FLOT versus SOX as immunochemotherapy backbones for neoadjuvant or conversion therapy in gastric cancer: efficacy, toxicity, and postoperative safety in a real-world cohort

Objective To compare FLOT and SOX as chemotherapy backbones for neoadjuvant or conversion immunochemotherapy in gastric cancer, with emphasis on pathological efficacy, treatment-related toxicity, treatment feasibility, postoperative safety, and exploratory survival outcomes. Methods This retrospective real-world cohort study included 148 patients with gastric cancer who received preoperative immune checkpoint inhibitor-based therapy, with or without targeted therapy, followed by gastrectomy with D2 lymphadenectomy from 2021 to 2025. Patients were grouped according to chemotherapy backbone: FLOT-based immunochemotherapy (n = 75) or SOX-based immunochemotherapy (n = 73). The primary endpoint was grade 3 or higher treatment-related adverse events. Secondary endpoints included pathological complete response, major pathological response, ypN0 status, R0 resection, adverse event-related treatment modification, postoperative complications, disease-free survival, and overall survival. Exploratory survival analyses included Kaplan–Meier estimation and Firth-penalized Cox proportional hazards regression to account for the limited number of survival events. All subgroup analyses were exploratory and hypothesis-generating. Results FLOT and SOX achieved comparable pathological efficacy. Major pathological response occurred in 42.7% of patients in the FLOT group and 45.2% in the SOX group, while pathological complete response occurred in 18.7% and 27.4%, respectively. ypN0 status, clinical-to-pathological downstaging, and R0 resection rates were also similar. Grade 3 or higher adverse events were numerically more frequent with FLOT than SOX (46.7% vs. 32.9%), as were adverse event-related dose reduction or treatment interruption (36.0% vs. 21.9%). However, postoperative complications were comparable between groups (21.3% vs. 23.3%). Sensitivity analyses excluding targeted therapy showed consistent findings. Exploratory survival analyses were limited by 32 DFS events and 16 deaths and by markedly shorter follow-up in the SOX group. Although the unadjusted hazard ratios numerically favored FLOT for both DFS and OS, multivariable Firth-penalized Cox models substantially attenuated these estimates (DFS adjusted HR, 1.08; 95% CI, 0.50–2.34; OS adjusted HR, 1.56; 95% CI, 0.53–4.60). Accordingly, no definitive conclusions regarding survival superiority, inferiority, or equivalence could be drawn. Conclusion In this cohort, FLOT and SOX showed broadly comparable pathological efficacy and postoperative complication rates, whereas FLOT was associated with a numerically greater preoperative toxicity and treatment-modification burden. SOX may therefore represent a balanced option in selected patients, but these findings require prospective validation.