Optimal First- and Second-Line Treatment Regimens in Patients with Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis

Background: Although novel treatment regimens for advanced hepatocellular carcinoma (HCC) continiue to be developed, however, the relative efficacy of and safety is unclear because there have been few head-to-head randomised controlled trials (RCTs). We aimed to compare and rank the efficacy and safety of first- and second-line treatments for patients with advanced HCC. Methods: In this systematic review and network meta-analysis, electronic databases (PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov) were systematically searched for phase III randomised controlled trials comparing any two or three treatment methods in the first- and second-line setting for advanced HCC from the inception of each database to July 2020. Eligible studies had to report at least one of the following clinical outcome measures: overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and adverse events (AEs). Findings: We analysed 22 trials (eleven in the first-line setting and 11 in the second-line setting) involving 7250 patients. For first-line regimens, atezolizumab+bevacizumab was most likely to be ranked first for cumulative 1-year OS (cumulative probability 53%), lenvatinib for both 6-month PFS (50%) and DCR (40%), followed by atezolizumab+bevacizumab (32% and 28% for PFS and DCR, respectively). With respect to safety, linifanib had the highest probability of grade ≥3 AEs (51%) and sorafenib+erlotinib had the most favourable safety profile for reducing them (40%). For second-line regimens, regorafenib had the highest probability of achieving the best cumulative 1-year OS (surface under the cumulative ranking curve [SUCRA], 0·945) followed by cabozantinib (0·814). Cabozantinib had the best clinical efficacy for prolonging 6-month PFS (0·922) and enhancing DCR (0·954) followed by regorafenib (0·821 and 0·894, respectively). For grade ≥3 AEs, cabozantinib had the highest probability (SUCRA, 0·953) followed by regorafenib (SUCRA, 0·854), everolimus (SUCRA, 0·663), and pembrolizumab (SUCRA, 0·314) successively. Interpretation: This network meta-analysis shows that combination of atezolizumab and bevacizumab had the best performance regarding improving OS with acceptable toxicity in patients with advanced HCC not previously treated with systemic therapy. Regorafenib was the best treatment regimen in enhancing OS in patients with disease progression during first-line treatment with sorafenib.  Funding:  National Nature Science Foundation of China Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All analyses were conducted on the basic of previous published studies; therefore, no ethical approval and patients’ consent were required.