Preoperative CROSS is the Preferred Treatment for Locally Advanced - - PowerPoint PPT Presentation

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 8th edition Staging:

– Siewert I-II considered esophageal cancers – Siewert type III lesions are considered gastric cancers

Gastroesophageal Tumor Molecular Subtypes

Nature 2017: 541, 169–175

164 esophageal tumors, 359 gastric adenocarcinomas and 36 additional adenocarcinomas at the GEJ

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
• utcomes.

Prognostic Value of Pathologic Response

• Analysis of 824 patients, 72% E/GEJ, 28% G
• Preoperative chemotherapy
• OS 92.2 mo TRG 1 vs. 27.9 mo TRG 3

Schmidt et al, Brit J of Cancer 2014 (110): 1712-1720

• Analysis of 480 patients , 54% E/GEJ, 46 % G
• Preoperative chemotherapy
• OS 128.6 mo with TRG1 vs. 61.9 mo with TRG2

and 40.1 mo with TRG3

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 Paclitaxel 50 mg/m2 XRT 41.4 Gy

Esophagectomy

§ Esophageal cancer (SCC

• r adenocarcinoma)

§ cT1N1M0 or cT2-3N0-1M0 § N=363

R

1:1

1° Endpoint: OS

Esophagectomy

Van Hagen, et al., NEJM 2012; 366: 2074-2084; Shapiro et al. Lancet Oncol. 2015;16(9):1090

• 26% GEJ tumors
• 75% adenocarcinoma

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

(N=178)

Surgery Alone

(N=188)

HR (95% CI) P value Locoregional Progression 39 (22%) 72 (38%) 0.45 (0.30-0.66) < 0.0001 Distant Progression 70 (39%) 90 (48%) 0.63 (0.46-0.87) 0.0040 Overall Progression 87 (49%) 124 (66%) 0.58 (0.44-0.76) < 0.0001

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 Relapse 18% (p 0.04) 38% 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

Primary Site Total # of Resections R0, % 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 #

TOPGEAR

G/GEJ; T3/4 or LN+ (N=752) ECF(X) x 3 à Surgery à ECF(X) x 3 NCT01924819 ECF(X) x 2 à CRT 45Gy + CF(X) à Surgery à ECF(X) x 3

NEO-AEGIS

cT2-3, N0-1 E/GEJ (N=366) CROSS CRT à Surgery NCT01726452 ECX à Surgery à ECX

ESOPEC

cN+, cT2-4a, E/GEJ (N=438) CROSS CRT à Surgery NCT02509286 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 AVELUMAB

IV Q14D Days 29, 43, 57.

CHEMORADIATION

23 fractions, total 41.5 Gy Carboplatin/Paclitaxel, Days 1, 8, 15, 22, 29.

SURGICAL RESECTION

Day 80-100.

ADJUVANT AVELUMAB

IV Q14D x 6 Start ≤ 12 wks.

Stage II/III Esophageal Cancer (including GEJ)

Run-In Phase: N=6 Expansion Cohort: N=18 1° Endpoint Part 1: Safety and Tolerability 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.