1. A BALANCED APPROACH TO THE TREATMENT OF ESOPHAGEAL CANCER

4. DEFINITIONS ●PREOPERATIVE THERAPY = INDUCTION THERAPY = NEOADJUVANT 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 AfterPreop Chemotherapyfor Esophageal Cancer?

8. Preop (Induction or Neoadjv) Chemotherapy  Surgery SeriesHistologyRx regimen# ptsMed Surv OS RTOG8911SCCAPreop/Postop 21315 mos20% INT-0113Adenoca-54% Cisplatin/5FU(5- yr) KelsenSurgery alone22716 mos20% MRCSCCAPreop 40017 mos43% Adenoca-66%Cisplatin/5FU(2-yr) Surgery alone40213 mos34% MAGICAdenocaPreop/Postop 25324 mos36% Cunningham Epirub/Cis/5FU(5- yr) Surgery alone25020 mos23% FranceAdenocaPreop/Postop 113NS38% Boige Cisplatin/5FU(5-yr) Surgery alone111NS24%

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 AfterPreop Chemoradiotherapyfor Esophageal Cancer?

11. Questions ● What is the standard of care? ● Is more (intensification) better? ● Does any 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 # Pts6261 % 5-year028 Survival % Local6647 Failure JAMA 1999

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

15. INT 0123 64.8 Gy 50.4 Gy MEDIAN2-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 (%) 111Total40 44LN-75 67LN+26

18. Surgeryvs. CMT SurgeryCMT (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 30Preop4.5 M39 26Surg1.8 M16 (p = 0.02)(p = 0.005)

20. Preop CMT Randomized Trials TRIALSURVIVALCOMMENTS U MichiganNo15% not S.S. WalshYes6% survival for surgery EORTCNo (+DFS)Unconventional design AustralasianNoOnly 35 Gy SeoulNo- CALGB 9781Yes56/500 pts.

21. Preop CMT Meta-analysis Am J Surg 2002 9 trials, 1116 pts Preop CMT vs. Surgery 3-Yr Survival (odds ratio) - all patients2.50 (p=0.038) - concurrent CMT0.45 (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-YrLocalGrade IV SurvFailToxicity Surgery30%**29%32% RT/Chemo40%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  ORDefin. Preop CT  CT-RT pCR33%- Mortality134 (p=0.03) 2-yr LF3658 (p=0.003) Med Surv16 m15 m 3-Yr Surv3124 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 can 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 None7615 Stage I1334 pCR4248 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) 69Yes133 166No 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 52negative33 13positive7 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? Brϋcher 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% ofesophagectomies at MDACC were for salvage % Cervical% Op% 5-Yr #AnastomosisMortalitySurvival Planned9937625 Salvage13611525

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 oftrimodality 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