Systemic treatment paradigms for unresectable and advanced hepatocellular carcinoma in Europe

The management of unresectable and advanced hepatocellular carcinoma (HCC) has been transformed by the introduction of immune checkpoint inhibitor-based combinations, which have improved response and survival and expanded first-line treatment options. The availability of multiple effective regimens has introduced new challenges in therapeutic decision making. In the absence of validated predictive biomarkers or head-to-head comparisons, first-line treatment selection remains largely guided by clinical characteristics, contraindications and anticipated toxicity, while the optimal sequencing of therapy following first-line immunotherapy remains uncertain. Locoregional therapies continue to play an important role in selected patients with liver-confined disease, further broadening the range of therapeutic strategies available in clinical practice. In Europe, these evolving treatment paradigms are implemented within a heterogeneous landscape of regulatory approval, reimbursement and access, resulting in important differences in care across countries. In this Series paper, we discuss contemporary systemic treatment strategies for HCC from a European perspective, focusing on treatment selection and sequencing, the role of predictive biomarkers and locoregional therapies, and disparities in access to effective treatments. Generating prospective evidence to inform treatment selection and sequencing, while ensuring more timely and equitable access to effective therapies will be essential to optimise HCC care across Europe.