Diagnosis, Staging and Treatment in Malignant Mesothelioma

Diagnosis, Staging and Treatment in Malignant Mesothelioma Paul Baas EIS on Chest Tumors Geneva, April 1th 2007 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? Not Diagnostic 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 N1 N2 N3 no regional LN metastases ipsilateral bronchopulmonary and/or hilar LN subcarinal, ipsilateral internal mammary or mediastinal LN 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 JCO 1999 Patients Gemcitabine Platin Nowak BJC 2002 53 1000 d1,8,15 Cis 100 33% 11.2 ms v. Haarst BCJ 2002 25 1250 d1,8 Cis 80 16% 9.6 ms Favaretto Cancer 2002 50 1000 d1,8,15 Carbo AUC 5 26% 15 ms 21 1000 d1,8,15 Cis 100 48% 9.5 ms Response Survival (median) First line Phase 3 studies Therapy # patients MST Response Rate P-value Cis (Vogelzang) Pem/Cis Cis (EORTC) Ral/Cis 222 226 124 125 9.3 12.3 8.8 11.2 16.7% <0.001 41.3% 19.4% 0.046 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 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 Phase II trial of Bevacizumab in MM Gemcitabine Cisplatin Bevacizumab 6 cycles Gemcitabine Cisplatin Placebo Randomized double blind Phase II Stratification: histology, PS Bevacizumab To be presented again at ASCO 2007 106 pts Placebo 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 off study responders/stable disease 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