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Diagnosis Staging and Treatment in malignant mesothelioma

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All Disease : mesothelioma and asbestos : information including symptoms, diagnosis, misdiagnosis, treatment, causes, patient stories..

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									Diagnosis, Staging and
     Treatment in
Malignant Mesothelioma
What have we learned in the last
          20 years?
                  Diagnosis

• Diagnosis is made on HISTOLOGY

• Cytology: Only in 35% of cases (epithelial)

• A pathology panel is preferred

• Clinical information can help
How deep is your biopsy?


         Diagnostic
        Not Diagnostic
               Early diagnosis?
• Screening?

• Tumor markers:
  – Mesothelin (SMRP)/Osteopontin/Cyfra 21-1/CEA


• Thoracoscopic/Fluorescence diagnosis in
  patients at risk?
           Staging Questions
• 7 staging systems available: Which to choose?

• Is surgery required for staging?

• How to interpret the N status?!?

• Impact of PET scanning?
                      MPM: IMIG 1995
Regional lymph nodes (N)
NX      cannot be assessed

N0        no regional LN metastases

N1        ipsilateral bronchopulmonary and/or hilar LN

N2        subcarinal, ipsilateral internal mammary or mediastinal LN

N3        contralateral mediastinal, internal mammary or hilar LN
          and/or ipsi/contralateral supraclavicular or scalene LN

Rusch VW (IMIG). Chest 1995; 108:1122-28. Pleural mesothelioma. AJCC 2002
                  Staging
• Surgery is required in most instances

• PET scan is promising but its place has still
  to be defined in prospective studies

• There is a need for a new simpler staging
  system
   Confirmed prognostic factors
         in mesothelioma
Edwards, 2000
• cell type
• haemoglobin
• white cell count
• performance
  status
• gender
              n=142
    Stage not always a prognostic factor
      Therapeutic approaches
• Chemotherapy

• Chemotherapy with targeted agents

• Combined modality treatment
  – Chemotherapy, Surgery and Radiation therapy
             Chemotherapy
• Over 2 decades have been devoted to small
  phase II studies

• Single agent activities < combination

• Overall response rates 0 – 48%

• Phase III studies have been reported
Mixing Chemotherapy
        Phase 2 first line studies:
  Platin and gemcitabine combinations
                Byrne     Nowak     v. Haarst    Favaretto
              JCO 1999   BJC 2002   BCJ 2002    Cancer 2002
Patients        21         53          25            50
Gemcitabine    1000       1000       1250           1000
              d1,8,15    d1,8,15      d1,8        d1,8,15
Platin        Cis 100    Cis 100     Cis 80     Carbo AUC 5
Response        48%        33%        16%          26%
Survival       9.5 ms    11.2 ms     9.6 ms        15 ms
(median)
     First line Phase 3 studies
 Therapy      # patients   MST    Response   P-value
                                    Rate
    Cis          222       9.3     16.7%
(Vogelzang)                                  <0.001
 Pem/Cis         226       12.3    41.3%

   Cis           124       8.8     19.4%
 (EORTC)                                     0.046
  Ral/Cis        125       11.2    45.5%
   Phase 3 UK-NCRI Trial ‘MS01’
• Comparing chemotherapy (MVP or Vinorelbin) with ASC:
  End-points:
   – Survival
   – Quality of Life
   – Response Rates

• Recruitment began in Sept 2000, initial target 840, later
  reduced to 420

• Closed to recruitment July 2006, 407 patients randomised
      Phase 2 second line studies
• >11 studies
      •   bortezomib,
      •   antineoplaston,
      •   bevacizumab,
      •   erlotinib + bevacizumab,
      •   imatinib,
      •   carboplatin + vinorelbin,
      •   AZD 2171,
      •   PXD2171,
      •   etc
    Phase 3 second line Chemotherapy
• Pemetrexed vs. BSC
• Doxorubicin +/- Onconase
   – ranpirnase, Alphacell corp
   – selective degradation of t-RNA  apoptosis
   – To recruit 300 patients; started 1997
• Vorinostat
   – suberoylanilide hydroxamic acid, SAHA, Zolinza, Merck
   – Binds to histone deacetylase in nucleus
   – After 220 patients interim analysis now 660 planned

 www.clinicaltrials.gov
  A Randomized Phase III Trial Comparing
      Pemetrexed Plus BSC Versus BSC
In Previously Treated Patients With Advanced
       Malignant Pleural Mesothelioma

                    Jacek Jassem
         Medical University of Gdansk, Poland

       R Ramlau, A Santoro, W Schuette, A Chemaissani,
     S Hong, J Blatter, S Adachi, A Hanauske, C Manegold



             Presented at ESMO 2006 Turkey
              Study Design and Treatment
 Phase III, randomized, open-label
 Stratification
     - PS, sex, histology,WBC, investigational site and previous raltitrexed therapy
 Pemetrexed 500 mg/m2 q3 i.v. with supplementation plus BSC
  or BSC alone
 Up to 8 cycles of treatment (additional cycles if requested)
 Post study treatment allowed
 121 vs. 120 patients
         Conclusions 2nd line study

 Improvement in PFS, TTP, ORR compared to BSC
  alone
 No statistical difference in survival, the cross-over
  design might have influenced this
 Patient compliance is satisfactory and treatment is
  well tolerated (7-11% hematological toxicity).
           New approaches
• Chemotherapy with targeted agents
• Maintenance therapy
• Low dose chemotherapy
• Exploit the immunological effect of
  gemcitabine
• Gene therapy
• Immunization therapy
   NVALT Thalidomide study Phase III

                                                Thalidomide
                                                100-200 mg/day
  Pemetrexed
                              SD
  Cisplatin or
                              CR            Primary endpoint:
  Carboplatin
                                            time to progression
  X  4 cycles                PR

                                                No treatment

Statistics: 216 pts are required to demonstrate an improvement in TTP
by 50% with thalidomide, assuming a median TTP of 5 months in the control arm
March 2007: 103 patients included
               Phase II trial of Bevacizumab in MM


Stratification:                   Gemcitabine
histology, PS                     Cisplatin                                            Bevacizumab
                                  Bevacizumab

     106 pts
                                        6 cycles                                       To be presented
                                                                                     again at ASCO 2007
                                  Gemcitabine
                                  Cisplatin                                           Placebo
                                  Placebo
Randomized double blind Phase II
                                                                    MST all patients 15.7 months
            Participating centers: U Chicago, UC Davis, U Penn, MDACC, MSKCC, Dana Farber, Johns Hopkins
EORTC 08031 feasibility study
           Patients with "resectable" MPM

             3 courses of chemotherapy

 progressive disease         responders/stable disease

      off study            Extra pleural pneumonectomy

                             Radiation therapy (54Gy)

                                     follow-up
  Mesothelioma trial 08031

• 1ary endpoint : success of teatment :
        full protocol, alive after 90 days
        no progression, no G3 - G4 toxicity
• 2ary endpoint : survival, toxicity


• one stage Fleming design : 52 patients
    – if < 26 successes     trial stopped
                  trimodality treatment not feasible
    – if ≥ 26 successes     trial stopped
                   trimodality treatment feasible

       48/52 patients entered March 2007
                   Conclusions
•   Prognostic factors are very important
•   Diagnosis based on histology and by expert panel
•   Standard chemotherapy with platinum and anti-folate
•   No standards for 2nd line therapy
•   Role of targeted agents is becoming clear
•   Insight in molecular/genetic analysis is required
•   Combined modality treatment only in selected patients

								
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