Editorial: aspirin and NSAID for chemoprevention of hepatocellular carcinoma—ready for their use?

Abstract

Hepatocellular carcinoma (HCC) is a highly lethal malignancy. Its incidence and mortality are steadily increasing in Western countries.1 This is related to the rapidly rising prevalence of nonalcoholic fatty liver disease (NAFLD),2 low adherence to screening strategies and refractoriness to therapeutic interventions.3 Even after curativeintended treatments such as ablation or resection, recurrence rates are high. Once the tumour progresses to an advanced stage of the disease, available therapies yield limited efficacy in preventing disease progression. Therefore, it is reasonable to consider that preventing HCC is the optimal strategy for decreasing the mortality. Patients with cirrhosis represent the target population for preventive measures. Chemoprevention in atrisk patients could theoretically be the turning point of this scenario. Preliminary data suggest that antiplatelet and nonsteroidal antiinflammatory drugs (NSAID) may hamper hepatocarcinogenesis through inhibition of cyclooxygenase2 (COX2) enzyme, plateletdegranulation and interaction between platelets, leukocytes and endothelial cells.4,5 Emerging data from observational studies and clinical trials have suggested thataspirin and other NSAIDs may play a role in reducing HCC incidence among individuals with chronic liver disease.6,7 In a recent issue of Alimentary Pharmacology & Therapeutics, Tan et al report a metaanalysis that included 19 studies with 147 283 participants, aimed to address whether NSAID or antiplatelet therapy reduce HCC incidence, recurrence and liverrelated mortality. The studies included adults with viral hepatitis infection, alcoholassociated liver disease and nonalcoholic fatty liver disease. They observed that aspirin was associated with a reduced incidence of HCC and liverrelated mortality, but with an increased risk of gastrointestinal bleeding. Furthermore, there was a decreased risk of HCC recurrence, which was more evident in individuals receiving nonaspirin NSAIDs.8 Although these results reinforce the potential role of aspirin and other NSAIDs in chemoprevention of HCC, these results need to be validated before routine clinical use of these agents in patients with chronic liver diseases. It is noteworthy that studies are generally heterogeneous and different aetiologies may have different mechanisms of carcinogenesis. Besides, dose and duration required to achieve a positive effect remains elusive. Concurrent use of other drugs such as statins and metformin,9 are frequent in aspirin users due to their association with metabolic syndrome, and their additive chemopreventive effect should be evaluated.10 Finally, the effect of age, gender, degree of fibrosis, active infection or alcohol consumption, portal hypertension, and liver function impairment may modify the effect of chemopreventice strategies and should be further studied. It is important to keep in mind that individuals at risk for HCC have underlying liver disease and may have impaired renal function, coagulopathy, portal hypertension and risk of gastrointestinal bleeding. Therefore, toxicity is a key concern when prescribing aspirin and NSAID in this population. Observational studies may fail to report the real incidence of severe interventionrelated adverse events such as fatal haemorrhage, acute kidney injury and liver function deterioration. Chemoprevention randomized trials typically require a large sample size and a long observation period. Nevertheless, these are the only reliable source of evidence to change clinical practice whenever there is a fine line separating harms and benefits. In summary, Tan et al provide new data that is a valuable addition to the medical literature on the chemoprevention strategies for HCC.