Real-World Comparative Effectiveness of FOLFOX, FOLFIRI, and CapOx as Second-Line Chemotherapy for Advanced Biliary Tract Cancer

Background Advanced biliary tract cancer (BTC) has a poor prognosis following progression on first-line gemcitabine plus cisplatin. However, evidence comparing second-line chemotherapy regimens remains limited. This study aimed to compare the effectiveness and safety of fluorouracil, leucovorin, and oxaliplatin (FOLFOX); fluorouracil, leucovorin, and irinotecan (FOLFIRI); and capecitabine plus oxaliplatin (CapOx). Patients and Methods Adults with advanced BTC who received first-line gemcitabine plus cisplatin followed by second-line FOLFOX, FOLFIRI, or CapOx between January 2010 and July 2025 were identified from the TriNetX Global Collaborative Network. Patients who subsequently received molecularly targeted therapies were excluded. The study included 825 patients receiving FOLFOX, 184 receiving FOLFIRI, and 149 receiving CapOx; after 1:1 propensity score matching, the respective comparisons included 182 and 149 patients per group. Overall survival (OS) and treatment-related adverse events were compared between the matched cohorts. Results The median OS was comparable between FOLFOX and FOLFIRI (5.7 months vs. 5.8 months, P=.958) and between FOLFOX and CapOx (5.7 months vs. 5.8 months, P=.803). The overall adverse event profiles were also comparable. However, FOLFOX was associated with lower rates of neutropenia but higher rates of thrombocytopenia than FOLFIRI. In contrast, FOLFOX and CapOx demonstrated similar toxicity despite modest differences in anemia and thrombocytopenia. Conclusion This real-world study demonstrates comparable survival outcomes among FOLFOX, FOLFIRI, and CapOx as second-line chemotherapies for advanced BTC. These findings support individualized regimen selection based on patient characteristics and toxicity profiles.