Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 21, 2021; 27(19): 2415-2433
Published online May 21, 2021. doi: 10.3748/wjg.v27.i19.2415
Selection of first-line systemic therapies for advanced hepatocellular carcinoma: A network meta-analysis of randomized controlled trials
Yue Han, Wei-Hua Zhi, Fei Xu, Chen-Bo Zhang, Xiao-Qian Huang, Jian-Feng Luo
Yue Han, Wei-Hua Zhi, Fei Xu, Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Chen-Bo Zhang, Xiao-Qian Huang, Jian-Feng Luo, Department of Biostatistics, School of Public Health, Fudan University, Shanghai 200034, China
Author contributions: Han Y, Zhi WH, and Xu F made contributions to the literature search; Zhi WH and Xu F were involved in figure preparation; Han Y and Luo JF made contributions to the study design; Luo JF and Huang XQ were involved in collecting the data; Luo JF, Huang XQ, and Zhang CB were involved in analyzing the data; Han Y, Luo JF, and Zhi WH made contributions to the data interpretation; Han Y and Zhi WH were involved in manuscript writing; Zhang CB and Han Y made contributions to the verification of the data.
Conflict-of-interest statement: The authors have no declarations of interest to declare.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Yue Han, PhD, Doctor, Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan 3rd Alley, Dongcheng District, Beijing 100021, China.
Received: January 26, 2021
Peer-review started: January 26, 2021
First decision: February 27, 2021
Revised: March 10, 2021
Accepted: April 21, 2021
Article in press: April 21, 2021
Published online: May 21, 2021

The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma (HCC) used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.


To systematically review and compare response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma.


We searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC. Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments.


In total, 1398 articles were screened and 27 included. Treatments compared were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. For overall response rate, lenvatinib ranked 1/19, followed by atezolizumab plus bevacizumab and nivolumab. For progression-free survival (PFS), atezolizumab + bevacizumab was ranked 1/15, followed by lenvatinib. With the exception of atezolizumab + bevacizumab [hazard ratios (HR)PFS = 0.90; 95% confidence interval (CI): 0.64-1.25], the estimated HRs for PFS for all included treatments vs lenvatinib were > 1; however, the associated 95%CI passed through unity for bevacizumab plus erlotinib, linifanib, and FOLFOX4. For overall survival, atezolizumab plus bevacizumab was ranked 1/25, followed by vandetanib 100 mg/d and donafinib, with lenvatinib ranked 6/25. Atezolizumab + bevacizumab was associated with a lower risk of death vs lenvatinib (HRos = 0.63; 95%CI: 0.44-0.89), while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity. Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13, respectively, for the lowest incidence of treatment terminations due to adverse events, followed by sorafenib (5/13), lenvatinib (10/13), and atezolizumab + bevacizumab (13/13).


There is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.

Keywords: Hepatocellular carcinoma, Systemic therapy, Meta-analysis, Lenvatinib, First-line, Immune therapy

Core Tip: The present network meta-analysis is the first to compare data from randomized trials of all first-line systemic therapies for hepatocellular carcinoma including chemotherapy, targeted drugs, immunotherapy, and combination therapies. Furthermore, the analysis represents a comprehensive cross comparison of outcomes, including tumor response rates, survival, and safety and included a sub-analysis in patients with hepatitis B virus infection. Our results showed that atezolizumab plus bevacizumab was ranked first for progression-free survival and overall survival but also had the highest rate of discontinuations due to adverse events. Lenvatinib ranked first for overall response rate and second for progression-free survival.