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Highlights of the Day: Non-Colorectal Cancer

Highlights of the Day: Non-Colorectal Cancer. Charles D. Blanke, M.D., F.A.C.P., F.R.C.P.C. University of British Columbia/BC Cancer Agency. DISCLOSURES. Speaker / Consultant : Novartis Pfizer Astra-Zeneca Oncothyreon Roche. Non-Colorectal Cancer Highlights.

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Highlights of the Day: Non-Colorectal Cancer

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  1. Highlights of the Day: Non-Colorectal Cancer Charles D. Blanke, M.D., F.A.C.P., F.R.C.P.C. University of British Columbia/BC Cancer Agency

  2. DISCLOSURES Speaker / Consultant : Novartis Pfizer Astra-Zeneca Oncothyreon Roche

  3. Non-Colorectal Cancer Highlights • Epidemiology and background • Key findings in esophagogastric cancers • Key findings in pancreatic cancer • Key findings in hepatobiliary cancers • Future directions

  4. 2009 Epidemiology of Non-Colorectal Cancers: • 8% of all United States’ cancers • 15% of all US cancer deaths

  5. Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: Results from a multicenter randomized phase III study. A. van der Gaast, P. van Hagen, M. Hulshof, M.I. van Berge Henegouwen, G.A. Nieuwenhuijzen, J.T. Plukker, J.J. Bonenkamp, E.W. Steyerberg, H.W. Tilanus. CROSS study group Courtesy van der Gaast Abstr 4004

  6. CROSS Study: Background • Meta-analyses/two modern phase III trials suggest a survival benefit from pre-operative chemoradiation in esophageal cancer • The evidence is stronger for adenocarcinoma histology • Other optimal patient selection factors remain unknown • It may increase post-operative mortality

  7. CROSS Active Treatment Arm Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29 Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE) Major eligibility: Adeno- or squamous histology; N1 or >T2, PS < 2 Primary objective: Median overall survival 22 months (versus 16)

  8. CROSS: Major Results • 93% received all courses chemotherapy • 95% went to operating room • ~23% had >grade 3 toxicity from pre-op therapy • R0 resection rate: 92% versus 67% p<0.001 • ~26% had pathologic complete remissions • Post-operative morbidity and mortality almost identical

  9. CROSS: Overall Survival CRTx Surgery HR 0.67 95% CI (.49 - .91) P=0.012 HR 0.67 95% CI (0.49 - 0.91) • 1-year survival 82 versus 70% • 2-year survival 67 versus 52% • Median survival 49 versus 26 months Adapted van der Gaast

  10. CROSS: Investigators’ Conclusions • Neoadjuvant chemoRT with weekly carbo- and paclitaxel followed by surgery improves survival over surgery alone • Pre-operative chemoRT did not increase morbidity

  11. Surgery alone vs. chemoradiotherapy followed by surgery for localized esophageal cancer: analysis of a randomized controlled phase III trial FFCD 9901 C. Mariette, JF Seitz, E Maillard, F Mornex, PA Thomas, JL Raoul, V Boige, D Pezet, C Genet, L Bedenne Fédération Française de Cancérologie Digestive Dpt of digestive and oncological surgery University Hospital Lille FRANCE Courtesy Dr. Mariette Abstr 4005

  12. FFCD: Methods • Neoadjuvant CRT group (CRT+S group, n=97) 45Gy/25F/5 weeks with 2 courses of concomitant CT 5FU 800mg/m2/day D1-D4 + cisplatin 75mg/m2 D1 or D2 vs. • Surgery alone group (S group, n=98) • Major eligibility: Adeno- or squamous histology; T1-2N0-1 or T3N0, PS < 1 • Primary objective: Increase overall survival from 35% to 50%

  13. FFCD: Major Results • ~23% had >grade 3 toxicity from pre-op therapy • 86% went to surgery • R0 resection rate: 88% versus 84% (S alone) • Post-operative mortality: 7.1% v. 1.1%, p= 0.054

  14. FFCD: Overall Survival

  15. FFCD Trial: Investigators’ Conclusions • Neoadjuvant chemoRT added to surgery does not improve survival • …….nor any oncologic outcome • Due to higher post-operative mortality with pre-operative therapy

  16. Chemoradiotherapy in Esophageal Cancer: Questions Raised • Why were the results so different? • ?Different chemotherapy or RT • Was it the varying histology? • What do we do now with early stage esophageal cancer patients?

  17. Systemic Therapy in Advanced Gastric Cancer: Background • >4 randomized trials show an OS advantage for chemotherapy • Chemotherapy improves QOL in incurable patients • Median survival with modern drugs ~ 8-10 months • ~10% or more of patients are long-term survivors • Combination chemo- is better than single-agent • ?how many • Trastuzumab only “standard” biologic

  18. AVAGAST: a randomized, double-blind placebo-controlled, phase III study of first-line capecitabine and cisplatin + bevacizumab or placebo in patients with advanced gastric cancer (AGC) Y-K Kang, A Ohtsu, E Van Cutsem, SY Rha, A Sawaki SR Park, H-Y Lim, J Wu, B Langer, MAShah on behalf of AVAGAST investigators Courtesy Kang Abstr LBA4007

  19. AVAGAST: Study Design 19 Cape or 5FU/Cisplatin (XP) + Placebo q3w Locally advanced or metastatic gastric cancer R Cape or 5FU/Cisplatin (XP) + Bevacizumab q3w Methods: Eligibility: Adenocn stomach or GEJ; PS < 2 Primary objective: OS (10 to 12.8 mo) Adapted Kang

  20. AVAGAST: Major Results • Interim analysis skipped • 95% PS <1; vast majority gastric origin • Adverse events exactly as expected • ORR with bevacizumab 46% v. 37%, p = 0.03

  21. AVAGAST: Overall Survival by Region

  22. AVAGAST: Investigators’ Conclusions • Primary endpoint (overall survival) not met • Secondary endpoints indicate clinical activity bev + chemo in gastric cancer • Heterogeneous efficacy results across geographic regions • Biomarker analysis ongoing

  23. AVAGAST: Questions Raised • Should “the world” use bev in gastric cancer now? • Should Americans use bev now? • Why did they do so poorly with chemotherapy alone? • Will correlative work help us?

  24. Advanced Pancreatic Cancer: Background • Lots of positive phase II trials; ~zippo in phase III • No new chemotherapy for last 5 years • Total failure of bevacizumab and cetuximab • We clearly need to understand more about the biology of the disease

  25. RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin, irinotecan and oxaliplatin) VS GEMCITABINE AS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC ADENOCARCINOMAProdige 4 - ACCORD 11/0402 trial:final results T. Conroy, F. Desseigne, M. Ychou, M. Ducreux, O. Bouché, R. Guimbaud, Y. Bécouarn, C. Montoto-Grillot, S. Gourgou-Bourgade, A. Adenis, FNCLCC-FFCD Prodige group Centre Alexis Vautrin, Nancy; Centre Léon Bérard, Lyon; Centre Val d'Aurelle, Montpellier; Institut Gustave Roussy, Villejuif; Centre Hospitalier R. Debré, Reims; Institut Claudius Regaud, Toulouse; Institut Bergonié, Bordeaux; Fédération Nationale des Centres de Lutte Contre le Cancer - BECT, Paris; Centre Oscar Lambret, Lille; FRANCE Abstr 4010

  26. Experimental Arm: FOLFIRINOX Oxaliplatin 85 mg/m2 over 2 hours, Leucovorin 400 mg/m2 over 2 hours, Irinotecan 180 mg/m2 in 90 mn infusion, 5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 on 46-h infusion. 1 cycle = 14 days Bolus 5-FU 400 mg/m2 2 h Oxaliplatin 85 mg/m2 Leucovorin 400 mg/m2 Continuous 5-FU 2.400 mg/m2 Irinotecan 180 mg/m2 2 h 46 h 1 h 30 q2wks Courtesy Dr. Conroy

  27. Prodige 4 - ACCORD 11/0402: Study Details • Eligibility: • Measurable disease • < 75 years old • PS 0 or 1 • Primary objective: Overall survival (7 10 months)

  28. Efficacy Results Overall Survival Median 11.1 versus 6.8 months • PFS 6.4 versus 3.3 months • ORR 31 versus 9.4% Adapted Conroy

  29. Safety *1 toxic death each arm Adapted Conroy

  30. PRODIGE 4-ACCORD: Authors’ Conclusions • Using FOLFIRINOX requires vigilant patient “selection, education, monitoring, and active management” • The regimen will be tested in the adjuvant setting • FOLFIRINOX is the new worldwide standard of care

  31. Questions Raised by PRODIGE 4-ACCORD • Can the trial be methodologically criticized? • Why have other combination trials been negative? • Is FOLFIRINOX the new “worldwide standard”? • How about in specific subsets of pancreatic ca pts? • Does the trial require confirmation?

  32. HCC: Background • Most patients are not candidates for cure • Transcatheter arterial chemoembolization (TACE) is an effective option that improves survival • 70-80% or TACE-treated pts progress and die from HCC • Sorafenib improves survival in advanced HCC • The combination is attractive

  33. Phase II Trial of Study in Asia of the Combination of TACE (Transcatheter arterial chemoembolization) with Sorafenib in Patients with Hepatocellular Carcinoma Trial (START): 2nd Interim Safety and Efficacy Analysis Y.H. Chung, B. Kim, C.Y. Chen, T.Y. Lee, J. Wang, J. Yoon, K. Seetalarom, S.H. Bae, C.P. Li, Y. Chao Courtesy Dr. Chung Abstr 4026

  34. Study design TACE* Doxorubicin: 30-60mg + Sorafenib** 400mg bid Adapted Chung HCC patients - BCLC B - ECOG PS 0, 1 - Child-Pugh score < 7 - Size of largest tumor <= 10cm - TACE naïve Primary objective: Safety (NCI CTCAE version 3.0) Secondary objective: Efficacy Repeated every 6 to 8 weeks *Patients treated until “no vital tumor” **Patients then maintained on sorafenib

  35. START Results • 63 (50) very healthy patients were reported on • 62% had grade 3/4 AEs • Efficacy: 30% CR and 60% PR/SD

  36. 42 year old female, multiple lesions, 2 cycles of TACE and SorafenibAfter 2 cycles of TACE + Sorafenib there was complete necrosis of tumour.

  37. START Author Conclusions • TACE + sorafenib is safe and tolerable • And, the regimen appears to have good response rates • A robust trial is necessary to really evaluate efficacy

  38. Questions Raised by START • Did it change standard of care? • Who can we give this regimen to?

  39. Other Potentially Important UGI Work • Abstr 4019: Bev can be safely added to ECX in pre-op gastric cancer cases • Abstr LBA4012: Post-op resected panc canc pts given 5FU/cis/RT/INF live a long time • Abstr 4008: FOLFOX4 does not/does improve OS over adria alone (HCC)

  40. ASCO 2010 UGI Highlights • Pre-operative chemoRT works in esoph cancer • Bevacizumab not to be given to all advanced gastric cancer patients • But, some may benefit a lot • FOLFIRINOX: A new possibility in advanced pancreatic cancer

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