Association Between Aspirin Use and Biliary Tract Cancer Survival

Introduction Biliary tract cancers (BTCs) are rare, with a worldwide incidence of <2/100,000 individuals.1 The five-year survival rate is ~5-15%, with a median survival of <1 year.1 Between 60-70% of patients present with late-stage disease (e.g. inoperable or metastatic tumors) owing to lack of symptoms.2 Consequently, there is a critical need for treatments that improve BTC survival. Aspirin has been proposed as a treatment to reduce cancer mortality as it may slow cancer growth through the inhibition of both cyclooxygenase-2, which promotes inflammation and cell proliferation,3 and platelet aggregation, which may slow the metastatic spread of cancer.4 We investigated post-diagnosis aspirin use and BTC survival. Methods We obtained data, including all-cause deaths, on adult patients diagnosed with BTC between 1990-2017 from the United Kingdom’s Clinical Practice Research Datalink (CPRD), an electronic medical record database. We identified cancers using Read codes for gallbladder cancer (GBC), cholangiocarcinoma, ampulla of Vater cancer (AVC), and overlapping lesions of the biliary tract. We excluded patients with previous cancer, except for non-melanoma skin cancer. Ever use of post-diagnosis aspirin was defined as ≥1 prescription recorded in the CPRD on or after the BTC diagnosis date. We used Cox proportional hazards regression models to estimate the cancer site-specific hazard ratios (HRs) and 95% CIs for the association between time-dependent post-diagnosis aspirin use and overall survival. Patients who received an aspirin prescription within 30 days of diagnosis entered the model as users. The time scale began at diagnosis until death, exit, or end of follow-up (truncated at 10 years). We adjusted for the following covariates a priori: age at diagnosis, sex, comorbidities, statin use at diagnosis, indicators of a healthy lifestyle, and year of diagnosis. We fit separate models for each BTC type and stratified the baseline hazard by pre-diagnosis aspirin use (yes/no). We estimated adjusted survival curves using a marginal approach to remove the sex and age effects on aspirin use, accounting for the time-dependent exposure.5 We conducted analyses using SAS (version 9.4; SAS Institute Inc) and survival curves in R Studio (version 1.1.453). Results Among the eligible 2,934 BTC patients, 667 (23%) had GBC; 1,559 (53%) cholangiocarcinoma; 224 (8%) AVC; and 484 (16%) overlapping. There were 2,415 deaths (82%) with a median survival of 5.8 (IQR: 2 – 15) months. Two-hundred and fifty-six (9%) patients were aspirin users at baseline, with an additional 349 (12%) patients initiating aspirin after diagnosis. Ninety-six percent of aspirin users were prescribed a 75 mg dose. Compared to non-users, aspirin users were more likely to be older, current statin users, and pre-diagnosis aspirin users, and to have heart disease and comorbidities. Aspirin use was associated with decreased risk of death in GBC (HR: 0.63, 95% CI: 0.48, 0.83), cholangiocarcinoma (HR: 0.71, 95% CI: 0.60, 0.85), AVC (HR: 0.44, 95% CI: 0.26, 0.76), and overlapping BTC patients (HR: 0.68, 95% CI: 0.50, 0.92) (Table). The survival probabilities are shown in the Figure. Incident users with no previous history of aspirin use had a larger benefit from post-diagnosis aspirin use than prevalent users, though all had a reduction in risk. Discussion We observed a reduced risk of death for post-diagnosis aspirin users across all BTC types. Platelet activation protects tumor cells from elimination, enhances metastatic cell growth, and enables cancerous cells to spread via the bloodstream.4,6 Aspirin may slow metastatic spread of cancer cells through inhibition of platelet aggregation, improving BTC survival.1 A limitation of our analysis is the lack of data on stage and chemotherapy regimens received (if any). However, most BTCs are diagnosed at late stage2 with <10% of patients presenting with resectable tumors and 50% of tumors metastasizing to the lymph nodes.1 The survival benefit of aspirin observed in our study are on par with the current standard of care.2