There are limited data investigating whether use of NSAIDs, including the specific classes of NSAIDs (aspirin versus non-aspirin), have differential effects within anatomic subsites of the colorectum. Some evidence from cohort studies suggests a stronger association between NSAID use and proximal versus distal colon cancer (7–8), but the evidence regarding rectal cancer is mixed, likely attributable to small case numbers in the existing literature (7, 9). Anatomic subsites within the colorectum derive from different embryonic origins (10–11), and different risk factors for colon versus rectal cancer have been documented (12). Furthermore, there are very little data on whether NSAIDs provide a chemoprotective benefit among individuals at increased risk of developing colorectal cancer due to the presence of a family history of the disease. Given that colorectal cancer is the third most commonly diagnosed cancer in the U.S. (13), the potential population attributable benefit for chemoprevention is substantial in this subgroup of people.

Those who used any NSAIDs, aspirin, or non-aspirin NSAIDs had a reduced risk of colorectal cancer (any NSAIDs HR = 0.80, 95% CI: 0.73, 0.87; aspirin HR= 0.91, 95% CI: 0.85, 0.98; and non-aspirin NSAIDs HR= 0.82, 95% CI: 0.77, 0.87) compared to non users (Table 2); these risks were evident for both men and women and the sex interactions with the outcome of colorectal cancer were not statistically significant (P-interaction_{any NSAIDs*sex} = 0.70, P-interaction_aspirin*sex = 0.41, P-interaction_{non-aspirin NSAIDs*sex} = 0.92), nor were tests for interaction between BMI or smoking status and NSAID use (data not shown). Furthermore, analyses stratified by sex, BMI or smoking status revealed consistent associations across strata; and thus stratified tables are not presented for these factors. For aspirin users, there was a statistically significant reduction in rectal cancer risk (HR=0.83, 95% CI: 0.72, 0.96), but not colon cancer (HR=0.94, 95% CI: 0.86, 1.02). In contrast, the use of non-aspirin NSAIDs resulted in a reduced risk for all subsites within the colorectum (Table 2). Assessment of individuals who used both aspirin and non-aspirin NSAIDs, individuals who used one type but not the other, as well as mutually adjusting for both classes of NSAIDs, did not materially alter our inferences.

Examining frequency of use of NSAIDs in relation to colorectal cancer risk revealed further decreases in risk as the frequency of use increased. Relative to no use, daily use of any NSAID was associated with a reduced risk of colorectal cancer across all subsites. Specifically, daily users of aspirin compared to nonusers had a reduced risk of distal colon (HR=0.84, 95% CI: 0.71, 0.99, P-trend <0.01) and rectal (HR=0.76, 95% CI: 0.64, 0.90, P-trend <0.001) cancers (Table 2); and daily use of non-aspirin NSAIDs compared to nonusers resulted in risk reductions for both proximal and distal colon cancers (HR=0.65, 95% CI: 0.54, 0.78, P-trend < 0.0001; HR: 0.69, 95% CI: 0.55, 0.87, P-trend <0.001, respectively, Table 2). Interestingly, decreases in risk were also evident among those who took non-aspirin NSAIDs weekly or even monthly.

We repeated our analyses after excluding individuals who developed colorectal cancer during the first 2 years of follow-up since symptoms of undiagnosed colorectal cancer could alter participants’ use of NSAIDs; however, no appreciable changes were noted in the associations. No evidence of subsite heterogeneity was detected in any of the analyses. The heterogeneity test for cancer of the colon versus rectum among daily aspirin users relative to never users approached statistical significance (P_{heterogeneity} =0.09); as did the test for colon versus rectal cancer among daily non-aspirin NSAIDs users relative to non-users (P_{heterogeneity} =0.06), but given the number of comparisons these results may be due to chance alone. In addition, no appreciable differences in HRs were detected among n = 41,404 individuals who reported a personal history of heart disease on the baseline questionnaire; of these individuals, 81% reported taking aspirin in the past 12 months, of whom 61% reported daily use.

A number of previously published cohort studies have assessed aspirin or non-aspirin NSAIDs use and incidence of colorectal cancer (8–9, 18–26), although only two cohort studies, the Nurses’ Health Study (NHS) (18, 20) and the Health Professionals’ Follow-up Study (HPFS) (21), were defined as “good” quality in the U.S. Preventive Services Task Force reports on the use of aspirin and non-aspirin NSAIDs for primary prevention of colorectal cancer (3–4). To the best of our knowledge, only one new cohort study of primary, incident colorectal cancer (7) has been published since the U.S. Preventive Services Task Force ended accruement for inclusion in its 2007 systematic reviews (3–4), although an update to the HPFS was published in 2008 (9).

The NHS, which examined 962 colorectal cancer cases over 20 years of follow-up in nearly 83,000 average risk women reported a dose dependent reduction in colorectal cancer risk with years of regular aspirin use (defined as consumption of 2 or more standard tablets / week), as well as a reduction with increasing dose per week. However, the authors reported a reduced risk in colon cancer but not rectal cancer in site-specific analyses (18) whereas we noted reductions in risks for both colon and rectal cancers. Results from 47,363 males enrolled in the HPFS were comparable to those from the NHS; although aspirin use was associated with decreased rectal cancer risk, and this association was stronger than that noted for proximal or distal colon cancers (9). However, the authors cautioned that a limited number of cases were available for each subsite and confirmatory studies are needed. Tests for subsite heterogeneity were not reported in the HPFS, but the overlapping confidence intervals suggest that the difference was not statistically significant. Results from the Iowa Women’s Health Study reported greater reductions in risk of proximal colon cancer compared to cancer of the distal colon and rectum among aspirin users, although that study had fewer cases than HPFS and our study (7).

Our investigation found reductions in colon and rectal cancers among individuals who reported aspirin and non-aspirin NSAIDs use, particularly at increased frequencies of use. Results from our study suggesting that monthly use of any NSAID or non-aspirin NSAIDs (defined as no greater than 2–3 times per month) was associated with protection from colorectal cancer was unexpected; but demonstrates that it is possible that use of NSAIDs just 2–3 times per month could be enough to elicit an effect. However, it is also possible that participants misclassified their exposure or that current monthly users may have used NSAIDs frequently enough in the past to confer a protective benefit. Furthermore, since the frequency of “use of any NSAID“ defaulted to the higher frequency if an individual reported use of both classes of NSAIDs, these results could be biased by the individuals who were taking both aspirin and non-aspirin NSAIDs monthly; however, this is unlikely since only 1.2 % (data not shown) of the monthly users reported use of both classes of NSAIDs.

Unlike the previous cohort studies, which had fewer than 230 cases of rectal cancer; data were available for over 1,000 cases of rectal cancer in our study. Our data support the observation made in the HPFS regarding a stronger inverse association between aspirin use and rectal cancer than that observed for cancer of the proximal or distal colon. Although we noted a greater reduction in risk for rectal cancer than colon cancer with daily aspirin use, the evidence for subsite heterogeneity did not reach statistical significance, suggesting that the magnitudes of these associations are not materially different. Results from a population-based case-control study of incident distal colorectal cancer also reported more potent effects of aspirin use for rectal and rectosigmoid cancers than for sigmoid cancer among 1,057 incident cases and 1,019 controls from North Carolina (27). Although neither the NHS nor HPFS reported the relationship between non-aspirin NSAIDs use and colon subsites, Smalley and colleagues (8) noted the protective benefit of non-aspirin NSAIDs use was more pronounced for proximal colon cancer compared to distal colon cancer, as did results from the Iowa Women’s Health Study (7) and our study. Proximal colon tissue has an embryonic origin different from that of tissue distal to the splenic flexure (10–11) and cancers of the proximal colon, distal colon, and rectum differ in regard to their epidemiological, clinical and histological parameters (27–30). Thus, it is possible that investigation of risk factors, such as NSAID use, by colorectal subsite could provide valuable insight in to the etiology of colorectal cancer. Specific to NSAID use, COX-2 expression may vary depending on colorectal tumor location (31–32), although it is unclear whether it is over- or under-expressed in rectal tumors compared with colon tumors. In the future, if confirmatory studies continue to show a more protective effect on the proximal colon and safer COX inhibitors are available in the marketplace, then more widespread use of this class of drugs may be warranted given that colonoscopy may be less effective in identifying right-sided neoplasia. Indeed, results from a recent pooled analysis of five randomized trials of daily aspirin use indicated that the decrease in colon cancer risk was driven by reductions in cancer of the proximal, but not distal colon. In addition, no reduction in rectal cancer risk with aspirin use was observed in the pooled analysis. The authors hypothesize that overexpression of COX-2 in the distal colon may lead to less complete COX-2 inhibition with aspirin use in the distal colon relative to the proximal colon (33). The lack of an association of distal and rectal cancer with aspirin use in the combined analyses of these trials is intriguing, although the small case numbers must be noted: in total there were only 100 cases of distal colon cancer and 119 cases of rectal cancer. Furthermore, trial participants were overwhelmingly male.

A unique feature of our study was the ability to analyze over 26,000 individuals with a higher risk of colorectal cancer due to having a first degree relative with this malignancy. Few studies have examined the association of NSAIDs use in this higher risk group. Coogan and colleagues (34) examined two case-control studies to assess whether family history of colorectal cancer in a parent or sibling modified the association of NSAIDs use with colorectal cancer; although they reported similar risk reductions in the two risk groups, both studies had fewer than 200 cases with a family history of the disease. Our results suggest that the protective benefit of NSAIDs among individuals with a positive family history of colon cancer is similar to, if not greater than, the risk reduction experienced in the general population. However, the risk reductions among the family history subgroup were not statistically significantly lower than those of the general study population, although the small number of cases for each subsite among the positive family history group must be noted. Overall, the risk of developing colon cancer among those with a positive family history was lower than expected. We attribute this to bias given the older age of participants at study entry, as well as possible differential screening prior to study entry among individuals with a family history of the disease. The limited case numbers is an important reminder to interpret these results with caution, but if true, these results could tip the risk-benefit equation in favor of use of these drugs in high-risk groups.

Although the published evidence for a chemopreventive role of NSAIDs among individuals at an increased risk for colorectal cancer due to a family history of this disease is limited, evidence for groups with known hereditary conditions linked to colorectal cancer is available; for example, use of celecoxib or sulindac reduced the incidence of colorectal polyps in patients with familial adenomatous polyposis (35–36). However, no protective effect of 600 mg aspirin was shown in a randomized clinical trial of 1,071 carriers of Lynch syndrome (hereditary nonpolyposis colorectal cancer) (37). Although we lacked information on whether individuals in our study had been diagnosed with either of these hereditary conditions, familial adenomatous polyposis and Lynch Syndrome are thought to contribute to less than 5%–6% of all colorectal cancers in the general population (12). Furthermore, colorectal cancer related to these genetic conditions typically occurs at a young age of onset; the median age of individuals with a family history of colon cancer in our study was 62.8.years at the time the risk factor questionnaire was administered.

A limitation of our study is the absence of data on duration of NSAIDs use. Previous studies have suggested that duration of aspirin use of 10 years or more and duration of non-aspirin NSAIDs use of 2–5 years and longer is required to achieve a reduction in colorectal cancer risk (9, 18, 20–21, 38–41). Subanalysis of individuals in our cohort with self-reported history of heart disease at baseline, our rough proxy for longer duration of use, yielded HRs similar to those of the overall cohort. In addition, use of NSAIDs was only ascertained at one time point and we lacked information regarding NSAIDs use during the cohort follow-up period. There is the distinct possibility that individuals changed their pattern of NSAID use during the follow-up period; this would likely bias the results toward the null. Our study also lacked information on dose and indication for NSAIDs use. In particular, we were unable to distinguish between use of low-dose aspirin (typically 81 milligrams) versus full strength (typically 325 milligram) tablets. Two randomized trials of aspirin and colorectal cancer incidence have failed to demonstrate a benefit of low-dose aspirin therapy after 5 and 10 years of follow-up (42–43), and cohort studies suggest that dosage much greater than that achieved with daily low-dose aspirin use is necessary to derive colorectal cancer protection (9, 18, 21). Recently, however, results from 20-year follow-up of five randomized trials indicated that use of at least 75 milligrams daily was effective in the reduction of both colorectal cancer incidence and mortality (33). Thus, the possible attenuation of effect due to heterogeneity in dose among aspirin users in our study may be less than previously assumed. All data in our investigation were self-reported as part of a questionnaire; thus, misreporting of both exposure and confounding variables is possible, as well as the potential for residual confounding. Finally, our cohort was comprised of older adults (mean age = 62.8 y), and results may not be applicable to other age groups.

Our study has numerous strengths, including being the largest cohort to date to have evaluated the association of NSAIDs type and colorectal cancer by anatomic subsite as reported in state cancer registries. Our analysis of NSAIDs use and colorectal cancer risk among individuals with a first degree relative with history of the disease is one of only a few studies to examine this higher risk subgroup. Although some of the risk estimates suggest a greater risk reduction of colorectal cancer in those with a positive family history of this malignancy, some of the case numbers for daily users with a positive family history were small and the differences in the HRs with the general study population were not statistically significant. In addition, multiple interactions were tested and the possibility of chance findings cannot be eliminated. Thus, the findings for NSAID use among individuals with a family history of colon cancer should be interpreted with caution. Lastly, the risks associated with long-term NSAIDs use, including gastrointestinal and cardiovascular complications are well-documented and serious (3–4). Recommendation of chemopreventive NSAIDs use among individuals with a family history of colorectal cancer at this time is premature.

In summary, our results suggest that weekly or daily use of NSAIDs is associated with colorectal cancer protection in the general population, as well as in individuals with a first degree relative with colon cancer. The strength of the association varies by drug class, but generally a dose-response relationship is observed between increased frequency of use and cancer protection. The potential harms associated with NSAIDs use must be considered before translating these results into clinical practice.