Received: 10 March 2022 | Revised: 3 May 2022 | Accepted: 21 May 2022 DOI: 10.1111/liv.15320 ORIGINAL ARTICLE (DIRECT VIA EEO) Outcome of liver cancer patients with SARS-­CoV-­2 infection: An International, Multicentre, Cohort Study Sergio Muñoz-­Martínez1,2,3,4 | Victor Sapena1,2,4,5 | Alejandro Forner1,2,3,4 | 1,2,3,4 1,2,3,4 6 Jordi Bruix | Marco Sanduzzi-­Zamparelli | José Ríos | 7 8 9,10 Mohamed Bouattour | Mohamed El-­Kassas | Cassia R. G. Leal | 11 12,13,14 15,16 Tudor Mocan | Jean-­Charles Nault | Rogerio C. P. Alves | 17,18 19 20 Helen L. Reeves | Leonardo da Fonseca | Ignacio García-­Juárez | 21 22 23 David J. Pinato | María Varela | Saleh A. Alqahtani | Mario R. Alvares-­da-­Silva24 | Juan C. Bandi25 | 26,27 28 Lorenza Rimassa | Mar Lozano | Jesús M. González Santiago29 | 29,30 31 32 Frank Tacke | Margarita Sala | María Anders | Anja Lachenmayer33 | 34 35 36 37 Federico Piñero | Alex França | Maria Guarino | Alessandra Elvevi | 38 39 40 Giuseppe Cabibbo | Markus Peck-­Radosavljevic | Ángela Rojas | 41 42 43 Mercedes Vergara | Chiara Braconi | Sonia Pascual | Christie Perelló44 | 45 46 47 48 Vivianne Mello | Carlos Rodríguez-­Lope | Juan Acevedo | Rosanna Villani | 49 50,51 8 Clemence Hollande | Valérie Vilgrain | Ahmed Tawheed | 52 53 Carmem Ferguson Theodoro | Zeno Sparchez | Lorraine Blaise12,13,14 | Daniele E. Viera-­Alves15,16 | Robyn Watson18 | Flair J. Carrilho54 | Carlos Moctezuma-­Velázquez20 | Antonio D'Alessio21,26 | Massimo Iavarone55 | 1,2,3,4 Maria Reig 1 Unitat d'Oncologia hepàtica, Liver Unit, Hospital Clínic, Barcelona, Spain 2 BCLC group, IDIBAPS, Barcelona, Spain 3 CIBEREHD, Barcelona, Spain 4 Universitat de Barcelona (UB), Barcelona, Spain 5 Medical Statistics Core Facility, Institut D'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona, Spain 6 Department of Clinical Farmacology Hospital Clinic and Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain 7 AP-­HP, Hôpital Beaujon, Liver Cancer Unit, Clichy, France 8 Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt 9 Gastroenterology, Hospital Universitário Antônio Pedro, Universidade Federal Fuminense, Rio de Janeiro, Brazil 10 Gastroenterology, Hospital Federal do Servidores do Estado, Rio de Janeiro, Brazil 11 3rd Medical Department, "Octavian Fodor" Institute for Gastroenterology and Hepatology, Cluj-­Napoca, Romania Abbreviations: BCLC, Barcelona clinic liver cancer; BSC, best supportive care; CI, confidence interval; COVID-­19, coronavirus disease 2019; HCC, hepatocellular carcinoma; HR, Hazard ratio; iCCA, intrahepatic cholangiocarcinoma; IQR, interquartile range; SARS-­CoV-­2 , severe acute respiratory syndrome. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2022 The Authors. Liver International published by John Wiley & Sons Ltd. Liver International. 2022;42:1891–1901.  wileyonlinelibrary.com/journal/liv | 1891 1892 | MUÑOZ-­MARTÍNEZ et al. 12 Liver unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-­Seine-­Saint-­Denis, Assistance-­Publique Hôpitaux de Paris, Bobigny, France 13 Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France 14 Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology. Université de Paris, team « Functional Genomics of Solid Tumors, Paris, France 15 Gastroenterology, Hospital do Servidor Publico Estadual de São Paulo, Sao Paulo, Brazil 16 Bp Beneficência Portuguesa de São Paulo, Sao Paulo, Brazil 17 Liver Unit, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 18 Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK 19 Clinical Oncology, Sao Paulo Clinicas Liver Cancer Group. Instituto do Cancer do Estado de Sao Paulo. Hospital das Clínicas. University of Sao Paulo School of Medicine, Sao Paulo, Brazil 20 Gastroenterology Department, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico 21 Department of Surgery and Cancer, Imperial College London, London, UK 22 Liver Unit, Department of Digestive Disease, Hospital Universitario Central de Asturias, IUOPA, ISPA, Universidad de Oviedo, Oviedo, Spain 23 Liver Transplant, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia 24 GI/Liver Unit, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 25 Hepatology Unit, Hospital Italiano, Buenos Aires, Argentina 26 Department of Biomedical Sciences, Humanitas University, Rozzano, Italy 27 Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS, Humanitas Research Hospital, Rozzano, Italy 28 Aparato Digestivo, Hospital Universitario Infanta Leonor, Madrid, Spain 29 Department of Gastroenterology and Hepatology, Salamanca University Clinic Hospital, IBSAL, CIBERehd, Salamanca, Spain 30 Department of Hepatology and Gastroenterology, Charité-­Universitätsmedizin, Campus Virchow-­K linikum and Campus Charité Mitte, Berlin, Germany 31 Gastroenterology, Hepatology Unit, Hospital Doctor Josep Trueta, IDIBGI (Institut d'Investigació Biomèdica de Girona), CIBERehd, Girona, Spain 32 Hospital Aleman, Hepatología, Buenos Aires, Argentina 33 Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland 34 Liver Unit, Hospital Universitario Austral, Pilar, Argentina 35 Medicine, Federal University of Sergipe, Aracaju, Brazil 36 Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy 37 Division Gastroenterology and Center for Autoimmune Liver Diseases San Gerardo Hospital University of Milano -­Bicocca School of Medicine, Monza, Italy 38 Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy 39 Innere Medizin & Gastroenterologie, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria 40 SeLiver group. Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla-­CIBERehd, Seville, Spain 41 Unitat d'Hepatologia, Servei d'Aparell Digestiu, Parc Taulí Sabadell Hospital Universitari, Institut d'Investigació i Innovació I3PT, Universitat Autònoma de Barcelona, Barcelona, Departament de Medicina, Universitat Autònoma de Barcelona, CIBERehd. Instituto Carlos III, Madrid, Spain 42 Medical Oncology, Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK 43 Liver Unit. HGU Dr. Balmis. CIBERehd. ISABIAL, Alicante, Spain 44 Gastroenterology and Hepatology, University Hospital Puerta de Hierro, Majadahonda, Spain 45 Oncology, AMO CLINIC, Salvador, Brazil 46 Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain 47 South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK 48 Department of Medical and Surgical Sciences, Foggia, Italy 49 AP-­HP, Hôpital Beaujon, Liver Cancer Unit, Clichy, France 50 Université de Paris, Paris, France 51 Department of Radiology, Hôpital Beaujon, AP-­HP. Nord, Clichy, France 52 Department of Gastroenterology, Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niteroi, Brazil 53 3rd Medical Department, Institute for Gastroenterology and Hepatology, University of Medicine and Pharmacy, Cluj-­Napoca, Romania 54 Sao Paulo Clínicas Liver Cancer Group. Instituto do Cancer do Estado de Sao Paulo. Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil 55 Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico –­Division of Gastroenterology and Hepatology, Milan, Italy MUÑOZ-­MARTÍNEZ et al. | 1893 Correspondence Massimo Iavarone, Foundation IRCCS Ca’ Abstract Granda Ospedale Maggiore Policlinico Background & Aims: Information about the impact of severe acute respiratory syn- –­Division of Gastroenterology and Hepatology, Milan, Italy. drome coronavirus 2 (SARS-­CoV-­2) in patients with liver cancer is lacking. This study Email: massimo.iavarone@gmail.com; characterizes the outcomes and mortality risk in this population. massimo.iavarone@policlinico.mi.it Methods: Multicentre retrospective, cross-­sectional, international study of liver can- Maria Reig, BCLC group, Liver Unit, IMDiM, CIBERehd, IDIBAPS, Hospital cer patients with SARS-­CoV-­2 infection registered between February and December Clínic, c/ Villarroel, 170, Escala 11, 4a 2020. Clinical data at SARS-­CoV-­2 diagnosis and outcomes were registered. planta, 08036 Barcelona. Spain. Email: mreig1@clinic.cat Results: Two hundred fifty patients from 38 centres were included, 218 with hepa- tocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). Funding information Spanish Health Ministry; Ricerca Corrente, The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in Grant/Award Number: RC2019/105-­01, the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at RC2018/105-­01 and RC2017/105-­01; European Association for the Study of SARS-­CoV-­2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a the Liver (Andrew Burroughs Fellowship); median follow-­up of 7.20 (IQR: 1.84–­11.24) months, 100 (40%) patients have died, Cancer Treatment and Research Trust (CTRT); Wellcome Trust Strategic Fund, 48% of the deaths were SARS-­CoV-­2-­related. Forty (18.4%) HCC patients died Grant/Award Number: PS3416; Cancer within 30-­days. The death rate increase was significantly different according to Research UK (CR UK) centre, Grant/ Award Number: C9380/A26813, C18342/ the BCLC stage (6.10% [95% CI 2.24–­12.74], 11.76% [95% CI 4.73–­22.30], 20.69% A23390 and C9380/A18084; Instituto de [95% CI 11.35–­31.96] and 34.52% [95% CI 17.03–­52.78] for BCLC 0/A, B, C and D, Salud Carlos III, Grant/Award Number: PI18/0358, PI15/00145, CD18/00126, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49–­4.31; p = .5032) PI19/00819, FI19/00222, 16-­0 026, in BCLC-­B versus 0/A, and 3.13 (95% CI 1.29–­7.62; p = .0118) in BCLC-­C versus 0/A PI044031, PI18/00768, PI18/00542 and PI13/01229; Bristol Myers Squibb and in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, Celgene; Cancer Research UK, Grant/ and 12 deaths were related to SARS-­CoV-­2 infection. Award Number: RCCPDB-­Nov21/100008 Conclusions: This is the largest cohort of liver cancer patients infected with SARS-­ Handling Editor: Dr. Luca Valenti CoV-­2. It characterizes the 30-­day mortality risk of SARS-­CoV-­2 infected patients with HCC during this period. KEYWORDS COVID-­19, hepatocellular carcinoma, liver cancer, mortality 1 | I NTRO D U C TI O N result of the assessments done because of COVID-­19 infection diagno- sis and those who had a history of liver cancer. After the start of the Coronavirus Disease 2019 (COVID-­19) in 2019, all A microsimulation model on five cancers (breast, cervix, colorec- countries worldwide made a huge effort to face up to the health issues tal, prostate and stomach) found that delays in diagnosis will result in a derived from the pandemic. In December 2020 the first SARS-­CoV-­2 worse cancer stage at presentation, leading to worse survival outcomes.8 vaccine was authorized by the U.S. Food and Drug Administration, Liver cancer was not represented in that model and such data should while it was granted a conditional marketing authorization by the be confirmed in the liver cancer realm. A second harm of the pandemic European Medicines Agency.1 Nevertheless, just after the first wave, is the COVID-­19-­related and non-­COVID-­19-­related mortality.9 In the further waves emerged and the sequelae of the pandemic will prob- liver cancer setting, the mortality analysis is complex because almost all ably continue for years. Our previous study2 showed that all treat- hepatocellular carcinoma (HCC) patients and some of the intrahepatic ments, except systemic therapy, had relevant interruptions during the cholangiocarcinoma (iCCA) patients present underlying cirrhosis. first wave around the World. Indeed, 48% of the centres decreased the Iavarone et al.10 evaluated the 30-­day mortality rate in cirrhotic pa- number of physicians devoted to managing liver cancer. Gandhi et al.3 tients but only 22% of them had active or history of liver cancer. Thus, also assessed the impact on COVID-­19 in 14 Asia-­Pacific countries and there is neither mortality data nor information about the impact of the observed similar results. One of the main harms of the pandemic ac- liver cancer stage in the outcome of patients diagnosed as a result of cording to Muñoz et al.2 was the delay in liver cancer diagnosis because SARS-­CoV-­2 diagnosis. Lai et al.11 analysed the indirect excess deaths (be- of the modification of screening, reported in 80.9% of the participat- cause of pandemic-­induced healthcare service reconfiguration) on cancer ing centres. A similar impact of COVID-­19 was also reported for other patients from the United Kingdom. They concluded that cancer services cancers4–­7 and in the current study, here we characterize the profile and had only partially recovered with the lockdown easing. They also sug- evolution of those patients incidentally diagnosed with liver cancer as a gested that this situation may contribute to substantial excess mortality 1894 | MUÑOZ-­MARTÍNEZ et al. and multimorbidity among cancer patients. According to their analysis, the 1-­year liver cancer mortality in patients without comorbidities or with Keypoints one or two comorbidities are 50.2%, 50.3% and 49.5% respectively. Here, Data regarding clinical profile and outcomes of liver can- again there is neither information about the liver cancer stage nor the cer patients with SARS-­CoV-­2 infection were lacking. This impact of the 30-­day mortality rate. They pointed out the urgent need to international project aims to characterize these patients´ better understand and mitigate these excess mortality risks. The present outcomes and generate clinical data useful for informed analysis is the second part of the Liver cancer outcome in the COVID-­19-­ prognosis prediction in this population. pandemic (CERO-­19) which aims to address the outcome of SARS-CoV-2 on liver cancer patients and to understand the confounding factors at the time of analysing their mortality. The specific aims of the present analysis were (1) to describe The clinical variables registered were the presence of cirrhosis (yes/ the profile of patients with liver cancer as a result of the tests no), Child-­Pugh status previous to and at SARS-­CoV-­2 infection, liver performed because of SARS-­C oV-­2 infection as well as their disease aetiology, date of SARS-­CoV-­2 diagnosis, liver cancer stage at outcome; (2) to analyse the 30-­d ay mortality rate of liver cancer the moment of SARS-­CoV-­2 diagnosis by BCLC staging12,13 system for patients with SARS-­C oV-­2 infection. This information will be key HCC patients and TNM-­8th edition staging system14 for iCCA, the last to understand the outcome of liver cancer patients who started liver cancer treatment (if any) received before SARS-­CoV-­2 infection oncologic treatments before or during the pandemic as well as diagnosis, patient's liver cancer treatment after the resolution of the the evolution of new liver cancer diagnosed during SARS-­C oV-­2 SARS-­CoV-­2 infection, if there was need to stop or delay the liver can- infection. cer treatment because of SARS-­CoV-­2 infection, and if there was liver cancer progression, specifying the date and pattern of the progression. The centres specified for each patient if hospitalization because 2 | PATI E NT S A N D M E TH O DS of SARS-­CoV-­2 diagnosis was needed, SARS-­CoV-­2 infection treat- ment (including use of antibiotics, anti-­thrombotic prophylaxis and 2.1 | Patients corticosteroids), dates of start and end of the treatment and their outcome. The last follow-­up date until 30th June 2021 or death This is a multicentre, retrospective, cross-­sectional and international date were registered, specifying if death was SARS-­CoV-­2 infection-­ study that evaluated the clinical outcomes of liver cancer patients related or not related, claryfing the cause in the latter. diagnosed with SARS-­CoV-­2. Centres around the world were invited to participate as described in CERO-­19 project. 2 The inclusion criteria were (1) patients older than 18 years old; (2) 2.4 | Statistical analysis with de novo or history of HCC or iCCA and (3) who were infected with SARS-­CoV-­2 between February and December 2020. Continuous or ordinal variables were expressed as median and inter- SARS-­CoV-­2 diagnosis was defined according to each centre local quartile range [IQR: 25th–­75th percentiles]. Categorical data were policy: Positive result on a reverse-­transcription PCR (RT-­PCR) assay expressed as absolute frequency and percentages (%). of a specimen collected on a nasopharyngeal swab, positive antigen The 30-­day mortality rate and their 95% confidence intervals test and/or radiological changes compatible with SARS-­CoV-­2 diag- (95% CI) were calculated using Kaplan–­Meier method. The 30-­day nosis in a patient with clinical signs of SARS-­CoV-­2 infection. SARS-­CoV-­2-­related death rate (or non-­SARS-­CoV-­2-­related death) was calculated with Kaplan–­Meier method using the non-­SARS-­ CoV-­2-­related death (or SARS-­CoV-­2-­related death) as competing 2.2 | Data collection risk. Cox regression models with non-­SARS-­CoV-­2-­related death as competing risks were used to estimate sub-­distribution Hazard The study was approved by the institutional review board Ratios (HR) and their 95% CI. (HCB/2020/0454). Each centre was responsible to obtain the local ap- The level of significance was set at 5% (two-­sided). All statistical proval for the project in their centre. The study complied with the provision analyses were performed using SAS 9.4 software (SAS Institute). of the Good Clinical Practice guidelines and the Declaration of Helsinki. The data registry started from the date of the first SARS-­CoV-­2 infection described in each country, allowing patient's inclusion from 3 | R E S U LT S February 2020 until December 2020. 3.1 | Baseline characteristics 2.3 | Variables A total of 252 patients were registered. Two patients were excluded (one had a focal nodular hyperplasia and the second a non-­specified The study used REDCap® for data collection. Included patients were de-­ liver cancer different to HCC or iCCA). Therefore, 250 patients from identified and assigned to an individual-­anonymized alphanumeric code. 38 centres were included between February 1st, and December MUÑOZ-­MARTÍNEZ et al. | 1895 31st, 2020. Table S1 describes the centres included in Europe, (80%) were cirrhotic. Their BCLC stage at SARS-­CoV-­2 infection was America, Asia and Africa. BCLC-­0 in 1 (1.8%), A in 22 (40.0%), B in 8 (14.5%), C in 14 (25.5%) Figure 1 describes the flow chart of the study. Sixty-­one (24.4%) and D in 10 (18.2%). In the BCLC-­A stage, there were 19 (86.4%) patients had de-­novo liver cancer diagnosis (54 [90.2%] HCC and 6 patients with a single nodule and 3 (13.6%) patients with up to 3 [9.8%] iCCA), 163 (65.2%) had a history of HCC, and 26 (10.4%) had nodules and up to 3 cm each. a history of iCCA. Only one patient was diagnosed with hepato-­ cholangiocarcinoma (HCC-­iCCA). The demographic and clinical characteristics of the patients are 3.3 | HCC diagnosis prior to SARS-­CoV-­2 infection reported in Table 1. The median age was 66.5 [IQR 60–­73] and 64.5 [IQR 57–­74] years, 156 (71.6%) and 18 (56.3%) patients were male, One hundred and sixty-­three (74.8%) patients had HCC history prior 185 (84.9%) and 7 (21.9%) patients had cirrhosis in the HCC and to SARS-­CoV-­2 infection. Their BCLC stage at SARS-­CoV-­2 infec- iCCA cohorts respectively. The main aetiology was HCV (37.6%) in tion was BCLC-­0 in 11 (6.8%), A in 48 (29.5%), B in 43 (26.4%), C in HCC patients and 62.5% of the iCCA patients had no liver disease 44 (27.0%) and D in 17 (10.4%). In the BCLC-­A stage, there were 32 history. One hundred and thirty-­nine (55.6%) patients were hospital- (66.7%) patients with a single nodule and 16 (33.3%) patients with ized because of SARS-­CoV-­2 and 108 (77.7%) of them received spe- up to 3 nodules and up to 3 cm each. Twenty (12.3%) patients had cific SARS-­CoV-­2 treatment according to the local medical practice. been treated with resection, 77 (47.2%) with loco-­regional treat- One hundred (40%) patients died after a median follow-­up of ments, 44 (27%) with systemic treatments, 17 (10.4%) were on Best 7.20 (IQR: 1.84–­11.24) months, 48 (48%) were SARS-­CoV-­2-­related Supportive Care (BSC) and 1 (0.6%) patient was being evaluated for and 34 (70.1%) of them had cirrhosis. The other 52 (52%) patients liver transplantation. died because of non-­SARS-­CoV-­2-­related causes and 86.5% of them Sixty-­nine (42.3%) of the 163 patients with prior HCC diagnosis were cirrhotic. One hundred and eight patients received treatment and with established cancer treatment plan had to stop treatment or because of SARS-­CoV-­2 treatment, the most frequent were azithro- had it delayed because of SARS-­CoV-­2 infection. Forty-­four (63.8%) mycin (49.1%) and corticosteroids (42.6%), rest of the reported treat- of these patients, restarted treatment after the resolution of the ments are available in Table S2. infection. Fifty-­t wo patients (20.8%) died within the first 30 days of SARS-­ From the diagnosis of SARS-­CoV-­2 infection, the median fol- CoV-­2 infection, and 43 (82.7%) of the deaths were SARS-­CoV-­2-­ low-­up was 7.20 [2.20–­10.79] months, 53 (33.7%) patients with a related. The 30-­day mortality rate in the whole cohort was 20.87% history of HCC developed HCC progression: new intra-­hepatic le- (95% CI: 15.8–­25.9). sion in 21 (39.6%), growth of intra-­hepatic lesions in 16 (30.2%), new extra-­hepatic lesions in 12 (22.6%), and growth of extra-­hepatic le- sions in 4 (7.6%) patients. 3.2 | HCC patients 3.2.1 | HCC diagnosis coinciding with SARS-­CoV-­2 3.4 | 30-­day mortality rate in HCC patients infection (de novo) Forty (18.4%) patients died within the 30-­days of SARS-­CoV-­2 infec- Fifty-­five patients had their first HCC diagnosis coincidentally with tion. Table 2 shows the 30-­day mortality rate according to the history SARS-­CoV-­2 infection (54 HCC and one HCC-­iCC), 44 patients of HCC, Child-­Pugh class and cause of death. The 30-­day mortality rate n = 252 From 38 centers 2 patients excluded: • 1 focal nodular hyperplasia. • 1 liver cancer different to HCC or iCCA. n = 250 Liver cancer patients F I G U R E 1 Flowchart of the study. During the inclusion period, 252 patients HCC iCCA HCC-iCCA were registered; two patients were n = 217 n = 32 n=1 excluded and 250 were included in the (86.8%) (12.8%) (0.4%) study analysis. HCC, hepatocellular de novo Liver cancer 54 (25.2%) 6 (18.8%) 1 (100%) carcinoma; iCCA, intrahepatic cholangiocarcinoma. History of Liver cancer 163 (74.8%) 26 (81.2%) 1896 | MUÑOZ-­MARTÍNEZ et al. TA B L E 1 Baseline characteristics by liver cancer and outcome TA B L E 1 (Continued) iCCA iCCA Patient profile HCC (n = 218)a (n = 32) Patient profile HCC (n = 218)a (n = 32) Age (years), median [IQR] 66.5 [60–­73] 64.5 [57–­74] Deaths, n (%) 81 (37.2) 19 (59.4) Gender (Males), n (%) 156 (71.6) 18 (56.3) SARS-­CoV-­2 related deaths, 36 (44.4) 12 (63.2) n (%) Cirrhosis (Yes), n (%) 185 (84.9) 7 (21.9) 30-­day posterior to SARS-­ 40 (18.4) 12 (37.5) Child-­Pugh classification at SARS-­CoV-­2 diagnosis, n (%) CoV-­2 infection deaths, A 104 (56.2) 3 (42.8) n (%) B 63 (34.1) 2 (28.6) Abbreviations: BCLC, Barcelona clinic liver cancer; HBV, hepatitis B C 17 (9.2) 2 (28.6) virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; iCCA, Not available 1 (0.5) -­ intrahepatic cholangiocarcinoma; IQR, interquartile range; NAFLD, non-­alcoholic fatty liver disease; SARS-­CoV-­2, severe acute respiratory Non-­cirrhotic 33 (15.1) 25 (78.1) syndrome coronavirus 2. Aetiology, n (%) a One patient with HCC-­iCCA. HCV 82 (37.6) 4 (12.5) b Combination: NAFLD and HCV (1); NAFLD and HBV (1); Alcohol and Alcohol 44 (20.2) 3 (9.4) HCV-­HBV co-­infection (1); HCV, NAFLD and autoimmune hepatitis (1); Graft-­versus-­host disease and Non-­alcoholic steatohepatitis (1). NAFLD 38 (17.4) 3 (9.4) c Hemochromatosis (2), autoimmune hepatitis (2), biliary cholangitis (1), HBV 19 (8.7) -­ schistosomiasis (1). Alcohol and HCV 9 (4.1) -­ d NAFLD and biliary cirrhosis (1), Primary sclerosing cholangitis (1). e Alcohol and NAFLD 7 (3.2) -­ TNM 8th edition staging system of iCCA. f Combination of previousb 5 (2.3) -­ Percentage calculated from 49 patients that received systemic treatment. Other 6 (2.8)c 2 (6.2)d Non-­liver disease 6 (2.8) 20 (62.5) was 12.96% (95% CI 4.00–­21.92) in de-­novo HCC patients and 20.25% Co-­infection HCV + HBV 2 (0.9) -­ (95% CI 14.08–­26.41) in those with HCC history. It was 14.42 (95% Liver cancer stage, n (%) BCLC stage TNMe CI 7.67–­21.18), 16.11% (95% CI 6.96–­25.25) and 52.94% (95% CI 0: 12 (5.5) IA: 5 (15.6) 29.21–­76.67), in Child-­Pugh A, B and C patients respectively. Table S3 A: 70 (32.1) IB: 2 (6.3) shows the 30-­day mortality rate according to the presence of cirrhosis. B: 51 (23.4) II: 2 (6.3) The 30-­day mortality was 14.74% (95% CI 10.39-19.8) in the C: 58 (26.6) IIIA: 1 (3.1) SARS-­CoV-­2-­related deaths using non-­SARS-­CoV-­2-­related deaths D: 27 (12.4) IIIB: 8 (25) as competing risks, and 3.69% (95% CI 1.73–­6.83) in the non-­SARS-­ IV: 14 (43.7) CoV-­2-­related deaths, using SARS-­CoV-­2-­related deaths as compet- Liver cancer treatment 163 (74.8) 26 (81.3) ing risks (Table 2). received before SARS-­ The 30-­day mortality rate, considering non-­SARS-­CoV-­2-­related CoV-­2 diagnosis (liver deaths as competing risks, increased along with the BCLC stage: 0/A cancer history patients), 6.10% (95% CI 2.24–­12.74), B 11.76% (95% CI 4.73–­22.30), C 20.69% n (%) (95% CI 11.35–­31.96) and D 34.52% (95% CI 17.03–­52.78); p = .0017. Locoregional 77 (47.2) -­ The same effect persisted even after excluding the BCLC-­D patients History of systemic 44 (27) 19 (73.1) (p = .0313). Table 3 shows the results of the competing risk Cox re- treatment gression models that expose a sub-­distribution of the Hazard Ratio Resection 20 (12.3) 3 (11.5) (HR) of 1.45 (95% CI 0.49–­4.31; p = .5032) in BCLC-­B versus 0/A, Liver transplant 4 (2.5) -­ and of HR = 3.13 (95% CI 1.29–­7.62; p = .0118) in BCLC-­C versus BSC 17 (10.4) 2 (7.7) 0/A. None 1 (0.6) 1 (3.8) Eight patients had non-­SARS-­CoV-­2-­related deaths during the Not specified -­ 1 (3.8) first 30-­day period. Table 4 describes the main causes of death. Six Enrolled in a clinical trial (Yes), 8 (16.3) -­ out of nine (75%) were BCLC-­D when infected and all but 1 died be- n (%)f cause of acute on chronic liver failure or HCC progression. Hospitalization due SARS-­ 123 (56.4) 16 (50) CoV-­2 infection (Yes), n (%) Received SARS-­CoV-­2 101 (46.3) 7 (21.9) treatment (Yes), n (%) 3.5 | iCCA patients Follow-­up time (days), median 224 [70–­352] 103 [IQR] [12–­266] Twenty-­six patients had prior diagnosis of iCCA and 6 were diag- nosed coincidentally with SARS-­CoV-­2 infection. MUÑOZ-­MARTÍNEZ et al. | 1897 TA B L E 2 30-­day mortality rate in HCC patients Events Patients at risk Mortality rate (95% CI) p-­value According to history of HCC de novo HTC 7 55 12.96 (4.00–­21.92) 0.2237 History of HCC 33 163 20.25 (14.08–­26.41) According to Child-­Pugh scorea,b A 15 104 14.42 (7.67–­21.18) 0.0005 B 10 63 16.11 (6.96–­25.25) C 9 17 52.94 (29.21–­76.67) Events Competing risks Patients at riskc Rate (95% CI) b According to cause of death SARS-­CoV-­2 related 32 8 218 14.74 (10.39–­19.8) Non-­SARS-­CoV-­2 related 8 32 218 3.69 (1.73–­6.83) Abbreviations: 95% CI, 95% confidence interval; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; SARS-­CoV-­2, severe acute respiratory syndrome coronavirus 2. a Six non-­cirrhotic patients not included. b Includes de novo HCC and history of HCC patients. c One patient with HCC-­iCCA. TA B L E 3 30-­day SARS-­CoV-­2-­related death mortality rate according to BCLC stage p-­value BCLC Competing Patients at 30-­day mortality rate, BCLC-­D stagea Eventsb eventsc riske %(95% CI) pd excludedd HR (95% CI) p 0 or A 5 1 82 6.10 (2.24–­12.74) .0017 0.0313 Ref. B 6 1 51 11.76 (4.73–­22.30) 1.45 (0.49–­4.31) .5032 C 12 0 58 20.69 (11.35–­31.96) 3.13 (1.29–­7.62) .0118 D 9 6 27 34.52 (17.03–­52.78) -­ Total 32 8 218 Abbreviations: 95% CI: 95% confidence interval; BCLC: Barcelona Clinic Liver Cancer; HR: hazard ratio; SARS-­CoV-­2: severe acute respiratory syndrome coronavirus 2. a At SARS-­CoV-­2 diagnosis. b 30-­day SARS-­CoV-­2-­related deaths. c 30-­day non-­SARS-­CoV-­2-­related deaths. d Grey's test. e One patient HCC-­iCCA. TA B L E 4 30-­day non-­SARS-­CoV-­2-­related causes of death in The cancer stage according to the TNM 8th edition at the time of HCC patients SARS-­CoV-­2 infection of patients with coincidentally iCCA diagnosis Cause of death n (%) BCLC stage (n)a was IA in 1 (16.7%), IIIB in 1 (16.7%) and IV in 4 (66.6%) patients. On HCC progression 2 (25) B (1), D (1) the other hand, cancer stage in patients with iCCA history was IA in Decompensated cirrhosis with HCC 2 (25) D (2) 4 (15.4%), IB in 2 (7.7%), II in 2 (7.7%), IIIA in 1 (3.8%), IIIB in 7 (26.9%) progression and IV in 10 (38.5%) patients. Decompensated cirrhosis without HCC 1 (12.5) D (1) Of the 32 patients with iCCA diagnosis, 19 (59.4%) died; 12 progression (63.2%) were SARS-­CoV-­2-­related deaths and 7 (36.8%) were Acute-­on-­Chronic liver failure 2 (25) A (1), D (1) non-­SARS-­CoV-­2-­related. Otherb 1 (12.5) D (1) TOTAL 8 (100) Abbreviations: BCLC, Barcelona clinic liver cancer; HCC: hepatocellular 3.6 | iCCA diagnosis prior to SARS -­CoV-­2 infection carcinoma. a At the time of SARS-­CoV-­2 diagnosis. Ten (38.5%) of the 26 patients with prior iCCA diagnosis and with an b Other: 1 patient died because of liver transplant rejection (BCLC-­D). established cancer treatment plan had to stop or delayed it because 1898 | MUÑOZ-­MARTÍNEZ et al. of SARS-­CoV-­2 infection. Only 2 (20%) of these patients, restarted Our results could be useful for clinicians to inform patients and iCCA treatment after the resolution of the infection. families about HCC prognosis in the context of the SARS-­CoV-­2 Table 1 describes the profile of these 26 patients. infection. In accordance with our results, 33.7% of patients with a During a median of 2.43 (0.33–­8.78) months of follow-­up from history of HCC developed HCC progression during the follow-­up, the diagnosis of SARS-­CoV-­2 infection, 10 (38.5%) patients with a while 40 (18.4%) patients with HCC (de novo or history) died within history of iCCA developed tumour progression. the first 30 days. However, only four deaths were for HCC progres- sion, three were BCLC-­D when infected and only one death was because of HCC progression when patients at end-­stage (BCLC-­D) 4 | DISCUSSION were excluded. Additionally, the risk of 30-­day SARS-­CoV-­2-­related death was similar between BCLC-­0/A and B stage [HR = 1.45 (95% To the best of our knowledge, this is the largest cohort of liver cancer CI 0.49–­4.31; p = .5032)] but was significantly different between patients infected with SARS-­CoV-­2 around the world. Our data are BCLC-­C versus 0/A stage (HR = 3.13 [95% CI 1.29–­7.62; p = .0118]). complementary to Iavarone et al.10 and Kim et al. publications.15 Both These results could be explained by the higher rate of liver dysfunc- cohorts were focused on patients with liver disease history but only tion in the BCLC-­C stage and by the treatment received at that stage. 11 and 19 HCC patients were included respectively. In addition, the The results of this project may help the researchers at the time of present cohort is the first that describes the outcome of de-­novo liver analysing the results of the ongoing Clinical Trials where the included cancer patients in whom the diagnosis was done during the SARS-­ patients may have been infected with SARS-­CoV-­2. Indeed, this data CoV-­2 infection. Lastly, despite there are no information in the litera- can be used as a reference for designing Clinical Trials. Nowadays, the ture about SARS-­CoV-­2 and cholangiocarcinoma and we are reporting SARS-­CoV-­2-­related-­cirrhosis complication and/or HCC progression-­ the largest cohort of infected iCCA patients, the results should be related death in the context of SARS-­CoV-­2 infection will have to considered only as descriptive because of the low number of patients be considered as new causes of early treatment discontinuation. included (n = 32). This could see as a limitation of the study but we Accordingly, the expected number of patients who will stop or delay would like to highlight the lack of data of iCCA in the literature and oncologic treatments for the reasons mentioned above as well as the mention that is the largest cohort in this field. number of patients who will die because of SARS-­CoV-­2 or cirrhosis Our study showed the 30-­day mortality rate of HCC patients who complication/HCC progression in the context of SARS-­CoV-­2 infec- were under different cancer treatments during the first wave of the tion should be taken into account when the sample size is calculated SARS-­CoV-­2. Nevertheless, as the SARS-­CoV-­2 infection could be ac- in future research projects. Indeed, underestimating these new factors quired after being fully vaccinated,16–­18 these results could be used may negatively impact the accuracy of clinical trial assumption about as reference for the evolution of HCC patients who are infected by expected events and needed sample size. SARS-­CoV-­2 because of non-­vaccination or waning immune defence. As the SARS-­CoV-­2 infection is slowly weaning at different rates As shown, the 30-­day mortality rate was increased along the BCLC around the world, the results that we present will be of historical im- stage (p = .0017) and that increment was maintained even when the portance. It is important to register the impact of worldwide events, BCLC-­D patients, who have a median survival lower than 3 months, were as we did for liver cancer. A noteworthy result is that 24.4% of the excluded (p = .0313). HCC progression or liver-­related deaths were the patients had a coincidental and incidental liver cancer diagnosis orig- causes of non-­SARS-­CoV-­2-­related deaths in all of the 8 patients who died inated from tests for SARS-­CoV-­2 infection, which is a reminder of within the first month. Based on this information, it can be suggested that the importance of screening programmes. Finally, our data might the non-­SARS-­CoV-­2-­related deaths were associated with the impact of help further studies to describe the impact of SARS-­CoV-­2 vaccina- the SARS-­CoV-­2 infection in the liver function or because of the result of tion and the change in mortality associated with the new strains on stopping/delaying HCC treatment. It is already known that infections are liver cancer patients with SARS-­CoV-­2 infection. events related to death in cirrhotic patients because of acute-­on-­chronic The retrospective nature of the study is associated with variability in liver failure. However, Iavarone et al. reported that the 30-­day mortality the local policy for hospitalization and management of the SARS-­CoV-­2 rates were higher in patients with cirrhosis and COVID-­19 than in those infection. In addition, despite of the fact all patients with de novo liver with bacterial infections.10 Our results on the rate of 30 day-­mortality rate cancer had viable tumour, the study did not have central revision of the death according to the BCLC stage as well as the causes of non-­SARS-­ image's technique to confirm the viability of the cancer in the cohort CoV-­2-­related deaths reinforce the importance of characterising the ef- of patients with a history of liver cancer at the time of infecting with fect of this new infection on the HCC patient's outcome. SARS-­CoV-­2. However, we registered BCLC stage at the time of the For this reason, this study adds valuable information for physi- SARS-­CoV-­2 diagnosis independently of the previous HCC treatment. cians at clinical practice and for clinical researchers at the clinical trial level. The 30-­day mortality rate was 12.96% (95% CI 4.00–­ 21.92) in de novo HCC patients and 20.25% (95% CI 14.08–­26.41) 5 | CO N C LU S I O N S in those with HCC history, but because of the small sample size and because of the confounder introduced by the HCC stage at the time This is the largest cohort of liver cancer patients infected with SARS-­ of infection these results should be considered only as descriptive. CoV-­2. It characterizes the risk of 30-­day SARS-­CoV-­2 death. The MUÑOZ-­MARTÍNEZ et al. | 1899 results can be used as reference for informing about HCC prognosis Pharma, Ipsen, BMS, Eisai, Roche, AstraZeneca, Sirtex Medical. M. El-­ in the context of the SARS-­CoV-­2 infection. Kassas. Consulting fees from Roche and EVA Pharma. Payment hono- raria for lectures from Inspire, Spimaco and Roche. Payment for expert AC K N OW L E D G E M E N T S testimony from EVA, Janssen and ROCHE. Travel support by Roche, SM-­M. Received grant support from Bristol Myers Squibb and MSD and EVA Pharma. President of Egyptian Association for Research Celgene for the “Title of Expert in Immuno-­Oncology, VII Edition” and Training in HepatoGastroenterology (EARTH). C. Guedes Leal. organized by the University of Navarra, Spain. A. Forner. Received Lectures fees from IPSEN, AstraZeneca, Roche and Bayer. T. Mocan. grant support from Instituto de Salud Carlos III (PI13/01229 and Received travel grants from Bayer. J-­C.Nault. Received research grant PI18/00542). J. Bruix. received grant support from Instituto de Salud from Ipsen and Bayer. R. Pinheiro-­Alves. Payment of honoraria for Carlos III (PI18/00768), AECC (PI044031) and WCR (AICR) 16-­0026. lectures from Bayer, Abbvie and Sirtex Medical. H. L. Reeves. Cancer M. Sanduzzi-­Zamparelli. Received grant support from Instituto de Research UK (CR UK) HUNTER Accelerator Award (C9380/A26813). Salud Carlos III (FI19/00222). H. Reeves. is supported by funding Grant support for Helen Reeves, paid to Institution. Consulting fees from Cancer Research UK (CR UK) centre grant C9380/A18084; from SIRTEX, and Boston Scientific (payments to institution). Payment CR UK programme grant C18342/A23390 and CR UK Accelerator honoraria for lectures from Bayer and Eisai. L. da Fonseca. Lectures award HUNTER C9380/A26813. D. J. Pinato. is supported by grant fees from BMS, Roche and Bayer. D. J. Pinato. Received lecture fees funding from the Wellcome Trust Strategic Fund (PS3416) and ac- from ViiV Healthcare and Bayer Healthcare and travel expenses from knowledges grant support from the Cancer Treatment and Research BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, Trust (CTRT) and infrastructural support by the Cancer Research UK EISAI, Roche and AstraZeneca; received research funding (to insti- Imperial Centre, the Imperial College Experimental Cancer Medicine tution) from MSD and BMS. M. Varela. Reports receiving consult- Centre (ECMC) and the NIHR Imperial Biomedical Research Centre. J. ing fees from Astra-­Zeneca, Bayer, Eisai-­MSD, BMS, Roche; lectures M. González Santiago. Received grant support from Instituto de Salud fees from Bayer, Boston, Gilead, Eisai-­MSD, AbbVie; travel fees from Carlos III (PI19/00819). Á. Rojas. Sara Borrell postdoctoral fellowships Astra-­Zeneca, Bayer. M. R. Alvares-­da-­Silva. Has received Research from Instituto de Salud Carlos III CD18/00126. C. Braconi. Consulting grants, advisory board or speaker for AbbVie, Bayer, Biolab, Intercept, honoraria from Incyte. She is the recipient of a Lord Kelvin Adam Ipsen, Gilead, MSD, Novartis, Genfit and Roche. L. Rimassa. Reports Smith readership from University of Glasgow. D'Alessio is supported receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, by the NIHR Imperial BRC and by grant funding from the European Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, Association for the Study of the Liver (Andrew Burroughs Fellowship). IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, M. Iavarone. Ricerca Corrente RC2017/105-­01”, “Ricerca Corrente Taiho Oncology, Zymeworks; lectures fees from AbbVie, Amgen, RC2018/105-­01”, “Ricerca Corrente RC2019/105-­01. M. Reig. re- Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; ceived grant support from Instituto de Salud Carlos III (PI15/00145 travel fees from AstraZeneca; and institutional research funding from and PI18/0358) and the Spanish Health Ministry (National Strategic Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Plan Against Hepatitis C). CIBERehd is funded by the Instituto de Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Salud Carlos III. Some of the authors of this article are members of Roche, Zymeworks. M. Lozano. Lectures and educational presenta- the European Reference Network (ERN) RARE-­LIVER. Some of the tions: Abbvie. Travel/accommodations, meeting expenses covered by authors of this article are members of the European Network for the Bayer, Gilead, Abbvie. J. M. González Santiago. JMGS received fund- Study of Cholangiocarcinoma (ENS-­CCA) and participate in the ini- ing from the Fondo de Investigaciones Sanitarias, Instituto de Salud tiative COST Action EURO-­CHOLANGIO-­NET granted by the COST Carlos III, Spain (PI19/00819). F. Tacke. Has received research grants Association (CA18122) and European Commission Horizon 2020 pro- from Allergan, Gilead, Inventiva and BMS (to his institution). M. Sala. gramme (ESCALON project #825510). Travel/ accommodation/meeting expenses: Bayer. Eisai. Speaker fees: Bayer. M. Anders. Received speaker honoraria from Bayer, Roche, C O N FL I C T O F I N T E R E S T LKM-­Biotoscana, RAFFO. A. Lachenmayer. Consultancy CAScination, S. Muñoz-­Martínez. Speaker fees from Bayer and travel funding Advisory Board Johnson&Johnson and Histosonics. F. Piñero. Received from Bayer and Eisai. He received grant support from Bristol Myers speaker honoraria from Bayer, Roche, LKM-­Biotoscana, RAFFO. Squibb and Celgene. V. Sapena. Travel grants from Bayer. Consultancy Research Grants from INC Argentinean National Institute of Cancer, fees from LEO-­Pharma. A. Forner. Lecture fees from Bayer, Gilead, Roche. G. Cabibbo. Consultancy fees from Bayer, Ipsen and Eisai. M. Roche, Boston Scientific and MSD; consultancy fees from Bayer, Peck-­Radosavljevic. Consultant for Bayer, Eisai, Guerbet, Intercept, AstraZeneca, Roche, Boston Scientific, SIRTEX, Exact Science and Ipsen, Lilly, Roche; Speaker fees from Bayer, BMS, Eisai, Intercept, Guerbert. J. Bruix. Consultancy: AbbVie, ArQule, Astra, Basilea, Ipsen, Lilly, MSD, Roche. Vergara. Travel grants from Bayer, Gilead, Bayer, BMS, Daiichi Sankyo, GlaxoSmithKline, Gilead, Kowa, Lilly, MSD and Abbvie. Lectures sponsored by Gilead, Abbvie, Intercept, Medimune, Novartis, Onxeo, Polaris, Quirem, Roche, Sanofi-­Aventis, Eisai and MSD. Consultancy: Eisai. C. Braconi. Consulting hono- Sirtex, Terumo/Grants: Bayer and Ipsen. M. Sanduzzi-­Zamparelli. raria from Incyres. S. Pascual. Consulting fees from Eisai and Roche. received speaker fees and travel grants from Bayer and BTG, MSD. Honoraria for lectures from Eisai, Chiari, Bayer, Educational events M. Bouattour. Consultant, Advisory Board and Travel support: Bayer Gilead. Travel funding from Gilead. Participation in monitoring Board 1900 | MUÑOZ-­MARTÍNEZ et al. or Advisory Board: Eisai and Roche. C. Perelló. Received speaker hono- Ángela Rojas https://orcid.org/0000-0003-0853-4800 raria and travel grants from Bayer, Gilead Sciences and Eisai. V. Mello. Mercedes Vergara https://orcid.org/0000-0002-6971-8657 Fee lectures from Bayer and Roche. C. Rodríguez-­Lope. Travel grants Chiara Braconi https://orcid.org/0000-0003-4835-1259 from Bayer. Lecture fees and advisory board from Eisai. J. Acevedo. R. Sonia Pascual https://orcid.org/0000-0002-4265-5019 Villani. Research grant from Abbvie. C. Holland. Honoraria for lectures Christie Perelló https://orcid.org/0000-0003-0234-2330 from IPSEN and travel support from Roche. C.F. Theodoro. Received Carlos Rodríguez-­Lope https://orcid.org/0000-0002-6713-8800 speaker fees from Bayer. Z. Sparchez. Speaker honoraria from Bayer, Juan Acevedo https://orcid.org/0000-0003-4507-2422 AbbVie and Neola (Gilead). Travel grants from Neola (Gilead), AbbVie, Rosanna Villani https://orcid.org/0000-0001-9875-019X Bayer. D. E. Viera-­Alves. Payment of honoraria for lectures from Clemence Hollande https://orcid.org/0000-0002-2287-0635 Novartis and Pfizer. R. Watson. Cancer Research UK (CR UK) HUNTER Ahmed Tawheed https://orcid.org/0000-0002-9382-8733 Accelerator Award (C9380/A26813) salary support paid to institu- Carmem Ferguson Theodoro https://orcid.org/0000-0001-6605-1060 tion. A. D'Alessio. Travel support from Roche. M. Iavarone. Received Carlos Moctezuma-­Velázquez https://orcid.org/0000-0003-2367-2742 speaker honoraria from Bayer, Gilead Sciences, BMS, Janssen, Ipsen, Massimo Iavarone https://orcid.org/0000-0003-3493-6504 MSD, BTG-­Boston Scientific, AbbVie, Roche, EISAI and was consult- Maria Reig https://orcid.org/0000-0002-5711-9534 ant for BTG-­Boston Scientific, EISAI, Bayer and Guerbet. M. Reig. Consultancy: Bayer-­Shering Pharma, BMS, Roche, Ipsen, AstraZeneca, REFERENCES Lilly, BTG and UniversalDX. Paid conferences: Bayer-­Shering Pharma, 1. European Medicines Agency. EMA recommends COVID-­19 Vaccine BMS, Gilead, Lilly, Roche and UniversalDX. Research Grants (from the Janssen for authorisation in the EU. Eur Med Agency. 2021;1-­4. https://www.ema.europa.eu/en/news/ema-­recom​m ends​- ­c ovid​ Institution): Bayer-­Shering Pharma, Ipsen. -­19-­vacci​ne-­moder​na-­autho​risat​ion-­eu (accessed October 10, 2021) The rest of the authors declare no conflict of interests. 2. Muñoz-­Martínez S, Sapena V, Forner A, et al. Assessing the impact of COVID-­19 on liver cancer management (CERO-­19). JHEP Rep. ORCID 2021;3:100260. doi:10.1016/j.jhepr.2021.100260 3. Gandhi M, Ling W-­H, Chen C-­H, et al. Impact of COVID-­19 on hepa- Sergio Muñoz-­Martínez https://orcid.org/0000-0003-0663-0575 tocellular carcinoma management: a multicountry and region study. J Victor Sapena https://orcid.org/0000-0003-4379-6486 Hepatocell Carcinoma. 2021;8:1159-­1167. doi:10.2147/jhc.s329018 Alejandro Forner https://orcid.org/0000-0002-9014-4950 4. Mallet V, Beeker N, Bouam S, et al. Prognosis of French COVID-­19 Jordi Bruix https://orcid.org/0000-0002-9826-0753 patients with chronic liver disease: a national retrospective co- hort study for 2020. J Hepatol. 2021;75:848-­855. doi:10.1016/j. Marco Sanduzzi-­Zamparelli https://orcid. jhep.2021.04.052 org/0000-0003-3795-3705 5. Pomej K, Scheiner B, Hartl L, et al. COVID-­19 pandemic: impact José Ríos https://orcid.org/0000-0002-0716-8784 on the management of patients with hepatocellular carcinoma at a Mohamed Bouattour https://orcid.org/0000-0002-3919-4135 tertiary care hospital. PLoS One. 2021;16:e0256544. doi:10.1371/ Mohamed El-­Kassas https://orcid.org/0000-0002-3396-6894 journal.pone.0256544 6. Balakrishnan A, Lesurtel M, Siriwardena AK, et al. Delivery of Tudor Mocan https://orcid.org/0000-0001-7785-6403 hepato-­pancreato-­biliary surgery during the COVID-­19 pan- Jean-­Charles Nault https://orcid.org/0000-0002-4875-9353 demic: an European-­African Hepato-­Pancreato-­Biliary Association Helen L. Reeves https://orcid.org/0000-0003-0359-9795 (E-­AHPBA) cross-­sectional survey. HPB. 2020;22:1128-­1134. Leonardo da Fonseca https://orcid.org/0000-0002-0216-3618 doi:10.1016/j.hpb.2020.05.012 7. Aghemo A, Masarone M, Montagnese S, Petta S, Ponziani FR, Ignacio García-­Juárez https://orcid.org/0000-0003-2400-1887 Russo FP. Assessing the impact of COVID-­19 on the management David J. Pinato https://orcid.org/0000-0002-3529-0103 of patients with liver diseases: a national survey by the Italian as- María Varela https://orcid.org/0000-0003-4288-2593 sociation for the study of the Liver. Dig Liver Dis. 2020;52:937-­941. Saleh A. Alqahtani https://orcid.org/0000-0003-2017-3526 doi:10.1016/j.dld.2020.07.008 8. Ward ZJ, Walbaum M, Walbaum B, et al. Estimating the impact of Mario R. Alvares-­da-­Silva https://orcid. the COVID-­19 pandemic on diagnosis and survival of five cancers in org/0000-0002-5001-246X Chile from 2020 to 2030: a simulation-­based analysis. Lancet Oncol. Juan C. Bandi https://orcid.org/0000-0001-9733-1938 2021;22:1427-­1437. doi:10.1016/s1470-­2045 Lorenza Rimassa https://orcid.org/0000-0001-9957-3615 9. Pinato DJ, Patel M, Scotti L, et al. Time-­dependent COVID-­19 mortal- ity in patients with cancer: an updated analysis of the on covid regis- Mar Lozano https://orcid.org/0000-0001-7099-0810 try. JAMA Oncol. 2021;8:114. doi:10.1001/JAMAONCOL.2021.6199 Jesús M. González Santiago https://orcid. 10. Iavarone M, D'Ambrosio R, Soria A, et al. High rates of 30-­day org/0000-0003-4667-4492 mortality in patients with cirrhosis and COVID-­19. J Hepatol. Frank Tacke https://orcid.org/0000-0001-6206-0226 2020;73:1063-­1071. doi:10.1016/j.jhep.2020.06.001 11. Lai AG, Pasea L, Banerjee A, et al. Estimated impact of the María Anders https://orcid.org/0000-0002-2238-5322 COVID-­19 pandemic on cancer services and excess 1-­year mortal- Anja Lachenmayer https://orcid.org/0000-0002-5879-5737 ity in people with cancer and multimorbidity: near real-­time data Maria Guarino https://orcid.org/0000-0002-0460-4122 on cancer care, cancer deaths and a population-­based cohort study. Giuseppe Cabibbo https://orcid.org/0000-0002-0946-3859 BMJ Open. 2020;10:1-­9. doi:10.1136/bmjopen-­2020-­0 43828 Markus Peck-­Radosavljevic https://orcid. 12. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301-­1314. doi:10.1016/S0140-­6736(18)30010-­2 org/0000-0002-0597-2728 MUÑOZ-­MARTÍNEZ et al. | 1901 13. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia- 18. Kustin T, Harel N, Finkel U, et al. Evidence for increased breakthrough Criado Á, et al. BCLC strategy for prognosis prediction and treat- rates of SARS-­CoV-­2 variants of concern in BNT162b2-­mRNA-­ ment recommendation: The 2022 update. J. Hepatol. [Internet]. vaccinated individuals. Nat Med. 2021;27:1379-­1384. doi:10.1038/ 2022 [cited 2022 May 21];76:681-693. Available from: https:// S41591-­021-­01413-­7 pubmed.ncbi.nlm.nih.gov/34801630/ 14. Amin MB, Edge S, Greene F, et al. AJCC cancer staging manual 8th S U P P O R T I N G I N FO R M AT I O N Edition. Definitions. Spinger; 2020:489-­539. doi:10.32388/b30ldk 15. Kim D, Adeniji N, Latt N, et al. Predictors of outcomes of COVID-­19 Additional supporting information may be found in the online in patients with chronic liver disease: US multi-­center study. Clin version of the article at the publisher’s website. Gastroenterol Hepatol. 2021;19:1469–­1479.e19. 16. Vaccine breakthrough infections: the possibility of getting COVID-­19 after getting vaccinated n.d. https://www.cdc.gov/coron​aviru​s/2019-­ How to cite this article: Muñoz-­Martínez S, Sapena V, Forner ncov/vacci​n es/effec​t iven​e ss/why-­m easu​re-­effec​t iven​e ss/break​ A, et al.. Outcome of liver cancer patients with SARS-­CoV-­2 throu​gh-­cases.html (accessed October 9, 2021). infection: An International, Multicentre, Cohort Study. Liver 17. Bergwerk M, Gonen T, Lustig Y, et al. Covid-­19 breakthrough infections in vaccinated health care workers. N Engl J Med. Int. 2022;42:1891-1901. doi: 10.1111/liv.15320 2021;385:1474-­1484. doi:10.1056/nejmoa2109072