenous drug and maintained by
technique because repeated lary ngoscopy and
inhalation anesthesia; it may be initiated
intubation carry the risk of airway edema and
and maintained with an intravenous
trauma to the lary ngeal structures. Intensity -
agent, or, as shown in this procedure, it
modulated radiotherapy and tomotherapy
may be initiated and maintained by an
techniques often allow the radiation oncologist to
inhaled agent. The 2-year-old patient with
use a supine rather than a prone position for
stage IV neuroblastoma is seated on a
irradiation of the craniospinal axis, for example.
trusted caregiver’s lap while the
Management of the airway in a supine patient is
anesthesiologist administers the drug. A
far easier for the anesthesiologist. This is an
therapist is diverting the child by giving a
example of how the anesthesiologist and
“high five” because “you are being so
pediatric radiation oncologist can collaborate to
cooperative.” The child received twice-
ease each other’s contribution to the care of the
daily radiotherapy for 12 days.
child.
Page 490An adjunct for airway
management during pediatric radiotherapy is the LMA. The LMA (Fig. 21.4 ) is a silicone
tube, the distal end of which has an elliptical-shaped cuff that, when correctly inserted and
inflated, forms a low-pressure seal around the lary nx and allows spontaneous ventilation in a
variety of body positions without the need for endotracheal intubation. Therefore, the LMA
provides many of the advantages of endotracheal intubation: relief of upper airway
obstruction without the disadvantages of repeated lary ngoscopy and intubation. The LMA has
been used for radiotherapy in children as y oung as 3 weeks of age. Grebenik et al. (13)
reported the use of the LMA for pediatric radiotherapy in 25 children who received more
than 300 anesthetics. They observed no complications directly related to the use of the LMA.
Morris and Marjot (14) reported one case of
posterior phary ngeal wall edema that
corresponded to the area of contact between the
posterior surface of the LMA and the
orophary nx in a child repeatedly anesthetized
with an LMA for radiotherapy. Moy lan and Luce
(15) reported more than 2500 anesthetics given
to 145 children with an LMA over a 4-y ear
period for radiotherapy. They raised the concern
that a prone position for radiotherapy with the
neck partially flexed can produce kinking of the
LMA, with the possibility of airway obstruction.
A reinforced LMA may help alleviate this
problem (16). Generally speaking, LMA use is
most successful in the supine position, though
lateral and prone LMA placement is possible.
Figure 21.2 A: Intensity-modulated

radiotherapy delivered from multiple
directions by a linear accelerator is
facilitated in this anesthetized child with
a thermoplastic head immobilization
device combined with a polyurethane
foam–customized head and neck support.
The gas mask is incorporated into the
head immobilization device, and the
treating therapist has placed beam setup
marks directly on the device. The
capnometry monitor is entering the
airway tubing at the top. B: This 35-
month-old girl with recurrent
medulloblastoma received craniospinal
irradiation over a course of 37 days. This
picture was taken on her final day of
therapy during the primary tumor site
boost.
Figure 21.3 To minimize the effects of

external beam irradiation on the
mandible and neck of this child with
embryonal rhabdomyosarcoma on the
tongue, resected with positive margins,
daily fractionated radiotherapy was
administered via an orthovoltage
intraoral cone while the child was
anesthetized. A: The mouth is held open
with a standard surgical mouth gag used
commonly in the operating room. The
anesthesiologist stabilizes the gas tubes
attached to the airway. B: The tumor bed
is painted with methylene blue to make
it easy to identify. The tongue is pulled
forward with a plastic towel clip over
gauze. A lead shield, inside a surgical
glove, is placed behind the tongue to
shield the floor of the mouth. C: The
intraoral cone is docked. The tongue is
held in place by the towel clip, which is
pulled taut by a strap seen in the far right
of the picture. The child is alive and well,
with satisfactory speech development, 4
years after radiotherapy.
Figure 21.4 A mobile anesthesia machine such as the
Narkomed Mobile (Drager) with a remote screen for data and
alarms is suitable for the radiotherapy suite.
Page 491In summary, general inhalation anesthesia has the following features that make
it an attractive technique for pediatric radiotherapy : onset is rapid, depth is easily controllable,
administration is not generally unpleasant, recovery is rapid, the incidence of nausea and
vomiting is low, and airway patency is well preserved.
Figure: Inhalation Anesthetic Agents
Commonly Used in Pediatric Radiation
Therapy
Figure:
Anesthesia for radiation therapy may be initiated with an intravenous drug and maintained
by inhalation anesthesia; it may be initiated and maintained with an intravenous agent, or,
as shown in this procedure, it may be initiated and maintained by an inhaled agent. The 2-
year-old patient with stage IV neuroblastoma is seated on a trusted caregiver’s lap while the
anesthesiologist administers the drug. A therapist is diverting the child by giving a “high five”
because “you are being so cooperative.” The child received twice-daily radiotherapy for 12
days.
Figure:
A: Intensity-modulated radiotherapy delivered from multiple directions by a linear
accelerator is facilitated in this anesthetized child with a thermoplastic head immobilization
device combined with a polyurethane foam–customized head and neck support. The gas
mask is incorporated into the head immobilization device, and the treating therapist has
placed beam setup marks directly on the device. The capnometry monitor is entering the
airway tubing at the top. B: This 35-month-old girl with recurrent medulloblastoma received
craniospinal irradiation over a course of 37 days. This picture was taken on her final day of
therapy during the primary tumor site boost.
Figure:
To minimize the effects of external beam irradiation on the mandible and neck of this child
with embryonal rhabdomyosarcoma on the tongue, resected with positive margins, daily
fractionated radiotherapy was administered via an orthovoltage intraoral cone while the
child was anesthetized. A: The mouth is held open with a standard surgical mouth gag used
commonly in the operating room. The anesthesiologist stabilizes the gas tubes attached to
the airway. B: The tumor bed is painted with methylene blue to make it easy to identify. The
tongue is pulled forward with a plastic towel clip over gauze. A lead shield, inside a surgical
glove, is placed behind the tongue to shield the floor of the mouth. C: The intraoral cone is
docked. The tongue is held in place by the towel clip, which is pulled taut by a strap seen in
the far right of the picture. The child is alive and well, with satisfactory speech development,
4 years after radiotherapy.
Figure:
A mobile anesthesia machine such as the Narkomed Mobile (Drager) with a remote screen
for data and alarms is suitable for the radiotherapy suite.
INTRAVENOUS ANESTHETICS
Intravenous anesthesia is also a popular and effective technique for pediatric radiotherapy.
Intravenous anesthesia relies on either intermittent or continuous infusion of anesthetic agent
into a peripheral or central vein in order to maintain a therapeutic concentration (17).
Although it is not a new concept (sodium thiopental was administered by continuous drip as
early as 1944), the advent of newer, short-acting anesthetic drugs, better equipment for
infusing these drugs, and an improved understanding of pharmacokinetics in pediatric patients
have led to a resurgence of interest in this technique. Postulated advantages of intravenous
anesthesia include fewer peaks and troughs in serum concentration of drug, providing a
steady -state serum concentration. Proponents of intravenous anesthesia contend that this
steady -state concentration results in a more rapid induction of and emergence from
anesthesia when compared with inhaled anesthetics. The time to emergence for short-
duration cases (less than 45 minutes) is likely to be rapid with either technique. With longer
cases, the emergence with inhalational anesthesia may even be quicker, depending on the
depth of anesthesia. The use of intravenous anesthesia does not require an anesthesia
machine, but still requires an oxy gen source as well as a patient monitoring sy stem.
There is an extensive body of experience with ketamine in the radiotherapy suite
(18,19,20). Since its release in the early 1970s, this dissociative anesthetic has been widely
used for radiation therapy in children. Ketamine produces excellent analgesia and amnesia of
short duration. Ketamine is easy to administer (it can be given intramuscularly if there is no
intravenous access) (21), and is felt to preserve respiration and airway patency more
effectively than inhaled anesthetics. One series described a child with a phary ngeal tumor
who experienced airway obstruction with halothane anesthesia. When ketamine was
substituted for halothane, the patient had an uneventful anesthetic treatment, which resulted in
satisfactory conditions for radiotherapy (22).
Ketamine and midazolam can be used to produce repetitive intravenous anesthesia for a
child undergoing radiation therapy. Ketamine is a phency clidine derivative that produces
dissociative anesthesia, characterized by electroencephalographic evidence of dissociation
between the thalamus and the limbic sy stem. The drug has a rapid onset of action, a short
duration, and high lipid solubility. It does not produce significant depression of ventilation.
There is an increase in sy stemic and pulmonary arterial blood pressure, cardiac output,
cardiac work, and my ocardial oxy gen needs. The drug is metabolized extensively by hepatic
microsomal enzy mes. There have been case reports of tolerance developing with repeat
administration of ketamine (23).
Ketamine is not a panacea. There are several caveats to its use. Ketamine has ocular
effects that have implications for radiotherapy. The onset of ketamine anesthesia often is
accompanied by ny stagmus (more commonly horizontal than vertical). Ny stagmus with
ketamine usually is transient; however, if it persists, it may be impossible to use a hanging lens
block in an anterior field for the treatment of retinoblastoma. Ketamine can also produce
involuntary movement of other muscle groups (jerking), which is undesirable in pediatric
radiotherapy. Ketamine raises blood pressure and heart rate. Its use in the setting of elevated
intracranial pressure (ICP) is contraindicated because it causes ICP to increase. Although
ketamine generally preserves respiratory drive and airway patency, apnea can occur after
an intravenous bolus. In addition, it is a potent sialogogue, and copious secretions often
accompany its use. Secretions can cause airway obstruction. Ketamine also sensitizes the
airway to irritable stimuli, and reflex lary ngeal closure (lary ngospasm) often occurs. A
dry ing agent such as atropine or gly copy rrolate should be given in conjunction with ketamine.
Page 492Finally, emergence from ketamine anesthesia often is characterized by
hallucinations and nightmares. The incidence of emergence reactions ranges from 10% to
30% in adult patients. Emergence reactions are much less common in children. The reason
for this difference is not known. Whatever the mechanism, the occurrence of these
emergence reactions can be reduced if a benzodiazepine such as diazepam or midazolam is
used.
Benzodiazepines are rarely used as the sole agents for radiotherapy in children.
Diazepam (Valium) is painful to administer when given intravenously, and its duration of
action exceeds the duration of most radiotherapy sessions.
Midazolam (Versed) is a water-soluble benzodiazepine that is two to three times as potent
as diazepam. It is short acting and not painful when given intravenously, but when used by
itself it does not produce satisfactory sedation for radiotherapy. A plateau in sedative effect
often accompanies its use, so additional dosing does not produce the desired clinical effect. In
the event that a patient receives an overdose of benzodiazepine or demonstrates an
exaggerated clinical effect, the drug can be displaced from its receptor by flumazenil, a
benzodiazepine antagonist. Flumazenil should not be used in patients who chronically receive
benzodiazepines, as it can precipitate acute withdrawal.
Barbiturates are sedative–hy pnotic drugs that depress the activity of the central nervous
sy stem (CNS). These drugs produce sleep within seconds of intravenous administration.
Awakening is rapid and occurs by redistribution of the drug from the CNS. Barbiturates are
given as an intravenous bolus or as a bolus followed by a continuous infusion. The short-acting
barbiturates thiopental and methohexital have been used in pediatric radiotherapy (24,25).
Side effects include apnea, hiccoughs, lary ngospasm, and paradoxical CNS excitation. Some
radiotherapists use droperidol, a buty rophenone derivative with pharmacologic actions similar
to those of haloperidol and phenothiazines, generally followed by pentobarbital for
intravenous anesthesia.
Narcotic analgesics produce sedation as a side effect. Potent sy nthetic opioids such as
fentany l, sufentanil, alfentanil, and remifentanil may be used to supplement intravenous
anesthesia, but their use is limited by their ability to depress respiration, cause chest wall
rigidity, and produce tolerance. These side effects of narcotics make opiate anesthesia
undesirable for radiotherapy. Radiotherapy is not a painful procedure; narcotics should not be
necessary. Mixed opiate agonist–antagonists such as nalbuphine and butorphanol are touted as
producing sedation and analgesia with less respiratory depression (plateau effect), and may
be useful adjuncts in anesthesia for radiotherapy.
Propofol is an intravenous anesthetic that has hy pnotic–sedative properties. The active
ingredient, 2,6-diisopropy lphenol, is formulated in an emulsion of soy bean oil, gly cerol, and
egg lecithin. This formulation gives it a milky -white appearance. It is a highly lipid-soluble
compound and therefore has a rapid distribution into the CNS and a rapid elimination, which
has made it a popular anesthetic agent for day surgery and short procedures. It can be given
via a central venous line or a peripheral intravenous catheter. When it is given peripherally,
pain on injection is common. This pain can be reduced by administering the drug with
lidocaine. Propofol has been increasingly used by anesthesiologists in pediatric radiotherapy
and, at some centers, is the drug-of-choice. It is given as an intermittent bolus or as a bolus
followed by continuous infusion. Awakening is rapid, and the incidence of side effects is low.
When it is administered as a rapid intravenous bolus, apnea and hy potension are common.
However, when the dosage is fractionated and administered slowly, spontaneous respiration
and blood pressure are preserved. Propofol appears to possess antiemetic properties, which
adds to its appeal.
Rapid and safe induction of anesthesia with propofol in children usually entails a loading
dose of 2.5 mg/kg administered intravenously. The dosage is higher in nonpremedicated
children. Maintenance of anesthesia is achieved by continuous infusion of 2.5 mg/kg/hr if it is
supplemented by analgesics and nitrous oxide. Tachy phy laxis with propofol is rare (26,27).
Fast awakening after the propofol infusion is stopped results from its short elimination half-life
and the lack of substantial accumulation during administration over a long period. The
elimination half-life after a single injection is even shorter in children than in adults.
Respiratory depression during injection of propofol anesthesia can occur primarily through
an overly rapid injection. Controlled administration of the induction dose, using an automatic
pump, guarantees a slow and steady injection. Clinically significant respiratory depression
during the maintenance phase of sedation can be avoided by stabilizing the infusion rate using
an automatic pump (28).
Scheiber et al. (29), from the University Hospital of Essen in Germany, reported 155
propofol anesthetic sessions performed on consecutive pediatric radiation therapy patients
with a mean age of 30 months. The mean duration of anesthesia was 18 minutes. There were
no clinically important complications involving respiration, circulation, or neurologic
functions except for one transient episode of desaturation managed by suctioning and change
in head position. Children awakened spontaneously at an average of 4 minutes after the
propofol infusion was discontinued. No tachy phy laxis or unpleasant side effects were
observed.
A lipid-based anesthetic agent such as propofol can support rapid microbial growth at
room temperature. Bennett et al. (30) documented the association of propofol with
postoperative infections. Eleven of 74 children receiving radiotherapy at Duke University
Medical Center in the 1990s who had a central venous line developed proven sepsis (15%)
with fever and a positive blood culture drawn through the central line. Of these 11 children, 8
had received prior chemotherapy (73%). Six of the 11 had been anesthetized with propofol
(55%), 4 with a short-acting barbiturate induction plus inhalation anesthetic (36%), and 1 with
inhalation anesthesia alone (9%). The pathogens cultivated from these 11 children included
Staphylococcus, Bacillus, Streptococcus, Enterobacter, and Candida (31). These cases
occurred prior to the addition of antimicrobial preservatives to propofol, which were added
by the manufacturer in response to such reports. One formulation of the drug (Diprivan)
contains EDTA; newer generic versions contain sodium metabisulfite or benzy l alcohol. Since
the addition of preservatives, there have been no documented postoperative infections
attributed to propofol. When infections do occur, they appear to be associated with a lapse in
aseptic technique.
Page 493There are four potential sources of central venous access colonization
producing sepsis: the skin insertion site, the catheter hub, hematogenous seeding of the
catheter, and infusate contamination such as might be caused by propofol (32). In the setting
of anesthesia for pediatric external beam radiotherapy, one is concerned about the possible
contamination of the catheter through repeated use by the anesthesiologist, as well as other
catheter-related complications, such as breakage to thrombosis. A more recent study of 170
patients undergoing daily radiation therapy demonstrated a 19.7% complication rate.
Peripherally inserted central catheter (PICC) lines had the highest complication rate at 38%,
central lines had a complication rate of 20.5%, and indwelling port-a cath lines a 13.6%
complication rate. Port-a caths were accessed following induction on Monday mornings, and
left accessed until Friday in this study. The authors recommend indwelling ports as the line of
choice in patients undergoing daily radiotherapy (33). It is well known that there is a high
incidence of central venous line sepsis in a variety of high-risk settings including patients
receiving chemotherapy or total parenteral nutrition, burn unit patients, and those in the
intensive care unit (31,32). The risk of sepsis with repeated catheter use in such settings ranges
from 5% to 29%. Therefore, though catheter infections should be minimized by strict
adherence to aseptic technique, there is alway s the potential for sepsis in the child whose
central venous line is accessed repeatedly, regardless of the anesthetic technique. The
pediatric radiation oncologist must work closely with the anesthesia team to be sure that the
appropriate equipment is provided in the radiation treatment area to assure an aseptic process
for drug administration.
Dexmedetomidine has become a popular agent for intravenous sedation and anesthesia
in pediatric patients. It is a highly specific alpha-2 adrenergic receptor agonist that provides
sedation with less respiratory depression than narcotics. Although apnea is possible, it
generally preserves minute ventilation and is considered a safer agent for sedation in patients
with potential respiratory compromise. The most common hemody namic effect in children
is brady cardia, which may require pharmacologic therapy with an anticholinergic agent such
as atropine or gly copy rrolate (34). Though no studies have y et evaluated the safety of daily
exposure to dexmedetomidine in children or adults, a case report describes the successful use
of dexmedetomidine as the sole sedative for 9 of 12 treatments in a 21-month-old undergoing
radiotherapy for a posterior fossa tumor (35). One disadvantage of dexmedetomidine
compared to propofol is its slow rate of onset.
SEDATION OR ANESTHESIA?
Conscious sedation as a medically controlled state of depressed consciousness allows

protective reflexes to be maintained, retains the patient’s ability to maintain a patent airway
independently and continually, and permits appropriate response by the patient to phy sical
stimulation or verbal commands (e.g., “open y our ey es”). General anesthesia is a medical
state of unconsciousness, usually accompanied by a loss of protective reflexes, including the
inability to maintain a patent airway independently and to respond to phy sical stimulation or
verbal commands.
The drugs commonly used for sedating y oung children in radiation therapy include
chloral hy drate, which is administered by an oral or rectal route; phenobarbital, which may
be administered orally, rectally, or intravenously ; fentany l, which is available for
administration orally, intramuscularly, or intravenously ; midazolam, for intramuscular or
intravenous use; meperidine, which may be administered orally, rectally, or intramuscularly ;
promethazine, which is a sedative agent administered orally or intramuscularly ;
chlorpromazine, which may be administered orally or intramuscularly ; or droperidol, which
may be administered intramuscularly or intravenously. Chloral hy drate has principally a
sedative effect. Pentobarbital has both sedative and hy pnotic effects. Fentany l has analgesic
and amnesic effects. Meperidine is primarily an analgesic. Promethazine and
chlorpromazine have principally sedative effects, whereas droperidol has both tranquilizing
and sedative effects.
Some institutions first attempt to sedate a child for radiation before using general
anesthesia. For phy sicians who first use chloral hy drate, the dosage is 75–100 mg orally or
rectally. If adequate sedation is not achieved in 20 minutes, a second dose of 25 mg/kg can be
given if the lesser dose of 75 mg/kg was used initially. The maximum dosage should not
exceed 2000 mg. An alternative is midazolam 0.05–0.2 mg/kg given by slow intravenous push
over 3–5 minutes and titrated to effect. It is generally recommended to give oxy gen by mask
during the procedure. Some phy sicians prefer meperidine 0.5–1 mg/kg, with a maximum of
20 mg, to be given by slow intravenous push over 3–5 minutes. If sedation fails, general
anesthesia is administered by an anesthetist. The criteria for consulting an anesthesiologist
include the need for a regular boosting of chloral hy drate, unsatisfactory sedation, or
unsatisfactory radiation therapy caused by patient motion.
A retrospective review of the clinical experience with sedation and anesthesia for
pediatric radiation therapy published by investigators from the King Faisal Specialist Hospital
and Research Center of Riy adh, Saudi Arabia (28) demonstrated a high rate of unsatisfactory
conditions with sedation alone. They attempted to sedate children and, if that failed, then
moved to general anesthesia. In a series of 1033 consecutive treatments, 86% included
general anesthesia, and 14% were performed with conscious sedation. With the use of
general anesthesia, satisfactory control of motion for radiotherapy was achieved in 97% of
cases. Conscious sedation gave a satisfactory result in only 68% of cases (p = 0.0001). The
highest success rate was achieved with propofol anesthesia in 837 procedures. Only 7% of
these procedures had at least one complication, and satisfactory treatment was achieved in
98% of cases.
Although the authors of this study argue that, except for retinoblastoma cases, phy sicians
should use conscious sedation with midazolam before moving to general anesthesia, the data
may not support this view. Conscious sedation often does not achieve a sufficiently stable
child for precision radiation therapy, the uncertain duration of times to achieve anesthesia
may make it difficult to operate a radiation therapy department on schedule, and the
significant incidence of complications all may argue for a policy of moving directly to
anesthesia under the direction of an anesthetist rather than conscious sedation administered by
a radiation oncologist in an attempt to avoid anesthesia. Because anesthesia is almost alway s
needed any way, especially for y ounger children, the attempt to use conscious sedation may
create unnecessary delay s.
Page 494A retrospective review of 3833 procedures at St. Jude’s Children’s Research
Hospital further confirmed the safety and reliability of general anesthesia for radiotherapy in
children. All children received propofol anesthetics, some with adjuncts such as
benzodiazepines, opioids, and/or ketamine. The median age was 3½ y ears (range 5 months–
21 y ears). The complication rate was low (1.3%) and most were considered minor airway
complications such as oxy gen desaturation, cough, or apnea; none required advanced airway
interventions (36). More recently, a study from a free-standing proton radiation therapy
center has found a 0.0074% complication rate among pediatric patients presenting for general
anesthesia (37). A retrospective review of 9328 anesthetics performed with total intravenous
anesthesia and spontaneous ventilation resulted in an anesthetic complication rate of 0.05%
(38).
It is crucial to have adequate monitoring capabilities when either sedating or
anesthetizing children for radiation therapy. A daily evaluation process should include
checking presedation vital signs and evaluating any contraindications such as presence of an
upper respiratory tract infection, acute pulmonary problems, allergy, or other problems that
may alter the appropriate drug dosage. The child is monitored during therapy with a closed-
circuit television monitor that is clearly visible outside the radiation therapy room. A display
of the pulse oximeter should be visible. Emergency equipment including a pediatric
emergency cart, suction machine, Ambu bag, face mask, defibrillator, oral airway, and
emergency drug box should be readily available. After each daily sedation, the child should
be kept in the radiation therapy department until it is evident that the effects of sedation have
worn off and the child is able to take fluids and has stable vital signs. Meticulous chart
documentation is essential (39,40,41).
ANESTHESIA MONITORING
Unrecognized hy poventilation is the primary cause of morbidity and mortality in pediatric

anesthesia (39). The respiratory depressant effects of many anesthetic agents combined with
the propensity for airway obstruction as a consequence of positioning for radiotherapy make
anesthesia for pediatric radiotherapy a procedure requiring attention to details. The need to be
phy sically removed from the patient during radiation delivery adds to the challenge of
adequate monitoring.
What constitutes appropriate monitoring for children receiving sedatives and general
anesthetics? The American Academy of Pediatrics Section on Anesthesiology and the
American Society of Anesthesiologists have published guidelines (39,42). The standards for
basic intraoperative monitoring of the American Society of Anesthesiologists state:
during all anesthetics, the patient’s oxygenation, ventilation, circulation, and

temperature shall be continually evaluated. Qualified anesthesia personnel
shall be present in the room throughout the conduct of all general anesthetics,
regional anesthetics, and monitored anesthesia care. In the event there is a
direct known hazard, for example, radiation, to the anesthesia personnel that
might require intermittent remote observation of the patient, some provision
for monitoring the patient must be made.
The minimum monitoring standards for all patients undergoing anesthesia in any setting
are continuous display of the electrocardiogram (ECG), arterial blood pressure and heart rate
determined and evaluated at least every 5 minutes, pulse oximetry, capnometry, and
monitoring of the fraction inspired oxy gen in the breathing circuit.
Provisions made for monitoring in radiotherapy suites include closed-circuit television
screens on which are display ed the patient and the oxy genation, ventilation, circulation, and
temperature monitors and/or leaded glass windows through which the patient and monitors
can be viewed while the radiation treatment is delivered (Fig. 21.5 ).
Figure 21.5 The laryngeal mask airway is a silicon tube. The distal end of the tube has an
elliptical-shaped cuff that, when correctly inserted and inflated, forms a low-pressure seal
around the larynx and allows spontaneous ventilation without the need for endotracheal
intubation. (Photographed by permission of Gensia, Inc., San Diego, CA.)
Early reports of anesthesia for radiotherapy relied on visual inspection of patient color as
a monitor of adequacy of oxy genation. However, the unreliability of direct observation for
detecting cy anosis is known (43). Pulse oximetry is an accurate, noninvasive, continuous
measure of arterial oxy gen saturation. A pulse oximeter is an optical sensor that measures the
concentration of oxy hemoglobin by transmitting red and infrared light through tissue beds
such as a finger, earlobe, or nose. The use of a pulse oximeter is mandatory for any patient
receiving sedative or anesthetic drugs. The Oxisensor (Nellcor, Inc.), a disposable pediatric
digit oxy gen transducer, can be used for these children. It is an expensive device, but with
proper handling it can be reused from day to day (32). The pediatric pulse oximeter using
Masimo Signal Extraction Technology (Masimo Corporation, Irvine, CA) may be more
sensitive than conventional pulse oximeters in detecting hy poxic events (44) (Fig. 21.6 ).
It is important to emphasize that in patients
receiving supplemental oxy gen, decreasing
oxy gen saturation as measured by a pulse
oximeter is a late sign of hy poventilation. How is
ventilation best monitored? The first report of
anesthesia for radiotherapy used continual visual
observation of the thorax and abdomen
combined with a wisp of cotton placed over the
mouth. The cotton fibers moved in and out with
inspiration and expiration, respectively,
amplify ing air movement. Amplifiers are used Figure 21.6 The anesthetized child is
because the anesthesiologist cannot be monitored, in the accelerator vault, with
phy sically present while radiation therapy is the electrocardiogram, pulse oximetry,
being delivered. While the anesthesiologist will and capnometry. Notice that the gas
rely on the oximeter, ECG, capnometry (vide delivery mask is well integrated into the
infra), and a video monitor tracing of respiration, radiotherapy head stabilization device.
several amplifiers of ventilation were described
for use in radiotherapy prior to the era of remote electronic monitoring. These amplifiers
may still be used, in conjunction with modern monitoring, to good effect. Visual amplifier
methods include attaching a cotton-tipped applicator to the thorax and observing via a closed-
circuit television monitor the excursions of the cotton tip with inspiration and expiration and
placing a small light box on the patient’s abdomen or chest and observing on the television
monitor the movement of the light bulb with each respiratory cy cle. Aural amplifiers allow
the anesthesiologist to hear the patient’s breath sounds from outside the treatment area. An
esophageal or precordial stethoscope can be connected to an audio amplifier, and the output
can be heard on a speaker or earphone.
Page 495Observation of the movements of the reservoir breathing bag by the
anesthesiologist is an excellent monitor of gas exchange. This technique is applicable to
patients anesthetized with inhalational agents whose tracheas are intubated, those who have an
LMA in place, or those who have a simple face mask applied over the nose and mouth. If the
breathing bag cannot easily be seen on the closed-circuit monitor or through the leaded glass
window, its movements can be amplified by a stick made of tongue blades. One end of the
stick is attached to the neck of the breathing bag with a piece of tape, and a flag of white paper
is placed at the opposite end of the stick. This long lever arm greatly accentuates the
movements of the breathing bag and serves as an amplifier of ventilation.
The gold standard for assessing ventilation is capnometry. Capnometry is the quantitative
measurement of the partial pressure of CO2 produced by the patient during the ventilatory
cy cle. Capnography is the continuous graphic display of CO2 concentration as a function of
time. End-tidal CO2 analy sis is a mean of assessing alveolar ventilation, airway patency, and
the functioning of the breathing circuit and ventilator. End-tidal CO2 monitoring has been
shown to be an effective monitor in pediatric anesthesia, capable of the early detection of
many potentially life-threatening events such as apnea, bronchospasm, and disconnections in
the breathing circuit (45).
The adequacy of circulatory function during the administration of anesthesia is assessed
by continuous display of the ECG and by measurement of blood pressure. Noninvasive,
automated oscillometric blood pressure determination (DINAMAP, Criti Kom, Inc., Tampa,
FL) is readily available and uniquely suited for remote monitoring of blood pressure. The
ECG and DINAMAP display s are viewed indirectly on the closed-circuit monitor or directly
through a leaded glass window if the radiotherapy suite is so equipped.
No matter how rigorous the adherence to recommendations and guidelines intended to
promote high-quality care, it is impossible to guarantee specific patient outcomes. The
provision of anesthesia for radiotherapy carries with it the additional challenge of remote
monitoring of patients whose airway s may be compromised not only by their underly ing
disease but also by the constraints of positioning for the procedure (Figs. 21.7 and
21.8 ). A postanesthetic recovery area must be established for care following the
anesthetic. Nursing staff trained in recovery room nursing need be present to assist with
emergence from anesthesia. Administration of an antiemetic drug such as ondansetron is
considered in all patients as radiation therapy can promote nausea (46).
Figure 21.7 A: The face mask is secured with straps and
provides a stable, unobstructed airway. End-tidal CO2 is
monitored via sidestream capnography. The pediatric pulse
oximetry probe fits most children and is reusable. B: The entire
body is stabilized in a polyurethane custom foam mold.
Figure 21.8 Monitoring from immediately outside the
treatment room is accomplished with a video screen displaying
the child, an intercom system for audio, and a video monitor
displaying the electrocardiogram, respiratory wave, and fraction
of inspired oxygen. An additional camera allows viewing of the
patient simultaneously.
Figure:
The laryngeal mask airway is a silicon tube. The distal end of the tube has an elliptical-shaped
cuff that, when correctly inserted and inflated, forms a low-pressure seal around the larynx
and allows spontaneous ventilation without the need for endotracheal intubation.
(Photographed by permission of Gensia, Inc., San Diego, CA.)

Figure:
The anesthetized child is monitored, in the accelerator vault, with the electrocardiogram,
pulse oximetry, and capnometry. Notice that the gas delivery mask is well integrated into
the radiotherapy head stabilization device.
Figure:
A: The face mask is secured with straps and provides a stable, unobstructed airway. End-tidal
CO2 is monitored via sidestream capnography. The pediatric pulse oximetry probe fits most
children and is reusable. B: The entire body is stabilized in a polyurethane custom foam mold.
Figure:
Monitoring from immediately outside the treatment room is accomplished with a video
screen displaying the child, an intercom system for audio, and a video monitor displaying the
electrocardiogram, respiratory wave, and fraction of inspired oxygen. An additional camera
allows viewing of the patient simultaneously.
ANESTHETIC IMPLICATIONS OF UNDERLYING DISEASE
Page 496Radiotherapy is used to treat several different pediatric malignancies. In the Duke
series, the diagnoses leading to treatment with external beam radiotherapy under anesthesia
were primary CNS tumor (28%), retinoblastoma (26%), neuroblastoma (18%), acute
leukemia (9%), rhabdomy osarcoma (7%), Wilms tumor (5%), Langerhans cell histiocy tosis
(4%), and other (3%) (Fig. 21.9 ). It is not surprising that the diagnoses leading to
radiotherapy under anesthesia differ somewhat from the most common diagnoses of cancer
in childhood. Leukemia is an uncommon indication for radiotherapy under anesthesia
because it is, in general, a malignancy of older children, and the role of radiation therapy in
leukemia is limited. Diseases associated with y ounger children for which radiotherapy is
more frequently used dominate the list (31). Many of these malignancies have implications
for the pediatric anesthesiologist. Children with supratentorial brain tumors can have elevated
ICP. Management of anesthesia for patients with elevated ICP includes the avoidance of
drugs that can raise ICP, such as ketamine. Anesthetic techniques that result in elevations in
arterial CO2 tension can produce intracranial hy pertension by increasing cerebral blood flow.
Some neuroblastomas secrete catecholamines and cause sy stemic hy pertension. Blood
pressure elevations are associated with abdominal palpation. This problem is rare in pediatric
radiotherapy because the tumor is not manipulated—the most common indications for
radiotherapy in neuroblastoma are treatment of the tumor bed as part of a high-dose
chemotherapy /marrow rescue procedure for advanced disease or for the palliative treatment
of metastases.
Wilms tumors often are massive and can impair ventilation by increasing intra-
abdominal pressure. An occasional child with a Wilms tumor will undergo endotracheal
intubation for respiratory failure before presenting to the radiation oncologist for
radiotherapy. These tumors can also extend into the inferior vena cava and renal vein,
producing renovascular distortion and sy stemic hy pertension.
Children with Hodgkin disease, non-Hodgkin ly mphomas, and T-cell acute ly mphoblastic
leukemia can present with anterior mediastinal masses. These masses can produce tracheal
compression and impair ventilation. They can also produce superior vena cava sy ndrome by
compressing the great veins. Some patients with anterior mediastinal masses are referred to
the pediatric radiation oncologist for external beam therapy before tissue biopsy. Radiation
therapy before tissue biopsy is recommended in some of these patients because the induction
of anesthesia for surgery in some patients with anterior mediastinal masses can be fatal.
Death on induction of general anesthesia in these patients is caused by either the inability to
ventilate because of airway compression or the inability of the heart to circulate blood
because of tumor encroachment on the right heart or pulmonary circulation (47). Prospective
identification of children with anterior mediastinal masses who are at risk for
cardiorespiratory collapse on induction of general anesthesia involves a thorough history and
phy sical examination aimed at eliciting signs and sy mptoms of airway and cardiovascular
impairment. Laboratory studies useful in assessing preanesthetic risk include a chest
radiograph, computed tomography scan, and upright and supine flow–volume loops. The
pediatric radiotherapist may treat patients with anterior mediastinal masses for whom the
risks of general anesthesia are felt to outweigh the benefits of obtaining tissue before the
institution of therapy. These patients should not receive anesthesia or sedation.
Page 497In addition to these considerations, the pediatric anesthesiologist must consider
the associated implications of treating malignancy in children. These implications include the
cardiac, hematologic, pulmonary, immunologic, and neurologic impairments caused by
chemotherapy (45).
Anemia is one of the most common problems in children with cancer. Anemia
decreases oxy gen delivery to the tissues. Oxy gen delivery is the product of the arterial
oxy gen content and the cardiac index. If oxy gen delivery to the tissues is inadequate, organ
sy stem failure occurs. The minimum acceptable hemoglobin value in anesthetized children is
unknown. Hemoglobin values as low as 7 g/dL may be adequate if the patient has normal
cardiovascular compensatory mechanisms. However, many patients cannot compensate for
low levels of hemoglobin because they have
chemotherapy -induced my ocardial dy sfunction.
Children receiving sy stemic chemotherapy
in concert with radiation therapy may be
immunocompromised. Consequently, they may
be more prone to upper respiratory tract
infections, a condition which may increase the
risk of anesthesia significantly, especially when
an airway device such as an LMA is used (48).
Patients should be assessed before each
anesthetic for presence of fever, cough, or
increased mucus production, all of which are
associated with increased complications.
Children with moderate to severe sy stemic
illness should likely delay treatment for a day or
two to lessen the risk of general anesthesia (49).
The anthracy cline antibiotic
chemotherapeutic agents doxorubicin and
daunorubicin are cardiotoxic. These drugs have
both an acute and a chronic effect. Acute
toxicity manifests as rhy thm and conduction
disturbances such as supraventricular
tachy cardia, ventricular ectopic beats, and heart
block. Chronic toxicity manifests as a
cardiomy opathy, which can progress to left
ventricular failure in 2–10% of patients. Factors
that increase the risk of anthracy cline
cardiotoxicity include dosages greater than 550
mg/m 2, age y ounger than 1 y ear, concurrent
use of other chemotherapeutic agents such as
cy clophosphamide and cisplatin, and a history of
mediastinal irradiation.
Figure 21.9 A–C: The nurse is at the
Pulmonary toxicity occurs in 5–10% of
bedside in the recovery area in the
patients treated with the antibiotic
radiotherapy department. Oxygen,
chemotherapeutic agent bleomy cin. Bleomy cin
suction, and pulse oximetry monitoring
produces interstitial pulmonary fibrosis, which
are immediately available.
results in restrictive lung disease. The damage is
thought to be caused by oxy gen free radical
formation. The role of exogenous oxy gen in promoting the pulmonary toxicity of bleomy cin
is controversial. However, it is prudent to avoid inspired oxy gen concentrations >28% when
anesthetizing patients who have been treated with bleomy cin, provided that they maintain
satisfactory levels of arterial oxy gen tension.
On rare occasions, the child undergoing anesthesia for radiotherapy has received a prior
course of irradiation to the head and neck or lungs. The anesthesiologist should be aware that
these children may be at higher risk for lary ngeal edema after instrumentation of the airway
and for difficulty in maintaining oxy genation (50,51,52,53).
Figure:
A–C: The nurse is at the bedside in the recovery area in the radiotherapy department.
Oxygen, suction, and pulse oximetry monitoring are immediately available.
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CH A P TER 22
Psychosocial Aspects of Radiotherapy for
the Child and Family with Cancer
Shulamith Kreitler, Myriam Weyl Ben Arush, Elena Abigail Krivoy, Hana
Golan, Michal Yalon Oren, and Amos Toren
Page 499As cure can be achieved in a large majority of pediatric cancer patients, long-term
effects and quality of life of the survivors are nowaday s the principal challenges to pediatric
oncologists. In recent y ears, it has become increasingly clear that the psy chosocial effects of
a treatment are an integral part of the treatment and should be considered when evaluating its
overall effect and its impact on the patient’s quality of life.
The rate of pediatric cancer survival has reached about 80% and is increasing. Health
professionals, parents, and pediatric patients are increasingly aware of the effects of
treatment. Hence, there is a growing body of studies of the psy chosocial correlates and
effects of pediatric cancer treatments. Some of the effects are direct, while others are
indirect and result from a variety of effects of radiation therapy (RT) on phy sical functions.
COGNITIVE EFFECTS OF RADIOTHERAPY
A large number of studies deal with investigating and assessing the cognitive effects of
radiotherapy. The bulk of these studies focus on the cognitive effects of cranial radiotherapy
(CRT), since it is in this domain that cognitive effects are likely to be most easily detectable.
Up to 40% of childhood cancer survivors who were exposed to CRT may experience
neurocognitive impairment in one or more specific domains (1). Recent y ears have
witnessed a remarkable advancement in the number and quality of studies focusing on
cognitive effects following CRT (2). This surge of interest has led to an increase in
information about the kind of cognitive effects of RT as well as the relations between these
effects and various characteristics of RT. Nevertheless, the findings need to be considered
with caution for two main reasons. First, although in this chapter special care was taken to
include only studies that refer directly to the effects of RT per se, it is likely that many of the
children participating in these studies did not undergo exclusively RT but in addition surgery
and chemotherapy that could have also impacted cognition in unspecified way s. Second,
many of the children treated with RT got the treatment as a cure for brain tumors, which
could have affected cognition independently of the RT.
The effects of radiation on the brain are usually described in terms of three stages: the
acute phase, often associated with a sudden neurologic deterioration, the subacute phase (or
early delay ed, 2–6 weeks after radiotherapy ) when the “somnolence sy ndrome” may occur
attended by fatigue and a transient exaggeration of the neurologic signs, and, finally, the late
phase in which various gradual neurocognitive deficits show up (3,4). Most of the reported
findings refer to the third phase.
Effects of RT on Intelligence
A large number of studies report the effects of RT on intelligence (Table 22.1 ). The studies
vary greatly in the characteristics of the samples and the administered doses of RT. However,
the majority support the general conclusion that CRT brings about a decline of about 5–20
points in IQ, which according to many studies, but not all, tends to be more pronounced if the
RT dose has been higher and the child who got RT is y ounger. The decline in IQ persists over
time, even to over 10 y ears after RT. There is evidence that the decline in IQ may be due at
least partly to a decreased rate of acquiring new information (24).
Table 22.1 Studies about the Effects of RT on IQ Scores
Effects of RT on Specific Cognitive Functions

Several studies focused on identify ing the effects of CRT on more specific cognitive functions
than overall intelligence. Deficits in cognitive functioning following CRT are evident in
attention, executive functioning, processing speed, working memory, and memory, all of
which contribute to declines in intellectual and academic abilities (10,25). Monje (26)
reported that CRT is associated with a progressive decline in cognitive function, prominently
memory function, whereby impairment of hippocampal neurogenesis is thought to be an
important mechanism. Children with acute ly mphoblastic leukemia (ALL), who had been
treated with RT, were compared in cognitive functioning with ALL patients, who had been
treated only with chemotherapy, and with healthy controls (8). The comparison showed that
the group which got RT had deficits in working memory and processing speed relative to
healthy controls. Further, differences in working memory mediated the observed differences
in IQ between the CRT group and controls. However, processing speed did not fully account
for the working memory deficit in the CRT group. The data suggest that deficits in processing
speed and working memory following CRT may underlie the frequently reported declines in
IQ.
Page 501A review by Bhatia and Landler (17) showed that affected children are
particularly prone to problems with receptive and expressive language, attention span, and
visual and perceptual motor skills. They most often experience academic difficulties in the
areas of reading, language, and mathematics. In another study, a follow-up for 59.6 months
after termination of therapy showed a modest but significant decline in reading scores, while
mathematics and spelling performance remained stable (27). Mulhern et al. (28) showed that
the decline in the reading, decoding, and spelling skills is independent of the risk level of the
disease. The deficits in the cognitive skills required in academic setups account for the
frequently reported school problems and poor academic performance of children who have
undergone CRT (29).
Many long-term survivors of medulloblastoma treated with RT had significant school
problems (72%), impairments of attention and processing speed (79%), learning and
memory difficulties (88%), language disabilities (56%), and deficits in visual perception
(50%), or executive functions (64%) (30). Similarly, in 31 patients (with medulloblastoma or
ependy moma) treated with standard dose or reduced dose of RT, there were significant
declines in visual–motor integration, visual memory, verbal fluency, and executive
functioning. There was no evidence for decline in verbal memory and receptive vocabulary
(18,31).
An earlier study with pediatric cancer survivors from a large variety of diagnostic
groups showed that CRT was associated with deficits in several, primarily nondominant
hemispheric neuropsy chological functions, most likely to be reflected in nonverbal
intelligence, perceptual abilities, and distractibility (32). Further evidence about the effects of
CRT on cognition comes from a study which showed that academic achievement, verbal
knowledge and reasoning, and perceptual–motor abilities were significantly lower among
CRT-treated groups of patients and that there were significant negative associations between
CRT dose estimates for cortical regions and perceptual–motor abilities (7). In a group of 138
survivors (73 with acute leukemia and 65 with solid tumors), who had been diagnosed before
the age of 15 y ears, had been treated over 2 y ears, and were evaluated at least 10 y ears after
diagnosis, assessment of cognitive functioning showed that the most affected cognitive areas
were comprehension, arithmetic ability, attention, visual and verbal memory, causative
reasoning, and visual–motor coordination. No relationship was found between sensory
sequelae (that were mostly mild) and cognitive capacities (19).
In a group of pediatric patients with malignant posterior fossa tumors, some of whom
were treated with reduced-dose CRT and some with standard dose, tested 1 y ear after
treatment and at several time points later, no significant differences in cognitive performance
were found between the groups. Their performance declined for spelling, mathematics, and
reading according to achievement tests and ratings by parents and teachers. However, data
analy ses revealed that there was no loss of skills but a reduced rate of skill acquisition (29).
Further, comparing 16 children with brain tumor, who had been treated with CRT or local RT,
with a group of children diagnosed with ALL who did not get RT, showed that the former
group was assessed by mothers and teachers as functioning with a significantly decreased
tempo on a visual analog scale. Low speed and hy poactivity seemed to limit the majority of
these children in school and daily life activities (16).
Page 502A special emphasis has been placed on two distinct cognitive functions:
memory and attention, both because deficits in these functions showed up in a great number
of studies and because they may be responsible for further cognitive difficulties and hence
also for lower academic achievements in general. Memory deficits following CRT are a
recurrent finding. Thus, Massimo et al. (33) also reported a study with 60 children diagnosed
with ALL, treated between 1974 and 1978 with or without CRT, who were in complete
remission. A psy chological investigation performed at least 2 y ears after terminating therapy
showed one clear finding: All those who underwent CRT had memory impairment. Another
study showed that children treated with CRT for medulloblastoma had verbal memory
deficits in retrieval and recognition following RT (34,35).
Attention deficits following RT were reported by Mulhern et al. (20). Kiehna et al. (36)
evaluated 120 patients with primary brain tumors, aged 2–24.4 y ears (median, 9.2 y ears),
before CRT, weekly during CRT, and serially up to 60 months after the start of CRT.
Evaluations of attention were done by means of the computerized Conners’ Continuous
Performance Test, which provides scores for errors of omission (inattentiveness), errors of
commission (impulsivity ), reaction time, and an overall index of performance. Before CRT,
patients had mild inattentiveness. During CRT, impulsivity decreased significantly. After CRT,
inattentiveness increased significantly, and global attention disorders were associated with
different ty pes of brain tumors. A decline in impulsivity and relative stability of the other
evaluated scores over the course of CRT show the absence of early radiation-related
cognitive sequelae.
A further study on attention was performed on 22 children (mean age at diagnosis 7.62
y ears) about 2.5 y ears after treatment termination, in order to examine the relationship
between auditory attention span, time elapsed since the initiation of RT (M = 2.43 y ears), and
adaptive functioning, assessed by the Vineland Adaptive Behavior Scales. Attention span was
found to mediate the relationship between time since the initiation of RT and daily living skills.
These findings were specific to attention and reflected neither a generalized
neuropsy chological decline nor the effect of increasing time since RT. Thus, they suggest that
time since RT may directly decrease attention and that poor attention in turn may be
associated with lower adaptive functioning in daily life tasks (37).
Several studies dealt specifically with the issue of identify ing RT factors likely to reduce
cognitive impairment following RT. A 5-y ear investigation of 123 children (age 3.8–5.3 y ears)
with ependy moma showed that conformal and intensity modulated RT resulted in relative
sparing of functional outcomes including IQ and adaptive behaviors, but not of
communication skills (38). A study of 50 children newly diagnosed with supradentorial
ependy moma (median age 6.5 y ears) showed that cognitive impairment may be limited by
use of focal irradiation methods (39). Further, it was shown that proton RT was associated with
good cognitive results in 32 pediatric cancer patients with low-grade gliomas in the brain or
spinal cord (40). Another study with 76 children (mean age 3.3 y ears) irradiated for
infratentorial ependy moma also showed that radiation dose was correlated negatively with
cognitive decline (41). A large-scale critical review of the cognitive effects of RT damage to
the brain showed that the following conditions are most probably related to impairment:
higher doses to parts of the brain versus lower doses to the whole brain, RT during the
postnatal brain development, and occurrence of late delay ed effects (3 y ears after RT) (42).
Some studies focused on identify ing the brain regions which are likely to affect
cognition. Thus, a review of studies on medulloblastoma indicated that the area most likely to
be involved in deteriorated cognitive functioning is the posterior cerebellar lobes (43). In
pediatric patients with infratentorial ependy moma, sparing RT portions of the anterior and
posterior cerebellum was related to better scores in IQ, as well as reading and spelling scores
(41). In patients treated by RT for posterior fossa brain tumors, cognitive processing speed
was affected deleteriously by damage to white matter tracts in the brain (44). A prospective
study with 19 pediatric patients receiving CRT and 66 healthy controls, assessed at baseline
and 6, 15, and 27 months after treatment termination showed relationships between reduced
performance on verbal learning and increasing dose to the cerebellum, as well as between
reduced performance on visual perception and increasing dose to the left temporal lobe (45).
The conclusions are that neuroprotective strategies need to be applied for preserving critical
cognitive functions dependent on specific irradiated brain regions. In sum, CRT brings about
decline in a whole range of specific cognitive functions, both verbal and nonverbal, especially
memory, attention, and processing speed, as well as global intellectual functioning as revealed
in IQ scores, school performance, and academic achievements. The impairment shows up
within 1–2 y ears after treatment termination and is progressive. It is likely that impairment in
some functions affects further functions. Factors responsible for increased severity of
impairments are y ounger age when RT is applied (especially lower than 5 y ears) and high-
dose RT (at least standard dose).
Further Factors Involved in Cognitive Functioning

Several studies found further variables affecting the cognitive impairment. Possible predictors
of lower cognitive functioning were investigated in a study of children with ALL, 5–14 y ears
old, in continuous complete remission and without evidence of current or past CNS disease,
evaluated 9–11 months after diagnosis. IQ was found to be unrelated to history of somnolence
sy ndrome. IQ and achievement were unrelated to age at irradiation, irradiation–examination
interval, and radiation dosages. The strongest predictor of IQ and achievement was parental
social class (46). Again, in ALL survivors with complete remission for 3.5 y ears, parental
education levels accounted for more of the neuropsy chologic variability than other factors,
such as age at diagnosis, ty pe of therapy, or gender of child (47). In children treated with RT
for craniophary ngioma, more rapid decline was correlated with being female and having
received preradiation chemotherapy, while in children treated for low-grade glioma, older
age at RT was a protective factor and baseline performance in the Vineland Adaptive
Behavior Scales predicted subsequent decline (48). In a further group, in addition to
statistically significant evidence for cognitive impairment, absence from school during
treatment and age at diagnosis were more predictive of reading and spelling academic
achievement than having received CRT (32).
Page 503A recommendation voiced by many researchers and practitioners in this field
is that patients at risk for cognitive deficits should undergo a neuropsy chological evaluation at
baseline, at transition points in academic education, and/or annually in order to assess their
difficulties and their vocational or educational progress (17). In addition, it is recommended to
develop and apply targeted cognitive rehabilitation and training programs in order to remedy
the specific cognitive deficits or even forestall them before the damage spreads. Some initial
attempts have already been reported (49,50). In a study in progress, a special cognitive
rehabilitation program based on the Kreitler meaning sy stem has been applied in individual
meetings with pediatric cancer patients after termination of RT. The cognitive performance of
the children was tested by a cognitive questionnaire and the mindstreams program pre- and
posttraining. So far, seven children participated and all evidenced significant improvement in
cognitive performance (51).
Several kinds of factors seem to be involved in regard to the cognitive impairment noted
often in children who underwent RT. The major ones seem to be the initial diagnosis, the
dosage and extent of RT, the age of the child when RT was applied, and the kind of
environment in which the child functions. It appears that up to now, not enough research
efforts have been invested in clarify ing the relative contribution of each of these factors to the
overall effect and to the possibility of compensating for a negative impact of one factor by
enhancing the positive impact of another factor. The child’s environment is the main factor
whose positive impact can be enhanced more readily than that of the other factors.
Surprisingly, this is the factor that has been studied to a lesser extent than the others. It includes
components, such as psy chosocial support by parents and the health professionals, belief in
the child’s ability to overcome difficulties, enhancement of achievement motivation, and a
host of other positive contributions to the child’s sense of well-being on all levels. The chances
for success of well-designed interventions are high because cognitive abilities or deficits are
only one of the factors that determine the overall level of functioning at school or at work.
Figure: Studies about the Effects of RT on IQ
Scores
SOCIAL AND BEHAVIORAL EFFECTS OF RT
In view of the difficulties and crises that children undergo in the course of the disease, the
treatments, and their sequelae, it can be expected that they may suffer from difficulties in
behavioral adjustment. A body of studies shows that children who had undergone RT tend to
have problems in two major domains: in social adjustment and in mood (Table 22.2 ). The
problems persist bey ond the termination of treatment. It has also been noted that the child’s
behavioral adjustment depends in addition on stress in the family and coping of the parents
(59).
Table 22.2 Behavioral and Social Effects of RT
Depression seems to be the most salient psy chiatric sy mptom that persists even 10 y ears
after termination of treatment in children treated with RT (60,61,62), particularly CRT (63).
It may be assumed that body image defects may play an important role in the child’s
adjustment. Few studies dealt mainly with this issue. In one study, 110 survivors of ALL
disease who were free of disease for at least 1 y ear were administered a psy chosocial
assessment battery by telephone. Those who received CRT had poorer self-image in regard
to their body than the others (64). Notably, tumors of CNS treated by CRT may cause
endocrine morbidities attended by negative effects on growth, which may cause in the
pediatric patients concerns with body image appearance and composition (65).
It seems that many of the pediatric cancer survivors are at risk for having problems in
social adjustment and interpersonal relations in general. Given the stability of poor peer
relationships and known linkages between peer problems and subsequent academic and
psy chiatric difficulties, it is evident that more attention should be devoted to the social
adjustment of the pediatric cancer patients so as to diagnose as early as possible likely
problems and launch intervention projects for their minimization.
Figure: Behavioral and Social Effects of RT
CHILDREN’S DISTRESS IN THE COURSE OF RT
There are several obvious reasons why it may be expected that children undergoing RT are
likely to be distressed and anxious. First, the treatment is given under special unfamiliar
conditions to the child, which differ from those of chemotherapy ; second, the child stay s
alone during the treatment; and third, the child is required not to move during the treatment.
Anesthesia that is often used for the alleviation of RT-related anxiety may have various
shortcomings, such as increased risks for medical complications, and difficulties in eating and
sleeping (66) (Fig. 22.1 ).
One study focused on the distress instead of children prior to their first RT experience
which was to be a simulation session in which no RT was administered but the procedural
demands and overall experience were identical to actual RT (67). The participants were 80
pediatric cancer children with various diagnoses, 2–7 y ears old, with no or mild degrees of
functional impairment, about to receive RT in an outpatient clinic. After explaining the study,
and before the simulation was introduced, information about distress in the children was
obtained directly from the children through a behavioral observational checklist and by
checking their heart rate, and indirectly from the parents by means of questionnaires that
they were asked to fill (State-Trait Anxiety Inventory and a questionnaire about RT). The
findings showed that 65% of children manifested at least some degree of anticipatory
behavioral distress, while 16% manifested high distress both in their behavior and heart rate.
The major factors that contributed to the child’s high level of distress were y ounger age of the
child and higher expectations of the parents that the child would experience distress, which in
turn was at least partly a function of the child’s y oung age. Notably, the parents’ anxiety levels
were unrelated to their expectations of the child’s distress reactions.
Page 504A further study (68) with a similar sample of 79 children applied anesthesia as
a measure of distress prior to the simulation session, in addition to the above-described
measures of Observation Scale of Behavioral Distress and heart rate. At simulation, 62% of
patients required pharmacologic intervention for completing the procedure. Further, y ounger
age and higher behavioral distress predicted the use of anesthesia for the simulation. Higher
baseline heart rate predicted lower behavioral distress. Notably, a prone position during
simulation was related to increases in behavioral distress and higher heart rate.
In sum, the reported studies provide clear evidence that pediatric cancer patients are
prone to experience distress prior to the simulation session, in the simulation session, and in the
course of administration of RT proper. These findings confirm a host of informal observations
of health professionals about the distress of children undergoing RT. Further supporting
evidence comes from studies showing that children treated with RT may suffer from
depression at the time of treatment and later (62,63).
Page 505Effects of RT on the Children’s Quality of Life

In recent y ears, some studies introduced the construct of quality of life in order to describe
the psy chological distress of children undergoing RT. An advantage of quality of life is that it
is a subjective and phenomenologically -based construct. As such, it enables describing the
experiences of children from their point of view. Descriptions of this kind, sometimes referred
to as “subclinical impairments of quality of life” (69), refer to different sy mptoms which
reduce the children’s level of quality of life, such as fatigue (70), salivary gland dy sfunction
(71), the risk of infertility (72), sleep disorders (73), and even decline in intelligence level
(23). Notably, pediatric oncologists asked about the uses of RT as a palliative care tool claimed
that it is underutilized because it has little impact on quality of life (74). The role of RT in
pediatric palliative care should probably be investigated. However, it needs to be emphasized
that in assessing quality of life, the responses provided by children may differ from those
reported by proxy by the parents (23). Therefore, the parents’ reports should not be used for
replacing the responses provided directly by the children, but rather as complementary
sources of information (75).
Intervention Procedures for Reducing Distress during RT

Various psy chosocial procedures have been
utilized in the hope of minimizing the use of
anesthesia or sedation for the administration of
RT in children.
Bucholtz (76) emphasized the need for
developing skills in nurses designed to provide
comfort to the children and their parents in the
RT setup. An interesting behavioral procedure
designed to teach cooperation and motion control
to preschoolers and older children with special
needs was described by Slifer et al. (77). Out of
10 children (3–7 y ears old), 8 benefited from the
behavioral program based on the use of an
audiovisual sy stem and were not in need of
sedation or anesthesia for completing RT (Fig.
22.1 ). A recent study based on interviews
with nurses showed increase in sense of the
children’s security produced by providing
individualized preparation and information
through teamwork of the nurse and anesthetic
personnel with the child and family (78).
Another study (79) focused on children 2–5
y ears old who are commonly assumed to be in
need of sedation for RT. They presented
outcome data on 63 children in this age range
indicating that sedation can be minimized in this
age group by means of an effective play
preparation program. Over a 5-y ear period
(1994–1999) in a pediatric oncology center, of
1030 treatment day s, only 111 day s required Figure 22.1 A–C: Pediatric radiation
sedation (10.8%), for the whole age range. No oncology waiting room, Sheba Medical
general anesthetics were given. Only 6 patients Center, Tel Aviv, Israel.
were sedated for the whole of their treatment
(9.5%), with 52 patients requiring no sedation at all (82.5%).
There have also been attempts to develop full-fledged programs for alleviating the
children’s stress and anxiety. Thus, one program was designed to provide the children and
their families with coping strategies that would minimize the necessity for anesthesia (80).
The program is based on preparing the children and the parents for the procedure, while
attending flexibly to the needs of each particular child. After apply ing the program with 55
children, the reports showed increases in satisfaction with care among the child, family, and
staff involved.
Page 506Klosky et al. (81) developed an interactive intervention program for reducing
RT distress among pediatric cancer patients in a simulation session. The effects were
measured in the children by occurrence of sedation, observed behavioral distress, and heart
rate, and in the parents by anxiety questionnaires. Seventy -nine children receiving RT
simulation were assigned randomly to an interactive intervention group or a modified control
group. The intervention included a 7-minute filmed modeling of the procedure, exposure to
an interactive Barney character, and passive auditory distraction by use of a noninteractive
Barney character (so as to emphasize the need for immobility in the simulation room). In the
control group, the children were exposed to a cartoon video, a noninteracting children’s
control character and stories on a cassette in the simulation room. The results showed that
children in the intervention group had lower heart rate than the control participants, but there
were no differences between the groups in sedation of distress manifested in behavior.
Another intervention that has potential for reducing RT-related distress in pediatric cancer
patients is based on a psy choeducational approach (82). The study focused on 223
consecutive pediatric cancer patients receiving 4141 RT fractions during 244 RT courses
between February 1989 and January 2006. The experimental group included 90 RT courses
corresponding with 1561 RT fractions; the control group included 154 RT courses
corresponding with 2580 RT fractions. The intervention included talks with the patient and the
parents about practical aspects of the upcoming RT and an age-appropriate explanation of the
RT treatment and procedure, implemented by picture books, play ful inclusion of toy s, and a
reward sy stem using beads as tokens for every completed RT session. Attendance by one of
two specially trained nurses at least for preparing the CT, RT simulation, and the first RT
session and as weekly visits during the RT itself was accomplished, so that each patient was
met on the average five times for the duration of 5–7.5 hours. The groups did not differ in age
at RT, gender, diagnosis, localization of RT, and positioning during RT. The major result was
that following the intervention there was a reduction in the need for using anesthesia: in the
experimental group, 9% of the children needed anesthesia as compared to 21% in the control
group. Further, the median age of cooperating patients without anesthesia decreased from 3.2
to 2.7 y ears.
Several recent studies describe a variety of interventions designed to alleviate the distress
of children undergoing RT minimizing the use of anesthesia. A study with 20 pediatric cancer
patients undergoing RT showed that encouraging them to produce, together with their parents,
a personalized video of their experience of RT proved to be a valuable means for overcoming
the children’s fear of the unknown, for providing understanding of treatment processes, for
increasing the children’s readiness to undergo treatment, and for reducing overall anxiety by
enhancing cognitive distraction (83). A mixed method study design was applied for
investigating the effects of music therapy on the distress and coping of the children (n = 11,
6–11 y ears old) in their first RT treatment. The intervention consisted in preparing a music CD
by means of an interactive computer-based software and listening to it during RT. The
children who listened to their CD were lower in distress and used social withdrawal as a
coping strategy less often than controls (84).
In sum, the psy chosocial intervention programs show the utility of preparations of this
kind for reducing the distress and anxiety of the children, increasing their cooperation with the
procedure and minimizing the need for apply ing anesthesia. LeBaron and Zeltzer (85,86)
have pioneered the use of guided imagery and hy pnotherapy for reducing pain and anxiety
in children with cancer. Other means for overcoming the anxiety of children evoked by RT
may be based on art therapy, play therapy, music therapy, role play ing, drama, and
production of stories. These and other psy chological procedures that could be applied for
reducing the distress of undergoing RT are described by Kreitler et al. (87). Developing,
apply ing, and evaluating such programs would render it possible to select in each case the
best program in line with the needs of the child, the utility of the intervention, and the
resources of the clinic or hospital.
Figure:
A–C: Pediatric radiation oncology waiting room, Sheba Medical Center, Tel Aviv, Israel.
INTERVIEW
The Views of the Children and the Parents about RT

In order to get a more comprehensive view of the problems and difficulties involved in
undergoing RT from the perspective of the patients, we conducted a preliminary survey
based on individual guided interviews with 20 children and 20 parents (not of the interviewed
children) in two major medical centers in Israel. The random sample included parents of
children, 7–17 y ears old, of varied diagnoses, all of whom were either in the last phase of RT
or terminated the treatment 0–10 day s previously : 55% got RT to the head, 15% to neck, 5%
to the chest, 15% to the abdomen, and 10% to the limbs. The random sample of interviewed
children (age range 6–15 y ears) of varied diagnoses got RT to the head (35%), face (10%),
neck (10%), abdomen (15%), chest (10%), back (5%), and limbs (15%). The major questions
posed to both children and parents were whether the child has undergone RT, for how long,
and to which part of the body ; awareness of short-term and long-term side effects of RT; any
difficulties concerning RT that the children had; any particular behaviors of the children noted
during RT; the difficulties the children had experienced during RT; comparing the difficulty of
RT to chemotherapy and to what has been expected prior to RT; and suggestions for rendering
RT easier.
Results Based on Interviewing Parents

Of the parents, 80% claimed that RT had immediate or short-term effects on their children,
which were mainly the following: nausea, diarrhea, reddening of the skin in the treatment
area, loss of hair in the treatment area, tiredness, somnolence, headaches, and impaired
gustatory and olfactory sensations; and 85% claimed they knew of possible long-term effects,
which were mainly cognitive impairment (40%), fertility difficulties (30%), problems in
regard to growing and overall development (40%), and the risk of a secondary cancer (20%).
Concerning difficulties of RT, the parents mentioned the emotional difficulty (50%) and
the technical difficulty they had to get to the hospital every day (60%). Concerning the
difficulties of the children, the parents mentioned in particular the difficulty of waiting for the
treatment in a waiting room shared by children and adults, getting the treatment in an
unfamiliar unit, the fear evoked by the noise of the machine, and stay ing alone in the
treatment room. All parents (100%) noted that RT was easier than chemotherapy. However,
but 20% claimed that RT was more difficult, 45% claimed it was easier, and 35% claimed it
was as they had expected.
Page 507The major suggestions of the parents for rendering RT easier referred to three
issues. First, information: 85% emphasized the desirability of improving the provision of
information about RT beforehand as well as in the treatment, using verbal materials
implemented by films, videos, and modeling. Second, site of RT: 80% emphasized the
desirability of using waiting rooms and treatment rooms designed specifically only for the
use of children, provided with toy s, pictures, music, and other objects for distracting and
relaxing the children. Third, support: 85% emphasized the necessity of providing continuous
psy chosocial support to the parents and the children (75%) prior to the treatment and in the
course of it.
Results Based on Interviewing the Children

Most children (95%) distinguished between chemotherapy and RT, although some claimed
that RT was a phase of chemotherapy. Concerning side effects, the majority (70%) listed
several short-term side effects, mainly feeling sick, losing hair, feeling tired, difficulty to
concentrate, pain, nausea, lack of appetite, feeling sad, and feeling lonely. A higher
percentage (90%) said that they knew about long-term effects, and mentioned fertility
problems (90%); body image deformities (90%; e.g., irregularities in the skin, brown dirty -
looking skin, short neck, remaining small and not growing up tall as other children, shorter
limb, baldness forever); various phy sical disorders (75%; malignancies, heart problems,
endocrine disorders, remaining in general “weak” or vulnerable in regard to diseases); and
various social and interpersonal issues (35%; e.g., being rejected by other kids, not finding
friends or partners because of phy sical deformities or unaesthetic appearance).
Concerning difficulties of the treatment, children (80%) mentioned the difficulty of
having to come every day to the hospital for getting RT and the unpleasantness (i.e., anxiety,
fear, tension, sense of being abandoned) associated with being alone in the RT room (85%).
Especially frequent were descriptions of the experiences the children had in the RT room. For
example, one 8-y ear-old child said, “I feel as if all the world recedes far away and gets
smaller and smaller, and I am the last dot in that increasing emptiness.” Another 12-y ear-old
said, “When I get into the room, I am afraid that when I get out there will be no one to meet
me and I will be alone outside too.” Only a few children (30%) referred to the difficulty of
the technical setup, but mentioned in this context only the unpleasantness of getting the
treatment in an unfamiliar ward. In comparison to chemotherapy, 60% said RT was easier,
whereas 40% said they are equally difficult although for different reasons. As compared to
prior expectations (mainly because of misleading information they had received), 60%
claimed that RT was more difficult than they had expected, 20% claimed it was easier, and
20% claimed it was as they had expected beforehand (Fig. 22.2 ).
The major suggestions of the children for rendering RT easier referred to decreasing the
feeling of loneliness in the RT room, for example, by enabling the child to hear the voice of
the parents or nurse outside, by listening to
music, or by seeing projected pictures. Other
suggestions referred to being able to discuss the
experience with someone from the staff or the
family every day and getting the treatment in
some place close to home.
Another group of 20 children (age range 7–
17 y ears) who had undergone RT was
interviewed more recently. The results were, on
the whole, similar to those obtained with the
former group, except for a more pronounced Figure 22.2 A 7-year-old with
(100%) concern about fertility and body image leukemia receiving cranial irradiation;
deformations and the frequent mentioning (75%) immobilization thermoplastic mark and
of depression and mood swings following RT. wrapped to avoid falling.
Some Comments Concerning the Interviews

Both sets of interviews indicate that the parents and the children identify RT as a distinct phase
of the treatment and are, on the whole, aware of the common short-term and long-term
effects of RT. The emphasis of the parents on the need for more information coincides with
the results of a recent study which shows that although the parents feel knowledgeable about
neurocognitive late effects of RT, they continue to have a need for further information, and
those who reported high emotional distress wanted the information earlier than the others
(88).
The interviews with the children highlighted the emotional distress of the children in the
RT room. Many children do not share the commonly expressed attitude toward RT as easier
than chemotherapy. In addition, children brought to the fore a specific domain of long-term
side effects that has not received sufficient attention in the psy chosocial studies up to now.
These are the effects of RT on the body image. Children noted specifically changes in limbs,
skin, stature, body sy mmetry, scalp, and hair, that may affect the functioning of their body
and change their phy sical appearance. The functional and aesthetic problems associated with
the damaged body image may affect the children’s functioning also in other domains. The
children themselves mentioned that an impaired phy sical appearance may affect the attitude
of peers to them in the present and perhaps also in the future and thus alienate them at school
and affect negatively their academic achievements. The distress of the children that may be
caused by the difficulties of coping with phy sical handicaps and impaired phy sical
appearance deserves the awareness and attention of health professionals no less than the
distress of children in the course of the RT itself.
Figure:
A 7-year-old with leukemia receiving cranial irradiation; immobilization thermoplastic mark
and wrapped to avoid falling.
SUMMARY
Page 508The major reviewed domains include cognitive effects, behavioral and social
effects, and distress in the course of RT, complemented by a more recent concern with
quality of life. The major cognitive effects of CRT and RT are declines in general intelligence
and specific deficits in nonverbal and verbal cognitive functions, mainly memory and
attention, that increase with time since RT and are especially notable in children who have
received RT at a y ounger age. The dose and location of RT seem to play a role in determining
the degree of cognitive impairment. Positive results of some cognitive intervention programs
are a potentially important indication of arresting the cognitive decline following RT. Yet,
there are indications that overall academic performance may be a function of factors
additional to the cognitive deficits and sometimes overriding the deficits. The major social
and behavioral effects concern interpersonal relations and possible difficulties in social
adjustment. Children are conscious of short-term and long-term effects of RT, and emphasize
in particular the risks for fertility, body image changes, and mood swings including
depression. Various programs for alleviating the distress of children during the administration
of RT are underway. Yet, it appears that children still suffer unduly in the course of RT,
mainly because of the need to be alone and without moving in the treatment room.
Psy chosocial interventions designed to alleviate distress in the course of RT and also after
termination of treatment are highly recommended for improving the children’s quality of life
during the course of treatment and in later y ears.
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Table of Contents

1. Pediatric Radiation Oncology

Nancy J. Tarbell, MD, FASTRO

Edward C. Halperin, MD, MA

© 2016 by Wolters Kluwer.

© 2011, 2004, 1999 by Lippincott Williams & Wilkins, a Wolters Kluwer

Library of Congress Cataloging-in-Publication Data

David H. Abramson, MD, FACS

Myriam Weyl Ben Arush, MD

Smita Bhatia, MD, MPH

Steve E. Braunstein, MD, PhD

Louis S. Constine, MD, FASTRO

Jasmine H. Francis, MD, FACS

Heather J. Frederick, MD, MHSc

Alison M. Friedmann, MD, MSc

Edward C. Halperin, MD, MA

John A. Kalapurakal, MD, FACR

Shulamith Kreitler, PhD

Elena Abigail Krivoy, MSc

Anne Laprie, MD, PhD

Monika Metzger, MD, MSc

Scott R. Schulman, MD, MHSc

Eric Yi-Liang Shen, MD

Nancy J. Tarbell, MD, FASTRO

Amos Toren, MD, PhD, MHA

Suzanne L. Wolden, MD, FACR

Michal Yalon Oren, MD, PhD

Torunn I. Yock, MD, MCH

“Every child begins the world again.”

Adults generally get cancer of places where

Phy sicians have a tendency to be comforted by scientific and/or epidemiological

Is God willing to prevent evil, but not able?

Figure 2.1 Outcome in childhood ALL

Pharmacokinetics and pharmacogenetics impact tolerance and efficacy of

Staging: Risk Categories for ALL

Staging: CNS Involvement in ALL

Treatment: CNS Preventive Therapy

Page 16Current Recommendations for Preventive CNS Therapy

Treatment of Established CNS Leukemia

Page 17Radiotherapeutic Management

Volume and Dose

Treatment of Other Extramedullary Sites

Other Sites of Extramedullary Disease

CNS Disease: Radiation Therapy

Page 20Hematopoietic Stem Cell Transplantation (HSCT)

HSCT in Children and Adolescents

Acute Lymphoblastic Leukemia

Dosage (Hematologic Malignancies)

Advances in neuroimaging have improved the accuracy of diagnosis in CNS tumors,

Table 3.2 Genetic Syndromes Related to Pediatric CNS Tumors

Neurofibromatosis is a common congenital disorder associated with CNS tumors.

Page 29Supratentorial tumors generally present with localizing neurologic sy mptoms;

Figure 3.2 A: JPA of (L) thalamus,

The use of single-fraction radiosurgery for primary management of pediatric low-grade

Page 38Radiotherapeutic Management

Gangliogliomas are uncommon, biologically benign neoplasms comprised of neuronal and

Supratentorial malignant gliomas represent approximately 6% of brain tumors in children.

Radiation therapy is a primary component of initial management of pediatric malignant

Page 42Radiotherapeutic Management

Page 44Radiotherapeutic Management

Stereotactic or 3D conformal techniques (photon or proton IMRT) based on image-

Table 3.3 Craniopharyngioma—Outcome in Children

Medulloblastoma is a primitive cerebellar tumor of neuroectodermal origin. The tumor is the