The role of radiotherapy in the management of combined hepatocellular-cholangiocarcinoma: current evidence and future perspectives

Abstract

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and highly aggressive hybrid malignancy characterized by apoor prognosis and high recurrence rates due to its dual histological nature. In the absence of established standard-of-care protocols,clinical management strategies are frequently extrapolated from the guidelines for its components, hepatocellular carcinoma andintrahepatic cholangiocarcinoma (iCCA). This review evaluates the evolving role of radiotherapy (RT) as an integral part of the multidisciplinarycare for cHCC-CCA. Adjuvant RT may be considered for patients exhibiting high-risk pathological features, such as positiveor close resection margins, lymphovascular invasion, and perineural invasion. For unresectable disease unfeasible for surgeryor transarterial therapies, definitive RT using intensified doses, analogous to iCCA protocols, is employed to improve local control. High-precision modalities, particularly particle therapies such as proton or carbon ion RT, are emphasized as preferred options fordelivering ablative doses while minimizing toxicity and preserving functional liver reserve. Furthermore, preliminary clinical evidencesuggests a potential synergy between RT and immune checkpoint inhibitors, with reported cases demonstrating complete responsesor successful conversion to curative-intent resection. While current evidence remains limited to retrospective cohorts and case series,the strategic integration of precision RT offers a rational pathway for optimizing outcomes in cHCC-CCA, necessitating furtherprospective validation.