Chemotherapy for Advanced Peritoneal Mesothelioma | Mesothelioma Applied Research Foundation

Chemotherapy for Advanced 

Peritoneal Mesothelioma presented by Robert N. Taub, MD, PhD of Columbia University at the Mesothelioma Applied Research Foundation conference in New York, NY on September 28, 2012. www.curemeso.org

Chemotherapy for Advanced Peritoneal Mesothelioma | Mesothelioma Applied Research Foundation from Mesothelioma Applied Research Foundation

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• 1. Columbia University Mesothelioma Center www.mesocenter.org Robert N. Taub MD PhD, director Peritoneal mesothelioma programClinical Trials, Treatment, QOL(surgery, intracavitary/systemic/targeted therapies)Preclinical/Laboratory studies molecular biology, drug discovery, pharmacokinetics, intracellular platinum distribution, experimental peritoneography
• 2. Mesothelioma Defined--A primary malignant tumor arising in the lining membrane of the lung (pleura), heart (pericardium), intestines (peritoneum), or testis (tunica vaginalis).Pleural mesothelioma = ~ 3,100 cases/yrPeritoneal (Abdominal ) Mesothelioma = ~ 450 cases/yrOthers (pericardial, testicular = <100 cases/yr
• 3. Peritoneal MesotheliomaNormal Mesothelioma Ascites
• 4. •Mesothelioma and AsbestosDr. G. Zhibin, taken Nov 2011/ IMIG 2012 Asbestos spinning, Chrysotile Insulation Asbestos spinning, 2011,Yuyao, China Johns Mannville, NJ 1934, NJ------------------------------------------------------------------------------------- Other causes: -Zeolites – asbestos-like mineral (found in US Southwest, Turkey) -Therapeutic radiation for Cancer- (Breast, Prostate, Uterus, Hodgkins) -SV40 viral infection may be cofactor. -Familial, genetic: (BAP1 mutation) may be cofactor.
• 5. HYPOTHESES:Initiation/Growth Pathways Progression/Growth Pathways 1. Asbestos chemically induces Receptor 3. NF2 (Merlin) Hippo/ Phosphorylation LATS/ YAP Cascade? and/or DNA Oxidation ? 2. Asbestos physically 4. Mutated BAP-1 epigenetic “Harpoons” Macrophages effects on histones, genes? and/or their chromosomes? None of these fully explain how mesothelioma develops.
• 6. Diagnosis of Mesotheliomas A tissue biopsy, read by a pathologist, is always needed. Epithelial Biphasic Sarcomatous Epithelial/Sarcomatous Malignant Mesotheliomas may be: epithelial /tubulopapillary (80%, not good); biphasic epithelial/ sarcomatoid, (15%, bad); or pure sarcomatoid ( 5-10%, worst). -----------------------------------------------------------------------------------Some “mesotheliomas” which present with abdominal distentionmay be benign, seldom require surgery or chemotherapy. To be certain,second pathology opinions and/ or special tests may be needed Benign cystic Well-differentiated papillary “mesothelioma” “mesothelioma”
• 7. 1. Peritoneal Mesothelioma: two (or three) different diseases? Tubulopapillary- Sarcomatous/ Epithelial - Biphasic No pain, No pain, Much pain, 0-2+ ascites 1-4 + ascites No ascites Superficial Intermediate Invasive Median Survival, Tubulopapillary vs. Non Tubulopapillary (160 patients operated on at CPMC) Different Genes: Epithelial v biphasic gene microarrays, Unsupervised clustering, 15 patients
• 8. The Challenge of Genome Instability: Different mesothelioma cells may eachshow different, very abnormal chromosomes• Normal karyotype • Mesothelioma karyotype
• 9. Loss in Chromosome 14qFrequency of chromosome loss and gain comparison between asbestos induced cases (red, 10 pts ) and radiation induced cases (blue, 7 pts ) Original Copy Number Analysis of Chromosome 14 including All Peritoneal Mesothelioma Patients (n=31) Chen et al, IMIG 2012
• 10. Treatment of Abdominal Mesothelioma• CYTOREDUCTIVE SURGERY + LOCAL / REGIONAL CHEMOTHERAPY• SYSTEMIC CHEMOTHERAPY----------------------------------------------------• EXPERIMENTAL : Targeted Agents• EXPERIMENTAL: Immunotherapies• EXPERIMENTAL: Gene therapy
• 11. Combined Therapy of Peritoneal Mesothelioma• SURGERY: Exploratory Laparotomy, Omentectomy, Cytoreduction, Implant Bilateral Subcutaneous Mediport i.p. Catheters, Heated CHEMOTHERAPY “Wash”• Repeated (q 1-2wk)Intraperitoneal CHEMOTHERAPY with alternating Doxorubin with Cisplatin, 4 of each.• SURGERY: 2nd-Look Laparotomy, Resection of remaining tumor, Removal of Mediports, Heated I.P. CHEMOTHERAPY• Follow-up q 3mo X6, q 6mo X3, then yearly X3
• 12. Exploratory Laparotomy, Omentectomy, Cytoreduction,Implant Bilateral Subcutaneous Mediport i.p. Catheters
• 13. Bilateral Mediport- Attached Intraperitoneal Catheters. MEDIPORT
• 14. Closed System in OR: Roller Pump withConstant Recirculation and Temperature:Cisplatin 75- 100 mg/m2 +/- Mitomycin 10 mg/m2 + in 1- 2 liters N/S @ 41ºC for 90 min
• 15. Inter-Institutional Operative Variables Columbia v Others • Limited Exploration/Omentectomy; Second- Look Surgery (two operations) v Radical Pleurectomy/ Extirpative Surgery (one op.) • HIPEC: Cisplatin 50-75mg, 41.5o C, 90 min, v Cisplatin 100-200mg +/- Mitomycin C, 42.5o C, 60-90 min. • Outpatient i.p. chemo X8, Dox/Cisplatin v no outpt i.p. chemo, v 5d i.p. chemo.
• 16. Chemotherapy for Mesothelioma, Response RatesPemetrexed + DDP 42% (corrected, 20.5%) in randomized Phase III. Median Survival 12.5 mo. FDA approved. –Ralitrexed + DDP, (~20%RR) Randomized Phase III Median Survival 11.6 mo.Gemcitabine + Cisplatin or Oxaliplatin( 20-40% in Phase II)—not tested in Phase III.Doxorubicin +Cisplatin (21-28% in Phase III, 1993)Mitomycin + Cisplatin (21-28% in Phase III, 1993)Single Agents: Navelbine, pemetrexed, Doxil, gemcitabine---less than 12%
• 17. Mesothelioma Experimental Targeted Treatment (I am probably leaving out some treatments) Preclinical Clinical Humanized NGR-TNF* Anti-Mesothelin Ab SSIP-dsFv-P38 EGFR Inhibitors VEGF Inhibitors HDAC Inhibitors Miscellaneous Morab009* Gefinitib Bevacizumab Vorinostat Ranpirnase Not yet BAY 94-9343* Erlotinib Vatalanib Panobinostat Interferon alphaTested, not Cediranib Valproic Acid Interferon gammaFully Vaccines-anti WT1 terribly PDGF Inhibitors Semaxanib Belinostat Rapamycin Imatinib Sorafenib Bortezomib tested, anti mesothelin effective Dasatinib Dendritic Cell Vaccine Sunitinib Thalidomide Cycle Inhibitors CBP501 but PARP Inhibitors Adenovirus -HSV-thymidine Olaparib PI3 Inhibitors IMC A12 hopeful Kinase Temsirolimus *Available at Columbia
• 18. How should patients choose treatment?1. Conventional v. Experimental Treatment: Previously untreated patients who are symptomatic from advancing disease should first choose conventional chemotherapy treatment with a recognized record of objective responses and/or tumor shrinkage. Previously untreated asymptomatic patients might first choose experimental treatment, to increase their available options; they can get conventional treatment at a later time.
• 19. Choosing Conventional Treatment? Patients should ask their doctor to justify his choice of treatment --- literature experience, personal experience of expected benefits and possible risks, number of patients personally treated, whether QOL is being measured. A second medical opinion is always important, even if the first opinion is obtained at a major academic Cancer Center. Patients cared for by community oncologists should abide by their opinions. If local oncologists are unfamiliar with the treatment, patients should arrange periodic visits at a major center to review the treatment being given.
• 20. Choosing Experimental Treatment? 1. More than 80% of experimentally tested Phase I and Phase II drugs are deemed ineffective. Hesitate before enrolling. Do not pin your hopes on any one drug, be prepared to try several therapies. Second opinions are particularly important. MARF can provide you with a list. 2. Choose late-stage Phase III studies or investigator-initiated Phase II studies with a clear rationale that you comprehend, where care will be provided by the investigator both during and after the trial. 3. Ask whether the investigator will cover additional costs of care that might be incurred if there are unexpected adverse events or side effects. 4. The investigator (not a surrogate) should personally spell out all the risks and possible benefits of the study and answer all questions. There should be many questions. 5. Ask to speak with other patients who have gone through the trial. The trial should have a QOL component.
• 21. In 10 years…• There will be fewer asbestos-related peritoneal mesothelioma cases in the US, more in China.• Drug treatment will be determined by genomics.• Surgical and intraperitoneal treatment for peritoneal mesothelioma will at least be better standardized; at best, unnecessary.
• 22. Paradigm of tumor formation
• 23. The Challenge of Personalized Treatment Chromosome ? ?? ? Great Selection Great Selection of Of targets? missiles?
• 24. Hypothesis• 1. Peritoneal Mesothelioma comprises not one but several diseases, which may differ in cell of origin, cellular appearance, and mechanism of development: And recognizably, in clinical symptoms and course.
• 25. Chemotherapy for MesotheliomaPemetrexed (MTA, Alimta®) + cisplatin (41% (20.5% on review) in randomized Phase III) v cisplatin aloneGemcitabine + Cisplatin (12-44% in Phase II)Ralitrexed + Oxaliplatin (~40% Phase II)Gemcitabine + Oxaliplatin (~40% Phase II)Doxorubicin + Cisplatin (12-28% in Phase III)Mitomycin + Cisplatin (12-28%in phase III)Gemcitabine alone (7% in phase II)
• 26. Columbia Mesothelioma Center Current Combined Treatment of Peritoneal MesotheliomaNormal Mesothelioma – Debulking Surgery, I.P. Portacath – I.P. Chemo (Dox, Cisplatin, IFN) – 2nd Surgery, Hot Chemoperfusion
• 27. Conclusion: Optimism• Advances in molecular biology and genetics of mesothelioma.• Improved, more selective surgical and combined modality treatment• Discovery of new drugs• Environmental elimination of asbestos