What is the optimal pre-op therapy for esophagus and GE junction cancers? Michael G. Haddock M.D. Mayo Clinic Rochester, MN

Esophageal and GEJ Cancer CT  S or CT/RT  S

Proposition Chemoradiation is preferred over chemotherapy alone as preop therapy for esophageal and GE junction cancers

Assumptions Stage: T2-4, N0 or N+, M0 Performance status 0-1 Good candidate for surgery medically Surgery is indicated Locoregional control is important Can’t cure patient unless locoregional disease is eliminated

What is the evidence for preop chemoradiation as a strategy?

Esophageal Cancer: Preop RT + CT Dublin Trial 113 pts, all ACA surgical resection alone 40 Gy / 15 fractions 5FU, 15 mg/kg/day x 5 d, weeks 1,6 surgery CDDP, 75 mg/m2 weeks 1,6 R Walsh, NEJM 335:462-467, 1996.

Esophageal Cancer: Preop RT + CT Dublin Trial Results hospital median 3 yr 5 yr treatment mortality survival S S* surgery alone (55) 4% 12 mo. 6% 5% preop RT/CT (58) 9% 17 mo. 32% 29% p = 0.01 *crude survival, all patients followed > 5 yrs Walsh, NEJM 335:462-467, 1996 and Dis Esophagus 15:121-124, 2002

Esophageal Cancer: Preop RT + CT Dublin Trial Results Survival (%) Multimodal therapy (n=58) Surgery alone (n=55) Months Walsh et al: NEJM 335:465, 1996

Esophageal Cancer: Preop RT + CT CALGB C-9781 500 pts/ 5 yrs SQC or ACA T1-3 NxM0 Resectable Not more than 2 cm into cardia surgery alone 5-FU + CDDP + 50.4 Gy R followed by surgery Closed Early (56 pts) due to poor accrual Tepper, JCO 2008;26:1086-1092

CALGB 9781 Overall survival (%) Years from study entry P<0.008 Trimodality (30) Surgery (26) Years from study entry Adapted from Krasna et al: ASCO GI Symposium, 2006 Original: www.asco.org

TROG Phase III trial Preop CT/RT vs S alone Med S LRR Surgery 19 mo 40% 35 Gy/15 CDDP  S 22 mo 21% 5-FU 257 pts T1-3N0-1 37% SQC R Burmeister, Lancet Oncology 2005; 6:659-68

Adapted from Burmeister, Lancet Oncology 2005; 6:659-68

Adapted from Burmeister, Lancet Oncology 2005; 6:659-68

FFCD 9901 Preop CT/RT vs S alone 195 pts 30 centers 9 years SQC 137 ACA 57 3-yr S 5-yr S Hosp. mort. Surgery 53% 34% 3.4% 45 Gy CDDP S 48% 41% 11.1% 5-FU R P = 0.94 P = .05 Mariette, JCO 32:2416-2427, 2014

FFCD 9901 Preop CT/RT vs S alone 195 pts 30 centers 9 years SQC 137 ACA 57 LRR DM Surgery 29% 29% 45 Gy CDDP S 15% 23% 5-FU R P = .02 P = .31 Mariette, JCO 32:2416-2427, 2014

Kaplan-Meier estimates of overall survival by treatment arm measured from study entry to death resulting from any cause. Mariette C et al. JCO 2014;32:2416-2422 ©2014 by American Society of Clinical Oncology

CROSS Phase III trial Preop CT/RT vs S alone Med S 5-yr S Surgery 24 mos 34% 41.4 Gy CBDCA S 49 mos 47% paclitaxel 366 pts T2-3N0-1 84 SQC 275 ACA R P = 0.003 pCR 23% ACA 49% SQC Hospital mortality 4% in both arms Van Hagen, N Eng J Med 2012;366:2074-84

CROSS Phase III trial Preop CT/RT vs S alone Adapted from Van Hagen, N Eng J Med 2012;366:2074-84

CROSS Phase III trial Preop CT/RT vs S alone Adapted from Van Hagen, N Eng J Med 2012;366:2074-84

CROSS Phase III trial Preop CT/RT vs S alone LRR peritoneal heme mets Surgery 34% 14% 35% 41.4 Gy Carbo S 14%* 4% 29% paclitaxel 374 pts T2-3N0-1 90 SQC 282 ACA R P < .001 P < .001 P = .025 *Relapse in RT fields: 5% V. Oppedijk, JCO 2014;32:385-391

Preoperative Chemoradiation Summary Study LR Control Benefit Survival Benefit Walsh Not reported Yes CALGB 9781 TROG Yes, in SQC FFCD 9901 Not significant CROSS

What is the evidence for preop chemotherapy without radiation as a strategy?

Esophageal Cancer: Neoadjuvant Chemo MRC-OE02 802 pts, resectable SQC (247) ACA (533) Med S 2 yr S 5-FU Surgery 17 mo 43% CDDP Surgery 13.5 mo 34% R P = 0.004 Preoperative radiotherapy allowed (9%), same on both arms MRC Lancet 359:1727-33, 2002

MRC-OE02 Survival (%) Years CS P=0.004 S Pt at risk (events) Adapted from MRC Lancet 359:1727-33, 2002

Esophageal Cancer Neoadjuvant Chemo: INT 0113, RTOG 8911 Med S 2 yr S LF 16.1 mo 38% 27% 16.8 mo 40% 29%* Preop* CDDP 5-FU x3 Surgery R 443 pts 207 SQC 236 ACA *1.5% neutropenic sepsis deaths *29% LF in R0, 41% in R1 Kelsen, NEJM339:1979, 1998

Esophageal Cancer Neoadjuvant Chemo: INT 0113, RTOG 8911 Overall survival (%) Surgery (n=234) Chemotherapy plus surgery (n=233) Years No. of patients at risk Chemotherapy surgery 136 73 42 28 15 Surgery 138 81 45 27 16

Chemotherapy compared to Chemoradiotherapy?

Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) T3-4 GE junction ACA Arm A PLF I PLF II PLF III (3 weeks) Surgery Week 1 6 7 13 14 17 20-21 PLF I PLF II 15 x 2 Gy in 3 weeks Surgery PE (1 week) Arm B PLF: Cisplatin 50mg/m2, 1h, d 1, 15, 29. Leukovorin/5-FU 500 mg/m2 d 1, 8, 15, 22, 29, 36 PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5 Stahl, JCO 27:851, 2009

Phase III Study of Preoperative ChemoRT or Chemo in GE Junction ACA (POET) T3-4 GE junction ACA Endpoint CT alone CT + RT pCR 2% 16% ypN0 38% 64% 3-yr Survival 28% 47% Stahl, JCO 27:851, 2009

Adapted from Stahl, JCO 27:851, 2009

Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) Overall Survival Strata 5FU/CDDP  S (2% pCR) CTCDDP/etop/ 30 Gy/15S (16% pCR) Survival Arm B (60) P=0.07 Arm A (59) Years Adapted from Stahl, JCO 27:851, 2009

Survival distribution function Phase III Study of Preoperative ChemoRT or Chemo in GE Junction Adenocarcinoma (POET) Freedom from Local Tumor Progression Strata Randomized Arm A Censored randomized Arm A Randomized Arm B Censored randomized Arm B Survival distribution function Arm B Arm A P=0.06 Years Adapted from Stahl, JCO 27:851, 2009

Esophageal Cancer Locoregional Relapse Phase III trial results Surgery alone CT  Surgery CT/RT  Surgery FNCLCC/FFCD 26% 24% INT 0113 29% 27% OE02 23% TROG 40% 21% FFCD 9901 15% CROSS 36% 14% POET 41%

Australian Meta-Analysis Chemotherapy and RT vs Surgery Alone Study Nygaard Apinop LePrise Bosset Urba Walsh Burmeister Lee All (published) Tepper All 0.2 0.5 1 2 5 Favors chemoradiotherapy surgery alone Val Gebski et al: Lancet Oncol 8:226, 2007 CP1320703-1

Australian Meta-Analysis Chemotherapy vs Surgery Alone Study Roth Nygaard Maipang Schlag Law Kelsen Ancona MRC All 0.2 0.5 1 2 5 Favors chemotherapy Favors surgery alone Val Gebski et al: Lancet Oncol 8:226, 2007 CP1320703-2

Australian Meta-Analysis Hazard ratio for all cause mortality for preoperative chemoRT was 0.81 (P = 0.002) Hazard ratio for all cause mortality for preoperative chemotherapy was 0.90 (P = 0.05) Val Gebski, et al. Lancet Oncol 8:226-34, 2007

Australian Meta-Analysis Update Compared 12 CT/RT trials and 7 CT trials All cause mortality HR for CT/RT vs. CT alone: 0.88 (p= 0.07) Sjoquist, Lancet Oncol 12:681-92, 2011

Preop CT/RT for Esophageal Ca Conclusions 5 Phase III trials show benefit in S or LC or both compared to S alone CT alone trials mixed results CT/RT better than CT in direct comparison (POET) Meta-analysis suggests CT/RT better than CT alone