Comparative efficacy and safety of neoadjuvant and perioperative systemic therapies for resectable locally advanced gastric and gastroesophageal junction adenocarcinoma: a network meta analysis of randomized controlled trials

The optimal neoadjuvant or perioperative systemic strategy for resectable locally advanced gastric cancer (LAGC) and gastroesophageal junction adenocarcinoma (GEJA) remains uncertain. This study compared clinically defined treatment classes rather than individual regimens. PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched through April 30, 2026. Eligible randomized controlled trials (RCTs) enrolled patients with resectable LAGC/GEJA and evaluated neoadjuvant or perioperative systemic therapy. Outcomes were overall survival (OS), event free survival (EFS), pathologic complete response (pCR), major pathologic response (MPR), R0 resection, and postoperative complications. Network meta-analysis pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analyses examined clinically refined treatment node definitions. Thirty six RCTs involving 8925 patients were included. Fifteen trials contributed to OS, 19 to EFS, 18 to pCR, 11 to MPR, 34 to R0 resection, and 24 to postoperative complications. Chemotherapy plus immunotherapy (CHEMO + IO) had the highest SUCRA values for OS and EFS (97.9% and 92.9%, respectively). Compared with surgery based control (SBC), CHEMO + IO was associated with improved OS (HR, 0.50; 95% CI, 0.36 to 0.70) and EFS (HR, 0.52; 95% CI, 0.36 to 0.76). For pCR, CHEMO + IO was superior to taxane based triplet chemotherapy (TAX3) (OR, 3.33; 95% CI, 2.30 to 4.83), platinum fluoropyrimidine doublet chemotherapy (PF2) (OR, 4.83; 95% CI, 3.20 to 7.29), and anthracycline based chemotherapy (ACT) (OR, 9.94; 95% CI, 3.90 to 25.34). CHEMO + IO improved MPR versus PF2 (OR, 2.54; 95% CI, 1.32 to 4.91). Chemotherapy plus targeted therapy (CHEMO + TAR) and CHEMO + IO were associated with higher odds of R0 resection than SBC (OR, 3.47; 95% CI, 1.78 to 6.74; and OR, 2.98; 95% CI, 1.55 to 5.72, respectively). Postoperative complications did not differ significantly. Sensitivity analyses using refined node definitions generally supported these findings. Based on network estimates and SUCRA rankings, CHEMO + IO showed favorable treatment class signals across survival and pathological outcomes without a clear increase in postoperative complications. These findings should be interpreted in light of the certainty and directness of the available evidence and do not establish a universal treatment hierarchy. Treatment selection should consider direct trial evidence, efficacy, safety, biomarkers, patient fitness, and treatment feasibility. PROSPERO registration number: CRD420261410576.