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World J Gastrointest Oncol. Dec 15, 2021; 13(12): 2076-2087
Published online Dec 15, 2021. doi: 10.4251/wjgo.v13.i12.2076
Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy
Takuya Sho, Kenichi Morikawa, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Taku Shigesawa, Mugumi Kimura, Masato Nakai, Goki Suda, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto
Takuya Sho, Kenichi Morikawa, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Taku Shigesawa, Mugumi Kimura, Masato Nakai, Goki Suda, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto, Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
Author contributions: Sho T and Morikawa K planned the contents of manuscript; the manuscript was drafted by Sho T and Morikawa K and was revised by all authors.
Supported by the Japan Agency for Medical Research and Development (AMED), No. JP20fk0210053, JP20fk0310103, JP20fk0210072, JP20fk0210056, JP20fk0310101 and 20fk0210067; JSPS KAKENHI Grant Number No. JP20K08371 and JP19K18956.
Conflict-of-interest statement: Professor Kenichi Morikawa received research grants from Gilead Sciences, Inc., Bristol Myers Squibb, Otsuka Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Professor Goki Suda received research grants from Bristol Myers Squibb and MSD K. K. Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb, Gilead Sciences, Inc., and MSD K. K., collaborative, funded research grants from Gilead Sciences, Inc. and Abbvie G. K., and research grants from Bristol Myers Squibb, MSD K. K., Otsuka Pharmaceutical Co., Ltd., and Shionogi & Co., Ltd. Takuya Sho, Akinori Kubo, Ren Yamada, Takashi Kitagataya, Taku Shigesawa, Megumi Kimura, Masato Nakai, Goki Suda, Mitsuteru Natsuizaka, and Koji Ogawa declare that they have no conflicts of interest.
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: Kenichi Morikawa, MD, PhD, Assistant Professor, Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Kita 15 Nishi 7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan.kenichi.morikawa@med.hokudai.ac.jp
Received: March 29, 2021
Peer-review started: March 29, 2021
First decision: June 16, 2021
Revised: July 8, 2021
Accepted: September 16, 2021
Article in press: September 16, 2021
Published online: December 15, 2021
Processing time: 260 Days and 14.5 Hours
Abstract

The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.

Keywords: Hepatocellular carcinoma; Lenvatinib; Molecular targeted agent; TACE-refractory; TACE-unsuitable; Barcelona Clinic Liver Cancer intermediate stage

Core Tip: For about 10 years, first-line systemic chemotherapy for patients with advanced hepatocellular carcinoma (HCC) had been limited to sorafenib. The Phase III clinical trial of lenvatinib for patients with advanced HCC showed lenvatinib to be non-inferior to sorafenib with respect to overall survival (OS). The OS of patients is still far from satisfactory, and there is a great unmet medical need for more effective therapies. This review focuses on the current understanding of the therapeutic efficacy and safety of lenvatinib in the world and outlines the role of lenvatinib in the new era of chemotherapy for HCC.