effect of nsaids on the recurrence of nonmelanoma skin cancer
TRANSCRIPT
Effect of NSAIDs on the recurrence of nonmelanoma skin cancer
Maria V. Grau1*, John A. Baron
1,2, Bryan Langholz
3, Margaret Karagas
1, E. Robert Greenberg
1,
Therese A. Stukel4 and Jack S. Mandel5
1Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH, USA2Department of Medicine, Dartmouth Medical School, Lebanon, NH, USA3Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA, USA4Institute for Clinical Evaluative Sciences, Toronto, ON, Canada5Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
Experimental studies have consistently shown a protective effect ofnonsteroidal antiinflammatory drugs (NSAIDs) against nonmela-noma skin cancers (NMSC). However, little human epidemiologicalresearch has been done in this regard. We used data from the SkinCancer Chemoprevention Study to explore the association ofNSAID use and with the risk of basal-cell carcinoma (BCC) andsquamous-cell carcinoma (SCC). 1,805 subjects with a recent his-tory of NMSC were randomized to placebo or 50 mg of daily b-car-tene. Participants were asked about their use of over-the-counterand prescription medications at baseline and every 4 months duringthe trial. Skin follow-up examinations were scheduled annually witha study dermatologist; confirmed lesions were the endpoints in thestudy. We used a risk set approach to the analysis of grouped timessurvival data and unconditional logistic regression to compute oddsratios [ORs] for various exposures to NSAIDs. The use of NSAIDswas reported in over 50% of questionnaires. For BCC, NSAIDsexhibited a weak protective effect in crude analyses, which attenu-ated markedly after adjustment. For SCC, the use of NSAIDs in theyear previous to diagnosis reduced the odds by almost 30%(adjusted OR5 0.71, 95% CI 0.48–1.04). When we accounted forfrequency of use, results for BCC were not striking, and there wereinconsistent suggestions of an inverse association with SCC. Therewere some indications of a modest, nonsignificant reduction on thenumber of BCCs and SCCs with NSAID use. Our data suggest aweak and inconsistent chemopreventive effect of NSAIDs on BCCand SCC.' 2006 Wiley-Liss, Inc.
The chemopreventive effect of nonsteroidal antiinflammatorydrugs (NSAIDs), particularly aspirin, on nonmelanoma skin cancer(NMSC) has been repeatedly shown in animal1–5 and in in vitrostudies.6,7 In humans, some experimental studies have reported thattopical or oral NSAIDs may lead to regression of skin neoplasms.8–10
Findings from both observational studies11–17 and clinical tri-als18–20 are consistent with a protective effect of NSAIDs againstcolorectal neoplasia, but few epidemiological studies have investi-gated the preventive effects of NSAIDs on risk of nonmelanomaskin cancer,21,22 the most commonly occurring cancer in the Cau-casian population.23,24 However, results from 1 single-arm, un-blinded study and from a randomized trial of topical diclofenacfor treatment of actinic keratoses, a well-known precursor of SCC,have been encouraging.25,26 In the present analysis, we used datafrom a skin cancer chemoprevention trial,27 to explore the rela-tionship between NSAID use and the occurrence of nonmelanomaskin cancer, both basal-cell carcinomas (BCC) and squamous-cellcarcinomas (SCC).
Material and methods
The Skin Cancer Prevention Study was a randomized, doubleblind trial of oral b-carotene for the prevention of nonmelanomaskin cancer in patients with a recent history of these tumors.Details of the study design and methods have been described else-where.27,28 The study involved 4 clinical centers: Dartmouth-Hitchcock Medical Center in Hanover, NH (also the coordinatingcenter), the University of California at Los Angeles School ofMedicine, the University of California Medical School in SanFrancisco and the University of Minnesota Schools of Medicineand Public Health, Minneapolis. Enrollment of patients began in
February 1983. Eligible subjects had at least 1 histologically con-firmed basal-cell or squamous-cell carcinoma after January 1, 1980.Eligibility was assessed through review of medical records anddermopathology reports. Of the 5,232 potentially eligible patients,1,968 entered a 1-month placebo run in period and 1,805 subjectswere randomized to receive either 50 mg of b-carotene (BASF,Wyandotte, Mich.) daily or placebo.
At baseline, subjects completed a questionnaire regarding demo-graphic characteristics, sun exposure history, previous skin cancers,health behaviors, current use of over-the-counter and prescriptionmedications and usual frequency of vegetable consumption. Astudy dermatologist assessed the skin type of each subject, sum-marizing its reactivity to sun exposure (erythema versus tanning),presence of solar damage and number and cell types of known pre-vious skin cancers.
Every 4 months, participants completed interval questionnairesthat included items regarding recent medical history and skinexaminations and diagnoses since the previous questionnaire. Sub-jects were also asked what over-the-counter products and prescrip-tion medications had been used, although no information on dosesor frequency of use was obtained. Skin follow-up examinationswere scheduled annually with a study dermatologist; biopsies wereperformed on all lesions that were suspicious for cancer. Skinlesions removed in interim examinations were also tracked. Alllesions were examined independently by a local pathologist as wellas by the study dermatopathologist. If the 2 readings disagreed withregard to the presence or absence of nonmelanoma skin cancer, athird reading by a consultant dermatopathologist was used for a finaldiagnosis. The primary endpoint of the study was the occurrence ofincident NMSC.
During the trial, 3,975 skin lesions in 1,093 participants (61%)were identified as possible cancers and removed. We excludedfrom the analysis lesions not confirmed microscopically (n 5 49),those that were recurrence of a previous cancer (n 5 286), malig-nant melanomas (n 5 3) and nonneoplastic lesions (n 5 1,685).Thus, 1,952 microscopically confirmed new skin cancers from 702of the 1,805 randomized subjects (39%) were included in the pres-ent analysis (1,747 BCCs, 204 SCCs and 1 baso-squamous carci-noma). Given the high level of agreement between local and studydermatopathologists (96%), we included the local pathologist’sdiagnoses when the slides were not available for coordinating cen-ter review (n 5 52). Of the 702 patients with confirmed cancers,570 had only BCCs, 51 had only SCCs and 81 had both.
Every 6 months, an external safety and data-monitoring commit-tee reviewed study data. This committee considered that we had suf-ficient data to evaluate the main study hypothesis in the summer of1989, and participants were instructed to stop taking study pills onSeptember 30, 1989.
*Correspondence to: Section of Biostatistics and Epidemiology, Ever-green Center, Suite 300, 46 Centerra Parkway, Lebanon, NH 03766, USA.Fax:1603-650-3473. E-mail: [email protected] 10 October 2005; Accepted 5 December 2005DOI 10.1002/ijc.21878Published online 22 February 2006 inWiley InterScience (www.interscience.
wiley.com).
Int. J. Cancer: 119, 682–686 (2006)' 2006 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Statistical analysis
To evaluate the association of NSAID use with the occurrenceof NMSC, properly accounting for the time-dependent nature ofNSAID use, we used a risk set approach to the analysis of groupedtime survival data.29 Each 12-month period after randomization(except the first) was considered as 1 study year. The first studyyear was 15 months long to cover the time permitted in our proto-col for the first annual follow-up appointment. Skin cancers wereattributed to the study year of diagnosis. When the trial ended, 141patients were in the first half of their fourth study year and there-fore were censored at the end of the third year; 549 patients werein the first half of the fifth year and censored at the end of thefourth. In this analysis, we do not consider events that occurred af-ter the end of a patient’s fifth study year.
Of the 1,805 subjects randomized in the study, 84 never had anannual follow-up evaluation. Of the remaining 1,721 subjects, 1,019remained cancer-free during the study and 702 had at least 1NMSC. Randomization to b-carotene supplementation did not con-fer a significant reduction of risk for NMSC.27 In the present analy-sis, we defined risk sets for each study year as the group of all sub-jects who underwent that year’s follow up dermatological examwithout a prior incident NMSC since randomization. In each riskset, cases were subjects diagnosed with a NMSC at that year’s an-nual examination or during an interim exam during that year, andcontrols were those who remained cancer-free up to that point in thestudy. A subject could be classified as a control in 1 risk set and sub-sequently become a case in a later one. To account for each type ofNMSC, we applied the same approach to SCC and BCC separately.
In the overwhelming majority of instances, all 3 interval ques-tionnaires for a study year were completed before that year’s studyexam [in 96.4 % of subject study years]. Overall, 1,256 subjects(70%) reported use of NSAIDs in at least 1 interval questionnaireduring the study. Of these, around 87% only took medicationscontaining aspirin (alone or in combination with other NSAIDs)
and 13% exclusively used nonaspirin NSAIDs. Exposure wasdefined in 2 ways: as a binary variable indicating the report ofNSAID use (including aspirin) in any questionnaires for a givenstudy period, and as an ordered categorical variable that accountedfor duration of exposure. In the latter case, we computed the pro-portion of completed questionnaires during the study period indi-cating NSAID use and defined a categorical variable as: none, spo-radic use (less or half of questionnaires positive for NSAID use)and frequent use (more than half of the questionnaires positive).
To account for possible latencies of NSAID effect, we consid-ered different exposure periods: reported use of NSAIDs at base-line, exposure during the same study year as the exam, exposureduring the previous year and exposure during the same and theprevious study years. To overcome possible response bias (as sub-jects who completed interval questionnaires could be differentfrom those who do not), we repeated the analyses including onlysubjects who had completed the 3 questionnaires submitted duringa given year. Subjects without interval questionnaires in a studyperiod had missing information for the exposure in the corre-sponding risk set.
As appropriate for grouped time risk set data, unconditionallogistic regression was applied to compute odds ratios (ORs) forvarious exposures to NSAIDs; covariates in the full models wereage, sex, center, skin type, number of nonmelanoma skin cancersprior to study entry and number of completed questionnaires.Given the null effects of the randomized treatment assignment,this variable was not included in the final analyses.
We also accounted for multiple NMSC using overdispersed Pois-son regression models. To ensure that NSAID use preceded the skincancer diagnosis, we first considered the association of baseline usewith the total number of NMSCs diagnosed during the trial. Second,we used the first 2 study years to classify NSAID use, and took asendpoints the number of diagnosed NMSC in the 3 later years. Wealso repeated these analyses independently for SCC and BCC.
Results
Baseline characteristics of cases and controls are summarized inTable I. Cases were older and more likely to be male than con-trols. As expected, cases were more likely to have high/moderaterisk skin type and a higher number of previous skin cancers.
Compliance with interval questionnaires and use of medicationscontaining aspirin is described in Table II. About 98% of partici-pants completed at least 1 questionnaire in any given study period,and about 85% completed all 3 questionnaires. The response ratein the last study period was somewhat lower, reflecting the factthat the study ended prematurely and some information was cen-sored as of the end of the previous year. Among subjects with atleast 1 questionnaire, about 50% reported use of NSAIDs in eachrisk set. Among those with all questionnaires completed, morethan a fourth indicated a regular use of aspirin, i.e., use in all 3questionnaires.
Table III shows the ORs for the association of incident BCCand SCC with NSAID use at different times in relation to diagno-sis. For BCC, the crude estimates suggested a significant protec-tive trend for baseline use (crude OR 5 0.79, 95% CI: 0.65–0.95)and a borderline significant trend for use in the same and the previ-ous year as the diagnosis (crude OR 5 0.85, 95% CI: 0.70–1.03).
TABLE I – DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OFSTUDY PARTICIPANTS
Characteristic Controls N 5 1,019 (%) Cases N 5 702 (%)
Age (mean 6 SD) 62.1 (10.3) 64.3 (9.1)Males (%) 638 (62.6) 548 (78.1)Study center (%)
Dartmouth 270 (26.5) 151 (21.5)UCLA 136 (13.4) 177 (25.2)UCSF 148 (14.5) 142 (20.2)Minnesota 465 (45.6) 232 (33.1)
Skin type1 (%)Burns 411 (40.3) 376 (53.6)Moderate 406 (39.8) 252 (36.0)Tans 202 (19.8) 73 (10.4)
Number of previous skin cancers2 (%)1 623 (61.6) 188 (26.8)2 201 (19.9) 143 (20.4)3 78 (7.7) 87 (12.4)4–5 68 (6.7) 122 (17.4)6–9 27 (2.7) 80 (11.4)>10 14 (1.4) 81 (11.6)
1One case with missing information.–2Eight controls and 1 casewith missing information.
TABLE II – COMPLIANCE WITH QUESTIONNAIRES AND NSAID USE BY RISK SET TIME
Risk-set time Total subjectsCompliance with interval questionnaires NSAID use
At least 1 questionnaire (%) 3 questionnaires (%) At least 1 positive questionnaire (%)1 3 positive questionnaires (%)2
1 1640 1621 (98.8) 1508 (92.0) 738 (45.5) 312 (20.7)2 1310 1284 (98.0) 1153 (88.0) 643 (50.1) 285 (24.7)3 1120 1105 (98.7) 958 (85.5) 600 (54.3) 272 (28.4)4 912 899 (98.6) 784 (86.0) 516 (57.4) 247 (31.5)5 500 487 (97.4) 375 (75.0) 214 (43.9) 113 (30.1)
1Among subjects with at least 1 completed questionnaire.–2Among subjects with 3 questionnaires.
683EFFECT OF NSAIDS ON THE RECURRENCE OF NONMELANOMA SKIN CANCER
However, these trends were attenuated after adjustment (adjustedOR for baseline use 0.89, 95% CI: 0.70–1.09 and for use in thesame and previous year 0.91, 95% CI: 0.74–1.12). These resultsdid not change when the analysis was restricted to subjects whowere fully compliant with the questionnaires (data not shown).
Associations with SCC tended to be somewhat stronger. Therewas an inverse association of risk with NSAID use during the pre-vious year (adjusted OR5 0.71, 95% CI: 0.48–1.04) and duringthe same and previous year (adjusted OR 5 0.79, 95% CI: 0.52–1.21). The findings for all BCC were very similar to those for allNMSC (data not shown).
We accounted for intensity of exposure by examining the propor-tion of completed questionnaires that indicated NSAID use during agiven study interval (Table IV). In this analysis, we did not includebaseline use, since it was a one-time report in the initial question-naire. For BCC, the ORs for frequent use of NSAIDs did not sug-gest significant associations in any of the exposure periods consid-ered (Table IV). For SCC, there was an inverse association of spo-radic use with risk. For example, the adjusted OR for NSAID use inthe same or the previous year was 0.45 (95% CI: 0.28–0.87). How-ever, ORs for frequent use were much closer to the null (Table IV).Again, results for all BCC were very similar to those for all NMSC(data not shown).
To evaluate the effect of NSAIDs on the number of recurrences,we used 2 approaches. First, we studied the relationship betweenNSAID use reported at the intake questionnaire and the number ofcancers diagnosed during the trial (Table V). For BCC, baselineNSAID use conferred a significant reduction of risk in the crudeanalysis (unadjusted ratio of the average number of tumors 0.86,95% CI: 0.66–0.95). Adjustment lowered this point estimate, butstatistical significance was lost (adjusted ratio 5 0.78, 95% CI:0.66–1.12). We obtained similar estimates for all NMSC. Resultsfor SCC were also not striking.
In addition, we explored the association between NSAID use dur-ing the first 2 years of the study and the average number of NMSCdiagnosed in the subsequent 3 years. Again, there were suggestionsof a reduction in the number of BCCs among NSAID users in thecrude models, but not after adjustment (adjusted ratio 5 0.91, 95%CI: 0.74–1.13). When we took into account the frequency of use,the rate was nonsignificantly lower for sporadic users (adjustedratio5 0.78, 95% CI: 0.59–1.03), but not for frequent users. Resultsfor all NMSC were virtually the same. Overall, rates for SCC werelower for NSAID users than for nonusers, but this was compatiblewith a chance association in all analyses (Table V).
Discussion
In this closely monitored cohort of high risk subjects, there wereonly inconsistent, weak suggestions of an inverse association ofuse of aspirin and other NSAIDs with the incidence of NMSC inyears following use. At most, our data suggest a weak chemopre-ventive effect of NSAID use on SCC in the year prior to diagnosis,and on the number of BCCs and SCCs.
The chemopreventive attributes of NSAIDs against carcinogen-esis have been widely recognized.30–32 In relation to the skin, theeffect of NSAIDs, particularly aspirin, on carcinogenesis has beeninvestigated in a few in vitro studies7,33 and in many animal stud-ies; the majority have reported an anticarcinogenic effect ofNSAIDs.1–6,33–36 Uncontrolled human studies have reported adecrease in the number of new skin tumors or regression of exist-ing ones with the use of topical or oral NSAIDs, supporting the an-tineoplastic properties of these drugs.8–10,37
In spite of this, little human epidemiological research has beendone to explore this association. Two population-based studies21,22
that used administrative databases assessed the risk of various can-cers, including NMSC, in relation to use of NSAIDs, with null
TABLE III – ASSOCIATION OF RISK OF NONMELANOMA SKIN CANCER WITH NSAID USE AT VARIOUS TIMES BEFORE DIAGNOSIS
NSAID useBasal-cell carcinomas Squamous-cell carcinomas
Controls1 Cases1 Crude OR2 Adjusted OR3 Controls1 Cases1 Crude OR2 Adjusted OR3
Baseline 1488/4936 164/651 0.79 (0.65–0.95) 0.89 (0.73–1.09) 1889/6597 36/132 0.93 (0.63–1.37) 0.95 (0.64–1.42)Same year 2524/4868 297/629 0.88 (0.75–1.04) 0.92 (0.77–1.10) 3307/6475 60/126 0.90 (0.63–1.28) 0.94 (0.66–1.36)Previous
year2196/4873 244/639 0.88 (0.74–1.05) 0.96 (0.80–1.15) 2904/6487 43/128 0.67 (0.46–0.98) 0.71 (0.48–1.04)
Same andpreviousyears4
1846/4833 198/624 0.85 (0.70–1.03) 0.91 (0.74–1.12) 2412/6420 40/123 0.76 (0.51–1.14) 0.79 (0.52–1.21)
1n NSAID users/N total.–2Risk set time and total number of questionnaires completed included in the model.–3Adjusted for age, sex, center,risk set time, number of skin cancers prior to study entry, skin type and total number of questionnaires completed.–4Subjects who reported useof NSAIDs the 2 years versus those who did not take any NSAIDs during those years (numbers represent the sum of cases and controls from the5 risk sets).
TABLE IV – ASSOCIATION OF NONMELANOMA SKIN CANCER RISK WITH DURATION OF NSAID USE DURING VARIOUS PERIODS BEFORE DIAGNOSIS
NSAID use1 Basal-cell carcinomas Squamous-cell carcinomas
Controls Cases Crude OR Adjusted OR2 Controls Cases Crude OR Adjusted OR2
Same yearNone 2344 332 1.00 (Reference) 1.00 (Reference) 3618 66 1.00 (Reference) 1.00 (Reference)Sporadic 650 79 0.87 (0.67–1.13) 0.86 (0.65–1.13) 846 9 0.51 (0.25–1.04) 0.57 (0.28–1.16)Frequent 1874 218 0.89 (0.74–1.07) 0.94 (0.78–1.15) 2461 51 1.04 (0.72–1.51) 1.07 (0.73–1.57)
Previous year3
None 1718 183 1.00 (Reference) 1.00 (Reference) 2445 52 1.00 (Reference) 1.00 (Reference)Sporadic 481 63 1.25 (0.92–1.69) 1.29 (0.93–1.77) 673 6 0.43 (0.18–1.00) 0.48 (0.20–1.12)Frequent 1309 118 0.88 (0.69–1.12) 0.96 (0.74–1.24) 1770 29 0.80 (0.50–1.26) 0.85 (0.53–1.36)
Same/previous years4
None 1347 149 1.00 (Reference) 1.00 (Reference) 1927 45 1.00 (Reference) 1.00 (Reference)Sporadic 917 96 0.98 (0.75–1.29) 1.05 (0.79–1.39) 1285 12 0.42 (0.22–0.80) 0.45 (0.28–0.87)Frequent 1279 124 0.91 (0.70–1.17) 1.01 (0.77–1.32) 1731 33 0.84 (0.53–1.33) 0.91 (0.57–1.45)
1NSAID use defined by the proportion of completed questionnaires during the study period indicating use: none (no questionnaires positivefor NSAID use), sporadic use (less or half of questionnaires positive for NSAID use) and frequent use (more than half of the questionnaires posi-tive).–2OR adjusted for age, sex, skin type, number of previous NMSC, center, number of questionnaires completed and risk set time.–3Risk set1 not included in this analysis.–4Risk sets 1 and 2 not included in this analysis.
684 GRAU ET AL.
results. However, a randomized trial has provided good evidenceof the therapeutic properties of NSAIDs, showing the efficacy oftopical diclofenac against actinic keratoses, proliferative lesionsthat are thought to be precursors of SCCs.25 Another single-arm,open-label study of topical diclofenac and actinic keratosis reachedsimilar positive conclusions.26
The best-known mechanism of action of NSAIDs is the inhibi-tion of COX-2, the inducible isoform of the cyclooxygenaseenzyme, implicated in inflammation and promotion of neoplastictumors.30,31,38–40 Overexpression of COX-2 seems to be a factorin almost all types of neoplasia, and in various stages of carcino-genesis.3,30–32,41,42 In the skin, experimental studies have shownthat acute UVB exposure can cause COX-2 overexpression in mu-rine and human skin and high levels of the enzyme are present inneoplastic lesions following UV irradiation.33,39–41 Furthermore,many in vitro and animal studies provide strong evidence for a roleof COX-2 as an endogenous promoter of skin neoplasia.3,34,41,43–45
However, our data only show inconsistent suggestions of effects ofNSAIDs on BCC and SCC.
One potential explanation for our mixed findings could be thatthe NSAID use we observed was too short to have affected theoccurrence of NMSC. For colorectal cancer, for example, 10–20years of consistent use may be required for a protective effect.30
Unfortunately, our data do not permit us to assess the associationof risk with the duration of use. Also, we observed a limited num-ber of SCCs, and had only limited statistical power to detect sig-nificant associations for this endpoint. Another plausible reasoncould be inaccuracies in the assessment of NSAID use, since ourquestionnaires did not collect information about dose or frequencyof use and this measurement error could have biased our findings.Moreover, patients were not asked specifically about use of aspirinor other NSAIDs, possibly leading to underreporting. If this af-fected cases and controls equally, the result would be a conserva-
tive bias in our estimates. Finally, confounding seems to be an im-portant factor in the analysis, since our estimates were often closerto the null and in the full multivariate models.
Nonetheless, our analysis has several strengths. To our knowl-edge, our study is the first to address the association between use ofaspirin and other NSAIDs and the risk of NMSC in a closely moni-tored cohort of high risk patients. We used data from a carefullycontrolled cohort of patients that were part of a randomized clinicaltrial. Study dermatologists performed annual exams and removedall suspicious lesions. Biopsy specimens were read locally and uni-formly by the coordinating center pathologist and the level of agree-ment was 96%. We used several statistical approaches to analyzethe data, exploring different exposure periods, and various case–control definitions within the cohort design. We also explored thepossibility of separate associations for BCC and SCC, acknowl-edging the many indications that BCC and SCC are biologicallydistinct: essential differences in histogenesis,46–49 molecular path-ways50,51 and vascularization patterns.52,53 The major limitationof our study is the lack of data regarding the doses and duration ofNSAID use in our subjects.
Thus, despite the role of COX-2 in skin carcinogenesis, our studyprovides only weak suggestions of chemopreventive effect of NSAIDson BCC and SCC. Of course, these results must be interpreted in thecontext of the limitations of our data. At this point, more observatio-nal and randomized studies would be very valuable, especially stud-ies that can assess more closely the duration of NSAID use.
Acknowledgements
We are indebted to the subjects of the Beta Carotene Skin CancerTrial, as well as to Nicholas Lowe, J. Corwin Vance, Peter Elias andSteven K. Spencer, all of whose enthusiasm and cooperation wereessential for the successful completion of the study.
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TABLE V – ASSOCIATION OF NSAID USE ON THE AVERAGE NUMBER OF NONMELANOMA SKIN CANCERS DIAGNOSED
NSAID useBasal-cell carcinomas Squamous-cell carcinomas
Avg. # NMSC1 Crude ratio of mean no. Adjusted ratio of mean no.2 Avg. # NMSC1 Crude ratio of mean no. Adjusted ratio of mean no.2
Association of NSAID use at baseline with NMSC diagnosed during the studyNone 1.01 1.00 (Reference) 1.00 (Reference) 0.11 1.00 (Reference) 1.00 (Reference)Any 0.86 0.86 (0.66–0.95) 0.78 (0.66–1.12) 0.09 0.81 (0.49–1.34) 0.89 (0.57–1.40)Association of NSAID use during the first 2 years in the study with the number of NMSC diagnosed during the last 3 years of follow up3
None4 0.62 1.00 (Reference) 1.00 (Reference) 0.07 1.00 (Reference) 1.00 (Reference)Any 0.44 0.69 (0.52–0.93) 0.91 (0.74–1.13) 0.05 0.68 (0.41–1.13) 0.80 (0.50–1.29)
Sporadic4 0.40 0.60 (0.40–0.88) 0.78 (0.59–1.03) 0.06 0.77 (0.41–1.44) 0.94 (0.53–1.67)Frequent4 0.48 0.76 (0.54–1.08) 1.02 (0.80–1.30) 0.04 0.61 (0.32–1.15) 0.69 (0.38–1.25)
1Avg. # NMSC5 total number of NMSC/number of subjects.–2Ratio of mean number of tumors adjusted for age, sex, center, time of follow up,number of previous NMSC and skin type.–354 subjects without any questionnaires in the first 2 years of the study are excluded from these analy-ses.–4NSAID user defined by the proportion of completed questionnaires indicating use during years 1 and 2 of the study: none (no questionnaires positivefor NSAID use), sporadic use (less or half of questionnaires positive for NSAID use) and frequent use (more than half of the questionnaires positive).
685EFFECT OF NSAIDS ON THE RECURRENCE OF NONMELANOMA SKIN CANCER
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