Hepatocellular carcinoma (HCC) is a well-known complication of cirrhosis and chronic viral hepatitis. Approximately two thirds of HCC cases in the United States are associated with either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.¹ While the lifetime risk of HCC among those with chronic HBV infection is not known, it is thought to be higher than for HCV (which is ≥5%),² particularly among those born in endemic areas where HBV is commonly acquired in infancy. Patients with HBV infection are 100-fold more likely to develop HCC than uninfected persons, and have a 0.5% annual incidence of HCC—at least among Asian men.³ Among patients with cirrhosis from any cause, it is estimated that 1% to 4% per year develop HCC.⁴ In addition, a substantial proportion of patients with chronic HBV infection develop HCC in the absence of cirrhosis.⁵

Overall survival rates for HCC are poor. However, they may be substantially higher when HCC is detected at an early stage when potentially curative therapies can be employed. Thus, high-risk individuals should be screened for HCC with ultrasound of the liver every 6 to 12 months. High-risk HBV carriers include Asian men ≥40 years and women ≥50 years, Africans >20 years, cirrhotics, those with a family history of HCC, patients with high HBV DNA levels, and those with active hepatic inflammation.³

Given that chronic viral hepatitis is such an important cause of HCC, and that this cancer has such a poor prognosis, it is critical to consider whether viral hepatitis-related HCC can be prevented. Clearly, HBV-related HCC can be avoided by preventing HBV infection through vaccination. This has already been demonstrated in countries where universal infant vaccination has been adopted, such as Taiwan.^6-8 More recent evidence suggests that antiviral therapy of chronic hepatitis B may prevent the development of HCC. For example, results of a randomized controlled trial of lamivudine versus placebo in patients with chronic hepatitis B and advanced fibrosis showed that antiviral therapy effectively reduced the risk of developing complications of liver disease, including HCC (Fig. 1).⁹ Furthermore, the REVEAL-HBV study showed good correlation between high serum levels of HBV DNA and subsequent development of HCC (Fig. 2). One could speculate that lowering the serum level of HBV DNA with antiviral therapy may reduce the risk of HCC, but this requires confirmation.¹⁰

Vaccination and antiviral therapy to prevent HCC represent examples of primary prevention. However, it appears that secondary prevention in individuals successfully treated for HCC may also be possible. Patients treated for HCC have a high risk of redeveloping HCC. Even with potentially curative treatments such as resection and radiofrequency ablation, HCC may recur adjacent to the site of the original tumor. Five-year survival following partial hepatectomy at Memorial Sloan-Kettering Cancer Center in New York was 57% for patients with lesions <5 cm and 32% for patients with >10-cm tumors.¹¹ Presumably recurrence and poor survival are attributable to a focus of HCC that persisted despite treatment and then emerged with time. However, de novo HCC remains a substantial risk and accounts for some cases of HCC following potentially curative treatment. The presumption is that with such forms of treatment, a diseased liver—already prone to develop HCC—is left in place, so new tumors occur at an increased frequency. In contrast, with liver transplantation, the diseased liver is removed, resulting in a much lower rate of HCC recurrence. Unfortunately, liver transplantation is not available to all patients with HCC because of cost, limited access to sufficient donated organs for transplantation, and the prevalence of co-morbid illnesses that prevent transplantation.

A randomized controlled trial published by Muto and colleagues in 1996¹² was one of the first to offer hope of secondary prevention of HCC. Polyprenoic acid, a retinoid compound not available in the United States, was used following resection or ethanol injection for HCC. After a median of 38 months, HCC recurred or appeared de novo in 27% of the polyprenoic-acid group compared with 49% of the placebo group (P = .04). Subsequent studies in HBV¹³ and HCV infection^14,15 suggest that antiviral therapy postresection may also decrease the risk of HCC recurrence. For example, 236 HBV-infected patients were randomized after resection for HCC to either interferon or placebo. Interferon prolonged overall survival from 38.8 months in the control group to 63.8 months (P = .0003), although median disease-free survival was not significantly longer (17.7 versus 31.2 months; P = .142).¹³

HCC is a highly lethal cancer with few therapeutic options that are effective long-term, especially for advanced cases. The National Institutes of Health has identified prevention of HCC as the most important goal for liver cancer research.¹⁶

References

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