key: cord-0868116-21rt6yvm
authors: Muñoz-Martínez, Sergio; Sapena, Victor; Forner, Alejandro; Nault, Jean-Charles; Sapisochin, Gonzalo; Rimassa, Lorenza; Sangro, Bruno; Bruix, Jordi; Sanduzzi-Zamparelli, Marco; Hołówko, Wacław; El Kassas, Mohamed; Mocan, Tudor; Bouattour, Mohamed; Merle, Philippe; Hoogwater, Frederik J.H.; Alqahtani, Saleh A.; Reeves, Helen L.; Pinato, David J.; Giorgakis, Emmanouil; Meyer, Tim; Villadsen, Gerda Elisabeth; Wege, Henning; Salati, Massimiliano; Mínguez, Beatriz; Di Costanzo, Giovan Giuseppe; Roderburg, Christoph; Tacke, Frank; Varela, María; Galle, Peter R.; Alvares-da-Silva, Mario Reis; Trojan, Jörg; Bridgewater, John; Cabibbo, Giuseppe; Toso, Christian; Lachenmayer, Anja; Casadei-Gardini, Andrea; Toyoda, Hidenori; Lüdde, Tom; Villani, Rosanna; Matilla Peña, Ana María; Guedes Leal, Cassia Regina; Ronzoni, Monica; Delgado, Manuel; Perelló, Christie; Pascual, Sonia; Lledó, José Luis; Argemi, Josepmaria; Basu, Bristi; da Fonseca, Leonardo; Acevedo, Juan; Siebenhüner, Alexander R.; Braconi, Chiara; Meyers, Brandon M.; Granito, Alessandro; Sala, Margarita; Rodríguez Lope, Carlos; Blaise, Lorraine; Romero-Gómez, Manuel; Piñero, Federico; Gomez, Dhanny; Mello, Vivianne; Pinheiro Alves, Rogerio Camargo; França, Alex; Branco, Fernanda; Brandi, Giovanni; Pereira, Gustavo; Coll, Susanna; Guarino, Maria; Benítez, Carlos; Anders, Maria Margarita; Bandi, Juan C.; Vergara, Mercedes; Calvo, Mariona; Peck-Radosavljevic, Markus; García-Juárez, Ignacio; Cardinale, Vincenzo; Lozano, Mar; Gambato, Martina; Okolicsanyi, Stefano; Arraez, Dalia Morales; Elvevi, Alessandra; Muñoz, Alberto E.; Lué, Alberto; Iavarone, Massimo; Reig, Maria
title: Assessing the impact of COVID-19 on liver cancer management (CERO-19)
date: 2021-02-23
journal: JHEP Rep
DOI: 10.1016/j.jhepr.2021.100260
sha: cba9ddfa3d65479b453e08ac1614a894b6c83cbd
doc_id: 868116
cord_uid: 21rt6yvm

BACKGROUND: The coronavirus 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). This project has evaluated if the schedule of LC screening or procedures has been interrupted /delayed because of the COVID-19 pandemic. MATERIAL AND METHODS: An international survey evaluated the impact of COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. RESULTS: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia and Africa (73.7%, 17.1%, 5.3%, 2.6% and 1.3% per continent, respectively). Eighty-seven per cent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening program, 50% cancelled curative and/or palliative treatments for LC, and 44.0% cancelled the liver transplantation program. Forty-five out 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service prior to COVID-19 pandemic (n=19/37). CONCLUSION: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with LC. Modifications in screening, diagnostic and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision making.

An international survey evaluated the impact of COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. While recent studies have described the mortality in cancer patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection as reaching 28.9% to 33.6%, a relatively modest 4.4% to 5.5% has been reported patients cohorts including hepatobiliary cancers [1, 2] . In the case of hepatocellular carcinoma (HCC) and some intrahepatic cholangiocarcinoma (iCCA), almost all patients also have underlying cirrhosis, Marjot et al. reported that baseline liver disease stage and alcohol-related liver disease were independent risk factors for death from SARS-CoV-2 infection, increasing the risk of hepatic decompensation [3, 4] . Even in the absence of these significant complications in liver cancer 

The answers to the survey were expressed as absolute frequencies and percentages (%). The survey was developed and performed using the SurveyMonkey ® platform. Raw data and results were directly extracted from the platform. SAS software ® (v9.4) was used when more accurate approaches were required and to generate the figures.

The survey was open from May 2020 to June 2020. Ninety-one centres were contacted or expressed interest to be involved and 81 survey responses were received (89% response). Five were excluded: 4 due to duplication and 1 because their data was incorporated with that from another centre.

The final analysis was based on information from 76 Despite the modifications in management of clinical trials activities, 58.1% of the centres were able to recruit new patients during COVID-19 pandemic, but only 9.7% of centres declared that the recruitment rate was similar to that before the pre-COVID-19 pandemic. In 46.2% of centres virtual visits by video or phone calls were done, and 29.9% of centres were forced to postpone visits (not transformed into virtual). Table 3 Notably, the approach maintained in almost all centres (93.2%) was systemic treatment LC patients. This may have been associated with the stage of the disease, stage being one of the priority criteria identified at the time of maintaining the planned schedule. The fact that the most widely used systemic therapies were oral tyrosine kinase inhibitors, which can be selfadministered by the patient at home rather than requiring a visit to the hospital, is also likely to have played a role.

Unfortunately, the disruption in screening programmes due to this health care crisis raises the possible consequence of a shift towards a more advanced stage at diagnosis. Additionally, delays of interventional procedures such as transplant, resection or ablation may impact on tumour progression, dissemination and ultimately prognosis. Previous studies [10, 11] indicated that progression associated with poorer outcomes occurred as a consequence of waiting or delaying interventions beyond two months. Hanna et al. described a significant association between cancer treatment delay and increased mortality for 13 out of 17 indications analyzed, although LC was not one of those analyzed [12] . Rich et al. have recently shown that the rate of liver tumour growth at early stages is very heterogeneous [13] .

This may be something that could be further evaluated in the context of screening ultrasound delays due to COVID-19 pandemic. Obviously, tumour stage at diagnosis will be one of the most relevant, as tumour growth is assumed to be faster along its evolution [14] [15] [16] . We should also keep in mind that the detection of changes in outcome or tumour progression during the delayed interventions may translate into a marginal impairment without clinically relevant consequences. It must also be noted in advance that any suggestion we raise in the future will not have the background that would be provided by a randomized controlled trial comparing conventional timing vs. delayed intervention. Despite this limitation, our future data will be instrumental in the identification of those areas where the changes induced by the J o u r n a l P r e -p r o o f pandemic have been beneficial or detrimental. If the outcome at any step of the health care pathway is clearly worse, we would have an estimation of the deleterious consequences of COVID-19 pandemic beyond the infection itself. This may inform us on the most appropriate measures to be adopted in the future; either while this pandemic persists or repeats, as is happening with the current second wave, or should another public health crisis emerge in the future.

The move from face-to-face visits to phone call visits encouraged during the pandemic may improve patient care going forward, being potentially acceptable and preferable in some patients. The pandemic also reinforced the role of nurses [17, 18] , who were already part of LC teams in 76.3% of the centres, with their activity and responsibility appearing to have increased. In some groups, where nurses were not previously part of the team, the COVID-19 crisis has promoted investment in their growing roles, in education and counselling of patients and their families.

The benefits and challenges related to the use of remote visits by nurses and physicians for cancer patients will be seen in the next months/years [17] [18] [19] . Not all patients and families will be successfully served by remote visits and our data already reveal that there are several characteristics that may favour face-to-face or phone call visits. The age of the patient (which is a factor associated with severity in SARS-CoV-2 infected patients in cancers different to LC) [2] as well as the patient address and distance to the hospital (which could be associated with increased risk of exposure on their way to and from the hospital) were the less frequent factors considered to switch from face-to-face visit to a phone call visit in clinical practice.

However, in patients included in treatments in clinical trials we observed that younger age of the patients and lack of comorbidities were criteria to favour phone call visits. This difference could be mainly related to the type of information to be given during a conventional clinical J o u r n a l P r e -p r o o f practice visit related to diagnosis or/and tumour progression or the type of visit in the setting of treatments in clinical trials with experimental agents at risk of adverse events (first or follow-up visit). Indeed, since recruitment into treatments in clinical trials had been impacted (only 9.7% of centres maintained the same recruitment rate they had before the pandemic), almost all the visits within treatments in clinical trials have been devoted to follow-up assessments rather than new patient recruitment. As previous studies had shown [20, 21] , maintaining treatments in clinical trials activities requires a great effort and reorganization of the LC team, to define a protocol to continue with these activities while protecting patients from contracting SARS-CoV-2 infection.

The results of this survey describe the major changes that occurred in LC management in 76 high volume centres around the world. However, 73.7% of centres that answered the survey were from Europe. In addition, the Italian and Spanish centres represented 55.4% of the European centres. Thus, the results of the survey could be overestimated by these 2 countries which were severely affected by the first wave. Supplementary Table S3 describes Figure 1 . Areas in which pre-pandemic clinical practices were modified expressed as percentages.

Grey bars represent the centres´ percentage that had to modify the clinical practice in the main areas mentioned in the figure´s left part. Grey bars represent the percentage of centres that used each of the criteria mentioned in the figure´s left part to maintain pre-defined schedules of diagnostic and staging procedures. 

Hospital do Servidor Publico Estadual de São Paulo

Division of Oncology -Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital

Hospital Federal de Bonsucesso

Hepatology section

Institut Català d'Oncologia

National Institute of Medical Sciences and Nutrition Salvador Zubirán

Granada Ospedale Maggiore Policlinico -Division of Gastroenterology

Clinical Portrait of the SARS-CoV-2 Epidemic in European Patients with Cancer

Presenting features and early mortality from SARS-CoV-2 infection in cancer patients during the initial stage of the COVID-19 pandemic in Europe

Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study

High rates of 30-day mortality in patients with cirrhosis and COVID-19

Journal Pre-proof Impact of COVID-19 on the management of hepatocellular carcinoma in a high-prevalence area

ILCA Guidance for Management of HCC during COVID-19

Pandemic 8 th

Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic

Surveillance and Monitoring of

Hepatocellular Carcinoma During the COVID-19 Pandemic

Treatment of hepatocellular carcinoma during the COVID 19 outbreak: The Working Group report of

Estimation of lead-time bias and its impact on the outcome of surveillance for the early diagnosis of hepatocellular carcinoma

Delay in treatment of early-stage hepatocellular carcinoma using radiofrequency ablation may impact survival of cirrhotic patients in a surveillance program

Mortality due to cancer treatment delay: systematic review and meta-analysis

Hepatocellular carcinoma demonstrates heterogeneous growth patterns in a multi center cohort of patients with cirrhosis

Predicting the probability of progression-free survival in patients with small hepatocellular carcinoma

Analysis of inter-patient variations in tumour growth rate

Estimation of Solid Tumor Doubling Times from Progression-Free Survival Plots Using a Novel Statistical Approach

Navigating the COVID-19 Pandemic as an Oncology Nurse

Oncology Nursing During a Pandemic: Critical Reflections in the Context of COVID-19 2020

Virtual empathy and liver cancer

COVID 19 and liver cancer clinical trials: Not everything is lost

Early Impact of COVID-19 on the Conduct of Oncology Clinical Trials and Long-Term Opportunities for Transformation: Findings From an

Use of Chest Imaging in the Diagnosis and Management of COVID-19: A WHO Rapid Advice Guide