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Title: First-line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Patient-Level Network Meta-Analysis
Authors: Fong K.Y. 
Zhao J.J.
Sultana R. 
Lee J.J.X. 
Lee S.Y.
Chan S.L.
Yau T.
Tai D.W.M. 
Sundar R. 
Too C.W. 
Keywords: Hepatocellular carcinoma
Issue Date: 23-Aug-2022
Publisher: S. Karger AG
Citation: Fong K.Y., Zhao J.J., Sultana R., Lee J.J.X., Lee S.Y., Chan S.L., Yau T., Tai D.W.M., Sundar R., Too C.W. (2022-08-23). First-line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Patient-Level Network Meta-Analysis. Liver Cancer. ScholarBank@NUS Repository.
Rights: Attribution-NonCommercial 4.0 International
Abstract: Introduction: Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab. Thereafter, several novel first-line combination therapies have demonstrated favorable outcomes. The efficacies of these treatments in relation to current and previous standards of care are unknown, necessitating an overarching evaluation. Methods: A systematic literature search was conducted on PubMed, EMBASE, Scopus, and the Cochrane Controlled Register of Trials for phase III randomized controlled trials investigating first-line systemic therapies for aHCC. Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were graphically reconstructed to retrieve individual patient-level data. Derived hazard ratios (HRs) for each study were pooled in a random-effects network meta-analysis (NMA). NMAs were also conducted using study-level HRs for various subgroups, according to viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion, and extrahepatic spread. Treatment strategies were ranked using p scores. Results: Among 4,321 articles identified, 12 trials and 9,589 patients were included for analysis. Only two therapies showed OS benefit over sorafenib: combined anti-programmed-death and anti-VEGF pathway inhibitor monoclonal antibodies (Anti-PD-(L)1/VEGF Ab), including atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar (HR = 0.63, 95% CI = 0.53–0.76) and tremelimumab-durvalumab (HR = 0.78, 95% CI = 0.66–0.92). Anti-PD-(L)1/VEGF Ab showed OS benefit over all other therapies except tremelimumab-durvalumab. Low heterogeneity (I2 = 0%) and inconsistency (Cochran’s Q = 0.52, p = 0.773) was observed. p scores for OS ranked Anti-PD-(L)1/VEGF Ab as the best treatment in all subgroups, except hepatitis B where atezolizumab-cabozantinib ranked highest for both OS and PFS, as well as nonviral HCC and AFP ≥400 μg/L where tremelimumab-durvalumab ranked highest for OS. Conclusion: This NMA supports Anti-PD-(L)1/VEGF Ab as the first-line therapy for aHCC and demonstrates a comparable benefit for tremelimumab-durvalumab which also extends to certain subgroups. Results of the subgroup analysis may guide treatment according to baseline characteristics, while pending further studies.
Source Title: Liver Cancer
ISSN: 2235-1795
DOI: 10.1159/000526639
Rights: Attribution-NonCommercial 4.0 International
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