2011-11-10 19:58:12 UTC

Controversies in Hepatocellular Carcinoma Screening

Nov. 10, 2011


Jorge A. Marrero, MD, MS

Keith S. Henley, MD, Collegiate Professor of Gastroenterology; Director, Multidisciplinary Liver Tumor Clinic, Division of Gastroenterology, University of Michigan, Ann Arbor


To understand the concept of screening and surveillance, it is better to start with definitions. Screening is a one-time application of a test to a group of individuals at risk for developing a disease, but who are not clinically suspected of having the disease. Surveillance is the repeated application of a screening test to a group at risk for a disease, but who are not clinically suspected of having the disease. Hepatocellular carcinoma (HCC) meets the criteria established for performing surveillance for a disease.1 The goal of surveillance is to reduce mortality from the disease being evaluated. A large study showed a 37 percent reduction in HCC-related mortality in those who underwent surveillance compared to those randomized to no surveillance.2 There is clear evidence that surveillance for HCC should be performed.

The incidence of HCC is rising and it is expected to continue to increase over the next decades. With this rising incidence, it is of utmost importance to identify those patients at risk for developing this tumor. Cirrhosis is the most important risk factor for the development of HCC. Though chronic hepatitis C (HCV) and hepatitis B (HBV) infection are responsible for the majority of HCC cases, other types of liver disease such as genetic hemochromatosis, alcoholic and non-alcoholic fatty liver disease, among others, also increase the risk of this tumor.3 Patients with chronic HBV from Asia and Africa, as well as those with a family history of HCC, are also at an increased risk of developing HCC. The interval for performing surveillance in patients at risk for HCC has been established to be six months.3 Therefore, patients with cirrhosis, regardless of the cause, form the target group for performing surveillance every six months.

Alpha-fetoprotein (AFP) and hepatic ultrasound have been the standard tests utilized for the surveillance of patients at risk of developing HCC. More recently, however, AASLD guidelines on HCC recommended utilizing ultrasound alone for the surveillance of HCC.3 I disagree with these recommendations given the significant amount of evidence supporting the combination of AFP and ultrasound as surveillance tests for HCC.

First, a large randomized trial showed a reduction in mortality utilizing the strategy of AFP and ultrasound.2 Second, population-based cohorts have shown that AFP is adequate for the surveillance of patients at risk for HCC.4 Third, the strategy of AFP and ultrasound surveillance has been shown to be cost-effective.5 Fourth, a large prospective study in patients with chronic HCV infection confirmed that the combination of AFP and ultrasound appears to be complementary for the early detection of HCC.6 In fact, AFP improves the performance of ultrasound in early stage HCC to 71 percent. Therefore, the evidence shows that surveillance for HCC should be performed with the combination of AFP and ultrasound.

However, there are drawbacks to the performance of AFP and ultrasound as surveillance tests for HCC. AFP is not specific for HCC, and its sensitivity in early stage HCC is low at 66 percent. Ultrasound suffers from being operator-dependent; its reproducibility as a surveillance test has not been tested and its sensitivity is low at 63 percent.7 Even though these tests are not specific for HCC (such as chronic viral hepatitis causing elevations of AFP, and fatty liver causing focal abnormalities on ultrasound), cost-effective5 and cost-utility8 analyses have concluded the benefit of surveillance with AFP and ultrasound.

I am often asked about using CT scan or MRI scan for the surveillance for HCC. Recall that surveillance is done in patients at risk for HCC, but not when clinically suspected (i.e., a patient with HCV cirrhosis with normal liver function, no complication of liver disease and doing well). CT scan has never been studied in a screening or surveillance setting, so its use in this capacity is not recommended.

CT also causes significant radiation exposure, and if done every six to 12 months, lacks cost-effectiveness. MRI also lacks studies evaluating it as a surveillance test, and if performed every six to 12 months, its cost also would become prohibitive. My recommendation is that CT or MRI should be done in those where there is a clinical suspicion of HCC or when there is an abnormal surveillance test (i.e., AFP or ultrasound), not for routine surveillance.

To conclude, surveillance should be performed every six months in patients at risk for HCC, and AFP and ultrasound should be tests utilized for surveillance.


1. Smith RA. Screening fundamentals. J Natl Cancer Inst Monogr 1997;22:15-19.
2. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–422.
3. Bruix J, Sherman M. Management of Hepatocellular Carcinoma: An Update. Hepatology 2010;53(3):1020-2.
4. McMahon BJ, Bulkow L, Harpster A, Snowball M, Lanier A, Sacco F, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 2000 Oct;32:842-6.
5. Lin OS, Keeffe EB, Sanders GD, Owens DK. Cost-effectiveness of screening for hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. Aliment Pharmacol Ther 2004;19:1159–1172.
6. Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, Morgan TR, et al. Des-gamma-Carboxy Prothrombin and alpha- Fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma. Gastroenterology 2010;138:493–502.
7. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30:37-47.
8. Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Jackson S, Ryder S, et al. Surveillance of cirrhosis for hepatocellular carcinoma: a cost-utility analysis. Br J Cancer 2008;98:1166–1175.

Dr. Marrero was a one-time advisory board member and consultant to Bayer HealthCare and Bristol-Myers Squibb. He received research support from Bayer HealthCare, Bristol-Myers Squibb and Onyx Pharmaceuticals, Inc. Dr. Marrero is also an associate editor for The American Journal of Gastroenterology, and is on the editorial board of Hepatology.



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