The Association between NSAID Use and Colorectal Cancer Mortality: Results from the Women's Health Initiative

Inflammation plays a role in the initiation and promotion of colorectal tumors (1–4); data from randomized trials and large cohorts have consistently shown that nonsteroidal anti-inflammatory drug (NSAID) use reduces the risk of colorectal adenomas, invasive colorectal cancer (CRC), and disease recurrence (5–11). A meta-analysis including 2 randomized aspirin trials and 30 observational studies of NSAID use highlighted the importance of the duration of medication use (12); reductions in CRC incidence were greater for randomized treatment assignments ≥5 years, and reductions in observational studies were most pronounced with ≥10 years use.

Recent reports also indicate that NSAID use may play a role in case-fatality after a CRC diagnosis (13–18). Meta-analyses of randomized aspirin trials showed significant associations between lower CRC mortality, reduced frequency of metastatic disease, and aspirin use (19–21). However, the 2 largest trials included in the meta-analyses recruited only men. Furthermore, the literature to date is not conclusive on the role of nonaspirin NSAIDs in CRC mortality, and the relationship between the duration of overall NSAID use and CRC mortality has not been established.

We investigated the association between NSAID use and CRC mortality in the Women's Health Initiative (WHI), a large, well-characterized cohort of postmenopausal women with available information on duration and amount of use for aspirin and nonaspirin NSAIDs.

The WHI is composed of 161,808 postmenopausal women, ages 50 to 79 years, enrolled from 40 clinical centers across the United States. Women participated in either a series of randomized clinical trials (CT) or an observational study (OS). Recruitment occurred between October 1, 1993 and December 31, 1998; details of recruitment have previously been published (22, 23). At enrollment, women provided written informed consent for participation. Human Subjects Review Committees at all participating institutions approved the WHI study protocol. For this analysis, women who reported a prior CRC at the time of study enrollment (n = 946) or had no follow-up information (n = 725) were excluded, leaving 160,143 eligible women.

WHI participants attended baseline screening visits, during which they completed a series of self-administered questionnaires, collecting detailed information on demographics, family history of cancer, reproductive history, physical activity, and medical history. Physical measurements, including height and weight, were measured at baseline.

Participants were asked to bring prescription and over-the-counter medications used regularly (at least twice a week for the previous 2 weeks) to their clinic visit to facilitate completion of interviewer-administered questionnaires about current medication use (24). Women were asked the following questions about NSAIDs: (i) “Do you take aspirin pills or powders, for example, Anacin, Bufferin, and BC pain reliever?” (ii) “Do you take ibuprofen tablets or capsules, for example, Advil, Motrin, or Nuprin?” (iii) “Do you take Naprozyn, Naproxen, Aleve, Indocin, Clinorial, Feldene, or other anti-inflammatory pain pills?” A question inquiring about use of acetaminophen was included on the questionnaire; acetaminophen use was not classified as NSAID use. Women who indicated that they did take NSAIDs completed a medication questionnaire, providing information on the strength (milligrams) and duration (years) of use. A separate questionnaire was completed for each medication a woman reported currently using. Women enrolled in the CT provided updated medication data annually, while follow-up medication questionnaires were administered approximately 3 years after study enrollment for both CT and OS women.

Women were defined as users at baseline if they reported use of any NSAID on a baseline medication questionnaire. Women who reported NSAID use on a medication questionnaire completed approximately 3 years (2.5–3.5 years) after study enrollment were considered NSAID-users at year 3. If a woman did not report NSAID use on the baseline questionnaire or at the time of the year 3 follow-up questionnaire, she was considered a nonuser at that respective time point.

Women who reported NSAID use on both the screening medication questionnaire and the year 3 medication questionnaire were classified as “continued users.” Women who reported NSAID use at baseline but did not report use at year 3 were considered “discontinued” users, whereas those who did not report NSAID use at baseline but did report use at year 3 were considered “initiated” users.

Information from the completed baseline medication questionnaire detailing the medication strength (milligrams) and reported duration (years) was used to further investigate the association between NSAID use and CRC mortality. Because women could report use of multiple NSAIDs at baseline, only the maximum value of the variable of interest for each participant was considered in the analysis. For example, if a woman reported aspirin and ibuprofen use at baseline, only the duration value for the medication the woman reported using the longest was considered.

WHI participants were followed for outcomes through March 2005. Women were then invited to participate in the WHI Extension Study; those who refused to participate were administratively censored at the end of 2005. As of August 2007, 115,400 women were enrolled in the Extension Study, with outcome follow-up continuing through 2010.

Disease outcomes were identified through annual medical updates. Reported cases of CRC were locally confirmed based on medical record review and centrally adjudicated; disease characteristics were coded according to Surveillance, Epidemiology, and End Results standards by specially trained staff (25). Cause of death was determined by centralized medical record and death certificate review at a WHI clinical center; regular linkages to the National Death Index were conducted to ensure complete mortality ascertainment (26).

The primary outcome of interest in this investigation was mortality due to CRC. Time to CRC mortality was calculated as the time from study enrollment to the recorded date of death due to CRC. Among women who developed CRC, time to case-fatality was calculated as the time from diagnosis to date of death due to CRC. For all analyses, participants alive and free of the endpoint at the date of last follow-up were administratively censored. Women dying of causes other than CRC were administratively censored at their date of death.

Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between NSAID use at baseline and CRC mortality. Cox regression models included the following baseline covariates: age, body mass index (BMI), smoking, personal history of cardiovascular disease, diabetes, and ulcerative colitis, family history of CRC, receipt of colonoscopy, and study arm enrollment (CT vs. OS). Regression models that examined baseline medication strength or duration parameterized exposures based upon the quartile distribution among women reporting current use of the specified NSAID at baseline.

To examine extended NSAID use, regression models were evaluated comparing CRC mortality between women who were continued users and the following groups: (i) discontinued users, (ii) initiated users, and (iii) women who did not report use at either baseline or year 3. Models that considered NSAID use reported on the year 3 medication questionnaire included only women who survived at least 3 years after study enrollment (n = 156,440). Cox regression models restricted to women who developed CRC were run for all comparisons outlined above to investigate the association between NSAID use and case-fatality. Results from case-fatality models are presented without adjustment for stage at diagnosis, given that stage may be in the causal pathway between NSAID use and CRC mortality. Exploratory models including stage were also run.

Exploratory analyses examined whether observed associations between NSAID use and CRC mortality differed by study arm (i.e., one OS strata and separate strata for each CT arm). Analyses also explored whether associations differed according to baseline BMI (<25.0, 25.0–29.9, ≥30.0), or tumor site at diagnosis (proximal, distal/rectal). Because NSAIDs may play a greater role in altering colorectal carcinogenesis in the absence of other known risk factors, we examined associations according to whether women received a colonoscopy before baseline interview. The proportional hazards assumption was evaluated using Schoenfeld residuals for CRC mortality, with no violations observed.

Because NSAID data was available for all study participants at baseline and year 3, in order to examine pre-diagnostic use, we conducted analyses eliminating women diagnosed with CRC prior to year 3 (n = 1,559 CRC cases; 343 CRC deaths). To account for women who were ill at baseline potentially using NSAIDs at higher rates, we conducted sensitivity analyses restricted to participants who did not die (from any cause) within the first year after enrollment (n = 159,385). Less than 5% of observed deaths (492 of 15,068) were due to CRC. Because NSAID use may be associated with multiple causes of death, censoring women who died from non-CRC causes may be informative. To address this potential bias, we estimated the cause-specific hazard of mortality using a proportional risk model (27). This model generated an estimate for the association between NSAID use and CRC-specific mortality in the presence of mortality from other causes, in contrast to the Cox model, which estimated the association between NSAID use and CRC-specific mortality without directly accounting for death due to other causes.

After an average follow-up of 11 years, 2,119 women developed CRC. Of the 15,608 women who died during follow-up, CRC was the cause of death for 492. Approximately 36% of CRC cases reported current use of any NSAID at baseline (Table 1). Nearly half the women using NSAIDs at baseline reported <3 years of use, whereas 19% reported ≥10 years of use. Approximately 55% of baseline NSAID users reported use of aspirin, and 10% of baseline users reported use of both aspirin and nonaspirin NSAIDs (n = 5,883).

There was no overall association between NSAID use at baseline and CRC mortality (Table 2). However, women who reported continued use (both baseline and year 3 use) experienced a significant reduction in CRC mortality (HR: 0.72; 95% CI 0.54, 0.95) compared with all noncontinuous users, including women who either initiated use after baseline or who discontinued their baseline use prior to year 3. Women who were nonusers at both baseline and year 3 were more likely to be true nonusers; compared with continued NSAID users, women who consistently reported no NSAID use experienced 45% higher rates of CRC mortality (HR: 1.45; 95% CI 1.08, 1.85).

Results showed marginal evidence of an inverse, duration-dependent relationship (Table 3) between lower CRC mortality and increasing durations of NSAID use reported at baseline (P trend = 0.12). Use for ≥10 years was associated with lower CRC mortality (HR: 0.64; 95% CI 0.40, 1.01) compared with no baseline use. Among the baseline NSAID-users, each quartile increase in the duration of use was associated with a 14% reduction in the risk of CRC mortality (HR: 0.86; 95% CI 0.75, 1.00).

Effect estimates for baseline and continued aspirin use were similar to those reported for use of any NSAID. In contrast, estimates for nonaspirin NSAID use were not consistent with an association with CRC mortality. This may be attributable to differing patterns of usage according to NSAID type. Approximately 25% of women using aspirin at baseline reported ≥10 years of use, compared with only 11% of nonaspirin NSAID users. We examined each medication type with adjustment for the other; effect estimates for baseline use remained null for both types. However, continued aspirin use was marginally associated with lower CRC mortality (HR: 0.72; 95% CI 0.51, 1.03), whereas independent results for continued nonaspirin NSAID use were null (HR: 0.86; 95% CI 0.56, 1.31).

We found no association between NSAID use and case fatality after CRC diagnosis, regardless of NSAID type (Table 4) or amount of use (data not shown). Results accounting for stage did not differ from those reported.

Exploratory analyses revealed no suggestion of heterogeneity in the association of NSAID use with CRC mortality according to study arm enrollment, BMI, tumor site at diagnosis, or receipt of colonoscopy (data not shown). Results of the sensitivity analysis excluding women who died within the first year after study enrollment did not differ in direction or magnitude from those reported. When we removed women from our analyses who were diagnosed with CRC prior to year 3, continued NSAID use remained associated with lower CRC mortality (HR: 0.73; 95% CI 0.54, 1.00); baseline use was not statistically significantly associated with CRC mortality, although the result was more consistent with a reduction in mortality risk (HR: 0.80; 95% CI 0.62, 1.02).

Results from the proportional risk model were consistent with those reported; continued NSAID use was significantly associated with lower CRC mortality, even in the presence of other causes of death (HR: 0.87; 95% CI 0.83, 0.91).

Results suggested that NSAID use, particularly aspirin use, is associated with lower CRC mortality among postmenopausal women who use these medications for longer durations and more consistently over time. Women who reported NSAID use ≥10 years at baseline experienced 36% lower CRC mortality than nonusers at baseline, and women who reported use at baseline and year 3 had 28% lower CRC mortality than women reporting inconsistent NSAID use.

Our observation of an association with long-term use is consistent with evidence from prior studies. Significant reductions in CRC incidence were observed in the Nurses' Health Study and the Health Professional's Follow-up Study only after 10 years and 6 to 10 years of aspirin use, respectively (9, 10). Recent meta-analyses of randomized trials have cited greatest benefit against CRC mortality for aspirin treatment durations of at least 5 to 7.5 years (19, 21). Of interest is our observation that the highest quartile of usage reported among these women was ≥6 years of use; 3 quarters of the baseline NSAID use was < 6 years, which may have been inadequate to observe an overall reduction in CRC mortality.

Although no trend was observed between CRC mortality and increasing NSAID medication strength, compared with nonusers at baseline, women in the highest quartile (>325 mg) experienced significantly lower CRC mortality. No substantive differences were observed according to aspirin strength in the recent meta-analysis of aspirin treatments ranging from 30 to 1,200 mg, although there was a suggestion of a lesser effect for 30 mg (19). Observational studies investigating CRC case-fatality have not reported on associations according to medication strength; however, the one prior study that reported no association between aspirin use and CRC case-fatality investigated only low-dose (75 mg) aspirin (28).

No association between CRC incidence and aspirin use was observed in a prior study of women enrolled in the WHI OS (29). The average duration of aspirin use in that report was only 1.7 years, which may have been inadequate to confer any risk reduction. Potentially more important was the short duration of follow-up: 631 CRC cases were reported, with an average follow-up of 6.4 years. Data from randomized trials for CRC incidence showed that a latency period of approximately 10 years was necessary to realize the benefit of aspirin (12, 21). We also observed evidence that NSAIDs may play a more complicated role for cases diagnosed recently after baseline; removal of these cases resulted in less conservative estimates of the effect of baseline use on CRC mortality. The earlier WHI report observed an increased risk of CRC occurring in the first year after study enrollment among NSAID users. Inclusion of these cases, along with the short duration of follow-up, could have precluded the detection of an overall reduction in CRC risk.

Despite reporting an association with longer, more consistent NSAID use, we were not able to detect an overall association between NSAID use at baseline and CRC mortality. This may be attributed to limitations in measuring medication exposures in this study sample. First, the referent group of nonusers was composed of women who were not using at the specified time point (i.e., baseline); however, these women may have used NSAIDs at other time points. Nearly 20% of nonusers at baseline reported use at year 3, and women were not asked about former NSAID use during screening visits, increasing the possibility for “unexposed” women to have some degree of exposure history. Second, a major limitation was the inability to assess NSAID use at a comparable time for all cases. For example, reported use at baseline for a woman diagnosed within the first 3 years may have constituted current use relative to diagnosis, but for women diagnosed 5 years after enrollment, baseline use may have represented former use. Finally, we were unable to account for treatment in the case-fatality analyses. Stage at diagnosis often predicts treatment, and we were able to consider analyses that accounted for stage. The examination of detailed treatment information could shed light on potential pharmaceutical interactions that may impact upon patient prognosis.

Despite limitations, our results demonstrated a biologically plausible effect. The primary targets of these medications are the prostaglandin synthases, particularly COX-2 (30–32); even low doses of aspirin (81 mg) have been shown to alter COX-2 levels in colorectal tissue (33). The role of COX-2 in promoting colorectal neoplasia has been well documented; overexpression in colorectal tumors has been observed in multiple studies (34, 35), and COX-2 expression has been linked to the size and prognosis of initiated colorectal tumors (36–38). COX-2-mediated inflammatory signaling facilitates the initiation and promotion of fatal CRC through mechanisms including adaption to a hypoxic tumor microenvironment (39), alteration of cellular apoptotic mechanisms (40), and promotion of metastasis through changes in cellular motility (41) and angiogenesis (42, 43). An increasing amount of NSAID exposure over many years could be expected to alter COX-2 expression, and thereby colorectal tumor initiation and promotion.

The WHI study represents a large and well-characterized cohort of postmenopausal women. Available data allowed us to investigate various durations and medication strengths of aspirin and nonaspirin NSAID use in relation to CRC mortality. Our results add to the current literature, supporting an association between lower rates of CRC mortality and prolonged NSAID use, particularly longer and more consistent aspirin use, in postmenopausal women.

No potential conflicts of interest were disclosed.

Conception and design: A.E. Coghill, A.I. Phipps, J. Wactawski-Wende, P.A. Newcomb

Development of methodology: A.A. Bavry, P.A. Newcomb

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J. Wactawski-Wende, D.S. Lane, A. LaCroix

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.E. Coghill, A.I. Phipps, A.A. Bavry, P.A. Newcomb

Writing, review, and/or revision of the manuscript: A.E. Coghill, A.I. Phipps, A.A. Bavry, J. Wactawski-Wende, D.S. Lane, A. LaCroix, P.A. Newcomb

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): P.A. Newcomb

Study supervision: J. Wactawski-Wende, D.S. Lane, P.A. Newcomb

Research supported by National Heart, Lung, and Blood Institute contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This publication was also supported by the National Cancer Institute, National Institutes of Health (R25 CA94880, K05 CA152715, T32 CA09168-32).

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