Outcome of Liver Cancer Patients With SARS-CoV-2 Infection

An International, Multicentre, Cohort Study

Sergio Muñoz-Martínez; Victor Sapena; Alejandro Forner; Jordi Bruix; Marco Sanduzzi-Zamparelli; José Ríos; Mohamed Bouattour; Mohamed El-Kassas; Cassia R. G. Leal; Tudor Mocan; Jean-Charles Nault; Rogerio C. P. Alves; Helen L. Reeves; Leonardo da Fonseca; Ignacio García-Juárez; David J. Pinato; María Varela; Saleh A. Alqahtani; Mario R. Alvares-da-Silva; Juan C. Bandi; Lorenza Rimassa; Mar Lozano; Jesús M. González Santiago; Frank Tacke; Margarita Sala; María Anders; Anja Lachenmayer; Federico Piñero; Alex França; Maria Guarino; Alessandra Elvevi; Giuseppe Cabibbo; Markus Peck-Radosavljevic; Ángela Rojas; Mercedes Vergara; Chiara Braconi; Sonia Pascual; Christie Perelló; Vivianne Mello; Carlos Rodríguez-Lope; Juan Acevedo; Rosanna Villani; Clemence Hollande; Valérie Vilgrain; Ahmed Tawheed; Carmem Ferguson Theodoro; Zeno Sparchez; Lorraine Blaise; Daniele E. Viera-Alves; Robyn Watson; Flair J. Carrilho; Carlos Moctezuma-Velázquez; Antonio D'Alessio; Massimo Iavarone; Maria Reig

Disclosures

Liver International. 2022;42(8):1891-1901.

Abstract and Introduction

Abstract

Background & Aims: Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population.

Methods: Multicentre retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February and December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered.

Results: Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 (IQR: 1.84–11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24–12.74], 11.76% [95% CI 4.73–22.30], 20.69% [95% CI 11.35–31.96] and 34.52% [95% CI 17.03–52.78] for BCLC 0/A, B, C and D, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49–4.31; p = .5032) in BCLC-B versus 0/A, and 3.13 (95% CI 1.29–7.62; p = .0118) in BCLC-C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS-CoV-2 infection.

Conclusions: This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period.

Introduction

After the start of the Coronavirus Disease 2019 (COVID-19) in 2019, all countries worldwide made a huge effort to face up to the health issues derived from the pandemic. In December 2020 the first SARS-CoV-2 vaccine was authorized by the U.S. Food and Drug Administration, while it was granted a conditional marketing authorization by the European Medicines Agency.^[1] Nevertheless, just after the first wave, further waves emerged and the sequelae of the pandemic will probably continue for years. Our previous study^[2] showed that all treatments, except systemic therapy, had relevant interruptions during the first wave around the World. Indeed, 48% of the centres decreased the number of physicians devoted to managing liver cancer. Gandhi et al.^[3] also assessed the impact on COVID-19 in 14 Asia-Pacific countries and observed similar results. One of the main harms of the pandemic according to Muñoz et al.^[2] was the delay in liver cancer diagnosis because of the modification of screening, reported in 80.9% of the participating centres. A similar impact of COVID-19 was also reported for other cancers^[4–7] and in the current study, here we characterize the profile and evolution of those patients incidentally diagnosed with liver cancer as a result of the assessments done because of COVID-19 infection diagnosis and those who had a history of liver cancer.

A microsimulation model on five cancers (breast, cervix, colorectal, prostate and stomach) found that delays in diagnosis will result in a worse cancer stage at presentation, leading to worse survival outcomes.^[8] Liver cancer was not represented in that model and such data should be confirmed in the liver cancer realm. A second harm of the pandemic is the COVID-19-related and non-COVID-19-related mortality.^[9] In the liver cancer setting, the mortality analysis is complex because almost all hepatocellular carcinoma (HCC) patients and some of the intrahepatic cholangiocarcinoma (iCCA) patients present underlying cirrhosis.

Iavarone et al.^[10] evaluated the 30-day mortality rate in cirrhotic patients but only 22% of them had active or history of liver cancer. Thus, there is neither mortality data nor information about the impact of the liver cancer stage in the outcome of patients diagnosed as a result of SARS-CoV-2 diagnosis. Lai et al.^[11] analysed the indirect excess deaths (because of pandemic-induced healthcare service reconfiguration) on cancer patients from the United Kingdom. They concluded that cancer services had only partially recovered with the lockdown easing. They also suggested that this situation may contribute to substantial excess mortality and multimorbidity among cancer patients. According to their analysis, the 1-year liver cancer mortality in patients without comorbidities or with one or two comorbidities are 50.2%, 50.3% and 49.5% respectively. Here, again there is neither information about the liver cancer stage nor the impact of the 30-day mortality rate. They pointed out the urgent need to better understand and mitigate these excess mortality risks. The present analysis is the second part of the Liver cancer outcome in the COVID-19-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 profile of patients with liver cancer as a result of the tests performed because of SARS-CoV-2 infection as well as their outcome; (2) to analyse the 30-day mortality rate of liver cancer patients with SARS-CoV-2 infection. This information will be key to understand the outcome of liver cancer patients who started oncologic treatments before or during the pandemic as well as the evolution of new liver cancer diagnosed during SARS-CoV-2 infection.

1 2 3 4 5

Next Section

Table 1. Baseline characteristics by liver cancer and outcome
Patient profile	HCC (n = 218)^a	iCCA (n = 32)
Age (years), median [IQR]	66.5 [60–73]	64.5 [57–74]
Gender (Males), n (%)	156 (71.6)	18 (56.3)
Cirrhosis (Yes), n (%)	185 (84.9)	7 (21.9)
Child-Pugh classification at SARS-CoV-2 diagnosis, n (%)
A	104 (56.2)	3 (42.8)
B	63 (34.1)	2 (28.6)
C	17 (9.2)	2 (28.6)
Not available	1 (0.5)	-
Non-cirrhotic	33 (15.1)	25 (78.1)
Aetiology, n (%)
HCV	82 (37.6)	4 (12.5)
Alcohol	44 (20.2)	3 (9.4)
NAFLD	38 (17.4)	3 (9.4)
HBV	19 (8.7)	-
Alcohol and HCV	9 (4.1)	-
Alcohol and NAFLD	7 (3.2)	-
Combination of previous^b	5 (2.3)	-
Other	6 (2.8)^c	2 (6.2)^d
Non-liver disease	6 (2.8)	20 (62.5)
Co-infection HCV + HBV	2 (0.9)	-
Liver cancer stage, n (%)	BCLC stage	TNM^e
	0: 12 (5.5)	IA: 5 (15.6)
	A: 70 (32.1)	IB: 2 (6.3)
	B: 51 (23.4)	II: 2 (6.3)
	C: 58 (26.6)	IIIA: 1 (3.1)
	D: 27 (12.4)	IIIB: 8 (25)
		IV: 14 (43.7)
Liver cancer treatment received before SARS-CoV-2 diagnosis (liver cancer history patients), n (%)	163 (74.8)	26 (81.3)
Locoregional	77 (47.2)	-
History of systemic treatment	44 (27)	19 (73.1)
Resection	20 (12.3)	3 (11.5)
Liver transplant	4 (2.5)	-
BSC	17 (10.4)	2 (7.7)
None	1 (0.6)	1 (3.8)
Not specified	-	1 (3.8)
Enrolled in a clinical trial (Yes), n (%)^f	8 (16.3)	-
Hospitalization due SARS-CoV-2 infection (Yes), n (%)	123 (56.4)	16 (50)
Received SARS-CoV-2 treatment (Yes), n (%)	101 (46.3)	7 (21.9)
Follow-up time (days), median [IQR]	224 [70–352]	103 [12–266]
Deaths, n (%)	81 (37.2)	19 (59.4)
SARS-CoV-2 related deaths, n (%)	36 (44.4)	12 (63.2)
30-day posterior to SARS-CoV-2 infection deaths, n (%)	40 (18.4)	12 (37.5)

Abbreviations: BCLC, Barcelona clinic liver cancer; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; iCCA, intrahepatic cholangiocarcinoma; IQR, interquartile range; NAFLD, non-alcoholic fatty liver disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
^aOne patient with HCC-iCCA.
^bCombination: NAFLD and HCV (1); NAFLD and HBV (1); Alcohol and HCV-HBV co-infection (1); HCV, NAFLD and autoimmune hepatitis (1); Graft-versus-host disease and Non-alcoholic steatohepatitis (1).
^cHemochromatosis (2), autoimmune hepatitis (2), biliary cholangitis (1), schistosomiasis (1).
^dNAFLD and biliary cirrhosis (1), Primary sclerosing cholangitis (1).
^eTNM 8th edition staging system of iCCA.
^fPercentage calculated from 49 patients that received systemic treatment.

Table 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)	0.2237
According to Child-Pugh score^a,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 risk^c	Rate (95% CI)
According to cause of death^b
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.
^aSix non-cirrhotic patients not included.
^bIncludes de novo HCC and history of HCC patients.
^cOne patient with HCC-iCCA.

Table 3. 30-day SARS-CoV-2-related death mortality rate according to BCLC stage
BCLC stage^a	Events^b	Competing events^c	Patients at risk^e	30-day mortality rate, %(95% CI)	p^d	p-value BCLC-D excluded^d	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.
^aAt SARS-CoV-2 diagnosis.
^b30-day SARS-CoV-2-related deaths.
^c30-day non-SARS-CoV-2-related deaths.
^dGrey's test.
^eOne patient HCC-iCCA.

Table 4. 30-day non-SARS-CoV-2-related causes of death in HCC patients
Cause of death	n (%)	BCLC stage (n)^a
HCC progression	2 (25)	B (1), D (1)
Decompensated cirrhosis with HCC progression	2 (25)	D (2)
Decompensated cirrhosis without HCC progression	1 (12.5)	D (1)
Acute-on-Chronic liver failure	2 (25)	A (1), D (1)
Other^b	1 (12.5)	D (1)
TOTAL	8 (100)

Abbreviations: BCLC, Barcelona clinic liver cancer; HCC: hepatocellular carcinoma.
^aAt the time of SARS-CoV-2 diagnosis.
^bOther: 1 patient died because of liver transplant rejection (BCLC-D).

Authors and Disclosures

Sergio Muñoz-Martínez^1–4, Victor Sapena^1,2,4,5, Alejandro Forner^1–4, Jordi Bruix^1–4, Marco Sanduzzi-Zamparelli^1–4, José Ríos⁶, Mohamed Bouattour⁷, Mohamed El-Kassas⁸, Cassia R. G. Leal^9,10, Tudor Mocan¹¹, Jean-Charles Nault^12–14, Rogerio C. P. Alves^15,16, Helen L. Reeves^17,18, Leonardo da Fonseca¹⁹, Ignacio García-Juárez²⁰, David J. Pinato²¹, María Varela²², Saleh A. Alqahtani²³, Mario R. Alvares-da-Silva²⁴, Juan C. Bandi²⁵, Lorenza Rimassa^26,27, Mar Lozano²⁸, Jesús M. González Santiago²⁹, Frank Tacke^29,30, Margarita Sala³¹, María Anders³², Anja Lachenmayer³³, Federico Piñero³⁴, Alex França³⁵, Maria Guarino³⁶, Alessandra Elvevi³⁷, Giuseppe Cabibbo³⁸, Markus Peck-Radosavljevic³⁹, Ángela Rojas⁴⁰, Mercedes Vergara⁴¹, Chiara Braconi⁴², Sonia Pascual⁴³, Christie Perelló⁴⁴, Vivianne Mello⁴⁵, Carlos Rodríguez-Lope⁴⁶, Juan Acevedo⁴⁷, Rosanna Villani⁴⁸, Clemence Hollande⁴⁹, Valérie Vilgrain^50,51, Ahmed Tawheed⁸, Carmem Ferguson Theodoro⁵², Zeno Sparchez⁵³, Lorraine Blaise^12–14, Daniele E. Viera-Alves^15,16, Robyn Watson¹⁸, Flair J. Carrilho⁵⁴, Carlos Moctezuma-Velázquez²⁰, Antonio D'Alessio^21,26, Massimo Iavarone⁵⁵ and Maria Reig^1–4

¹Unitat d'Oncologia hepàtica, Liver Unit, Hospital Clínic, Barcelona, Spain
²BCLC group, IDIBAPS, Barcelona, Spain
³CIBEREHD, Barcelona, Spain
⁴Universitat de Barcelona (UB), Barcelona, Spain
⁵Medical Statistics Core Facility, Institut D'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona, Spain
⁶Department 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
⁷AP-HP, Hôpital Beaujon, Liver Cancer Unit, Clichy, France
⁸Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
⁹Gastroenterology, Hospital Universitário Antônio Pedro, Universidade Federal Fuminense, Rio de Janeiro, Brazil
¹⁰Gastroenterology, Hospital Federal do Servidores do Estado, Rio de Janeiro, Brazil
¹¹3rd Medical Department, "Octavian Fodor" Institute for Gastroenterology and Hepatology, Cluj-Napoca, Romania
¹²Liver unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France
¹³Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
¹⁴Centre 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
¹⁵Gastroenterology, Hospital do Servidor Publico Estadual de São Paulo, Sao Paulo, Brazil
¹⁶Bp Beneficência Portuguesa de São Paulo, Sao Paulo, Brazil
¹⁷Liver Unit, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
¹⁸Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
¹⁹Clinical 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
²⁰Gastroenterology Department, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico
²¹Department of Surgery and Cancer, Imperial College London, London, UK
²²Liver Unit, Department of Digestive Disease, Hospital Universitario Central de Asturias, IUOPA, ISPA, Universidad de Oviedo, Oviedo, Spain
²³Liver Transplant, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
²⁴GI/Liver Unit, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
²⁵Hepatology Unit, Hospital Italiano, Buenos Aires, Argentina
²⁶Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
²⁷Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS, Humanitas Research Hospital, Rozzano, Italy
²⁸Aparato Digestivo, Hospital Universitario Infanta Leonor, Madrid, Spain
²⁹Department of Gastroenterology and Hepatology, Salamanca University Clinic Hospital, IBSAL, CIBERehd, Salamanca, Spain
³⁰Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
³¹Gastroenterology, Hepatology Unit, Hospital Doctor Josep Trueta, IDIBGI (Institut d'Investigació Biomèdica de Girona), CIBERehd, Girona, Spain
³²Hospital Aleman, Hepatología, Buenos Aires, Argentina
³³Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
³⁴Liver Unit, Hospital Universitario Austral, Pilar, Argentina
³⁵Medicine, Federal University of Sergipe, Aracaju, Brazil
³⁶Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
³⁷Division Gastroenterology and Center for Autoimmune Liver Diseases San Gerardo Hospital University of Milano -Bicocca School of Medicine, Monza, Italy
³⁸Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
³⁹Innere Medizin & Gastroenterologie, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
⁴⁰SeLiver group. Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla-CIBERehd, Seville, Spain
⁴¹Unitat 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
⁴²Medical Oncology, Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
⁴³Liver Unit. HGU Dr. Balmis. CIBERehd. ISABIAL, Alicante, Spain
⁴⁴Gastroenterology and Hepatology, University Hospital Puerta de Hierro, Majadahonda, Spain
⁴⁵Oncology, AMO CLINIC, Salvador, Brazil
⁴⁶Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
⁴⁷South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK
⁴⁸Department of Medical and Surgical Sciences, Foggia, Italy
⁴⁹AP-HP, Hôpital Beaujon, Liver Cancer Unit, Clichy, France
⁵⁰Université de Paris, Paris, France
⁵¹Department of Radiology, Hôpital Beaujon, AP-HP. Nord, Clichy, France
⁵²Department of Gastroenterology, Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niteroi, Brazil
⁵³3rd Medical Department, Institute for Gastroenterology and Hepatology, University of Medicine and Pharmacy, Cluj-Napoca, Romania
⁵⁴Sao 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
⁵⁵Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico –Division of Gastroenterology and Hepatology, Milan, Italy

Correspondence
Massimo Iavarone, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico–Division of Gastroenterology and Hepatology, Milan, Italy. Email: massimo.iavarone@gmail.com; massimo.iavarone@policlinico.mi.it
Maria Reig, BCLC group, Liver Unit, IMDiM, CIBERehd, IDIBAPS, Hospital Clínic, c/Villarroel, 170, Escala 11, 4a planta, 08036 Barcelona. Spain. Email: mreig1@clinic.cat

Conflict of Interest
S. Muñoz-Martínez. Speaker fees from Bayer and travel funding from Bayer and Eisai. He received grant support from Bristol Myers Squibb and Celgene. V. Sapena. Travel grants from Bayer. Consultancy fees from LEO-Pharma. A. Forner. Lecture fees from Bayer, Gilead, Roche, Boston Scientific and MSD; consultancy fees from Bayer, AstraZeneca, Roche, Boston Scientific, SIRTEX, Exact Science and Guerbert. J. Bruix. Consultancy: AbbVie, ArQule, Astra, Basilea, Bayer, BMS, Daiichi Sankyo, GlaxoSmithKline, Gilead, Kowa, Lilly, Medimune, Novartis, Onxeo, Polaris, Quirem, Roche, Sanofi-Aventis, Sirtex, Terumo/Grants: Bayer and Ipsen. M. Sanduzzi-Zamparelli. received speaker fees and travel grants from Bayer and BTG, MSD. M. Bouattour. Consultant, Advisory Board and Travel support: Bayer Pharma, Ipsen, BMS, Eisai, Roche, AstraZeneca, Sirtex Medical. M. El-Kassas. Consulting fees from Roche and EVA Pharma. Payment honoraria for lectures from Inspire, Spimaco and Roche. Payment for expert testimony from EVA, Janssen and ROCHE. Travel support by Roche, MSD and EVA Pharma. President of Egyptian Association for Research and Training in HepatoGastroenterology (EARTH). C. Guedes Leal. Lectures fees from IPSEN, AstraZeneca, Roche and Bayer. T. Mocan. Received travel grants from Bayer. J-C.Nault. Received research grant from Ipsen and Bayer. R. Pinheiro-Alves. Payment of honoraria for lectures from Bayer, Abbvie and Sirtex Medical. H. L. Reeves. Cancer Research UK (CR UK) HUNTER Accelerator Award (C9380/A26813). Grant support for Helen Reeves, paid to Institution. Consulting fees from SIRTEX, and Boston Scientific (payments to institution). Payment honoraria for lectures from Bayer and Eisai. L. da Fonseca. Lectures fees from BMS, Roche and Bayer. D. J. Pinato. Received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche and AstraZeneca; received research funding (to institution) from MSD and BMS. M. Varela. Reports receiving consulting fees from Astra-Zeneca, Bayer, Eisai-MSD, BMS, Roche; lectures fees from Bayer, Boston, Gilead, Eisai-MSD, AbbVie; travel fees from Astra-Zeneca, Bayer. M. R. Alvares-da-Silva. Has received Research grants, advisory board or speaker for AbbVie, Bayer, Biolab, Intercept, Ipsen, Gilead, MSD, Novartis, Genfit and Roche. L. Rimassa. Reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lectures fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel fees from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. M. Lozano. Lectures and educational presentations: Abbvie. Travel/accommodations, meeting expenses covered by Bayer, Gilead, Abbvie. J. M. González Santiago. JMGS received funding from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819). F. Tacke. Has received research grants from Allergan, Gilead, Inventiva and BMS (to his institution). M. Sala. Travel/accommodation/meeting expenses: Bayer. Eisai. Speaker fees: Bayer. M. Anders. Received speaker honoraria from Bayer, Roche, LKM-Biotoscana, RAFFO. A. Lachenmayer. Consultancy CAScination, Advisory Board Johnson&Johnson and Histosonics. F. Piñero. Received speaker honoraria from Bayer, Roche, LKM-Biotoscana, RAFFO. Research Grants from INC Argentinean National Institute of Cancer, Roche. G. Cabibbo. Consultancy fees from Bayer, Ipsen and Eisai. M. Peck-Radosavljevic. Consultant for Bayer, Eisai, Guerbet, Intercept, Ipsen, Lilly, Roche; Speaker fees from Bayer, BMS, Eisai, Intercept, Ipsen, Lilly, MSD, Roche. Vergara. Travel grants from Bayer, Gilead, MSD and Abbvie. Lectures sponsored by Gilead, Abbvie, Intercept, Eisai and MSD. Consultancy: Eisai. C. Braconi. Consulting honoraria from Incyres. S. Pascual. Consulting fees from Eisai and Roche. Honoraria for lectures from Eisai, Chiari, Bayer, Educational events Gilead. Travel funding from Gilead. Participation in monitoring Board or Advisory Board: Eisai and Roche. C. Perelló. Received speaker honoraria and travel grants from Bayer, Gilead Sciences and Eisai. V. Mello. Fee lectures from Bayer and Roche. C. Rodríguez-Lope. Travel grants from Bayer. Lecture fees and advisory board from Eisai. J. Acevedo. R. Villani. Research grant from Abbvie. C. Holland. Honoraria for lectures from IPSEN and travel support from Roche. C.F. Theodoro. Received speaker fees from Bayer. Z. Sparchez. Speaker honoraria from Bayer, AbbVie and Neola (Gilead). Travel grants from Neola (Gilead), AbbVie, Bayer. D. E. Viera-Alves. Payment of honoraria for lectures from Novartis and Pfizer. R. Watson. Cancer Research UK (CR UK) HUNTER Accelerator Award (C9380/A26813) salary support paid to institution. A. D'Alessio. Travel support from Roche. M. Iavarone. Received speaker honoraria from Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, Roche, EISAI and was consultant for BTG-Boston Scientific, EISAI, Bayer and Guerbet. M. Reig. Consultancy: Bayer-Shering Pharma, BMS, Roche, Ipsen, AstraZeneca, Lilly, BTG and UniversalDX. Paid conferences: Bayer-Shering Pharma, BMS, Gilead, Lilly, Roche and UniversalDX. Research Grants (from the Institution): Bayer-Shering Pharma, Ipsen.
The rest of the authors declare no conflict of interests.