Strategies in Surveillance: Hepatocellular Carcinoma

As with most cancers, early diagnosis and treatment of hepatocellular carcinoma (HCC) may result in more effective treatment and improved outcomes.^1,2Unfortunately, most patients with HCC are diagnosed at a late stage, when therapeutic options are limited and prognosis is poor.^2,3

There has been a modest improvement in 5-year survival rates for localized HCC in the United States, from 12.5% (1992-1995) to 26.9% (2000-2007), due to improvement in surgical interventions for early disease and better monitoring of at-risk populations.^1,4More recently, targeted therapies such as sorafenib have emerged as viable options for patients with advanced disease (in whom no effective therapy had previously shown benefit), with the potential to improve survival.⁵

Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are at risk for HCC, and robust surveillance programs in these populations can help to improve the chance of early diagnosis.⁴Other targetable populations for HCC surveillance include those with alcohol abuse and those with nonalcoholic fatty liver disease.²Giannini and coworkers recently outlined some of the basic tenets for effective screening and surveillance in HCC, which include:

• Use of tests with a high specificity, high sensitivity, and low morbidity
• Overall acceptability of the surveillance testing by the target population
• Use of standardized recall procedures to allow for definitive diagnoses
• Availability of an acceptable and effective therapy for HCC, such that the application of surveillance testing can ultimately reduce disease-specific mortality2

For example, major US and European guidelines for HCC management recommend surveillance using assessments with liver ultrasound every 6 months. Liver ultrasound has no morbidity and can have relatively high sensitivity and specificity when properly applied. Such assessments are also noninvasive, easily performed, and of relatively low cost.²

Other guidelines, such as those of the National Comprehensive Cancer Network (NCCN), recommend screening using plasma alpha-fetoprotein (AFP) levels and liver ultrasound at intervals ranging from 6 to 12 months.¹It is also important to have a well-defined recall policy, which outlines the criteria for confirming, or ruling out, a diagnosis of HCC, should an abnormal surveillance test be obtained. Recall of patients should also be conducted at a time that allows for the most optimal and timely treatment.^2,3

There has also been an evolution in HCC diagnostic criteria to reduce the need for procedures such as percutaneous biopsy, which may be inherently risky, especially for patients with underlying liver disease.¹

Despite the apparent benefit of HCC surveillance in susceptible populations and the availability of effective treatments, however, its use in clinical practice remains controversial, and there has been some evidence of underutilization.²A systematic review by Singal and coworkers, using available literature sources from 1990 through 2011, examined the use of HCC surveillance in US patients.⁶In the 9 studies that met the criteria for inclusion in the analysis, a pooled surveillance rate (as defined within each study) of 18.4% was identified, with a range of surveillance from 11% to 64%. Notably, higher rates of surveillance were found among patients from clinics with a gastroenterology/hepatology subspecialty compared with those being followed in primary care clinics (51.7% vs 16.9%;P< .001).

Clinical Pearls

• Most patients with HCC are diagnosed at a late stage, when treatments are of limited or no benefit.
• Early diagnosis and treatment of HCC can enable the use of effective treatments and improve outcomes in populations at high risk.
• Major guidelines recommend surveillance in patients at high risk for HCC, such as those with HCV, HBV, and those with alcohol abuse and nonalcoholic fatty liver disease.
• Surveillance methodologies for HCC are noninvasive and relatively low cost, such as liver ultrasound and plasma alpha-fetoprotein assessment.
• There is evidence that HCC surveillance in susceptible populations is largely underutilized in clinical practice.
• Low-cost interventional and educational initiatives can help to increase surveillance for HCC in high-risk populations

Thus, despite the recommendation for surveillance by major societies, including the American Association for the Study of Liver Diseases (AASLD), the study demonstrates the relative underutilization of surveillance in clinical practice, with most studies reporting use under 30%.⁶The study found high utilization rates (60%-80%) in patients who were followed by gastroenterologists or hepatologists compared with those followed in a primary care setting, as well as a lower surveillance rate in non-Caucasian patients and in those having lower socioeconomic status.⁶

Although HCC screening and surveillance appear most likely to occur in patients who are followed by a liver disease specialist, evidence also shows that low-cost interventional programs to reduce surveillance barriers and improve adherence to guidelines can improve HCC screening rates among susceptible populations in the real-world setting.^2,7In one recent study of patients with high-risk viral hepatitis (N = 22), Kennedy and coworkers found that roughly half of patients (46%) had the first (1 cycle) of surveillance, but at 2 years (n = 4 surveillance cycles) no patients (0%) had received the recommended surveillance.⁷Using an intervention with improved physician and patient education and system redesign, these investigators showed that, at 3 years after the first audit, surveillance adherence rates at the first and fourth cycle could be improved to 92% and 64%, respectively.⁷

Despite the lack of high-quality evidence showing a reduction in mortality, Morris Sherman, PhD, MB, from the University of Toronto, University Health Network, at Toronto General Hospital and president of the Canadian Association for Study of the Liver, in a recent review cited abundant lesser quality evidence to this effect, and emphasized the recommendations of the major continental and national liver societies, which call for surveillance to be undertaken in high-risk populations.³

References

1. Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma.CA Cancer J Clin. 2012;62(6):394-399.
2. Giannini EG, Cucchetti A, Erroi V, Garuti F, Odaldi F, Trevisani F. Surveillance for early diagnosis of hepatocellular carcinoma: how best to do it?World J Gastroenterol. 2013;19(47):8808-8821.
3. Sherman M. Surveillance for hepatocellular carcinoma.Best Pract Res Clin Gastroenterol. 2014;28(5):783-793.
4. Simard EP, Ward EM, Siegel R, Jemal A. Cancers with increasing incidence trends in the United States: 1999 through 2008 [published online ahead of print January 4, 2012].CA Cancer J Clin. doi:10.3322/caac.20141.
5. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma.Hepatology. 2008;48(4):1312-1327.
6. Singal AG, Yopp A, S Skinner C, Packer M, Lee WM, Tiro JA. Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review.J Gen Intern Med. 2012;27(7):861-867.
7. Kennedy NA, Rodgers A, Altus R, McCormick R, Wundke R, Wigg AJ. Optimisation of hepatocellular carcinoma surveillance in patients with viral hepatitis: a quality improvement study.Intern Med J. 2013;43(7):772-777.