Retrospective Cohort Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2019; 25(27): 3607-3618
Published online Jul 21, 2019. doi: 10.3748/wjg.v25.i27.3607
Intermediate-advanced hepatocellular carcinoma in Argentina: Treatment and survival analysis
Federico Piñero, Sebastián Marciano, Nora Fernández, Jorge Silva, Margarita Anders, Alina Zerega, Ezequiel Ridruejo, Gustavo Romero, Beatriz Ameigeiras, Claudia D’Amico, Luis Gaite, Carla Bermúdez, Virginia Reggiardo, Luis Colombato, Adrián Gadano, Marcelo Silva
Federico Piñero, Ezequiel Ridruejo, Marcelo Silva, Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
Federico Piñero, Margarita Anders, Ezequiel Ridruejo, Marcelo Silva, Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
Sebastián Marciano, Carla Bermúdez, Adrián Gadano, Hospital Italiano de Buenos, Cuidad Autónoma de Buenos Aires, Buenos Aires C1424BYE, Argentina
Nora Fernández, Luis Colombato, Hospital Británico, Cuidad Autonoma de Buenos Aires, Buenos Aires C1280AEB, Argentina
Jorge Silva, Hospital G Rawson, San Juan 5400, Argentina
Margarita Anders, Hospital Aleman, Cuidad Autonoma de Buenos Aires, Buenos Aires C1280AEB, Argentina
Alina Zerega, Sanatorio Allende from Córdoba, Córdoba 5016, Argentina
Ezequiel Ridruejo, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC), Ciudad de Buenos Aires 1431, Argentina
Gustavo Romero, Hospital Udaondo, Cuidad Autonoma de Buenos Aires C1264AAA, Argentina
Beatriz Ameigeiras, Hospital Ramos Mejía, Ciudad de Buenos Aires C1221ADC, Argentina
Claudia D’Amico, Centro Especialidades Medicas Ambulatorias (CEMA), Mar del Plata, Buenos Aires 7600, Argentina
Luis Gaite, Clínica de Nefrología, Santa Fe 3000, Argentina
Virginia Reggiardo, Hospital del Centenario, Rosario, Santa Fe S2002KDT, Argentina
Author contributions: Piñero F, Silva M contributed to concept and design, writing of article; Marciano S, Fernández N, Silva J, Anders M, Zerega A, Ridruejo E, Ameigeiras B, D’amico C, Gaite L, Bermúdez C, Romero G, Reggiardo V, Colombato L and Gadano A contributed to data recording, critical review of the manuscript; Piñero F contributed to statistical analysis.
Institutional review board statement: The study was reviewed and approved by the Austral University, School of Medicine and the Bioethics Institutional Committee of the Austral University Hospital (CIE approval study protocol number 14-039) and from each Bioethics Institutional Committee from all participating centers.
Informed consent statement: All study participants from the prospective cohort, or their legal guardian, provided informed written consent prior to the study enrollment. From the retrospective cohort, all study investigators signed a confidential agreement. We submit the informed consent (IC) and it’s Spanish version approved by the Austral University, School of Medicine and the Bioethics Institutional Committee of the Austral University Hospital (CIE approval study protocol number 14-039).
Conflict-of-interest statement: Piñero F has received Advisory Board and speaker honoraria and he is consultant for BAYER Cono Sur; research grants from the Argentinean National Institute of Cancer (INC ID-190), Argentinean National Ministry of Science and Technology Development (PICT 2017, FONCYT) and from the Latin American Liver Research Educational and Awareness Network (LALREAN). Silva M has received has received speaker honoraria and is a consultant for Abvie, Gador, Bristol-Myers Squibb, Merck, BAYER and research grants from the Argentinean National Institute of Cancer (INC ID-190), Argentinean National Ministry of Science and Technology Development (PICT 2017, FONCYT).
STROBE statement: All procedures followed were in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: Federico Piñero, MD, MSc, Academic Research, Doctor, Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Av. Presidente Perón 1500, Pilar, Buenos Aires B1629HJ, Argentina. fpinerof@cas.austral.edu.ar
Telephone: +54-230-4482000 Fax: +54-230-4482236
Received: March 19, 2019
Peer-review started: March 19, 2019
First decision: April 30, 2019
Revised: May 5, 2019
Accepted: June 25, 2019
Article in press: June 26, 2019
Published online: July 21, 2019
Processing time: 122 Days and 10.6 Hours
ARTICLE HIGHLIGHTS
Research background

Although liver cancer or hepatocellular carcinoma (HCC) is currently the 5th most common cancer and the 2nd cause of death from cancer worldwide, in Argentina represents the sixteenth most frequent cancer. Transarterial chemoembolization (TACE) and systemic treatment with sorafenib are the standards of treatment for patients with intermediate and advanced stage HCC.

Research motivation

The rise of new therapeutic modalities such as radioembolization, the combination of antian-giogenic agents with locoregional therapies and other first and second line systemic options, open up a new paradigm for the treatment of HCC.

Research objectives

Our aim was to describe the treatments performed in the real life setting before the approval of these new systemic options.

Research methods

This longitudinal observational cohort study was conducted between in 14 different regional hospitals from Argentina between 2009 and 2016. Study data were registered into a web-based electronic system. Patients with intermediate (BCLC-B) or advanced (BCLC C-D) HCC were included. Patients were excluded if (1) clinical baseline data was missing; (2) BCLC stage was either 0 or A, in which potentially curative treatments are recommended such as liver resection (LR), percutaneous ethanol injection (PEI)/radiofrequency ablation (RFA) or liver transpla-ntation (LT); and (3) patients with BCLC-B-D who underwent liver transplantation. Baseline tumor and patients characteristics at HCC diagnosis, as well as treatments performed were registered. Each treatment was discussed at each center on a case-by-case basis. Imaging tumor reassessment after treatments were done according to RECIST 1.1 criteria as recommended by international Western guidelines. Median survival was assessed for each BCLC stage from the date of treatment until last patient follow-up or death. For survival analysis, Cox regression analysis estimating hazard ratios (HR) and 95%CI for baseline variables related with mortality was performed. Kaplan Meier survival curves were compared using the log-rank test (Mantel-Cox).

Research results

A total of 327 consecutive adult patients with intermediate and advanced HCC were included, of which 41.3% of the patients were in BCLC stage B (n = 135), 19.9% in stage C (n = 65) and 38.8% in stage D (n = 127). Corresponding median survival for BCLC stages were as follows: Stage B 15 mo (IQR 5-26 mo), stage C 5 mo (IQR 2-13 mo) and stage D 3 mo (IQR 1-13 mo)(Figure 1). TACE was performed in 126 patients (38.5%); 77 were BCLC-B, 22 were BCLC-C and 27 patients were BCLC-C. Among BCLC-B patients (n = 135), 57% received TACE (n = 77) whereas 43% did not (Table 2). Median number of TACEs sessions was 2 (IQR 1-3 sessions). Survival was significantly better in BCLC-B patients treated with TACE HR 0.29 (CI: 0.21-0.40) with a median survival of 15 mo (IQR 7-25 mo), when compared with BCLC-B without TACE and BCLC-C or D patients treated with TACE. According to tumor reassessment after the first TACE by RECIST 1.1 criteria, patients with complete response (CR) achieved a better overall survival with a HR of 0.15 (CI: 0.04-0.56, P = 0.005). Table 3 describes baseline patient characteristic treated with sorafenib (n = 82). Of these, 43.9% were BCLC-B, 43.9% BCLC-C and 12.2% BCLC-D. Among BCLC-B patients who received sorafenib, 15 were TACE naïve and 21 received a median number of TACEs of 3 (IQR 2-4) until disease progression (n = 7) or no response or un-TACE-able (n = 14). Among BCLC-C patients (n = 65), 55.4% were treated with sorafenib and those not treated with sorafenib received BSC (n = 21) and other treatments (4 patients TACE, 1 TARE and patients 3 LR). Corresponding median survival in all patients treated with sorafenib was 4.5 mo (IQR 2.3-11.7 mo); 5.2 mo (IQR 3.7-12.6 mo) in BCLC-B, 3.8 mo (IQR 1.9-9.9 mo) in BCLC-C and 3.2 mo (IQR 2.0-14.1 mo) in BCLC-D. In BCLC-B patients treated with sorafenib after progression (n = 36), the sequential treatment of sorafenib following TACE presented better survival since systemic treatment when compared to those patients who received sorafenib without prior treatment with TACE [HR = 0.26 (CI: 0.09-0.71); P = 0.013].

Research conclusions

In conclusion, in this dual cohort study from Argentina, we describe the treatments performed in the real life setting before the approval of new systemic options.

Research perspectives

Knowing the real life setting is of interest, in order to assess the most common therapeutic decision making processes and management in these patients. Our results highlights unmet needs and improvement areas in public health among developing regions such as Argentina, particularly to promote early and correct treatments in each stage, prior to the introduction of new treatments for HCC.