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Highlights 2007: Non-colorectal GI cancer

Alan P. Venook, M.D. University of California, San Francisco. Highlights 2007: Non-colorectal GI cancer. Highlights: non-colorectal GI. Pancreas cancer Phase III trials Gastric cancer Genetic risk Esophageal / GE junction / gastric Prediction of outcome Preoperative therapies S-1.

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Highlights 2007: Non-colorectal GI cancer

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  1. Alan P. Venook, M.D. University of California, San Francisco Highlights 2007:Non-colorectal GI cancer

  2. Highlights: non-colorectal GI • Pancreas cancer • Phase III trials • Gastric cancer • Genetic risk • Esophageal / GE junction / gastric • Prediction of outcome • Preoperative therapies • S-1

  3. Highlights: non-colorectal GI • Pancreas cancer • Phase III trials • Gastric cancer • Genetic risk • Esophageal / GE junction / gastric • Prediction of outcome • Preoperative therapies • S-1

  4. Highlights: non-colorectal GI • Pancreas cancer • Gemcitabine +/- cetuximab • Gemcitabine +/- bevacizumab

  5. PA Philip, J Benedetti, C Fenoglio-Preiser, M Zalupski, H Lenz, E O’Reilly, R Wong, J Atkins, J Abbruzzese, C Blanke On behalf of SWOG, CALGB, NCIC, and the CTSU Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in Patients with Locally Advanced or Metastatic Pancreatic AdenocarcinomaSouthwest Oncology Group Protocol S0205

  6. S0205 Study Schema Gemcitabine + Cetuximab • Stratify • Locally advanced versus metastatic • Prior pancreatectomy • Yes versus No • Performance status • 0/1 versus 2 R A N D O M I Z E Gemcitabine

  7. 5.9 6.4 S0205: Primary EndpointSurvival in All Patients HR = 1.09 (95% CI: 0.93, 1.27)

  8. 3.0 3.5 S0205: Progression-Free Survival in All Patients HR = 1.13 (95% CI: 0.97, 1.31)

  9. S0205: Objective Tumor Response

  10. H.L. Kindler, D. Niedzwiecki, D. Hollis, E. Oraefo, D. Schrag, H. Hurwitz, H.L. McLeod, M.F. Mulcahy, R. L. Schilsky, R. M. Goldberg A double-blind, placebo-controlled randomized Phase III trial of Gemcitabine plus Bevacizumab versus Gemcitabine plus placebo in Patients with Advanced Pancreatic Cancer:A preliminary analysis of Cancer and Leukemia Group B

  11. CALGB: Gemcitabine +/- bevacizumabKindler, et al… • Median OS: 5.7 v. 6.0 months • Median failure-free survival: 4.8 v. 4.3 months • RR: 13% v. 11% • Stopped and unblinded at interim analysis due to futility

  12. Lowlights: pancreas cancerOverall survival • Gemcitabine +/- cetuximab: 6.4 v. 5.9 mo • Gemcitabine +/- bevacizumab: 5.7 v. 6.0 mo

  13. Lowlights: pancreas cancerOverall survival • Gemcitabine +/- cetuximab: 6.4 v. 5.9 mo • Gemcitabine +/- bevacizumab: 5.7 v. 6.0 mo • Gemcitabine +/- erlotinib: 6.24 v. 5.91 mo* • Moore et al, JCO, 2007 • The standard is unsatisfactory and new drugs and study designs are needed * Statistically significant

  14. Highlights: non-colorectal GI • Pancreas cancer • Phase III trials • Gastric cancer • Genetic risk • Esophageal / GE junction / gastric • Prediction of outcome • Preoperative therapies • S-1

  15. Hereditary Diffuse Gastric Cancer: Natural History, Pathology, Screening Limitations, and Prophylactic Total Gastrectomy in CDH1 Mutation CarriersbyHenry Lynch*, Carlos Caldas, Debrah Wirtzfeld, Carlos Vaccaro, Wendy Rubinstein,Scott Weissman, Pardeep Kaurah, Niki Boyd,Rebecca Fitzgerald, David Huntsman

  16. b-catenin binding site Loss of E-cad is a defining feature of both DGC and lobular breast cancer

  17. Criteria for CDH1 mutation testing modified to reflect current data • Family with two or more cases of GC, with at least 1 DGC diagnosed before the age of 50. (>40%)* • 3 or more first/second-degree relatives with confirmed diffuse gastric cancer, irrespective of age. • Isolated individual diagnosed with DGC at less than 35 years from a low incidence population (>10%)* • Isolated personal history of both DGC and LBC (unknown)* • Family with multiple LBC with or without DGC in first or second degree relatives (unknown)* • * Percentage mutation pick up rate from low incident populations • Modified from Caldas et al. J Med Genet, 1999 and Suriano et al. Clin Can Res, 2005

  18. Currently 31/39 (80%) of prophylactic gastrectomies reviewed in total had occult DGC’s All cancers were very superficial, the rate of progression of these lesions and the the secondary mutations required for invasion of the muscularis propria are unknown <1% 44-60% 50-80% 3% 26-43% 28-33% F Carneiro, D Huntsman et al J Pathol 2004; 203: 681–687

  19. Highlights: non-colorectal GI • Pancreas cancer • Phase III trials • Gastric cancer • Genetic risk • Esophageal / GE junction / gastric • Prediction of outcome • Preoperative therapies • S-1

  20. M. A. Shah, H. Yeung, D. Coit, R. Trocola, D. Ilson, J. Randazzo, L. Tang, M. Brennan, C. Divgi, D. P. Kelsen A phase II study of preoperative chemotherapy with irinotecan and cisplatin for gastric cancer: FDG-PET/CT predicts patient outcome

  21. FDG-PET/CT predicts outcome in gastric caShah, et al… • N = 42 locally advanced disease • 31/42 PET avid • Neoadjuvant irinotecan / cisplatin • SUV drop from baseline to d35 correlates with path response, but d15 does not • Cut-off of 45% decrease d35 SUV: • DFS >23 months v. 14.4 months

  22. S. Rao, D. Cunningham, M. Benson, R. Te Poele, L. Welsh, N. Starling, A. Norman, C. Saffrey, P. Workman, P. Clarke A prospective study to evaluate the role of gene expression profiles in predicting clinical outcome of patients receiving preoperative chemoradiotherapy for oesophagogastric cancer

  23. Gene expression predicts outcome in gastric caRao, et al… • Neoadjuvant chemotherapy • N = 35 (esophagus, 23; GE junction, 12) • Two distinct gene clusters: • N = 17 poor prognosis -- 2 yr survival = 17% • N = 18 good prognosis -- 2 yr survival = 55% • Affected pathways: tyrosine kinase signaling and cell growth

  24. V. Boige, J. Pignon, B. Saint-Aubert, P. Lasser, T. Conroy, O. Bouche, P. Segol, L. Bedenne, P. Rougier, M. Ychou Final results of a randomized trial comparing pre-operative 5-FU / cisplatin to surgery alone in adenocarcinoma of stomach and lower esophagus: FNLCC ACCORDO7-FFCD 9703 trial

  25. Neoadjuvant therapy v. surgery aloneBoige, et al… • Neoadjuvant 5-FU/cisplatin; resectable gastric or GE junction • N = 224 (accrued over 8 years) • R0 resection: 73% v. 84% favoring combined rx • 5 yr DFS: 21% v. 34% • OS: 24% v. 38% • Neoadjuvant 5-FU/cisplatin improves outcomes

  26. Michael Stahl on behalf of the German Oesophageal Cancer Study Group PreOperative Chemotherapy or Radiochemotherapy in Esophago-gastric Adenocarcinoma TrialPOET

  27. Treatment Arm A Week Arm B PLF 2 x 6 weeks PLF, 3 weeks Surgery 1 13 17 21 PLF 2 x 6 weeks 15 x 2 Gy, 3 weeks Surgery PE, 1 week P: Cisplatin E: Etoposide LF: Leukovorin / 5-FU

  28. Logrank p = 0.07 HR Arm B vs. A 0.67 (0.41-1.07) Arm B 47.4% Arm A 27.7% OS: Follow-up 45.6 mo

  29. Abstract: 4512 Individual patient data-based meta-analysis assessing the interest of pre-operative chemotherapy in resectable oesophageal carcinoma Thirion P.,Michiels S., Le Maître A., Tierney J. The Meta‑Analysis of Chemotherapy in Esophagus Cancer Collaborative Group

  30. Materials • 12 eligible trials identified - 2,290 patients • 9 available trials (10 comparisons) - 2,102 patients (92%) • Median follow up across trials: 5.3 years (range: 4.9 - 6.0)

  31. No. Deaths / No. Entered Chemo preop Control Study O-E Variance Hazard Ratio HR [95% CI] Queen Mary 52/74 64/73 -13.3 27.8 Italy 35/48 37/48 -2.4 17.8 Songkla 20/24 16/22 5.7 8.5 MRC EO-02 280/400 316/402 -34.7 148.4 RTOG 8911 204/233 197/234 5.9 100.1 MD Anderson 11/17 16/19 -2.7 6.7 Scandinavia 2 53/56 50/50 -0.9 25.6 Scandinavia 2R 46/53 52/58 0.8 24.2 Oeso-2 44/58 52/64 -3.3 23.7 Rotterdam 61/85 72/84 -14.9 31.9 0.87 [0.79;0.95] Total 806/1048 872/1054 -59.8 414.6 0.25 1.00 4.00 Test for heterogeneity: p = 0.03 Chemo preop better | Control better Chemo preop effect: p = 0.003 Primary End-point: Overall Survival

  32. No. Events / No. Entered Category O-E Var Hazard ratio HR [95% CI] Chemo preop Control Adenocarcinoma 282/385 315/392 -29.5 148.4 Squamous cell 450/564 471/563 -15.0 226.7 0.0 0.5 1.0 1.5 2.0 Test for interaction: p = 0.21 Chemo preop better | Control better Sub-group Analyses • The overall survival and disease-free survival benefit of the addition of pre-operative chemotherapy was seen across: • Age (50<, 50-60, >60) • Gender • Initial PS • Histological Type

  33. Esophagus / GE junction conclusions • Data supports the roles of chemotherapy and radiation in the management of resectable cancers • Surgery as a single modality is probably suboptimal

  34. S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur Anti-tumor activity 5-FU DPD OPRT GI toxicity F-b-Ala Neurotoxicity Myelotoxicity 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7

  35. S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur Anti-tumor activity CDHP Oxo 5-FU DPD OPRT GI toxicity F-b-Ala inhibit inhibit Neurotoxicity Myelotoxicity 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7

  36. S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur Anti-tumor activity CDHP Oxo 5-FU DPD OPRT GI toxicity F-b-Ala inhibit inhibit Neurotoxicity Myelotoxicity 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7

  37. Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912) • N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, • W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu • Gastrointestinal Oncology Study Group • of Japan Clinical Oncology Group

  38. 5-FUci 800 mg/m2, continuous inf, days 1-5 q 4 weeks CPT-11 + CDDP CPT-11 70 mg/m2, div, days 1&15 CDDP 80 mg/m2, div, day 1 q 4 weeks Randomization Stratified by (minimization) ・Institution ・PS 0/1/2 ・Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx S-1 S-140mg/m2, po, bid, days 1-28 q 6 weeks BSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100 mg/body/day 1.5 < BSA 120 mg/body/day Continued until disease progression, unacceptable toxicities, patient’s refusal

  39. (%) 100 PFS Response rate 50 0 12 24 (months) P-value† Median n HR 95%C.I. 5-FUci - 2.9M 234 - - CPT-11+CDDP <0.001 4.8M 236 0.69 0.57-0.83 S-1 0.001 4.2M 234 0.75 0.62-0.90

  40. Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment of advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment of stomach cancer H. Narahara1, W. Koizumi2, T. Hara3, A. Takagane4, T. Akiya5, M. Takagi6, K. Miyashita7, T. Nishizaki8, O. Kobayashi9, S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group; SPIRITS

  41. Central Randomization • (dynamic balancing) • Adjustment Factors: • Institute • PS • Unresectable vs Recurrent S-1 alone S-1: 40-60 mg BID for 28 days q6wks AGC No prior Chemo. R S-1 + CDDP S-1: 40-60 mg BID for 21 days q5wks CDDP: 60 mg/m2 iv on day 8

  42. Estimated probability (%) Log-rank p-value: 0.0366 HR: 0.774 [ 95% CI: 0.608 – 0.985] Median follow-up time (M): 34.6 11.0 13.0 Months

  43. Fisher’s Exact Test p-value: 0.0018 • Criteria : RECIST (Extramural Review)

  44. Highlights: non-colorectal GI • Pancreas cancer • Phase III trials • Gastric cancer • Genetic risk • Esophageal / GE junction / gastric • Prediction of outcome • Preoperative therapies • S-1

  45. Highlights: non-colorectal GI • Pancreas cancer • Phase III trials • Gastric cancer • Genetic risk • Esophageal / GE junction / gastric • Hepatocellular carcinoma • Sorafenib

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