david h ilson md phd n.
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  1. David H. Ilson, MD, PhD The Role of Preoperative Approaches in Localized Gastro Esophageal Cancers 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 CancerUS 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 CancerMULTIMODALITY 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

  10. 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.)

  11. 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

  12. Primary End-point: Overall Survival

  13. 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

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

  15. 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

  16. Chemoradiotherapy Alone (5-FU/Cis/RT) or ChemoRT  Surgery: FFCD 9102 455 pts treated, 259 responders randomized: Non responders excluded. Bedenne et al JCO 25: 1160; 2007

  17. 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

  18. 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

  19. Preop ChemoRT: Phase III *1 of 4 trials positive

  20. Preop ChemoRT: Phase III *1 of 4 trials positive

  21. Preop ChemoRT: Phase III *1 of 4 trials positive

  22. CALGB 9781: Esophageal Cancer, Preop Chemo RT vs Surgery Alone Of 500 planned patients, 56 accrued R A N D O M I Z A T I O N Surgery N = 26 Cisplatin + 5-FU + RT + Surgery N= 30 Tepper JCO 24: Abs 4012, 181, 2006

  23. 9781 Survival by ArmP =0.0130

  24. 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)

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

  26. 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

  27. 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

  28. Preop Chemo vs Chemo RT: Meta Analysis Gebski et al, Lancet Oncol 8: 226-234; 2007

  29. 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

  30. 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

  31. 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