Aspirin and the Risk of Colorectal Cancer in Women
Edward Giovannucci, M.D., Kathleen M. Egan, M.P.H., David J. Hunter, M.D., Meir J. Stampfer, M.D., Graham A. Colditz, M.D., Walter C. Willett, M.D., and Frank E. Speizer, M.D.
Background Most data suggest that the regular use of aspirinreduces the risk of colorectal cancer, but some apparently conflictingevidence exists. The effects of the dose and the duration ofaspirin consumption on the risk of colorectal cancer are notwell understood.
Methods We determined rates of colorectal cancer according tothe number of consecutive years of regular aspirin use (definedas two or more tablets per week) among women in the Nurses'Health Study who reported regular aspirin use on three consecutivequestionnaires (1980, 1982, and 1984) and compared the ratesin this group with the rates among women who said they did notuse aspirin. Cases of cancer occurring from 1984 through 1992(the eight years after the 1984 questionnaire) were included.
Results From 1984 through 1992, we documented 331 new casesof colorectal cancer during 551,651 person-years of follow-up.Women who consistently took two or more aspirin tablets perweek had no appreciable reduction in the risk of colorectalcancer as compared with nonusers after four years (relativerisk, 1.06; 95 percent confidence interval, 0.78 to 1.45) orafter five to nine years (relative risk, 0.84; 95 percent confidenceinterval, 0.55 to 1.28). There was a slight reduction in riskamong women who took aspirin for 10 to 19 years, but it wasnot statistically significant (relative risk, 0.70; 95 percentconfidence interval, 0.41 to 1.20). However, there was a statisticallysignificant reduction after 20 years of consistent use of aspirin(relative risk, 0.56; 95 percent confidence interval, 0.36 to0.90; P for trend = 0.008). The maximal reduction in risk wasobserved among women who took four to six tablets per week;higher doses had a similar apparent benefit. Controlling forrisk factors for colorectal cancer, including diet, did notchange the results, and the earlier diagnosis and removal ofcolorectal adenomas among aspirin users did not account forthe results.
Conclusions Regular aspirin use, at doses similar to those recommendedfor the prevention of cardiovascular disease, substantiallyreduces the risk of colorectal cancer. However, this benefitmay not be evident until after at least a decade of regularaspirin consumption.
Substantial evidence suggests that the regular use of aspirinand other nonsteroidal antiinflammatory agents (NSAIDs) reducesthe risk of colorectal cancer. Case–control studies haveconsistently found an inverse association between the use ofaspirin and the occurrence of colorectal cancer,1,2,3,4,5 andthree prospective studies have found a lower risk of colorectalcancer6,7 and lower mortality from the disease8,9 among aspirinusers. Patients with rheumatoid arthritis who regularly takeaspirin and other NSAIDs have a reduced incidence of gastrointestinaltumors, primarily of the stomach and large bowel,10,11,12 andsulfasalazine, an antiinflammatory salicylate, may reduce therisk of colorectal cancer among patients with ulcerative colitis.13Regular aspirin use is also associated with a lower than averagerisk of sporadic colorectal adenomas,5,7,14,15 the precursorsof most nonfamilial cancers.16 Moreover, sulindac, another antiinflammatorydrug, causes the regression of polyps in patients with familialadenomatous polyposis.17 In rodent models, aspirin18,19 andother cyclooxygenase inhibitors such as indomethacin,20,21 piroxicam,22,23and sulindac24 inhibit carcinogenesis in the colon.
One cohort study found no association between aspirin and theincidence of colorectal cancer, however,25 and in an interventiontrial using low-dose aspirin (one tablet on alternate days)there was no reduction in the number of cases of colorectalcancer during the first six years of follow-up.26 The latterresult could mean that an effect on colorectal cancer requiresmore than six years of regular aspirin consumption or a higherdose of aspirin, or that a causal association does not exist.To help resolve these issues, we undertook an analysis of therelation between the use of aspirin and the risk of colorectalcancer in a large cohort of women enrolled in the Nurses' HealthStudy.
Methods
The Nurses' Health Study
The Nurses' Health Study cohort was established in 1976, when121,701 U.S. female registered nurses between 30 and 55 yearsof age returned a mailed questionnaire that elicited informationabout known or suspected risk factors for breast cancer andcardiovascular disease.27 Every two years since then, we havemailed follow-up questionnaires to these women to update informationon risk factors and major medical events. In 1980, the questionnairewas expanded to include an assessment of diet and patterns ofuse of aspirin and other NSAIDs. In total, 89,446 Nurses' HealthStudy participants completed the sections on medication usein 1980; had no previous diagnosis of cancer (excluding nonmelanomaskin cancer), familial polyposis syndrome, or ulcerative colitis;and completed a food-frequency questionnaire in 1980.
Identification of Cases of Colorectal Cancer and Adenomas
The identification of cases of colorectal cancer has been describedpreviously in detail.28 Briefly, follow-up questionnaires weremailed to all participants in 1982, 1984, 1986, 1988, 1990,and 1992. We attempted to contact nonrespondents through repeatedmailings, including the use of certified mail, and by telephone.Among the 89,446 women, the follow-up rate was 96 percent ofthe total possible person-years through 1992. Deaths in thecohort were identified on the basis of reports from family membersor the Postal Service and by a search of the National DeathIndex; we estimate that we have identified over 98 percent ofthe deaths in this cohort through these sources.29
When a subject (or her next of kin, in the case of participantswho had died) reported a diagnosis of cancer of the colon orrectum on a follow-up questionnaire, we asked for permissionto obtain hospital records and pathology reports related tothis diagnosis. A study physician blinded to the subjects' exposurestatus reviewed the medical records to extract information onthe histologic type, anatomical location, and stage of the cancer.We included only cases of adenocarcinoma and excluded carcinomain situ from this analysis. We documented 501 cases of colorectalcancer from June 1, 1980, to May 31, 1992.
We identified cases of adenoma, as reported previously,30 usingmethods similar to those described above for cancers. Between1980 and 1990, we confirmed through histopathological reports564 cases of adenomatous polyp of the distal colon or rectum(371 colonic and 193 rectal) in the subjects. We obtained informationon the size of adenomas from the endoscopy reports (the preferredsource) or pathology reports for 479 of the 564 cases.
Assessment of Aspirin Use
The women provided information about regular aspirin use in1980, 1982, 1984, and 1988. The 1980 questionnaire asked whetherthe respondents currently took "any of the following vitaminsor medications in most weeks," and listed "aspirin (includesBufferin, Anacin, etc.)" and "other nonsteroidal analgesics(Motrin, Indocin, Tolectin, Clinoril)," among other drugs. Ifthe answer was yes, the participant was asked to record thenumber of pills or capsules taken each week and the number ofyears she had used the medication. In 1982, the question wasphrased, "Are you currently taking any of the following medicationsat least once per week?" If the answer was yes for aspirin,the respondent was then asked how many aspirin tablets or capsulesshe took per week (1 to 3, 4 to 6, 7 to 14, or 15 or more).In 1984 and 1988, we inquired about the average number of dayseach month when aspirin was taken (none, 1 to 4, 5 to 14, 15to 21, or 22 or more) and the number of aspirin tablets usuallytaken on those days (1, 2, 3 to 4, 5 to 6, or 7 or more). Aspirinuse was evaluated in terms of the usual number of pills takenper week. Some regrouping of responses was required to adjustfor the differing ways in which aspirin-use habits were recordedfrom 1980 through 1988. Women who reported taking fewer thantwo aspirin tablets per week were defined as non-regular users.
Regular aspirin use, defined as the consumption of two or moreaspirin tablets per week, was highly prevalent in this cohort;between 41 and 65 percent of the women reported regular aspirinuse in the biennial questionnaires. Among women who returnedall four questionnaires, 15 percent reported regular aspirinuse in each questionnaire, and 15 percent consistently reportedno aspirin use over the eight-year period.
The reasons for aspirin use were not assessed for the entirecohort, but a questionnaire was sent in 1990 to a sample of100 women who reported taking one to six aspirin per week (90percent response) and 100 women who reported taking seven ormore aspirin per week (92 percent response) on the 1980, 1982,or 1984 questionnaire.31 The major reasons for use among womentaking one to six aspirin and seven or more aspirin per weekwere headache (32 percent and 18 percent, respectively), arthritisor other musculoskeletal pain (30 percent and 50 percent), acombination of headache and musculoskeletal pain (16 percentand 15 percent), the primary prevention of cardiovascular disease(9 percent and 8 percent), and other reasons or "could not recall"(13 percent and 9 percent).
Statistical Analysis
The cohort of 89,446 women contributed person-time from themonth of their return of the 1980 questionnaire to the monthof diagnosis of colorectal cancer, the month of death from othercauses, or the end of the study period (May 31, 1992). We computedrates of incidence by dividing the number of new cases of colorectalcancer by the number of person-years in that aspirin-use categoryand computed the relative risk by dividing this incidence rateby that of nonusers. We used the Mantel–Haenszel summaryestimator and proportional-hazards modeling to adjust for age(in five-year categories) and potentially confounding variablesand to calculate 95 percent confidence intervals. All reportedP values are two-tailed.
We first examined the association between aspirin use in 1980and the occurrence of newly diagnosed colorectal cancer up to1992. Reported regular use of aspirin on any given questionnairerepresented a mixture of short-term and long-term users. Thus,to assess long-term, consistent use more accurately, we focusedour analyses on women who reported aspirin use on the 1980,1982, and 1984 questionnaires and their subsequent risk of colorectalcancer from 1984 to 1992. From 1984 to 1992, we documented 331new cases of colorectal cancer during 551,651 person-years.
We further evaluated relative risk according to the number ofyears of regular use (1 to 4, 5 to 9, 10 to 19, or >20 years),updating this variable every 2 years. For example, if a womanbegan using aspirin in 1982 and continued aspirin use in 1984and 1986, she was considered a user of one to four years' durationin 1984 and 1985, and of five to nine years' duration in 1986and 1987. The reported duration of use at base line was usedto evaluate previous long-term use. For example, a woman whoreported regular use of 7 years' duration in 1980 and who continuedto report aspirin use in 1982 and 1984 was assumed to have usedaspirin for 12 years in 1985. We also conducted analyses todetermine whether a higher rate of removal of co-lorectal adenomasamong aspirin users could account for a lower risk of cancer,if any. Because of the small number of women who used NSAIDs,the study had insufficient power to examine NSAIDs separately.
Results
We initially explored the characteristics of women who wereregular users of aspirin, defined as those taking two or moreaspirin tablets per week, in 1980. The women who took aspirinregularly were approximately equivalent to the nonusers in age(46.7 and 46.5 years, respectively); body-mass index, definedas the weight in kilograms divided by the square of the heightin meters (24.6 vs. 24.1); and the proportions of current smokers(30 percent vs. 28 percent) and former smokers (28 percent vs.27 percent) in the group. Consumption of alcoholic beverageswas somewhat higher among aspirin users (7.1 vs. 6.3 g per day).The dietary intake of animal fat was identical in the two groups(52.3 g per day) and that of dietary fiber was very similar(16.5 vs. 16.9 g per day). The intake of other major nutrientswas similar among users and nonusers of aspirin. Thus, for awide range of characteristics, the two groups had only minordifferences.
During 12 years of follow-up, we observed a slightly but notsignificantly lower risk of colorectal cancer among users ofaspirin than among those who did not use aspirin in 1980 (multivariaterelative risk, 0.86; 95 percent confidence interval, 0.71 to1.04; P = 0.12). The inverse association between the use ofaspirin and the risk of colorectal cancer became stronger asaspirin use was reported on subsequent questionnaires (Table 1).Women who reported on three consecutive questionnaires thatthey took aspirin had a 38 percent lower risk than women whowere not using aspirin regularly. Controlling for a family historyof colorectal cancer, the number of pack-years of smoking morethan 35 years in the past28 (divided into four categories),body-mass index (in quintiles), physical-activity level (inquintiles), alcohol consumption (in five categories), and quintilesfor the dietary intake of red meat, methionine, folate, fiber,calcium, and vitamin D had virtually no effect on the relativerisks and confidence intervals (Table 1). Among women who reportedconsistent use of aspirin from 1980 to 1984, the relative riskof colorectal cancer was 0.72 in 1985 and 1986, 0.62 in 1987and 1988, 0.61 in 1989 and 1990, and 0.55 in 1991 and 1992.A significant inverse association was evident at a level offour to six aspirin per week (Figure 1), but no further trendwas seen for doses above three aspirin tablets per week (relativerisk, 0.99 for each additional aspirin per week above three;95 percent confidence interval, 0.96 to 1.01; P for trend =0.35).
Figure 1. Multivariate Relative Risks of Colorectal Cancer and 95 Percent Confidence Intervals According to the Level of Aspirin Use among Women Who Used Aspirin from 1980 through 1984, as Compared with Nonusers.
Relative risks have been adjusted for age, family history of colorectal cancer, pack-years of smoking more than 35 years in the past, body-mass index, physical-activity level, and dietary intake of animal fat, dietary fiber, folate, methionine, alcohol, red meat, vitamin D, and calcium in 1980.
We found little reduction in the risk of colorectal cancer duringthe first 9 years of regular aspirin use, as compared with therisk among nonusers (relative risk, 0.97; 95 percent confidenceinterval, 0.74 to 1.27), but for 10 or more years of use therelative risk was 0.63 (95 percent confidence interval, 0.42to 0.94). There was a clear reduction in risk among women whohad used aspirin regularly for at least 20 years (Figure 2).Among women who had used aspirin for 10 to 19 years, we sawa slight reduction in risk, but this effect was not statisticallysignificant. The reduction in risk was similar for cancer ofthe colon and cancer of the rectum and for colorectal cancersthat were metastatic at the time of diagnosis (Table 2). Basedon a small number of cases, a similar association with 20 ormore years of aspirin use was noted for colorectal cancers thatwere fatal within the follow-up period (relative risk, 0.59;95 percent confidence interval, 0.24 to 1.46).
Figure 2. Age-Adjusted Relative Risks of Colorectal Cancer and 95 Percent Confidence Intervals According to the Number of Consecutive Years of Regular Aspirin Use among Users as Compared with Nonusers of Aspirin.
P for trend over time = 0.008. Regular aspirin use was defined as the consumption of two or more tablets per week.
Table 2. Relative Risk of Colorectal Cancer in 1984 through 1992, According to Number of Consecutive Years of Regular Aspirin Use.
We examined whether a difference in the frequency of endoscopicexamination between users and nonusers of aspirin, which couldhave made a difference in the rate of removal of premalignantadenomas, accounted for our results. Only a small percentageof the women had undergone endoscopy before the study began(Table 3). During the study, endoscopy performed because ofthe presence of overt or occult fecal blood or for other reasons,including screening, was more frequent among women who tookaspirin than among those who did not. However, among women whounderwent endoscopy because of fecal blood, adenomas 1 cm ormore in diameter were found in 3.2 percent of those who tookmore than 14 aspirin a week and in 4.0 percent of nonusers (age-standardizedpercentages). Thus, despite a slightly higher rate of endoscopy,women who took aspirin had fewer large adenomas (0.38 percentof all aspirin users vs. 0.40 percent of nonusers).
Table 3. Frequency of Endoscopy and Detection of Adenomas According to the Level of Aspirin Use as Reported in 1980.
Discussion
We found a decreased risk of colorectal cancer among women whotook aspirin for 10 or more consecutive years. The full reductionin risk was seen at a level of four to six tablets per week,and higher doses had a similar apparent effect; however, ourconclusion about the relation between the dose of aspirin andthe reduction in risk is based on relatively few cases and requiresconfirmation. Controlling for diet, alcohol intake, smoking,body-mass index, physical-activity level, and family historyof colorectal cancer did not alter the results. This study waslimited to women, but previous reports1,2,3,4,5,6,7,8,9,10,11,12,13,14,15indicate a similar benefit in men.
Did methodologic biases influence our findings? Women who regularlytook aspirin were more likely to have undergone endoscopy thanwomen who took no aspirin, partly because they more often hadevidence of occult or overt fecal blood. Bleeding from tumorscould have increased the rate of detection of asymptomatic canceramong users of aspirin, thereby causing us to underestimatethe protective influence of aspirin. Earlier detection of colorectalcancer may also reduce mortality, which can be an additionalbenefit of aspirin. And gastrointestinal bleeding due to aspirincould increase the rate of detection of premalignant adenomatouspolyps, whose removal could in turn reduce the incidence ofcancer. However, in our study fewer adenomas were removed fromthe women who used aspirin. It is thus unlikely that aspirin-inducedgastrointestinal bleeding was responsible for the lower riskof colorectal cancer.
Women with undiagnosed cancer or polyps may have had one ormore episodes of gastrointestinal bleeding before 1980, leadingthem to avoid aspirin. If so, proportionally fewer women whoused aspirin in 1980 may have had undetected premalignant ormalignant lesions, producing a spurious inverse associationbetween aspirin use and cancer. However, such a source of biasis implausible because the greatest decrease in rates of colorectalcancer among aspirin users appeared only after 10 or more yearsof use. Even so, a bleeding premalignant adenoma could precedecancer by 10 or more years. Thus, we have to consider the possibilitythat the lower prevalence of adenomas among regular aspirinusers was an artifact of the cessation of aspirin use by womenwho had bleeding adenomas. However, the vast majority of peoplewho discontinue taking aspirin do so because of abdominal discomfortand upper gastrointestinal bleeding, rather than bleeding fromadenomas, which is rare.32,33 Moreover, among women who underwentendoscopy for reasons related to fecal blood, aspirin userswere in fact less likely to have large adenomas than nonusersof aspirin (Table 3).
Various mechanisms that might explain the effect of aspirinon colorectal cancer have been discussed in detail by Marnett,34though none are established. Aspirin is a potent, irreversibleinhibitor of cyclooxygenase, an enzyme necessary for the synthesisof prostaglandins, eicosanoids that may influence tumor growth.Aspirin has also been shown to inhibit phospholipase activity,35which is important in various aspects of intracellular signaling.36
Participants in a recent interdisciplinary research workshopsponsored by the American Cancer Society concluded that thecombined evidence from different research disciplines stronglysupports the view that aspirin reduces the incidence of colorectalcancer.37 Because of the competing risks and benefits of aspirinwith respect to cardiovascular disease and gastrointestinalirritation and bleeding,37,38 we need to understand better thedose and duration of aspirin use required for effective prophylaxisbefore firm recommendations are made. Unfortunately, the performanceof clinical trials with colorectal cancer as the end point ishindered by high costs, the requirement that studies last manyyears, and ethical concerns related to the proved cardiovascularbenefit of aspirin.39 For these reasons, the conference participantsrecommended that intervention trials focus on colorectal adenomas.
Randomized interventional trials of the effect of aspirin onthe rate of recurrence of adenomas would be useful in establishingcausality, but they would not provide data on dose–responserelations and the duration of therapy that would be directlyrelevant to the prevention of cancer. Observational studieshave generally not been designed specifically to obtain informationabout the amount and duration of aspirin treatment. Our analysissuggests that four to six aspirin tablets per week — dosesthat may prevent cardiovascular disease — can substantiallylower the risk of large-bowel cancer. Whether the very low doses(for example, 80 mg per day) that are probably efficacious inpreventing cardiovascular disease are also sufficient for thechemoprevention of colorectal cancer is unclear, but preliminaryevidence40 suggests that 80 mg of aspirin given once a day cansignificantly modulate rectal epithelial levels of prostaglandinE2 and prostaglandin F2. Whether this alteration is associatedwith a reduction in risk remains unknown.
Our results provide direct evidence that the risk of colorectalcancer is reduced only after 10 or more years of aspirin use;these findings may thus explain why a randomized interventionaltrial26 of aspirin did not detect any effect on the risk ofcolorectal cancer during 6 years of follow-up. The epidemiologicfindings, the unequivocal effect of NSAIDs in causing the regressionof small adenomas related to familial polyposis,17 and the periodof 10 years or more generally required for a small adenoma tobecome malignant41 indicate that aspirin may influence onlythe small-adenoma stage of colonic carcinogenesis. An earlyinfluence of aspirin is also supported by some data on animals18,42though not all.19 The potential regular use of aspirin at moderatedoses as a means to prevent colorectal cancer certainly requiresfurther evaluation, particularly since aspirin may be effectiveat the same low doses recommended for the prevention of cardiovasculardisease.
Supported by research grants (CA 40356 and CA 55075) from theNational Cancer Institute and in part by Faculty Research Awards(FRA-398 and FRA-455) from the American Cancer Society (to Dr.Colditz and Dr. Hunter).
We are indebted to Karen Corsano, Barbara Egan, Lori Ward, andJill Arnold for their expert help.
Source Information
From the Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital (E.G., D.J.H., M.J.S., G.A.C., W.C.W., F.E.S.), and the Departments of Epidemiology (K.M.E., D.J.H., M.J.S., G.A.C., W.C.W.) and Nutrition (E.G., M.J.S., W.C.W.), Harvard School of Public Health — all in Boston.
Address reprint requests to Dr. Giovannucci at the Channing Laboratory, 180 Longwood Ave., Boston, MA 02115.
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Aspirin and the Risk of Colorectal Cancer in Women
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Extract |
Full Text
N Engl J Med 1996;
334:119-122, Jan 11, 1996.
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. Whether this alteration is associated with a reduction in risk remains unknown. 
