Malignant

Pleural
Mesothelioma

Revised March 2010

People We Know
Merlin Olsen, 2010

Steve McQueen, 1980

Navy Admiral
Elmo Zumwalt, 1999
Minnesota Congressman
Bruce Vento, 2000

Evolutionary biologist
Stephen Jay Gould, 2001
Epidemiology
 80% cases associated with documented asbestos exposure
 Highest risk associated with crocidolite, chrysolite and amosite
 Other etiologies implicated
 Therapeutic radiation
 Intrapleural thorium dioxide
 Inhalation of other fibrous silicates
 Erionite or zeolite
 Latency period 20-40+ years
 Peak mortality expected in 2020-2030
 Median survival
 8-18 months from time of diagnosis
 Lifetime risk of MM among asbestos workers is 8-13%
 Annual incidence with exposure increases
 3.5X for males
 1.4X for females

Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000

Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers
 Asbestos fibers
 Serpentine
 Curly, pliable

 Amphiboles
 Crocidolite, amosite,
tremolite,
anthrophyllite,
actinolite
 Long, needle-like

www.som.tulane.edu/.../ AsbestosMinerals.jpg
Incidence of MPM
Countries Males (per 100K) Females (per 100K)
UK and Netherlands 7.4-8.8 0.8-1.3

Western Europe 2.9-4.2 0.7-1.3

Germany, Spain, 1-1.9 0.2-0.5

Ireland
Eastern Europe 0.6-1.0 0.3-0.5

United States 1.5-2.2 0.3-0.4

South Africa >5.4 >2.3

Western Australia >4.8 >0.3

Treasure, T and Sedrakyan, A Pleural mesothelioma: little evidence,
still time to do trials Lancet 2004 364:1183-1185
 U.S. Mortality 1999
Table 7-1. Malignant mesothelioma: Number of deaths by sex, race, and age, and median age at death, U.S. residents age 15 and over, 1999
Sex Race Age Group (yrs)
Under-
Median
No. of lying 15 25 35 45
Site 55- 65- 75- Age
Deaths Cause M F W B O - - - - 85+
64 74 84 (yrs)
(%) 24 34 44 54

Pleura 252 90.1 219 33 240 10 2 - - 2 12 32 101 86 19 72.0

Peritoneum 92 90.2 62 30 90 2 - - - 2 10 23 31 20 6 69.5

Other Sites 427 90.4 345 82 407 14 6 1 2 3 23 61 134 154 49 74.0

Unspecified 1,773 92.9 1,424 349 1,673 83 17 1 2 26 94 279 572 654 145 73.0

13
Any Site 2,485 94.3 1,995 490 2,355 105 25 2 4 33
8
389 818 888 213 73.0

Center for Disease Control, National Institute for Occupational Safety and Health
All Cause Mortality in U.S. in 1999
Compressed Mortality
Age
Death Count Population Crude Death Rate
Data for
1999-1999 Description
Years:

Location: The United States (FIPS=00) 25-34 years 41,066 40,178,406 102.2

25-34 years through 85 years

35-44 years 89,256 45,076,677 198.0
Ages:
and over
45-54 years 152,974 36,577,819 418.2
Race: All Races
55-64 years 238,979 23,778,026 1,005.0
Gender: Both Genders
65-74 years 452,600 18,418,909 2,457.3
Grouped by: Age
75-84 years 698,590 12,224,914 5,714.5

Crude Rate
100,000 85 years and over 646,141 4,154,018 15,554.6
Calculated per:

Total Deaths = 2,319,606

Total Population = 180,408,769
(age > 25)
Suggested United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC),
Citation: National Center for Health Statistics (NCHS), Office of Analysis, Epidemiology, and Health Promotion (OAEHP), Compressed
Mortality File (CMF) compiled from CMF 1968-1988, Series 20, No. 2A 2000, CMF 1989-1998, Series 20, No. 2E 2003 and CMF
1999-2001, Series 20, No. 2G 2004 on CDC WONDER On-line Database.
 Statistics From 1999
# deaths from mesothelioma = 2,485 = 0.00107
Total # deaths all causes 2,319,606 (0.1%)

# deaths from mesothelioma

= 2,485 = 0.000014
Total U.S. Population
180,408,769 (0.0014%)

United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics
(NCHS), Office of Analysis, Epidemiology, and Health Promotion (OAEHP), Compressed Mortality File (CMF) compiled from CMF
1968-1988, Series 20, No. 2A 2000, CMF 1989-1998, Series 20, No. 2E 2003 and CMF 1999-2001, Series 20, No. 2G 2004 on CDC WONDER On-line Database.
Litigation Crisis
Legal Costs/Societal Impact
Senate Testimony by Steven
Kazan. "Economic Cancer,"
Lawyer News, September 23,
2002
. . .2001 actuarial study that
estimates the cost of
asbestos litigation in the
United States eventually
reaching $200 billion, a
legal liability situation that
has already bankrupted nine
defendants in the past year.
It goes on to analyze a new
report by the Rand Institute
for Civil Justice that claims
the asbestos litigation has *200 billion is approximately 2%
spread to touch 85% of of the Gross National Product for
corporate America. 2000
www.kazanlaw.com
Occupations at Risk
Mortality by Occupation
Table 7-8. Malignant mesothelioma: Proportionate mortality ratio (PMR)
adjusted for age, sex, and race by usual occupation, U.S. residents age
15 and over, selected states, 1999

95% Confidence Interval

COC Occupation Number of Deaths PMR
LCL UCL

585 Plumbers, pipefitters, and steamfitters 18 4.76 2.81 7.51

057 Mechanical engineers 6 3.04 1.11 6.62

575 Electricians 12 2.42 1.25 4.22

156 Teachers, elementary school 13 2.13 1.13 3.64

COC = Census Occupation Code

The PMR is defined as the observed number of deaths with the condition of interest in a specific
industry/occupation, divided by the expected number of deaths with that condition.

Center for Disease Control, National Institute for Occupational Safety and Health
Asbestos Trivia
 Low level of asbestos fibers found in general public
 Urine, feces, mucus
 Found in environment, drinking water, etc.
 Rural air typically contains 10 fibers/cubic meter
 A typical person breathes about 1 cubic meter air in 1 hour
 City levels of asbestos fibers are generally 10X higher
 Asbestos containing homes typically contain 30-60,000
fibers/cubic meter
 EPA proposal limits concentration of asbestos fibers to 7
million fibers (>5 microns in length)/liter drinking water
 Most drinking water contains < 1 million fibers/liter
 Some have as much as 10-300 million fibers/liter
 OSHA limits the number of fibers 5 microns or larger to
100,000/cubic meter of workplace air for 8 hour shifts
 July 12, 1989 EPA banned new uses of asbestos
 Uses established prior to this date are permissible

www.atsdr.cdc.gov/toxprofiles
Environmental Risks
 Rates of MPM development highest in Anatolia
region of Turkey
 50% of males from one village died of MPM
 Six family clusters identified
 Possible 6 generation pedigree
 Autosomal dominant pattern of inheritance with
incomplete penetrance
 May represent genetic
predisposition

Volcanic tuffs
Pathogenesis
 Exact mechanism of carcinogenicity unknown
 Carcinogenicity associated with fiber length
 >5 microns length
 <2.5 micron diameter
 Inhaled fibers engulfed by macrophage
 Long fibers not cleared, and chronic inflammatory process ensues
 Magnitude of risk depends on
 Level and duration of exposure
 Time since exposure occurred
 Age at time of exposure
 Tobacco history
 Type and length of fibers
 Asbestos fibers induce rat protooncogenes
 c-fos, c-jun
 Multiple chromosomal abnormalities associated with MM
 Deletions of 1p, 3p, 9p, and 6q
 Loss of chromosome 22
 Defined and putative tumor suppressing genes
 SV40 virus
 Potential Mechanisms for Damage
Inhalation of asbestos fibers

Chrysotile fibers biodegraded

Biopersistence of crocidolite

Fibers phagocytosed by
macrophages, mesothelial cells and fibroblasts

Mesothelial cells release

IL-8, Monocyte chemoattractant protein-1, fibronectin

Inflammatory cell recruitment, fibroblast and mesothelial cell proliferation

Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers

 Potential Mechanisms of Carcinogenicity
Inhalation of Asbestos Fibers

Fibers engulfed by macrophage

Autophosphorylation
Inflammatory response Of
Mitotic spindle Oxygen radicals released Epidermal Growth
interference Factor Receptor

Induction of DNA repair enzymes

Increased expression
Aneuploidy C-fos, C-jun
Chromosomal damage
DNA synthesis

Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers

Potential Role of Simian Virus 40
 A DNA tumor virus
 First suspected in 1991
 60% hamsters with SV40 injected into their hearts developed
pleural mesothelioma in the absence of asbestos exposure
 100% hamsters developed pleural mesothelioma after SV40
injected intrapleurally
 In some studies, as many as 50% human mesothelioma
tumors coexpress SV40
 Not applicable to other countries (Turkey, Finland)
 May be related to SV40 infected polio vaccines
 SV40 DNA inserts itself into host DNA
 Disrupts genes, including tumor suppressing genes
 Produces proteins capable of inhibiting tumor suppressor genes,
DNA repair
Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers
Clinical Presentation
 Mean age approximately 60 years
 Early stage
 Dyspnea, non-specific pleurisy, moderate effusions
 Later stages
 Moderate chest tightness
 Progressive pain, cough, dyspnea
 Dullness to percussion
 Palpable chest wall mass
 Usually unilateral disease
 Approximately 10% have bilateral
involvement at presentation

 Death usually is due to progressive dyspnea and

respiratory insufficiency
 Metastasis seen in approximately 50% at autopsy
 Presenting Symptoms
Retrospective study of 322 Canadian patients with MM:
90%
90
80%
84
70%
60%
50%
40%
30%
29
20%
10% 3 <1 3
0%

Ruffie P et al. Diffuse malignant mesothelioma of the

pleura in Ontario and Quebec: a retrospective study of
322 patients Journal of Clinical Oncology 7(8):1157-68,
1989.
 Traditional Staging
Butchart, 1976
LOCALIZED
I Disease confined within the capsule of the parietal
pleura: ipsilateral pleura, lung, pericardium and diaphragm
METASTATIC
II Stage I plus positive intrathoracic LNs
III Local extension into: chest wall or mediastinum, heart,
diaphragm, peritoneum, with/without
extrathoracic or contralateral LNs
IV Distant metastatic disease
Not a valid tool for stratifying for survival outcomes

Pistolesi, M and Rusthoven, J Malignant

pleural mesothelioma CHEST 2004
126:1308-1329
Malignant mesothelioma. www.nci.nih.gov
Proposed Tumor Staging
7th World Conference of the International Association for the Study of Lung Cancer

T1a Ipsilateral pleura

T1b T1a + foci tumor in visceral pleura
T2 T1b + diaphragm, confluent visceral tumor or
pulmonary parenchyma Ia T1a N0 M0
T3 T1b + endothoracic fascia, mediastinal fat, solitary Ib T1b N0 M0
chest tumor or non-transmural pericardium
T4 T1b + diffuse chest wall tumor, transdiaphragmatic II T2 N0 M0
peritoneum, contralateral pleura, mediastinal
organ, spine or transmural pericardium or myocardium IIIAny T3 M0
N0 No regional lymph node mets Any N1 M0
N1 Ipsilateral bronchopulmonary or hilar lymph node Any N2 M0
N2 Ipsilateral mediastinal lymph node, subcarinal lymph
IV Any T4
node, internal mammary node
N3 Ipsilateral supraclavicular node, contralateral Any N3
mediastinal node, internal mammary node, Any M1
supraclavicular node
M0 No distant mets
M1 Distant mets

Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers

Malignant Mesothelioma www.nci.nih.gov/cancertopics
Investigative Options

An Open and Closed Case

Radiographic Findings
 Extensive nodular or lobular thickening of pleura
 Pleural effusions
 Asbestos related plaques
 Chest wall, bone or organ invasion best seen by
CT or MRI

Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000

Pleural Thickening

sprojects.mmi.mcgill.ca/. ../plpsdo_radio.htm
Pleural Plaques

Emedicine.com
Pleural Mass

Emedicine.com
CT v MRI in Asbestos-related Pleural Disease
 21 pts with confirmed long-term asbestos exposure
 CT and MRI
 4 readers
 Interobserver agreement for pleural plaque detection
was moderate for both
 Kappa 0.72 for MRI, and 0.73 for CT

 Considered „good‟ agreement

 Sens MRI 88%

 Pleural thickening, pleural effusion

 Interobserver agreement better with MRI

Weber, et al. Asbestos-related pleural disease: value of dedicated magnetic resonance

imaging techniques Invest Radiol 2004 39:554-564
 PET v CT
 Retrospective review 18
CT PET
pts with MPM
True + 3 5
 Utility of PET in detecting
True - 5 9
 Mediastinal LNs
 Distant metastases
False + 4 2
False - 4 0
CT PET
Conclusions
Sens 43 100 1. MPM metastasizes more commonly than
previously thought
Spec 56 82 2. PET is better than CT for staging
3. May aid in better selection of candidates
PPV 43 71 for aggressive multimodality therapy
NPV 56 100 4.Benard, et al found Sens 83%, Spec 75%

Schneider, et al Positron emission tomography with F18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma
Thorac Cardiovasc Surg 2000 120:128-33
Benard, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722
MRI and PET Images

Benard, et al Metabolic imaging of malignant pleural mesothelioma with

fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722
 Value of PET in T Status
T Status by PET
T0-T3 T4 Total #
Patients
Surgical/Pathologic T0-T3 29 3 32
T status
T4 17 4 21
Total # Patients 46 7 53

Conclusion: PET is relatively poor at defining locoregional disease

Flores, et al Positron emission tomography defines metastatic disease but not locoregional disease in patients with
malignant pleural mesothelioma J Thorac Cardiovasc Surg 2003 126:11-15
Value of PET in N Status
N Status by PET
N0 and N2 Total #
N1 Patients
Pathologic N N0 and 19 3 22
Status N1
N2 8 1 9

Total # Patients 27 4 31

Conclusion: PET may be useful in assessing node status

Flores, et al Positron emission tomography defines metastatic disease but not locoregional disease in patients with
malignant pleural mesothelioma J Thorac Cardiovasc Surg 2003 126:11-15
Thoracentesis
 Highly viscous
 Often bloody
 Exudative Mesothelioma
 Lymphocyte predominant
 Protein 4-5 g/dl
 LDH often >600 IU/l
 Pleural fluid cytology often
inadequate
 Diagnosis achieved in 20-30%
cases
 Epithelioid mesothelioma Adenocarcinoma
similar to adenocarcinoma
 Sarcomatous type similar to
fibrosarcoma,
hemangiopericytomas
Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers
Maskell, et al. Standard pleural biopsy versus CT-guided cutting-needle biopsy
for diagnosis of malignant disease in pleural effusions: a randomised controlled
trial Lancet 2003 361:1326-31
Imp.ualberta.ca
Dpalm.med.uth.tmc.edu
 Cytology
 Criteria for identifying MPM are not highly specific
 Abundance of cells with cytoplasmic characteristics of
mesothelioma cells
 Abundant dense cytoplasm
 Cell engulfment
 Intercellular windows
 Small peripheral vacuoles
 Presence of collagen and/or
basement membrane-like
material and hyaluronic acid
in background
 Orangiophilic squamous-like cells

Whitaker, D The cytology of malignant mesothelioma

Cytopathology 2000 11:139-151
Closed Pleural Biopsy
 Often provides inadequate tissue for diagnosis
 Diagnosis achieved in approximately 20% cases
 Pleural fluid cytology + closed pleural biopsy results in a
diagnosis approximately 35-40%
 Effectively increases yield by 7-26%
 Abram‟s needle versus CT-guided biopsy
 UK study of 47 pts with suspected malignant pleural effusions
 20 pts had a final diagnosis of MPM
Sens Spec NPV PPV
Abram’s 55% 100% 72% 100%
CT-guided 88% 100% 94% 100%

Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers

Maskell, et al. Standard pleural biopsy versus CT-guided cutting-needle biopsy for
diagnosis of malignant disease in pleural effusions: a randomised controlled trial
Lancet 2003 361:1326-31
Thoracoscopy
 Indications
 Mesothelioma suspected
 Tissue diagnosis not confirmed
 95% diagnostic yield in malignancy
 Able to visualize tumor
 Firm, gray
 Thick rind

Benard, et al Metabolic imaging of malignant pleural mesothelioma with

fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722
Gross Pathologic Appearance

Benard, et al Metabolic imaging of malignant pleural mesothelioma with

fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722
Histology

Classifications of Malignant
Pleural Mesothelioma
Epithelial
 Comprises ~ 54% of all MPM
 Large nuclei with prominent nucleoli
 Eosinophilic cytoplasm
Epithelioid Mesothelioma
 Can mimic other tumors
 Example: adenocarcinoma, giant cell, small
cell, clear cell, signet cell, glandular, myxoid,
microcystic and adenoid cystic carcinomas

Adenocarcinoma

www.mesothelioma-asbestos-lung-cancer.com/ inf...

Imaging of Diseases of the Chest.

Armstrong. Mosby. Toronto 2000 Edcenter.med.cornell.edu
Sarcomatoid
 ~ 21% of MPM
 Less common
 More aggressive
Sarcomatoid Mesothelioma  Spindle-shaped cells
resembling fibrosarcomas and
leiomyosarcomas
Fibrosarcoma

www.mesothelioma-asbestos-lung-cancer.com

Imaging of Diseases of the Chest.

Armstrong. Mosby. Toronto 2000 www.geocities.com
Mixed
 Approximately 25% of all MPM
 Features of epithelioid and sarcomatoid

Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000

Diagnostic Aids
Technique MPM Adeno CA
Histology
Periodic Acid Schiff Negative Positive
Mucicarmine Negative Positive
Immunostaining
Carcinoembryonic Assay Negative Positive (75%)
Leu M-1 Negative Positive
Vimentin Positive Negative
Cytokeratin Positive Negative
Electron microscopy Long microvilli Short microvilli

Whitaker, D The cytology of malignant mesothelioma Cytopathology 2000 11:139-151

Asbestos Fibers

www.medicine.creighton.edu
Immunostaining

Fig. 2A. Malignant mesothelioma, mixed

type, stained for calretinin. The epithelial
component is strongly stained, while the
sarcomatous component is moderately
stained. Fig. 2C. Cell block from pleural exudate with
adenocarcinoma stained for calretinin. The normal
mesothelial cells are stained, while tumour cells are
unstained. www.nordiqc.org
 Treatment

Palliation v Aggressive Therapy

 Pleurodesis
 Viallat, et al CHEST 1996 evaluated the efficacy of
thoracoscopic talc poudrage in malignant pleural effusions
 360 patients
 24% had MPM
Mesothelioma Pleural mets Overall
N=85 N=242 N=327
Complete 78.8 88.5 85.9
Response %
Partial 5.9 3.7 4.3
response %
Failure % 15.3 7.8 9.8
Poudrage = thoracoscopic application of sclerosing agent with sprayer
Pneumatic pump sprayer used in this study

Viallat, et al Thoracoscopic talc poudrage pleurodesis for malignant effusions

CHEST 1996 110:1387-93
Definitions
 P/D (Pleurectomy/Decortication)
 Removal of
 Visceral, parietal, pericardial pleura from apex of lung
to diaphragm
 EPP (Extrapleural pneumonectomy)
 En bloc resection of
 Visceral and parietal pleura
 Lung
 Pericardium
 Ipsilateral diaphragm

Pistolesi, M and Rusthoven, J Malignant pleural mesothelioma: update, current management,

and newer therapeutic strategies CHEST 2004 126:1318-1329
 Pleurectomy in MPM
 Results of pleurectomy trials
Author Year # % %
Location Patients Morbidity Mortality Median
survival

Martini et al 1975 14 22 10
Memorial Sloan-Kettering Ca Ctr
Achatzy et al 1989 118 6 8.5 9 months

Germany
Brancatisano et al 1991 45 16 2.2 16 months
Australia
Soysal et al 1997 100 22 1
Turkey

Roberts, J Surgical treatment of mesothelioma: pleurectomy CHEST 1999 116:446s-449s

Pleuropneumonectomy
 Aggressive cytoreductive component of multimodality therapy
 EPP, chemo, adjuvant radiotherapy
 Appropriate for only a minority of MPM patients
 General exclusion criteria include:
 FEV1 <1 L/min
 EF <45%
 Room air PCO2 >45
 Room air PO2 <65
 Operative mortality rate approximately 4%
 Overall morbidity is about 24%
 Survival rates
 Overall 36% and 14% (2 and 5 years, respectively)
 Epithelial tumors 52% and 21%
 Sarcomatous or Mixed tumors 16% and 0%
 Conclusions
 Survival increased for a select few
 Morbidity remains high
 No reference to quality of life Grondin, S and Sugarbaker, D Pleuropneumonectomy
in the treatment of malignant pleural mesothelioma
CHEST 1999 116:450S-454S
 Survival After Surgery
 120 pts
Overall Survival
 MPM Butchart Stage I
 Good performance status

Survival Based on Node Status

 EPP with adjuvant

chemoradiation therapy
 Positive nodes indicate
worse prognosis

Sugarbaker and Garcia Multimodality therapy for malignant pleural mesothelioma CHEST 1997 112:272-275S
Chemotherapy
 No single therapy has consistently improved survival by >20%
 Phase II study of gemcitabine with cisplatin associated with a 48%
response rate without improvement in survival
 Phase III study of pemetrexed (antifolate agent) and cisplatin versus
cisplatin
 Survival 12 v. 9 months
 Time to progression 6 v. 4 months
 Significant neutropenia and leukocytopenia
 Despite B12 and folate supplementation
 Most common SEs (nausea, vomiting, fatigue)
 Mitomycin C, Vinblastine and Cisplatin
 150 patients with inoperable MPM
 15% response rate
 69% had stable disease
 69% achieved improvement in symptoms
 71% had decreased pain Kindler, H Malignant pleural mesothelioma Curr Treat Options Oncol
 62% had decreased cough 2000 1:313-326
 50% had decreased dyspnea Vogelzang, et al. Phase III study of pemetrexed in combination with
cisplatin versus cisplatin alone in patients with
 Median overall survival 7 months malignant pleural mesothelioma J Clin Oncology
003 21:2636-2644
Andreopoulou, et al. The palliative benefits of MVP chemotherapy in
patients with malignant mesothelioma Ann Oncol
2004 15:1406-12
Survival With Chemotherapy
 Histologically confirmed mesothelioma
 Good functional status
 Expected to survive > 2 months
 No prior chemotherapy
 “Adequate” organ function

Treatment Regimens # Eligible % Response Median

Patients Rate Survival (Mos)
Mitomycin & Cisplatin 37 26 8.1
Doxorubicin & Cisplatin 39 14 8.8
Carboplatin 41 7 7.1
DHAC 41 17 6.7
Trimetrexate 18 12 3.9
Edatrexate 20 25 9.6
Paclitaxel 35 9 5.0

Herndon, et al. Factors predictive of survival among 337 patients with mesothelioma treatedbetween 1984 and 1994 by the cancer and
leukemia group b CHEST 13:723-31
Survival Predictors
N = 337

Excellent Poor
Performance Status Performance Status

Age < 49 Age > 49 WBC < 15.6 WBC > 15.6
1.4 mos
12.5 mos Chest Pain
Hgb > 14.6

Weight Loss
14.5 mos WBC > 9.8
Hgb > 11.2 Hgb < 11.2

9.6 mos 4.9 mos

Herndon, et al. Factors predictive of survival among 337 patients with mesothelioma treated
between 1984 and 1994 by the cancer and leukemia group b CHEST 13:723-31
Pemetrexed and Cisplatin
Survival
Disease Progression

Vogelzang, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone
in patients with malignant pleural mesothelioma J Clin Oncology 003 21:2636-2644
Radiation
 No survival benefit to radiation therapy alone
 Side effects limit dose
 Higher doses radiation tolerated after EPP
 Small field dosing effective at decreasing
biopsy tract seeding
 Effective in palliative care

Pistolesi, M and Rusthoven, J. Malignant Pleural Mesothelioma:

Update, Current Management, and Newer Therapeutic Strategies
CHEST 2004: 126:1318-1329
Radiation Therapy Trials
# of
Dose
Investigators Patient Outcome
(cGy)
s
2000-
University of Iowa 3 Symptomatic improvement
3000
Brompton/Royal 5000- 1 asymptomatic x 4 yrs, 2 effusion
12
Marsden 5500 controlled
Joint Center for 6 >4000 4 symptomatic relief
Radiotherapy 23 >4000 1 symptomatic relief
Institute Gustave- 3500- 4 alive at 1-41 mos, 10 dead at 1-37
14
Roussy 5000 mos. Median survival 15 mos
Thomas Jefferson 2 local control of cancer at 20-40
9 6000
Medical Center months
Peter MacCallum
66 symptomatic improvement median
Cancer 111 8-60
survival 5 months
Institute
Chun et al., http://www.vh.org/adult/provider/radiology/LungTumors/Mesothelioma/Text/MesoRadiation.html
 Mesothelioma Treatment Trials
Study # Pts Age F Epithelioid Treatment In-Hospital Median
Yrs (%) (%) deaths Survival
(months) OR
3.0 non epith
Sugarbaker 183 57 73 56 EPP/C/R 3.8 19 1.7 + margin
4% mortality 2.0 EP nodes
50% morbidity
1999 mean
Maggi 32 53 33 100 EPP/C/R 6.2 Unclear I (6)
II (10)
6% mortality
2001 median III (16)

Rusch 61 62 17 68 EPP/R 7.9 17 Survival

8% mortality 33.8 m I-II
2001 median 10 m III-IV

Aziz 51 <60 - 54 EPP/C 9.1 35 90/70-T1

85/36-T2
9% mortality 2002 1/3 yr survival
Lee 26 69 19 73 EPP/C/R 6.9 18
6% mortality
2002 median
Ahamad 28 59 7 79 EPP/R NA 24 65%
1yr survival
2003 mean
Stewart 53 57 - 87 EPP/R 7.5 17 EPP v
debulking
8.5% mortality 2004 median R Not No statistical
extensive significance

Treasure and Sedrakyan Pleural mesothelioma: little evidence, still time to do trials Lancet 2004 264:1183-85
Treatment Options: Local Disease
 Solitary mesotheliomas
 Surgical resection en bloc

 Intracavitary mesothelioma
 Palliative surgery
 Pleurectomy and decortication
 With/without postoperative radiation
 Extrapleural pneumonectomy
 Palliative radiation
 Pleural effusions
 Pleurodesis
Pistolesi, M and Rusthoven, J. Malignant Pleural Mesothelioma:
Update, Current Management, and Newer Therapeutic Strategies
CHEST 2004: 126:1318-1329
Treatment Options: Advanced Disease
 Symptomatic treatment
 Drain effusions
 Pleurodesis
 Palliative surgical resection in select patients
 Palliative radiation
 Chemotherapy
 Permetrexed (antifolate) and cisplatin increases survival by approximately
3 months
 Multimodality clinical trials
 Intracavitary chemotherapy
 Better results seen with intraperitoneal mesothelioma

Association of Cancer Online Resources

Assessing Quality of Life
 Chest pain and dyspnea are the most common symptoms at
presentation
 Questionnaires frequently used to assess QOL
 European Organization for Research and Treatment of Cancer
(EORTC) Core Quality of Life Questionnaire (QLQ-C30)
 Lung Cancer Module (QLQ-LC13)
 Nowak, et al., 2004 validated use of above questionnaires
 At time of diagnosis, role function and social function more
impaired than previously suspected
 Worst rated symptoms
 Fatigue
 Dyspnea
 Pain
 Insomnia
 Appetite loss
 Cough
 Dyspnea scores correlated well with FVC
Nowak, A, Stockler, M, Byren, M Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity, and results of using the European Organization
for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module J Clin Oncol 2004 22:3172-3180
Management
 Treatment of advanced disease is largely palliative
 Chemotherapy
 Surgery
 Radiation
 Doxorubicin produces partial response in 15-20%
 No single agent induces > 20% response
 Operative mortality pleurectomy/decortication < 2%
 Mortality with extrapleural pneumonectomy 6-30%
 Radiation useful to alleviate pain
 Duration short
 Pleural sclerosis minimizes recurrent pleural effusions
 Talc pleurodesis effective and inexpensive
 Thoracoscopic pleurodesis more effective than medical pleurodesis
Prognostic Indicators
 Poor prognosis
 Thrombocytosis
 Fever of unknown origin
 Sarcomatous or mixed histology
 Age > 65
 Poor performance status
 Better prognosis
 Epithelial histology
 Stage I disease
 Good performance status
 Absence of chest pain
 Symptomatic < 6 months prior to diagnosis
 Absence of weight loss
 Absence of involvement of visceral pleura
Summary
 Smoking NOT associated with increased risk of developing MPM
 HOWEVER, smoking increases risk of developing bronchogenic carcinoma when
combined with asbestos exposure!
 Risk approximately 50x greater

 Thorough occupational history helpful at determining pts at risk

 ~30% of patients have no known exposure to asbestos

 CT-guided biopsy may be more cost-effective than thoracentesis

 PET useful in early detection of LN involvement and distant mets

 MPM metastasizes earlier than once thought

 Pts with negative LNs benefit from aggressive multimodality therapy

 Pts with advanced disease benefit from palliative therapy

www.lung.ca/diseases/cancer
References
Benard, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722
Center for Disease Control, National Institute for Occupational Safety and Health Community Health Sciences Dept., St. George‟s Hospital Medical School
Dpalm.med.uth.tmc.edu
Emedicine.com
Grondin, S and Sugarbaker, D Pleuropneumonectomyin the treatment of malignant pleural mesothelioma CHEST 1999 116:450S-454S
Flores, et al Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma J Thorac
Cardiovasc Surg 2003 126:11-15
Herndon, et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the cancer and leukemia group b CHEST
13:723-31
Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000
Imp.ualberta.ca
Kindler, H Malignant pleural mesothelioma Curr Treat Options Oncol 2000 1:313-326
Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers
Malignant mesothelioma. www.nci.nih.gov
Maskell, et al. Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial
Lancet 2003 361:1326-31
Mesotheliomacenter.org
Nowak, A, Stockler, M, Byren, M Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity, and results of using the European
Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module J Clin Oncol 2004 22:3172-3180
Pistolesi, M and Rusthoven, J. Malignant Pleural Mesothelioma: Update, Current Management, and Newer Therapeutic Strategies CHEST 2004 126:1318-1329
Roberts, J Surgical treatment of mesothelioma: pleurectomy CHEST 1999 116:446s-449s
Ruffie P et al. "Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 322 patients." Journal of Clinical Oncology 1989
7(8):1157-68
Schneider, et al Positron emission tomography with F18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma Thorac
Cardiovasc Surg 2000 120:128-33
Seattlepi.nwsource.com
Treasure, T and Sedrakyan, A Pleural mesothelioma: little evidence, still time to do trials Lancet 2004 364:1183-1185
United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health
Statistics (NCHS), Office of Analysis, Epidemiology, and Health Promotion (OAEHP), Compressed Mortality File (CMF) compiled from CMF
1968-1988, Series 20, No. 2A 2000, CMF 1989-1998, Series 20, No. 2E 2003 and CMF 1999-2001, Series 20, No. 2G 2004 on CDC
WONDER On-line Database.
Viallat, et al Thoracoscopic talc poudrage pleurodesis for malignant effusions CHEST 1996 110:1387-93
Vogelzang, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma Journal of Clinical
Oncology 2003 21:2636-2644
Whitaker, D The cytology of malignant mesothelioma Cytopathology
2000 11:139-151
www.atsdr.cdc.gov/toxprofiles
www.kazanlaw.com
www.lung.ca/diseases/cancer
www.som.tulane.edu/.../ AsbestosMinerals.jpg
 Kappa
 Measure of agreement between two observers
 Interrater reliability
 A descriptor rather than an indicator of
statistical significance
= Observed – Expected agreement
1 – Expected agreement
Excellent agreement 0.93 – 1.0
Very good agreement 0.81 – 0.92
Fair agreement 0.41 – 0.60
Poor agreement 0.01 – 0.20
No agreement
Basic & Clinical Biostatistics. 3rd ed. Beth Dawson and Robert Trapp.
Behavior Modeling . . .
Aiding The War Effort . . .
Immediate Release January 22, 1943
The men who sail the ships of the American merchant marine will soon be
supplied with free cigarettes for use during long voyages with materials for the
war effort, the War Shipping Administration announced today.

Through an arrangement with a leading cigarette manufacturer, the

WSA has established a program whereby the cigarettes will be distributed
free of charge to seamen aboard all vessels of the Victory Fleet.

The idea was presented to the WSA by the manufacturer as a contribution to

the war effort. Cigarettes will be made available to merchant seamen
immediately. Shipments are to be made to representatives of the WSA
at various ports and will be marked "For distribution to Seamen of the
Merchant Marine." WSA officers in the ports will insure distribution in the
proper manner.

http://www.usmm.net/cigarette.html