A BALANCED APPROACH TO THE TREATMENT OF ESOPHAGEAL CANCER

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)

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

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

With a Balanced Approach to Rx, Is There a Role for Surgery AfterPreop Chemotherapyfor Esophageal Cancer?

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

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

With a Balanced Approach to Rx, Is There a Role for Surgery AfterPreop Chemoradiotherapyfor Esophageal Cancer?

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……

RTOG Week FU 1000 mg/m2 x 4 d  CDDP 75 mg/m2 d 1  RT 50 Gy RT 64 Gy

RTOG RTChemoRT # Pts6261 % 5-year028 Survival % Local6647 Failure JAMA 1999

INT 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 Gy 5-FU/CDDP X Gy

INT 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

INT First Failure (%) 64.8 Gy50.4 Gy # Total LR LR persistence LR failure Distant failure 10 15

En Bloc Esophagectomy Altorki and Skinner Ann Surg patients (10% had preop therapy) Mortality (%):5 Local Fail (%):8 #Group5-Yr Surv (%) 111Total40 44LN-75 67LN+26

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

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)

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.

Preop CMT Meta-analysis Am J Surg trials, 1116 pts Preop CMT vs. Surgery 3-Yr Survival (odds ratio) - all patients2.50 (p=0.038) - concurrent CMT0.45 (p=0.005)

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

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

INT 0116 Adjuvant Gastric Trial 3-YrLocalGrade IV SurvFailToxicity Surgery30%**29%32% RT/Chemo40%19%41%

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

Stahl, M. et al. J Clin Oncol; 23: 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)

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

Stahl, M. et al. J Clin Oncol; 23: 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)

FFCD 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%)

Bedenne, L. et al. J Clin Oncol; 25: 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)

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

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?

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

Does pCR Predict Outcome? Rohatgi et al, MDACC, Cancer 2005, 2006 ● 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) 69Yes No 34 p = 0.002

Does Post-CMT Biopsy Predict pCR? Yang et al, MDACC, Dis Eso 2004 ● 65 pts, GE junction ● Gy + 5-FU based CT ● Post-treatment Bx within 30 days before surgery #Biopsy% pCR 52negative33 13positive7 p = 0.44

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

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

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 = ) 18-FDG-PET(p = 0.015)

Planned vs. Salvage Surgery Swisher et al, MDACC J ThoracCardiovasc Surg 2002 ● retrospective review ● <2% ofesophagectomies at MDACC were for salvage % Cervical% Op% 5-Yr #AnastomosisMortalitySurvival Planned Salvage

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

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)

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

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

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