World Journal of WJ G Gastroenterology Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2019 July 21; 25(27): 3607-3618 DOI: 10.3748/wjg.v25.i27.3607 ISSN 1007-9327 (print) ISSN 2219-2840 (online) ORIGINAL ARTICLE Retrospective Cohort Study 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 ORCID number: Federico Piñero Federico Piñero, Ezequiel Ridruejo, Marcelo Silva, Hospital Universitario Austral, Facultad de (0000-0002-9528-2279); Sebastian Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina Marciano (0000-0002-7983-1450); Nora Fernández Federico Piñero, Margarita Anders, Ezequiel Ridruejo, Marcelo Silva, Latin American Liver (0000-0002-5026-8887); Jorge Silva Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, (0000-0002-0214-9744); Margarita Argentina Anders (0000-0002-2238-5322); Alina Zerega (0000-0002-3678-5204); Sebastián Marciano, Carla Bermúdez, Adrián Gadano, Hospital Italiano de Buenos, Cuidad Ezequiel Ridruejo Autónoma de Buenos Aires, Buenos Aires C1424BYE, Argentina (0000-0002-3321-0683); Gustavo Romero (0000-0002-4100-2067); Nora Fernández, Luis Colombato, Hospital Británico, Cuidad Autonoma de Buenos Aires, Beatriz Ameigeiras Buenos Aires C1280AEB, Argentina (0000-0001-8754-2053); Claudia D'Amico (0000-0002-3246-6580); Jorge Silva, Hospital G Rawson, San Juan 5400, Argentina Luis Gaite (0000-0002-5180-1954); Carla Bermudez Margarita Anders, Hospital Aleman, Cuidad Autonoma de Buenos Aires, Buenos Aires (0000-0003-0082-9006); Virginia C1280AEB, Argentina Reggiardo (0000-0003-3990-5790); Luis Colombato Alina Zerega, Sanatorio Allende from Córdoba, Córdoba 5016, Argentina (0000-0001-7859-6842); Adrián Gadano (0000-0002-3590-2472); Ezequiel Ridruejo, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” Marcelo Silva (CEMIC), Ciudad de Buenos Aires 1431, Argentina (0000-0002-2287-7351). Gustavo Romero, Hospital Udaondo, Cuidad Autonoma de Buenos Aires C1264AAA, Author contributions: Piñero F, Argentina Silva M contributed to concept and design, writing of article; Marciano Beatriz Ameigeiras, Hospital Ramos Mejía, Ciudad de Buenos Aires C1221ADC, Argentina S, Fernández N, Silva J, Anders M, Zerega A, Ridruejo E, Ameigeiras Claudia D’Amico, Centro Especialidades Medicas Ambulatorias (CEMA), Mar del Plata, B, D’amico C, Gaite L, Bermúdez C, Romero G, Reggiardo V, Buenos Aires 7600, Argentina Colombato L and Gadano A Luis Gaite, Clínica de Nefrología, Santa Fe 3000, Argentina contributed to data recording, critical review of the manuscript; Virginia Reggiardo, Hospital del Centenario, Rosario, Santa Fe S2002KDT, Argentina Piñero F contributed to statistical analysis. Corresponding author: Federico Piñero, MD, MSc, Academic Research, Doctor, Hepatology Institutional review board and Liver Transplant Unit, Hospital Universitario Austral, Av. Presidente Perón 1500, Pilar, statement: The study was Buenos Aires B1629HJ, Argentina. fpinerof@cas.austral.edu.ar reviewed and approved by the Telephone: +54-230-4482000 Austral University, School of Fax: +54-230-4482236 Medicine and the Bioethics Institutional Committee of the Austral University Hospital (CIE WJG https://www.wjgnet.com 3607 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina approval study protocol number 14-039) and from each Bioethics Abstract Institutional Committee from all BACKGROUND participating centers. Hepatocellular carcinoma (HCC) represents the sixteenth most frequent cancer in Informed consent statement: All Argentina. The rise of new therapeutic modalities in intermediate-advanced HCC study participants from the opens up a new paradigm for the treatment of HCC. prospective cohort, or their legal guardian, provided informed AIM written consent prior to the study To describe real-life treatments performed in patients with intermediate- enrollment. From the retrospective advanced HCC before the approval of new systemic options. cohort, all study investigators signed a confidential agreement. METHODS We submit the informed consent This longitudinal observational cohort study was conducted between 2009 and (IC) and it’s Spanish version approved by the Austral 2016 in 14 different regional hospitals from Argentina. Included subjects had University, School of Medicine and intermediate-advanced Barcelona Clinic Liver Cancer (BCLC) HCC stages (BCLC the Bioethics Institutional B to D). Primary end point analyzed was survival, which was assessed for each Committee of the Austral BCLC stage from the date of treatment until last patient follow-up or death. University Hospital (CIE approval Kaplan Meier survival curves and Cox regression analysis were performed, with study protocol number 14-039). hazard ratios (HR) calculations and 95% confidence intervals (95%CI). Conflict-of-interest statement: Piñero F has received Advisory RESULTS Board and speaker honoraria and From 327 HCC patients, 41% were BCLC stage B, 20% stage C and 39% stage D. he is consultant for BAYER Cono Corresponding median survival were 15 mo (IQR 5-26 mo), 5 mo (IQR 2-13 mo) Sur; research grants from the and 3 mo (IQR 1-13 mo) (P < 0.0001), respectively. Among BCLC-B patients (n = Argentinean National Institute of 135), 57% received TACE with a median number of 2 sessions (IQR 1-3 sessions). Cancer (INC ID-190), Argentinean Survival was significantly better in BCLC-B patients treated with TACE HR = National Ministry of Science and Technology Development (PICT 0.29 (CI: 0.21-0.40) than those without TACE. After tumor reassessment by 2017, FONCYT) and from the Latin RECIST 1.1 criteria following the first TACE, patients with complete response American Liver Research achieved longer survival [HR = 0.15 (CI: 0.04-0.56, P = 0.005)]. Eighty-two Educational and Awareness patients were treated with sorafenib, mostly BCLC-B and C (87.8%). However, Network (LALREAN). Silva M has 12.2% were BCLC-D. Median survival with sorafenib was 4.5 mo (IQR 2.3-11.7 received has received speaker honoraria and is a consultant for mo); which was lower among BCLC-D patients 3.2 mo (IQR 2.0-14.1 mo). A total Abvie, Gador, Bristol-Myers of 36 BCLC-B patients presented tumor progression after TACE. In these patients, Squibb, Merck, BAYER and treatment with sorafenib presented better survival when compared to those research grants from the patients who received sorafenib without prior TACE [HR = 0.26 (CI: 0.09-0.71); P Argentinean National Institute of = 0.013]. Cancer (INC ID-190), Argentinean National Ministry of Science and CONCLUSION Technology Development (PICT 2017, FONCYT). In this real setting, our results were lower than expected. This highlights unmet needs in Argentina, prior to the introduction of new treatments for HCC. STROBE statement: All procedures followed were in accordance with Key words: Hepatocellular carcinoma; Therapeutics; Survival; Real-life the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved. guidelines. Core tip: Trans-arterial chemoembolization and systemic treatment with sorafenib or Open-Access: This article is an open-access article which was lenvatinib are the standards of treatment for patients with intermediate and advanced selected by an in-house editor and stage hepatocellular carcinoma (HCC). The rise of new current therapeutic modalities fully peer-reviewed by external such as radioembolization, the combination of antiangiogenic agents with locoregional reviewers. It is distributed in therapies and other first and second line systemic options, open up a new paradigm for accordance with the Creative the treatment of HCC. In this dual cohort study, we describe the treatments performed in Commons Attribution Non Commercial (CC BY-NC 4.0) the real life setting before the approval of these new systemic options. Our real-data license, which permits others to outcomes, lower than expected, highlight unmet needs and improvement areas in the distribute, remix, adapt, build daily practice prior to the introduction of new treatments for HCC. upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and Citation: Piñero F, Marciano S, Fernández N, Silva J, Anders M, Zerega A, Ridruejo E, the use is non-commercial. See: Romero G, Ameigeiras B, D’Amico C, Gaite L, Bermúdez C, Reggiardo V, Colombato L, http://creativecommons.org/licen Gadano A, Silva M. Intermediate-advanced hepatocellular carcinoma in Argentina: Treatment ses/by-nc/4.0/ and survival analysis. World J Gastroenterol 2019; 25(27): 3607-3618 URL: https://www.wjgnet.com/1007-9327/full/v25/i27/3607.htm Manuscript source: Invited manuscript DOI: https://dx.doi.org/10.3748/wjg.v25.i27.3607 Received: March 19, 2019 Peer-review started: March 19, 2019 WJG https://www.wjgnet.com 3608 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina First decision: April 30, 2019 INTRODUCTION Revised: May 5, 2019 Accepted: June 25, 2019 According to the latest estimates made by the International Agency for Research on Article in press: June 26, 2019 Cancer [IARC (http://gco.iarc.fr)] for the year 2018, Argentina has an incidence rate Published online: July 21, 2019 of 212 cases per 100000 inhabitants[1]. This figure places it within the countries of the world with medium-high incidence of cancer (range 177 to 245.6 per 100000 P-Reviewer: Hoyos inhabitants) and in seventh place in Latin America. Although liver cancer or hepa- S-Editor: Ma RY tocellular carcinoma (HCC) is currently the 5th most common cancer and the 2nd cause L-Editor: A of death from cancer worldwide, in Argentina represents the sixteenth most frequent E-Editor: Wang J cancer (www.argentina.gob.ar/salud/instituto-nacional-del-cancer)[1]. Given that in more than 90% of the cases this tumor develops in patients with cirrhosis or chronic infection with hepatitis B or C virus, the diagnostic, staging and therapeutic management in our country is mainly done by hepatologists or hepato- biliary surgeons, rather than clinical oncologists[2]. Transarterial chemoembolization (TACE) and systemic treatment with sorafenib or lenvatinib are the standard treatments for patients with intermediate and advanced stage HCC[3-5]. The rise of new therapeutic modalities such as radioembolization, the combination of antiangiogenic agents with locoregional therapies and other first and second line systemic options, open up a new paradigm for the treatment of HCC. In this dual cohort study, we aimed to describe treatments performed in the real life setting before the approval of these new systemic options. It is of interest to know the real life context, in order to evaluate the therapeutic management in these patients and gaps that should be explored more thoroughly as areas of public health impro- vement. MATERIALS AND METHODS Study design, setting and participating centers This longitudinal observational cohort study was conducted in 14 different regional hospitals from Argentina. Two cohorts of consecutive adult patients (> 17 years of age) with newly diagnosed HCC were included. Between January 1 2009 and September 1 2014, a retrospective cohort was followed-up until death or last ambulatory visit until January 1 2016 (Cohort 1). A second prospective cohort was included from September 2 2014, followed until January 1 2016 (Cohort 2). Parti- cipating centers appointed a study coordinator responsible for data collection. Sites were instructed to enroll all eligible patients on a sequential basis and to record data from medical charts into a web-based electronic system. In cases of conflicting or missing data, central revision and resubmission was requested. Cohort characteristics and study variables Patients with intermediate (BCLC-B) or advanced-end stage (BCLC C-D) HCC were included[6,7]. Criteria for inclusion required patients to be adult recipients with newly diagnosed HCC either by pathological criteria or imaging evaluation as recomm- ended by international Western guidelines[6,7]. Intermediate stage or BCLC B includes patients with preserved liver function with multifocal tumors, in the absence of cancer related symptoms, vascular invasion or extrahepatic spread. In these patients the recommended treatment is TACE. Advanced-stage HCC (BCLC C) comprises patients with preserved liver function, good performance status or ECOG 1-2, with extrahepatic spread (lymph node involvement or metastases) or vascular invasion. In this subgroup, sorafenib or lenvatinib are the recommended treatments. As lenvatinib has been recently approved in our country (March 2019), this cohort includes patients treated under sorafenib. Best supportive care (BSC) or symptomatic treatment is recommended for patients with unpreserved liver function (Child Pugh C) or ECOG > 2 or cancer related symptoms[8]. Patients were excluded if (1) clinical baseline data was missing; (2) BCLC stage was either 0 or A; and (3) patients with BCLC-B-D who underwent liver transplantation. Baseline characteristics at HCC diagnosis included patients demographics, performance status (ECOG grade 0-4), grade of liver fibrosis (I-IV) assessed by liver biopsy or elastography or other non-invasive measurements or by clinical data (including imaging data, presence of gastro-esophageal varices or ascites or spleno- megaly > 120 mm diameter, or other complications related to portal hypertension), Child Pugh score; selected laboratory variables, serum alpha-fetoprotein (AFP) levels and tumor characteristics at diagnosis, as well as treatments performed. Computed tomography (CT) or magnetic resonance images (MRI) were evaluated considering tumor number and diameter, vascular invasion and extrahepatic or lymph node metastasis. WJG https://www.wjgnet.com 3609 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina Tumor treatment after HCC diagnosis was reviewed, namely: Liver resection (LR), radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), sorafenib and best supportive care (BSC). 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[6,7]. Study end-points Primary end point analyzed was survival, which was assessed for each BCLC stage from the date of treatment until last patient follow-up or death. Secondary objectives were to (1) describe treatments performed in each BCLC stage; (2) to evaluate the sequential treatment of TACE-sorafenib in BCLC-B patients; and (3) to evaluate adverse events and tolerability of sorafenib in the daily practice. All procedures followed were in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement[9]. This study was approved by the Austral University School of Medicine and by each center; complied with the ethical standards (institutional and national) and with Helsinki Declaration of 1975, as revised in 2008. Statistical analysis Statistical significance is expressed as P < 0.05. Categorical data were compared using Fisher’s exact test or Chi-Square test. Continuous variables were compared with Student’s T test or Mann-Whitney U test according to their distribution, respectively. Multiple comparisons for continuous data were done according to its distribution with ANOVA or Kruskal Wallis tests as appropriate. Dummies for ordinal variables were assessed. For survival analysis, Cox regression analysis estimating hazard ratios (HR) and 95%CI for baseline variables related with mortality was performed. Proportional hazards through graphic and statistical evaluation (Schoenfeld residual test) were done. Kaplan Meier survival curves were compared using the log-rank test (Mantel-Cox) Collected data was analyzed using STATA 13.0. RESULTS From a total of 721 consecutive adult patients with HCC during the study period, 327 patients with newly diagnosed intermediate and advanced HCC were included. Patients who received a liver transplant in BCLC-B (n = 16), BCLC-C (n = 2) and BCLC-D (n = 28) were excluded. Table 1 describes the main baseline patient characteristics. Overall, 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). Treatments performed during the whole follow-up period were LR (n = 36), RFA or PEI (n = 19), TACE (n = 126), TARE (n = 6), sorafenib (n = 82) and BSC (n = 146). Outcomes were assessed in all patients during follow-up with a median survival of 12.0 mo (IQR 4.0-27.0 mo). 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). Characteristics and management of patients treated with TACE TACE was performed in 126 patients (38.5%); 77 were BCLC-B, 22 were BCLC-C and 27 patients were BCLC-D. According to the type of endovascular treatment, 43.6% of the patients were treated with conventional TACE (cTACE), 45.2% with TACE with drug eluting beads (TACE-DCbeads) and 11.2% with transarterial embolization (TAE). 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); 40%, 26% and 34% of these patients received 1, 2 and 3 or more sessions, respectively. Other treatments than TACE were performed in BCLC-B patients, as follows: RFA or PEI in 7 patients, liver resection in 21 patients, sorafenib in 15 patients and BSC in 5 patients. Of the 22 BCLC-C patients who were treated with TACE, 13 had non-main portal trunk vascular invasion and 12 patients had extrahepatic disease (lymph node metastasis in 5, bone metastasis in 3 and 4 patients with lung involvement). Sorafenib was the following treatment performed in 7 patients. Among BCLC-D, 27 patients received TACE, 19 were Child Pugh C, 10 patients presented performance status ECOG 3-4, 2 patients presented non-main portal trunk vascular invasion and 1 had extrahepatic disease (lymph node metastasis). Best supportive care following TACE was done in all patients except for 1 who received sorafenib in this latter group. Survival was significantly better in BCLC-B patients treated with TACE HR 0.29 WJG https://www.wjgnet.com 3610 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina Table 1 Patients’ baseline characteristics Variable Values Age, yr (± SD) 63 ± 10 Male gender, n (%) 265 (81.3) Non-cirrhotic liver, n (%) 41 (12.5) Child Pugh A/B/C, n (%) 137 (42)/98 (30)/92 (28) Etiology of liver disease, n (%) Hepatitis C virus 99 (30.3) Alcohol 77 (23.5) NASH 35 (10.7) Cryptogenic 37 (11.3) Hepatitis B virus 22 (6.7) 1 Cholestatic 4 (1.2) Autoimmune - Hemochromatosis 6 (1.8) Miscellaneous 36 (11.0) Comorbidities, n (%) 141 (43.1) Diabetes mellitus, n (%) 84 (25.7) Ascites, n (%) Mild 76 (23.3) Moderate-severe 77 (23.5) Encephalopathy, n (%) Grade I-II 78 (23.8) Grade III-IV 6 (1.8) CSPH, n (%) 212 (64.8) ECOG 0-2, n (%) 262 (80.1) 1 Cholestatic: Primary Biliary Cholangitis, Primary and Secondary Sclerosing Cholangitis. NASH: Non- alcoholic steatohepatitis; CSPH: Clinically significant portal hypertension defined as presence of at least one of the following: Ascites, gastroaesophaguel varices or hepatic encephalopathy. (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 (Figure 2A). According to tumor reassessment after the first TACE, patients with complete response (CR) achieved a better overall survival with a HR of 0.15 (CI: 0.04-0.56. P = 0.005) (Figure 2B). Characteristics and management of patients treated with sorafenib 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, 15 were TACE naïve and 21 received a median number of 3 TACE sessions (IQR 2-4 sessions) until disease progression (n = 7) or no response (n = 14). Among BCLC-C patients (n = 65), 55.4% were treated with sorafenib, 21 received BSC and 8 patients received other treatments (4 patients TACE, 1 TARE and patients 3 LR). Median sorafenib treatment duration was 4.0 mo (IQR 2-11 mo). The most frequent sorafenib starting dose was 400 mg/d in 41% of the patients, followed by 800 mg/d in 32%. During follow-up, 55% of the patients achieved 800 mg full-dose of treatment, 35.4% had dose reductions (n = 29) of which in 21 patients dose-reduction were associated with drug-related adverse events. Most frequent adverse events (AEs) were fatigue (n = 27), diarrhea (n = 16), dermatologic events (n = 5), hand-foot-skin reaction (n = 3), and hypertension (n = 1). Permanent treatment discontinuation was observed in 12.2% of the patients secondary to treatment AEs (n = 10), tumor progression in 26.8%, (n = 22) and death in the rest of the patients. In 37 out of 82 patients in which radiologic evaluation after sorafenib initiation was performed, complete and partial responses were observed in 1.2% (n = 1) and 2.4% (n = 2), respectively. In these subgroup, median time to progression since sorafenib initiation was 7.3 mo (IQR 2.1- 10.7 mo). 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 (Figure 3). When comparing BCLC- WJG https://www.wjgnet.com 3611 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina Figure 1 Figure 1 Cumulative survival stratified by Barcelona Clinic Liver Cancer staging in the overall cohort. BCLC: Barcelona clinic liver cancer. B and C vs BCLC-D treated patients, although it did not reach statistical significance, a better survival curve was observed in BCLC-B/C patients with a HR of 0.63 (CI: 0.31- 1.27; P = 0.19). Sequential treatment with Sorafenib after TACE and impact on survival Imaging evaluation after the first TACE in BCLC-B patients was registered in 64 out of 77 patients in median time from TACE to evaluation of 5 wk (IQR 4-6 wk). According to RECIST 1.1 criteria tumor response was as follows: partial response in 62.5% (n = 40), stable disease 15.6% (n = 10), complete response in 12.5% (n = 8), and disease progression in 9.3% (n = 6). Thus, overall objective response (ORR) and disease control rates (DCR) were 75% and 90.7% after first TACE, respectively. In BCLC-B patients treated with sorafenib after progression (n = 36), the sequential treatment of sorafenib following TACE presented better survival when compared to those patients who received sorafenib without prior treatment with TACE [HR = 0.26 (CI: 0.09-0.71); P = 0.013] (Figure 4). Median number of TACEs in these patients prior to systemic treatment was 3 sessions (IQR 2-4 sessions). Among those patients not treated with TACE prior to sorafenib initiation, prior treatments were RFA/PEI (n = 4) and LR (n = 5). DISCUSSION This is the first observational study of treatments performed in the real life setting from Argentina in patients with intermediate to advanced stage HCC and one of the only ones to report post-treatment survival in Latin America. Knowing the real life treatment patterns is of interest to highlight unmet needs in the daily practice prior to the introduction of new treatments for HCC. In this cohort we observed that in the majority of patients in intermediate stage, the most frequent treatment in daily practice was TACE. The effect on survival was beneficial in these patients in particular when treatment was established in accor- dance with Western clinical practice recommendations [ 6 , 7 ] . In patients with unpreserved liver function or BCLC-C, TACE was performed in a smaller proportion with heterogeneous effect on survival. On the other hand, those patients in BCLC-B stage with complete tumor response after TACE showed a better survival. Likewise, a non-negligible proportion of BCLC-B patients started sorafenib in the absence of prior TACE as a decision of “treatment stage migration”[10]. In the era of sequential treatment recommendation, in those BCLC-B patients with tumor progression after TACE[11], a better survival with sorafenib was observed with respect to those patients without prior TACE. Knowing the therapeutic decisions in the daily practice is important because it reflects the gaps between interventional studies evaluating efficacy in ideal situations WJG https://www.wjgnet.com 3612 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina Table 2 Stratified analysis comparing transarterial chemoembolization treatment in barcelona clinic liver cancer stage B BCLC stage B overall (n = BCLC stage B with TACE BCLC stage B without Variable P value 135) (n = 77) TACE (n = 58) Age, yr (± SD) 65 ± 10 65 ± 8 65 ± 11 0.86 Male gender, n (%) 111 (82.2) 68 (88.3) 43 (74.1) 0.03 Non-cirrhotic liver, n (%) 23 (17.0) 7 (9.1) 16 (27.6) 0.006 Etiology, n (%) 0.11 HCV 42 (31.1) 25 (32.5) 17 (29.3) HBV 8 (5.9) 5 (6.5) 3 (5.2) Alcohol 29 (21.5) 21 (27.3) 8 (13.8) Etiology, nNASH 14 (10.4) 6 (7.8) 8 (13.8) Etiology, nOthers 42 (31.1) 20 (25.9) 22 (37.9) Child Pugh A/B, n (%) 88 (65.2)/47 (34.8) 48 (62.3)/29 (37.7) 40 (69.0)/18 (31.0) 0.42 1 CSPH , n (%) 67 (49.6) 45 (58.4) 22 (37.9) 0.018 Median nº HCC nodules 2 (2-3) 2 (1-3) 2 (1-4) 0.39 (IQR) Median largest HCC 65 (43-100) 60 (43-88) 69.5 (45-114.5) 0.11 diameter, mm, (IQR) Bilobar involvement, n (%) 53 (39.3) 30 (39.0) 23 (39.7) 0.72 Diffuse HCC pattern, n (%) 5 (3.7) 2 (2.6) 3 (5.2) 0.72 Median AFP, ng/mL (IQR) 26.7 (4.7-248.5) 27.5 (5.1-202.85) 24.4 (4.3-285) 0.91 AFP > 200 ng/mL, n (%) 36 (27.3) 19 (25.0) 17 (30.4) 0.49 AFP > 400 ng/mL, n (%) 30 (22.7) 17 (22.4) 13 (23.2) 0.91 AFP > 1000 ng/mL, n (%) 18 (13.6) 11 (14.5) 7 (12.5) 0.74 Vascular invasion, n (%) - Extrahepatic disease, n (%) - 1 Clinically significant portal hypertension defined as presence of at least one of the following: Ascites, gastro-aesophagueal varices or hepatic encephalopathy. AFP: Alpha-feto protein; TACE: Transarterial chemoembolization; BCLC: Barcelona clinic liver cancer. and those in the real-life setting. The BRIDGE study is an example, among others, of how therapeutic decisions in patients with HCC are complex, demanding a fine knowledge not only of tumor extension, but also of liver disease and its complica- tions[12]. That is why the role of hepatologists is of utmost importance in the treatment of these patients. In our cohort, most of the patients were screened, diagnosed and treated by hepatologists, both in referral or local centers. Treatment with TACE has been established as the gold standard for intermediate stage HCC since more than 10 years ago[3,4]. Two randomized, placebo-controlled trials have shown its survival benefit [3,4] ; results further underlined in a meta- analysis[13]. However, clinical and tumor heterogeneity, which are characteristic of BCLC-B patients, results in a diversity of established treatments[12]. In our analysis, we excluded BCLC-B patients who underwent transplantation, given that we considered performing a pure analysis in this stage. The same went for BCLC-D patients. In the original trials of TACE, a median survival was close to eighteen months[3,4,14] whereas in more recent observational studies, median survival of forty months has been reported[15]. In our study, median survival in BCLC-B patients treated with TACE was fifteen months. Survival was significantly better in BCLC-B patients treated with TACE with a 71% relative risk reduction of death when compared with BCLC-B without TACE and BCLC-C or D patients treated with TACE. According to tumor reassessment by RECIST 1.1 criteria after the first TACE, patients with complete response had the highest survival benefit, as previously reported elsewhere[16]. Systemic treatment of HCC is remarkably changing given the introduction of alternative therapies in first line such as lenvatinib[17] and second-line including regorafenib[18], cabozantinib[19] and ramucirumab[20]. In our country, as in many others from Latin America, approval of these new treatments usually takes between 12 and 24 mo later than other developed regions of the world. In 2009 and 2017, sorafenib and regorafenib were approved in our country, respectively. Recently, the use of lenvatinib has also been approved, not yet included in the daily practice. Treatment with immunotherapy, either with nivolumab[21] or pembrolizumab[22], has not been approved by the National Regulatory Agency in our country (ANMAT). WJG https://www.wjgnet.com 3613 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina Figure 2 Figure 2 Characteristics and management of patients treated with transarterial chemoembolization. A: Kaplan Meier survival curves according to Barcelona Clinic Liver Cancer stage and treatment with/without trans-arterial chemoembolization; B: Survival according to radiological response after the first transarterial chemoembolization (TACE) evaluated by RECIST 1.1 criteria. BCLC: Barcelona clinic liver cancer. Argentina is a South American country with a wide extension, a great socio- cultural heterogeneity with a large variety in health care systems. In many cases, the main barrier for the access to health system is the authorization by insurances to carry out diagnostic studies or therapies due to costs or other barriers. This problem is common in Latin America[23]. In this study, the use of sorafenib slightly exceeded half of BCLC-C patients, presenting better survival when compared with those patients in the same stage but without systemic treatment. We observed that in our cohort, median survival with the use of sorafenib was strikingly low, being no more than 5 months. This lower than expected outcome can be explained, in part, by the delay in starting treatment, due to a wide range of authorizations and complex administrative processes. This might have leaded to a significant slowness in the initiation of systemic treatment. Moreover, most of the patients were initially treated with half dose rather than full dose. It is noteworthy of mention that sorafenib tolerance was similar to that reported from first (SHARP and Asia-Pacific)[5,24] and second line (RESORCE)[18] clinical trials, with a rate of definitive treatment discontinuation due to related adverse events of 12.2%. On the other hand, in those patients in whom radiological response was evaluated, median time to progression under treatment with sorafenib was similar than that previously reported[18]. Finally, we observed that there was an inadequate use of sorafenib in patients with unpreserved liver function or BCLC-D that was associated with a poor prognosis, demonstrating an inadequate and inefficiency use of resources. Our study has limitations. In particular, given that it was mainly a retrospective cohort study, exposed to different selection and information biases. Specifically, neither radiological evaluation assessing time to progression was homogeneous nor there was a centrally blinded evaluation through all participating centers. However, we enrolled a group of centers presenting similar decision making processes trying to homogenize the sample. In conclusion, in this dual cohort study from Argentina, we described the treatme- nts performed in the real life setting before the approval of new systemic options. Knowing this life context is of interest, in order to assess the most common therap- eutic decision making processes and management in these patients. In this real setting, our results highlights unmet needs and improvement areas in public health among developing regions, particularly to promote early and correct treatments in each stage, prior to the introduction of new treatments for HCC. ACKNOWLEDGEMENTS On behalf of the Latin American Liver Research, Education and Awareness Network (LALREAN). WJG https://www.wjgnet.com 3614 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina Table 3 Characteristic of patients treated with sorafenib Variable Overall (n = 82) BCLC stage B (n = 36) BCLC stage C (n = 36) BCLC stage D (n = 10) P value Age, yr (± SD) 63 ± 9 63 ± 8 62 ± 10 63 ± 8 0.86 Male gender, n (%) 68 (82.9) 29 (80.6) 31 (86.1) 8 (80.0) 0.88 Non-cirrhotic liver, n (%) 9 (11.0) 3 (8.3) 5 (13.9) 1 (10.0) 0.78 Etiology, n (%) 0.11 HCV 28 (34.1) 16 (44.4) 11 (30.6) 1 (10.0) HBV 4 (4.9) 2 (5.6) 1 (2.8) 1 (10.0) Alcohol 18 (21.9) 9 (25.0) 8 (22.2) 1 (10.0) NASH 10 (12.2) 4 (11.1) 4 (11.1) 2 (20.0) Others 22 (26.8) 5 (13.9) 12 (33.3) 5 (50.0) Child Pugh A/B/C, n (%) 48 (58)/30 (37)/4 (5) 25 (69)/11 (31)/- 21 (58)/15 (42)/- 2 (20)/4 (40)/4 (40) CSPH1, n (%) 45 (54.9) 21 (58.3) 18 (50.0) 6 (60.0) 0.66 Median nº HCC nodules (IQR)2 2 (1-4) 2 (2-4) 2 (1-4) 1.5 (1-2) 0.25 Median largest HCC diameter, mm, 70 (47-100) 65 (46-90) 87 (48.5-130) 57.5 (39-121) 0.56 (IQR)2 Bilobar involvement, n (%) 30 (37.0) 10 (27.8) 18 (50.0) 3 (30.0) 0.33 Diffuse HCC pattern, n (%) 6 (7.4) 2 (5.6) 3 (8.3) 1 (10.0) 0.35 Median AFP, ng/mL (IQR) 103 (7.0-1069) 30 (7.2-739) 150 (6.3-1210) 649 (16-2198) 0.26 AFP > 200 ng/mL, n (%) 35 (43.7) 12 (34.3) 16 (45.7) 7 (70) 0.13 AFP > 400 ng/mL, n (%) 30 (37.5) 10 (28.6) 13 (37.1) 7 (70) 0.06 AFP > 1000 ng/mL, n (%) 21 (25.9) 5 (14.3) 12 (33.3) 4 (40) 0.13 Vascular invasion, n (%) 27 (33.3) - 25 (69.4) 3 (30.0) < 0.0001 Extrahepatic disease, n (%) 19 (23.5) - 18 (50.0) 1 (10.0) < 0.0001 1 Clinically significant portal hypertension defined as presence of at least one of the following: ascites, gastro-aesophagueal varices or hepatic encephalopathy. 2 Intrahepatic nodules. AFP: Alpha-feto protein; TACE: Transarterial chemoembolization; BCLC: Barcelona clinic liver cancer. Figure 3 Figure 3 Corresponding survival curves for patients treated with Sorafenib stratified by Barcelona Clinic Liver Cancer stages. BCLC: Barcelona clinic liver cancer. WJG https://www.wjgnet.com 3615 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina Figure 4 Figure 4 Survival in Barcelona Clinic Liver Cancer stage B patients under tumor progression with the sequential treatment of transarterial chemoembolization-sorafenib. BCLC: Barcelona clinic liver cancer. 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 WJG https://www.wjgnet.com 3616 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina 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. REFERENCES 1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90 [PMID: 21296855 DOI: 10.3322/caac.20107] 2 Piñero F, Marciano S, Fernández N, Silva J, Zambelo Y, Cobos M, Zerega A, Ridruejo E, Miguez C, Ameigeiras B, D'Amico C, Gaite L, Coronel M, Bermúdez C, Rosales C, Romero G, McCormack L, Reggiardo V, Colombato L, Gadano A, Rubinstein F, Silva M; Argentinean Association for the Study of Liver Diseases (A. A.E.E.H). Adherence to Barcelona Clinic Liver Cancer therapeutic algorithm for hepatocellular carcinoma in the daily practice: a multicenter cohort study from Argentina. Eur J Gastroenterol Hepatol 2018; 30: 376-383 [PMID: 29509603 DOI: 10.1097/MEG.0000000000001049] 3 Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solà R, Rodés J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359: 1734-1739 [PMID: 12049862 DOI: 10.1016/S0140-6736(02)08649-X] 4 Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164-1171 [PMID: 11981766 DOI: 10.1053/jhep.2002.33156] 5 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390 [PMID: 18650514 DOI: 10.1056/NEJMoa0708857] 6 European Association for the Study of the Liver; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018; 69: 182- 236 [PMID: 29628281 DOI: 10.1016/j.jhep.2018.03.019] 7 Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, Murad MH, Marrero JA. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018; 67: 358-380 [PMID: 28130846 DOI: 10.1002/hep.29086] 8 Bruix J, Reig M, Sherman M. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. Gastroenterology 2016; 150: 835-853 [PMID: 26795574 DOI: 10.1053/j.gastro.2015.12.041] 9 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61: 344-349 [PMID: 18313558 DOI: 10.1016/j.jclinepi.2007.11.008] 10 Reig M, Darnell A, Forner A, Rimola J, Ayuso C, Bruix J. Systemic therapy for hepatocellular carcinoma: the issue of treatment stage migration and registration of progression using the BCLC-refined RECIST. Semin Liver Dis 2014; 34: 444-455 [PMID: 25369306 DOI: 10.1055/s-0034-1394143] 11 Hucke F, Sieghart W, Pinter M, Graziadei I, Vogel W, Müller C, Heinzl H, Waneck F, Trauner M, Peck- Radosavljevic M. The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE. J Hepatol 2014; 60: 118-126 [PMID: 24012941 DOI: 10.1016/j.jhep.2013.08.022] 12 Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS, Sherman M. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int 2015; 35: 2155-2166 [PMID: 25752327 DOI: 10.1111/liv.12818] 13 Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37: 429-442 [PMID: 12540794 DOI: 10.1053/jhep.2003.50047] 14 Dunning JJ, Mullins PA, Scott JP, Solis E, Schofield PM, Large SR, Wallwork JW. Cardiac WJG https://www.wjgnet.com 3617 July 21, 2019 Volume 25 Issue 27 Piñero F et al. Intermediate-advanced HCC in Argentina transplantation and cancer. Am J Cardiol 1991; 67: 327 [PMID: 1990809 DOI: 10.1007/s00270-009-9711-7] 15 Burrel M, Reig M, Forner A, Barrufet M, de Lope CR, Tremosini S, Ayuso C, Llovet JM, Real MI, Bruix J. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol 2012; 56: 1330- 1335 [PMID: 22314428 DOI: 10.1016/j.jhep.2012.01.008] 16 Choi J, Shim JH, Shin YM, Kim KM, Lim YS, Lee HC. Clinical significance of the best response during repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma. J Hepatol 2014; 60: 1212-1218 [PMID: 24486088 DOI: 10.1016/j.jhep.2014.01.014] 17 Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391: 1163-1173 [PMID: 29433850 DOI: 10.1016/S0140-6736(18)30207-1] 18 Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389: 56-66 [PMID: 27932229 DOI: 10.1016/S0140-6736(16)32453-9] 19 Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med 2018; 379: 54-63 [PMID: 29972759 DOI: 10.1056/NEJMoa1717002] 20 Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20: 282-296 [PMID: 30665869 DOI: 10.1016/S1470-2045(18)30937-9] 21 El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389: 2492- 2502 [PMID: 28434648 DOI: 10.1016/S0140-6736(17)31046-2] 22 Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open- label phase 2 trial. Lancet Oncol 2018; 19: 940-952 [PMID: 29875066 DOI: 10.1016/S1470-2045(18)30351-6] 23 Piñero F, Poniachik J, Ridruejo E, Silva M. Hepatocellular carcinoma in Latin America: Diagnosis and treatment challenges. World J Gastroenterol 2018; 24: 4224-4229 [PMID: 30310255 DOI: 10.3748/wjg.v24.i37.4224] 24 Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. 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