Surveillance for hepatocellular carcinoma (HCC) — now ranking fourth among causes of cancer-related death worldwide and on the rise in the U.S. — needs improvement to boost survival rates, two researchers argued.
Despite some improvement in survival, the overall prognosis for HCC remains poor, according to Fashia Kanwal, MD, MSHS, of Baylor College of Medicine in Houston, and Amit G. Singal, MD, MS, of UT Southwestern Medical Center in Dallas, writing in Gastroenterology. They recommended closer adherence to surveillance recommendations as well as better biomarkers and other tools to detect HCC early in at-risk patients.
“The upward trend in HCC incidence underscores the importance of effective HCC surveillance strategies in the U.S., particularly among emerging at-risk cohorts such as those with NAFLD [non-alcoholic fatty liver disease] and post-SVR [sustained viral response] hepatitis C virus [HCV] cirrhosis,” the authors wrote.
Yet while the majority of society guidelines recommend semiannual surveillance for those at risk, its effectiveness is still being debated, the authors noted. Despite consensus on the benefit of surveillance after SVR in HCV patients with cirrhosis, uncertainty remains whether HCC risk will sufficiently decrease over time to allow discontinuation. Recent data suggest it should probably continue for at least the intermediate term, according to Kanwal and Singal.
They also noted that HCC surveillance is seriously underutilized. Despite demonstrated tumor detection, one review found that just 18.4% of high-risk U.S. patients are monitored for HCC (although it surpasses 50% in specialist care settings), with non-Caucasians and low-income people having the lowest rates.
In another study, the most common reason for underuse was providers’ failure to order surveillance in cirrhosis patients. It found that electronic medical record reminders to prescribers significantly improved surveillance rates from 18.2% to 27.6% (P<0.001) in a Veterans Affairs system setting.
Kanwal and Singal recommended HCC surveillance every 6 months for all patients with cirrhosis from any etiology and subgroups of patients with non-cirrhotic HBV.
“The latter includes Asian men over 40 and Asian women over 50 and African persons over age 20,” Kanwal told MedPage Today. (However, the recommendation does not apply to U.S.-born African Americans with chronic HBV infection.)
“This is a very balanced review covering the major challenges we face today, outlining the benefits and harms of surveillance and how we need to go forward in the future,” Augusto Villanueva, MD, PhD, of Mount Sinai School of Medicine in New York City, told MedPage Today.
“It makes the point that all cirrhotic patients need surveillance and for high-risk patients, the benefits of surveillance outweigh the risks. It highlights the need for new tools to better stratify risks in patients who do not yet have cirrhosis,” continued Villanueva, who was not involved in the review. Some 2% to 7% of patients with cirrhosis develop HCC each year.
The review outlined three main areas for future development and validation aimed at improving HCC surveillance.
New tools are needed to permit more personalized assessment of HCC risk, especially in patient populations with virologically cured HCV, suppressed HBV, and NAFLD. In addition, biomarkers to identify at-risk groups among patients with non-cirrhotic NAFLD should be identified and validated.
Noting the paucity of existing stratification tools, the authors referred to a recent study outlining models for predicting HCC risk after antiviral therapy for HCV. Four indicators accounted for most of the predictive value: age, platelet count, serum aspartate/alanine aminotransferase ratio, and albumin, with smaller contributions from sex, race-ethnicity, HCV genotype, body mass index, hemoglobin, and serum alpha-fetoprotein.
“Studies are needed that evaluate and incorporate new as well as established factors to create novel risk stratification indices that are applicable to patients with cirrhosis from all etiologies. These will allow personalized estimation of the downstream risk of HCC in patients with cirrhosis across diverse etiologies,” the authors wrote.
A novel gene signature in tissue adjacent to the tumor has proven accurate in stratifying patients for HCC recurrence and may identify a subgroup of low-risk patients who do not require surveillance, they noted. This, however, would need a blood-based surrogate to facilitate adoption in clinical practice.
Although MRI surveillance could improve early tumor detection, it would not likely be cost-effective for all at-risk patients and might best be reserved for those prone to ultrasound failure. And while abbreviated MRI might reduce cost, a more efficient strategy would be to improve existing blood-based biomarkers.
New serum- and imaging-based HCC biomarkers used in combination with other data would facilitate accurate detection of early and very early HCC. “This framework (biomarker + demographic and clinical data + surveillance history) is likely to be an essential platform for future application of biomarkers for early HCC detection, including novel biomarkers,” Kanwal and Singal wrote.
Several new biomarkers, radiological and serological are in the testing phase. “Until we have highly sensitive and specific biomarkers, clinicians should continue to use ultrasound-based surveillance, with or without [alpha-fetoprotein], with efforts on maximizing ultrasound quality and surveillance utilization,” Kanwal said.
Enhancing the value of surveillance
Many patients experience harms from false-positive or inconclusive monitoring tests. The benefits and harms of HCC surveillance should be determined in large prospective studies with diverse populations, followed by interventions to reduce the associated physical, psychological, and financial harms, the authors recommend. They referred to a single-center cohort study of 680 cirrhosis patients in which surveillance-related physical harms over 3 years were reported in 187 (27.5%) patients, with 66 (9.7%) having multiple CT/MRI examinations and three (0.4%) undergoing invasive testing such as biopsy.
In another study, presented at the 2017 American Association for the Study of Liver Diseases meeting, of 999 patients monitored for more than 2 years, 256 had abnormal imaging but only 69 were diagnosed with HCC. Of the 37 who continued with CT/MRI, 32 experienced severe harms defined as at least four CT/MRI exams or biopsy.
Among the authors’ recommendations are interventions to increase HCC surveillance as well as cost-effectiveness models to examine long-term comparative effectiveness of surveillance strategies, particularly in emerging at-risk populations.
Kanwal and Singal wrote that the outlined targets for future research “will likely help the field move towards precision surveillance, where surveillance tests and intervals are tailored to individual HCC risk.”
Kanwal reported funding from Merck. Singal disclosed ties to Bayer, Wako Diagnostics, Roche, Exact Sciences, and Glycotest.
Villanueva disclosed ties to Guidepoint, Fujifilm, Exact Sciences, Nucleix, NGM, and Exelixis.