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Esophageal and Gastric Cancer: How do we sort out the treatment options?

David H. Ilson, MD, PhD. Esophageal and Gastric Cancer: How do we sort out the treatment options?. Gastrointestinal Oncology Service Memorial Sloan-Kettering Cancer Center. Disclosure. Research Funding Sanofi-aventis Genentech Bristol-Myers Squibb/Imclone.

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Esophageal and Gastric Cancer: How do we sort out the treatment options?

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  1. David H. Ilson, MD, PhD Esophageal and Gastric Cancer: How do we sort out the treatment options? Gastrointestinal Oncology Service Memorial Sloan-Kettering Cancer Center

  2. Disclosure • Research Funding • Sanofi-aventis • Genentech • Bristol-Myers Squibb/Imclone

  3. Esophageal and Gastric CarcinomaUS Incidence in 2008 • 37,970 new cases • Gastric: 21,500 (57%) • Esophagus: 16,470 (43%) • Decline in Gastric Cancer , Esophageal Squamous Cancer Incidence • Increase in Adenocarcinoma of the esophagus, GE JX, cardia • Esophageal cancer more virulent: • 87% fatality rate • Gastric: 52% Jemal et al, CA 58: 71-96; 2008

  4. Oral Presentations: Esophageal and Gastric Cancer, Phase III • Adjuvant Therapy • Igaki (Abs 4510): Esophageal Cancer • Pre versus Post op chemo in squamous cancer • Kang (Abs LBA 4511): Gastric Cancer • Adding IP and IV cisplatin to MMC / oral doxifluridine after resection • Advanced Disease • Ridwelski (Abs 4512): Gastric Cancer • Docetaxel + cisplatin versus 5-FU + cisplatin

  5. Esophageal CancerTrials of Adjuvant Therapy • Preoperative  surgery • Preop Chemo  Surgery • Preop Concurrent RT + Chemo + / - Surgery

  6. A randomized trial of postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus neoadjuvant chemotherapy for clinical Stage II/IIIsquamous cell carcinoma of the thoracic esophagus (JCOG 9907) H. Igaki, N. Ando, H. Kato, M. Shinoda, H. Shimizu, T. Nakamura, S. Ozawa, H. Yabusaki, N. Aoyama, A. Kurita, H. Fukuda Japan Esophageal Oncology Group (JEOG) of Japan Clinical Oncology Group (JCOG), Japan 6

  7. Prior JCOG Trials in Esophageal Squamous Cancer • Similar stage patients, similar sample size and design • JCOG 8806: Surgery vs post op vindesine + cisplatin, 205 pts • Negative Trial • OS 5 year 45% for surgery, 48% for post op chemo (NS) • JCOG 9204: Surgery vs post op 5-FU + cisplatin, 242 pts • Primary: DFS 5 year • Negative Trial • DFS 45% for surgery, 55% for chemo (NS) • OS in node + patients: 38%  52% post op chemo (P = 0.041) • Unplanned subset analysis Ando J Card Thor S 114: 205; 1997 Ando J Clin Oncol 24: 4592;2003

  8. Scheme Randomization Balanced with minimization by institution, cN0 / cN1 Post-op CTx (standard arm A) Pre-op CTx (test arm B) Surgery 2 x FP 2 x FP Surgery In pN0,no CTx FP: cisplatin + 5FU 5-FU 800mg/m2 d1-5 ci cisplatin 80mg/m2 d1 div • Surgery • Transthoracic esophagectomy • with lymphadenectomy (>D2) 8

  9. Igaki et al, Abstract 4510 • Primary Endpoint: increase PFS by 10-13% for preoperative arm • Adequately powered trial • Protocol excluded pathologic N0 pts on post op arm (38 pts) from chemo • Based on analysis of prior post op trial: no benefit in N0 • Arms balanced by preclinical stage • Therapy tolerable and feasible • Primary endpoint not reached • Median PFS: 2 year (post op) versus 3 year (pre op, NS) • OS 5 year 38% post op  60% pre op (HR 0.64, p = 0.014)

  10. 2nd Interim Analysis To decide early publication or not @ Mar. 2007, all 330 pts Overall survival (OS) Progression-free survival (PFS) Pre 5yOS=60.1% Pre Median PFS=3.0y Post Median PFS=2.0y Post 5yOS=38.4% Years after randomization Years after randomization Unadjusted one-sided stratified logrank P = 0.0444> 0.0254 (alpha) Hazard ratio = 0.76(94.91%CI: 0.56–1.04) Unadjusted two-sided logrank P =0.013 Hazard ratio by Cox model = 0.64 (95%CI: 0.45–0.91, p=0.014) DSMC recommended the early publication 10

  11. Igaki et al, Abstract 4510 • A large number of post op pts did not receive chemo • Preop: 17 pts (10%) did not receive chemo • Post op: 85 pts (51%) did not receive chemo • Includes 38 path N0 pts excluded per protocol (23%) • Another 28% failed to receive post op chemo • Trial did not reproduce results from post op arm of prior study • 61% OS prior post op trial • 38% OS current post op trial • Different populations, pathologic staging on the prior trial compared to clinical staging on the current trial • Adequacy of clinical staging: EUS and PET scan were not performed • ? Treatment arms truly balanced by stage

  12. Subgroup Analyses: updated OS Clinical Stage Data in Nov 2007 Stage III (non-T4) Stage II Pre (n=80) 5yOS=69.7% Pre (n=84) 5yOS=52.1% Post (n=78) 5yOS=49.3% Post (n=88) 5yOS=36.5% Years after randomization Years after randomization Hazard ratio by Cox model = 0.48 (95%CI: 0.28–0.83) Two-sided P = 0.0088 Hazard ratio by Cox model = 0.94 (95%CI: 0.61–1.46) Two-sided P = 0.79 Pre-op chemotherapy may be more beneficial in Stage II 12

  13. Igaki et al, Abstract 4510 • Current Preop Trial: only Stage II patients benefit • Prior post op trial benefit limited to path N + pts • Dose this trial prove that pre op chemo is superior to post op chemo in esophageal squamous cancer? • No • Unplanned subset analyses generate hypotheses and not conclusions • Large number of pts did not receive chemotherapy • Adequacy and accuracy of pre treatment clinical staging

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

  15. Esophageal Cancer: Preop Chemotherapy • Positive trials • U.K. MRC OEO-2 • 802 pts • Adeno 66%, Squamous 31% • 2 preop cycles of 5-FU + Cisplatin • 9% increase in 2 year OS • Decreased to 6% increase in 5 years OS (17%23%) • 10% operative mortality MRC Lancet 359: 1727; 2002 Cunningham NEJM 355: 11; 2006

  16. Meta Analysis Preop Chemo in Esophageal Cancer: Thirion (ASCO 2007) • Squamous and adeno • 9 trials OS: 2102 pts • Overall survival improvement for preop chemo (HR 0.87, p = 0.0033) • 4% improvement in OS at 5 yrs • Squamous 4% • Adeno 7%

  17. Preop Chemo in Esophageal Squamous Cancer • Marginal benefit from larger trials and meta analysis • Operative mortality risk = survival benefit • Data do no support this approach as the optimal standard of care in squamous cancer

  18. Preop Chemo in Esophageal Squamous Cancer • Primary chemo + radiotherapy: U.S. standard of care for locally advanced disease • Curative potential without surgery (RTOG) • Responding patients (FFCD) • Absence of a clear survival benefit for addition of surgery • Surgery for biopsy positive / non responding patients after therapy • Surgery for younger, fitter patients • Early stage disease: • Surgery alone or Chemoradiotherapy alone

  19. Gastric Cancer:Adjuvant Therapy Standards of Care • Post op Chemo oral S-1 (Japan) • 10% improved 5 yr OS • 1000 pts, D2 resection • Post op Chemo 5-FU / LV + radiotherapy (U.S.) • 10% improvement in 5 yr OS • Pts with less than a D1-D2 resection • Pre and post op Chemo ECF (U.K.) • 13% improvement in 5 yr OS • without radiotherapy Sakuramoto NEJM 357: 1810;2007 Macdonald NEJM 345: 725; 2001 Cunningham NEJM 355: 11; 2006

  20. Rationale: Intraperitoneal Chemotherapy • Peritoneal recurrence in up to 40-50% of patients after gastric resection • IP chemo increases exposure to chemo agents by 10-100 + fold • No confirmed phase III trials of IP therapy

  21. Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer: A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)(AMC 0101) (NCT00296322) Yoon-Koo Kang, Heung-Moon Chang, Dae Young Zang, Jae-Lyun Lee, Tae Won Kim, Dae Hyun Yang, Se Jin Jang, Jeong Hwan Yook, Sung Tae Oh, Byung Sik Kim Asan Medical Center, Seoul, Hallym University Hospital, Anyang, Korea

  22. ASCO 2008 Abs 4531: Adjuvant MMC + FU + / - IV Cisplatin after D2 resection (AMC 0201) • MMC x 1, Doxifluridine orally x 3 mos • vs • MD + IV Cisplatin x 6, Doxifluridine x 12 mos • MD: 67% 3 yr relapse free survival • MDP: 65% 3 yr relapse free survival • No improvement with addition of IV cisplatin or extended therapy • Current Trial (AMC 0101) MMC + FU  + IV cisplatin + extended doxifluridine • + IP cisplatin x 1 intra op • Mitomycin administered earlier on • Serosa positive gastric cancer

  23. Treatment Schema Grossly Serosa(+), Non-Metastatic Gastric Cancer At surgery RANDOMIZATION Stratified by center, stage iceMFP arm Mf arm 100 mg for 2h before closure Intraperitoneal CDDP 3 - 6 weeks after surgery MMC 15 mg/m2 iv D1 Stage I, IV(M1) MMC 4 weeks later 20 mg/m2 iv Protocol off CDDP DFUR DFUR CDDP DFUR DFUR CDDP DFUR DFUR CDDP DFUR CDDP DFUR CDDP DFUR DFUR DFUR DFUR 460 – 600 mg/m2 po daily Cisplatin 60 mg/m2 iv D1 every 4 weeks DFUR DFUR DFUR DFUR DFUR

  24. Recurrence Free Survival 1.00 0.75 Recurrence free proportion 0.50 0.25 HR 0.695 [ 95% C.I.: 0.536 - 0.902 ] P = 0.006 by log-rank test 0 0 12 24 36 48 60 72 months after randomization

  25. Overall Survival 1.00 0.75 Surviving proportion 0.50 0.25 HR 0.710 [ 95% C.I.: 0.531-0.950 ] P = 0.02 by log-rank test 0 0 12 24 36 48 60 72 months after randomization

  26. Recurrences P=0.02

  27. Intraperitoneal Cisplatin, Gastric Cancer • Well designed and conducted phase III trial • Adequately powered • Ineligible patients common • Randomization was intraoperative prior to final pathology reading • Appropriate exclusion of metastatic disease, positive margins • Arms balanced, therapy tolerable, no increased operative complications

  28. Intraperitoneal Cisplatin, Gastric Cancer • Achieved primary endpoint of improved relapse free survival: • 3 yr RFS 50%  60% • Reduced peritoneal and distant recurrence • Suggests a potential benefit for IP cisplatin, early start of mitomycin

  29. Intraperitoneal Cisplatin, Gastric Cancer • Four variables confound conclusion that IP chemo is superior in serosa + gastric cancer • Trial also included early MMC, extending doxifluridine, adding IV cisplatin • Companion AMC 0201 trial • No benefit for extended chemo or addition of cisplatin • Confirmatory trial in which only variable is IP chemotherapy

  30. Esophago-Gastric Cancer: Metastatic Disease • CIV 5-FU + cisplatin • 4-5 day infusion • RR 20-30% • Med S 8-9 months • Adding a third drug: • Epirubicin (ECF), protracted 5-FU CIV: RR 40-45%, Med S 9 mos • 25-40% have locally advanced, non metastatic disease • Docetaxel (DCF): RR 36%, Med S 9 mos • 10% increment in response rate • 1-2 month increment in survival • Capecitabine = 5-FU, Oxaliplatin = Cisplatin

  31. DCF vs CF: Toxicity Van Cutsem J Clin Oncol 2006

  32. 4512 Docetaxel–cisplatin (DC) versus 5-fluorouracil–leucovorin–cisplatin (FLC) as first-line treatment for locally advanced or metastatic gastric cancer: Preliminary results of a Phase III study K Ridwelski, J Fahlke, C Schmidt, E Kettner, U Keilholz, D Quietzsch, M Assmann, M Stauch, K Zierau, H Lippert

  33. Objectives Primary objective • Time to tumor progression (TTP) increase from 40% to 60% in patients without progression at 6 months Secondary objectives • Toxicity • Overall response rate (ORR) • Overall survival (OS)

  34. Study design DC Docetaxel 75 mg/m2 iv over 1 h, day 1 Cisplatin 75 mg/m2 iv over 1 h, day 1 Repeated q3w for up to 6 cycles RANDOM I Z A T I ON Chemotherapy-naïve patients with metastatic or locally advanced (stage III-IV) gastric cancer FLC 5-FU 2000 mg/m2 iv over 24 h Leucovorin 500 mg/m2 iv over 2 h Both on days 1, 8, 15, 22, 29, 36 + Cisplatin 50 mg/m2 iv over 1 h, days 1, 15, 29 Repeated q7w for up to 4 cycles (cisplatin omitted in Cycle 4) 273 patients randomized between October 2001 and September 2006 from 21 centers in Germany Data available for 270 patients

  35. Results Median follow up: 8.2 months 9.5 months DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin; OS, overall survival; TTP, time to progression

  36. Response to treatment p = 0.244 Confirmed response per RECIST DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin; ORR, overall response rate

  37. Safety DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin

  38. DC vs CF • DC is not superior to CF, DC = CF • Contrasts the V325 study: D + CF superior to CF • CF well tolerated on this dose and schedule • Use colorectal cancer like schedule for cisplatin or oxaliplatin + FU • Weekly or two weekly infusional FU • Single digit toxicities

  39. Colorectal Scheduling: Gastric Cancer, Weekly infusional 5-FU + every 2 week Oxaliplatin or Cisplatin Al Batran J Clin Oncol 26: 1435; 2008

  40. DC vs CF • DC = CF, failed to achieve primary endpoint of superiority • Contrast to V325 study, three drug DCF superior to CF • Toxicity of DCF limits its general use • If DCF is used: • Lower starting doses • Consider colorectal like scheduling of drugs • Marginal differences in outcome for three drugs: Doublets better platform for future study • Adding targeted agents • Perioperative therapy or added to radiotherapy

  41. Gastric Cancer Chemotherapy: What regimen to use?

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