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
Abstract
BACKGROUND

Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available.

AIM

To evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time.

METHODS

A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups.

RESULTS

Fifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ) vs 4 (2.9-11.8) mo (REG), P = 0.0226]. Twenty percent of patients received third-line therapy. After matching, PFS and DCR were not significantly different after a median follow-up of 6.2 (2.7-11.7) mo (REG) vs 5.2 (4-7.2) mo (CBZ), P = 0.6925. There was no difference in grade 3/4 toxicities, dose reductions, or interruptions. The OS of CP-A patients was 8.3 (5.2-24.8) vs 4.9 (1.6-11.7) mo (CP-B), P = 0.0468. The MA of risk factors for progression over time identified C-reactive protein (CRP) > 10 mg/L, neutrophil-to-lymphocyte ratio (NLR) > 3, and aspartate aminotransferase (AST) > 45 IU as predictive factors.

CONCLUSION

This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.

Keywords: Hepatocellular carcinoma; Regorafenib; Cabozantinib; C-reactive protein; Neutrophil-lymphocyte ratio

Core Tip: One limited population of advanced hepatocellular carcinoma patients has sustained disease control using tyrosine kinase inhibitors (TKIs) as first-line systemic therapy. Patients with preserved liver function and performance status progress to second-line systemic therapy. Only two broad-spectrum TKIs are approved for this indication in France, and no direct comparative studies are available. Immune checkpoint inhibitors are currently the standard of care as first-line therapy in combination with an anti-angiogenic agent and will most likely change the treatment strategy of second-line therapy. No biomarkers are available to guide treatment, but serum inflammation-related factors may provide additional support.