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Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Gastric Cancers

Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Gastric Cancers. David H. Ilson, MD, PhD Associate Attending Physician GI Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY. Upper GI Cancer: US Incidence in 2007.

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Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Gastric Cancers

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  1. Challenging Cases in Cancer: Integration of Findings from ASCO 2007Gastric Cancers David H. Ilson, MD, PhD Associate Attending Physician GI Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY

  2. Upper GI Cancer: US Incidence in 2007 • 93,150 new cases gastric, esophageal, pancreatic, hepatobiliary cancer • 8% of new cancers • 81% fatality rate • 15% of American cancer deaths • Decline in gastric cancer incidence • Increase in esophageal , GE JX, cardia adeno • Increase in hepatocellular Ca Jemal et al, CA Cancer J Clin 57: 43-66; 2007

  3. Gastric Cancer: Current Therapy • Adjuvant • Post op 5-FU/LV + RT: increases 5-yr OS by 10% (U.S. Standard, INT 116) • Pre and Post op ECF: increases 5-yr OS by 13% (U.K. Standard, MAGIC trial)

  4. Case 1: GE Junction Adenocarcinoma • A 79-year-old male presents with increasing dysphagia, 15 pound weight loss, odynophagia • Past history: NIDDM, BPH, hypercholesterolemia • EUS: T3N1 adenocarcinoma, 50% circumferential • CT scan: distal esophageal mass • PET scan: uptake in the primary, SUV • The patient is admitted from clinic for complete dysphagia, and has endoscopy and Polyflex stent placement

  5. Case 1: GE Junction Adenocarcinoma PET scan CT scan

  6. Case 1: GE Junction Adenocarcinoma Which treatment option would you recommend? • Esophagectomy • Preop chemotherapy with ECF followed by esophagectomy and post op ECF • Preop combined chemoradiotherapy followed by surgery • Primary combined chemoradiotherapy without surgery

  7. The patient received induction chemo with weekly carboplatin and paclitaxel for 3 treatments. Dysphagia improved post stent and with chemotherapy PET scan: response to induction chemo (SUV 9.7  5.3), EGD: response, stent was removed Combined chemotherapy with weekly carbo/paclitaxel and RT 5040 cGy was administered EGD post therapy x 2 (4 and 8 weeks after RT): treatment related stricture dilated, biopsy negative Repeat PET scan 2 months post RT: SUV further reduced, 3.1 Surgery deferred Case 1: GE Junction Adenocarcinoma PET 1 PET 2 PET 3

  8. Case 1: GE Junction Adenocarcinoma

  9. GE Junction and Esophageal Cancer: Adjuvant Therapy • Survival with surgery alone: 20-40% • Adjuvant trials in esophageal cancer have evaluated preop therapy • Preop Chemotherapy • Preop Chemo + radiotherapy • Most common U.S. practice

  10. Esophageal Cancer: Preop Chemotherapy • Negative Trials • U.S. INT 113 • 3 pre, 3 post op cycles of 5-FU + Cisplatin • 440 pts • Adeno 54%, Squamous 46% • No improvement in R0 resection rate, disease free or overall survival • Path CR 2.5% Kelsen et al, NEJM 339: 1979; 1998

  11. Esophageal Cancer: Preop Chemotherapy • Positive trials • U.K. MRC OEO-2 • 2 preop cycles of 5-FU + Cisplatin • 802 pts • Adeno 66%, Squamous 31% • 6% increase in R0 resection rate, 9% increase in 2-year OS • Path CR 4% • U.K. MAGIC: pre and post op ECF in gastric cancer • 25% of 500 pts had GE junction or distal esophageal adeno • No improvement in R0 resection rate, 13% increase in 5-year OS • No Path CRs MRC Lancet 359: 1727; 2002, Cunningham NEJM 355: 11; 2006

  12. Esophageal Cancer: Consensus on Adjuvant Therapy • Something more than surgery alone should be done • Adenocarcinoma • Preoperative chemotherapy improves overall survival • MAGIC: 13% improvement at 5 yr • MRC 0E0-2: 9% improvement at 2 yr • No clear impact on rate of R0 resection • Addition of RT to chemotherapy • Improves rates of curative resection in some trials • Achieves pathologic complete responses in 10-30% • Phase III trials: only 2 of 5 recent trials showed a survival benefit for preop chemo + RT MRC Lancet 359: 1727; 2002, Cunningham NEJM 355: 11; 2006

  13. Preop Chemo in Esophageal and Gastric Cancer: FFCD / FNLCC CT + S (N = 113) S (N = 111) Preop CT (2-3 cycles) (N = 98) 89% Surgery (N = 109) 96% Surgery (N = 110) 99% Postop CT (N = 145) CT = 5-FU + Cisplatin Boige, et al. ASCO 2007. Abstract 4510

  14. Surgical and Pathological Results Boige, et al. ASCO 2007. Abstract 4510

  15. Overall Survival 5-year DFS: 24% (16 - 33%) vs. 38% (28 - 47%) Boige, et al. ASCO 2007. Abstract 4510

  16. Disease-free Survival 5-year DFS: 21% (14 - 30%) vs. 34% (26 - 44%) Boige, et al. ASCO 2007. Abstract 4510

  17. Preop Chemotherapy in Esophageal Adenocarcinoma • Survival benefit for preop chemotherapy with CF (cisplatin and 5-FU) • 14% improvement in 5-yr OS, HR 0.69 • Similar to survival for gastric cancer in MAGIC trial • 13% rate of improvement in R0 resection rate • Impact on tumor downstaging: not statistically significant Boige, et al. ASCO 2007. Abstract 4510

  18. Preop Chemotherapy in Esophageal Adenocarcinoma • Major impact was reduction in systemic recurrence • Systemic: 56% for surgery  42% for chemo + surgery • Local: 26% for surgery = 24% for chemo + surgery • Similar results for CF compared to ECF-MAGIC • Epirubicin may not be needed • Role of epirubicin? • OEO-05 (U.K. MRC) • Preop ECF vs. CF in esophageal cancer Boige, et al. ASCO 2007. Abstract 4510

  19. Preop Chemotherapy in Esophageal Adenocarcinoma • Preop Chemo in esophageal and GE JX adeno improves survival • Relative small sample 224 pts, differences of 10-15% come down to outcomes in only 10-15 patients • Preoperative staging • EUS not performed • Accuracy of pre-therapy stage ? • No stratification for stage Boige, et al. ASCO 2007. Abstract 4510

  20. Individual Patient Data-based Meta-analysis Assessing Pre-operative Chemotherapy in Resectable Oesophageal Carcinoma • Individual patient data from preop chemo trials (esophageal squamous and adenocarcinoma) • 9 trials OS (2102 pts) • 7 trials DFS (1849 pts) • 2 dominant trials: • U.S. INT 113 (467 pts) • U.K. MRC OEO-2 (802 pts) • Slightly more than 50% of patients had squamous ca • Preop Chemo: Overall survival improvement with a HR of 0.87 (P = 0.0033) • Translates into 4.3% improvement in OS at 5-yrs Thirion P, et al. ASCO 2007. Abstract 4512

  21. Primary End-point: Overall Survival Thirion P, et al. ASCO 2007. Abstract 4512

  22. Secondary End-point: DFS Thirion P, et al. ASCO 2007. Abstract 4512

  23. Individual Patient Data-based Meta-analysis Assessing Pre-operative Chemotherapy in Resectable Oesophageal Carcinoma • Although overall survival benefit independent of histology • Adeno: 20%  27% • Squamous: 16%  20% • Other endpoints: • R0 resection rate improved by 5% • Post Operative Mortality: not increased with preop chemo • Conclusions: Preop chemotherapy • Modest improvement in 5-yr OS (4.3%) • Greater effect for adenocarcinoma then squamous cell carcinoma of the esophagus Thirion P, et al. ASCO 2007. Abstract 4512

  24. Abstract 4511 Preoperative Chemotherapy (CTX) Versus Preoperative Chemoradiotherapy (CRTX) In Locally Advanced Esophagogastric Adenocarcinomas: First Results of A Randomized Phase III Trial M. Stahl, M. K. Walz, M. Stuschke, N. Lehmann, M. H. Seegenschmiedt, J. Riera Knorrenschild, P. Langer, M. Bieker, A. Königsrainer, W. Budach, H. Wilke

  25. Cisplatin 50 mg/m2 Folinic Acid 500 mg/m2 5-FU 2 g/m2 for 2.5 courses Arm A(N = 60) Patients with locally advanced esophagogastric adenocarcinoma Cisplatin 50 mg/m2 Etoposide 80 mg/m2 Radiation 30 Gy for 3 wks Cisplatin 50 mg/m2 Folinic Acid 500 mg/m2 5-FU 2 g/m2 for 2 courses Arm B(N = 60) Trial Design Stahl M, et al. ASCO 2007. Abstract 4511

  26. Results at Surgery Stahl M, et al. ASCO 2007. Abstract 4511

  27. Pathohistologic Results Stahl M, et al. ASCO 2007. Abstract 4511

  28. Mortality After Surgery Fisher’s exact P = 0.26 Stahl M, et al. ASCO 2007. Abstract 4511

  29. 1.00 0.75 CRTX 47.4% 0.50 Survival Distribution Function 0.25 CTX 27.7% 0 0 1 2 3 4 5 6 Years Overall Survival Log rankP = .07HR arm B vs. A: 0.67 (0.41-1.07) Follow-up: 45.6 mos Stahl M, et al. ASCO 2007. Abstract 4511

  30. 1.00 CRTX 76.5% 0.75 0.50 Survival Distribution Function CTX 59.0% 0.25 0 0 1 2 3 4 5 6 Years Freedom from Local Tumor Progression Log rankP = 0.06HR arm B vs. A: 0.45 (0.19 -1.05) Stahl M, et al. ASCO 2007. Abstract 4511

  31. Preop Chemo vs. Preop Chemo RT • Preop Chemo and Preop Chemo RT are feasible • No difference in rate of R0 resection, + RT • Higher post op mortality, + RT in multi institution trial • Strong trend favoring improved OS, + RT • 20% at 3 years (P = 0.07) • Strong trend favoring improved local PFS, + RT • 18% at 3 years (P = 0.06) Stahl M, et al. ASCO 2007. Abstract 4511

  32. Preop Chemo vs. Preop Chemo RT • Cannot conclude that the addition of RT improves outcome • Trial underpowered for primary endpoint • Further trials of pre and post op chemo ± RT are warranted • Netherlands: CRITICS Trial • Preop ECX  Surgery  • Post op chemo ± RT • Korea: • Preop Capecitabine + Cisplatin  Surgery  • Cape/Cis ± RT Stahl M, et al. ASCO 2007. Abstract 4511

  33. Gastric/Esophageal Cancer: Current Therapy • Gastric Cancer: • Metastatic: 5-FU + cisplatin, RR of 20%, Med S 8-9 mos • Epirubicin (ECF), docetaxel + CF (DCF): • 35-40% RR, med survival 9 mos • Capecitabine, oxaliplatin = CIV 5-FU, cisplatin

  34. Gastric Cancer Chemotherapy: What Regimen to Use? • Docetaxel + CF > CF: toxicity • Irinotecan + CIV 5-FU = CF: less toxicity • Oxaliplatin + Capecitabine: non inferior • Doublets: Platin: + Irinotecan or Taxane or Fluor Flour: + Irinotecan or Taxane or Platin

  35. Case 2: GE Junction Adenocarcinoma • A 50-year-old man presents with increasing solid food dysphagia and a 20 pound weight loss. • EGD reveals a GE junction mass with a biopsy revealing adenocarcinoma. • A CT scan reveals multiple hepatic mets, lung and adrenal mets. • Past history is only noted for asthma. • PS 0. PET Scan CT Scan

  36. Case 2: GE Junction Adenocarcinoma Which treatment option would you recommend? • Single agent 5-FU or capecitabine • 5-FU/Cisplatin or FOLFOX • ECF, ECX, or EOX • DCF: Docetaxel, 5-FU, Cisplatin • FOLFIRI • Irinotecan + Cisplatin

  37. Case 2: GE Junction Adenocarcinoma • Phase III trials indicate that ECF is superior to FAMTX, and that DCF is superior to CF • The patient was treated on a phase II trial of modified DCF • Docetaxel 40 mg/m2 day 1 • Bolus 5-FU 400 mg/m2, Leucovorin 400 mg/m2 day 1, followed by 5-FU 1000 mg/m2/day x 2 days • Cisplatin 40 mg/m2 day 3 • Cycled every 2 weeks • + Bevacizumab 10 mg/kg day 1 • Scans every 6 weeks showed progressive response, dysphagia resolved, PET scan normalized in the liver • Dose reductions of 5-FU and docetaxel for mucositis • No significant neutropenia or diarrhea • Patient continues on therapy at 6 months

  38. Case 2: GE Junction Adenocarcinoma CT Scan 1 PET Scan 1 PET Scan 2 CT Scan 2

  39. Gastric / Esophageal Cancer Abstracts: ASCO 2007 • Metastatic disease: gastric cancer • S-1 vs. S-1 + Irinotecan • S-1 vs. 5-FU vs. 5-FU/Cisplatin • S-1 vs. S-1/Cisplatin • DCF vs. Docetaxel + Capecitabine

  40. S-1 • S-1: novel oral fluorouracil formulation • FT: Tegafur, 5-FU prodrug + • CDHP: DPD inhibitor + • Oxo: bowel protectant • Molar ratio of 1.0: 0.4: 1.0 • Developed as orally absorbed 5-FU preparation with potentially less bowel toxicity

  41. S-1 • CDHP: inhibits DPD, which degrades 5-FU • 180-fold higher DPD inhibitory activity than Uracil • A high blood level of 5-FU retained when CDHP is combined with FT • CDHP enhances oral FT uptake by blocking degradation by DPD in the bowel

  42. S-1 • Oxo: orotate phosphoribosyltransferase inhibitor • Oxo: inhibits conversion of FT to FU in the bowel • Reducing GI toxicity

  43. S-1: Mechanism of Action

  44. Irinotecan Plus S-1 (IRIS) Versus S-1 Alone as First-line Treatment for Advanced Gastric Cancer: Preliminary Results of a Randomized Phase III Study • S-1 vs. S-1 + Irinotecan • 326 pts • RR 27% vs. 42% (P = 0.035) • Grade 3/4 neutropenia: 9% vs. 27% • Grade 3/4 diarrhea: 6% vs. 16% • OS pending (powered to detect 3.5 mos inc OS) Chin K, et al. ASCO 2007. Abstract 4525

  45. 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) • S-1 vs. CIV 5-FU vs. irinotecan/cisplatin 704 pts, primary endpoint irinotecan arm: increase 1-yr OS by 10% • Grade 3/4 neutropenia, nausea, diarrhea • 65% for IC vs. 1-5% for S-1 or 5-FU • 21% for IC vs. 0-1% for S-1 or 5-FU • 9% for IC vs. 1-8% for S-1 or 5-FU • RR: IC: 38% 5-FU: 9% S-1: 28% • PFS: 4.8 mos 2.9 mos 4.2 mos • OS 12.3 mos 10.8 mos 11.4 mos • Irinotecan/cisplatin and S-1 are superior to 5-FU, S-1 single agent approaches combination therapy activity Boku, et al. ASCO 2007. Abstract LBA4513

  46. Randomized Phase III Study of S-1 Alone Versus S-1 + Cisplatin In the Treatment for Advanced Gastric Cancer (The SPIRITS trial) SPIRITS • S-1 vs. S-1 + Cisplatin • S-1 40-60 mg BID x 3 weeks alone, vs. S-1 + Cisplatin 60 mg/m2 day 8, 2 weeks rest • Primary endpoint OS: 8 mos  12 mos, 284 pts • S-1: Active single agent, superior to CIV 5-FU alone • Combination + cisplatin superior • S-1 + Cisplatin a new standard in Japan • FLAGS: Western trial of 5-FU vs. S-1 + Cisplatin Narahara et al. ASCO 2007. Abstract 4514

  47. Weekly Docetaxel-based Chemotherapy Combinations in Advanced Esophago-gastric Cancer • DCF in gastric cancer: 35% RR, TTP 5.6 mos, OS 9.2 mos • 82% grade 3/4 neut., 30% neut. fever, 20% diarr and stomatitis • Phase II: • DCF: Doc 30 mg/m2 day 1 and 8, 5-FU 200 mg/m2/day x 21 days, Cisplatin 60 mg/m2 day 1 vs. • DX: Doc 30 mg/m2 day 1 and 8, Cape 1200 mg/m2/day x 14 days Tebbutt et al. ASCO 2007. Abstract 4528

  48. Challenging Cases in Cancer: Integration of Findings from ASCO 2007Pancreatic Cancer

  49. Pancreatic Cancer: Current Therapy • Primary Disease: Surgical Resection: • Only curative option • <20-30% operable • 5 yr survival 0-20% • Adjuvant: • Chemo + RT: post op 5-FU/XRT (U.S) • Chemo Alone: 5-FU + leucovorin (Europe, ESPAC trial), or Gemcitabine alone (Europe, CONKO trial) • Metastatic Disease: • Gemcitabine 1000 mg/m2/wk, 30 minute infusion • RR 6%, median survival 5.6 mos, 1-yr survival 18% • Gem + second drug: negative phase III trials for 5-FU, cisplatin, irinotecan, oxaliplatin, capecitabine • Gem + Erlotinib increases 1-year survival • ECOG: Gemcitabine FDR = Gemcitabine FDR + Oxaliplatin (10% RR, med. Surv. 6 months)

  50. Case 3: Pancreatic Adenocarcinoma • A 56 year old man with worsening diabetic control presents with abdominal pain and a 20 pound weight loss • A CT scan reveals a pancreatic mass and innumerable hepatic metastases, • Liver biopsy reveals pancreatic adenocarcinoma • Past history is notable for now insulin dependent diabetes, hypertension, peptic ulcer disease and hypercholesterolemia. • PS is 0

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