Retrospective Cohort Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2022; 14(8): 1510-1527
Published online Aug 15, 2022. doi: 10.4251/wjgo.v14.i8.1510
Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching
Xavier Adhoute, Marie De Matharel, Laurent Mineur, Guillaume Pénaranda, Dann Ouizeman, Clemence Toullec, Albert Tran, Paul Castellani, Armelle Rollet, Valérie Oules, Hervé Perrier, Si Nafa Si Ahmed, Marc Bourliere, Rodolphe Anty
Xavier Adhoute, Paul Castellani, Valérie Oules, Hervé Perrier, Si Nafa Si Ahmed, Marc Bourliere, Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13000, France
Marie De Matharel, Dann Ouizeman, Albert Tran, Rodolphe Anty, Department of Gastroenterology and Hepatology, Hôpital Universitaire de l’Archet, Nice 06000, France
Laurent Mineur, Clemence Toullec, Armelle Rollet, Department of Oncology, Institut Sainte-Catherine, Avignon 84000, France
Guillaume Pénaranda, Department of Biostatistics, AlphaBio Laboratory, Marseille 13000, France
Author contributions: Adhoute X, De Matharel M, Mineur L, Castellani P, Perrier H, Toullec C, Si Ahmed SN, Tran A, Ouizeman D, Bourliere M, Anty R and Oules V are physicians in charge of the patients; Adhoute X, De Matharel M, Rollet A and Mineur L collected the data; Pénaranda G performed statistical analyses; Adhoute X, De Matharel M and Anty R wrote the manuscript.
Institutional review board statement: The study was reviewed and approved by the Fondation Hopital Saint Joseph Institutional Review Board.
Informed consent statement: This study was based on a retrospective analysis of clinical data. Therefore, the Institutional Review Board waived the requirement for informed patient consent. The ethics committee of our institution (Hôpital Saint-Joseph) authorized this work.
Conflict-of-interest statement: Xavier Adhoute: Board member, Consultancy (Bayer, Ipsen, Eisai, Servier); Laurent Mineur: Board member, Consultancy (Ipsen, Amgen, Travel, Mundipharma, Eisai); Clemence Toullec: Board member, Consultancy (Amgen, Bayer, BMS, Ipsen, Merck-Serono, MSD, Pierre-Fabre, Sanofi, Servier); Albert Tran: Board member, Consultancy (Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen); Valérie Oules: Consultancy (Gilead, Abbvie); Paul Castellani: Consultancy (Gilead, Abbvie); Marc Bourlière: Board member, Consultancy (Merck-Schering Plow, Gilead, Janssen, Vertex, Boehringer-Ingelheim, BMS, Roche, Abbvie, GSK); Si Nafa Si Ahmed: Consultancy (Gilead); Hervé Perrier: Consultancy (Sanofi); Rodolphe Anty: Board member, Consultancy (Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen); Guillaume Pénaranda, Armelle Rollet, Dann Ouizeman and Marie De Matharel have no conflicts of interest.
Data sharing statement: Attached is the registration number of the Public Directory of Data Projects (No. F20210311142439). This is the website's link: https://www.health-data-hub.fr/projets/traitement-systemique-du-carcinome-hepatocellulaire-apres-sorafenib-etude-de-cohorte.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xavier Adhoute, PhD, Doctor, Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, 26 Bd Louvain, Marseille 13000, France. xvadhoute@gmail.com
Received: March 21, 2022
Peer-review started: March 21, 2022
First decision: April 25, 2022
Revised: May 8, 2022
Accepted: July 16, 2022
Article in press: July 16, 2022
Published online: August 15, 2022
Processing time: 142 Days and 12.7 Hours
ARTICLE HIGHLIGHTS
Research background

Switching to a second line of systemic therapy will theoretically concern most patients with advanced hepatocellular carcinoma (HCC), especially after sorafenib. The strict selection criteria in phase III trials result in a lack of data for many patients from current practice. Inflammation acts as a powerful tumor promoter.

Research motivation

Two multi-targeted tyrosine kinase inhibitors (TKIs) [Regorafenib (REG), Cabozantinib (CBZ)] are currently the only available therapeutic options in France in this situation based on phase III trials after sorafenib. There are also no direct comparative studies between the "approved" second-line molecules or any predictive biomarker correlated with treatment activity.

Research objectives

To assess both efficacy and safety of REG and CBZ as second-line systemic treatment after sorafenib in a "real-life" study. To investigate the relevance of serum inflammation-related markers as predictive factors for tumor progression over time in this setting. The current lack of treatment-guiding biomarkers and the safety profile of TKIs are limiting factors for this sequencing.

Research methods

This is an indirect propensity score-matched comparative study based on recent retrospective data recorded in three French centers. We focused on progression-free survival and disease control rates of patients treated with REG or CBZ, and on factors associated with tumor progression over time.

Research results

Both efficacy and safety of REG and CBZ are comparable in this real-life study, and CBZ is still a third-line therapeutic option. Elevated levels of pretherapeutic inflammation-related markers [C-reactive protein (CRP) serum level, neutrophil-to-lymphocyte ratio (NLR)] are associated with poorer survival by using TKIs as second-line treatment for HCC.

Research conclusions

In light of the limited tumor control rate with TKIs and the positive results of first- (anti-programmed death ligand-1 + anti-vascular endothelial growth factor) and second-line (anti-human cytotoxic T-lymphocyte antigen-4 + anti-programmed death receptor-1) combination therapies, the therapeutic "landscape" of advanced HCC will be changed in the second-line setting. We propose a 2-mo online progression risk calculation based on CRP serum level, NLR, and aspartate aminotransferase level to estimate the disease course under ITKs treatment.

Research perspectives

The tumor microenvironment plays a key role in the suppression of an effective lymphocyte response. TKIs exhibit anti-angiogenic and immunomodulatory properties. Combinations of TKIs and immune checkpoint inhibitors are currently being evaluated as second-line systemic therapy for HCC.