Review of systemic therapy in HCC with an approach to response assessment in clinical practice.

Systemic therapy for hepatocellular carcinoma (HCC) has undergone rapid transformation over the past decade, significantly expanding treatment options and improving survival for patients with advanced disease. Guided by the Barcelona Clinic Liver Cancer staging system, systemic therapy is primarily indicated for advanced-stage HCC and select intermediate-stage cases with preserved liver function. Immune checkpoint inhibitor-based combination regimens have redefined first-line therapy, demonstrating substantial improvements in overall survival and response rates. As systemic and locoregional treatments increasingly converge, radiologists are encountering more complex imaging scenarios requiring nuanced interpretation. Assessment of treatment response in HCC relies on integration of imaging findings, biomarkers, and clinical parameters. Although Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 remains the primary response assessment method in clinical trials, its size-based criteria may not fully capture biologic response in HCC, where therapy can induce necrosis or decreased vascularity without substantial tumor shrinkage. Modified RECIST (mRECIST), which evaluates viable enhancing tumor, may better reflect treatment effect in certain contexts; however, higher response rates by mRECIST have not consistently translated into improved overall survival. Atypical response patterns such as pseudoprogression and hyperprogression may further complicate evaluation in the immunotherapy era but remain uncommon in HCC. Emerging evidence suggests that combining systemic therapy with locoregional therapies such as transarterial chemoembolization, transarterial radioembolization, and stereotactic body radiation therapy may improve disease control and survival in selected patients, further increasing imaging complexity. In routine clinical practice, radiology reports should emphasize global disease burden assessment, "the forest, not the trees," while clearly describing mixed responses, tumor-in-vein, and extrahepatic disease. In cases of temporally overlapping systemic and locoregional therapies, a compartmentalized approach integrating RECIST or mRECIST principles with LI-RADS treatment response algorithm for recently treated lesions, "the forest and the trees," is recommended to support multidisciplinary decision-making. Advanced imaging techniques including perfusion imaging, radiomics, and artificial intelligence-based modeling offer promising tools for earlier and more precise response assessment but remain largely investigational. As therapeutic paradigms continue to evolve, radiologists play a central role in guiding management decisions. A comprehensive, multidisciplinary approach that integrates imaging interpretation with clinical context and treatment history is essential to accurately assess response and optimize care in patients with HCC receiving systemic therapy.