Exploring the optimal regimen in advanced hepatocellular carcinoma: a protocol of individual patient data network meta-analysis of randomized controlled trials

Background: Advanced hepatocellular carcinoma (HCC) poses a substantial global disease burden. Since the approval of sorafenib in 2007, an increasing number of treatment regimens have demonstrated encouraging survival benefits in first-line treatment of advanced HCC. However, this expansion of therapeutic options has also introduced complexity into clinical decision-making. This study aims to provide high-quality evidence to inform clinical practice by comparing all first-line treatment regimens for advanced HCC. Methods: We will systematically search PubMed, Embase (Ovid), and the Cochrane Library (Ovid) from January 1, 2007, to March 3, 2026. Supplementary searches will be performed in clinical trial platforms and conference abstracts. All randomized controlled trials (RCTs) and high-quality observational studies (for prior information only) comparing active first-line treatment regimen for advanced HCC will be included. Primary outcomes are overall survival, grade ≥3 serious adverse events, and the incremental safety-effectiveness ratio. Secondary outcomes include progression-free survival, objective response rate, the incidence of all adverse events and treatment discontinuation due to adverse events. The risk of bias of included RCTs will be assessed using the Risk of Bias 2.0 tool, and the certainty of evidence for each outcome will be evaluated with the Confidence in Network Meta-Analysis (CINeMA) application. Study selection, data extraction, and quality assessment will be performed independently by two reviewers, with any disagreements adjudicated by a third reviewer. Individual patient data will be reconstructed from published Kaplan-Meier curves, and treatment effects will be evaluated using restricted mean survival time. Subgroup analyses will be performed based on PD-L1 expression, etiology, Barcelona Clinic Liver Cancer stage, alpha-fetoprotein concentration, macrovascular invasion, and extrahepatic spread. Bayesian network meta-analysis will be performed using R with the gemtc package. Discussion: Our study is expected to inform clinical guidelines and support personalized therapeutic decisions for advanced HCC. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420251126975.