Data from this prospective cohort study suggest that regular use of aspirin, but not ibuprofen, was associated with a reduced prostate cancer risk. Overall decreases in prostate cancer risk associated with regular aspirin use were modest, although there was some evidence of further risk reduction with more frequent use, particularly among men who were older than age 65 or who had a prior history of cardiovascular-related diseases or arthritis.
The lack of an association between ibuprofen use and prostate cancer risk in this analysis is likely attributed in part to the low prevalence of ibuprofen use in the PLCO cohort. Previous studies of ibuprofen have conflicting results. Although few studies reported reduced risk of prostate cancer in association with non-aspirin NSAID use (Dasgupta et al, 2006
; Mahmud et al, 2011
), some studies reported increased (Murad et al, 2011
) or no risk (Platz et al, 2005
; Brasky et al, 2010
). Laboratory data indicate that both aspirin and ibuprofen can inhibit prostatic carcinogenesis (Attiga et al, 2000
; Andrews et al, 2002
; Lloyd et al, 2003
). In a study that compared the effect of various non-prescription NSAIDs (including aspirin and ibuprofen) on prostate tumour cell survival, ibuprofen was the most effective in suppressing proliferation and inducing apoptosis, particularly at clinically prescribed doses (Andrews et al, 2002
Owing to the potential adverse effects of aspirin, such as gastrointestinal tract and renal toxicity, it is useful to identify subgroups of men for whom use of aspirin is particularly beneficial. In analyses restricted to men with a history of cardiovascular-related diseases and men with a history of arthritis, we observed inverse associations between frequency of aspirin use and prostate cancer risk. Although the questionnaire lacked data on specific dose and duration of NSAID use, our results of lower risk among men older than 65 years and among those who have history of cardiovascular diseases and arthritis suggest that the reduction in prostate cancer risk is likely conferred by aspirin taken at generally low doses (such as for cardiovascular disease) for long duration (among older men). This notion is further supported by the current common medical practice, where for the purpose of coronary artery disease prevention doctors prescribe the lower dose aspirin (81
) for the majority of patients (about 60%) and regular dose aspirin (325
) for about 35% (Campbell et al, 2007
Several sources of bias, including confounding and detection bias, could have affected the observed associations of aspirin and ibuprofen use with prostate cancer risk. Men who take NSAIDs daily for preventive purposes may be more health conscious and more likely to engage in positive health-related behaviours, such as maintaining a healthy diet and exercising regularly, which could influence their risk for prostate cancer. However, controlling for physical activity, dietary fat consumption, and other dietary factors suspected to decrease prostate cancer risk, including lycopene and vitamin E intake, did not materially alter the risk estimates for either NSAID. Confounding may further exist if NSAID use is related to a physical condition that directly affects prostate cancer risk (Psaty et al, 1999
). Although adjustment for several factors, including arthritis and hypertension, did not alter the results, residual confounding by unknown factors cannot be ruled out.
The intriguing association between aspirin use and prostate cancer risk among men with cardiovascular-related diseases merits further investigation. Reasons for the inverse relation between aspirin use and prostate cancer risk observed among men with cardiovascular-related diseases are unknown, but recent studies suggest that prostate cancer and cardiovascular disease share common risk factors, such as hyperlipidemia and chronic inflammation, and that regular statin use lowers the risk of prostate cancer (Platz et al, 2006
; Flick et al, 2007
; Jacobs et al, 2007
; Taylor et al, 2008
). It should be noted that the prevalence of daily aspirin use was greater among men who reported a history of cardiovascular-related diseases or diabetes than men without these conditions. In the PLCO cohort, diabetes, a major risk factor for cardiovascular disease, had divergent relations with prostate cancer by tumour aggressiveness. In these men, diabetes was associated with a reduced risk of total prostate cancer but an increased risk of aggressive prostate cancer among men who were lean or physically active (Leitzmann et al, 2008
). Additional adjustment for history of diabetes, however, did not materially change the association between aspirin use and prostate cancer risk in our analysis.
Surveillance bias is possible but not likely to account for the suggestive association between aspirin use and prostate cancer risk. In theory, NSAID users, being either more health conscious or more burdened with other medical problems, may be under closer medical surveillance than non-users, thereby increasing their chances for early detection of prostate cancer. Such bias, if any, is likely minimal in our study, as men participating in the screening arm of the PLCO Trial had an equal opportunity for cancer detection – a unique difference from prior studies – with screening visits scheduled annually over the first 5 years of follow-up. To account for any residual difference in adherence to annual screening between NSAID users and non-users, the total number of screening visits across the follow-up period for each individual was treated as a confounding variable (Weiss, 2003
), but it yielded no substantial change in the magnitude or direction of risk associated with NSAID use.
Although recall bias was minimised by the prospective study design, exposure misclassification could have occurred if there were any changes in NSAID use related to symptoms of undiagnosed prostatic disease within the last 12 months before enrolment. This would be most likely to affect those men diagnosed with prostate cancer earlier in the follow-up period. Although excluding the 15% of cases who were diagnosed within the first year of follow-up (i.e., probably prevalent cases) from the analysis did weaken the association between daily aspirin use and prostate cancer risk, there was no meaningful difference in the HRs for cancers diagnosed within the first year of follow-up and cancers diagnosed after the first year of follow-up. Another unresolved issue is whether NSAIDs are more effective at inhibiting tumour progression than initiation. Two studies have suggested that frequent aspirin use reduces risk for advanced or metastatic prostate cancer (Norrish et al, 1998
; Leitzmann et al, 2002
). In contrast, another cohort study showed about a 24% reduction in prostate cancer risk with daily aspirin use, the magnitude of which did not differ between local and regional/distant disease (Habel et al, 2002
). Given that our male cohort originated from the screening arm of the PLCO Trial, participants were screened annually. Therefore, cancer cases were more likely to be caught early. Thus, few cases of metastatic cancer were diagnosed, with almost half of the metastatic cancer cases detected within 1 year of the initial screening visit. Under these circumstances, only regular aspirin use in relation to advanced prostate cancer could be examined. We found a slightly lower risk for aggressive compared with non-aggressive tumours, indicating that aspirin might be more influential in hindering the progression than development of prostatic tumours.
Even though the underlying mechanisms have yet to be precisely delineated, the potential benefit of aspirin does support the prevailing hypothesis that chronic inflammation contributes to prostate carcinogenesis. As a response in the repair of damaged or infected prostatic tissue, chronic inflammation may promote neoplastic development and growth by triggering specific cytokines and growth factors, activating COX-2 in macrophages and epithelial cells, and inducing oxidative stress (Lucia and Torkko, 2004
). Accordingly, increasing attention has been devoted to the focal lesions of epithelial atrophy associated with chronic inflammation and a high proliferative index, collectively known as proliferative inflammatory atrophy. These lesions have been commonly observed in the peripheral zone of the prostate where most tumours originate, found in close proximity to both adenocarcinoma and high-grade prostatic intraepithelial neoplasia, and associated with COX-2 upregulation (Zha et al, 2001
; Platz and De Marzo, 2004
Despite numerous strengths, including low attrition, nearly complete histological confirmation of cancer cases, comprehensive baseline data on potential confounders, and equal access for prostate cancer screening among participants, this study had several limitations. Data on frequency of aspirin and ibuprofen use were collected at a single point in time (during the last 12 months), without record of dose (pill count), duration, or indication for use. Therefore, there might be some misclassification of NSAID use because the assessment relied only on baseline self-reports. However, although there might be an underestimation because people tend to increase the frequency or the dose of use of NSAID by age, this underestimation is expected to be non-differential because the reporting was before the development of cancer. In fact this underestimation, if it biased our results at all, would bias the results towards the null. Thus, our estimates are conservative. In addition, misclassification might have occurred because of the use of some prescription and/or over-the-counter NSAID that the respondent might overlooked. However, if there is misclassification, it would most likely be non-differential, therefore potentially attenuating our results.
The prevalence of regular aspirin use in this study (31%), nevertheless, was comparable to that noted in the other US-based cohort studies of prostate cancer, which ranged from 17% (for daily use) to 59% (for use in the past month; Paganini-Hill et al, 1989
; Schreinemachers and Everson, 1994
). In a US study on patterns of aspirin use among adults ages 45–64, the prevalence of aspirin use among white men was 31%, with increasing trends in prevalence noted both across the study period (1987 to 1989) and with older age. In addition, a recent report from the Household Component of the Medical Expenditure Panel Survey by the Agency for Health Care Research and Quality concluded that 19.3% of the adult US non-institutionalised individuals report aspirin use either daily or every other day. The use increases by age, and almost 50% of individuals older than 65 years old reported daily use (Soni, 2007
). Exposure assessment was also limited by not taking into account the use of other specific NSAIDs and by not verifying self-reported data on NSAID use through medical record review. However, misclassification due to the use of COX-2 selective inhibitors, such as celecoxib and rofecoxib, was probably minimal, as these ‘new generation' NSAIDs were first introduced in 1999, which was toward the end of the trial recruitment period. Although the extent and impact of exposure misclassification cannot be determined, extensive measurement error would most likely lead to risk attenuation.
In addition, as the majority of the participants are White, the results might not be generalisable to other races. Another limitation of this type of data is left truncation, such that participants who enter the cohort at a certain age have obviously not died or developed cancer before that age. Subjects who died or developed cancer before enrolment would clearly not be included in the cohort, thus resulting in left truncation. However, we used PROC PHREG in SAS/STAT software (Version 9.2, SAS Institute Inc., Cary, NC, USA), which allows late entry models. This analysis method handles the left truncated data therefore alleviates this limitation.
Another limitation that should be noted is the competing mortality due to aging or other medical conditions. However, in the competing risk sensitivity analysis, the inverse associations we observed between NSAID use and prostate cancer are unlikely to be due to an increased risk of death among men who take NSAIDs; since the results were essentially the same for the analysis with and without death included as a competing risk.
In summary, this prospective cohort study suggests that aspirin use was associated with a reduced prostate cancer risk, in particular, in certain subgroups of men. Additional studies with more detailed exposure measurement are warranted to evaluate the dose, duration, and timing of NSAID use in relation to prostate cancer risk. The association between non-selective and selective COX-2 inhibitors, as well as non-COX inhibitors, should also be investigated. Coupled with laboratory-based research, these efforts should further expand our knowledge of the mechanisms by which NSAIDs, particularly aspirin, may influence prostate carcinogenesis.