Chemopreventive strategies in hepatocellular carcinoma

Key Points

  • Antiviral therapies directed against HBV and HCV are universally effective in primary and secondary prevention of hepatocellular carcinoma (HCC), but are associated with substantial costs and adverse effects

  • Statin use is associated with decreased risk of HCC, potentially by inhibiting Myc activation and through inhibition of the mevalonate pathway

  • In patients with diabetes, the use of metformin might reduce the risk of HCC through mTOR inhibition, whereas insulin and insulin-secreting agents might increase the risk of HCC

  • Aspirin has also been shown to decrease risk of hepatitis-B-associated HCC in animal models, with early epidemiological studies also showing a favourable association

  • Dietary agents, such as coffee, vitamin E, fish rich in n-3 polyunsaturated fatty acids and dietary polyphenols, might also have antineoplastic effects against HCC

  • Randomized controlled trials for chemopreventive agents are logistically and ethically challenging; prospective cohort studies that adjust for relevant confounders might be well-suited to inform us about these agents


Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well-designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents.

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Figure 1: Pathogenesis of HCC and targets for chemopreventive agents.
Figure 2: Proposed algorithm for chemoprevention in patients at risk of hepatocellular carcinoma.


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The work of L. R. Roberts is supported by the NIH (grant nos.: CA100882, CA128633, and CA165076), the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567), the Mayo Clinic Cancer Center (CA15083), and the Mayo Foundation.

Author information




S. Singh contributed to researching data for the article, discussion of content, writing and reviewing/editing the manuscript before submission. P. P. Singh and W. Sanchez contributed to researching data, discussion of content and reviewing/editing the manuscript before submission. L. R. Roberts contributed to discussion of content, writing and reviewing/editing the manuscript before submission.

Corresponding author

Correspondence to William Sanchez.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Studies of nucleoside/nucleotide-based antiviral therapies against hepatitis B as primary prevention of hepatocellular cancer. (DOC 28 kb)

Supplementary Table 2

Studies of interferon-based therapies against hepatitis C on primary prevention of hepatocellular carcinoma (DOC 52 kb)

Supplementary Table 3

Summary of observational studies on the chemopreventive effect of statins against hepatocellular cancer in (a) at-risk patients and (b) general population (DOC 28 kb)

Supplementary Table 4

Summary of observational studies on the cancer-modifying effects of antidiabetic medications in primary prevention of hepatocellular carcinoma in patients with diabetes mellitus. (DOC 29 kb)

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Singh, S., Singh, P., Roberts, L. et al. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 11, 45–54 (2014).

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