1. A BALANCED APPROACH TO THE TREATMENT OF ESOPHAGEAL CANCER

4. DEFINITIONS ● PREOPERATIVE THERAPY = INDUCTION THERAPY = NEO ADJUVANT THERAPY ● POSTOPERATIVE THERAPY = ADJUVANT THERAPY ● COMBINED MODALITY = > 1 TREATMENT MODALITY -i.e. a bi-modality approach: -preop chemotherapy followed by surgery -i.e. a tri-modality approach: -initial surgery followed by postop (adjuvant) chemoradiotherapy; or other multimodality combinations)

5. SUMMARY ● SURGERY + ADDITIONAL MODALITY IS REQUIRED FOR pT3 N1 TUMORS ● DEFINITIVE CHEMORADIOTHERAPY FOR SCCA IS AN ACCEPTABLE STANDARD ● PREOP (Neoadjuvant) & POSTOP (Adjuvant) COMBINATION CHEMOTHERAPY FOR RESECTABLE ESOPHAGUS or GEJ ADENOCA IS AN ACCEPTABLE APPROACH

6. SUMMARY ● PRE-OP (Neoadj) CONCOMITANT CHEMO-RADIOTHERAPY FOR RESECTABLE ADENOCA OF ESOPHAGUS OR GEJ IS A DE-FACTO ACCEPTABLE STANDARD FOR ● ROLE OF PREOP CHEMOTHERAPY (WITHOUT XRT) FOR RESECTABLE SCCA IS POORLY DEFINED AND NOT RECOMMENDED ● EARLY RESPONSE TO FDG-PET MAY PREDICT RESPONSE FROM PREOP THERAPY

7. With a Balanced Approach to Rx, Is There a Role for Surgery After Preop Chemotherapy for Esophageal Cancer?

8. Preop (Induction or Neoadjv) Chemotherapy  Surgery Series Histology Rx regimen # pts Med Surv OS RTOG8911 SCCA Preop/Postop 213 15 mos 20% INT-0113 Adenoca-54% Cisplatin/5FU (5-yr) Kelsen Surgery alone 227 16 mos 20% MRC SCCA Preop 400 17 mos 43% Adenoca-66% Cisplatin/5FU (2-yr) Surgery alone 402 13 mos 34% MAGIC Adenoca Preop/Postop 253 24 mos 36% Cunningham Epirub/Cis/5FU (5-yr) Surgery alone 250 20 mos23% France Adenoca Preop/Postop 113 NS 38% Boige Cisplatin/5FU (5-yr) Surgery alone 111 NS 24%

9. META-ANALYSIS OF PREOP CHEMOTHERAPY (Thirion et al, ASCO 2007) ● 4% BENEFIT WITH PREOP CHEMOTHERAPY @ 5 YRS ● 7% SURVIVAL BENEFIT FOR ADENOCA WITH PREOP CHEMOTHERAPY ● 4% SURVIVAL BENEFIT FOR SCCA WITH PREOP CHEMOTHERAPY

10. With a Balanced Approach to Rx, Is There a Role for Surgery After Preop Chemoradiotherapy for Esophageal Cancer?

11. Questions ● What is the standard of care? ● Is more (intensification) better ? ● Does a ny approach (pre/postop CMT) help? ● Can we identify responders preop? ● Lastly, what do you do when……

12. RTOG 85-01 Week 1 5 8 11 5-FU 1000 mg/m2 x 4 d  CDDP 75 mg/m2 d 1  RT 50 Gy RT 64 Gy

13. RTOG 85-01 RTChemoRT # Pts 62 61 % 5-year 0 28 Survival % Local 66 47 Failure JAMA 1999

14. INT 0123 - Schema 5-FU/CDDP X 4 + 64.8 Gy 5-FU/CDDP X 4 + 50.4 Gy S T R A T I F Y Weight loss > or < 10% Tumor size < or > 5 cm Histology Adeno Squamous R A N D O M I Z E

15. INT 0123 64.8 Gy 50.4 Gy MEDIAN 2-YR 50.4 Gy 17.6 M 38% 64.8 Gy 12.9 M 29% p=0.14 (log-rank) 50.4 Gy 64.8 Gy 109 107 59 42 24 17 6 6

16. INT 0123 - First Failure (%) 64.8 Gy50.4 Gy # 107 109 Total LR 61 60 LR persistence 44 42 LR failure 17 18 Distant failure 10 15

17. En Bloc Esophagectomy Altorki and Skinner Ann Surg 2001 • 111 patients (10% had preop therapy) • Mortality (%): 5 • Local Fail (%): 8 #Group5-Yr Surv (%) 111 Total 40 44 LN- 75 67 LN+ 26

18. Surgeryvs. CMT Surgery CMT (INT 0133)(RTOG 85-01) Median survival 18 months 14 months 5-year survival 20% 27% Rx-related death 6% 2% Local Failure 31% + 30%* 45% * 30% had R1-2 resection

19. Does Preop CMT Improve Surgery? CALGB 9781 Accrual goal: 500 pts Entered: 56 pts, stages I-III Median F/U: 6 Yr % Survival #ArmMedian5-Yr 30 Preop 4.5 M 39 26 Surg 1.8 M 16 (p = 0.02) (p = 0.005)

20. Preop CMT Randomized Trials TRIAL SURVIVALCOMMENTS U Michigan No 15% not S.S. Walsh Yes 6% survival for surgery EORTC No (+DFS) Unconventional design Australasian No Only 35 Gy Seoul No - CALGB 9781 Yes 56/500 pts.

21. Preop CMT Meta-analysis Am J Surg 2002 • 9 trials, 1116 pts • Preop CMT vs. Surgery • 3-Yr Survival (odds ratio) - all patients 2.50 (p=0.038) - concurrent CMT 0.45 (p=0.005)

22. With a Balanced Approach to Rx, Is There a Role for Adjuvant Treatment Following Surgery for Esophageal Cancer?

23. Does Postop CMT Improve Surgery? T3 and/or N1-2 (85%) 5-FU/LV x 4 + 45 Gy Surgery alone INT 0116, NEJM 2001 • 603 entered, 556 eligible • Stages IB- IV (non-M1) • 20% GE Junction

24. INT 0116 Adjuvant Gastric Trial 3-Yr Local Grade IV SurvFail Toxicity Surgery 30%** 29% 32% RT/Chemo 40% 19% 41%

25. German Oesophageal Cancer Study Group 172 pts SCC FU/LV/VP16/ VP16/CDDP CDDP X 3 40 Gy Surg FU/LV/VP16/ VP16/CDDP CDDP x 3 T4 or T3 obst : 65 Gy T3 : 60Gy + 4 Gy brachy Stahl et al JCO 2005

26. Stahl, M. et al. J Clin Oncol; 23:2310-2317 2005 Fig 3. Kaplan-Meier plots showing (A) overall survival from the date of randomization among patients allocated to preoperative chemoradiation and surgery (arm A, n = 86) or chemoradiation without surgery (arm B, n = 86) and (B) survival as randomized among patients treated according to their treatment arm excluding cross-over patients (arm A, n = 75; arm B, n = 81)

27. German Oesophageal Cancer Study Group (%)Preop CT  CT-RT  OR Defin. Preop CT  CT-RT pCR 33% - Mortality 13 4 (p=0.03) 2-yr LF 36 58 (p=0.003) Med Surv 16 m 15 m 3-Yr Surv 31 24 Stahl et al JCO 2005

28. Stahl, M. et al. J Clin Oncol; 23:2310-2317 2005 Fig 4. Kaplan-Meier plots showing the freedom from locoregional progression among patients allocated to preoperative chemoradiation and surgery (arm A) or chemoradiation without surgery (arm B)

29. FFCD 9102 • 445 pts (cT3 N0-1) SCCA: Pre-op (Neoadjuvant or Induction) 5-FU/CDDP/RT x 2 (46 Gy or 30 Gy split course) Surgery • 259 pts > PR 5-FU/CDDP/RT x 2 x 3 (20 Gy or 15 Gy split course) • Median (18 vs. 19 m) and 2-yr surv (34% vs. 40%)

30. Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007 Fig 3. Overall survival of the patients with esophageal cancer responding to induction chemoradiation who were randomly assigned to either surgery (arm A) or continuation of chemoradiation (arm B)

31. Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007 Fig 1. Treatment Design of the Federation Francophone de Cancerologie Digestive 9102 trial

32. FFCD 9102 ● 9% operative mortality (1% with CMT) ● Only responders were randomized ● Bias against surgery: it may be most helpful in pts. with residual disease ● Does pCR predict outcome and c an responders be accurately identified?

33. Does pCR Predict Outcome? Berger et al, FCCC, JCO 2005 ● 131 pts (78% adeno) ● Preop 45 Gy + 5-FU based CT ● 14 months median F/U Downstaging#%5-Yr Surv None 76 15 Stage I 13 34 pCR 42 48 p=0.02 p=0.015

34. Does pCR Predict Outcome? Rohatgi et al, MDACC, Cancer 2005, 2006 ● 45-50.4 Gy + CT (+/- induction), 86% Adeno ● 69/235 (29%) had pCR ● pCR Adeno vs. SCC: 29% vs 31% ● Median F/U 37 M Median #pCRSurv (m) 69 Yes 133 166 No 34 p = 0.002

35. Does Post-CMT Biopsy Predict pCR? Yang et al, MDACC, Dis Eso 2004 ● 65 pts, GE junction ● 40-45 Gy + 5-FU based CT ● Post-treatment Bx within 30 days before surgery #Biopsy% pCR 52 negative 33 13 positive 7 p = 0.44

36. Does Post-CMT EUS Predict pCR? Kalha et al, MDACC, Cancer 2004 ● 83 pts. with adenocarcinoma ● T stage: 29% accurate ● N stage: 50% accurate ● 22 had EUS+ but had pCR at surgery

37. Does Post-CMT PET Predict Response? MSKCC (Downey)Leuven (Flamen) • 40 Pts • 38 Pts • 20% undetected M1 •  SUV  Path • 23 restaged after CMT > 80% 78% •  SUV  Path > 65% 100% ● Major resp: 16 vs. < 65% 30% 6 m median surv

38. Does Post-CMT PET Predict Survival? Br ϋ cher et al, 2006 GI ● 105 pts, SCC ● Preop CMT restage 3-4 wks surgery ● MVA + for survival Pathology (p = 0.0001) 18-FDG-PET (p = 0.015)

39. Planned vs. Salvage Surgery Swisher et al, MDACC J ThoracCardiovasc Surg 2002 ● 1987-2000 retrospective review ● <2% of esophagectomies at MDACC were for salvage % Cervical % Op % 5-Yr #AnastomosisMortalitySurvival Planned 99 37 6 25 Salvage 13 61 15 25

40. RTOG 0241 – Phase II Taxol/CDDP/5-FU/50.4 Gy (RTOG E-0113) “ Selective” surgery ● At least T1N0, all histologies ● Accrual 31/42 patients

41. Do Markers Predict Outcome After CMT? ● COX-2 mRNA (Xi, Clin Cancer Res, 2005) ● Microvessel Density (Hironaka, Clin Cancer Res 2002) ● p53, CDC25B, MT (Kishi, Br J Surg 2003) ● Serum proteomic spectra (Hayashida, Clin Cancer Res 2005)

42. CMT +/- Surgery: New Regimens ● Taxol/CDDP RTOG ● Irinotecan/CDDP MSKCC, CALGB ● Irinotecan/CDDP platform + - Bevacizumab MSKCC - Cetuximab DFCI ● Irinotecan/CDDP vs. Taxol/CDDP ECOG ● Oxaliplatin/5-FU SWOG, ACOSOG

43. Minsky’s Answers ● ChemoRT or surgery is standard – 25% 5-yr survival ● Advantage of trimodality therapy is 5-10% ● If T2-4N+: CMT then restage with PET, CT, EUS, Bx ● Squamous Cell: - cCR by all criteria observe - non-responding or any residual surgery ● Adenocarcinoma: less data but surgery for all ● Improve imaging/markers to identify pCR and new CMT

45. ACKNOWLEDGMENTS ● BA JOBE ● JG HUNTER ● L LEICHMEN ● BD MINSKY ● XX