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					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

				
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