Preoperative CROSS is the Preferred Treatment for Locally Advanced GEJ ISGIO November 1, 2018
Disclosures • Consulting: EMD Serono, Eli Lilly, FlatIron. • Research Funding: Taiho, EMD Serono.
Upper GI Tumor Classification and Staging 4 AJCC versions in 15 years - different • definitions! • Siewert Classification – Type I: center 1-5 cm proximal to GEJ – Type II: center 1 cm proximal to and 2 cm distal to the GEJ – Type III: center 2-5 cm distal to the GEJ with some involvement of GEJ. • Per AJCC 8 th edition Staging: – Siewert I-II considered esophageal cancers – Siewert type III lesions are considered gastric cancers
Gastroesophageal Tumor Molecular Subtypes 164 esophageal tumors, 359 gastric adenocarcinomas and 36 additional adenocarcinomas at the GEJ Nature 2017: 541 , 169–175
Approach to Locoregional GEJ Adenocarcinoma • Treatments are with curative intent. • Surgical resection alone is insufficient –> multimodality approach is the standard of care. • R0 resection is critical. • Completion of planned perioperative therapy is critical. • Pathological complete response is associated with the best outcomes.
Prognostic Value of Pathologic Response • Analysis of 480 patients , 54% E/GEJ, 46 % G • Analysis of 824 patients, 72% E/GEJ, 28% G • Preoperative chemotherapy • Preoperative chemotherapy • OS 128.6 mo with TRG1 vs. 61.9 mo with TRG2 • OS 92.2 mo TRG 1 vs. 27.9 mo TRG 3 and 40.1 mo with TRG3 Schmidt et al, Brit J of Cancer 2014 (110): 1712-1720 Becker et al, Annals of Surgery 2011 (253): 934-939
Rationale for Preoperative Chemoradiation • R0 resections are difficult to achieve. • Downsize the tumor à increase rates of R0 resection. • Downstage the tumor à increase pathological CR rates. • Preoperative therapies are better tolerated than post-operative treatments. Radiation field is smaller and more accurate.
CROSS Trial Design Neoadjuvant CRT: Carboplatin AUC2 Esophagectomy Paclitaxel 50 mg/m 2 XRT 41.4 Gy § Esophageal cancer (SCC R or adenocarcinoma) § cT1N1M0 or cT2-3N0-1M0 1:1 § N=363 1° Endpoint: OS Esophagectomy • 26% GEJ tumors • 75% adenocarcinoma Van Hagen, et al., NEJM 2012; 366: 2074-2084; Shapiro et al. Lancet Oncol. 2015;16(9):1090
CROSS Trial Results • R0 resection: 69 à 92% • Pathologic CR: 29%, for adeno 23% • Median OS: 24 mo à 49 mo Van Hagen, et al., NEJM 2012; 366: 2074-2084; Shapiro et al. Lancet Oncol. 2015;16(9):1090
Recurrence Patterns after CROSS ChemoXRT + Surgery Alone HR (95% CI) P value Surgery (N=188) (N=178) Locoregional 39 (22%) 72 (38%) 0.45 (0.30-0.66) < 0.0001 Progression Distant 70 (39%) 90 (48%) 0.63 (0.46-0.87) 0.0040 Progression Overall 87 (49%) 124 (66%) 0.58 (0.44-0.76) < 0.0001 Progression Shapiro et al. Lancet Oncol. 2015;16(9):1090
POET: Preoperative Chemotherapy vs. Chemotherapy + CRT in GEJ Adenocarcinoma • The only phase 3 trial comparing 2 modalities. • N=126, adeno of lower esophagus and cardia. • Siewert I-III, cT3-4. No Siewert 3 actually enrolled. • Study did not complete accrual. • ARM A (N=59): Weekly 5FU/cis x 15 à resection • ARM B (N=60): Weekly 5FU/cis x 12 à CRT 30Gy (cis/etop) à resection Stahl et al, Journal of Clinical Oncology 2009; 27: 851=856.
POET: Preoperative Chemotherapy vs. Chemotherapy + CRT in GEJ Adenocarcinoma CHEMO + CRT CHEMO pCR 14.4% 1.9% OS 30.8 mo 21 mo R1 resection 4.1 % 15.4 % Locoregional 18% (p 0.04) 38% Relapse Stahl et al, Journal of Clinical Oncology 2009; 27: 851=856; Stahl et al, Euro Journ of Cancer 2017; 81:183=190
Meta-Analysis: Preop CRT vs. Chemo 17 trials, 4188 patients. Pooled analysis from 17 trials. Clear advantage of either modality could not be established. Sjoquist et al, Lancet Oncology 2011; 12: 681-92
Recent Neoadjuvant Trials for E/GEJ Tumors Trial Regimen N Rate R0, % Path CR,% 3 yr OS Rate, % OEO5 (E+GEJ) CF x 2 451 59 1 39 ECX x 4 446 66 7 42 STO3 (64% E/GEJ) ECX x 3 533 64 8 50.3 ECX+ bev x3 530 61 11 48.1 FLOT4 (52% GEJ) ECX 360 74 6 48 FLOT 356 85 16 57 POET (GEJ) 5-FU/Cis 52 41 1.9 26.1 5-FU/Cis +CRT 49 88 14.3 47 CROSS (E+GEJ) No preop 188 69 N/A 44 CRT 178 92 29 58 Alderson, D et al, Lancet Oncol 2017; 18: 1249–60; Cunningham et a, Lancet Oncology 2017; 18:357-70; Al-Batran et al, JCO 35, no. 15_suppl (May 20 2017) 4004-4004; Stahl et al, European Journ Cancer 2017; 81:183-190; Shapiro et al. Lancet Oncol. 2015;16(9):1090
STO3: R0 Resection by Location Total # of Primary Site R0, % Resections Esophageal 116 66% Siewert, I 102 61% Siewert, II 148 72% Siewert, III 157 75% Gastric 304 87% Cunningham et a, Lancet Oncology 2017; 18:357-70
Ongoing Clinical Trials Trial Cohorts Treatments Study # ECF(X) x 3 à Surgery à ECF(X) x 3 G/GEJ; T3/4 or LN+ TOPGEAR NCT01924819 (N=752) ECF(X) x 2 à CRT 45Gy + CF(X) à Surgery à ECF(X) x 3 CROSS CRT à Surgery cT2-3, N0-1 E/GEJ NEO-AEGIS NCT01726452 (N=366) ECX à Surgery à ECX CROSS CRT à Surgery cN+, cT2-4a, E/GEJ ESOPEC NCT02509286 (N=438) FLOT à Surgery à FLOT
What Is the Best Approach to Resectable GEJ Tumors? • It is not a question of CROSS or not. • Chemoradiation has a role in management of these tumors. • The question remains how to augment CROSS to improve patient outcomes: • Induction Chemotherapy? • Immunotherapy? • Targeted agents? • Radiation changes?
Avelumab With Chemoradiation for Stage II/III Resectable Esophageal/GEJ Cancer (NCT03490292) PRE-OP ADJUVANT CHEMORADIATION Stage II/III SURGICAL AVELUMAB AVELUMAB Esophageal RESECTION 23 fractions, total 41.5 Gy Cancer Carboplatin/Paclitaxel, IV Q14D IV Q14D x 6 Day 80-100. (including GEJ) Days 1, 8, 15, 22, 29. Days 29, 43, 57. Start ≤ 12 wks. Run-In Phase: N=6 1° Endpoint Part 1: Safety and Tolerability Expansion Cohort: N=18 2° Endpoint Part 2: Path CR rate
Conclusions • Stage II/III GEJ adenocarcinoma is treated with curative attempt, but recurrence rates remain unacceptably high. • Multimodality approach is the mainstay of treatment. • Neoadjuvant CRT improves R0 resection and path CR rates. • Distant recurrences are a big concern. • Randomized data comparing neoadjuvant CRT to chemotherapy are lacking, but trials are ongoing. • Novel approaches are needed to improve current treatment strategies.
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