Neoadjuvant, adjuvant and perioperative systemic therapies in gastric and gastroesophageal junction adenocarcinoma: A network meta-analysis of randomized controlled trials.

Abstract

Surgery alone often provides suboptimal outcomes for patients with locally advanced (LA) gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, and additional perioperative therapy is required to improve survival outcomes. Recent evidence favors systemic treatment with perioperative chemotherapy (CT) over neoadjuvant chemoradiotherapy. Given the range of systemic therapies in this setting, we conducted a network meta-analysis (NMA) to compare their efficacy in resectable LA G/GEJ adenocarcinoma. Methods: A systematic review identified randomized controlled trials published up to August 20th, 2025, that enrolled patients with resectable G/GEJ adenocarcinoma. Eligible interventions included surgery combined with adjuvant, neoadjuvant, or perioperative CT ± immune checkpoint inhibitors (ICIs) or antiangiogenic agents. Trials evaluating radiotherapy were excluded. Hazard ratios (HR) for event-free survival (EFS) and overall survival (OS) were extracted or reconstructed. A Bayesian NMA with random-effects models (200, 000 iterations, 20, 000 burn-ins, 4 chains) was performed. HRs with 95% credible intervals (CrIs) were generated. Treatment rankings were assessed using the surface under the cumulative ranking curve (SUCRA). Results: A total of 50 trials (57 reports, 17, 841 patients) were included. The most frequent comparators were surgery alone and adjuvant doublet CT. Data from 35 trials (15, 328 patients) contributed to EFS analyses (16 regimens). Perioperative triplet CT + ICI showed a trend toward improved efficacy compared with perioperative triplet CT alone (HR 0.71; 95% CrI 0.50–1.00) and was superior to adjuvant triplet CT (HR 0.50; 95% CrI 0.30–0.79), but not to perioperative doublet CT + ICI (HR 0.76; 95% CrI 0.42–1.30). In ranking analyses for EFS, perioperative triplet CT + ICI had the highest SUCRA (0.94), followed by neoadjuvant triplet CT + adjuvant monotherapy CT (0.87) and perioperative doublet CT + ICI (0.76). For OS, 48 trials (16, 601 patients) were analyzed (16 regimens). Perioperative triplet CT + ICI improved OS versus adjuvant triplet CT (HR 0.58; 95% CrI 0.35–0.94) and neoadjuvant triplet CT (HR 0.45; 95% CrI 0.23–0.88), but not versus perioperative triplet CT (HR 0.78; 95% CrI 0.53–1.14) or perioperative doublet CT + ICI (HR 0.82; 95% CrI 0.44–1.49). In ranking analyses for OS, perioperative triplet CT + ICI achieved the highest SUCRA (0.94), followed by perioperative doublet CT + ICI (0.81) and perioperative triplet CT (0.78). Conclusions: Perioperative triplet CT + ICI achieved the most favorable SUCRA for EFS and OS, supporting this therapy as a potentially preferred systemic strategy for LA G/GEJ adenocarcinoma. However, overlapping CrIs of this regimen with perioperative triplet and perioperative doublet CT + ICI highlight residual uncertainty