Beyond second-line therapy: Strategic sequencing of systemic treatments in advanced hepatocellular carcinoma

Systemic therapy for advanced HCC has evolved from a linear, stepwise algorithm into a multidimensional and truly polyhedral process shaped by treatment response, liver function, and access to therapy. This review integrates evidence from phase II and III trials and real-world studies, including more than 4000 patients across different global regions, to outline how sequencing beyond first-line immunotherapy is redefining clinical practice. After immune-based combinations, tyrosine kinase inhibitors remain active and feasible options, achieving a median overall survival of ~10-11 months, while preservation of liver function consistently determines treatment eligibility and postprogression survival. Incorporation of the Barcelona Clinic Liver Cancer concept "upon response" refines classification for patients achieving major responses or conversion and aligns staging with contemporary treatment dynamics. The CUSE framework-encompassing complexity, uncertainty, subjectivity, and emotion-reframes sequencing as an adaptive, patient-centered, and multifaceted process that integrates toxicity, feasibility, and patient values alongside efficacy. By structuring diverse clinical inputs into a unified interpretive model, CUSE supports multidisciplinary reasoning and enhances conceptual coherence in treatment sequencing. Conversion therapy and "drug-off" strategies following complete or major responses represent emerging frontiers, emphasizing that sequencing in HCC now extends beyond second-line therapy. Additionally, preserving hepatic function and applying polyhedral, data-informed decision frameworks are key to sustaining eligibility and optimizing outcomes across the continuum of care.