key: cord-324809-16zvqizl
authors: Mehta, Neil; Parikh, Neehar; Kelley, R Katie; Hameed, Bilal; Singal, Amit G.
title: Surveillance and Monitoring of Hepatocellular Carcinoma During the COVID-19 Pandemic
date: 2020-07-08
journal: Clin Gastroenterol Hepatol
DOI: 10.1016/j.cgh.2020.06.072
sha: 
doc_id: 324809
cord_uid: 16zvqizl

Abstract The Coronavirus disease 2019 (COVID-19) pandemic is expected to have a long-lasting impact on the approach to care for patients at risk for and with hepatocellular carcinoma (HCC) due to the risks from potential exposure and resource reallocation. The goal of this document is to provide recommendations on HCC surveillance and monitoring, including strategies to limit unnecessary exposure while continuing to provide high-quality care for patients. Publications and guidelines pertaining to the management of HCC during COVID-19 were reviewed for recommendations related to surveillance and monitoring practices, and any available guidance was referenced to support the authors’ recommendations when applicable. Existing HCC risk stratification models should be utilized to prioritize imaging resources to those patients at highest risk of incident HCC and recurrence following therapy though surveillance can likely continue as before in settings where COVID-19 prevalence is low and adequate protections are in place. Waitlisted patients who will benefit from urgent LT should be prioritized for surveillance whereas it would be reasonable to extend surveillance interval by a short period in HCC patients with lower risk tumor features and those more than 2 years since their last treatment. For patients eligible for systemic therapy, the treatment regimen should be dictated by the risk of COVID-19 associated with route of administration, monitoring and treatment of adverse events, within the context of relative treatment efficacy.

The Coronavirus disease 2019 (COVID-19) pandemic continues to spread worldwide, with over 5.5 million confirmed cases and over 350,000 deaths. The surge of the pandemic has overwhelmed many health systems, leading to difficult decisions about clinical resource allocation. In response, many providers and health systems have restricted in-person encounters -including radiological imaging -and utilized telehealth visits to reduce exposure for both patients and providers. COVID-related risks may be especially relevant in patients with cirrhosis and hepatocellular carcinoma (HCC), for whom management often involves multiple interactions with the healthcare system (e.g. phlebotomy, radiological imaging, clinic visits, and HCC-directed treatments) but who may be more susceptible to severe COVID-related complications.

The COVID-19 pandemic is expected to have a long-lasting impact on the approach to care for all patients, including those with cirrhosis and HCC 1 . Many experts have predicted the need for social distancing and other precautions for at least the next 18-24 months. Even if COVID-19 transmission is drastically reduced or eliminated in the immediate future, recurrent outbreaks could occur over the next several years 2 . Therefore, the approach to HCC surveillance in patients with chronic hepatitis B (HBV) or cirrhosis, as well as HCC monitoring in those with HCC, with respect to resource allocation and disease management is not only a critical issue now but will potentially affect care delivery over several years. The goal of this document is to provide recommendations on HCC surveillance and monitoring during COVID-19, including strategies to limit unnecessary exposure while continuing to provide high-quality care for patients at risk for and with HCC. In settings where COVID-19 prevalence is low and adequate protections are in place, surveillance and monitoring can likely continue as before though these recommendations can be considered as needed.

A targeted literature search was performed to identify PubMed-referenced publications pertaining to management of hepatocellular carcinoma in the setting of the COVID-19 pandemic as of 6 May 2020 1,3-6 . A manual search of professional society websites identified existing guidelines (Table 1 ) as of the same date. These publications and guidelines were reviewed for recommendations related to surveillance and monitoring practices, and any available guidance was referenced to support the authors' recommendations when applicable.

The management considerations presented in this summary document were circulated for review to the multidisciplinary tumor board membership at the authors' respective institutions for input and represent a consensus opinion.

Professional society guidelines recommend semi-annual HCC surveillance using abdominal ultrasound, with or without alpha-fetoprotein (AFP), in high-risk individuals 11, 12 . This practice has been associated with increased early detection and improved survival in a large randomized controlled trial among HBV patients and several cohort studies in patients with cirrhosis 13, 14 . However, during the outbreak of the COVID-19 pandemic, most health systems deferred elective imaging, including HCC surveillance. In patients with COVID-19 infection, HCC surveillance should be deferred until recovery. In addition to concerns about persistent risk of COVID-19 exposure complicating re-opening of health systems, backlogs of patients waiting for deferred imaging may complicate availability of HCC surveillance imaging. Prioritizing HCC surveillance for those who derive the greatest benefit may be necessary; however, it may not be readily apparent how to best select these patients and the optimal surveillance strategies if ultrasound-based surveillance is not available.

Although surveillance is recommended in high-risk subgroups of patients with chronic HBV and all patients with cirrhosis, risk varies between patients and risk stratification models may be used to identify those with the highest HCC incidence. There are risk stratification models both among HBV patients, of which some have been validated in both Eastern and Western populations and cirrhosis patients, predominantly derived in Western populations (Table 2) 15 . To date, there has been limited validation of most models, so their clinical utility in routine practice has remained limited. However, in a restricted resource environment, components of these stratification systems could be used to identify patients who can be prioritized for surveillance and those who may be deferred.

Older age and male gender are consistent components of HCC risk stratification models.

Child-Turcotte-Pugh (CTP) score and presence of portal hypertension are other important risk factors for HCC; however, this must be balanced with likely increased susceptibility to COVID-19 in those with advanced liver dysfunction. Finally, liver disease etiology is a consistent risk factor, with active viremia associated with a 3-6% annual risk, whereas patients with non-alcoholic steatohepatitis (NASH), alcohol-related liver disease, or hepatitis C (HCV) cirrhosis after viral cure have a lower annual risk of 1-2% 21 . Patients with combinations of high risk features may be considered as the highest priority for surveillance receipt, whereas surveillance may be deferred in those with one or no risk factors.

Continued careful patient selection is critical, including not ordering HCC surveillance in patients unlikely to benefit. Patients with CTP C cirrhosis who are not transplant eligible are not recommended to undergo surveillance because of the competing risk of liver-related mortality.

Similarly, patients with other significant comorbidities (e.g. cardiovascular disease, malignancies) that limit life expectancy or treatment eligibility should not undergo surveillance.

Surveillance should also not be performed in certain subgroups at lower risk, e.g. HCV or NASH patients in absence of cirrhosis given marginal risk-benefit ratio 21, 22 . Preventing oversurveillance in populations unlikely to benefit is a practical way to minimize harms of surveillance, including possible COVID-19 exposure.

On the other hand, while some transplant centers have suspended or limited transplants to those with high MELD scores, the listed population could be considered a priority for surveillance receipt. Early detection (e.g. within Milan criteria) is critical in this population to prevent waitlist dropout and timely identification of HCC lesions allows patients to accrue waiting time with MELD exception. Additionally, surveillance can provide other information relevant to transplant decision making, such as development of portal vein thrombosis. Therefore, while some deferments of HCC surveillance may be necessary in the setting of a local COVID-19 outbreak, listed patients should likely be prioritized to receive surveillance as available.

As recommended by AASLD and EASL, deferring HCC surveillance by 2-3 months during times of limited radiologic capacity, such as those experienced during the COVID-19 pandemic, is likely safe. Recommendations to perform semi-annual surveillance were initially based on tumor doubling time from older studies demonstrating tumor doubling times of 4-6 months.

These data have since been replicated in contemporary cohort studies, although a metaanalysis suggests potential shorter doubling times in HBV-predominant populations 23, 24 . A large randomized control trial (RCT) from France demonstrated quarterly surveillance does not improve early HCC detection compared to semi-annual 25 . Although there is not a similar RCT evaluating longer intervals, retrospective cohort studies have shown semi-annual surveillance results in increased early detection and improved survival compared to annual surveillance, after adjusting for lead time bias 26 . However, the difference in survival benefit between the two intervals appears small, and both significantly improve survival compared to no surveillance.

There are also no data comparing semi-annual surveillance to intermediate length surveillance intervals between 8 and 10 months. Deferring HCC surveillance over short periods of time, as needed, is likely acceptable in light of an annual HCC incidence of 2-3%, suggesting ~98% of patients will not develop HCC over any single surveillance interval.

If ultrasound-based surveillance is not possible for extended periods of time, bloodbased biomarkers may be considered as an alternative strategy. Ultrasound with or without AFP achieve a sensitivity of ~63% for early HCC detection when used in combination, although performance may be lower in patients with NASH given increased concerns about poor ultrasound visualization 27, 28 . Although ultrasound is readily available in most areas, logistics of ultrasound-based surveillance, including need for a separate appointment, is a common patient-reported barrier to surveillance completion 29 . This issue may be increasingly problematic in times where social distancing is recommended and patients are concerned about in-person visits. Given potential concerns about lack of social distancing between the ultrasound operator and patient, MRI-based surveillance could also be considered though this strategy is limited by cost-effectiveness when applied to broad populations of cirrhosis patients.

An alternative strategy which could mitigate some issues is blood-based biomarkers, as these can be done the same day as a clinic visit without a separate appointment. Although several serum-based biomarkers have been proposed, none except AFP have undergone phase III or IV validation in cohort studies 30 . AFP has insufficient sensitivity and specificity to be used alone, although data suggest diagnostic performance is higher in patients with non-viral cirrhosis or HCV patients after virologic cure 31, 32 . Further, using longitudinal changes in AFP can increase accuracy for early HCC detection than single-threshold measurement at a cut-off of 20 ng/mL 33 . Given similar concerns about insufficient accuracy for other single biomarkers, there has been increasing interest in biomarker panels. The best evaluated to date is GALAD, which combines gender, age, and three biomarkers -AFP, AFP-L3, and DCP. The panel has demonstrated sensitivities of 60-80% for early stage detection in large multi-national case-control studies, including recent data among NASH patients 34, 35 . GALAD has shown superior performance to the component biomarkers, in part related to inclusion of gender and age in the biomarker algorithm. Although this performance needs to be validated in cohort studies prior to routine use in clinical practice, blood-based biomarkers such as GALAD, AFP-adjusted algorithms, or longitudinal AFP may be a reasonable alternative if ultrasound-based surveillance cannot be easily performed for extended periods of time. Although unknown, surveillance intervals would likely be unchanged from ultrasound-based surveillance as they are based on tumor doubling times and not test performance characteristics.

HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage 0/A (single lesion or 2-3 lesions, each <3cm) are typically treated with curative treatments including resection, ablation, or liver transplantation (LT); however, there is a persistent risk of recurrence after each treatment [36] [37] [38] [39] . Given that long-term survival can be achieved with early detection of HCC recurrence 40, 41 , ongoing HCC surveillance after curative therapy is recommended. Given higher HCC risk after curative therapy than in those with cirrhosis, surveillance is typically performed using cross-sectional imaging with multiphase abdominal CT or contrast-enhanced MRI with or without non-contrast CT chest. After resection (or ablation), less than 25% of recurrences are extra-hepatic 42 so the chest CT can likely be forgone outside of situations such as rising AFP with negative abdominal imaging -particularly if this requires a separate visit and there is limited radiologic capacity.

Similar to HCC surveillance among at-risk patients, surveillance after curative therapies for HCC has been associated with early stage detection and improved survival 43 . While recurrence can be seen for up to 10 years following resection or LT 36 Table   3) 44 . In contrast, recurrence after resection and ablation is very common and early detection is critical given the possibility of salvage transplant for those detected within Milan criteria 52, 53 .

Therefore, under normal circumstances, post-resection or ablation surveillance should be performed approximately every 3-4 months for the first 2 years followed by every 4-6 months for years 2-5. In periods of limited radiologic capacity, it would be reasonable to extend each recommend interval by a short period (e.g. extending 2-3 months), particularly in those with lower risk features (e.g. absence of poorly differentiated histology or microvascular invasion) and those more than 2 years beyond their treatment (Table 3) .

There is consensus that HCC patients should continue to receive local-regional therapy There is concern for serious COVID-19 infection in those receiving conventional TACE (cTACE with cytotoxic agents) because of systemic absorption with increased myelosuppression and therefore ILCA recommends other forms of LRT over cTACE (e.g. bland embolization, drug-eluting bead (DEB)-TACE, Y-90) 10 . Finally, consideration for earlier transition to systemic therapy could be considered in locally advanced HCC patients 56 .

There is limited guidance about timing and follow up of post-LRT surveillance with wide variation in interventional radiology practices 11, 57, 58 . Follow-up cross-sectional imaging should be performed approximately 4-6 weeks after TACE or ablation to assess response and determine need for repeat treatment 59 (Table 3 ). In contrast, arterial enhancement and washout can persist for several months after radiation-based treatment (SBRT, Y-90), complicating radiologic interpretation within the first couple months 60, 61 . Therefore, especially during the COVID-19 pandemic, imaging after Y-90 or SBRT can likely be delayed and performed ~3-4 months after therapy (Table 3) . AFP can also potentially be used as a marker for response to LRT with imaging being delayed in patients with a significant drop in AFP from baseline (e.g. >50%) 62 .

Patients without viable disease after any form of LRT are recommended to undergo follow-up imaging every 3-4 months 59 , although this also may be delayed in light of COVID-19 exposure risk, particularly for those with durable responses. In patients with worsening liver dysfunction, declining performance status, or other features that would preclude repeat treatment, imaging to assess response may also be deferred unless required for other reasons (e.g. transplant eligibility). In this climate, it is important to be able to risk stratify patients with HCC with moderate to high risk of waitlist dropout who will benefit from urgent LT during this period versus those with more indolent disease and a lower risk of dropout. Specifically, patients with a combination of favorable tumor characteristics (e.g. single lesion <3 cm, AFP <20 ng/mL, complete response to LRT) and liver function (e.g. CTP A cirrhosis and MELD score <13-15) appear to have a low-risk of waitlist dropout 65,66 . It would be appropriate to delay LT in such low-risk patients given lack of urgency and decreased LT survival benefit 66 and consider temporary inactivation.

There are now multiple systemic therapies available for patients with advanced stages of HCC. In the first-line setting, treatment options include the multikinase inhibitors, sorafenib 67,68 and lenvatinib 69 For multikinase inhibitors with daily oral dosing, safety monitoring includes frequent blood pressure measurement, skin inspection particularly of palms and soles for evolving palmarplantar erythrodysesthesia findings, and laboratory testing of electrolytes and liver function.

Rare but serious complications including hemorrhagic events and venous or arterial thromboembolism occur in a minority of patients [67] [68] [69] 71, 72 . In patients treated with immune checkpoint inhibitor-based regimens, safety monitoring by laboratory testing and clinical encounters generally occurs at the same frequency as infusions, at intervals ranging from two to six weeks depending on agent and dosing regimen [74] [75] [76] . Safety monitoring on immune checkpoint inhibitors requires vigilance for immune-related adverse events, which can range from more common events of mild rashes and arthralgias, to rare but potentially lifethreatening events such as encephalitis, hypophysitis, myocarditis, pneumonitis, hepatitis, and colitis 77 . Immune-mediated adverse events can evolve and progress rapidly and may require high doses of steroids, other immunosuppressive therapies, and hospitalization in severe cases.

In regions with high rates of COVID-19 transmission, safety monitoring via telemedicine may be an option for patients with access to technology 3, 4, 9 . For patients treated with multikinase inhibitors, telemedicine monitoring requires patient or caregiver access and training on sphygmomanometry. Digital photographs of palms, soles, and any other areas of skin change can be uploaded to an electronic medical record for provider review. Laboratory tests can be performed at a local laboratory or, in some cases, via mobile phlebotomy, to minimize exposures to patient and health system. In patients treated with immune checkpoint inhibitors, regular visits to an infusion center remain necessary, along with laboratory monitoring. Patients and caregivers require education on the risks and warning symptoms of immune-related adverse events which can require urgent medical evaluation 77 .

Regional COVID-19 exposure risk may impact choice of systemic therapy in advanced HCC based upon availability of local resources (e.g. infusion center, endoscopy, clinical trials) and risk of regimen-specific toxicities (e.g. immune-related adverse events which may require high doses of corticosteroids). Testing for active COVID-19 infection should be considered prior to initiation of therapies according to local institutional practice at the time of initiation, particularly for regimens with risk for immunosuppression 3, 8 . When considering first-line therapy options, the combination regimen of atezolizumab plus bevacizumab requires infusion of atezolizumab at three week intervals, along with a screening endoscopy within six months prior to treatment owing to risk of variceal hemorrhage associated with bevacizumab in prior phase 2 studies 70, 78, 79 . If endoscopy and/or infusion center services are not available in a pandemic setting, an alternate first line agent such as lenvatinib or sorafenib may offer a more favorable ratio of benefit to risk (Table 4 ). In the second-line and later treatment setting, the median durations of progression-free survival are longer, while rates of primary progressive disease are lower, for the multikinase inhibitors, regorafenib 71 (Table 4) , which may further increase COVID-19 transmission risk and severity. In regions with high rates of COVID-19 infection, an alternate regimen may be preferred.

For advanced HCC patients treated with systemic therapies, radiographic response is assessed using cross-sectional imaging of the chest, abdomen, and pelvis, usually within three months after treatment initiation 81 . Though radiographic response is the gold standard for assessment of progression, continuation of treatment until symptomatic progression is an accepted practice for patients treated with multikinase inhibitors 68, 69, 71, 72 . In regions with high community COVID-19 transmission, extended imaging intervals may be appropriate in patients without symptomatic progression on systemic therapy 10 . Beyond radiographic and clinical response assessment, serum AFP levels may also be a useful adjunct. Approximately 60-80% of patients with advanced HCC have elevated AFP at start of systemic therapy 82 . In patients with elevated AFP of at least 1.5 times upper limit of normal or 20 ng/mL at start of treatment, changes in AFP on treatment have shown association with outcomes on multiple types of systemic therapies, including sorafenib, cabozantinib, and ramucirumab [82] [83] [84] [85] . Stabilization or decline in serum AFP on treatment, commonly defined as a decrease of at least 20%, has been shown to correlate with prolonged progression-free and overall survival, while increases in AFP correlate with poor outcomes. Though optimal thresholds of AFP response and progression require further validation, serum AFP kinetics offer an additional tool for response assessment ( Figure 1 ) during the COVID-19 pandemic, when imaging may not be readily available and could confer additional risk of viral exposure.

The COVID-19 pandemic has dramatically changed the delivery of health care worldwide. The resource intensive management of patients with cirrhosis and HCC is particularly vulnerable to decreased health care resources during a pandemic. A principle of maximizing the risk-benefit ratio should be taken for the surveillance of HCC and monitoring of patients who have received therapies for HCC. Prioritizing imaging resources to those patients at highest risk of incident HCC and recurrence following therapy, while prioritizing those patients who are eligible for an imminent LT, is a judicious strategy to risk stratifying these patients. For patients eligible for systemic therapy, the landscape is changing rapidly, however the treatment regimen should be dictated by the risk of COVID-19 associated with: route of administration, monitoring and treatment of adverse events, within the context of relative efficacy for the treatment of HCC. These principles hold not only during times of active local transmission, but also in the post-pandemic period when prioritizing the backlog of patients in whom care was deferred due to limited health care resources. Patients at risk for and with HCC are among the highest acuity patients as a whole, but allocating resources to those with the highest likelihood of benefit while minimizing exposure risk to COVID-19 is a prudent approach in a limited resource environment. 

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**For HCC patients listed for liver transplant, UNOS requires cross-sectional imaging of abdomen + AFP at least every 3 months to maintain priority listing under normal conditions. During COVID-19, especially in patients at low risk for waitlist dropout, could consider extending this interval up to every 4-5 months. Can treat with extended dosing interval of 6 weeks to reduce infusion center visit frequency if clinically appropriate; consider multikinase inhibitor if infusion center not accessible Key: NA, not applicable; NR, not reported; *, reported only the rates of treatment-related rather than all-cause serious adverse events.