Diagnosis, Staging and Treatment in Malignant Mesothelioma

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Diagnosis, Staging and Treatment inMalignant
Mesothelioma

• Paul Baas
• EIS on Chest Tumors
• Geneva, April 1th 2007

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What have we learned in the last 20 years?
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Diagnosis

• Diagnosis is made on HISTOLOGY
• Cytology Only in 35 of cases (epithelial)
• A pathology panel is preferred
• Clinical information can help

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How deep is your biopsy?
Not Diagnostic
Diagnostic
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Early diagnosis?

• Screening?
• Tumor markers
• Mesothelin (SMRP)/Osteopontin/Cyfra 21-1/CEA
• Thoracoscopic/Fluorescence diagnosis in patients
  at risk?

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Staging Questions

• 7 staging systems available Which to choose?
• Is surgery required for staging?
• How to interpret the N status?!?
• Impact of PET scanning?

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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 1081122-28. Pleural
  mesothelioma. AJCC 2002

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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

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Confirmed prognostic factorsin mesothelioma

• Edwards, 2000
• cell type
• haemoglobin
• white cell count
• performance status
• gender

n142
Stage not always a prognostic factor
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Therapeutic approaches

• Chemotherapy
• Chemotherapy with targeted agents
• Combined modality treatment
• Chemotherapy, Surgery and Radiation therapy

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Chemotherapy

• Over 2 decades have been devoted to small phase
  II studies
• Single agent activities lt combination
• Overall response rates 0 48
• Phase III studies have been reported

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Mixing Chemotherapy
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Phase 2 first line studiesPlatin and
gemcitabine combinations
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First line Phase 3 studies
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(No Transcript)
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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

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Phase 2 second line studies

• gt11 studies
• bortezomib,
• antineoplaston,
• bevacizumab,
• erlotinib bevacizumab,
• imatinib,
• carboplatin vinorelbin,
• AZD 2171,
• PXD2171,
• etc

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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
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A Randomized Phase III Trial Comparing Pemetrexed
Plus BSC Versus BSC In Previously Treated
Patients With Advanced Malignant Pleural
MesotheliomaJacek JassemMedical 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
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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

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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).

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New approaches

• Chemotherapy with targeted agents
• Maintenance therapy
• Low dose chemotherapy
• Exploit the immunological effect of gemcitabine
• Gene therapy
• Immunization therapy

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NVALT Thalidomide study Phase III
Thalidomide 100-200 mg/day
Pemetrexed Cisplatin or Carboplatin X ? 4 cycles
SD CR PR
Primary endpoint time to progression
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
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Phase II trial of Bevacizumab in MM
Gemcitabine Cisplatin Bevacizumab
Stratification histology, PS
Bevacizumab
6 cycles
To be presented again at ASCO 2007
106 pts
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
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EORTC 08031 feasibility study
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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 lt 26 successes trial stopped
• trimodality treatment not feasible
• if 26 successes trial stopped
• trimodality treatment feasible

48/52 patients entered March 2007
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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