BRIEF COMMUNICATION

Association Between Nonsteroidal Anti-Inflammatory Drug Use and the Incidence of Pancreatic Cancer

Kristin E. Anderson, Trista W. Johnson, DeAnn Lazovich, Aaron R. Folsom

Affiliation of authors: Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis.

Correspondence to: Kristin E. Anderson, Ph.D., Division of Epidemiology, University of Minnesota, 1300 S. Second St., #300, Minneapolis, MN 55454 (e-mail: anderson_k{at}epi.umn.edu).

ABSTRACT

Laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit pancreatic cancer, but epidemiologic data to support this finding are limited. We conducted a prospective study from 1992 through 1999 among 28 283 postmenopausal women who lived in Iowa to examine the association between the self-reported use of aspirin and other NSAIDs and the incidence of pancreatic cancer. Eighty incident cases of pancreatic cancer were identified during 7 years of follow-up. The multivariate-adjusted relative risk of pancreatic cancer associated with any current use of aspirin versus no use was 0.57 (95% confidence interval = 0.36 to 0.90). There was a trend of decreasing risk of pancreatic cancer incidence with increasing frequency of aspirin use per week (Ptrend = .005). Nonaspirin NSAID use was not associated with incident pancreatic cancer. These data indicate that aspirin might be chemopreventive for pancreatic cancer.


Pancreatic cancer is rapidly fatal in most cases (1), and few risk factors for this disease are known (2). Epidemiologic and laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) are chemopreventive for colon and, possibly, other cancers (39). NSAIDs may also inhibit pancreatic carcinogenesis, but data to support this hypothesis are limited (1016). Here we report on the association between the current use of aspirin and other NSAIDs and pancreatic cancer incidence in a large cohort of postmenopausal women.

In 1986, the Iowa Women's Health Study (1720) selected a random sample of women, aged 55–69 years, who had valid Iowa driver's licenses to participate in a long-term study of anthropometric measures and cancer. A total of 41 836 women completed a detailed mailed questionnaire, which included written informed consent. These women constituted the Iowa Women's Health Study (IWHS) cohort. Extensive information collected on the study cohort allowed for analyses of other exposure and cancer associations. Follow-up questionnaires were sent to each woman in 1987, 1989, 1992, and 1997 to update her exposure information, residence, and vital status. Deaths among nonresponders to these follow-up questionnaires and among women who emigrated from Iowa were located through the National Death Index.

We ascertained cancer incidence among this cohort by linking to the State Health Registry of Iowa, which is part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)1 Program. Cases of pancreatic cancer (n = 80 for these analyses) were defined by the World Health Organization's International Classification of Disease for Oncology (ICD-O) topography code for pancreatic tumors (ICD-O code 25) (21). Women who were diagnosed with islet cell tumors were excluded from this study. This study was approved by the Institutional Review Board of the University of Minnesota, Twin Cities Campus.

NSAID use was first ascertained in 1992. Respondents were asked how often they took aspirin or aspirin-containing products (e.g., BufferinTM, AnacinTM, enteric-coated aspirin, EcotrinTM, and ExcedrinTM). The categories for frequency of current use were never, less than once per week, once per week, two to five times per week, and six or more times per week. A second question asked about the frequency of use of other NSAIDs (e.g., ibuprofen, AdvilTM, NuprinTM, MotrinTM, NaprosynTM, FeldeneTM, and ClinorilTM). Both questions directed respondents to exclude their use of acetaminophen or TylenolTM. The dose, past use, and reasons for using aspirin and other NSAIDs were not assessed.

We excluded women who reported in 1986 that they had a cancer other than skin cancer (n = 2293) and women who reported any incident cancer between 1986 and the 1992 survey (n = 2512). We further excluded women who died between 1986 and the 1992 survey, women who were alive but did not respond to the 1992 survey, and women with missing data for both of the NSAIDs questions (n = 8748). The remaining 28 283 women were followed for incident pancreatic cancer.

Follow-up time for each woman was calculated from the date she completed the 1992 questionnaire to the date of pancreatic cancer diagnosis, the date of death (if it occurred in Iowa), the date the woman moved out of Iowa (if known), the midpoint of the interval between the last follow-up contact and December 31, 1999 (if the date of departure from Iowa was unknown), or the midpoint between the date of last contact and the date of death (for women who died after moving from Iowa), whichever occurred first. We assumed that the women for whom none of these criteria applied were living in Iowa. Those women contributed follow-up time until December 31, 1999.

Relative risks (RRs), 95% confidence intervals (CIs), and tests for trends in RRs using ordinal categories of increasing frequency of medication use were calculated using proportional hazards regression models (i.e., the PHREG procedure in SAS statistical software) (22). All statistical tests were two-sided. The reference groups for these analyses were nonusers of aspirin or nonusers of other NSAIDs, depending on the exposure that was analyzed. When we simultaneously stratified aspirin and other NSAID use into ever-used versus never-used categories to assess their combined effect, the reference category was women who reported no current use of either type of medication.

Table 1Go shows the prevalence of participant characteristics according to the frequency of aspirin use. The prevalence of these characteristics according to the frequency of nonaspirin NSAID use was very similar (data not shown). Risk factors for pancreatic cancer during the approximately 198 000 person-years accrued in this study included age, prevalent diabetes (RR for prevalent diabetes versus no diabetes = 2.90; 95% CI = 1.61 to 5.23), and current smoking in 1992 (RR for current smoking versus no smoking = 3.99; 95% CI = 2.29 to 6.95). Body mass index, waist-to-hip ratio, reproductive factors in 1986, and alcohol drinking in 1992 were not associated with incident pancreatic cancer. Multivitamin use in 1986 was inversely associated with incident pancreatic cancer (RR for users versus nonusers = 0.45; 95% CI = 0.24 to 0.84).


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Table 1. Prevalence of participant characteristics by frequency of aspirin use
 
The multivariate-adjusted RR of pancreatic cancer for any use versus no use of aspirin was 0.57 (95% CI = 0.36 to 0.90). Increasing frequency of aspirin use was inversely associated with the incidence of pancreatic cancer (Table 2Go). Compared with that of nonusers, the multivariate-adjusted RRs of pancreatic cancer for women who reported using aspirin two to five times per week or six or more times per week were 0.47 (95% CI = 0.22 to 0.98) and 0.40 (95% CI = 0.20 to 0.82), respectively (Ptrend = .005). Adjustment for the use of other NSAIDs yielded nearly identical results, i.e., RRs of 0.47 (95% CI = 0.23 to 1.0) and 0.41 (95% CI = 0.20 to 0.83) for those who used aspirin two to five times per week and six or more times per week, respectively. The results were also essentially unchanged when we excluded eight women who were diagnosed with pancreatic cancer during the first year of follow-up: The multivariate-adjusted RR of pancreatic cancer for aspirin use six or more times per week compared with no use for 1993–1999 was 0.39 (95% CI = 0.17 to 0.86). When we stratified by follow-up period, the multivariate-adjusted RRs of pancreatic cancer for aspirin use six or more times per week compared with no use were 0.31 (95% CI = 0.07 to 1.45) for 1992–1995 and 0.38 (95% CI = 0.15 to 0.96) for 1995–1999. Use of nonaspirin NSAIDs was not associated with pancreatic cancer incidence (Table 2Go). The multivariate-adjusted RR of pancreatic cancer for any current use versus no use of nonaspirin NSAIDs was 1.19 (95% CI = 0.76 to 1.88). There was no relationship between the incidence of pancreatic cancer and increasing frequency of nonaspirin NSAID use (Ptrend = .97). These results were not substantively changed when we adjusted for aspirin use.


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Table 2. Association between aspirin and other NSAID use and incident pancreatic cancer*
 
We simultaneously stratified by ever- versus never-use of aspirin and other NSAIDs. Compared with a reference category consisting of women who reported never using either type of medication, the multivariate-adjusted RRs were 0.66 (95% CI = 0.39 to 1.11) for women who used both medications, 0.56 (95% CI = 0.36 to 0.88) for women who used only aspirin, and 1.21 (95% CI = 0.77 to 1.89) for women who used only nonaspirin NSAIDs. We found no evidence for an interaction between nonaspirin NSAID and aspirin use, although the number of cases for such an analysis was small.

The chemopreventive potential of NSAIDs is thought to involve, in part, the inhibition of cyclooxygenase 2 expression but probably includes other mechanisms as well (9,10,23,24). The differences we observed between aspirin and other NSAIDs and their associations with incident pancreatic cancer could reflect differences in their mechanisms of action (9,24). Alternatively, this difference may reflect either the relatively infrequent or short-term use of nonaspirin NSAIDs compared with the use of aspirin by the women in this cohort or poor reporting of use because of lack of familiarity with these drugs.

Our findings are consistent with those from two cohort studies and one case–control study that examined the relationship between NSAID use and pancreatic cancer (1316). In the National Health and Nutrition Examination Study I cohort, reported use of aspirin in the last 30 days was inversely associated with incident pancreatic cancer (RR = 0.67) (15). However, those results were based on only 30 cases of pancreatic cancer, and the 95% CI of the RR included 1.0. In a cohort study of rheumatoid arthritis patients, where NSAID use was inferred rather than directly assessed, the authors reported age-standardized incidence ratios for pancreatic cancer of 1.12 for men, 0.68 for women, and 0.83 for both sexes (16). A statistically nonsignificant inverse association between pancreatic cancer and self-reported use of NSAIDs (mostly aspirin) was reported in one case–control study (13). By contrast, in another case–control study (14), in which NSAID use was assessed by the number of prescriptions for NSAIDs participants obtained, seven prescriptions versus no prescriptions for NSAIDs in the 13–36 months prior to a pancreatic cancer diagnosis yielded an odds ratio of 1.49 (95% CI = 1.02 to 2.18). The finding of such an association in a case–control study could reflect bias, such as that resulting from the treatment of pain in patients with subclinical disease (25,26).

Our study has several strengths. The data were collected prospectively in a large population-based cohort and allowed us to control for multiple potential confounders while avoiding numerous potential biases. This study is limited by the number of incident pancreatic cancer cases; however, that number is more than twice the number of cases reported in either of the other published cohort studies. In addition, information on the dose and duration of NSAID use were not collected in our study, which precluded an analysis of short-term versus long-term use (27). Finally, the homogeneity of the study population—postmenopausal women, 98.2% of which were Caucasian—although not necessarily a limitation, restricts the generalizability of our results.

If the associations observed here are causal, we estimate that 43% of pancreatic cancer cases among nonusers of aspirin might be prevented by aspirin use (preventable fraction was based on the multivariate-adjusted RR of 0.57 for ever versus never use) (28). Further studies of pancreatic cancer and NSAID use, with detailed assessments of dose, duration, and drug type used, are warranted.

NOTES

Supported by Public Health Service grant R01CA39742 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

1 Editor's note: SEER is a set of geographically defined, population-based central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research. Back

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Manuscript received October 3, 2001; revised May 16, 2002; accepted May 28, 2002.


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