Survival Outcomes of Gemcitabine–Cisplatin–S‐1 Versus Gemcitabine–Cisplatin in Unresectable Biliary Tract Cancer: A Multicenter Retrospective Study With a Focus on Conversion Surgery

ABSTRACT Background Gemcitabine plus cisplatin (GC) has been the global standard for advanced biliary tract cancer (BTC). The triplet regimen gemcitabine–cisplatin–S‐1 (GCS) demonstrated superiority in the MITSUBA trial, but its real‐world effectiveness remains unclear. We compared survival outcomes of GCS versus GC, focusing on conversion surgery (CS). Methods We retrospectively analyzed 542 patients with unresectable BTC treated between 2017 and 2024 at 19 Japanese institutions. Patients received GC ( n = 310) or GCS ( n = 232). Survival was evaluated using multivariable Cox regression, 90‐day landmark analysis, and propensity score matching (PSM) to adjust for baseline imbalances. Results Patients treated with GCS achieved greater tumor shrinkage (median −23.0% vs. –10.0%, p = 0.014) and a higher CS rate (16.4% vs. 4.5%, p < 0.001) than GC. Median progression‐free survival was 8.6 versus 5.4 months ( p = 0.002), and median overall survival (OS) was 17.2 versus 11.6 months ( p = 0.006). In multivariable analysis, GCS was associated with a lower risk of death (HR 0.80, 95% CI 0.65–0.98, p = 0.035), with consistent results after PSM. Fifty‐two patients underwent CS, with comparable perioperative safety and R0 resection rates between regimens. Patients who underwent CS achieved markedly longer OS; in the overall cohort, median OS was 31.0 months in the GCS with CS group and not reached in the GC with CS group ( p = 0.131). Conclusions Treatment with GCS was associated with longer survival compared with GC in unresectable BTC, alongside a higher rate of conversion surgery, which was associated with favorable long‐term outcomes.