Among the 82 911 eligible women, we documented 962 cases of colorectal cancer during 1 592 017 person-years. Compared with participants who reported no aspirin use, women reporting the highest levels of use were older, slightly less apt to exercise regularly, and more likely to smoke and regularly use multivitamins, postmenopausal hormones, and NSAIDs. In addition, women who reported higher aspirin intake consumed slightly more alcohol and folate ().
Baseline Characteristics of the Study Cohort*
We observed a significantly lower risk of colorectal cancer among regular aspirin users (≥2 standard aspirin tablets per week) compared with non-regular users (multivariate RR, 0.77; 95% CI, 0.67–0.88), even after controlling for other known or suspected risk factors (). The effect was similar for both distal and proximal colon cancers; however, aspirin did not appear effective against rectal cancers (multivariate RR, 0.94; 95% CI, 0.72–1.23). In addition, regular use of aspirin appeared to offer a significant reduction in risk of early (stages I and II) cancers (multivariate RR, 0.67; 95% CI, 0.55–0.82) but not advanced (stages III and IV) cancers (multivariate RR, 0.86, 0.71–1.05).
Relative Risk of Colorectal Cancer According to Regular Aspirin Use*
To assess long-term, consistent aspirin use more accurately, we focused our analyses on women who reported regular aspirin use on the initial 3 consecutive biennial questionnaires and compared their incidence with women who were nonregular users on consecutive questionnaires (). The inverse association between aspirin and colorectal cancer risk became stronger as aspirin use was reported on subsequent questionnaires.
Relative Risk of Colorectal Cancer According to Consecutive Biennial Questionnaires Reporting Regular Aspirin Use*
We also assessed the effect of duration of regular aspirin use on colorectal cancer risk (). During the first 5 years of use, we did not observe any reduction in risk (multivariate RR, 1.04; 95% CI, 0.88–1.24) compared with nonusers. Beyond 5 years, we found progressively greater reduction in risk, although a significant benefit was not evident until more than 10 years of use (multivariate RR, 0.67; 95%, 0.54–0.85; P<.001 for trend). It did not appear that use beyond 20 years conferred any additional decrease in risk (multivariate RR, 0.68; 95% CI, 0.54–0.85).
Relative Risk of Colorectal Cancer According to Duration of Regular Aspirin Use*
The apparent benefit associated with aspirin use was substantially greater with increasing dose (). Compared with participants who took no aspirin, women who used the equivalent of 2 to 5 standard aspirin tablets per week experienced a modestly lower risk of colorectal cancer (multivariate RR, 0.89; 95% CI, 0.73–1.10), whereas women who used more than 14 tablets per week experienced the greatest risk reduction (multivariate RR, 0.68; 95% CI, 0.49–0.95; P<.001 for trend). This dose-relationship was observed for colon cancers (P<.001 for trend); however, for rectal cancer, even higher doses did not significantly influence risk (P=.26 for trend). Moreover, we observed a significant reduction in the risk for early (stages I and II) colorectal cancers among participants who reported use of 6 or more tablets per week (multivariate RR, 0.58; 95% CI, 0.41–0.84). However, for advanced (stages III and IV) colorectal cancer, a nonsignificant reduction in risk was confined to women using more than 14 tablets per week (multivariate RR, 0.72; 95% CI, 0.43–1.20). Similarly, 6 or more tablets per week offered a significant reduction in the risk of relatively low-grade (well- or moderately differentiated) tumors (multivariate RR, 0.72; 95% CI, 0.55–0.94), whereas any appreciable, although statistically non-significant, reduction in the risk of high-grade (poorly differentiated) lesions was observed only among participants who consumed more than 14 tablets per week (multivariate RR, 0.49; 95% CI, 0.19–1.27).
Relative Risk of Colorectal Cancer According to Aspirin Dose*
We considered the possibility that the influence of aspirin dose was due to more consistent long-term aspirin use among women taking higher doses. We therefore repeated our analysis after restricting the cohort to participants who reported consistent aspirin use on the initial 3 consecutive questionnaires (1980, 1982, and 1984) and those who reported no use on those 3 consecutive questionnaires. Among women who reported consistent aspirin use across 6 years, we continued to observe a significant reduction in cancer risk with increasing aspirin dose (P<.001 for trend).
We further examined whether the influence of aspirin dose differed according to duration of use. We therefore evaluated the influence of cumulative average aspirin dose consumed within the immediately preceding 10 years and that consumed more than 10 years in the past (). Updating data biennially, increasing aspirin dose within the immediately preceding 10 years was not associated with lower risk of colorectal cancer after controlling for aspirin intake more than 10 years in the past (P=.40 for trend). However, increasing aspirin dose greater than 10 years in the past was associated with progressively lower risk of colorectal cancer, even after adjusting for aspirin intake within the immediately preceding 10 years (P<.001 for trend).
We also evaluated the influence of NSAIDs on colorectal cancer risk (). Compared with nonregular users, women who regularly used NSAIDs (≥2 tablets per week) had a multivariate RR for colorectal cancer of 0.79 (95% CI, 0.64–0.97). As with regular aspirin use, it appeared that the effect of regular NSAID use was confined to cancers of the colon (multivariate RR, 0.71; 95% CI, 0.56–0.91); women who used NSAIDs regularly did not appear to have a significant benefit against rectal cancer (multivariate RR, 1.04; 95% CI, 0.72–1.52). Moreover, consistent with aspirin, the influence of NSAIDs on colorectal cancer also appeared to be strongly dose-dependent (P<.001 for trend).
Relative Risk of Colorectal Cancer According to NSAID Dose*
We considered the possibility that concurrent use of NSAIDs and aspirin may have influenced our findings. However, analyses mutually adjusting for use of the other agent did not materially alter the observed RRs associated with each dose category for aspirin (P≤.001 for trend) or for NSAIDs (P=.01 for trend). Moreover, the influence of aspirin or NSAIDs did not appear to differ when we limited our analyses to participants who reported regular use of one but not both medications. The multivariate RRs for regular aspirin use (≥2 standard tablets per week) was 0.79 (95% CI, 0.68–0.91) among women who did not use NSAIDs regularly. Similarly, the multivariate RRs for regular NSAID use (≥2 tablets per week) was 0.83 (95% CI, 0.62–1.10) among women who did not use aspirin regularly. Finally, compared with women who did not use either NSAIDs or aspirin, regular users of either drug had a multivariate RR of 0.77 (95% CI, 0.68–0.88).
To assess whether these associations reflected a nonspecific analgesic effect, we examined the influence of regular acetaminophen use on colorectal cancer risk. Because data on acetaminophen were not collected until 1990, we limited the cohort to follow-up after 1990. We did not observe an association between regular use of acetaminophen (≥2 tablets per week) and colorectal cancer risk (multivariate RR, 0.95; 95% CI, 0.67–1.34). Moreover, increasing acetaminophen dose was not associated with lower risk (P=.83 for trend). In contrast, the multivariate RRs were 0.80 (95% CI, 0.65–1.00) for regular use of aspirin (≥2 standard tablets per week) and 0.69 (95% CI, 0.50–0.96) for regular use of NSAIDs (≥2 tablets per week); increasing dose of either aspirin (P=.003 for trend) or NSAIDs (P=.008 for trend) was also consistent with our findings among the larger cohort.
Data in our cohort as well as a randomized controlled trial demonstrate an inverse association between use of post-menopausal hormones and colorectal cancer risk.17,18
Although we controlled for the use of current and past hormone use in all of our multivariate analyses, we also considered the possibility that the benefit we observed with aspirin was due to residual confounding by the duration of hormone use. However, the addition of duration of either past or current hormone use to our multivariate models did not change our results (RR for regular aspirin use=0.77; 95% CI, 0.67–0.88; P
<.001 for trend).
Aspirin-associated gastrointestinal bleeding may have also influenced the likelihood of participants having a positive fecal occult blood test result or undergoing endoscopy. Although we controlled for use of screening endoscopy in all of our multivariate analyses, we also evaluated the influence of aspirin among women who did not report having a positive fecal occult blood test result or did not undergo screening endoscopy. Among such women, the influence of aspirin was not materially altered (multivariate RR for regular aspirin use, 0.78; 95% CI, 0.68–0.90; P<.001 for trend).
The effect of aspirin use was not modified by the presence of a family history (≥1 first-degree relative) of colorectal cancer. Regular aspirin use was associated with a multivariate RR for colorectal cancer of 0.76 (95% CI, 0.57–1.02) among women with a family history of colorectal cancer and 0.78 (95% CI, 0.67–0.90) for those without a family history.
We also assessed the incidence of reported gastrointestinal bleeding according to intake of aspirin and NSAIDs. Over follow-up, there were 1687 reports of gastrointestinal bleeding requiring either a blood transfusion or hospitalization. The incidence of events per 1000 person-years was 0.77 among women who denied any aspirin use; 1.07 for 0.5 to 1.5 standard aspirin tablets per week; 1.07 for 2 to 5 aspirin per week; 1.40 for 6 to 14 aspirin per week; and 1.57 for more than 14 aspirin per week. Similarly, the incidence of events per 1000 person-years was 1.01 among women who denied any NSAID use; 0.99 for 0.5 to 1.5 NSAID tablets per week; 1.30 for 2 to 5 NSAID tablets per week; 1.71 for 6 to 14 NSAID tablets per week; and 1.91 for more than 14 NSAID tablets per week.
In our analyses, participants who died were censored at the date of their death. In a preliminary analysis, we also evaluated the relationship between aspirin use and death. Throughout follow-up, we confirmed 6974 deaths from any cause. The age-standardized incidence of death per 1000 person-years was 3.86 among women who denied any aspirin use; 2.70 for 0.5 to 1.5 standard aspirin tablets per week; 3.05 for 2 to 5 aspirin per week; 3.36 for 6 to 14 aspirin per week; and 4.20 for more than 14 aspirin per week.