Potential for Statins in the Chemoprevention and Management of Hepatocellular Carcinoma

Amedeo Lonardo; Paola Loria

Disclosures

J Gastroenterol Hepatol. 2012;27(11):1654-1664. 

In This Article

Beneficial Effects of Statins in Either Preventing or Curing HCC. Conflicting Evidence From Human Studies

Owing to the declining prevalence of competing etiologies, HCC is increasingly discovered against a background of metabolic disorders.[5,56] NAFLD is a major player and provides an essential milieu in the development of HCC in those with metabolic syndrome.[3,57] Owing to their potential therapeutic indication in NAFLD,[58] statins could hinder the development of HCC in this specific setting in as much as these two conditions are pathogenically linked to one another. Moreover, in theory, statins could exert a beneficial role in the chemoprevention/cure of HCC in those cases of HCC occurring in a viral chronic liver disease as well.

Table 2 details the available evidence for the benefits of statins based on studies conducted in humans.[59–63] There are no large multicentre randomized controlled trials investigating the potential benefits of using statins in patients either susceptible to develop HCC or with advanced and otherwise incurable disease.

A single clinical trial[59] supports the hypothesis that the use of statins might contribute to survival in those with unresectable HCC. This study reports an impressive 9-month longer survival in the pravastatin group. Nevertheless, the level of evidence provided by this study is limited by the low number of the 91 individuals recruited with unresectable HCC, all submitted to trans-arterial embolization (TAE) and 5-FU as a common pre-treatment before randomization which, moreover, was not blinded.[59]

Three population studies[61–63] suggest that statin use might be associated with decreased incidence of HCC.[61–63] Interestingly, such a preventive activity might not be limited to those statins-treated patients with diabetes as suggested by a previous study,[61] but could affect individuals living in an area where liver cancers occur in a viral rather than metabolic milieu.[62] Moreover, the finding of a dose-dependent activity of statins[63] gives further strength to the biological rationale for a putative action of statins in preventing HCC. However, results from these cohorts studies[61–63] need to be interpreted with caution. Despite one of their strengths being based on computerized[61–63] and population based database,[62,63] the papers by El-Serag,[61] Chiu[62] and Tsan,[63] further to being retrospective, failed to including smoking status and coffee consumption in the propensity score to statins prescription. Smoking has been identified as an independent risk factor for HCC.[64] Given that in a British study statins were given less often to current cigarette smokers than to non-smokers,[65] the seemingly protective effect of statins against HCC might be spurious owing to failure to evaluate perceived hepatological "contraindications" to use of statins and smoking status as potentially confounding factors. Coffee consumption is associated with raised serum cholesterol levels[66] on the one hand and protection from developing HCC[67] on the other hand. Therefore, it is plausible that these two populations of coffee drinkers and statins users overlap at least partially, potentially masking the truly beneficial effect of coffee consumption as a deceptive protection of statins.

Recall bias cannot be ruled out in the paper by Tsan; moreover, this paper was based on a random sampling of those carrying HBV infection, which raises the issue of inadvertent selection bias.[63] In addition, the inclusion of cases of HCC occurring as shortly as 6 months after the entry in the cohort[61] suggests the opportunity to conduct a longer follow-up to reveal changes in slow biological processes such as the development of HCC. The study by Chiu[62] was mismatched as far as risk factors for HCC were concerned, the prevalence of the chief risk factors for HCC (HBV and HCV infection,: alcoholic liver disease and diabetes) being significantly more common among cases than in controls (P < 0.001 for all comparisons).

The seemingly protective effect of statins could well result from a selection bias alone. For instance, given that the use of statins is associated with increased liver enzymes (in a quite small subset of individuals),[68] physicians might nevertheless be more prone to prescribe these drugs to individuals with less elevated liver enzymes, such as, for instance, alcoholic cirrhosis and carriers of HBV with a lower viral load, both populations being per se typically less prone to develop HCC.[69,70] Not surprisingly, the inclusion of the etiology of HCC into the statistical model attenuated the observed inverse association between the use of statins and HCC.[62] Moreover, pharmacy records of statins prescriptions used in some studies provides evidence for dispensing rather than true statins usage and strict adherence to medical prescription of these drugs.[62] In addition, cohort studies tend to discriminate poorly among the various subtypes of statins,[62] despite the recognized major chemical and biological differences that may occur among the various statins[55,68] Finally, studies have provided inconsistent results concerning the dose-response relationship protection of HCC exerted by statins.[62,63]

Not surprisingly, given the number of methodological limitations of the studies discussed above, the results from a recent robust meta-analysis conflict with previous cohort studies reported above and fully agree with a previous population-based Danish study with prospectively registered and virtually complete data on drug prescription and cancer diagnosis.[60] The Cholesterol Treatment Trialists' Collaboration study, collecting data from over 10 000 cases of cancer and over 3500 deaths from cancer among 175 000 randomized patients,[71] aimed at ruling out that statin treatment might be associated with increased risk of cancer, has failed to show any decrease in incidence and mortality for liver cancer.[71] The strength of this study results from it being based on individual patient data, so providing a reliable gauge of the potential association between statins and the development of various cancer types, including HCC, to a significantly larger extent than that offered by previous studies.[71]

In conclusion, on the basis of current evidence, the use of statins in the chemoprevention and treatment of HCC in humans cannot be recommended for clinical practice. However, given that preliminary studies are conflicting, further studies are needed.

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