Review Article: Systemic Treatments for Advanced Cholangiocarcinoma—State of the Art and Future Directions

BACKGROUND: Cholangiocarcinoma (CCA) is a heterogeneous group of biliary tract malignancies with increasing global incidence and poor prognosis. CCA is anatomically classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subtypes with distinct biological and clinical features. Most patients present with unresectable or metastatic disease, making systemic therapy the mainstay of treatment. AIMS: This review summarises recent advances in systemic therapy for advanced CCA, focusing on chemotherapy, immunotherapy, targeted therapy and future therapeutic directions. METHODS: A comprehensive review of recent clinical studies, treatment guidelines and emerging therapeutic advances in advanced CCA was conducted. Particular emphasis was placed on first-line and subsequent-line systemic therapies, molecular profiling, precision oncology and novel combination treatment strategies. RESULTS: Gemcitabine-cisplatin (GC) has remained the standard first-line chemotherapy for advanced CCA for over a decade. Recent phase III trials demonstrated improved survival with the addition of an immune checkpoint inhibitor (ICI) to GC, establishing chemoimmunotherapy as the current standard first-line treatment. Approximately 40%-50% of patients harbour actionable genomic alterations, including fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH) mutations. Targeted therapies against these alterations have shown meaningful clinical benefit and received US Food and Drug Administration (FDA) approval as second-line treatments. However, therapeutic resistance and molecular heterogeneity remain major challenges. CONCLUSIONS: Systemic treatment for advanced CCA is rapidly evolving toward biomarker-driven and immunotherapy-based strategies. Integration of molecular profiling and precision oncology may further improve individualised treatment and clinical outcomes.