Efficacy of systemic therapy for advanced hepatocellular carcinoma based on etiology: A systematic review and network meta-analysis of randomized phase III trials

Robust comparative data on the treatment efficacy of hepatocellular carcinoma (HCC) based on disease etiology are lacking. We conducted a network meta-analysis (NMA) and pairwise meta-analysis to evaluate the survival of patients with advanced HCC treated with systemic therapies based on etiology. PubMed/MEDLINE Ovid, Embase, Cochrane Library, CINAHL Databases, and trial registries were systematically searched for relevant studies from 1 January 2009 and 6 June 2024. Phase III randomized controlled trials of systemic therapies in advanced HCC patients with survival outcomes reported in at least one of the three etiology subgroups (hepatitis B virus , hepatitis C virus , or non-viral etiology) were recruited. Frequentist NMA was used to evaluate the comparative effectiveness of treatments and the P-score to rank the effectiveness of the treatments. A random-effects pairwise meta-analysis with pooled hazard ratios (HRs) and 95 % confidence intervals (CIs) was used to quantify the effect of treatments. The primary outcome was overall survival (OS) and the secondary outcome was progression free survival (PFS). A total of 29 RCTs encompassing 18,229 patients were included. In first-line trials. Atezolizumab + bevacizumab (atezo-bev) (P-score, 87 %) and STRIDE (P-score, 75 %) yielded the best OS benefits among all approved regimens in the HBV population; atezo-bev (P-score, 94 %) ranked the best in HCV patients. For non-viral aetiology, STRIDE (P-score, 79 %) ranked the best whereas atezo-bev (P-score, 29 %) ranked the worst. Pairwise MA showed that ICI + VEGF/VEGFRi has significantly different HR compared to control (sorafenib) in different etiology (HBV: 0.65, HCV: 0.72, and non-viral: 0.98, p = 0.01), while ICI has consistent HR compared to control irrespective of disease etiology (HBV: 0.81, HCV: 0.79, non-viral: 0.83, p = 0.94). Treatment efficacy of advanced HCC is affected by underlying liver disease. The survival benefit of ICI + VEGF/VEGFRi was mainly seen in viral-HCC.