Non-steroidal anti-inflammatory drugs: effects on mortality after colorectal cancer diagnosis

Abstract

Background

Non-steroidal anti-inflammatory drug (NSAID) use has been associated with decreased colorectal cancer (CRC) risk. However, NSAID effects on clinical outcomes after CRC diagnosis are not well-defined. We investigated the association of pre-diagnosis NSAID use and mortality after CRC diagnosis among women in the California Teachers Study (CTS) cohort.

Methods

Women under 85 years participating in the CTS, without prior CRC diagnosis at baseline (1995-1996), and diagnosed with CRC during follow-up through December 2005, were eligible for analysis of the association of pre-diagnosis NSAID use and mortality. NSAID use (including aspirin, and ibuprofen) was collected through a self-administered questionnaire. Cancer occurrence was identified through California Cancer Registry linkage. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) for death and 95% confidence intervals (CI).

Results

Among 621 CRC cases identified, 64% reported no pre-diagnosis regular NSAID use, 17% reported use 1-6 days/week, and 20% reported daily use; duration of NSAID use < 5 years was reported by 17% and ≥5 years reported by 18%. Regular pre-diagnosis NSAID use (1-3 days/week, 4-6 days/week, daily) vs. none was associated with improved overall survival (OS) (HR=0.71, 95% CI 0.53-0.95) and CRC-specific survival (CRC-SS) (HR=0.58, 95% CI 0.40-0.84) after adjustment for clinically relevant factors. Pre-diagnosis NSAID use ≥5 years (versus none) was associated with improved OS (HR=0.55, 95% CI 0.37-0.84) and CRC-SS (HR=0.40, 95% CI 0.23-0.71) in adjusted analyses.

Conclusions

When used regularly or over a prolonged duration prior to CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC cases.

Introduction

During the year 2007, an estimated 112,340 new cases of colon cancer and 41,420 cases of rectal cancer were diagnosed in the U.S., making colorectal cancer (CRC) the third most common cancer among U.S. men and women ¹. A wide body of evidence links use of non-steroidal anti-inflammatory drugs (NSAIDs) to reduced risk of CRC. First, rodent models show that NSAIDs inhibit intestinal cancer development ^2-8. Consistent with experimental data, clinical trial results involving familial adenomatous polyposis (FAP) patients demonstrate that the NSAIDs sulindac ^9-11, celecoxib ¹², and rofecoxib ¹³ prevent colorectal adenomas. Aspirin has been implicated in regression and prevention of premalignant colorectal adenomas in clinical trials ^{14, 15}, and various NSAIDs have been associated with reduced risk of CRC in the vast majority of cohort and case-control studies ^16-23. In addition to these studies demonstrating preventive effects on CRC risk, two important studies suggest that NSAID use after diagnosis of CRC may improve survival ^{24, 25}. In the male Health Professionals Study, for example, aspirin was associated with decreased risk of CRC or adenoma, and also with decreased risk of advanced stage CRC and fatal CRC ²⁴. However, these reports are limited to a cohort study of males, and an unpublished, secondary analysis of clinical trial data restricted to stage III colon cancer patients. Survival outcomes from key therapeutic trials involving NSAIDs among CRC patients have not yet been reported. Thus clear determination of potential survival benefits associated with NSAID use after CRC diagnosis has not been established. Using data from women in the California Teachers Study (CTS) cohort, we investigate the relationship between NSAIDs and mortality among CRC patients.

Material and Methods

Study Population

The California Teachers Study (CTS) is a prospective cohort of current, recent, and retired female public school teachers and administrators, who were members of the California State Teachers Retirement System at the time of study inception in 1995 ²⁶. Cohort members completed a detailed self-administered baseline questionnaire, described below. A total of 133,479 women comprise the CTS cohort. The CTS has been approved by the Institutional Review Boards of the State of California, the University of Southern California, the University of California at Irvine, the Northern California Cancer Center and the City of Hope National Medical Center.

To identify incident invasive colorectal cancers that occurred during follow-up of the CTS, we first delineated a cohort of eligible women. We excluded in a hierarchical manner women who 1) moved out of the state or whose history of invasive cancer during the follow-up period was unknown (n=10,443), 2) were more than 85 years old at baseline (n=1674), 3) had developed a prior malignancy (n=169); 4) lacked data on family history of CRC (n=3844); and 5) lacked data on frequency of NSAID use (n=3106). The resulting cohort consisted of 114,243 women.

Case Ascertainment and Follow-up

Incident diagnoses of invasive carcinoma of the colon and rectum (International Classification of Diseases for Oncology, ICD-O, topography codes C18.0-18.9, C19.9, and C20.9) were identified through annual linkages with the California Cancer Registry (CCR). The CCR also provided details on anatomic subsite within the colorectum and extent of disease. As part of a state mandate for cancer reporting the CCR receives reports on over 99% of all cancer diagnoses occurring in California residents ²⁷. Overall, 621 CTS participants considered eligible for analysis were diagnosed with invasive colorectal carcinoma during follow-up: 427 with colon cancer, 173 with rectal cancer, and 21 with large bowel cancer of unspecified site.

Follow-up was calculated from the date of diagnosis of colorectal cancer to the death, or the end of the follow-up period on December 31, 2005. Treatment during the first course of therapy was ascertained using available CCR data describing receipt of surgical resection and/or radiation therapy. Cause of death was recorded according to the International Classification of Diseases criteria in effect at the time of death ²⁸.

Assessment of Medication Use

The self-administered questionnaire asked “Have you taken any of the following medications regularly (at least once a week)?” Available options included 1) aspirin (Anacin, Bufferin, Excedrin) or 2) ibuprofen (Advil, Motrin, Nuprin). For positive responses, participants indicated the average number of days per week (frequency) (1-3, 4-6, or 7) and the total numbers of years duration (<1, 1, 2, 3-4, 5-9, or ≥10) of use. For the primary analyses, frequency of medication use was categorized into two categories: no use, or regular use (1-3 days per week, 4-6 days per week, or daily use). Duration was categorized as no use, duration less than 5 years, or duration greater than or equal to 5 years. The reconstituted NSAID variables in CTS were utilized for all analyses, as these accounted for combinations of aspirin and ibuprofen use.

Assessment of Colorectal Cancer Risk Factors

Family history of CRC was defined as having a first-degree relative diagnosed with CRC (parent, sibling, or child). Information on other potential colorectal cancer risk factors was collected in the baseline questionnaire including race/ethnicity, personal history or family history of colorectal polyps, body mass index (BMI), recreational physical activity, lifetime tobacco exposure, oral contraceptive use, hormone replacement use, years since last mammogram or Papanicolaou smear, and total daily intake of calcium, folate, fiber, iron, and energy (kcal) ²⁹.

Statistical Analyses

We used multivariable Cox proportional hazards regression analyses to estimate the association between NSAID or aspirin-only use and overall mortality or CRC-specific mortality. All models included the categorical variable for NSAID or aspirin-only use. Adjustment was made for variables known to predict survival in CRC: age, stage of CRC at presentation, site within the colorectum (i.e., colon or rectum), and family history of CRC. Other potential confounders were not included in models as their inclusion did not change risk estimates by more than 5%. Local, regional, and advanced (i.e. remote) stages at presentation were categorized according to the Surveillance, Epidemiology and End Results (SEER) summary stage indicator where available ³⁰. P-values were not adjusted for multiple comparisons. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc., Cary, N.C.).

Results

NSAID frequency prior to CRC diagnosis

Among the 621 CRC cases identified after formation of the cohort, the observed median duration between baseline NSAID assessment and CRC diagnosis was 5.2 years, (range 0 – 10.1 years, mean duration = 5.2 years) and the median follow-up duration after CRC diagnosis was 2.8 years (range 0-9.8 years, mean duration = 3.4 years). Table 1 presents the baseline characteristics of CRC cases in CTS stratified by frequency of NSAID use (no use vs. regular use – defined as daily use, use 4-6 times per week, or use 1-3 times per week). As can be seen in Table 1, these groups were similar across most of the variables considered. Regular NSAID users had a higher BMI than non-users, and were more likely to have had a recent mammogram. NSAID frequency usage, and duration of NSAID use among CRC cases is presented in Table 2. The majority (64%) of cases did not use NSAIDs regularly, whereas 20% were daily NSAID users. Among NSAID users, 39% (i.e., 87 of 224) reported use for 10 years or longer and 50% (i.e., 111 of 224) reported use for at least 5 years.

Table 1. Selected baseline characteristics in relation to NSAID use among 621 colorectal cancer cases in the California Teachers Study (1995-2005).

	Any regular NSAID use reported at baseline* (n=224)	No regular NSAID use reported at baseline (n=397)	P
Age at Diagnosis
Mean Age (years +/- SD)	65.0 +/- 11.6	63.2 +/- 12.6	0.08
Race
Caucasian	196 (88%)	353 (89%)	0.68
African-American	8 (4%)	19 (5%)
Others	20 (8%)	25 (6%)
Personal History of Polyps	15 (7%)	35 (9%)	0.35
Family History of Polpys	18 (8%)	42 (11%)	0.30
Family history of CRC in 1st degree relative	30 (13%)	41 (10%)	0.25
BMI (kg/m2, +/- SD)	27.0 +/- 6.0	25.2 +/- 5.1	0.0004
Total KCAL per day (mean +/- SD)	1518 +/- 564	1503 +/- 519	0.78
Total Daily Calcium Intake (mean mg, +/- SD)	743 +/- 416	698 +/- 430	0.23
Total Daily Iron Intake (mean mg, +/- SD)	10.9 +/- 4.2	10.9 +/- 4.1	0.96
Total Daily Fiber Intake (mean g, +/- SD)	14.9 +/- 6.4	14.8 +/- 6.6	0.94
Total Daily Folate Intake (mean mcg, +/- SD)	300 +/- 117	303 +/- 122	0.78
Stren & Mod Lifetime Phys Activity (mean hrs/wk +/- SD)	4.0 +/- 4.2	4.0 +/- 4.1	0.93
Active & Passive Lifetime Tobacco Exposure
None	27 (13%)	60 (16%)	0.72
Lifetime tobacco exposure in pack-years
Quartile 1 (0.05-10.04)	25 (12%)	52 (14%)
Quartile 2 (10.05-17.04)	34 (16%)	59 (15%)
Quartile 3 (17.05-31.54)	57 (27%)	97 (25%)
Quartile 4 (≥ 31.55)	72 (33%)	113 (30%)
Years Since Last Mammogram
Never had exam	6 (3%)	35 (9%)	0.009
Less than 1 year	127 (57%)	222 (57%)
1-2 years ago	71 (32%)	92 (24%)
3+ years ago	17 (8%)	41 (11%)
Had exam previously, but unspecified number of years ago	1 (0.5%)	1 (0.3%)
Years Since Last Pap Smear
Never had exam	1 (0.5%)	5 (1%)	0.57
Less than 1 year	116 (53%)	200 (54%)
1-2 years ago	66 (30%)	97 (26%)
3+ years ago	33 (15%)	69 (19%)
Had exam previously, but unspecified number of years ago	1 (0.5%)	2 (0.5%)
Tumor Site
Colon	156 (72%)	271 (72%)	0.87
Rectum	62 (28%)	111 (28%)
Histology
Adenocarcinoma	181 (82%)	315 (80%)	0.58
Carcinoma	14 (6%)	18 (5%)
Mucinous Carcinoma	24 (11%)	54 (14%)
Not Otherwise Specified (NOS)	3 (1%)	7 (2%)
Stage at Presentation
Local	102 (47%)	163 (43%)	0.48
Regional	76 (35%)	138 (36%)
Remote	39 (18%)	82 (21%)
Tumor Grade
Grade 1	14 7%)	35 (10%)	0.38
Grade 2	132 (69%)	223 (65%)
Grade 3	42 (22%)	83 (24%)
Grade 4	4 (2%)	3 (1%)
Primary treatment involved surgery	207 (92%)	361 (91%)	0.53
Primary treatment involved radiation therapy	17 (8%)	43 11%)	0.19
Primary treatment involved chemotherapy	19 (8%)	26 (7%)	0.37

^*Variable based on response to question regarding ever having used NSAIDs daily, 4-6 times/week, and 1-3 times/week vs. never having used them at least one time a week.

Table 2.

Patterns of NSAID frequency and duration of use among 621 CRC cases in the CTS.

Detailed NSAID Frequency
No Regular NSAID use	397 (64%)
1-3 days/week	75 (12%)
4-6 days/week	28 (5%)
Daily	121 (20%)
Duration of NSAID Use
No Regular NSAID use	397 (64%)
< 1year	32 (5%)
1 year	18 (3%)
2 years	22 (4%)
3-4 years	33 (5%)
5-9 years	24 (4%)
10+ years	87 (14%)
Unknown duration	8 (1%)

Associations of NSAID use with CRC Survival

Cause of death analysis revealed that 222 of the 621 identified CRC cases (36%) died during the study period. One hundred forty five of these 222 deaths (65%) were attributed to CRC. Fifteen of the 222 deaths (6.8% of all deaths) were due to heart disease.

The primary results are presented for analysis of regular NSAID use compared to no regular NSAID use. In the Cox models, after adjustment for age at diagnosis, family history of CRC in a 1^st degree relative, site (colon or rectum), stage at diagnosis, time from NSAID assessment to CRC diagnosis, treatment with surgery (yes/no), regular NSAID use was associated with a statistically significant decreased risk of death compared to no regular NSAID use (Table 3). For CRC-specific survival, the hazard ratio (HR) was 0.58 (95% confidence interval, CI 0.40-0.84); for overall survival, the HR was 0.71 (0.53-0.95). Restricting anlaysis to colon cancer cases, the multivariate relative hazards for regular NSAID use vs. no use revealed significant differences in overall survival (HR=0.68, 95% CI 0.48-0.97) and CRC-specific mortality (HR=0.57, 95% CI 0.36-0.90). No significant differences were observed when the analysis was limited to rectal cancer cases.

Table 3.

Univariate and multivariate adjusted^* overall survival analysis, and CRC-specific survival analysis for colorectal cancer cases by self-reported frequency of NSAID and aspirin use^**.

	Reported NSAID frequency		Reported Aspirin frequency
	No Regular NSAID use	Regular NSAID use**	No Regular Aspirin use	Regular Aspirin use***
Overall Mortality
Number of events	150	72	167	54
Number at risk	397	224	456	164
Unadjusted HR (95% CI)	1 (Reference)	0.83 (0.63-1.10)	1 (Reference)	0.89 (0.65-1.21)
Adjusted HR (95% CI)*	1 (Reference)	0.71 (0.53-0.95)	1 (Reference)	0.74 (0.54-1.01)
CRC-Specific Mortality
Number of events	103	42	113	32
Number at risk	397	224	456	164
Unadjusted HR (95% CI)	1 (Reference)	0.71 (0.49-1.01)	1 (Reference)	0.77 (0.52-1.14)
Adjusted HR (95% CI)*	1 (Reference)	0.58 (0.40-0.84)	1 (Reference)	0.62 (0.41-0.94)

^*Includes adjustment for age (years), family history of CRC in a 1^st degree relative, site (colon or rectum), stage at diagnosis, time from NSAID assessment to CRC diagnosis, and treatment with surgery.

^**Information on aspirin frequency missing for 1 case.

^***Includes NSAID use daily, 4-6 times/week, and 1-3 times/week.

Results for CRC cases based on duration of NSAID use are presented in Table 4. Colorectal cancer cases who reported using NSAIDs for at least 5 years prior to diagnosis had a statistically significant decreased risk of overall mortality after adjustment for clinically relevant factors compared to those reporting no NSAID use (HR=0.55, 95% CI 0.37-0.84). Similarly, a statistically significant decreased risk of CRC-specific mortality was observed for in the multivariable analysis for CRC cases reporting at least 5 years of NSAID use prior to diagnosis use compared to patients reporting no NSAID use (HR=0.40, 95% CI 0.23-0.71). No statistically significant associations with overall or CRC-specific mortality were observed for cases reporting less than 5 years duration of NSAID use compared to no NSAID use. Among colon cancer cases, at least 5 years duration of NSAID prior to diagnosis was associated with a significant reduction in CRC-specific mortality (HR=0.46, 95% CI 0.23-0.94), but not overall mortality (HR=0.65, 95% CI 0.40-1.05). No significant differences were observed for subset analysis of NSAID duration among rectal cancer cases. Time from NSAID assessment (at baseline) to CRC diagnosis was not significantly associated with survival (data not shown). Results shown in Tables 3 and 4 based on aspirin use rather than all NSAIDs are consistent with the results for all NSAID use.

Table 4.

Univariate and multivariate adjusted^* overall survival analysis, and CRC-specific survival analysis for all colorectal cancer cases by self-reported duration of NSAID and aspirin use^**.

	Reported NSAID Duration			Reported Aspirin Duration
	None	Less than 5 years	5 years or more	None	Less than 5 years	5 years or more
Overall Mortality
Number of events	150	30	42	167	26	24
Number at risk	397	105	111	456	65	92
Unadjusted HR (95% CI)	1 (Reference)	0.94 (0.66-1.34)	0.67 (0.45-0.99)	1 (Reference)	1.06 (0.70-1.60)	0.71 (0.46-1.08)
Adjusted HR (95% CI)**	1 (Reference)	0.83 (0.58-1.19)	0.55 (0.37-0.84)	1 (Reference)	1.02 (0.67-1.55)	0.53 (0.34-0.83)
CRC-Specific Mortality
Number of events	103	24	24	113	18	11
Number at risk	397	105	111	456	65	92
Unadjusted HR (95% CI)	1 (Reference)	0.87 (0.56-1.35)	0.50 (0.29-0.87)	1 (Reference)	1.08 (0.66-1.78)	0.48 (0.26-0.88)
Adjusted HR (95% CI)*	1 (Reference)	0.73 (0.46-1.15)	0.40 (0.23-0.71)	1 (Reference)	1.03 (0.62-1.72)	0.33 (0.18-0.63)

^*Includes adjustment for age (years), family history of CRC in a 1^st degree relative, site (colon or rectum), stage at diagnosis, time from NSAID assessment to CRC diagnosis, and treatment with surgery.

^**Data missing on NSAID and aspirin duration for 8 cases.

Discussion

In this analysis of women diagnosed with a first primary invasive CRC after enrolling in the large CTS cohort, we found that pre-diagnosis regular NSAID use and prolonged NSAID duration of use were independently associated with decreased overall mortality and CRC-specific mortality. Prolonged NSAID duration (>5 years) reported among women with subsequent diagnosis of CRC was associated with a 50% (unadjusted) and 60% (adjusted) lower risk of CRC-specific mortality. Aspirin-only survival effects were consistent with the effects observed for NSAIDs. These findings may have important implications for tertiary cancer prevention, if confirmed in other studies.

Since this was an analysis of pre-diagnosis NSAID use, it is possible that the improvement in survival associated with NSAID use may be a consequence of pre-diagnosis NSAID use leading to the development of more indolent, less aggressive cancers. Alternatively, pre-diagnosis NSAID use may simply reflect post-diagnosis NSAID use, and potentially beneficial effects of NSAID use on survival after CRC diagnosis. This is supported by data on our surviving CRC patients which show that 82% who reported regular NSAID use in the pre-diagnosis questionnaire also reported regular NSAID use in a later questionnaire that was completed in 2007 (data not shown). Despite numerous studies reporting NSAID effects on CRC risk, limited data are available that describe NSAID effects on survival among individuals with established colon or rectal cancer. In the male Health Professionals Study, aspirin was associated with decreased risk of advanced stage CRC and fatal CRC ²⁴. In a prospective analysis of 803 stage III colon cancer patients who received adjuvant chemotherapy (leucovorin-modulated 5-fluorouracil with or without irinotecan), consistent aspirin use among 74 patients was associated with statistically significant decreases in hazards ratios for disease recurrence and overall mortality ²⁵. Cyclooxygenase (COX)-2 over-expression is important in the progression of the colon adenoma-carcinoma sequence ³¹. Both the COX-2 selective and non-selective NSAIDs have been shown to induce apoptosis in colon cancer model systems ^{3, 4, 32}. Aspirin's preventive effect on CRC carcinogenesis is limited to lowering the risk of COX-2 over-expressing tumors ³³. A phase I clinical trial using celecoxib in combination with leucovorin-modulated 5-fluorouracil as treatment for advanced colorectal adenocarcinoma suggests that this regimen is safe, and worthy of further investigation ³⁴. Various NSAIDs have been used in phase I, II, and III clinical trials in combination with either radiation therapy or chemotherapy for regional and metastatic colorectal cancer ^34-36. However, the majority of these trials are currently in progress and survival outcomes are not yet reported. COX-2 inhibitors have been described as “cotherapeutic agents” in the treatment of colorectal cancer ³⁶, due to their primary effect to inhibit tumor growth rather than cause tumor regression ^{35, 37}. Therefore incorporating COX-2 inhibitors or non-selective NSAIDs into combination therapy with chemotherapy, radiation, other investigational chemopreventive agents, or targeted therapies such as vascular endothelial growth factor inhibitors (e.g., bevacizumab) and epidermal growth factor inhibitors (e.g., cetuximab, panitumumab) may prove beneficial.

NSAIDs exert their antiproliferative effects on colonic cells by inhibiting prostaglandin synthesis through reversible binding to cyclooxgenase and through other mechanisms. Aspirin has been noted to reduce the recurrence of adenomatous polyps in patients at moderate risk and with acceptable toxicity, but such is not the case for COX-2 selective inhibitors. Several randomized trials have demonstrated that COX-2 selective NSAIDs result in a substantial reduction in adenoma recurrence, but at the cost of significantly increased cardiovascular events ^{38, 39}. Thus COX-2 selective NSAIDs cannot be recommended routinely for CRC prevention. Whether similar adverse results will be seen with less selective NSAIDs awaits the results of ongoing trials. In light of these data, the U.S. Preventive Services Task Force has recommended that despite evidence of efficacy, NSAIDs are not warranted for CRC prevention among average-risk individuals due to cardiovascular and gastrointestinal toxicities ⁴⁰. Of note, only 6.8% of deaths in our study were to heart disease.

Family history itself was not associated with decreased risk of overall mortality or CRC-specific survival in our study. Despite convincing evidence that family history of CRC is a risk factor for colorectal polyps and cancer ^41-44, conflicting reports have emerged on the association of family history with survival after CRC diagnosis. Consistent with our findings, CRC family history was not associated with survival after CRC diagnosis in the Melbourne CRC cohort study ⁴⁵ or in a study from the Utah Population Database ⁴⁶. However, there is not a consensus on this issue, as new studies have emerged demonstrating survival benefits for colon cancer patients with family history of CRC compared to those without^47-50. It is possible that unique cohort characteristics (i.e., stage, gender, ethnicity) and statistical power account for the different observations about the effects of CRC family history on survival after diagnosis of CRC.

The present study was based on a prospective study design such that NSAID reporting pre-dated CRC diagnosis, with cases accrued during a median cohort follow-up of 10.1 years. Self-reported NSAID use was obtained from the baseline questionnaire, whereas survival effects may be more closely related to NSAID use after CRC diagnosis. Among our surviving CRC patients we have additional data on NSAID use obtained in 2007; although 82% of those who reported use of NSAIDs at baseline continued their use, 38% of the non-users from the pre-diagnosis questionnaire reported regular NSAID use in the later questionnaire. These subsequent NSAID assessments were collected in the final year of follow-up for mortality, meaning that deceased cases could not provide relevant data on NSAID use. Thus we cannot determine how changing patterns of NSAID use over time influenced CRC mortality. We also recognize that our findings could reflect effects of lead time bias if NSAID use were associated with earlier diagnosis due to early symptomatology (e.g., rectal bleeding). Our analyses of rectal cancer were limited in sample size and therefore, in the number of deaths occurring in this group, resulting in low statistical power to detect effects of NSAID use on survival. The study has several other important limitations, including a lack of information on screening practices such as fecal occult blood testing or use of endoscopy (colonoscopy or flexible sigmoidoscopy). It is recognized that screening may be associated with NSAID use, and thus differences in screening could theoretically explain the observed associations. In our analysis there were observed differences in the screening rates for mammograms but not Papanicolaou smears between CRC cases reporting regular NSAID use and no regular NSAID use, but stage of CRC at diagnosis did not vary by NSAID use (Table 1). Detailed NSAID history was not available, including information on the specific type of NSAID and dosage, information about NSAIDs other than aspirin or ibuprofen, and information on current or former use. Additionally, our study was underpowered to investigate risk differences based on tumor subsite location within the colon or rectum.

Our findings cannot support a general recommendation for NSAID use as tertiary prevention of colorectal cancer among CRC cases. However, they do justify future validation studies to better understand pre- and post-diagnostic NSAID use among CRC cases and underscore the importance of carrying out NSAID tertiary prevention CRC clinical trials, as being planned in the cooperative group setting. These findings clearly suggest that prior NSAID use patterns will be an important variable to consider when planning and interpreting future trials and that completed therapeutic trials demonstrating benefit may need to revisit whether prior NSAID use patterns were adequately addressed in the study design and analysis.