Discontinuing Immune Checkpoint Inhibitor–Based Therapy After Complete Response in Unresectable Hepatocellular Carcinoma: Evidence, Bias, and a Research Framework

Abstract: Immune checkpoint inhibitor (ICI)-based regimens can induce radiographic complete response (CR) in a small but clinically important subset of patients with unresectable hepatocellular carcinoma (HCC). Whether treatment can then be stopped safely remains unresolved. Evidence comes predominantly from retrospective cohorts and post hoc analyses: selected complete responders have durable disease control after cessation, but neither patient-selection criteria nor an optimal post-CR treatment duration has been validated. This structured critical narrative review distinguishes direct evidence in HCC complete responders from indirect HCC studies, local-treatment-assisted CR, and evidence from other tumors. Interpretation depends on the response criterion, confirmation of CR, reason for stopping, residual treatment exposure, and the alignment of treatment assignment with follow-up. Chronic liver disease adds competing mortality and can reduce the opportunity for salvage independently of tumor recurrence. We integrate these issues into a clinical assessment pathway and a framework for prospective research, with attention to recurrence phenotype, hepatic reserve, toxicity, treatment burden, and treatment-free outcomes. Priorities include reproducible CR definitions, longitudinal registries, comparisons of prespecified treatment strategies, and prospective evaluation of surveillance and salvage. Current evidence supports individualized discussion of cessation rather than its routine use after CR or a fixed treatment duration. Keywords: hepatocellular carcinoma, immune checkpoint inhibitor, complete response, treatment discontinuation, treatment-free remission, mRECIST, target-trial emulation, competing risks