Regular use of aspirin was associated with a 27% decreased risk of distal gastric adenocarcinoma, with the relation being especially strong (34% reduction in risk) for intestinal-type adenocarcinoma, which is believed to be more environment-related (i.e., associated with salt intake and other lifestyle factors) than the more genetics-related diffuse type. No association was found between nonaspirin NSAIDs and distal gastric adenocarcinoma or between either aspirin or nonaspirin NSAIDs and gastric cardia adenocarcinoma.
The magnitude of the inverse association found in this study between aspirin and gastric cancer is very similar to that seen in previous studies, in which reductions in risk from aspirin ranged from 20% to 47%, even though “regular use” was defined somewhat differently in each study (3
). In a recent study in the United Kingdom, Lindblad et al. (16
) did not find an association between gastric cancer and aspirin use, but the exposure data were limited to a prescription database, which did not contain information on use of NSAIDs that are widely available over the counter. However, the null association found in the present study between nonaspirin NSAIDs and gastric cancer is not what has generally been seen in the literature. Most studies have found an inverse relation with nonaspirin NSAIDs as well (10
), although 1 other study, a large population-based case-control study in Sweden, did not find an association (17
). When examining the association with nonaspirin NSAIDs, we adjusted for aspirin use, which, except for the analysis conducted within the National Institutes of Health–AARP Diet and Health Study (10
), most other investigators appeared not to do. In our population, 56% of nonaspirin NSAID users also identified themselves as aspirin users. When we did not adjust for aspirin use in our models for nonaspirin NSAID use, a suggestion of an inverse relation with nonaspirin NSAIDs appeared (for ≥6 years of regular nonaspirin NSAID use, HR
0.83, 95% CI: 0.50, 1.38).
Similarly to the present study, of the previous studies that analyzed cardia and distal gastric cancer separately, 4 studies (10
) found no association between NSAIDs and gastric cardia cancer, while 2 studies (14
) found similar reductions in risks of both cardia and distal gastric cancer. Note that unlike the case in the other studies, investigators in these 2 studies were not able to adjust for body mass index, one of the strongest risk factors for gastric cardia adenocarcinoma and one that was associated with NSAID use in our study. The findings of the current study also differ from those of a recent meta-analysis, which found significant inverse associations for NSAID use and risk of esophageal adenocarcinoma (10
). Seven of the 10 observational studies of NSAID use and esophageal adenocarcinoma found significant inverse associations (14
), but these were all case-control studies and thus potentially susceptible to recall bias. Of the 3 studies that observed no association (10
), 1 was a prospective cohort study (10
) and 1 was a nested case-control study (16
). Since the epidemiology of gastric cardia adenocarcinoma and esophageal adenocarcinoma differs greatly from that of distal gastric adenocarcinoma (25
), it is plausible that the effect of NSAIDs could vary between these different anatomic sites as well.
There are some limitations to the present study. Foremost is the absence of information on the H
status of study participants. Of the 2 studies on NSAIDs and gastric cancer in which investigators were able to stratify results by H
status, a significant reduction in risk of gastric cancer associated with NSAID use was seen only for H
-positive persons—although evidence for effect modification was found in only 1 of the 2 studies, probably because of the small numbers in the second study (17
). Because we were not able to separate our analyses by H
status, our findings are probably attenuated toward the null hypothesis of no association, indicating that the true inverse association with distal gastric cancer is potentially even stronger that what we found. This misclassification, though, is tempered by the fact that 4 of the 5 ethnic groups in our population (Japanese American, Native Hawaiian, African American, and Latino) have a 2- to 3-fold higher prevalence of H
than the general white population in the United States (26
); thus, most of the patients in our study were probably H
An additional concern about aspirin as the exposure of interest is that regular use could lead to chronic upper gastrointestinal tract symptoms (especially in those more susceptible to development of cancer), which would then account for the inverse association found between aspirin use and gastric cancer. However, our findings that regular use of aspirin does not reduce risk of gastric cardia cancer or esophageal cancer and that acetaminophen use does not reduce risk of distal gastric, gastric cardia, or esophageal adenocarcinoma suggest that the potential side effects of regular pain medication use do not necessarily lead to an earlier, precancerous diagnosis. Additionally, exclusion of cases diagnosed within 2 years of study entry from the analyses did not substantially change our findings.
Alternatively, persons who develop early symptoms may change their NSAID use as a result, confounding the association with gastric cancer. Of the 3 recent studies that have examined a history of upper gastrointestinal tract disorders in relation to the NSAID–gastric cancer association, 2 found no substantive change when stratifying by history of upper gastrointestinal disorders (15
). The third study found a stronger protective effect of NSAIDs among persons with a history of upper gastrointestinal disorders, although the difference in the risk reduction was not significant between persons with and without a history of such disorders (16
). Using lag times of 2–5 years prior to the date of case diagnosis for collection of exposure information in the 3 studies did not change the findings reported above when persons with and without a history of upper gastrointestinal disorders were compared.
Another limitation of the present study is the lack of detailed data on NSAID use. We did not have information on dose, which has been important in randomized trials for colon cancer and/or adenoma (2
), but this has not been a key factor in observational studies of gastric cancer. The information we did have on NSAID use came from self-reports, which, while not as precise as pharmacy records, was the only feasible way we could obtain information on over-the-counter medications. Because we collected our exposure information through questions about duration, not specific timing, we were unable to assess the latency period for an effect on risk.
To our knowledge, the present study included the largest number of gastric cancer cases in a prospective cohort study ever examined in relation to NSAID use. The nature of the Multiethnic Cohort, with its extensive baseline questionnaire, allowed for the exploration of many potential confounders. Additionally, the relatively large number of gastric cancer cases allowed us to look for interactions by ethnicity, smoking status, and sex. Furthermore, we were able to examine the associations of NSAID use with intestinal-type and diffuse-type distal gastric adenocarcinoma separately, as only 1 previous study of NSAIDs and gastric cancer had done (17
), and we found a similar result of an even stronger protective effect when limiting the outcome to intestinal-type adenocarcinoma.
In summary, our analyses suggest that regular use of NSAIDs (especially aspirin), defined as use at least 2 times per week for 1 month or longer, is inversely associated with risk of distal gastric adenocarcinoma, particularly of the intestinal type. This finding of at least a 30% reduction in risk is strongly consistent with previous observational studies of NSAID use and gastric cancer. In the only randomized controlled trial to examine NSAID chemoprevention—the COX-2 inhibitor rofecoxib—of which we are aware, Leung et al. (30
) found no protective effect of the drug in reducing gastric intestinal metaplasia after a 2-year period. However, it is possible that NSAID chemoprevention could be effective at a different stage in the development of gastric cancer, possibly closer to the actual endpoint of adenocarcinoma. We believe that the strength of the association consistently seen in observational studies, along with the high mortality rate associated with gastric cancer, supports the need for further research on the potential of NSAID chemoprevention trials among select high-risk populations.