The report is a product of the VA/HSR Evidence Synthesis Program.

Screening for Hepatocellular Carcinoma in Adults at Increased Risk

Takeaway: Despite a preponderance of observational studies and several randomized trials, evidence was very uncertain regarding the effectiveness and harms of hepatocellular carcinoma (HCC) screening in adults at increased risk. Evidence was also very uncertain regarding the comparative effects of different screening strategies including imaging modalities, intervals, and biomarkers. Thus, the current uncertainty of evidence makes HCC screening implementation and patient-clinician decision-making challenging.

Hepatocellular cancer (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide, although incidence and mortality vary by age, race or ethnicity, and sex. An estimated 41,210 Americans will be diagnosed with liver cancer in 2023, and 29,380 are expected to die from the disease, with Veterans at greater risk of HCC compared to the general population. Early identification of liver cancers may reduce disease-specific and all-cause mortality by providing an opportunity for potentially curative therapies (i.e., surgical resection, ablative therapy, or liver transplantation). A recent systematic review highlighted that HCC treatment costs, harms, and limited mortality benefits may lead some patients to forgo treatment, underlining the importance of more effective detection and treatment options.

Screening for HCC among adults at increased risk (especially those with cirrhosis) has been recommended by several specialty societies, typically through abdominal ultrasound imaging with AFP (alpha-fetoprotein) every six months. However, the National Cancer Institute’s Physician Data Query concluded that based on fair evidence, screening of persons at elevated risk does not result in a decrease in mortality from HCC and would result in rare but serious side effects. Recently, the AASLD (American Association for the Study of Liver Diseases) issued guidance regarding HCC screening and recommends HCC screening with semi-annual ultrasound plus AFP in at-risk individuals. The United States Preventive Services Task Force and other U.S. medical societies have not issued HCC screening guidelines. In addition to the question of whether HCC screening should be conducted, there are several questions about how to best implement HCC screening, if screening is effective and has acceptable harms, burden, and costs. They include:

• The optimal imaging technique (ultrasound, magnetic resonance imaging [MRI], or computed tomography [CT]);
• Whether AFP should or should not be included;
• How often to screen (e.g., 3, 6, or 12 months); and
• Whether the benefits and harms of screening vary by patient or liver disease characteristics.

VA’s Evidence Synthesis Program (ESP) Center located at the Minneapolis VA Health Care System recently conducted a systematic review in response to a request from VA’s National Gastroenterology and Hepatology Program for an evaluation of data regarding screening for HCC and, specifically, to identify the benefits and harms of HCC screening among adults at increased risk. Two previous reviews assessing the effectiveness of screening for HCC in chronic liver disease (Kansagara, et al., and Singal, et al.) were conducted in 2014 and 2022, respectively. This review provides an update. Investigators searched Embase and MEDLINE from July 1, 2020, through January 24, 2023, and identified 171 potentially relevant articles. Of these, 74 primary studies met eligibility criteria including 5 randomized controlled trials (RCTs) and 69 observational studies.

Summary of Findings

Evidence is very uncertain as to whether screening for HCC in individuals at increased risk reduces all-cause or HCC mortality. Evidence is also very uncertain as to the comparative effectiveness of varying screening strategies. While the available evidence is substantial in quantity, there are important methodological limitations precluding a reliable assessment of the effectiveness and harms of screening. Most studies analyzed only individuals who already had HCC, thus missing the intended target population for screening. Moreover, major methodological issues that limit certainty of the evidence included a combination of lead- and length-time bias and little controlling for confounders known to affect the receipt of screening and patient survival.

Investigators found very little data from studies that could provide more reliable information (e.g., cohort, case-control, RCTs) regarding screening among individuals at risk for HCC. Among these studies, methodological concerns and/or inconsistent findings limited conclusions. Further, only three studies were conducted in the U.S., with one reporting all-cause mortality and two reporting HCC mortality. One small RCT with a Veteran cohort with cirrhosis (some risk of bias concerns) found no significant reductions in HCC mortality among individuals screened with ultrasound plus AFP every 6 months vs CT every 12 months plus AFP every 6 months.

Limitations

This review was limited to English-language publications. There may be relevant studies published in non-English language. However, discussion with nominating partners and Technical Expert Panel members did not lead to an identification of important studies not included in this report. Also, the primary focus of this report is screening individuals at increased risk in the U.S.. Other limitations are primarily due to the existing evidence.

Implications for VA

Randomized trials evaluating the effectiveness, comparative effectiveness, harms, and costs of different screening strategies, including screening vs no screening, are needed to determine the net benefit of screening. Higher methodological quality observational studies would also provide valuable information. An ongoing VA-CSP (Cooperative Studies Program) trial is comparing screening with ultrasound + AFP vs abbreviated MRI among individuals with cirrhosis and increased HCC risk. However, this trial will not fully address whether screening reduces morbidity and mortality vs no screening. Until methodologically higher-quality studies are available, the current uncertainty in the evidence makes HCC screening implementation and patient-clinician decision-making challenging.

Future Research

Evidence gaps could be closed with RCTs comparing varying screening strategies, including screening vs no screening. Higher methodological quality observational studies are also needed.

Landsteiner A, Ullman K, Langsetmo L, Zerzan N, Kalinowski C, Haglund J, and Wilt TJ. Screening for Hepatocellular Carcinoma in Adults at Increased Risk: A Systematic Review. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #09-009; 2023.

To view the full report, go to: vaww.hsrd.research.va.gov/publications/esp/hcc.cfm (Intranet only).

ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of VA/HSR&D's Evidence Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers –; and to disseminate these reports throughout VA.

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