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Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and
Risk of Colorectal Cancer. JAMA. 2005;294(8):914–923. doi:10.1001/jama.294.8.914
Author Affiliations: Gastrointestinal Unit,
Massachusetts General Hospital and Harvard Medical School (Dr Chan), Channing
Laboratory, Department of Medicine, Brigham and Women’s Hospital and
Harvard Medical School (Drs Chan, Giovannucci, Schernhammer, Curhan, and Fuchs),
Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center (Drs Giovannucci,
Meyerhardt, and Fuchs), Departments of Epidemiology (Drs Giovannucci and Curhan)
and Nutrition (Dr Giovannucci), Harvard School of Public Health, and Department
of Medical Oncology, Dana-Farber Cancer Institute (Drs Meyerhardt and Fuchs),
Context Randomized trials of short-term aspirin use for prevention of recurrent
colorectal adenoma have provided compelling evidence of a causal relationship
between aspirin and colorectal neoplasia. However, data on long-term risk
of colorectal cancer according to dose, timing, or duration of therapy with
aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) remain limited.
Objective To examine the influence of aspirin and NSAIDs in prevention of colorectal
Design, Setting, and Participants Prospective cohort study of 82 911 women enrolled in the Nurses’
Health Study providing data on medication use biennially since 1980 and followed
up through June 1, 2000.
Main Outcome Measure Incident colorectal cancer.
Results Over a 20-year period, we documented 962 cases of colorectal cancer.
Among women who regularly used aspirin (≥2 standard [325-mg] tablets per
week), the multivariate relative risk (RR) for colorectal cancer was 0.77
(95% confidence interval [CI], 0.67-0.88) compared with nonregular users.
However, significant risk reduction was not observed until more than 10 years
of use (P≤.001 for trend). The benefit appeared
related to dose: compared with women who reported no use, the multivariate
RRs for cancer were 1.10 (95% CI, 0.92-1.31) for women who used 0.5 to 1.5
standard aspirin tablets per week, 0.89 (95% CI, 0.73-1.10) for 2 to 5 aspirin
per week, 0.78 (95% CI, 0.62-0.97) for 6 to 14 aspirin per week, and 0.68
(95% CI, 0.49-0.95) for more than 14 aspirin per week (P<.001 for trend). Notably, women who used more than 14 aspirin
per week for longer than 10 years in the past had a multivariate RR for cancer
of 0.47 (95% CI, 0.31-0.71). A similar dose-response relationship was found
for nonaspirin NSAIDs (P = .007 for trend).
The incidence of reported major gastrointestinal bleeding events per 1000
person-years also appeared to be dose-related: 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.
Conclusions Regular, long-term aspirin use reduces risk of colorectal cancer. Nonaspirin
NSAIDs appear to have a similar effect. However, a significant benefit of
aspirin is not apparent until more than a decade of use, with maximal risk
reduction at doses greater than 14 tablets per week. These results suggest
that optimal chemoprevention for colorectal cancer requires long-term use
of aspirin doses substantially higher than those recommended for prevention
of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding
must also be considered.
Recent randomized intervention trials have demonstrated that regular
use of aspirin in patients with a history of colorectal adenoma or cancer
reduces the risk of recurrent adenoma within 1 to 3 years.1-3 However,
whether aspirin similarly reduces risk of colorectal cancer and, if so, the
necessary dose and duration of use, remain unclear. Although short-term aspirin
use appears effective in reducing risk of adenoma, 2 randomized trials of
aspirin that have specifically examined colorectal cancer as an outcome did
not demonstrate a benefit after 5 or 10 years.4,5 Moreover,
intervention trials of adenoma or cancer have provided only limited and conflicting
data on the optimal dose of aspirin.1-5 Finally,
it remains uncertain whether nonaspirin nonsteroidal anti-inflammatory drugs
(NSAIDs), which share several underlying mechanisms with aspirin, exert a
similar antineoplastic benefit.
Thus, we prospectively examined the influence of aspirin and NSAIDs
on the risk of colorectal cancer in a large cohort of women enrolled in the
Nurses’ Health Study. This cohort, which provides detailed and updated
information on aspirin use, permitted a more comprehensive examination of
the effect of long-term aspirin use at a wide range of doses on the primary
prevention of sporadic colorectal cancer than would be feasible in a placebo-controlled
trial. An earlier examination of aspirin use and colorectal cancer in this
cohort did not observe a strong dose relationship; however, that analysis
was limited by the number of overall cases (n = 331), short follow-up
(8 years), and few participants in the higher-dose categories.6 In
the present study, we offer results that encompass 20 years of follow-up and
962 documented cases of colorectal cancer.
The Nurses’ Health Study was established in 1976, when 121 701
US female registered nurses aged 30 to 55 years completed a mailed questionnaire.
With a follow-up rate exceeding 90%, every 2 years we have mailed questionnaires
to update information and identify newly diagnosed cases of cancer. In 1980,
the questionnaire was expanded to include a validated assessment of diet and
patterns of aspirin and NSAID use.7 In 1992,
to assess the racial/ethnic composition of the cohort, we asked participants
to self-classify their race using investigator-defined classification options.
The institutional review board at the Brigham and Women’s Hospital,
Boston, Mass, approved this study; completion of the questionnaire was considered
to imply informed consent.
Since 1980, we assessed intake of aspirin biennially except in 1986.
In 1980, we asked women if they used “any of the following vitamins
or medicines in most weeks,” and listed “aspirin (includes Bufferin,
Anacin, etc)” and “other nonsteroidal analgesics (Motrin, Indocin,
Tolectin, Clinoril).” For each medication, participants were asked to
record the number of pills or capsules taken each week and the number of years
of use. In 1982, we inquired if they currently took aspirin at least once
a week and, if so, how many aspirin tablets per week (1-3, 4-6, 7-14, or ≥15).
In 1984 and 1988, we queried the average number of days per month of aspirin
use (none, 1-4, 5-14, 15-21, or ≥22) and the number of aspirin tablets
usually taken (1, 2, 3-4, 5-6, or ≥7). In 1990 and 1992, we asked women
about the number of days per month of use (none, 1-4, 5-14, 15-21, or ≥22)
in separate questions for aspirin, “other anti-inflammatory drugs (eg,
Ibuprofen, Naprosyn, Advil),” and “acetaminophen (eg, Tylenol).”
Although we did not query the number of tablets used per day in 1990 and 1992,
we sent a detailed supplementary questionnaire of current and lifetime analgesic
use to 4238 participants (91% response) in 1999. The median number of aspirin
tablets typically consumed was 1 standard (325-mg) tablet per day and the
median number of NSAID or acetaminophen tablets was 2 per day.8
In 1994 and 1996, we asked women about the frequency of aspirin use
(<1 day per month, 1-3 days per month, 1-2 days per week, 3-4 days per
week, 5-6 days per week, or daily), the number of aspirin tablets per week
(0, 0.5-2, 3-5, 6-14, or ≥15), if they used acetaminophen “≥2
times per week (eg, Tylenol)” and if they used other anti-inflammatory
medications “(eg, Advil, Motrin, Indocin).” In 1998, we asked
women on average how frequently they took aspirin (0 days per month, 1-3 days
per month, 1-2 days per week, 3-4 days per week, 5-6 days per week, or daily)
and how many aspirin tablets were taken per week (0, 0.5-2, 3-5, 6-14, or
≥15). Women were also asked, in separate questions, if they regularly used
acetaminophen “(eg, Tylenol),” or an NSAID “(eg, Advil,
Motrin, Indocin),” the days used per week (1, 2-3, 4-5, or ≥6 days),
and the tablets taken per week (1-2, 3-5, 6-14, or ≥15).
Early in the study, most women used standard-dose aspirin tablets of
325 mg8; however, to reflect overall secular
trends in consumption of low-dose (baby) aspirin, questionnaires after 1992
asked participants to convert intake of 4 baby aspirin to 1 adult standard-dose
tablet. As previously described, some regrouping of responses was required
to adjust for the differing ways in which aspirin-use habits were recorded.6,9 Cyclooxygenase 2 (COX-2) inhibitors
were not introduced in the United States until 1999; hence, we did not collect
information on their use in the present study. In 2004, we also asked participants
to report any major episodes of gastrointestinal bleeding that required either
hospitalization or a blood transfusion, and when they occurred. For the present
analysis, we included episodes of gastrointestinal bleeding through June 1,
2000. We did not specifically inquire about minor episodes of gastrointestinal
Reasons for aspirin use were not assessed for the entire cohort, but
a questionnaire was sent in 1990 to a sample of 100 women who reported taking
1 to 6 aspirin per week (90% response) and 100 women who reported taking 7
or more aspirin per week (92% response) on the 1980, 1982, or 1984 questionnaire.
The major reasons for use among women taking 1 to 6 aspirin and 7 or more
aspirin per week, respectively, were headache (32% and 18%, respectively),
arthritis and other musculoskeletal pain (30% and 50%), a combination of headache
and musculoskeletal pain (16% and 15%), cardiovascular disease prevention
(9% and 8%), and other reasons (13% and 9%).10
We requested written permission to acquire medical records and pathology
reports from women who reported colorectal cancer on our biennial questionnaires.
We identified deaths through the National Death Index and next of kin.11 For all deaths attributable to colorectal cancer,
we requested permission from next of kin to review medical records. A study
physician, blinded to exposure information, reviewed records to extract information
on histological type and anatomic location of the cancer.
Proximal colon cancers were defined as those from the cecum to and including
the splenic flexure; distal colon cancers were defined as those in the descending
and sigmoid colon. Rectal cancers were defined as those in the rectosigmoid
or rectum. We classified stage of cancer according to the sixth edition of
the American Joint Committee on Cancer’s cancer staging handbook.12 According to stage, the distribution of cases and
5-year overall survival were 21% and 92%, respectively, for stage I, 24% and
85% for stage II, 25% and 63% for stage III, 19% and 7% for stage IV, and
11% and 50% for cases of unknown stage. As a validation of our staging procedures,
we found our distribution of cases and survival rates to be comparable with
the National Cancer Data Base13 and the Surveillance,
Epidemiology, and End Results database, respectively.14
At baseline, we excluded women who did not complete the dietary questionnaire
or medication questions, recorded implausible dietary or aspirin data (eg,
responded “yes” to use but then recorded zero aspirin tablets
per week), or reported a history of cancer (except nonmelanoma skin cancer),
inflammatory bowel disease, a familial polyposis syndrome, or hereditary nonpolyposis
colorectal cancer. After these exclusions, 82 911 women were eligible
for analysis and accrued follow-up time beginning on the month of return of
the baseline 1980 questionnaire and ending on the month of diagnosis of colorectal
cancer, month of death from other causes, or June 1, 2000, whichever came
As previously described,15 to reduce
within-person variation and to better estimate long-term intake, we used the
cumulative average intake of aspirin as reported on all available questionnaires
up to the start of each 2-year follow-up interval. Consistent with previous
analyses of this cohort, women who reported taking 2 or more standard aspirin
tablets per week were defined as regular users, whereas those who reported
less aspirin use were defined as nonregular users.6,9 Based
on our prior analyses, we also examined duration of aspirin use by the number
of years of use reported in 1980 with updating of this variable every 2 years6,9 and estimated long-term, consistent
use more accurately by restricting some analyses to women who reported regular
aspirin use on consecutive biennial questionnaires and comparing their incidence
with that of women who were nonusers on consecutive questionnaires. We also
grouped women according to previously described categories of number of tablets
used per week to estimate dosage of aspirin.16
We calculated incidence rates of colorectal cancer for women in a specific
category of aspirin use by dividing the number of incident cases by the number
of person-years. We computed relative risks (RRs) by dividing the incidence
rate of disease in one category divided by the incidence rate in the reference
category. We used Cox proportional hazards modeling to control for multiple
variables simultaneously and to compute 95% confidence intervals (CIs). We
used the most updated information for all covariates prior to each 2-year
interval. We used SAS, version 8.2 (SAS Institute Inc, Cary, NC) for all analyses.
All P values are 2-sided, and P<.05 was considered statistically significant.
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 (Table 1).
We observed a significantly lower risk of colorectal cancer among regular
aspirin users (≥2 standard aspirin tablets per week) compared with nonregular
users (multivariate RR, 0.77; 95% CI, 0.67-0.88), even after controlling for
other known or suspected risk factors (Table 2). 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).
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 (Table 3).
The inverse association between aspirin and colorectal cancer risk became
stronger as aspirin use was reported on subsequent questionnaires.
We also assessed the effect of duration of regular aspirin use on colorectal
cancer risk (Table 4). 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).
The apparent benefit associated with aspirin use was substantially greater
with increasing dose (Table 5). 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 nonsignificant, 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).
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 (Table 5).
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
(Table 6). 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).
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
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.
Long-term, regular aspirin use (≥2 standard tablets per week) was
associated with a significant reduction in the risk of colorectal cancer in
an average-risk population. Notably, the greatest reduction in risk was observed
at cumulative doses of more than 14 standard tablets per week and a statistically
significant benefit was not evident until use was sustained for more than
10 years. Regular use of nonaspirin NSAIDs was also associated with comparable
risk reduction, with a similar dose-response relationship. Although our study
was limited to women, previous reports have also demonstrated a protective
effect for aspirin in men.19 The magnitude
of the potential risk reduction is within the range demonstrated in trials
of aspirin, calcium, and postmenopausal hormones in the prevention of adenoma
Results from 3 intervention trials of patients with prior colorectal
adenoma or cancer have demonstrated a benefit to aspirin use on the subsequent
risk of adenoma.1-3 Although
these studies have established causality, they were only able to examine limited
doses over short-term follow-up and yielded conflicting results. One trial
demonstrated that both 160 mg and 300 mg of soluble aspirin daily was effective3; a second trial, which examined only 1 dose, showed
that standard-dose aspirin reduced risk2; on
the other hand, a third trial did not observe any reduction in adenoma recurrence
in a group randomized to receive standard-dose aspirin but did observe a moderate
benefit in a group randomized to receive low-dose aspirin.1
Several lines of evidence support our findings that the anticancer benefit
of aspirin is highly dose-dependent. First, although 81 mg of aspirin daily
may be sufficient to inhibit colonic prostaglandins,21 higher
doses are needed to inhibit the COX-2 isoenzyme,22 which
appears to be directly relevant to colorectal neoplasia.23 Second,
experimental data suggest that aspirin may also work through non-COX mechanisms
that are maximized at higher doses.24-29 Finally,
a randomized trial of the COX-2 inhibitor celecoxib demonstrated that high
but not standard doses significantly reduced adenoma burden in patients with
familial polyposis,30 and a prior prospective
study in this cohort demonstrated that the strongest reduction in risk of
sporadic adenoma was also with more than 14 aspirin tablets per week.9 Other epidemiological studies have found consistent
dose relationships for both adenoma31-34 and
Our findings might appear to conflict with the recent observations from
the Women’s Health Study, a large placebo-controlled trial of low-dose
aspirin use with an average follow-up of 10 years. In this trial, participants
randomized to receive aspirin at a dose of 100 mg every other day experienced
no reduction in risk of colorectal cancer. However, in our cohort, a similar
low dose of aspirin also had no effect on the risk of colorectal cancer (multivariate
RR, 1.10; 95% CI, 0.92-1.31), although higher doses did confer progressively
greater reductions in cancer risk. Thus, in both our study and the Women’s
Health Study, aspirin at a dose equivalent to 50 mg/d appears to be inadequate
for prevention of colorectal cancer.5
Although short-term use of aspirin appears to reduce risk of adenoma,1-3,9 our present
study suggests that a statistically significant benefit against cancer is
evident only after a decade of use, consistent with other studies.6,39,40 Moreover, we also
show that the most relevant period of use is greater than 10 years in the
past. Taken together, these data are consistent with our present understanding
of the latency underlying the adenoma-carcinoma pathway and suggest that aspirin
may have a greater influence on tumor initiation rather than progression.
The short-term follow-up in the adenoma recurrence trials permitted
only an assessment of adenoma as a surrogate end point for cancer. However,
most adenomas do not progress to cancers,41 and
a previous randomized trial of aspirin examining colorectal cancer as an end
point, the Physicians’ Health Study, had null results.4 However,
our data suggest that the low dose (325 mg every other day) and short (5-year)
duration of randomized aspirin treatment in the Physicians’ Health Study
was insufficient to influence cancer risk.
Our study suggests that nonaspirin NSAIDs also reduce risk of colorectal
cancer in a dose-dependent manner. Other studies generally support our results,
although they have been limited by their retrospective design,42-47 did
not separately analyze aspirin and nonaspirin NSAIDs,40,44,47,48 or
relied primarily on prescription data with limited information on potentially
confounding risk factors.31,35,37,38,40,48-50
Although we observed that regular aspirin use was not associated with
substantially reduced risk of advanced (stage III or IV) cancers, there was
a suggestion that higher doses may be more effective. Previous prospective
studies have had limited ability to evaluate cancer risk according to contemporary
staging criteria.6,19,51 Although
our findings may be related to the latency of neoplasia and/or a delay in
diagnosis in cases of advanced cancer, it is possible that advanced tumors
represent a more aggressive form of the disease requiring higher aspirin doses.
In support of this hypothesis, we observed that participants with tumors with
high-grade histology, which correlates independently with poorer survival,14 may also require higher doses of aspirin to achieve
comparable benefit. Similarly, advanced tumors may express progressively greater
levels of COX-2,52 which is associated with
a more invasive phenotype that is reversible with NSAIDs in a dose-dependent
fashion.53 Notably, we also did not observe
a significant risk reduction with aspirin for rectal cancer. However, these
findings should be interpreted with caution given the limited number of cases
of rectal cancer. Further investigation is required to evaluate a range of
tumor characteristics, including tumor site and molecular markers, which may
influence differential response to chemopreventive agents.
Although previous studies have demonstrated an inverse relationship
between aspirin and colorectal cancer,6,19,31,36-40,43-48,51,54-57 the
present study differs in several important ways. First, because we collected
detailed, updated information on aspirin during 20 years of follow-up, we
were able to evaluate long-term use across a broad range of intake. Second,
we were able to estimate several distinct measures of aspirin use, including
dose, duration, consistency, and timing of use. Thus, our findings are less
prone to internal confounding because of correlations between these parameters
(eg, use at higher doses may reflect more consistent use). Third, we obtained
aspirin data prospectively, prior to diagnosis. Thus, any errors in recall
would have tended to attenuate rather than exaggerate true associations, and
biases related to incomplete data collection from participants with fatal
diagnoses were minimized. Fourth, since participants were all nurses, the
accuracy of self-reported aspirin use is likely to be high and more likely
to reflect actual consumption of these largely over-the-counter medications.
Fifth, we also collected detailed data on potential confounders and had a
high follow-up response rate. Finally, we were able to individually examine
aspirin and nonaspirin NSAIDs.
Several limitations of our study deserve comment. Our study was observational
and aspirin and NSAID use was self-selected. However, these agents were primarily
used for analgesia, particularly in the high-dose categories, and the effect
of acetaminophen, an analgesic used for similar maladies, but with a distinct
mechanism of action, was null for colorectal cancer. Moreover, adjustment
for a wide range of potential factors had minimal influence on our findings,
suggesting little potential for residual or uncontrolled confounding. Finally,
our findings have strong biological plausibility, and causality for the cancer
precursor has been demonstrated in 3 intervention trials.
Our results are not as definitive as would be those of a randomized
intervention trial designed to evaluate the effect of various doses of aspirin
on colorectal cancer risk. However, such a trial is not likely to be feasible,
given the need for a large number of participants and prolonged follow-up,
as well as ethical concerns, given the efficacy of currently accepted endoscopic
Consistent with other studies, we did observe an increase in the incidence
of reported major gastrointestinal bleeding with increasing aspirin dose.58-61 Based
on the incidence of colorectal cancer within this cohort, our results, if
proven causal, suggest that use of aspirin at the highest-dose category compared
with no use of aspirin would prevent 1 to 2 cases of colorectal cancer with
an excess of 8 episodes of major gastrointestinal bleeding for every 10 000
person-years. Further studies are warranted to thoroughly address this risk-benefit
profile in the context of other potential benefits and hazards of long-term
In our preliminary analysis, we did not note a substantial difference
in the age-standardized mortality rate within the various aspirin subgroups.
However, because aspirin may play a role in the prevention and treatment of
other chronic conditions (eg, cardiovascular disease), a more detailed analysis
accounting for potential biases introduced by the effects of incident disease
on mortality are needed.
Although selective COX-2 inhibitors are currently under investigation
in the prevention of colorectal neoplasia, their potential cardiovascular
risk, particularly with long-term use, may preclude their use in chemoprevention.62,63 Our study supports a possible role
for aspirin in cancer prevention, which has been demonstrated by prior adenoma
recurrence trials. However, any substantial impact of aspirin on cancer necessitates
early initiation and prolonged, consistent use. Moreover, optimal chemoprevention
may require substantially higher doses of aspirin than currently recommended
for the prevention of cardiovascular disease.64 Many
toxicities of aspirin, including gastrointestinal bleeding, are dose-dependent.58-61,65,66 Thus,
future studies will need to thoroughly consider the risk-benefit profile for
aspirin/NSAID chemoprevention among various risk groups and compare such a
strategy with other potential prevention efforts.
Corresponding Author: Andrew T. Chan, MD,
MPH, Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit St, GRJ
722, Boston, MA 02114 (firstname.lastname@example.org).
Author Contributions: Dr Chan had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Chan, Giovannucci,
Acquisition of data: Giovannucci, Meyerhardt,
Analysis and interpretation of data: Chan,
Giovannucci, Schernhammer, Fuchs.
Drafting of the manuscript: Chan, Giovannucci,
Critical revision of the manuscript for important
intellectual content: Chan, Giovannucci, Meyerhardt, Curhan, Fuchs.
Statistical analysis: Chan, Giovannucci, Schernhammer,
Obtained funding: Giovannucci, Fuchs.
Administrative, technical, or material support:
Study supervision: Fuchs.
Financial Disclosures: None reported.
Funding/Support: This study was supported by
grants CA 87969 and CA55075 from the National Cancer Institute, National Institutes
of Health. Dr Chan is a recipient of the American Gastroenterological Association/Foundation
for Digestive Health and Nutrition Research Scholar Award and career development
award CA107412 from the National Cancer Institute.
Role of the Sponsor: The National Cancer Institute,
the National Institutes of Health, the American Gastroenterological Association,
and the Foundation for Digestive Health and Nutrition had no role in the collection,
management, analysis, or interpretation of the data or the preparation, review,
or approval of the manuscript.
Acknowledgment: We acknowledge the continued
dedication of the participants in the Nurses’ Health Study. We also
acknowledge members of the Channing Laboratory at Brigham and Women’s
Hospital; in particular, Gideon Aweh, MS, Karen Corsano, MA, for their programming
assistance and Barbara Egan for her efforts in obtaining medical records.
Mr Aweh, Ms Corsano, and Ms Egan receive salary support from the National
Institutes of Health.
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