Journal of the National Cancer Institute Advance Access originally published online on June 24, 2008
JNCI Journal of the National Cancer Institute 2008 100(13):967-971; doi:10.1093/jnci/djn154
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
A Large Cohort Study of Nonsteroidal Anti-inflammatory Drug Use and Melanoma Incidence
Affiliations of authors: Division of Research, Kaiser Permanente Northern California, Oakland, CA (MMA); Department of Dermatology, University of California at San Francisco, San Francisco, CA (MMA); Department of Epidemiology, University of Washington, Seattle, Washington, DC (SSM, EW); Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, DC (SSM, EW)
Correspondence to: Maryam M. Asgari, MD, MPH, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612 (e-mail: maryam.m.asgari{at}kp.org).
 |
ABSTRACT |
|---|
 Top Abstract Context and CaveatsFundingReferencesNotes |
|---|
Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion (Pinteraction = .38), tumor thickness (Ptrend = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.
Prior knowledge Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. Study design Prospective cohort study to investigate whether commonly used over-the-counter and prescription NSAIDs are associated with melanoma risk. Contribution After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. Implications NSAIDs do not appear to be good candidates for the chemoprevention of melanoma. Limitations Detailed information on some known melanoma risk factors such as sunlight exposure and number of nevi was not available. The actual NSAIDs dose per day was not ascertained. The average follow-up was only 5 years, which may be insufficient to detect an effect because the lag time between the initiation and diagnosis of melanoma may be on the order of decades.
|
Epidemiological studies have demonstrated chemopreventative benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) for total cancer incidence and mortality (1,2) and for site-specific cancers such as those of the colon (3,4), breast (5), or prostate (6). Few epidemiological studies have examined the association of NSAIDs with melanoma risk and have found conflicting results (1,7–9). NSAIDs block cyclooxygenase enzymes, which inhibit the synthesis of proinflammatory molecules that play a role in tumor growth and development (10,11). Cyclooxygenase expression has been associated with melanoma invasion (12) and metastasis (13). Thus, NSAIDs could play a role in the chemoprevention of melanoma.
We conducted a prospective study of the Vitamins and Lifestyle (VITAL) cohort to investigate whether commonly used over-the-counter and prescription NSAIDs are associated with melanoma risk. The VITAL study recruited 77 719 men and women aged 50–76 years in western Washington state from October 1, 2000, through December 31, 2002, and ascertained detailed information about lifestyle, dietary, and cancer risk factors by use of a baseline questionnaire. Further study details have been published previously (14). This study was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board.
Participants were excluded if they reported a melanoma diagnosis at baseline (n = 1557), had missing data on NSAID use (n = 6652), or were nonwhite or did not report their race (n = 5701), leaving a total of 63 809 participants for this analysis. Participants self-reported NSAID exposure in the previous 10 years, noting years and frequency of their use of low-dose (81 mg) and regular- (325 mg) or extra-strength aspirin, ibuprofen, naproxen, and celecoxib or rofecoxib. Women also reported their intake of piroxicam and indomethacin. Ever use was defined as taking the medication at least once a week for a year in the 10-year period before baseline. Dose was computed as the average number of days per week of use for the 10 years before enrollment (ie, [days per week x years of use]/10).
Through linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident cases of malignant melanoma were identified between baseline and December 31, 2005. Cox proportional hazards models were used to estimate age- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for melanoma risk. Age was used as the time scale. We observed no violation of the proportional hazards by age with the Wald test. Nonusers of any NSAID were the common reference for all four drug exposures (ie, any NSAID; any NSAID excluding low-dose aspirin; regular- or extra-strength aspirin; and nonaspirin NSAIDs). The censor date was defined as the earliest date of withdrawal from the study (0.03%, n = 21), death (3.6%, n = 2720), out-of-area move (4.6%, n = 3486), or the end of follow-up on December 31, 2005. To control for confounding by indication, we adjusted for self-reported medical conditions that indicated (cardiovascular disease, chronic pain, arthritis) or contraindicated (kidney disease, gastric ulcer) NSAID use (as described in Table 1). Established or possible risk factors for melanoma were also included in the model; other lifestyle factors such as body mass index, total physical activity, and smoking history were not found to be confounding factors. To examine the association between participant characteristics and NSAID use (Table 1), odds ratios were calculated by logistic regression. All statistical tests were two-sided.
|
Among the 63 809 cohort participants, 40 200 (63%) regularly used any type of NSAIDs at least once a week for 1 year in the 10-year period before enrollment. Factors associated with regular NSAID use are given in Table 1. Multivariable associations between NSAID use and the risk of melanoma are summarized in Table 2. None of our four NSAID exposures examined (whether expressed as overall use, duration, or dose) was associated with melanoma risk. Compared with nonuse, no melanoma risk reduction was detected with use (
4 d/wk on average over the past 10 years) for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). We also observed no difference in melanoma risk among males (HR = 1.21, 95% CI = 0.85 to 1.71) or among females (HR = 1.01, 95% CI = 0.63 to 1.60; Pinteraction = .63) for dose of any NSAID.
|
There were 157 patients with in situ melanoma and 191 with invasive (including local, regional, and distant) melanoma. The association between dose of any NSAID use and the risk of in situ melanoma (HR = 1.17, 95% CI = 0.77 to 1.78, >4 days a week vs none) was not appreciably different than the risk of invasive melanoma (HR = 1.09, 95% CI = 0.75 to 1.57; Pinteraction = .38). Furthermore, we did not observe an association between dose of any NSAID use and the risk of metastatic melanoma, defined as regional or distant disease (HR = 1.09, 95% CI = 0.33 to 3.62; n = 23). Lastly, we did not detect an association between dose of any NSAID use and tumor thickness (n = 172 and Ptrend = .98).
In conclusion, we found no evidence to support an association between NSAID use and decreased melanoma risk. The lack of effect was persistent even though our NSAIDs variables accounted for frequency and duration of NSAID use and we considered the major classes of NSAIDs separately and combined. Our findings are consistent with a recently published large prospective study (6) that also found no association between duration of daily regular-strength aspirin use and the risk of incident melanoma. Although clinical reports of patients with surgically incurable or metastatic melanoma who demonstrated regression or complete remission with NSAID treatment have been published (15,16) and the rate of melanoma metastasis has been shown to be lower for patients using NSAIDs than nonusers (8), we did not observe an association between dose of any NSAID and tumor invasion, tumor thickness, or metastatic potential.
This study had several limitations, including the absence of detailed information on some known melanoma risk factors such as sunlight exposure and number of nevi. However, adjusting for risk factors of melanoma did not alter the risks in the multivariable model, and so it is unlikely that including residual risk factors would appreciably change the results. Also, the actual NSAID pills per day was not ascertained. Finally, the follow-up time between the 10-year period for which we had NSAID use data and cancer incidence was only 5 years on average, which may not be sufficient if the lag time between the initiation and diagnosis of melanoma is on the order of decades.
Strengths of this investigation include its prospective design, large cohort size, and the availability of baseline information on major potential confounding factors (including constitutional, personal, and family skin cancer history and patient numbers). In addition, we obtained data on long-term use of NSAIDs including commonly used over-the-counter NSAIDs.
We found no association between self-reported NSAID use and melanoma risk. Given the potential side effects of NSAIDs, including gastric ulcers, the search must continue for a good chemopreventive agent for melanoma.
|
Funding |
|---|
|
TopAbstractContext and CaveatsFundingReferencesNotes |
|---|
National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR 051037 to M.M.A.); National Cancer Institute (CA74846 to E.W., R25 CA94880 to S.S.M.).
|
NOTES |
|---|
|
TopAbstractContext and CaveatsFundingReferencesNotes |
|---|
The authors had full responsibility for study design; collection, analysis, and interpretation of the data; and the decision to submit the manuscript for publication.
|
REFERENCES |
|---|
|
TopAbstractContext and CaveatsFundingReferencesNotes |
|---|
1. Jacobs EJ, Thun MJ, Bain EB, Rodriguez C, Henley SJ, Calle EE. A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. J Natl Cancer Inst (2007) 99(8):608–615.
2. Bardia A, Ebbert JO, Vierkant RA, et al. Association of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs with cancer incidence and mortality. J Natl Cancer Inst (2007) 99(11):881–889.
3. Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg (1993) 80(12):1618–1619.[Web of Science][Medline]
4. Arber N, Eagle CJ, Spicak J, et al, PreSAP Trial Investigators. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med (2006) 355(9):885–895.
5. Harris RE, Kasbari S, Farrar WB. Prospective study of nonsteroidal anti-inflammatory drugs and breast cancer. Oncol Rep (1999) 6(1):71–73.[Web of Science][Medline]
6. Jacobs EJ, Rodriguez C, Mondul AM, et al. A large cohort study of aspirin and other nonsteroidal anti-inflammatory drugs and prostate cancer incidence. J Natl Cancer Inst (2005) 97(13):975–980.
7. Harris RE, Beebe-Donk J, Namboodiri KK. Inverse association of non-steroidal anti-inflammatory drugs and malignant melanoma among women. Oncol Rep (2001) 8(3):655–657.[Web of Science][Medline]
8. Ramirez CC, Ma F, Federman DG, Kirsner RS. Use of cyclooxygenase inhibitors and risk of melanoma in high-risk patients. Dermatol Surg (2005) 31(7 Pt 1):748–752.[Web of Science][Medline]
9. Ming ME, Shin DB, Bauer JA, Troxel AB. Statins, non-steroidal anti-inflammatory drugs (NSAIDs) and calcium channel blockers are prescribed less frequently for patient who later develop melanoma. Abstract. J Invest Dematol. Symposium Proceedings (2006) 126(suppl_1):49.[CrossRef]
10. Rao CV, Reddy BS. NSAIDs and chemoprevention. Curr Cancer Drug Targets (2004) 4(1):29–42.[CrossRef][Web of Science][Medline]
11. Kast RE. Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications. Med Oncol (2007) 24(1):1–6.[CrossRef][Web of Science][Medline]
12. Denkert C, Kobel M, Berger S, et al. Expression of cyclooxygenase 2 in human malignant melanoma. Cancer Res. (2001) 61(1):303–308.
13. Goulet AC, Einsphar JG, Alberts DS, et al. Analysis of cyclooxygenase 2 (COX-2) expression during malignant melanoma progression. Cancer Biol Ther (2003) 2(6):713–718.[Web of Science][Medline]
14. White E, Patterson RE, Kristal AR, et al. VITamins And Lifestyle cohort study: study design and characteristics of supplement users. Am J Epidemiol (2004) 159(1):83–93.
15. Lejeune FJ, Monnier Y, Rüegg C. Complete and long-lasting regression of disseminated multiple skin melanoma metastases under treatment with cyclooxygenase-2 inhibitor. Melanoma Res. (2006) 16(3):263–265.[CrossRef][Web of Science][Medline]
16. Wilson KS. Clinical activity of celecoxib in metastatic malignant melanoma. Cancer Invest (2006) 24(8):740–746.[CrossRef][Web of Science][Medline]
Manuscript received January 6, 2008; revised April 11, 2008; accepted April 14, 2008.
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 907.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||