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
Research background

The recent expansion of first-line systemic therapy options for patients with advanced hepatocellular carcinoma represents a significant advance in the treatment of this disease. However, the majority of clinical trials in first-line hepatocellular carcinoma management used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of the efficacy and safety of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.

Research motivation

Clinical trials of recently-approved therapies for hepatocellular carcinoma have revealed differing profiles of efficacy and safety, and comparative data to inform selection of first-line treatments for individual patients are limited. Furthermore, although lenvatinib is widely seen as a standard of care in real clinical practice, and is a recommended first-line therapy in most international treatment guidelines, there are limited head-to-head data comparing lenvatinib with other systemic therapies.

Research objectives

The objectives of this network meta-analysis were to systematically review and compare the response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma, and to provide a comparison between lenvatinib and other systemic therapies in this setting. The study also included a sub-group analysis of patients with hepatitis B virus infection, which is an important population in the Asia-Pacific region and has not been covered by other current meta-analyses.

Research methods

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 hepatocellular carcinoma. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments for endpoints including (where available) overall response rate, overall survival, progression-free survival, time-to-progression, incidence of Grade ≥ 3 adverse events, incidence of treatment interruptions due to adverse events, and incidence of dose reductions due to adverse events. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments.

Research results

Treatments included in the analysis were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. 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. Our findings show that first-line systemic treatment should be selected based on individualized treatment goals and provide valuable comparative data that can help to inform treatment decisions.

Research conclusions

Our findings suggest that there is no one single first-line treatment for advanced hepatocellular carcinoma associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.

Research perspectives

Future research should continue to evaluate new therapeutic strategies for hepatocellular carcinoma in the context of existing treatments, and provide further information to support treatment selection for individual patients.