An Ounce of Prevention Is Better Than a Pound of Cure: A Patient-Centered Approach to Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Though it is less commonly seen in the United States, age-adjusted incidence rates have tripled here over the last three decades, and overall survival remains poor for those with advanced disease. Host factors, including viral hepatitis, metabolic syndrome, alcohol use, and genetic disorders, contribute to HCC pathogenesis, both singly and in combination. HCC is notable for having particularly varied etiologies in different populations. Hepatitis B vaccination programs have begun to show dramatic decreases in HCC incidence, but for those with other underlying risk factors, primary prevention efforts have been disappointing. In the article that accompanies this editorial, Tsan et al provide compelling evidence for an association between statin use and a significantly lower risk of HCC development in patients with hepatitis C infection (HCV). The authors examine a population-based cohort of 260,864 patients infected with HCV from Taiwan between January 1, 1999, and December 31, 2010. Both dose and duration responses to statin use were seen, with a hazard ratio of 0.33 for HCC development in those taking higher cumulative daily doses. The results were statin specific, and were not seen with other lipid-lowering agents. Unlike most randomized trials evaluating statin use and cancer incidence, follow-up in this observational study was relatively long, at just over 10 years. Just as important, there was no increase in hepatotoxicity seen with use of statins in patients with underlying HCV, which has been a concern about using these agents in patients with liver disease. These data are consistent with several other observational studies suggesting that statins may decrease the risk of HCC in patients with other underlying liver diseases. In addition, Nielsen et al recently reported a decrease in overall and cancer-related mortality among statin users using the Danish Civil Registration System, a database enviable for its completeness. Statin use was also recently shown to be an independent predictor of decreased HCC recurrence after resection. Finally, there are at least two small randomized trials suggesting a survival benefit of giving pravastatin to patients with existing HCC. However, randomized data do not support a preventive effect for statins in HCC. A recent meta-analysis evaluated seven observational studies, as well as pooled data from 26 randomized controlled trials evaluating statin use. The authors found a 40% reduction in risk of HCC in the observational studies, but no benefit attributable to statins in the randomized trials. Such differences between observational studies and randomized trials are not unusual, and may reflect length of follow-up and patient selection factors such as risk and country of origin. Additionally, observational studies are susceptible to bias. The study by Tsan et al has several limitations related to its design. First, because the differences between the groups are seen after just 28 to 89 cumulative daily doses of statin therapy (hazard ratio [HR] 0.66), one might suspect that other nonbiologic factors are playing a role. Second, confounding by indication can be seen if those with more advanced liver disease are less likely to be given a statin because of concerns for hepatotoxicity (or less concern about high lipids) in patients with advanced cirrhosis. The authors stratify by cirrhosis status and still show that the protective effects persisted in both groups. However, it is possible that cirrhosis, especially compensated cirrhosis, may not have been diagnosed or recorded in most practice settings. The authors could have also excluded cases found early in the observational period to prevent inclusion of latent or prevalent HCC, and to make reverse causation less likely. In addition, more detailed HCV treatment data would have been interesting to assess. The authors acknowledge that not all possible confounders were adjusted for, including body mass index, smoking, and other indicators of health and socioeconomic status. Finally, concomitant use of potentially beneficial medications such as metformin was not adjusted for in the analysis. In support of the findings of Tsan et al, there is a biologic rationale for why statins may benefit patients with HCV. Statins inhibit cholesterol synthesis and block the formation of geranylgeranylated protein, both thought to be important for HCV replication. Statin use may also improve viral response to hepatitis C therapy. Finally, statins may act as anticancer agents, exerting antiproliferative effects via targeting hydroxymethylglutaryl coenzyme A reductase, and interfering with lipid rafts which mediate cell signaling and apoptosis. Perhaps most important, statins have shown clinical efficacy in the treatment of patients with metabolic syndrome, a constellation of problems including diabetes, hypertension, obesity, and hyperlipidemia. Age-adjusted prevalence rates of metabolic syndrome in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 12 APRIL 2