International Journal of

Radiation Oncology
biology

physics

www.redjournal.org

Guidelines

Expert Radiation Oncologist Interpretations

of Involved-Site Radiation Therapy Guidelines
in the Management of Hodgkin Lymphoma
Bradford S. Hoppe, MD, MPH,* and Richard T. Hoppe, MDy
*University of Florida Health Proton Therapy Institute, Jacksonville, Florida; and yStanford Cancer
Institute, Stanford, California
Received Jan 7, 2015, and in revised form Jan 29, 2015. Accepted for publication Feb 2, 2015.

Summary
Involved-site radiation therapy (ISRT) guidelines have
been developed to replace
involved-field radiation therapy guidelines that were
based on 2D radiation simulation techniques and treatment planning. A survey of
expert radiation oncologists
covering 7 different Hodgkin
lymphoma cases demonstrated variable interpretations of ISRT
guidelines. Further guidance
for involved-site field design
will be needed to reduce
variability among practicing
physicians.

Purpose: Recently, involved-site radiation therapy (ISRT) guidelines have been developed and published to replace the previous concept of involved-field radiation therapy
for patients with lymphoma. However, these ISRT guidelines may be interpreted in
different ways, posing difficulties for prospective clinical trials. This study reports survey results regarding interpretation of the ISRT guidelines.
Methods and Materials: Forty-four expert lymphoma radiation oncologists were
asked to participate in a survey that included 7 different cases associated with 9 questions. The questions pertained to ISRT contouring and asked respondents to choose
between 2 different answers (no correct answer) and a third write-in option allowed.
Results: Fifty-two percent of those surveyed responded to the questionnaire. Among
those who responded, 72% have practiced for >10 years, 46% have treated >20 Hodgkin lymphoma cases annually, and 100% were familiar with the ISRT concept. Among
the 9 questions associated with the 7 cases, 3 had concordance among the expert
radiation oncologists of greater than 70%. Six of the questions had less than 70%
concordance (range, 56%-67%).
Conclusions: Even among expert radiation oncologists, interpretation of ISRT guidelines is variable. Further guidance for ISRT field design will be needed to reduce variability among practicing physicians. 2015 Elsevier Inc. All rights reserved.

Introduction
The radiation treatment fields used for lymphomas have
evolved continuously over the past 50 years. In the 1950s
Reprint requests to: Richard T. Hoppe, MD, Stanford Cancer
Institute, Radiation Oncology, Rm.CC-G224, 875 Blake Wilbur
Dr Stanford CA 94305. Tel: (650) 723-5510; E-mail: rhoppe@stanford.
edu

Int J Radiation Oncol Biol Phys, Vol. 92, No. 1, pp. 40e45, 2015
0360-3016/$ - see front matter 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2015.02.008

and 1960s, radiation therapy was used primarily as a

palliative therapy, and radiation fields were typically
limited to symptomatic sites of disease. In the late 1960s,
studies by Peters (1) and Kaplan (2) advocated curative
Presented in part at the 56th Annual Meeting of the American Society
for Radiation Oncology, San Francisco CA, September 13-17, 2014.
Conflict of interest: none.
Supplementary material for this article can be found at
www.redjournal.org.

Volume 92  Number 1  2015

treatment of lymphoma by irradiating not only all sites of

known disease but also adjacent uninvolved sites. By
necessity, treatment fields became larger, and terms such as
mantle, inverted Y, extended field radiation therapy
(EFRT), and total lymphoid irradiation were introduced
to describe these fields, which contrasted with the previous
limited-field treatment now known as involved-field
radiation therapy (IFRT).
Beginning in the mid-1970s, however, combinedmodality therapy became more common in the treatment
of the lymphomas, and interest in reducing the extent of the
radiation fields resurged, leading to a renaissance in the use
of IFRT (3-6). In the context of these clinical trials, IFRT
was usually clearly defined. IFRT was based on the Ann
Arbor-defined lymphoid regions, and radiation treatment
planning included 2-dimensional (2D) simulation using
bony landmarks to define the borders of those lymphoid
regions. Outside its use in prospective clinical trials, IFRT
was more variably defined. In 2001, a survey among international expert radiation oncologists confirmed that there
were substantial discrepancies in the definition of field
designs for IFRT (7). Subsequently, Yahalom and Mauch
(7) published guidelines for the design of IFRT fields based
upon 2D imaging. However, much has changed over the
last decade, including improved diagnostic imaging with
photon emission tomography-computed tomography (PETCT) and the use of 3-dimensional (3D) treatment planning
with target volume contouring, such as gross tumor volume
(GTV), clinical target volume (CTV), internal target volume (ITV), and planning target volume (PTV).
In response to these changes in modern radiation
oncology practices, Girinsky et al (8) developed guidelines
for involved-node RT (INRT) to be used with European
Organization for Research and Treatment of CancerGroupe dEtude des Lymphomes de lAdulte (EORTCGELA) trials. These trials used the International Commission on Radiation Units (ICRU) Report 50/62 dose specifications and target delineation of a GTV, a CTV, and a
PTV, and that required 3D treatment planning (9). Although
results have been quite promising in successfully reducing
the field size without impacting event-free survival (10),
most centers throughout the world are unable to meet the
stringent criteria of INRT, which require prechemotherapy
evaluation by a radiation oncologist and a PET-CT scan
performed in the radiation treatment position and obtained
before chemotherapy. In response, the International Lymphoma Radiation Oncology Group (ILROG), an international group of radiation oncologists with special expertise
in the treatment of lymphoma, developed the concept of
involved-site RT (ISRT) and published guidelines to help
bridge the differences between IFRT and INRT.
ISRT guidelines incorporate the prechemotherapy definition of extent of disease based upon clinical studies,
including PET-CT, which may or may not be performed in
the treatment position, as well as the postchemotherapy
treatment planning CT. However, defining the CTV relies

Involved-site RT guidelines for lymphoma

41

upon the quality and accuracy of imaging; knowledge of

the spread patterns of the disease, as well as potential
subclinical extent of involvement and adjacent organ at risk
(OAR) constraints, all of which depend on clinical
judgment.
Guidelines for ISRT have been published for HL (11),
pediatric HL (12), and nodal non-HL (13). Despite their
wide acceptance, interpretation of the guidelines varies.
Consequently, a survey was developed to try to better understand the areas of consensus and lack of consensus for
ISRT contouring and formed the basis for this report.

Methods and Materials

Forty-two radiation oncologists known to be experienced in
treating HL according to their publications or participation
in lymphoma-related activities of the American Board of
Radiology, the American College of Radiology, Childrens
Oncology Group, or National Cancer Center Network were
asked to participate in completing a 9-question survey that
included 7 different cases, emphasizing contouring decisions for the definition of radiation treatment volumes.
These cases were chosen to represent a range of clinical
scenarios in defining treatment fields by ISRT criteria,
including sites of disease and patient age, sex, and responses to chemotherapy. Generally, respondents were
asked to select 1 of 2 different contouring options, although
they could also respond with other, a write-in option.
The following clinical scenarios were presented,
accompanied by pre- and postchemotherapy PET-CT imaging (as appropriate) and predefined contouring choices.

Case 1: stage IA, classical HL of left parotid lymph

node and nodes in levels IIA, IIB, III, IV, and V
A woman with stage IA classical HL involving a left parotid lymph node and nodes in levels IIA, IIB, III, IV, and
V, received 2 cycles of doxorubicin, bleomycin, vinblastine,
dacarbazine (ABVD) therapy and achieved a complete
response (CR) by PET and CT. The contouring choices
were to include elective coverage of the uninvolved neck
nodes in level IB (choice A) or to restrict treatment to levels
IIA-IV (choice B) (Fig. 1).

Case 2: stage IIAE, classical HL of the right parotid

gland and ipsilateral high neck
A 48-year-old man with stage IIAE classical HL involving
the right parotid gland and ipsilateral high neck achieved a
CR on PET-CT following 4 cycles of ABVD. The contouring choices were to define a CTV that included only the
initially involved nodes and postoperative parotid bed
(choice A) or to extend the field to include adjacent uninvolved nodes (choice B).

42

Hoppe and Hoppe

International Journal of Radiation Oncology  Biology  Physics

Fig. 1. For this question, respondents were asked to choose the contour in pink (level IIA-IV nodes) or the contour in green
(levels IB and IIA-IV).

Case 3: stage IB bulky classical HL involving the

mediastinum and extending anterior to the heart
with possible pericardial involvement

Case 5: stage IIB classical HL of supraclavicular

nodes, bulky mediastinal disease, and a
diaphragmatic node

A 22-year-old man presented with stage IB bulky classical

HL involving the anterior mediastinum with extension
anterior to the heart and possible pericardial involvement.
No subcarinal or hilar involvement was found. Following 6
cycles of ABVD, the patient experienced a CR on PET and
a partial response (PR) on CT. The contouring choices were
to include only the involved mediastinal lymph node levels
(choice B) or to include the uninvolved subcarinal nodes
(choice A) (Fig. 2). A second question related to contouring
the possible pericardial disease: whether to include the
entire prechemotherapy volume (choice A) or limit treatment to residual disease (choice B).

A 20-year-old woman presented with stage IIB classical

HL involving the supraclavicular nodes, bulky mediastinal
disease, and a diaphragmatic node. Following 6 cycles of
ABVD, she had CR in all sites of disease, except for some
residual PET avidity in the superior mediastinum. The
contouring question for this case related to whether the
mediastinum alone should be treated (choice B) or whether
all initially involved sites should be included in the CTV
(choice A). A second question related to the contouring of
the diaphragmatic nodal region: whether to treat just a
pericardial node (choice A) or treat the entire heart
(choice B).

Case 4: stage IIB classical HL of supraclavicular

region and mediastinum with diaphragmatic lymph
nodes

Case 6: stage IIB classical HL of bilateral neck and

supraclavicular, left axilla, bulky mediastinum, and
bilateral hila

A 19-year-old woman presented with stage IIB classical

HL involving the supraclavicular region and mediastinum
with diaphragmatic lymph nodes anterior to the liver.
Following 6 cycles of ABVD, she had CR on PET and PR
on CT. The contouring choices were to include the initial
extent of diaphragmatic adenopathy (choice B) or to limit
treatment to the portion of the diaphragmatic adenopathy
where she had achieved only a PR (choice A) (Fig. 3).

An 18-year-old woman presented with stage IIB classical

HL involving the bilateral neck and supraclavicular, left
axilla, bulky mediastinum, and bilateral hila. Following 6
cycles of ABVD, she had CR on PET-CT in all sites, except
for the superior mediastinum, where there was residual PET
avidity. The contouring question was whether to include
(choice A) or exclude (choice B) the left axilla in the ISRT
volume.

Volume 92  Number 1  2015

Involved-site RT guidelines for lymphoma

43

Fig. 2. For this question, respondents were asked to choose the contour in blue, which included only the initially involved
nodes, or the contour in orange, which included the uninvolved subcarinal nodes.

Case 7: stage IIA nodular lymphocyte-predominant

HL of bilateral iliac and inguinal regions
A 44-year-old man presented with stage IIA nodular
lymphocyte-predominant HL involving bilateral iliac and
inguinal regions, who was to be treated with RT alone. The
contouring question related to whether to contour and
include in the CTV only the PET-positive nodes (choice A)
or to extend the field cranially and caudally by 4 cm
(choice B).

Results
The response rate to the questionnaire was 52%. Seventytwo percent of the respondents reported they had been in
practice for at least 10 years; 46% treated more than 20
patients per year for HL; and 100% claimed familiarity
with the ILROG guidelines for ISRT. Responses to individual questions are summarized in Table 1.
In this 9-question survey, there was 100% agreement on
only 1 question and 70% or better agreement regarding
contouring in only 3 of 9 questions. The range of agreement
was 56% to 67% for the remaining 6 questions.

Discussion
Reducing radiation volumes in the treatment of patients
with lymphoma, especially in the context of combinedmodality therapy, can reduce radiation exposure to the
OARs and minimize the risk of late effects. Existing evidence supports a reduction from EFRT to IFRT (4, 14, 15),
and a further reduction to INRT does not appear to
compromise outcomes (10, 16). However, the strict definition of INRT requires a prechemotherapy evaluation by a
radiation oncologist and a prechemotherapy PET-CT scan
performed in the treatment position, which are not feasible
in most centers at this time. Nevertheless, reducing the
treatment volume from previous IFRT fields is warranted,
especially when pretreatment PET-CT imaging can document the initial extent of disease so effectively.
The ILROG tackled this issue by defining ISRT based on
prechemotherapy PET-CT, which need not be performed in
the treatment position, with preirradiation CT simulation
defining the treatment volumes. Such a guideline incorporates modern definitions of radiation volumes based
on ICRU criteria (17). In addition, this guideline defines a
CTV that is contingent on the quality and accuracy of

44

International Journal of Radiation Oncology  Biology  Physics

Hoppe and Hoppe

from 2 different contouring options in a series of 9 questions derived from 7 clinical scenarios. Neither option was
considered correct but merely intended to evaluate the degree of consensus. The 1 question for which there was
100% agreement (question 7) likely reflects the concern for
potential cardiac toxicity by extension of the field to
include the entire heart, especially as there was no pericardial involvement noted. The results indicated that these
guidelines, although generally accepted, can lead to various
interpretations. Although not tested in this survey, it is
likely that even greater variability in interpretation may
exist among general practice radiation oncologists.

Conclusions
Our findings suggest that more education and greater experience are required to improve concordance of volume
definition. This effort is already under way both through
ILROG-sponsored contouring workshops at the annual
American Society for Radiation Oncology meeting and
workshops at the International Congress on Malignant
Lymphoma, in Lugano, Italy, 2013 and 2015. In addition, this
study indicates that prospective trials that incorporate ISRT
should use precise definitions for common clinical scenarios.
Furthermore, careful quality control review of ISRT fields on
prospective clinical trials is warranted, similar to that found
with the German Hodgkin Study Group (18).
Fig. 3. For this question, respondents were asked to
choose the contour in blue, which included the area of
postchemotherapy residual disease only (outlined in pink),
or the contour in red, which included all of the nodes
involved prior to chemotherapy.
imaging, knowledge of the spread patterns of the disease as
well as potential subclinical extent of involvement, and
adjacent organ (OAR) constraints, all of which depend
somewhat on clinical judgment. These variables may lead
to differences in defining the CTV for individual patients.
In this study, expert radiation oncologists who were
familiar with the ILROG guidelines were asked to select
Table 1

Survey results
% of respondents who
chose

Clinical scenario
1
2
3
4
5
6
7

Question

Other

1
2
3
4
5
6
7
8
9

60
63
28
67
11
56
100
72
17

35
32
67
28
89
28
0
28
67

5
5
6
6
0
17
0
0
17

References
1. Peters MV. Prophylactic treatment of adjacent areas in Hodgkins
disease. Cancer Res 1966;26:1232-1243.
2. Kaplan HS. The radical radiotherapy of regionally localized Hodgkins disease. Radiology 1962;78:553-561.
3. Rosenberg SA, Kaplan HS. The evolution and summary results of the
Stanford randomized clinical trials of the management of Hodgkins
disease: 1962-1984. Int J Radiat Oncol Biol Phys 1985;11:5-22.
4. Noordijk EM, Carde P, Mandard AM, et al. Preliminary results of the
EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkins
disease. EORTC Lymphoma Cooperative Group. Groupe Pierre-etMarie-Curie. Ann Oncol 1994;5(suppl 2):107-112.
5. Engert A, Schiller P, Josting A, et al. Involved-field radiotherapy is equally
effective and less toxic compared with extended-field radiotherapy after
four cycles of chemotherapy in patients with early-stage unfavorable
Hodgkins lymphoma: Results of the HD8 trial of the German Hodgkins
Lymphoma Study Group. J Clin Oncol 2003;21:3601-3608.
6. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone
compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkins lymphoma. N Engl J Med
1998;339:21-26.
7. Yahalom J, Mauch P. The involved field is back: Issues in delineating the
radiation field in Hodgkins disease. Ann Oncol 2002;13(suppl 1):79-83.
8. Girinsky T, van der Maazen R, Specht L, et al. Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: Concepts
and guidelines. Radiother Oncol 2006;79:270-277.
9. ICRU. International Commission on Radiation Units and Measurements. Prescribing, recording, and reporting photon therapy. (Supplement to ICRU Report 50). |ICRU Report 62. 1999.
10. Maraldo MV, Aznar MC, Vogelius IR, et al. Involved node radiation
therapy: an effective alternative in early-stage hodgkin lymphoma. Int
J Radiat Oncol Biol Phys 2013;85:1057-1065.

Volume 92  Number 1  2015

11. Specht L, Yahalom J, Illidge T, et al. Modern radiation therapy for
Hodgkin lymphoma: field and dose guidelines from the International
Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol
Biol Phys 2014;89:854-862.
12. Hodgson DC, Dieckmann K, Terezakis S, et al. Implementation of
contemporary radiation therapy planning concepts for pediatric
Hodgkin lymphoma: Guidelines from the International Lymphoma
Radiation Oncology Group. Pract Radiat Oncol 2014;5:85-92.
13. Illidge T, Specht L, Yahalom J, et al. Modern radiation therapy for
nodal non-Hodgkin lymphoma-target definition and dose guidelines
from the International Lymphoma Radiation Oncology Group. Int J
Radiat Oncol Biol Phys 2014;89:49-58.
14. Bonadonna G, Bonfante V, Viviani S, et al. ABVD plus subtotal nodal
versus involved-field radiotherapy in early-stage Hodgkins disease:
Long-term results. J Clin Oncol 2004;22:2835-2841.

Involved-site RT guidelines for lymphoma

45

15. Sasse S, Klimm B, Gorgen H, et al. Comparing long-term toxicity and

efficacy of combined modality treatment including extended- or
involved-field radiotherapy in early-stage Hodgkins lymphoma. Ann
Oncol 2012;23:2953-2959.
16. 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;89:1053-1059.
17. International Commission on Radiation Units and Measurements.
[website] 2014. Available at: http://www.icru.org/. Accessed February
22, 2015.
18. Eich HT, Engenhart-Cabillic R, Hansemann K, et al. Quality control
of involved field radiotherapy in patients with early-favorable (HD10)
and early-unfavorable (HD11) Hodgkins lymphoma: an analysis of
the German Hodgkin Study Group. Int J Radiat Oncol Biol Phys 2008;
71:1419-1424.