1. The Role of Preoperative Approaches in Localized Gastro Esophageal Cancers David H. Ilson, MD, PhD Gastrointestinal Oncology Service Memorial Sloan-Kettering Cancer Center

2. Gastric and Esophageal Cancer Gastric and Esophageal Cancer: 1.39 million cases – 1.09 million deaths (78%) Esophageal Cancer: 386,000 deaths Gastric Cancer: 700,000 deaths Estimate 50% are locally advanced (700,000) – A 10% increment in survival = 70,000 lives saved Kamangar et al, J Clin Oncol 24: 2137-50; 2006

3. Esophageal and Gastric Cancer US Incidence in 2007 36,820 new cases – Esophageal: 15,560 – Gastric: 21,260 Esophageal: 90% fatality rate Decline in Gastric Cancer Incidence Increase in Adeno of the esophagus, GE JX, cardia Jemal et al, CA 57: 43-66; 2007

4. Esophageal Cancer: Surgery 1980’s, 1990’s Akiyama: 913 pts (Squamous), TTE (2, 3 field), 5 yr O.S. 43% Ando: 419 pts (93% Squamous), TTE (2, 3 field) / THE, 5 yr O.S. 40% Hulscher: 220 pts (Adeno), THE vs TTE: 5 yr O.S. 29-39% Akiyama Ann Surg 220:364;1994 Ando Ann Surg 232:225:2000, Hulscher NEJM 347:1662;2002

5. Esophageal Cancer MULTIMODALITY STUDIES Chemo followed by Surgery Concurrent RT + Chemo + / - Surgery

6. Esophageal Cancer: Adjuvant Therapy Pre Operative—Neoadjuvant Chemotherapy – Negative U.S., Positive U.K. trials Chemo + RT – Most common U.S. practice – Mixed results, Phase III

7. 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

8. 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

9. ASCO 2007: Boige et al, Abs 4510: Preop Chemo in Esophageal and Gastric Cancer: FFCD / FNLCC CT = 5-FU + Cisplatin

12. Preop Chemo in Esophageal Adeno: ASCO 2007, Abs 4510 Survival benefit for preop chemo 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 Major impact was reduction in systemic recurrence – Local: 26% for surgery, 24% for chemo + surgery – Systemic: 56% for surgery, 42% for chemo + surgery Epirubicin (ECF in MAGIC trial) may not be needed OEO-05 (U.K. MRC): Preop ECF versus CF in esophageal cancer (U.K.)

13. Esophageal Cancer: Met Analysis Preop Chemo: ASCO 2007, Abs 4512 Individual patient data for preop chemo in squamous cell and adenocarcinoma 9 trials OS: 2102 pts 7 trials DFS: 1849 pts Slightly more than 50% of patients had squamous ca Primary endpoint: overall survival improved by a HR of 0.87 (p = 0.0033) – Translates only into 4.3% improvement in OS

14. Primary End-point: Overall Survival

15. Meta Analysis of Preop Chemo: Esophageal Cancer (Abs 4512) Overall Survival Benefit independent of histology – Adeno:20%  27% – Squamous:16%  20% Other endpoints: – R0 resection rate improved by 5% Conclusions: – 4.3% OS improvement, 5% impact on resection rate modest – Greater effect for adeno then squamous cell carcinoma

17. Local Recurrence: 45%  Surgeon’s argument for resection after ChemoRT

18. RTOG 85-01: Adeno vs Squamous Carcinoma 5 year Survival: – Squamous Cancer: 21% (107 pts) – Adenocarcinoma: 13% (23 pts) Differential outcome by histology Long term survivors: Primary Chemo RT – Adeno and Squamous Cancer – Without surgery Cooper et al JAMA 1999

19. Chemoradiotherapy Alone (5-FU/Cis/RT) or ChemoRT  Surgery: FFCD 9102 AuthorPt No. Histol.TherapyMed. Surv. O.S.Local Control Bedenne259SquamChemo RT + S 17.7 mos 34% 2 yr 66% SquamChemo RT 19.3 mos 40% 2 yr 57% 455 pts treated, 259 responders randomized: Non responders excluded. Bedenne et al JCO 25: 1160; 2007

20. Preop ChemoRT  Surgery: Esophageal Cancer Path CR in 10-40% 5 yr OS 25-35% Phase III: small, inconclusive (<100-250 patients) – Curative Resection rates increased RT + chemo in some trials – Local Recurrence reduced – Trends toward ↑ Survival – Path CR: ↑ Survival

21. Prognostic Factors after Chemo RT Patients achieving a pathologic CR have 50- 70% long term survival Some series indicate pts with 90% treatment effect have similar survival to path CR pts Superior survival for N0 versus N1 disease Superior survival for T0-1 versus T2-4 post treatment Early response during induction chemotherapy on PET scan: Prognostic for improved survival Molecular prognostic factors

22. Preop ChemoRT: Phase III TrialTherapyPatients% Adeno %R0 Resection Path CR OS or Med Surv S / CRT FFCDSurgery2820%69%--26% 5 yr CRT81%26% Walsh*Surgery110100%NS--6% 3 yr* CRTNS25%32%* UrbaSurgery10075%90%--16% 3 yr CRT88%28%32% Burmeister Surgery25680%59%--19 mos CRT80%16%22 mos *1 of 4 trials positive

23. Preop ChemoRT: Phase III TrialTherapyPatients% Adeno %R0 Resection Path CR OS or Med Surv S / CRT FFCDSurgery2820%69%--26% 5 yr CRT81%26% Walsh*Surgery110100%NS--6% 3 yr* CRTNS25%32%* UrbaSurgery10075%90%--16% 3 yr CRT88%28%32% Burmeister Surgery25680%59%--19 mos CRT80%16%22 mos *1 of 4 trials positive

24. Preop ChemoRT: Phase III TrialTherapyPatients% Adeno %R0 Resection Path CR OS or Med Surv S / CRT FFCDSurgery2820%69%--26% 5 yr CRT81%26% Walsh*Surgery110100%NS--6% 3 yr* CRTNS25%32%* UrbaSurgery10075%90%--16% 3 yr CRT88%28%32% Burmeister Surgery25680%59%--19 mos CRT80%16%22 mos *1 of 4 trials positive

25. RANDOMIZATIONRANDOMIZATION Cisplatin + 5- FU + RT + Surgery Surgery CALGB 9781: Esophageal Cancer, Preop Chemo RT vs Surgery Alone N = 26 N= 30 Tepper JCO 24: Abs 4012, 181, 2006 Of 500 planned patients, 56 accrued

26. 9781 Survival by Arm P =0.0130

29. Preop Chemo versus Preop Chemo RT: ASCO 2007, Abs 4511 Trial limited to esophageal adenocarcinoma – Siewert’s I-III, distal esophagus, GE JX, cardia Careful preop staging by EUS and laparoscopy Only high risk T3-4 pts treated Balance of pts by pre therapy stage Therapy was feasible and tolerable Accrual goal was not met (33% planned)

34. Preop Chemo, Preop Chemo RT 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) Preop Chemo versus Preop Chemo RT: ASCO 2007, Abs 4511

35. Esophageal Cancer: Preop Chemo, RT, or Both? Esophageal Adeno: Preop Chemo – Improves survival – More feasible in a community setting – Higher op mortality with preop chemort Esophageal Adeno: Combined Preop RT + Chemo – Trends toward improved OS – Significant rate of pathologic CR – Cost of greater toxicity – Treated at high volume centers Operative mortality not increased with preop therapy

36. Esophageal Cancer: Preop Chemo, RT, or Both? Esophageal Squamous – Preop Chemo: less certain survival benefit – RT + Chemo: As primary therapy without surgery is acceptable Surgery after chemo rt: in selected patients, as the improved local control  no improvement in survival

37. Preop Chemo vs Chemo RT: Meta Analysis Gebski et al, Lancet Oncol 8: 226-234; 2007 TrialsPtsMort. Reduc HRP value 2 yr OS Chemo8172410%0.900.057% Adeno22%0.780.024 Squam12%0.880.12 Chemo RT10120919%0.810.00213% Adeno25%0.750.02 Squam16%0.840.04

38. Preop Therapy in Esophageal Cancer Is radiotherapy required as part of adjuvant therapy? Future Trial Questions – Preop Chemo + / - RT  Surgery – Preop Chemo  Surgery,  Post op Chemo + / - RT CRITICS Trial: the Netherlands; ECX Korean adjuvant trial: Capecitabine + Cisplatin

39. New Agents In Combined ChemoRT CALGB: Irinotecan/Cisplatin  Irino/Cis/RT  Surgery – Phase II 80302, serial PET scan ECOG: Irinotecan/Cis vs Paclitaxel/Cis + RT  surgery – Path CR’s 15% – Adenocarcinoma RTOG 04026: Paclitaxel, Cisplatin, RT + / - Cetuximab SWOG S0-356: Oxaliplatin + 5-FU + XRT: preop U.K.: MAGIC 2 Trial: Pre and post ECF + / - Bevacizumab, without RT

40. The Future? Better ID of patients achieving path CR: Surgery PET Scan: early response at 2-6 weeks during induction chemo is prognostic for improved survival – Treatment failures referred for surgery (MUNICON) – Failures change chemotherapy during subsequent RT Targeted agents: – Cetuximab: RTOG 04026, Chemort + / - Cetuximab – Bevacizumab: MAGIC 2, ECX + / - Bevacizumab Pharmacogenetics: chemo target polymorphisms (TS, ERCC-1) Pharmacogenomics: patient drug metabolism DNA Array