Abstract
Adenomatous polyps are known precursor lesions for colorectal cancer and some hyperplastic polyps also have malignant potential. The use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDS) is associated with a reduced risk of adenomatous polyps; however, less evidence exists regarding NSAID use and hyperplastic polyp risk. We conducted a colonoscopy-based case-control study including 2028 polyp cases (1,529 adenomatous and 499 hyperplastic) and 3,431 polyp-free controls. Multivariate logistic regression models were constructed to derived adjusted odds ratios (OR) and 95% confidence intervals (CI) as the measure of the association between NSAID use and polyp risk. Use of baby aspirin, regular aspirin, and non-aspirin NSAIDs, were associated with a reduced risk of adenomatous polyps (OR = 0.79; 95% CI 0.66–0.93, OR = 0.73; 0.58–0.90, and OR = 0.67; 0.53–0.86, respectively). Baby aspirin was also associated with a reduced risk of hyperplastic polyps (OR = 0.74; 0.56–0.97). Although a dose response was seen with adenoma risk and regular use of any NSAIDs (less than 7 doses per week, 7 doses per week, and greater than 7 doses per week), a dose response was not seen with hyperplastic polyps. We found no evidence of interaction between NSAID dose and duration and polyp risk. The use of any NSAID regardless of type was associated with a reduced risk of adenomatous polyps however regular aspirin and COX-2 inhibitors use was not associated with hyperplastic polyp risk.
Keywords: Colonic Polyps; Epidemiology; Anti-Inflammatory Agents, Non-Steroidal; hyperplastic polyp
Introduction
Colorectal cancer is the second leading cause of cancer-related mortality within the United States (1) and adenomatous polyps are established precursors for colorectal cancer (2). Although colorectal cancer screening tests are effective at reducing cancer-related mortality through the removal of cancer precursor lesions, the uptake rates for these procedures are low (3–5). Therefore there is considerable interest in potential chemopreventive strategies for reducing colorectal tumors. To date, the most rigorously studied agents have been the non-steroidal anti-inflammatory drugs (NSAIDs) (6–8).
In randomized clinical trials, NSAIDs and selective COX-2 inhibitors reduced the risk of recurrent adenomas by as much as 45% (9–14) . Emerging evidence suggests that some colorectal cancers may arise from certain hyperplastic polyps along the serrated neoplastic pathway. This pathway has several key differences to the classical adenoma-carcinoma pathway including early mutations in BRAF and CpG island methylation (15). As such, it is important to determine whether NSAIDs may also reduce the risk of hyperplastic polyps. Only a few studies have evaluated this hypothesis, and the sample sizes for these studies were small (16, 17).
In the general population it is estimated that approximately 5–27% of regular aspirin users concomitantly use non-aspirin NSAIDS (18–20). These numbers could be significantly greater as both aspirin and non-aspirin NSAIDs are available over-the-counter without requiring a prescription. Limited data exists examining the influence of both agents simultaneously on colorectal neoplasms. Although one might assume a synergistic effect, an earlier cohort study found the addition of non-aspirin NSAIDs to regular aspirin use in women did not offer additionally protect from proximal colorectal cancers (21). Herein, we report results from a large colonoscopy-based study involving 5459 patients that evaluated the association of regular use of aspirin, non-aspirin NSAID, or a combination of the two on adenomatous and hyperplastic polyp risk.
Materials and Methods
Study Participants
Participants were part of the Tennessee Colorectal Polyp Study, an on-going colonoscopy-based case-control study conducted in Nashville, Tennessee. Study methods have been published elsewhere (22). Briefly, eligible participants, aged between 40 and 75 years old, were identified from patients scheduled for either screening or diagnostic colonoscopies at the Vanderbilt Gastroenterology Clinic between February 1, 2003 and May 31, 2008 and the Veterans’ Affairs Tennessee Valley Health System Nashville campus between August 21, 2003 and May 30, 2007. Excluded from the study were patients with genetic colorectal cancer syndromes (such as hereditary non-polyposis colorectal cancer or familial adenomatous polyposis) or a prior history of inflammatory bowel disease, adenomatous polyps, or any cancer other than non-melanoma skin cancers. We excluded individuals with prior histories of colorectal adenomas or cancer to ensure that colonoscopy examinations would not be surveillance endoscopies. A total of 10,467 eligible individuals were contacted regarding study participation. Ninety-three percent (n = 9,745) were approached prior to colonoscopy examination and the remaining (n=722) were contacted after colonoscopy. Sixty-four percent of eligible individuals agreed to participant in the study and provided written informed consent. The Vanderbilt University and the Tennessee Valley Healthcare System Institutional Review Boards approved the study.
Exposure Assessment
Trained interviewers conducted a standardized telephone interview following colonoscopy to obtain information on medication use, demographics, medical history, family history, reproductive history, anthropometry, dietary, and other lifestyle factors. Interviewers were blinded to the results of the colonoscopy examination. Participants were asked to report if they had ever used in the past 15 years aspirin (regular or baby aspirin), or non-aspirin NSAIDs for at least 3 days a week over a duration of at least two months. Individuals responding “yes” to these questions were asked to report NSAID brands, duration of use, and frequency. Participants were asked to report on both prescription and over-the-counter NSAID use. For this analysis, we defined regular users as individuals taking aspirin or NSAIDS three or more times a week for a minimum duration of 1 year. We categorized NSAIDs users into specific subtypes based on the reported use patterns. These categories included users of regular aspirin only, users of baby aspirin only, users of non-aspirin NSAIDs (such as ibuprofen, naproxen, or indomethacin), users of selective COX-2 inhibitors only, and users reporting the use of two or more categories of NSAID, for example aspirin along with ibuprofen. Each NSAID subtype was the categorized into dosing groups (fewer than 7 doses a week, 7 doses a week, and greater than 7 doses a week) and duration groups (fewer than 5 years of continuous use and 5 or more years continuous use).
Among 6702 participants, 5,785 (86%) completed the telephone interview. We excluded 326 participants with incomplete data regarding prior use of NSAIDs. Our final study included 5,459 participants categorized as 3,431 polyp-free controls, and 2028 polyp cases including 1,146 cases with adenomatous polyps, 499 cases with hyperplastic polyps, and 383 cases with synchronous adenomatous and hyperplastic polyps. Because individual effect sizes for each NSAID category stratum were similar between combined adenoma only and synchronous adenoma and hyperplastic polyp cases we combined these two groups together for these analyses.
Statistical Methods
We compared age-adjusted differences between cases and controls using ANOVA for continuous variables or the Cochran-Mantel-Haenszel χ2 test for categorical variables. Unconditional logistic regression models were used to estimate the risk of colorectal polyps associated with NSAID use. All models were adjusted for age (continuous), sex (male, female), race (white, nonwhite), family history of colorectal cancer or adenomatous polyp in a first-degree relative (yes, no), educational attainment (high school or less, some college, college graduate, graduate or professional education), body mass index (continuous), total energy intake (continuous), cigarette use (current use, former use, never use), regular alcohol use (current use, former use, never use), regular physical activity in the last 10 years (yes, no), use of hormone replacement therapy-for women only (ever, never), indication for colonoscopy (screening, diagnostic), study site (VUMC, VA), and year of colonoscopy. We calculated tests for trend by rank ordering the exposure categories and including this variable within the model as a continuous term. We stratified each NSAID category by dose and duration and adjusted these models using the same covariates used for our main effects model. Dose analyses were not adjusted for duration of use and duration analyses were not adjusted for dose used. We then constructed logistic regression models for each polyp location and polyp size (< 1 cm, ≥ 1 cm). Polyps located from the cecum to just proximal of the splenic flexure were considered proximal, polyps located from the splenic flexure to the rectum were considered distal, and polyps found within the rectum were considered rectal polyps. For our analyses stratified by polyp location we excluded 239 cases that had synchronous proximal and distal polyps and 89 cases with both rectal and non-rectal polyps. For hyperplastic polyps we excluded 47 cases with polyps in multiple locations. To tests for possible interactions between aspirin use and non-aspirin NSAID use, we included the cross-product of aspirin dose in pills per day (0, ≤ 7, > 7) and non-aspirin NSAID dose in pills per day (0, ≤ 7, > 7) as a continuous variables within our models and used the likelihood ratio test to evaluate potential multiplicative interactions of the two variables by comparing the models with and without the cross product term of these variables. We used a similar procedure to test for interaction between medication dose and duration (0, < 5 years, ≥ 5 years) for aspirin use and non-aspirin NSAID use. All statistical calculations were performed using SAS version 9.2 (SAS Institute, Cary, NC).
Results
Age-adjusted characteristics of the study group are presented in Table 1. Participants with adenomatous or hyperplastic polyps were more likely to be male, currently smoking, using alcohol, less educated, less physically active, and have higher body mass indexes when compared to polyp-free controls. There was no difference between the groups with respect to family history of colorectal cancer or use of hormone replacement therapy. Cases were more likely to have undergone colonoscopy for diagnostic purposes.
Table 1.
Age-adjusted characteristics of adenomatous and hyperplastic polyp cases and controls
| Characteristic | Controls (N = 3431) |
Adenomatous (N = 1529) |
Hyperplastic (N = 499) |
ρ-value* |
|---|---|---|---|---|
| Age (years, mean ± SD) | 56.8 ± 7.7 | 58.8 ± 7.3 | 56.7 ± 7.0 | <0.0001 |
| Sex (female, %) | 43.9 | 27.5 | 31.0 | <0.0001 |
| Race (%) | ||||
| Caucasian | 87.5 | 86.0 | 90.9 | 0.05 |
| African American | 10.5 | 11.7 | 8.0 | |
| Other | 2.0 | 2.3 | 1.1 | |
| Smoking (%) | ||||
| Current | 12.7 | 28.3 | 33.8 | <0.0001 |
| Former | 35.1 | 36.5 | 38.1 | |
| Never | 52.2 | 35.2 | 28.1 | |
| Alcohol consumption (%) | ||||
| Current | 18.4 | 21.1 | 23.4 | <0.0001 |
| Former | 22.4 | 29.3 | 27.4 | |
| Never | 59.3 | 49.7 | 49.2 | |
| Family history of colon cancer or adenomatous polyp (yes, %) | 14.6 | 16.6 | 14.7 | 0.17 |
| Educational attainment (%) | ||||
| High school or less | 24.3 | 33.2 | 33.7 | <0.0001 |
| Some college | 28.4 | 29.2 | 30.1 | |
| College graduate | 20.7 | 19.8 | 18.6 | |
| Graduate or professional education | 26.6 | 17.9 | 17.6 | |
| Regularly exercised (%) | 57.8 | 49.8 | 54.4 | <0.0001 |
| Body mass index (kg/m2,mean ± SD) | 28.1 ± 5.8 | 28.9 ± 5.7 | 28.8 ± 5.9 | <0.0001 |
| Use of HRT (ever, %)† | 59.6 | 62.8 | 60.5 | 0.72 |
| Study site (%) | ||||
| Academic Center | 72.7 | 58.8 | 55.5 | <0.0001 |
| VA | 27.3 | 41.2 | 44.5 | |
| Indication for colonoscopy (%) | ||||
| Screening | 70.5 | 67.6 | 64.6 | 0.01 |
| Diagnostic/bleeding/other | 29.5 | 32.4 | 35.4 |
ANOVA for continuous variables and χ2 test for categorical
Women only (n = 2082)
For adenomatous polyps, there was a reduction in the odds ratio seen for all NSAID categories. (Table 2) Compared to individuals who were not using NSAIDs, effect sizes ranged from 0.79 (95% CI 0.66–0.93) for baby aspirin users to 0.60 (95% CI 0.47–0.76) for NSAID combination users. Baby aspirin use was associated with a statistically significant reduced odds ratio for hyperplastic polyps (0.74; 95% CI 0.56–0.97) compared to nonusers. (Table 2) A significant dose-response relationship was seen for all aspirin and non-aspirin NSAID categories and risk of adenomatous polyps. No clear dose response was seen with NSAID use and hyperplastic polyp risk. Longer duration of use of either aspirin or non-aspirin NSAID did not result in any additional reduction of polyp risk. (Table 2 and 4)
Table 2.
Association between aspirin and NSAID dose and duration of use and adenomatous and hyperplastic polyp risk, the Tennessee Colorectal Polyp Study
| Polyp types |
|||||
|---|---|---|---|---|---|
| Adenomatous | Hyperplastic | ||||
| Exposures | Control | n | OR*(95% CI) | n | OR*(95% CI) |
| NSAID use | |||||
| Never | 1654 | 748 | 1.00 | 238 | 1.00 |
| Baby aspirin only | 701 | 333 | 0.79 (0.66–0.93) | 92 | 0.74 (0.56–0.97) |
| Regular aspirin only | 352 | 177 | 0.73 (0.58–0.90) | 63 | 0.90 (0.65–1.25) |
| Non-aspirin NSAIDs only | 343 | 125 | 0.67 (0.53–0.86) | 49 | 0.73 (0.51–1.04) |
| COX-2 inhibitor only | 77 | 21 | 0.61 (0.36–1.02) | 11 | 0.98 (0.49–1.93) |
| Any combination of NSAIDS | 304 | 125 | 0.60 (0.47–0.76) | 46 | 0.69 (0.48–1.00) |
| Baby aspirin only, doses/week | |||||
| Never | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 7 | 53 | 27 | 1.03 (0.62–1.71) | 6 | 0.75 (0.31–1.84) |
| ≥ 7 | 648 | 306 | 0.77 (0.64–0.92) | 86 | 0.74 (0.56–0.99) |
| ρtrend | 0.01 | 0.10 | |||
| Baby aspirin only, duration (yrs) | |||||
| Never | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 5 | 341 | 150 | 0.76 (0.61–0.96) | 39 | 0.65 (0.45–0.95) |
| ≥ 5 | 360 | 183 | 0.81 (0.65–1.01) | 53 | 0.85 (0.60–1.21) |
| ρtrend | 0.02 | 0.07 | |||
| Regular aspirin only, doses/week | |||||
| Never | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 7 | 58 | 20 | 0.61 (0.36–1.06) | 11 | 1.13 (0.57–2.25) |
| 7 | 229 | 124 | 0.75 (0.58–0.97) | 34 | 0.71 (0.46–1.08) |
| > 7 | 65 | 33 | 0.76 (0.48–1.20) | 18 | 1.30 (0.73–2.32) |
| ρtrend | 0.04 | 0.22 | |||
| Regular aspirin only, duration (yrs) | |||||
| Never | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 5 | 117 | 48 | 0.61 (0.42–0.89) | 20 | 0.87 (0.51–1.47) |
| ≥ 5 | 235 | 129 | 0.78 (0.60–1.00) | 43 | 0.89 (0.61–1.31) |
| ρtrend | 0.01 | 0.81 | |||
| Single agent non-aspirin NSAID, doses/week | |||||
| None | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 7 | 81 | 27 | 0.81 (0.51–1.29) | 13 | 1.00 (0.53–1.88) |
| 7 | 124 | 45 | 0.72 (0.50–1.04) | 21 | 0.94 (0.56–1.56) |
| > 7 | 215 | 74 | 0.59 (0.43–0.80) | 26 | 0.60 (0.38–0.95) |
| ρtrend | 0.002 | 0.13 | |||
| Single agent non-aspirin NSAID, duration (yrs) | |||||
| Never | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 5 | 176 | 58 | 0.61 (0.44–0.85) | 17 | 0.49 (0.28–0.83) |
| ≥ 5 | 244 | 88 | 0.71 (0.53–0.93) | 43 | 0.97 (0.67–1.41) |
| ρtrend | 0.001 | 0.03 | |||
| Any combination of NSAID, doses/week | |||||
| None | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 7 | 38 | 21 | 0.92 (0.52–1.64) | 4 | 0.55 (0.19–1.63) |
| 7 | 85 | 44 | 0.80 (0.53–1.19) | 13 | 0.76 (0.40–1.44) |
| > 7 | 181 | 60 | 0.45 (0.32–0.62) | 29 | 0.67 (0.42–1.05) |
| ρtrend | < 0.0001 | 0.26 | |||
| Any combination of NSAIDs, duration (yrs) | |||||
| Never | 1654 | 748 | 1.00 | 238 | 1.00 |
| < 5 | 57 | 22 | 0.56 (0.33–0.95) | 9 | 0.63 (0.30–1.35) |
| ≥ 5 | 247 | 103 | 0.60 (0.46–0.79) | 37 | 0.71 (0.48–1.06) |
| ρtrend | 0.0002 | 0.15 | |||
Adjusted for age, gender, race, family history, education level, body mass index, energy intake, smoking status, alcohol use, physical activity, use of hormone replacement therapy, indication for colonoscopy, study site, and year of study enrollment.
Table 4.
Association between drug dose and duration of aspirin and non-aspirin NSAID and adenomatous polyp risk, the Tennessee Colorectal Polyp Study
| Adenomatous Polyp |
|||
|---|---|---|---|
| NSAID use | Controls | Cases | OR* (95% CI) |
| Never | 1654 | 748 | 1.00 |
| Aspirin only use | |||
| ≤ 7 doses a week | |||
| < 5 years of use | 400 | 174 | 0.73 (0.59, 0.91) |
| ≥ 5 years of use | 543 | 270 | 0.77 (0.64, 0.94) |
| > 7 doses a week | |||
| < 5 years of use | 32 | 15 | 0.69 (0.36, 1.31) |
| ≥ 5 years of use | 78 | 51 | 0.92 (0.61, 1.36) |
| P-interaction | 0.37 | ||
| Single agent non-aspirin NSAID | |||
| ≤ 7 doses a week | |||
| < 5 years of use | 84 | 27 | 0.62 (0.39, 0.99) |
| ≥ 5 years of use | 121 | 45 | 0.85 (0.59, 1.24) |
| > 7 doses a week | |||
| < 5 years of use | 92 | 31 | 0.60 (0.38, 0.93) |
| ≥ 5 years of use | 123 | 43 | 0.58 (0.40, 0.86) |
| P-interaction | 0.43 | ||
| Any combination of NSAID | |||
| ≤ 7 doses a week | |||
| < 5 years of use | 30 | 15 | 0.68 (0.35, 1.33) |
| ≥ 5 years of use | 93 | 50 | 0.89 (0.61, 1.30) |
| > 7 doses a week | |||
| < 5 years of use | 27 | 7 | 0.42 (0.18, 0.99) |
| ≥ 5 years of use | 154 | 53 | 0.45 (0.32, 0.64) |
| P-interaction | 0.83 | ||
Adjusted for age, gender, race, family history, education level, body mass index, energy intake, smoking status, alcohol use, physical activity, use of hormone replacement therapy, indication for colonoscopy, study site, and year of study enrollment.
There was no clear evidence of a joint effect between dose of aspirin and dose of non-aspirin NSAIDs and adenomatous polyp risk (Table 3). We found no evidence of an interaction between NSAID dose and duration of use with adenomatous polyp risk (Table 4).
Table 3.
Association between dose per week of aspirin and NSAID use and adenomatous polyp risk, the Tennessee Colorectal Polyp Study
| Non- aspirin NSAIDs, doses/week |
Aspirin, doses/week |
|||||
|---|---|---|---|---|---|---|
| None | ≤ 7 | > 7 | ||||
| Case/Controls | OR* (95% CI) | Case/Controls | OR* (95% CI) | Case/Controls | OR* (95% CI) | |
| None | 748/1654 | 1.00 | 444/943 | 0.76 (0.65–0.89) | 66/110 | 0.85 (0.60–1.20) |
| ≤ 7 | 72/205 | 0.75 (0.56–1.01) | 56/107 | 0.83 (0.58–1.19) | 9/16 | 0.81 (0.34–1.92) |
| > 7 | 79/232 | 0.58 (0.44–0.78) | 39/131 | 0.38 (0.26–0.57) | 16/33 | 0.65 (0.34–1.24) |
| P-interaction = 0.56 | ||||||
Adjusted for age, gender, race, family history, education level, body mass index, energy intake, smoking status, alcohol use, physical activity, use of hormone replacement therapy, indication for colonoscopy, study site, and year of study enrollment.
When stratified by polyp location, aspirin and non-aspirin NSAID use was associated with reduced risks of both proximal and distal adenomatous polyp although the effect sizes were slightly larger for adenomatous polyps located in the distal bowel. (Table 5) Aspirin and non-aspirin NSAID use was associated with a reduction in both large (≥ 1 cm) and small (< 1 cm) adenomatous polyp risks (Table 6). For large adenomas, regular use of aspirin and non-aspirin NSAID use was associated with an odds ratio of 0.64 (0.43–0.95) and 0.27 (0.15–0.48) respectively.
Table 5.
Association between aspirin and NSAID use and adenomatous and hyperplastic polyp risk stratified by polyp location, the Tennessee Colorectal Polyp Study
| Adenomatous Polyp |
|||||||
|---|---|---|---|---|---|---|---|
| Control | Proximal | Distal | Rectal | ||||
| Exposures | n | OR*(95% CI) | n | OR*(95% CI) | n | OR*(95% CI) | |
| NSAID use | |||||||
| Never | 1654 | 268 | 1.00 | 253 | 1.00 | 59 | 1.00 |
| Baby aspirin only | 701 | 139 | 0.90 (0.71–1.15) | 100 | 0.72 (0.55–0.94) | 33 | 0.99 (0.62–1.57) |
| Regular aspirin only | 352 | 66 | 0.79 (0.58–1.08) | 51 | 0.61 (0.43–0.87) | 17 | 0.92 (0.51–1.67) |
| Non-aspirin NSAIDs only | 343 | 60 | 0.90 (0.65–1.24) | 38 | 0.57 (0.39–0.84) | 10 | 0.73 (0.36–1.50) |
| Any combination of NSAIDS | 304 | 53 | 0.69 (0.49–0.98) | 33 | 0.46 (0.30–0.69) | 13 | 1.00 (0.52–1.91) |
| Hyperplastic Polyps |
|||||||
| Control | Proximal | Distal | Rectal | ||||
| n | OR*(95% CI) | n | OR*(95% CI) | n | OR*(95% CI) | ||
| NSAID use | |||||||
| Never | 1654 | 36 | 1.00 | 82 | 1.00 | 86 | 1.00 |
| Baby aspirin only | 701 | 16 | 0.81 (0.43–1.51) | 41 | 0.93 (0.61–1.42) | 22 | 0.56 (0.34–0.93) |
| Regular aspirin only | 352 | 5 | 0.52 (0.98–1.07) | 29 | 1.13 (0.70–1.83) | 19 | 0.84 (0.49–1.45) |
| Non-aspirin NSAIDs only | 343 | 7 | 0.77 (0.33–1.79) | 24 | 1.01 (0.61–1.65) | 13 | 0.58 (0.31–1.09) |
| Any combination of NSAIDS | 304 | 6 | 0.73 (0.29–1.84) | 12 | 0.54 (0.28–1.04) | 19 | 0.91 (0.52–1.58) |
Adjusted for age, gender, race, family history, education level, body mass index, energy intake, smoking status, alcohol use, physical activity, use of hormone replacement therapy, indication for colonoscopy, study site, and year of study enrollment.
Table 6.
Association between NSAID use and adenomatous polyp size
| Adenomatous Polyp* | ||||||
|---|---|---|---|---|---|---|
| NSAID use | Controls | n | ≥ 1 cm | N | < 1 cm | |
| Never | 1654 | 174 | 1.00 | 571 | 1.00 | |
| Baby aspirin only | 701 | 80 | 0.71 (0.52–0.97) | 253 | 0.81 (0.67–0.98) | |
| Regular aspirin only | 352 | 39 | 0.64 (0.43–0.95) | 137 | 0.75 (0.59–0.95) | |
| Non-aspirin NSAIDs only | 343 | 13 | 0.27 (0.15–0.48) | 112 | 0.80 (0.63–1.03) | |
| COX-2 inhibitor only | 77 | 3 | 0.34 (0.10–1.13) | 18 | 0.70 (0.41–1.22) | |
| Any combination of NSAIDS | 304 | 20 | 0.37 (0.22–0.62) | 105 | 0.66 (0.51–0.86) | |
| Aspirin only, doses/week | ||||||
| Never | 1654 | 174 | 1.00 | 571 | 1.00 | |
| < 7 | 119 | 8 | 0.60 (0.28–1.27) | 44 | 0.96 (0.65–1.40) | |
| 7 | 824 | 88 | 0.65 (0.48–0.87) | 303 | 0.77 (0.65–0.93) | |
| > 7 | 110 | 23 | 1.13 (0.68–1.90) | 43 | 0.78 (0.53–1.14) | |
| ρtrend | 0.006 | 0.02 | ||||
| Single agent non-aspirin NSAID, doses/week | ||||||
| None | 1654 | 174 | 1.00 | 571 | 1.00 | |
| < 7 | 81 | 2 | 0.27 (0.07–1.13) | 25 | 0.95 (0.59–1.54) | |
| 7 | 124 | 7 | 0.42 (0.19–0.94) | 38 | 0.83 (0.56–1.22) | |
| > 7 | 215 | 7 | 0.21 (0.09–0.46) | 67 | 0.72 (0.52–0.98) | |
| ρtrend | < 0.0001 | 0.18 | ||||
| Any combination of NSAID, doses/week | ||||||
| Never | 1654 | 174 | 1.00 | 571 | 1.00 | |
| < 7 | 38 | 7 | 1.25 (0.52–3.04) | 14 | 0.79 (0.41–1.51) | |
| 7 | 85 | 5 | 0.32 (0.12–0.83) | 39 | 0.95 (0.63–1.45) | |
| > 7 | 181 | 8 | 0.23 (0.11–0.50) | 52 | 0.51 (0.36–0.72) | |
| ρtrend | 0.0003 | 0.002 | ||||
Adjusted for age, gender, race, family history, education level, body mass index, energy intake, smoking status, alcohol use, physical activity, use of hormone replacement therapy, indication for colonoscopy, study site, and year of study enrollment
Discussion
Consistent with prior studies, we found a reduced risk for colon adenomas in regular users of aspirin or non-aspirin NSAIDs (23–25). Although we found slightly larger effect sizes in individuals reporting regular use of both aspirin and non-aspirin NSAIDs, our test for interaction did not reach statistical significance. In addition, we found no evidence of a statistical interaction between the dose and duration of use for aspirin or non-aspirin NSAIDs. Both baby aspirin and non-aspirin NSAIDs appeared protective for hyperplastic polyps, which is consistent with previous studies of hyperplastic polyps (26–29). We found no association between use of COX-2 inhibitors and hyperplastic polyp risk; however, we had few cases and limited power to detect a true effect. The association of aspirin or non-aspirin NSAIDs with adenomatous polyp risk appears to be more prominent for distal than proximal polyps although the difference was modest. Similar with prior studies we found greater effect sizes associated with regular NSAID use for larger adenomas (23, 30).
Overall we found a more pronounced effect of NSAIDS on adenomatous polyp risk as opposed to hyperplastic polyp risk. One possible mechanism for this difference in NSAID effects is likely related to the differential overexpression of COX-2 seen in adenomatous polyps as opposed to hyperplastic polyps. Although overexpression of COX-2 has been described in hyperplastic polyp specimens,(31) the strength of COX-2 overexpression is less in hyperplastic polyps compared to adenomatous polyps.(32, 33) Kawasaki et al. found that 28% of non-serrated adenomas had strong overexpression of COX-2 compared to only 4.2% of hyperplastic polyps.(33) In addition, COX-2 overexpression in serrated adenomas appeared to vary based on tumor location and polyp histopathology. For hyperplastic and sessile serrated polyps, distally located polyps tended to have stronger COX-2 overexpression although these sample sizes were small and this difference was not statistically significant. Other studies have also found that serrated adenomas have higher levels of COX-2 overexpression compared to hyperplastic polyps.(32, 34) When stratified by location we found stronger effects for most NSAID categories on hyperplastic polyps located distally or in the rectum but these findings should be interpreted with caution as our numbers were very small and our estimates unstable.
In our primary analysis, we found a protective effect of non-aspirin NSAIDs on hyperplastic polyp risk. Two prior studies have found a significant reduction in odds ratio for hyperplastic polyps in NSAID users compared to non-NSAID users (16, 17). In a large cross-sectional study including 391 cases, Lieberman found that daily NSAID use was associated with an adjusted odds ratio of 0.75 (0.56 – 0.99) for hyperplastic polyp risk compared to nonusers (16). In a small case-control study of 81 subjects with hyperplastic polyps and 480 controls, Martinez found an adjusted odds ratio of 0.34 (0.14 – 0.83) in daily non-aspirin NSAID users (17). In both of these studies, aspirin and non-aspirin NSAID users were combined into a single regular NSAID user category. In a third case-control study which included 219 hyperplastic polyp cases and 708 controls and evaluated aspirin and non-aspirin NSAIDs separately found a nonsignificant effect in non-aspirin NSAID users (OR = 0.60; 0.3–1.11) and no effect of aspirin use (OR = 1.0; 0.6–1.6) on hyperplastic polyp risk (35) however it was not reported whether the aspirin being used was baby aspirin versus regular aspirin. Wallace et al. pooled three large chemoprevention trials together with a total of 237 left-sided and 90 right-sided serrated polyps and found a protective effect of aspirin (both 81 mg and 325 mg) for right sided serrated polyps that was not seen for left-sided lesions.(36) It is not entirely clear why we found stronger effects with baby aspirin use than regular aspirin use in our study. Wallace et al. found a slight increased effect size for 81 mg of aspirin as opposed to 325 mg aspirin on serrated polyp risk which was more pronounced in distal polyps.(36) Of note, when the analysis included only advanced serrated adenomas, 325 mg of aspirin had larger effect sizes than 81 mg of aspirin. This might suggest that in less advanced serrated adenomas, and presumably those with lower COX-2 overexpression, baby aspirin may have a more pronounced effect than regular aspirin however this is speculative and there is no clear mechanism to explain these findings.
We found a possible suggestion of a weak joint effect between the simultaneous use of aspirin and non-aspirin NSAIDs although our interaction term was not statistically significant. In the Iowa Women’s Health Study, participants who occasionally used aspirin and regularly used non-aspirin NSAIDs seem to have the most benefit, however women who were regular users of both medications did not appear to derive additional benefit (21). Intriguingly, this is a similar pattern that we found in our study. Our data would suggest that the addition of aspirin to regular non-aspirin NSAID usage is unlikely to result in a synergistic reduction of adenoma risk.
Only a limited number of studies have evaluated sub-site specific NSAID effects with respect to colorectal adenomas. A randomized controlled trial by Baron et al. on adenoma recurrence noted no difference in effect by adenoma site; however, this was a trial of aspirin use and did not include non-aspirin NSAIDs (9). In observational studies, Chan et al. noted no association of aspirin use and the risk of adenoma by location; however, the effect size for distal adenomas (RR = 0.75, 0.66–0.84) was slightly lower than those for proximal adenomas (RR = 0.81, 0.65–1.01) (28). We found stronger evidence of sub-site differences with non-aspirin NSAIDs as opposed to aspirin use but these differences were not statistically significance and would be of little clinical importance.
Our study has several strengths. The TCPS is one of the largest colonoscopy-based case-control studies of colorectal polyps conducted, providing adequate power even for some analyses that were not possible in previous studies. Only patients with complete colonoscopies were included within the study ensuring an uncontaminated control groups. There are several weaknesses to the study. First, the TCPS is a case-control study and may be subject to recall bias. This bias, however, might be mitigated using an intermediate outcome such as adenomatous polyps. A second limitation is our ascertainment of non-aspirin NSAID use was based on participants’ retrospective recall of drug use patterns and thus might result in misclassification bias. This could result in an attenuation of our effect sizes. Finally, as part of the initial pathological review, all polyps of the serrated pathway were classified as hyperplastic polyps. Thus this category could represent a diverse group of clinically and pathologically distinct lesions with varying degrees of neoplastic potential.
In summary, baby aspirin, regular aspirin, non-aspirin NSAIDs, and COX-2 inhibitor use is associated with a reduced risk of adenomatous polyps while baby aspirin and non-aspirin NSAIDs use is associated with a reduced risk for hyperplastic polyp. Concomitant use of both aspirin and non-aspirin NSAIDs may offer a slight reduction in polyp risk compared to either agent by itself however this effect is modest and not likely to offset any possible increase in NSAID related adverse effects. We found no clear evidence of sub-site specific effects of NSAIDs for either adenomatous or hyperplastic polyps.
Acknowledgments
Grant support: This study was supported through the National Cancer Institute grant P50CA 95103 and R01CA97386. Dr. Murff is supported by K07CA114029 and R01CA143288. The survey was conducted by the Survey and Biospecimen Shared Resource supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA 68485)
Footnotes
Disclosures: The authors have nothing to disclose
References
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