Simple SummaryBiliary tract cancer is the second most common type of liver cancer. Patients often present when the disease has spread from the liver to other neighboring or distant parts of the body. Chemotherapy with the combination of gemcitabine and cisplatin has been the standard of care for this disease for the past decade. This study assessed patients whose disease continued to grow (progressing) despite one prior treatment of chemotherapy, based on a multidisciplinary discussion of individual cases. Patients who received antitumor therapy including a second treatment of chemotherapy (FOLFIRI), a minimally invasive, image-guided procedure or a combination of both, lived approximately 6, 9, and 15 months longer, respectively, than patients who did not receive tumor-specific therapy. Overall, the results of this study suggest that individualized treatment based on a multidisciplinary discussion may increase how long patients with biliary tract cancer progressing despite one prior treatment of chemotherapy live.AbstractBackground: Patients with unresectable biliary tract cancer (uBTC) who progress despite first-line gemcitabine plus cisplatin (GC) treatment have limited systemic options with a modest survival benefit. Data are lacking on the clinical effectiveness and safety of personalized treatment based on multidisciplinary discussion for patients with progressing uBTC. Methods: This retrospective single-center study included patients with progressive uBTC who received either best supportive care or personalized treatment based on multidisciplinary discussion, including minimally invasive, image-guided procedures (MIT); FOLFIRI; or both (MIT and FOLFIRI), between 2011 and 2021. Results: Ninety-seven patients with progressive uBTC were identified. Patients received best supportive care (n= 50, 52%), MIT (n= 14, 14%), FOLFIRI (n= 19, 20%), or both (n= 14, 14%). Survival after disease progression was better in patients who received MIT (8.8 months; 95% CI: 2.60–15.08), FOLFIRI (6 months; 95% CI: 3.30–8.72), or both (15.1 months; 95% CI: 3.66–26.50) than in patients receiving BSC (0.36 months; 95% CI: 0.00–1.24,p< 0.001). The most common (>10%) grade 3–5 adverse events were anemia (25%) and thrombocytopenia (11%). Conclusion: Multidisciplinary discussion is critical for identifying patients with progressive uBTC who might benefit the most from MIT, FOLFIRI, or both. The safety profile was consistent with previous reports.