NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project

Abstract

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC=679, ICC=225) from ten US-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Current aspirin use, versus nonuse, was inversely associated with HCC (HR=0.68, 95% CI=0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5 and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR=0.64, 95% CI=0.42-0.98) but not women (HR=1.34, 95% CI=0.89-2.01, pinteraction=0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.

Associations of NSAID and paracetamol use with risk of primary liver cancer in the Clinical Practice Research Datalink

“…Previous US-based large cohort studies suggested that NSAID use, specifically aspirin, was associated with lower risk of hepatocellular carcinoma (HCC) [9, 10]. In contrast, our study suggests a lack of association between NSAID use and liver cancer risk in the CPRD.…”

“…Experimental studies have shown that NSAIDs may inhibit liver cancer cellular growth and induce cell apoptosis by modifying cyclooxygenase (COX) enzymatic pathways which mediate inflammation [7, 8]. Two reports from large observational studies suggested that NSAID use, specifically aspirin, was associated with reduced risk of liver cancer [9, 10], but NSAID use was self-reported in these studies. Associations between prescription NSAID use and liver cancer have not been previously described.…”

Association Between Aspirin Use and Risk of Hepatocellular Carcinoma

“…Prospective evidence specifically addressing aspirin dose and duration is limited to 2 previous cohort studies that assessed aspirin use at only 1 point in time. 9,10 As individual patterns of medication use may change over time, prospectively updated medication data are important for accurately estimating risk, particularly in diseases with prolonged latency. 11,12 Moreover, it remains controversial whether nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), which share several mechanisms of action with aspirin, exert similar anti-HCC effects.…”

Complex roles of the old drug aspirin in cancer chemoprevention and therapy

“…Another retrospective study demonstrates that treatment of patients with chronic hepatitis B with aspirin and/or another antiplatelet agent clopidogrel (a P2Y12 ADP receptor antagonist) reduces the risk of HCC . Moreover, a pooled analysis of data from prospective cohort studies reveals that aspirin use inversely correlates with HCC risk, while the NSAID ibuprofen does not reduce HCC risk . In a chronic HBV‐induced HCC model, combination of aspirin and clopidogrel successfully prevents or delays hepatocarcinogenesis in mice .…”