key: cord-0738553-4zg7zeks
authors: Kudo, Masatoshi; Kurosaki, Masayuki; Ikeda, Masafumi; Aikata, Hiroshi; Hiraoka, Atsushi; Torimura, Takuji; Sakamoto, Naoya
title: Treatment of Hepatocellular Carcinoma (HCC) during the COVID‐19 Outbreak: The Working Group Report of JAMTT‐HCC
date: 2020-06-24
journal: Hepatol Res
DOI: 10.1111/hepr.13541
sha: b2c890efa101edaffda6d94dee0d3f2416d3f64a
doc_id: 738553
cord_uid: 4zg7zeks

This contingency guide was formulated on the premise that delivering standard treatment for hepatocellular carcinoma (HCC) has come under strain due to the COVID‐19 pandemic. Measures required are likely to vary largely across regions and individual institutions, depending on the level of the strain imposed by the pandemic (e.g., number of inpatients infected with COVID‐19 and the availability of resources, including personal protective equipment and inpatient beds). Also, models suggest that second and third waves of COVID‐19 will occur before effective vaccines and medicines become widely available in Japan (expected time, 2–3 years). This guide should serve as a good reference for best practices in the management of HCC in light of the possible risk of impending collapse of the healthcare system due to a surge in COVID‐19 infections.

infection. Although the mechanism underlying the development of hypoalbuminemia in these patients is unknown, it likely involves inflammation and under-nutrition. Increased concentrations of γ-glutamyl transferase (GGT), a biomarker for cholangiocyte injury, have been observed in 54% of patients infected with COVID-19 [19] .

A comparison of patients with severe and mild COVID-19 infection showed a significant deterioration of liver function in the former [25, 26] . Similar to SARS-CoV, SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) as a receptor to facilitate its entry into target cells. ACE2 is expressed on hepatocytes and cholangiocytes, with much higher expression levels in cholangiocytes (20 times fold). Thus, the mechanism underlying the development of liver dysfunction in COVID-19 may involve injury to cholangiocytes and hepatocytes [18, 27, 28] , as well as immune-mediated liver injury and hypoxemia [18, 27] .

Postmortem biopsy showed macrovesicular steatosis of the liver alongside mild lobular and portal inflammatory activity, suggesting either SARS-CoV-2 infection or drug-induced injury as the cause of liver dysfunction [29] .

Taken together, these findings suggest that liver function should be assessed in patients with COVID-19 by measuring concentrations of ALT, AST, alkaline phosphatase, GGT, albumin, total protein, and total bilirubin, as well as prothrombin time or INR. Liver function should also be monitored regularly in all infected patients, especially those with severe COVID-19, and those treated with investigational or off-label drugs.

Patients with cancer are at high risk of COVID-19 infection because they are prone to infections in general, due to systemic immunosuppression resulting from anticancer treatment (e.g., chemotherapy) [13] . Moreover, cancer patients infected with COVID-19 are likely to have a poor prognosis [14, 15] . Accordingly, similar to the recommendations of the ILCA guidelines [7] , patients with HCC should be treated at COVID-19-free institutions, when feasible. COVID-19-free institutions are defined as medical institutions with no COVID-19 patients or those specializing in HCC treatment with a small number of COVID-19 patients, who are completely under control to avoid nosocomial infection. Patients should be managed according to the Guidelines for Management of Liver Cancer [11] , but some modifications in HCC treatment strategies may be necessary if hospital admission and hospital stay for non-COVID-19 patients are restricted to prevent nosocomial infection, and to secure beds for patients with COVID-19 [7, 8] .

Use of telemedicine is desirable but has not yet been established in Japan. Thus, measures should reflect regional circumstances, such as extending the interval between hospital visits and conducting follow-up examinations by telephone [7, 8] .

Hospitalization is required for many procedures in HCC treatment, such as surgical resection, RFA, TACE, and hepatic arterial infusion chemotherapy (HAIC). In Japan, surgical resection and RFA are the main treatment options for patients with Barcelona Clinic Liver Cancer (BCLC) stage A HCC; TACE and molecular targeted therapy (MTT) are options for patients with BCLC stage B HCC; and MTT and HAIC are options for BCLC stage C HCC [11, 31] . Treatment in compliance with the guidelines is fundamental and important, even during the COVID-19 pandemic; however, treatment that reduces the risk of COVID-19 must also be considered. To avoid nosocomial COVID-19 and to ensure adequate inpatient beds for patients with COVID-19, hospital admission for HCC treatment should be avoided when feasible, and alternative or modified treatment modalities that can reduce the frequency of visits to healthcare facilities should be considered after fully discussing available options with the patient (Table 3 ). Further spread of COVID-19 will warrant examining the benefits of performing or postponing treatment for HCC from several perspectives, including the medical perspective and the perspective of efficient and effective allocation of medical resources. Shortages of healthcare staff, inpatient beds, and resources (e.g., personal protective equipment) in some institutions, as has happened in Europe and in some institutions in Japan, would preclude the treatment of HCC at those institutions. When feasible, these patients should therefore be referred to COVID-19-free institutions.

To avoid transmission of COVID-19 to healthcare professionals, patients should be tested for COVID-19 using PCR assay before surgery. Patients without comorbidities who are at increased risk of severe COVID-19 infection must be selected. Patients not requiring emergency surgery, based on the macroscopic classification, degree of differentiation, and staging of the tumor, should be advised to avoid hospital admission by postponing surgery. 

TACE should be considered based on the macroscopic classification, degree of differentiation, and tumor stage. The risk of complications and the risks and benefits of TACE should be assessed for patients with comorbidities that carry increased risks of severe COVID-19. The need for TACE should be evaluated by assessing indices such as the up-toseven criteria [35, 36] and albumin-bilirubin (ALBI) grade [37] . Systemic therapy should be considered for patients not indicated for TACE, including those classified as up-to-seven OUT or with ALBI grade 2 (especially mALBI grade 2b) [7, 31, 35, [38] [39] [40] [41] [42] [43] . Systemic therapy should also be considered when TACE is not indicated based on macroscopic classification and degree of differentiation; these include tumors beyond simple nodular type with extranodular growth, confluent multinodular type, or poorly differentiated type [44] [45] [46] .

Avoiding or postponing hospital admission and replacing TACE with systemic therapy, preferably using agents with high response rates such as lenvatinib, should be considered 

Patients most likely to benefit from systemic therapy should be selected based on performance status, ALBI grade, Child-Pugh score, and comorbidities. Immune checkpoint inhibitors have not yet been approved for HCC treatment in Japan (as of May 2020). If the risk of COVID-19 remains high when immune checkpoint inhibitors are approved, the interval between hospital visits should be extended to reduce the frequency of visits and the risk of COVID-19, as recommended by the ILCA and EASL guidelines [7] [8] [9] [51] [52] [53] [54] .

Selection of oral administration agents such as tyrosine kinase inhibitors or injection agents such as ramucirumab should be considered carefully to reduce the frequency of visits and 

The decision to perform HAIC should be based on assessment of both its necessity and risks, as well as the risk of COVID-19 infection associated with catheter placement in the hepatic artery. In the absence of obvious vascular invasion, systemic therapy is the preferred option [55] [56] [57] [58] . In addition, HAIC with regimens of cytotoxic anticancer agents that cause neutropenia and thrombocytopenia, or that require long hospital stay and frequent hospital visits, should be avoided as much as possible. Similarly, the risks and benefits of HAIC should be evaluated in patients with comorbidities that increase the risk of severe COVID-19.

HAIC should be considered if it can benefit such patients, including those unresponsive to systemic therapy or advanced vascular invasion [11, 31, [55] [56] [57] . However, when institutions face strains because of COVID-19, patients should be referred to COVID-19 free institutions. Safety of trial participants should always be the top priority in decision making and conducting clinical trials. Therefore, the benefit/risk assessment should be always monitored during conduct of clinical trials during the COVID-19 outbreak. When a trial subject is at excessive risks due to trial procedures or treatments, modification or even interruption of accrual should be considered. Due to the COVID-19 outbreak, the number of protocol deviation is expected to increase during the COVID-19 pandemic. Therefore, it is important for investigators to document the protocol deviation and closely communicate with regulatory authority and sponsor company. When supply of study medications is interrupted, patients should be considered alternative systemic therapy for HCC, such as sorafenib or lenvatinib as ILCA guidance suggests [7] .

This contingency guide was developed for two main reasons. First, the spread of COVID-19 in metropolitan areas in the Tokyo and Osaka regions, as well as in Hokkaido and Fukuoka, led to shortages of inpatient beds, healthcare staff, and other resources (e.g., personal protective equipment), especially at institutions that received patients with moderate to severe COVID-19. Thus, these affected institutions could not provide patients with standard HCC therapy. Second, it is vital to prepare for the same situation that may occur during the second and third waves of the COVID-19 pandemic. Although many institutions will likely be able to provide standard therapy for HCC as of May 31, 2020, when current restrictions are lifted, the second and third waves are projected to occur within a year, making it extremely important to determine how to deliver HCC treatments when institutions will likely come close to collapse. The authors hope that Japan can avoid an explosive surge of infections and the consequent disastrous effects on the healthcare system, as already seen in Chai X, Hu L, Zhang 

・Reduce hospital visits and use telemedicine to prevent hospital-acquired COVID-19 infection ・Where visits cannot be avoided, use personal protective equipment (PPE) in line with national guidance ・When bridging therapy or active monitoring is offered in place of potentially curative interventions, patients should be closely monitored, including with imaging methods and measurement of AFP, to reduce their risk of progressing beyond criteria for transplant, resection, or RFA ・Where feasible, cancer therapy should be offered in a 'COVID-free' institution ・Care should be maintained according to guidelines but consider minimal exposure to medical staff by telemedicine and telephone contacts wherever possible/required to avoid admission to hospital ・Early admission is recommended for patients with COVID-19 

・For patients in clinical trials, discussion with sponsors required to accommodate variations in follow-up schedule, trial-related procedures, and treatment location ・Select patients most likely to benefit, based on performance status, Child-Pugh score, and comorbidities ・First-line sorafenib or lenvatinib to replace trial recruitment and minimize hospital visits ・In regions where checkpoint inhibitors are approved, consider increased risks associated with attendance for infusion ・Manage patients by telemedicine to avoid hospital visits Dispense drugs by mail, perform blood and urine tests, and measure BP locally in the community; Consider omitting radiology response assessment and continue evaluating clinical progression by tolerance Alternative therapy: Active monitoring (with imaging where appropriate), Supportive palliative care ・Temporarily withdraw immune-checkpoint inhibitor therapy ・Decide whether to continue/reduce TKI in non-severe COVID-19 patients on a case-by-case basis 

World Health Organization (WHO): Coronavirus disease (COVID-19) Pandemic 2020

Labour and Welfare: Latest information on coronavirus disease 2019 (COVID-19)

Coronavirus Resources

ESMO): COVID-19 and cancer

COVID-19 rapid guideline: delivery of systemic anticancer treatments

COVID-19 & Liver Cancer

International Liver Cancer (ILCA): MANAGEMENT OF HCC DURING COVID-19 ILCA GUIDANCE

Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper

AASLD Clinical Insights for Hepatology and Liver Transplant Providers During the COVID-19

Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update

Guidance for treatment of hepatocellular carcinoma (HCC) during the COVID-19 outbreak: The Working Group Report of JAMTT-HCC

COVID-19 and Cancer: Lessons From a Pooled Meta-Analysis

SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China. JAMA oncology 2020 patients in SARS-CoV-2 infection: a nationwide analysis in China

Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in

Liver injury during highly pathogenic human coronavirus infections

Liver injury in COVID-19: management and challenges

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

A comparative study on the clinical features of COVID-19 pneumonia to other pneumonias

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical features of patients infected with 2019 novel coronavirus in

Clinical Characteristics of Coronavirus Disease 2019 in China

COVID-19 in a designated infectious diseases hospital outside

Lenvatinib as an Initial Treatment in Patients with Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh A Liver Function: A Proof-Of-Concept Study

Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions

Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade

Subclassification of patients with intermediate-stage (Barcelona Clinic Liver Cancer stage-B) hepatocellular carcinoma using the up-to-seven criteria and serum tumor markers

Binding Protein Glycosylation Isomer and Up-To-Seven Criteria as a Useful Predictor for Child-Carcinoma

Validation of Modified ALBI Grade for More Detailed Assessment of Hepatic Function in Hepatocellular Carcinoma Patients: A Multicenter Analysis

Validation of Newly Proposed Time to Transarterial Chemoembolization Progression in Intermediate-Stage Hepatocellular Carcinoma Cases

A New Treatment Option for Intermediate-Stage Hepatocellular Carcinoma with High Tumor Burden: Initial Lenvatinib Therapy with Subsequent Selective TACE

Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study

New classification of dynamic computed tomography images predictive of malignant characteristics of hepatocellular carcinoma

)F-Fluorodeoxyglucose Uptake in Hepatocellular Carcinoma as a Useful Predictor of an Extremely Rapid Response to Lenvatinib

Pretreatment heterogeneous enhancement pattern of hepatocellular carcinoma may be a useful new predictor of early response to lenvatinib and overall prognosis

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset

Extremely High Objective Response Rate of Lenvatinib: Its Clinical Relevance and Changing the Treatment Paradigm in Hepatocellular Carcinoma

A changing paradigm for the treatment of Intermediate-stage hepatocellular carcinoma: APPLE Expert Consensus Statement

Advice Regarding Systemic Therapy in Patients with Urological Cancers During the COVID-19 Pandemic

EAU Guidelines Office Rapid Reaction Group:An organisation-wide collaborative effort to adapt the EAU guidelines recommendations to the COVID-19 era

Term Recommendations for Non-Small Cell Lung Cancer Management During the COVID-19 Pandemic

ESMO management and treatment adapted recommendations in the COVID-19 era: Breast cancer

Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label

Sorafenib versus hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma: A Japanese multi-center large cohort study

Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial

Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial

European Medicines Agency: Guidance to sponsors on how to manage clinical trials during the COVID-19 pandemic

・Where feasible, cancer therapy should be offered in a 'COVID-free' institution, defined as an institution with no COVID-19 patients, or in an institution specializing in HCC treatment with a small number of COVID-19 cases, who are completely under control to avoid nosocomial infection ・Care should be maintained according to guidelines, to prevent hospital-acquired COVID-19 infection while securing sufficient beds for patients with COVID-19 ・Alternative therapies and ways to avoid hospitalization and reduce hospital visits as much as possible should be considered a fter consultation with individual patients ・Although use of telemedicine is desirable, treatment according to the regional environment, such as extending the interval between hospital visits and telephone follow-up for monitoring, is recommended

・Screening by PCR testing before surgery to prevent transmission of COVID-19 to healthcare professionals ・Select patients without comorbidities that increase the risk of severe COVID-19 ・Postpone surgery whenever possible, based on macroscopic tumor classification, differentiation, and grade of malignancy with tumor marker ・Consider alternative treatments such as RFA and bridging systemic therapy to shorten the in-hospital stay or to avoid hospitalization