Correspondence to: John A. Baron, MD, MS, MSc, Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756 (e-mail: john.a.baron{at} dartmouth.edu)
Could it really be that aspirin increases the risk of pancreatic cancer, as suggested in the article by Schernhammer et al. (1)? In many ways, aspirin has been a wonder child of chronic disease prevention. The drug is very effective in the secondary (chemo)prevention of cardiovascular disease and may also have a role in primary cardiovascular prevention (2). For neoplasia, clinical trials have recently established that aspirin can reduce the risk of sporadic colorectal adenomas (35), just as other nonsteroidal anti-inflammatory drugs (NSAIDs) cause regression of adenomas in familial adenomatous polyposis (6,7). Epidemiologic data also suggest that use of aspirin and other NSAIDs may reduce risk of cancers of the stomach and esophagus (8,9). Less consistent data suggest inverse associations with risk of cancers of the prostate and breast. The fact that observational data regarding colorectal neoplasia were confirmed in clinical trials raises the hope that findings regarding other cancer sites may also reflect causality, becauseat least for the gastrointestinal cancer sitesthe potential biases in the epidemiology are likely to be similar to those for colorectal cancer.
Of course there is no reason that all cancers in the abdomen should respond in the same way to aspirin and/or NSAIDs. Each malignancy may have its own pathways of carcinogenesis and its own set of risk factors and protective exposures. Unfortunately, it has been a challenge to study these issues in pancreatic cancer. This malignancy is relatively uncommon, and fatality is high. Epidemiologic and clinical research has been difficult; as a consequence, epidemiologic data are relatively limited, and the laboratory investigation is relatively scarce. There are only a few known risk factors for pancreatic cancer: cigarette smoking and, probably, type II diabetes mellitus and chronic pancreatitis (10). There is also no dominant etiologic factor around which to organize thinking about this malignancy, along the lines of cigarette smoking for cancers of the upper aerodigestive tract or estrogens for cancer of the endometrium. Quite simply, in comparison to other malignancies, there isn't a lot known about pancreatic cancer.
Could Schernhammer et al. (1) be reporting an artifactual result? The relative risks are only modestly elevated, and there was some evidence that, in the years before diagnosis, the pancreatic cancer caused the aspirin use, rather than vice versa. After omitting the 2 years before diagnosis, the relative risk for regular aspirin use decreased from 1.43 (95% confidence interval = 1.05 to 1.95) to 1.15 (95% confidence interval = 0.83 to 1.59). Nonetheless, the study is very well done: losses to follow-up are few, and detailed, high-quality data were collected. The trends in relative risks over duration of aspirin use were conventionally statistically significant, and meaningful associations were present for prolonged use. It is difficult to argue that prediagnostic symptoms would be present for more than a decade. In the end, it is hard to think of a conventional epidemiologic bias that could explain the findings, although it would have been useful to see data regarding associations with acetaminophen use as a potential contrast to NSAID use.
There have been previous epidemiologic investigations of the association between aspirin (or other NSAID) use and risk of pancreatic cancer. The findings have been conflicting. One cohort study with 80 patients with pancreatic cancer (11) showed an inverse association with use of aspirin but not with use of other NSAIDs. Another small cohort study (12) reported reduced risks in association with aspirin use in the 30 days before baseline interview, but there were only 30 patients with pancreatic cancer included in the analysis, and few details were provided. Two other casecontrol studies (13,14) were null overall. In contrast, two database investigations from the United Kingdom and Denmark (15,16) suggested increased risks with NSAID prescriptions. Many of these studies were hampered by various design limitations, but it is clear that aspirin and NSAID use is associated with risk of pancreatic cancer in a different way than with risk of cancers of the luminal gastrointestinal tract.
Several of these studiesand the report by Schernhammer et al. (1)could have been affected by bias introduced by the timing of the publication. In any ongoing study with accumulating data, the repeated analysis creates a situation in which findings might be published because they are interesting. This is a sort of data dredging analogous to early stopping in a clinical trialbut without a stopping rule. The result could be biased relative risk estimates (17). This process was recently documented with regard to an ongoing casecontrol study (18). The awkward point is that, in this circumstance, the investigators are doing what the scientific community would want to be done: monitoring the data and reporting interesting, relevant findings.
Is it plausible that aspirin could increase the risk of pancreatic cancer? NSAIDs have been found to decrease experimental pancreatic carcinogenesis in hamsters (19,20), and in vitro data also suggest antineoplastic effects in the pancreas (21,22). However, animal models and in vitro studies may not be relevant to humans. There appear to be no data regarding the similarity of the animal tumors or in vitro models to human cancer with regard to biologic behavior, molecular changes, and other characteristics. As Schernhammer et al. (1) point out, there are sparse epidemiologic data but many case reports suggesting that NSAIDs (though not prominently aspirin itself) can lead to acute pancreatitis. Even if this relationship is confirmed epidemiologically, the reported relationship is with acute pancreatitis, not chronic pancreatitis that has been associated with pancreatic cancer risk.
Although prostaglandins, such as prostaglandin E2, have been strongly implicated in carcinogenesis, it is likely that there are eicosanoids with anticarcinogenic properties. Aspirin increases expression of one of these, 13-S-hydroxyoctadecadienoic acid (13-S-HODE) (23). However, it decreases expression of prostaglandin I2 (prostacyclin), which has been shown to inhibit the malignant phenotype of neoplastic pancreatic cancer cells in nude mice (24).
There are no easy answers to the question of what aspirin and other NSAIDs do to pancreatic carcinogenesis. The findings by Schernhammer et al. (1) are provocative and force us to think carefully about the actions of aspirin and other NSAIDs and the mechanisms underlying pancreatic cancer. Fortunately, conflicting data from diverse threads of research are often a very effective push toward scientific progress.
NOTES
Editor's note: Dr. Baron is a member of the Advisory Board for the Nurses' Health Study.
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