Optimal neoadjuvant strategies for locally advanced gastric cancer (LAGC) remain contentious. The purpose of this study was to compare the survival prognosis and safety of LAGC receiving three different neoadjuvant modalities.

In this multicenter retrospective cohort, 670 patients with LAGC (Jan 2012 - Dec 2022) receiving neoadjuvant therapy followed by curative-intent gastrectomy were analyzed. Three cohorts were compared: neoadjuvant chemotherapy alone (NAC, n = 339), neoadjuvant chemoimmunotherapy (NACI, n = 233), and neoadjuvant chemoradiotherapy (NACRT, n = 98). Primary endpoints were overall survival (OS) and disease-free survival (DFS); secondary endpoints included local-regional control (LC), distant metastasis-free survival (DMFS), pathological complete response (pCR) and toxicity (CTCAE v5.0). Survival analyses used Kaplan-Meier/log-rank tests; Cox regression assessed hazard ratios (HRs); the categorical endpoints were analyzed by Chi-square or Fisher’s exact tests based on expected frequencies; significance was P < 0.05.

The NACRT group achieved significantly higher pCR rates (26.5% vs. 7.4% [NAC] and 16.3% [NACI]; P < 0.001). With median follow-up of 40.7 months, NACRT demonstrated superior 5-year OS (80.4% vs. 57.3% [NAC] and 50.8% [NACI], P < 0.001) and 5-year DFS (63.9% vs. 50.0% [NAC] and 44.0% [NACI]; P < 0.05). 5-year distant metastasis-free survival (DMFS) favored NACRT (77.9% vs. 59.3% [NAC], P = 0.004). Grade ≥ 3 toxicity was comparable (15.3% NACRT vs. 12.1% NAC vs. 12.5% NACI; P = 0.69).

Neoadjuvant chemoradiotherapy was correlated with favorable pCR and 5-year OS/DFS rates in LAGC patients, without increasing severe toxicity. Despite improved pCR rates with chemoimmunotherapy, survival benefits were absent. Chemoradiotherapy should be prioritized in LAGC management, with future trials exploring CRT-immunotherapy synergy.