Comparative Effectiveness of Adjuvant XELOX Versus TS-1 Monotherapy After D2 Gastrectomy for Stage III Gastric Cancer: A Real-World Nationwide Cohort Study

Adjuvant XELOX (capecitabine plus oxaliplatin) and TS-1 (S-1) monotherapy are both guideline-recommended following D2 gastrectomy for gastric cancer, yet head-to-head real-world data exclusively in stage III disease remain scarce. Using Taiwan’s National Health Insurance Research Database linked to the Taiwan Cancer Registry–Long Form, we identified stage III gastric cancer patients who underwent D2 gastrectomy (2010–2019) and received adjuvant XELOX or TS-1 for ≥3 months. Propensity score matching balanced chemotherapy and non-chemotherapy cohorts (1706/group). Overall survival (OS) was the primary endpoint; disease progression was defined as initiation of FOLFOX salvage chemotherapy (used as a pragmatic proxy for disease recurrence). A second propensity score matching was performed directly between XELOX (n = 533) and TS-1 (n = 893) groups, yielding 490 matched pairs with well-balanced baseline characteristics. Multivariable Cox regression was adjusted for sex, age, comorbidities, and Charlson Comorbidity Index. TS-1 was associated with significantly better OS (adjusted HR 0.73, 95% CI 0.61–0.86; p < 0.001) and lower progression (adjusted HR 0.38, 95% CI 0.23–0.62; p < 0.001) versus XELOX; the corresponding 3-year OS was approximately 65.4% for TS-1 versus 56.8% for XELOX, and extrapolated 5-year OS approximately 50.2% versus 41.7%, respectively (note: these 5-year estimates are Kaplan–Meier projections beyond the mean follow-up of ~2.6 years and carry substantial uncertainty; they should be interpreted with caution). Benefits were confined to stage IIIA (OS HR 0.64, 95% CI 0.45–0.89; p = 0.009; interaction p = 0.006; progression HR 0.29, 95% CI 0.11–0.76; p = 0.011), with comparable outcomes in IIIB and IIIC. Adjuvant TS-1 monotherapy was associated with superior OS and lower disease progression versus XELOX in stage III gastric cancer, particularly in stage IIIA; these findings are hypothesis-generating and warrant confirmation in prospective randomized trials, whereas in stage IIIB/IIIC outcomes were comparable between the two regimens.