Localized Gastric / GEJ Adenocarcinoma: Neoadjuvant and Perioperative Therapy

Localized Gastric / GEJ Adenocarcinoma: Neoadjuvant and Perioperative Therapy: overview

This algorithm organizes treatment of localized (non-metastatic) gastric and gastroesophageal junction adenocarcinoma by clinical stage, mismatch repair status and tumor site. Workup includes endoscopic ultrasound, CT, and diagnostic laparoscopy with peritoneal washings for cT1b or deeper tumors, plus MSI/MMR, HER2, PD-L1 and CLDN18.2 testing at diagnosis.

Very early tumors (cT1a N0 meeting endoscopic criteria) can be removed by EMR or ESD, and cT1b N0 tumors go to gastrectomy with D2 lymphadenectomy first, with adjuvant chemotherapy if pathology shows nodal disease. For cT2 or higher or node-positive disease in a fit patient, perioperative FLOT is the chemotherapy backbone, supported by FLOT4, which improved overall survival over ECF/ECX; MATTERHORN added durvalumab to perioperative FLOT, followed by durvalumab maintenance, and improved event-free survival, making FLOT plus durvalumab the preferred option. Patients who cannot take a triplet receive a perioperative doublet (FOLFOX or CAPOX); MAGIC established the perioperative approach with ECF. MSI-H/dMMR tumors gain little from perioperative chemotherapy, and neoadjuvant checkpoint inhibitors (NEONIPIGA, INFINITY) are an option to discuss at tumor board.

For GEJ adenocarcinoma, ESOPEC showed better overall survival with perioperative FLOT than with CROSS chemoradiation; patients treated with CROSS who have residual disease at surgery receive adjuvant nivolumab for one year (CheckMate 577). When surgery was done first, pathologic stage II to III disease is treated with adjuvant CAPOX for six months (CLASSIC) or S-1 for one year (ACTS-GC), and adjuvant chemoradiation (INT-0116) is reserved for less than D2 dissection or R1 resection. Two strategies did not help: adding pembrolizumab to perioperative chemotherapy (KEYNOTE-585) and adding postoperative chemoradiation after perioperative chemotherapy (CRITICS).

Trials behind this algorithm

MATTERHORN Janjigian YY et al, NEJM, 2025; PMID: 40454643
FLOT4 Al-Batran SE et al, Lancet, 2019; PMID: 30982686
MAGIC Trial Cunningham D et al, N Engl J Med, 2006; PMID: 16822992
ESOPEC Hoeppner J et al, NEJM, 2025; PMID: 39842010
Checkmate 577 Kelly et al. NEJM, 2021 PMID: 33789008
CLASSIC Noh SH et al, Lancet Oncol, 2014; PMID: 25439693
ACTS-GC Sakuramoto S et al, NEJM, 2007; PMID: 17978289
KEYNOTE-585 Shitara K et al, Lancet Oncol, 2024; PMID: 38134948
CRITICS Cats A et al, Lancet Oncol, 2018; PMID: 29650363

Background reading: Esophageal and gastric cancer board review notes.

Localized Gastric / GEJ Adenocarcinoma: Neoadjuvant and Perioperative Therapy: the algorithm in words

By clinical stage, MSI status and site, then adjuvant options after upfront surgery. Starting point: Localized gastric / GEJ adenocarcinoma EUS, CT, laparoscopy. Full background: Esophageal and gastric cancer notes.

cT1a N0 (first-line): Early: Endoscopic resection (EMR / ESD) (if criteria met; otherwise gastrectomy).
cT1b N0 (first-line): Surgery first: Gastrectomy + D2 lymphadenectomy (adjuvant chemo if upstaged (pN+)).
cT2+ or N+, fit (first-line): Preferred: Perioperative FLOT + durvalumab (MATTERHORN; then durvalumab x 10 cycles); Chemo backbone: Perioperative FLOT (4 + 4 cycles) (FLOT4 (OS benefit over ECF/ECX)); Not fit for FLOT: Perioperative FOLFOX or CAPOX (doublet; older standard ECF (MAGIC)).
MSI-H / dMMR (first-line): Tumor board: Neoadjuvant checkpoint inhibitor (NEONIPIGA, INFINITY (phase 2)).
GEJ adenocarcinoma (first-line): Preferred: Perioperative FLOT over CROSS (ESOPEC (OS benefit)); After CROSS, residual: Adjuvant nivolumab x 1 year (CheckMate 577).
Upfront surgery done (first-line): pStage II-III: Adjuvant CAPOX x 6 months (CLASSIC (after D2)); Alternative: Adjuvant S-1 x 1 year (ACTS-GC; stage III: add docetaxel); Less than D2 or R1: Adjuvant chemoradiation (INT-0116 (Macdonald)).
Did not help (first-line): Negative: Perioperative pembrolizumab + chemo (KEYNOTE-585 (EFS not significant)); Negative: Postop chemoradiation after periop chemo (CRITICS).

Simplified board-prep scaffold; verify against current guidelines and primary literature. Stage with EUS, CT chest/abdomen/pelvis and diagnostic laparoscopy with peritoneal washings (cT1b or higher) before choosing therapy. Test every tumor for MSI/MMR, HER2, PD-L1 and CLDN18.2 at diagnosis. Adding pembrolizumab to perioperative chemotherapy did not significantly improve EFS (KEYNOTE-585), and adding postoperative radiation to chemotherapy after adequate surgery did not help (CRITICS, ARTIST-2). Perioperative HER2-directed therapy remains investigational.