We found that reported use of aspirin or non-aspirin NSAIDs was associated with a significant 36% reduction in the risk of non-cardia gastric cancer consistent with the earlier studies. For ever use of aspirin in the previous 12 months, age-adjusted rates of gastric non-cardia cancer dropped from 11.0 in non-users to 7.0/100
000 person years in users. Although we did not find a significant association between use of aspirin or other NSAIDs with cardia cancer, the point estimate in our study was very close to the summary estimate from the meta-analysis, which showed a protective effect. Unlike most earlier observational studies, we found no such association with oesophageal adenocarcinoma.
Our finding in the NIH-AARP cohort study that aspirin or other NSAIDs had a protective association with gastric non-cardia adenocarcinoma is consistent with the literature published earlier, which is summarised in . It appears that aspirin and non-aspirin NSAIDs have similar effects, which may have implications for cancer prevention. Eradication of Helicobacter pylori
, the strongest risk factor for gastric non-cardia adenocarcinoma, may reduce its incidence (Talley, 2008
). However, recent studies suggest that H. pylori
may have health benefits, such as preventing asthma (Blaser et al, 2008
) or oesophageal adenocarcinoma (Islami and Kamangar, 2008
). Beyond the direct benefits and risks of eradication to the individual, the methods and consequences of attempted widespread eradication, such as increasing antibiotic resistance, must also be considered (Graham and Shiotani, 2008
). A single trial has tested the effect of the NSAID rofecoxib on subjects with gastric pre-neoplastic lesions over 24 months and found no evidence of benefit, but this study was small and did not use cancer as an end point (Leung et al, 2006
). The remarkably consistent observational results showing that NSAID use is associated with a reduced risk of gastric cancer may warrant a randomised trial in a suitable population at high risk for the disease in which side effects can be monitored closely.
The epidemiology of gastric cardia tumours in the United States is similar to that of oesophageal adenocarcinoma. The incidence of this tumour may have increased in recent years, but this change may have occurred because of changing patterns of diagnosis or because of the difficulty of separating adenocarcinomas in the gastric cardia from those in the oesophagus (Kubo and Corley, 2002
). We found no significant association between use of either aspirin or non-aspirin NSAIDs and risk of gastric cardia adenocarcinoma, but our point estimates are similar to the summary estimates from our meta-analysis, which suggests a significant protective effect.
We found no evidence that ever or daily aspirin use lowered the risk of oesophageal adenocarcinoma, for which, as shown in , our results are discordant with many earlier studies. Most of these showed some evidence, albeit not always significantly, that use of aspirin or non-aspirin NSAIDs was associated with reduced risk.
The reasons for these differences are not clear. Most earlier studies had retrospective designs and may be prone to reverse causality for NSAIDs, as subjects with reflux symptoms, and therefore at higher risk of oesophageal adenocarcinoma, may avoid using NSAIDs producing the appearance of protection among users. But at least one earlier prospective study found that NSAID use reduced risk of progression to oesophageal adenocarcinoma among subjects with Barrett's oesophagus (Vaughan et al, 2005
). Recently, in the same cohort, the association is found strongest among subjects with multiple molecular abnormalities that confer the greatest risk of progressing to cancer, but absent in those at the lowest risk (Galipeau et al, 2007
). One study using subjects with Barrett's oesophagus as controls found that oesophageal adenocarcinoma cases and subjects with Barrett's used aspirin and NSAIDs at similar rates, but this differed with long-term reflux symptoms (Tsibouris et al, 2004
). One small, short-term trial tested the effect of twice-daily treatment with 200
mg of celecoxib for 48 weeks on the proportion of dysplastic biopsies in subjects with Barrett's oesophagus and did not find any benefit (Heath et al, 2007
). A large trial of proton pump inhibitors with or without aspirin for the chemoprevention of oesophageal adenocarcinoma in men with Barrett's oesophagus is underway (Jankowski and Moayyedi, 2004
Our study has several strengths, being based on a large prospective cohort that provided adequate power and minimised recall bias, which may alter the associations found in case–control studies. We used subject-completed questionnaires that captured both over-the-counter and pharmacy-provided NSAIDs and information on many potentially confounding exposures, many of which (e.g., age, tobacco smoking, and physical activity) were similar among NSAID users and non-users. On the other hand, we captured only NSAID use over the previous 12 months and did not collect the duration of use, which could have caused misclassification of subjects who, for example, recently ceased NSAID use due to upper gastrointestinal symptoms. But, we did adjust for and stratify by antacid use without change in our risk estimates. We could not assess infection with H. pylori and infected subjects may have different patterns of NSAID use, which would lead to different confounding effects in the stomach and oesophagus. Finally, this study, being observational, is susceptible to confounding by other unmeasured or poorly measured confounders, supporting the need for randomised controlled trials.
In this large prospective cohort study, we found further evidence that regular use of aspirin or non-aspirin NSAIDs may reduce the risk of non-cardia gastric cancer; in contrast, this was not associated with reduced risk of oesophageal adenocarcinoma, thereby differing from most earlier studies.