Esophageal and GEJ Adenocarcinoma: Chemo + RT is the Preferred Treatment

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1 Esophageal and GEJ Adenocarcinoma: Chemo + RT is the Preferred Treatment David H. Ilson, MD, PhD Gastrointestinal Oncology Service Memorial Sloan-Kettering Cancer Center

2 Preop Therapy in Esophageal and GEJ Adenocarcinoma What are the important endpoints? R0 resection Pathologic Response N0 status Local Failure

3 Esophageal and GEJ Adenocarcinoma: Neoadjuvant Therapy Survival with surgery alone: < 20-40% Preop Chemo Preop Chemo + radiotherapy Most common U.S. practice Both approaches achieve modest survival improvements over surgery alone 6% to 14% Why include RT? All important endpoints (R0, pcr, N0. local failure) favor Chemo + RT over Chemo alone

4 Contemporary Trials Trial Regimen Eso / GEJ R0 OEO5 ECX x % CF x 2 59% STO3 ECX + / - Bev % (61-75%) FLOT4 ECX %* *GEJ + Gastric FLOT %* POET CF 59 70% CF EP + RT 60 72% CROSS Surgery %** **AC + Squam Carb/Pac/RT %** Alderson Lancet Oncol 2017; Cunningham Lancet Oncol 2017; Al-Batran J Clin Oncol 2017 Van Hagen NEJM 2012; Stahl J Clin Oncol 2009

5 Margin Status with Preop ECF/X Depends on Location: STO3 Patients % R0 Total Resected 834 Esophageal % Type % Type % Type % Stomach % Eso/GEJ % Cunningham Lancet Oncol 2017

6 INT 113: Preop CF, Outcome by Resection Kelsen JCO 25: 3719; 2007

7 Salvage R1 Resection with Post Op Chemo + RT: Large post op RT field poorly tolerated

8 Is poorer outcome, low R0 with chemo due to bad biology? No TCGA % of Esophageal and GEJ Adenocarcinoma are Genomically Unstable Tumors Genomically similar to Gastric Cancer 50% of gastric cancers are genomically stable Only 20-30% or less are the more favorable MSI-H or EBV Likely fewer of these cases in Western series Gastric, GEJ, and Esophageal are genomically similar IT IS ANATOMY, NOT BIOLOGY and RT is NEEDED! Nature 24: 2903; 2014

9 Contemporary Trials Trial Regimen Eso / GEJ PCR OEO5 ECX x % CF x 2 1% STO3 ECX + / - Bev 680 9% FLOT4 ECX 201 6% Ph 2* FLOT % Ph 2* POET CF 59 2% CF EP + RT 60 16% *GEJ + Gastric CROSS Surgery 141 0% Carb/Pac/RT % Alderson Lancet Oncol 2017; Cunningham Lancet Oncol 2017; Al-Batran J Clin Oncol 2017 Van Hagen NEJM 2012; Stahl J Clin Oncol 2009

10 N0 Status at Surgery Trial Treatment N0 OEO5 CF 30% ECX 39% STO3 ECX NR ECX + Bev NR FLOT ECX 41% FLOT 49% CROSS Surgery 24%* Car/Pac/RT 64%* POET CF 37% CF + EP/RT 68% *GEJ + Gastric **AC + Squam *Includes squamous cancer Alderson Lancet Oncol 2017; Cunningham Lancet Oncol 2017; Al-Batran J Clin Oncol 2017 Van Hagen NEJM 2012; Stahl J Clin Oncol 2009

11 Importance of N0 Status and Pathologic Response Rates of pathologic response remain relatively low for Chemo or Chemo + RT N0 status at surgery is highly prognostic Smyth MAGIC trial: 340 resection specimens Improved OS in pcr (5%) or near pcr (18%) Multivariate analysis: only N0 status at surgery was independently prognostic of survival Pathologic response was not prognostic for OS In N0 pts, no difference in 5 yr OS in path responder pts (66%) vs non responder pts (72%) Smyth J Clin Oncol 34: 2721; 2016

12 Contemporary Trials: Local Failure Trial Regimen Eso or GEJ Adeno OEO5 CF vs ECX %-13% STO3 ECX +/- Bev 680 NR FLOT4 FLOT vs ECX 401 NR CROSS Chemo+ RT %* Surgery %* POET Chemo + RT 60 23% Chemo 59 41% Local Failure *includes squamous cancers Alderson Lancet Oncol 2017; Cunningham Lancet Oncol 2017; Al-Batran J Clin Oncol 2017 Van Hagen NEJM 2012; Stahl J Clin Oncol 2009

13 Contemporary Trials Trial Regimen Eso / GEJ 3 yr OS OEO5 ECX x % STO3 ECX + / - Bev CF x 2 39% %-50% FLOT4 ECX % FLOT % POET CF 59 28% CF EP + RT 60 47% CROSS Surgery % *GEJ + Gastric *GEJ + Gastric Car/Pac/ RT % Alderson Lancet Oncol 2017; Cunningham Lancet Oncol 2017; Al-Batran J Clin Oncol 2017 Van Hagen NEJM 2012; Stahl J Clin Oncol 2009

14 Esophageal Cancer: Neoadjuvant Therapy Why include RT? Potential higher R0 resection rate over chemo alone Potential higher rate of path CR Enhance N0 status at surgery May be more important than path response Reduce local recurrence FLOT is superior to CF or ECX in R0 and pcr rate

15 Results for Current Preop Therapy Trials Largest series (OEO5, STO3): concerning rates of R0 resection with preop chemo alone Chemo + RT: superior rate of R0 FLOT is superior to ECX: R0 Chemo + RT: higher rate of path CR and more patients N0 post chemo + RT Achievement of N0 may be more important than response FLOT is superior to ECX: pathologic response, N0 status

16 Ongoing Randomized Trials of Preop Chemo + / - RT ESOPEC (NCT ) FLOT vs CROSS, Eso and GEJ, 438 pts NEO-Aegis (NCT ) ECF/X, FLOT vs CROSS, Eso and GEJ, 366 pts TOPGEAR (NCT ) Perioperative ECF/X, FLOT + / - Preoperative RT GEJ and Gastric cancer, 752 pts

17 Esophageal and GEJ Adenocarcinoma: Preop Chemo + RT is favored over Chemo Neoadjuvant Therapy Chemo RT is a standard alternative FLOT is the new standard periop chemo Comparative studies pending R0 resection, pcr, N0 status Favor chemo + RT On the Horizon: new agents from metastatic disease trials, identify pathways, networks from genomic analysis