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World J Gastrointest Oncol. Dec 15, 2021; 13(12): 2038-2049
Published online Dec 15, 2021. doi: 10.4251/wjgo.v13.i12.2038
Current status of first-line therapy, anti-angiogenic therapy and its combinations of other agents for unresectable hepatocellular carcinoma
Saleh A Alqahtani, Massimo G Colombo
Saleh A Alqahtani, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21287, United States
Saleh A Alqahtani, Liver Transplant Center, and Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
Massimo G Colombo, Liver Center, IRCCS San Raffaele Hospital, Milan 20132, Italy
Author contributions: Both the authors contributed equally in conception, literature review, drafting, editing, revising, finalizing, and submitting the manuscript to the journal.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Massimo G Colombo, MD, Professor, Liver Center, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan 20132, Italy. mcolombo46@yahoo.it
Received: February 15, 2021
Peer-review started: February 15, 2021
First decision: March 15, 2021
Revised: March 24, 2021
Accepted: October 15, 2021
Article in press: October 15, 2021
Published online: December 15, 2021
Abstract

Globally, hepatocellular carcinoma (HCC) is a frequently diagnosed malignancy with rapidly increasing incidence and mortality rates. Unfortunately, many of these patients are diagnosed in the advanced stages when locoregional treatments are not appropriate. Before 2008, no effective drug treatments existed to prolong survival, until the breakthrough multi-tyrosine kinase inhibitor (TKI) sorafenib was developed. It remained the standard treatment option for advanced HCC for 10 years, with a battery of other candidate drugs in clinical trials failing to produce similar efficacy results. In 2018, the REFLECT trial introduced another multi-TKI, lenvatinib, which has non-inferior overall survival compared with sorafenib. Thus, offering patients and their treating physicians two effective treatment options. Recently, immunotherapy-based drugs, such as atezolizumab and bevacizumab, have shown promising results in patients with unresectable HCC. This review summarizes clinical trial and real-world data studies of sorafenib and lenvatinib in patients with unresectable HCC. We offer guidance on the optimal choice between the two treatments and discuss the potential of immunotherapy-based combination; when more data become available, this will likely make the choice between sorafenib and lenvatinib somewhat obsolete.

Keywords: Hepatocellular carcinoma, Immune checkpoint inhibitor, Lenvatinib, Multi-tyrosine kinase inhibitor, Sorafenib

Core Tip: Recently, an immunotherapy-based combination of atezolizumab and bevacizumab was shown to prolong survival compared to sorafenib in unresectable hepatocellular carcinoma patients who did not receive prior therapy. In addition, the combination of lenvatinib and pembrolizumab has yielded promising results in the same patient setting. This review article summarizes the results obtained with sorafenib and lenvatinib in patients with unresectable hepatocellular carcinoma in pivotal clinical trials and real-world studies. We offer guidance on the optimal choice between sorafenib or lenvatinib in an individual patient and discuss the immunotherapy-based combination, which will likely make the choice between sorafenib and lenvatinib somewhat obsolete.