Abstract
BACKGROUND AND OBJECTIVE: Biliary tract cancers (BTCs), including gallbladder cancer and cholangiocarcinoma, represent a rare yet aggressive class of malignancies with limited therapeutic options and poor survival outcomes. BTCs have been traditionally managed with gemcitabine and cisplatin (GC), but this standard of care has shown limited efficacy due to early recurrence, high resistance rates, and molecular heterogeneity. This review comprehensively summarizes the latest developments in systemic therapies for BTCs, emphasizing recent advances in chemotherapy, targeted therapy, immunotherapy, and rational combination regimens. Particular focus is given to molecularly guided treatment strategies and the evolving role of biomarkers in personalizing therapy. METHODS: A thorough search of PubMed, EMBASE, Google Scholar, and the Cochrane Library was conducted for literature published from December 2010 to December 2024. Peer-reviewed clinical trials, meta-analyses, and relevant conference abstracts were examined, especially those related to emerging systemic treatments, molecular targets, and ongoing trials. Particular attention was given to dosing strategies and the integration of novel agents in optimizing patient outcomes. KEY CONTENT AND FINDINGS: Recent breakthroughs in molecular profiling have identified actionable alterations such as FGFR2 fusions, IDH1/2 mutations, HER2 amplification, and BRAF V600E mutations, enabling the development of targeted therapies with promising efficacy. Immune checkpoint inhibitors (ICIs), especially when combined with chemotherapy, have demonstrated survival benefits in landmark trials such as TOPAZ-1 and KEYNOTE-966. Additionally, novel regimens including nanoliposomal irinotecan and dual ICI combinations represent viable second-line options. The integration of genomic biomarkers and individualized treatment approaches is reshaping the therapeutic landscape of BTCs. CONCLUSIONS: Systemic therapy for BTCs is undergoing a transformative shift, driven by precision oncology and immunotherapeutic advances. Personalized treatment guided by molecular characteristics is now central to improving outcomes. Future efforts must prioritize the identification of biomarkers, clarification of resistance mechanisms, and optimization of multimodal treatment strategies to maximize patient benefit.