Aspirin initiation and dose-dependent risk reduction of oral squamous cell carcinoma in areca nut chewers.

Abstract

Oral cavity squamous cell carcinoma (OCSCC) driven by areca nut consumption-a Group 1 carcinogen affecting 600 million people globally-represents a significant unmet need in precision prevention. Despite the known role of COX-2-mediated inflammation in this etiologic niche, pharmacological strategies remain under-evaluated. We emulated a target trial using a nationwide matched cohort of 50,606 areca nut chewers from the Taiwan National Health Insurance Research Database (2008 to 2021). To minimize selection and immortal time biases, we utilized time-dependent exposure modeling and Fine-Gray subdistribution hazard models to account for competing mortality. Aspirin initiation was associated with a significantly lower risk of incident OCSCC (adjusted sHR, 0.75; 95% CI, 0.65-0.87; P<.001). We identified a robust dose-response relationship, with a 43% risk reduction observed in the high-cumulative-exposure group (≥ median cDDD; sHR, 0.57; 95% CI, 0.47-0.69). The exploratory estimated 5-year number needed to treat (NNT) was 249 for the high-dose group. Sensitivity analyses, including E-value assessment (2.89) and landmark tracking, confirmed the stability of this association against unmeasured confounding and reverse causality. Our findings provide large-scale human evidence that sustained aspirin use significantly alters the trajectory of oral field cancerization in areca nut chewers. This study identifies aspirin as a high-priority candidate for risk-stratified chemoprevention in global populations with high areca nut exposure.