Systemic treatment strategies for combined hepatocellular-cholangiocarcinoma: current evidence and future direction.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy characterized by biphenotypic differentiation and marked biologic heterogeneity. Owing to its low incidence, diagnostic complexity, and lineage plasticity, standardized systemic treatment strategies remain undefined. Molecular and pathologic studies suggest a progenitor cell origin, with tumors exhibiting genomic, transcriptomic, and immunologic features overlapping with both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. This heterogeneity contributes to variable therapeutic responsiveness and underscores the need for biologically informed treatment approaches. Current systemic treatment evidence is derived predominantly from retrospective analyses. Platinum-based cytotoxic chemotherapy has demonstrated modest but consistent clinical activity and remains the most commonly adopted palliative backbone. More recently, immunotherapy has shown encouraging anti-tumor activity, including combination strategies incorporating anti-angiogenic agents. Biomarker signals provide mechanistic rationale for immune-angiogenic therapeutic integration. Emerging platforms, including programmed cell death-1 (PD-1)/vascular endothelial growth factor (VEGF) bispecific antibodies, further expand the systemic treatment landscape. In parallel, multimodal strategies integrating locoregional interventions with systemic therapy are gaining traction, particularly for patients with liver-dominant disease. Despite these advances, prospective disease-specific trials remain lacking, and optimal therapeutic sequencing and patient selection strategies are yet to be defined. Future progress will depend on biomarker-driven trial design, incorporation of molecular lineage stratification, and rational combination approaches. A deeper understanding of the pathological and molecular architecture of cHCC-CC will be essential to establish optimized, disease-specific systemic treatment paradigms for this rare but clinically challenging malignancy.