Cholangiocarcinoma risk factors and the potential role of aspirin
Authors: Fabio Bagante, T. Clark Gamblin, Timothy M. Pawlik
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. See Article on Page 785 Cholangiocarcinoma (CC) is the second most common primary hepatobiliary cancer. Its classification is based on anatomical location: intrahepatic CC (ICC) originates within the liver, and extrahepatic CC (ECC) originates in the extrahepatic bile ducts. Epidemiological reports have demonstrated an increasing incidence of CC, with annual percentage changes of 2.3% and 0.14% for ICC and ECC, respectively, between 1973 and 2012.1 Defined risk factors include primary sclerosing cholangitis, hepatolithiasis, cirrhosis, and hepatitis infection. Other possible risk factors include smoking, diabetes, gallstones, and biliary cysts. Although these risk factors are associated with a subset of patients, the majority of cases are sporadic. Most epidemiological studies have focused on factors associated with heightened cancer risk; however, there has been increased interest in identifying factors associated with cancer prevention. To this end, Choi et al.2 report a large hospital‐based case‐control study of 2395 cases that examined whether aspirin use was protective against CC. Of note, the association of aspirin use and the incidence of cancer has been the object of extensive previous epidemiologic studies, suggesting that long‐term aspirin use is associated with a modest but significantly reduced risk for overall and gastrointestinal (GI) tract cancers.3 The proposed mechanism for the biological activity of nonsteroidal anti‐inflammatory drugs (NSAIDs) against cancer includes inhibition of the cyclooxygenase 2 (COX‐2) enzyme.4 Specifically, overexpression of COX‐2 has been demonstrated in CC cells.5 Several previous studies have investigated the role of NSAIDs and CC. In one study that used the General Practice Registration Database, which represents about 5 million people in the UK, NSAIDs were reported not to be associated with a decreased incidence of CC; however, the specific effect of aspirin was not reported.6 Conversely, in a separate case control study, aspirin use was reported to be associated with a nonsignificant reduction in the odds of developing all bile duct cancers.7 Several papers examining the association of aspirin use and the incidence of cancer have been based on data from randomized controlled trials that were investigating aspirin use for non‐cancer‐related reasons. For example, Rothwell et al.8 used individual patient data from randomized trials comparing daily aspirin use versus no aspirin use to determine the effect of aspirin on cancer death risk for GI and non‐GI cancers. In this study, the authors reported on 25,570 patients and noted that aspirin reduced death due to cancer by about 20%. Recently, Cao et al.3 analyzed two large prospective cohort studies in the United States that included 135,965 health care professionals who underwent follow‐up for as long as 32 years. The authors concluded that the benefit of aspirin on the prevention of GI cancers was associated with the use of aspirin for a minimum of 6 years. As result of these findings, in 2015 the US Preventive Services Task Force (USPSTF) recommended the use of aspirin to prevent colorectal cancer among certain subgroups of adults with specific cardiovascular risk profiles and, currently, aspirin is the first pharmacologic agent to be endorsed by the USPSTF for chemoprevention of a cancer in a population without a high risk of developing cancer.3 Choi et al. used a large single institution dataset that included roughly 2000 patients from a more than 14‐year time span. Using a case‐control study design, the authors analyzed the protective effect of aspirin among patients with an assortment of CC types (ICC, hilar CC, and distal CC). Specifically, the authors matched CC patients with patients selected from the Mayo Clinic Biobank in a 2:1 manner based on age, sex, race, and residence. Not surprisingly, the authors reported an increased risk of CC associated with risk factors such as primary sclerosing cholangitis and diabetes. Of more interest, there was also a significant inverse association of aspirin use with all CC subtypes, with adjusted odds ratios of 0.35 (95% confidence interval [CI], 0.29‐0.42), 0.34 (95% CI, 0.27‐0.42), and 0.29 (95% CI, 0.19‐0.44) for ICC, perihilar CC, and distal CC, respectively (all P < 0.001). This effect of aspirin use on the decreased long‐term incidence of CC was consistent with many previous reports that have examined other cancers.9 In a large systematic review, Algra and Rothwell9 compared the effects of regular aspirin use from observational versus randomized trials. Whereas the protective effect of aspirin was similar to that reported by Choi et al., the magnitude of the effect was somewhat less. Specifically, in many past observational and randomized trials, estimates of the effect of aspirin were associated with a 20%‐40% reduction in cancer risk.3 The authors highlighted how estimations of effect size were likely dependent on appropriately detailed recording and analysis of aspirin use. In light of this, one potential shortcoming of the study by Choi et al. was the reliance on electronic medical records to delineate aspirin users from nonaspirin users, as well as identification of duration and dose of therapy. Although such data were available in the medical records, accurate quantification of medication dosing and duration can be problematic.9 To this point, more than one‐half of cases did not have available information on the duration of aspirin usage. Information on other concurrent medications being taken by patients was also limited. Such missing data may have impacted data analyses and subsequent causal inferences. For example, Chaiteerakij et al. previously reported that treatment with metformin was associated with a 60% reduction of CC in diabetic patients. Lack of adjustment for metformin or other chemopreventive medications in the aspirin and nonaspirin groups may have unknowingly impacted the results. Finally, the study probably suffered from some residual confounding, because patients who were daily aspirin users likely had a different medical profile than their matched controls (e.g., patients were healthier if they were taking aspirin for prophylaxis but less healthy if they were taking it for therapeutic purposes). Although matching can mitigate some of the differences between the two groups, undoubtedly some residual bias remained. Furthermore, the "biobank"‐derived control patients were individuals who had been followed at the Mayo Clinic for a prolonged period and thus were likely different from the general population. Despite these limitations, the data by Choi et al. contribute to the growing body of data that support a chemopreventive role for aspirin use. Aspirin use is not without its own set of potential complications. Low‐dose aspirin therapy has been associated with GI side effects, which can range from dyspepsia and gastroduodenal erosions to symptomatic or complicated ulcers resulting in an annual incidence of upper GI bleeding of 0.6% and an increased relative risk of 2.6.10 In addition, the use of enteric‐coated or buffered preparations do not necessarily reduce the risk of GI complications.10 As such, further work is needed to characterize patient populations in which the benefits of routine aspirin use outweigh the risks, especially for a cancers that have a low baseline incidence (such as CC). Choi et al. are to be congratulated on their work, which adds to an already abundant literature on the topic of aspirin and cancer prevention. However, the retrospective design of the study, as well as the relative lack of detailed data on dosing, duration of use, and concomitant other medications, do not allow for definitive evidence to support routine recommendations for daily aspirin use. In an era of individualized medicine, future prospective trials should aim to identify those subsets of patients who might benefit the most from aspirin usage, as well as further delineate the underlying mechanism of action related to this potential chemopreventative approach.