VIEWS: 6 PAGES: 27 CATEGORY: Medications & Treatments POSTED ON: 8/17/2012
All Disease : mesothelioma and asbestos : information including symptoms, diagnosis, misdiagnosis, treatment, causes, patient stories..
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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