Advancements in surgical, locoregional, and systemic therapies have improved outcomes for early hepatocellular carcinoma (HCC), but most cases are diagnosed at later stages owing to the limitations and underuse of current surveillance modalities.

With fewer than 1 in 4 patients with cirrhosis surveilled for HCC, the American Gastroenterological Association (AGA) has issued a clinical practice update on risk stratification and emerging surveillance strategies. Published inGastroenterology the guidance comprises eight best practice statements.

“HCC is the third-leading cause of cancer-related death worldwide,” guidance panelist Fasiha Kanwal, MD, MD, MSHS, a professor of medicine in gastroenterology and director of the Institute for Clinical and Translational Research of Baylor College of Medicine in Houston, told Medscape Medical News. Major shifts in the epidemiology of HCC are having a downstream impact on prevention and risk reduction, including by surveillance, she added. “So the overall burden and the recent shifts make this update timely.”

Since the advent of effective antivirals, the most rapid increase in HCC incidence is occurring in patients with nonviral liver disease, she added. “The most notable driver in the United States is metabolic dysfunction-associated steatotic liver disease [MASLD], and this burden is anticipated to rise over the next few decades, but alcohol and hepatitis C virus are still important causes.”

Current guidelines recommend twice-yearly surveillance with ultrasound and alpha-fetoprotein (AFP) testing, but this strategy has suboptimal sensitivity, and imaging surveillance poses risks as well as challenges of implementation, the authors noted.

Recommendations

The best strategy for reducing HCC morbidity and mortality is to prevent cirrhosis. This includes vaccination and treatment of viral hepatitis, treating alcohol use disorder, managing metabolic syndrome, and addressing liver diseases at early stages.

The preferred surveillance strategy for at-risk patients currently remains semiannual ultrasound plus AFP testing. Surveillance offers a higher likelihood of early-stage detection, access to curative therapy, and improved survival.

Among noncirrhotic patients, only a subset of those with chronic hepatitis B virus (HBV) should undergo HCC surveillance. Surveillance is not advised for those without cirrhosis with other liver disease etiologies such as MASLD, given the low annual incidence rate.

Although the benefits of surveillance are well established, clinicians should consider the potential physical, psychological, and financial harms associated with the process.

Novel blood-based biomarkers, such as the GALAD score (gender, age, AFP L3, AFP, and des-g carboxyprothrombin) have shown excellent sensitivity and specificity for HCC in phase 2 studies. Radiologic biomarkers are also undergoing clinical validation, with some commercially available but lacking sufficient evidence to support their use in routine surveillance.

These assays should not replace guideline-recommended tests, the authors say, although their accessibility and potential cost-effectiveness may lead to broader use once they are validated.

Multicancer blood-based biomarker detection panels should not be used in the screening or surveillance of patients at risk for HCC.

Although many HCC risk-stratification scoring tools exist for patients with cirrhosis, few have undergone sufficient validation to support their use in clinical practice.

Finally, patients with chronic HBV infection but no cirrhosis can be stratified by scores on PAGE-B and REAL-B, according to their future HCC risk.

Although several novel biomarkers have shown potential in phase 2 and 3 validation studies, ultrasound plus AFP remains the recommended HCC surveillance strategy. “A recommendation to use GALAD was considered, but we opted not to move forward due to lack of sufficient evidence,” Kanwal said. “GALAD, however, is being evaluated in the National Cancer Institute-funded TRACER trial [National Liver Cancer Screening trial], and we will await these data before revisiting the recommendations.”

Results from ongoing phase 4 and 5 biomarker clinical utility trials, such as TRACER and the Preventing Liver Cancer Mortality Through Imaging With Ultrasound vs MRI (PREMIUM) trial are expected to guide the integration of novel biomarkers into clinical practice.

Refined Risk Stratification

Offering an outsider’s perspective on the AGA update, Amit Singal, MD, MS, a professor of medicine and chief of hepatology at UT Southwestern Medical Center in Dallas, said it effectively synthesizes the evolving landscape of HCC risk stratification and early detection into pragmatic, actionable guidance.

“While the authors highlight emerging risk stratification and surveillance strategies poised to shape future practice, they reaffirm that ultrasound plus AFP remains the current standard of care in patients with cirrhosis and those with high-risk chronic HBV infection,” he told Medscape Medical News.

The update underscores the need for refined risk stratification to enable precision surveillance strategies in patients with cirrhosis. “While robust, validated risk stratification models have been successfully incorporated into the management of patients with chronic HBV infection, models in cirrhosis have yet to demonstrate sufficient diagnostic performance in external validation cohorts,” Singal said.

MRI strategies and blood-based biomarkers represent promising emerging surveillance strategies,” he added. “Although both may improve sensitivity for early-stage HCC compared with ultrasound plus AFP, blood-based biomarkers offer the additional advantage of reducing patient barriers to adherence, thereby holding the greatest potential to improve overall effectiveness.”

The bottom line, said Kanwal, is that preventing cirrhosis is the most effective way to reducing the HCC burden. “We need to double down on improving adherence to current surveillance tests. This is the most practical way to increase the effectiveness of surveillance in the near term.”

Nicole E. Rich and Augusto Villanueva reported being supported by the National Institutes of Health.

Rich reported serving as a consultant or an adviser to Genentech, Eisai, Exelixis, and AstraZeneca. Villanueva reported receiving consulting fees from FirstWorld, Pioneering Medicine, and Genentech; advisory board fees from BMS, Roche, AstraZeneca, Eisai, and NGM Pharmaceuticals, as well as research support from Eisai. He reported holding stock options from Espervita and Atzeyo and is an inventor on a patent related to early HCC detection. Jorge A. Marrero reported being a consultant for Glycotest and a member of the data safety monitoring board for studies sponsored by AstraZeneca.

Singal reported serving as a consultant or advisory board member for FujiFilm Medical Sciences, Exact Sciences, Helio Genomics, Curve Biosciences, Roche, ImCare, Universal Dx, DELFI, and Bayer.