Effect of NSAIDs on the recurrence of nonmelanoma skin cancer

Int. J. Cancer: 119, 682–686 (2006)

' 2006 Wiley-Liss, Inc.





Effect of NSAIDs on the recurrence of nonmelanoma skin cancer

Maria V. Grau1*, John A. Baron1,2, Bryan Langholz3, Margaret Karagas1, E. Robert Greenberg1,

Therese A. Stukel4 and Jack S. Mandel5

1

Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH, USA

2

Department of Medicine, Dartmouth Medical School, Lebanon, NH, USA

3

Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA, USA

4

Institute for Clinical Evaluative Sciences, Toronto, ON, Canada

5

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA



Experimental studies have consistently shown a protective effect of February 1983. Eligible subjects had at least 1 histologically con-

nonsteroidal antiinflammatory drugs (NSAIDs) against nonmela- firmed basal-cell or squamous-cell carcinoma after January 1, 1980.

noma skin cancers (NMSC). However, little human epidemiological Eligibility was assessed through review of medical records and

research has been done in this regard. We used data from the Skin dermopathology reports. Of the 5,232 potentially eligible patients,

Cancer Chemoprevention Study to explore the association of

NSAID use and with the risk of basal-cell carcinoma (BCC) and 1,968 entered a 1-month placebo run in period and 1,805 subjects

squamous-cell carcinoma (SCC). 1,805 subjects with a recent his- were randomized to receive either 50 mg of b-carotene (BASF,

tory of NMSC were randomized to placebo or 50 mg of daily b-car- Wyandotte, Mich.) daily or placebo.

tene. Participants were asked about their use of over-the-counter At baseline, subjects completed a questionnaire regarding demo-

and prescription medications at baseline and every 4 months during graphic characteristics, sun exposure history, previous skin cancers,

the trial. Skin follow-up examinations were scheduled annually with health behaviors, current use of over-the-counter and prescription

a study dermatologist; confirmed lesions were the endpoints in the

study. We used a risk set approach to the analysis of grouped times medications and usual frequency of vegetable consumption. A

survival data and unconditional logistic regression to compute odds study dermatologist assessed the skin type of each subject, sum-

ratios [ORs] for various exposures to NSAIDs. The use of NSAIDs marizing its reactivity to sun exposure (erythema versus tanning),

was reported in over 50% of questionnaires. For BCC, NSAIDs presence of solar damage and number and cell types of known pre-

exhibited a weak protective effect in crude analyses, which attenu- vious skin cancers.

ated markedly after adjustment. For SCC, the use of NSAIDs in the Every 4 months, participants completed interval questionnaires

year previous to diagnosis reduced the odds by almost 30% that included items regarding recent medical history and skin

(adjusted OR5 0.71, 95% CI 0.48–1.04). When we accounted for

frequency of use, results for BCC were not striking, and there were examinations and diagnoses since the previous questionnaire. Sub-

inconsistent suggestions of an inverse association with SCC. There jects were also asked what over-the-counter products and prescrip-

were some indications of a modest, nonsignificant reduction on the tion medications had been used, although no information on doses

number of BCCs and SCCs with NSAID use. Our data suggest a or frequency of use was obtained. Skin follow-up examinations

weak and inconsistent chemopreventive effect of NSAIDs on BCC were scheduled annually with a study dermatologist; biopsies were

and SCC. performed on all lesions that were suspicious for cancer. Skin

' 2006 Wiley-Liss, Inc. lesions removed in interim examinations were also tracked. All

lesions were examined independently by a local pathologist as well

The chemopreventive effect of nonsteroidal antiinflammatory as by the study dermatopathologist. If the 2 readings disagreed with

drugs (NSAIDs), particularly aspirin, on nonmelanoma skin cancer regard to the presence or absence of nonmelanoma skin cancer, a

(NMSC) has been repeatedly shown in animal1–5 and in in vitro third reading by a consultant dermatopathologist was used for a final

studies.6,7 In humans, some experimental studies have reported that diagnosis. The primary endpoint of the study was the occurrence of

topical or oral NSAIDs may lead to regression of skin neoplasms.8–10 incident NMSC.

Findings from both observational studies11–17 and clinical tri- During the trial, 3,975 skin lesions in 1,093 participants (61%)

als18–20 are consistent with a protective effect of NSAIDs against were identified as possible cancers and removed. We excluded

colorectal neoplasia, but few epidemiological studies have investi- from the analysis lesions not confirmed microscopically (n 5 49),

gated the preventive effects of NSAIDs on risk of nonmelanoma those that were recurrence of a previous cancer (n 5 286), malig-

skin cancer,21,22 the most commonly occurring cancer in the Cau- nant melanomas (n 5 3) and nonneoplastic lesions (n 5 1,685).

casian population.23,24 However, results from 1 single-arm, un- Thus, 1,952 microscopically confirmed new skin cancers from 702

blinded study and from a randomized trial of topical diclofenac of the 1,805 randomized subjects (39%) were included in the pres-

for treatment of actinic keratoses, a well-known precursor of SCC, ent analysis (1,747 BCCs, 204 SCCs and 1 baso-squamous carci-

have been encouraging.25,26 In the present analysis, we used data noma). Given the high level of agreement between local and study

from a skin cancer chemoprevention trial,27 to explore the rela- dermatopathologists (96%), we included the local pathologist’s

tionship between NSAID use and the occurrence of nonmelanoma diagnoses when the slides were not available for coordinating cen-

skin cancer, both basal-cell carcinomas (BCC) and squamous-cell ter review (n 5 52). Of the 702 patients with confirmed cancers,

carcinomas (SCC). 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-

Material and methods ficient data to evaluate the main study hypothesis in the summer of

The Skin Cancer Prevention Study was a randomized, double 1989, and participants were instructed to stop taking study pills on

blind trial of oral b-carotene for the prevention of nonmelanoma September 30, 1989.

skin 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- *Correspondence to: Section of Biostatistics and Epidemiology, Ever-

Hitchcock Medical Center in Hanover, NH (also the coordinating green Center, Suite 300, 46 Centerra Parkway, Lebanon, NH 03766, USA.

center), the University of California at Los Angeles School of Fax: 1603-650-3473. E-mail: Maria.Grau@dartmouth.edu

Received 10 October 2005; Accepted 5 December 2005

Medicine, the University of California Medical School in San DOI 10.1002/ijc.21878

Francisco and the University of Minnesota Schools of Medicine Published online 22 February 2006 in Wiley InterScience (www.interscience.

and Public Health, Minneapolis. Enrollment of patients began in wiley.com).



Publication of the International Union Against Cancer

EFFECT OF NSAIDS ON THE RECURRENCE OF NONMELANOMA SKIN CANCER 683

Statistical analysis and 13% exclusively used nonaspirin NSAIDs. Exposure was

To evaluate the association of NSAID use with the occurrence defined in 2 ways: as a binary variable indicating the report of

of NMSC, properly accounting for the time-dependent nature of NSAID use (including aspirin) in any questionnaires for a given

NSAID use, we used a risk set approach to the analysis of grouped study period, and as an ordered categorical variable that accounted

time survival data.29 Each 12-month period after randomization for duration of exposure. In the latter case, we computed the pro-

(except the first) was considered as 1 study year. The first study portion of completed questionnaires during the study period indi-

year was 15 months long to cover the time permitted in our proto- cating NSAID use and defined a categorical variable as: none, spo-

col for the first annual follow-up appointment. Skin cancers were radic use (less or half of questionnaires positive for NSAID use)

attributed to the study year of diagnosis. When the trial ended, 141 and frequent use (more than half of the questionnaires positive).

patients were in the first half of their fourth study year and there- To account for possible latencies of NSAID effect, we consid-

fore were censored at the end of the third year; 549 patients were ered different exposure periods: reported use of NSAIDs at base-

in the first half of the fifth year and censored at the end of the line, exposure during the same study year as the exam, exposure

fourth. In this analysis, we do not consider events that occurred af- during the previous year and exposure during the same and the

ter the end of a patient’s fifth study year. previous study years. To overcome possible response bias (as sub-

Of the 1,805 subjects randomized in the study, 84 never had an jects who completed interval questionnaires could be different

annual follow-up evaluation. Of the remaining 1,721 subjects, 1,019 from those who do not), we repeated the analyses including only

remained cancer-free during the study and 702 had at least 1 subjects who had completed the 3 questionnaires submitted during

NMSC. Randomization to b-carotene supplementation did not con- a given year. Subjects without interval questionnaires in a study

fer a significant reduction of risk for NMSC.27 In the present analy- period had missing information for the exposure in the corre-

sis, we defined risk sets for each study year as the group of all sub- sponding risk set.

jects who underwent that year’s follow up dermatological exam As appropriate for grouped time risk set data, unconditional

without a prior incident NMSC since randomization. In each risk logistic regression was applied to compute odds ratios (ORs) for

set, cases were subjects diagnosed with a NMSC at that year’s an- various exposures to NSAIDs; covariates in the full models were

nual examination or during an interim exam during that year, and age, sex, center, skin type, number of nonmelanoma skin cancers

controls were those who remained cancer-free up to that point in the prior to study entry and number of completed questionnaires.

study. A subject could be classified as a control in 1 risk set and sub- Given the null effects of the randomized treatment assignment,

sequently become a case in a later one. To account for each type of this variable was not included in the final analyses.

NMSC, we applied the same approach to SCC and BCC separately. We also accounted for multiple NMSC using overdispersed Pois-

In the overwhelming majority of instances, all 3 interval ques- son regression models. To ensure that NSAID use preceded the skin

tionnaires for a study year were completed before that year’s study cancer diagnosis, we first considered the association of baseline use

exam [in 96.4 % of subject study years]. Overall, 1,256 subjects with the total number of NMSCs diagnosed during the trial. Second,

(70%) reported use of NSAIDs in at least 1 interval questionnaire we used the first 2 study years to classify NSAID use, and took as

during the study. Of these, around 87% only took medications endpoints the number of diagnosed NMSC in the 3 later years. We

containing aspirin (alone or in combination with other NSAIDs) also repeated these analyses independently for SCC and BCC.





TABLE I – DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF

Results

STUDY PARTICIPANTS

Baseline characteristics of cases and controls are summarized in

Characteristic Controls N 5 1,019 (%) Cases N 5 702 (%) Table I. Cases were older and more likely to be male than con-

trols. As expected, cases were more likely to have high/moderate

Age (mean 6 SD) 62.1 (10.3) 64.3 (9.1)

Males (%) 638 (62.6) 548 (78.1) risk skin type and a higher number of previous skin cancers.

Study center (%) Compliance with interval questionnaires and use of medications

Dartmouth 270 (26.5) 151 (21.5) containing aspirin is described in Table II. About 98% of partici-

UCLA 136 (13.4) 177 (25.2) pants completed at least 1 questionnaire in any given study period,

UCSF 148 (14.5) 142 (20.2) and about 85% completed all 3 questionnaires. The response rate

Minnesota 465 (45.6) 232 (33.1) in the last study period was somewhat lower, reflecting the fact

Skin type1 (%)

Burns 411 (40.3) 376 (53.6) that the study ended prematurely and some information was cen-

Moderate 406 (39.8) 252 (36.0) sored as of the end of the previous year. Among subjects with at

Tans 202 (19.8) 73 (10.4) least 1 questionnaire, about 50% reported use of NSAIDs in each

Number of previous skin cancers2 (%) risk set. Among those with all questionnaires completed, more

1 623 (61.6) 188 (26.8) than a fourth indicated a regular use of aspirin, i.e., use in all 3

2 201 (19.9) 143 (20.4) questionnaires.

3 78 (7.7) 87 (12.4) Table III shows the ORs for the association of incident BCC

4–5 68 (6.7) 122 (17.4) and SCC with NSAID use at different times in relation to diagno-

6–9 27 (2.7) 80 (11.4) sis. For BCC, the crude estimates suggested a significant protec-

>10 14 (1.4) 81 (11.6)

tive trend for baseline use (crude OR 5 0.79, 95% CI: 0.65–0.95)

1

One case with missing information.–2Eight controls and 1 case and a borderline significant trend for use in the same and the previ-

with missing information. ous year as the diagnosis (crude OR 5 0.85, 95% CI: 0.70–1.03).



TABLE II – COMPLIANCE WITH QUESTIONNAIRES AND NSAID USE BY RISK SET TIME

Compliance with interval questionnaires NSAID use

Risk-set time Total subjects

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)

1

Among subjects with at least 1 completed questionnaire.–2Among subjects with 3 questionnaires.

684 GRAU ET AL.



TABLE III – ASSOCIATION OF RISK OF NONMELANOMA SKIN CANCER WITH NSAID USE AT VARIOUS TIMES BEFORE DIAGNOSIS

Basal-cell carcinomas Squamous-cell carcinomas

NSAID use

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 2196/4873 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)

year

Same and 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)

previous

years4

1

n 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 use

of NSAIDs the 2 years versus those who did not take any NSAIDs during those years (numbers represent the sum of cases and controls from the

5 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 year

None 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)

3

Previous year

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)

1

NSAID use defined by the proportion of completed questionnaires during the study period indicating use: none (no questionnaires positive

for 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 set

1 not included in this analysis.–4Risk sets 1 and 2 not included in this analysis.





However, these trends were attenuated after adjustment (adjusted In addition, we explored the association between NSAID use dur-

OR for baseline use 0.89, 95% CI: 0.70–1.09 and for use in the ing the first 2 years of the study and the average number of NMSC

same and previous year 0.91, 95% CI: 0.74–1.12). These results diagnosed in the subsequent 3 years. Again, there were suggestions

did not change when the analysis was restricted to subjects who of a reduction in the number of BCCs among NSAID users in the

were fully compliant with the questionnaires (data not shown). crude models, but not after adjustment (adjusted ratio 5 0.91, 95%

Associations with SCC tended to be somewhat stronger. There CI: 0.74–1.13). When we took into account the frequency of use,

was an inverse association of risk with NSAID use during the pre- the rate was nonsignificantly lower for sporadic users (adjusted

vious year (adjusted OR5 0.71, 95% CI: 0.48–1.04) and during ratio 5 0.78, 95% CI: 0.59–1.03), but not for frequent users. Results

the same and previous year (adjusted OR 5 0.79, 95% CI: 0.52– for all NMSC were virtually the same. Overall, rates for SCC were

1.21). The findings for all BCC were very similar to those for all lower for NSAID users than for nonusers, but this was compatible

NMSC (data not shown). with a chance association in all analyses (Table V).

We accounted for intensity of exposure by examining the propor-

tion of completed questionnaires that indicated NSAID use during a Discussion

given study interval (Table IV). In this analysis, we did not include

baseline use, since it was a one-time report in the initial question- In this closely monitored cohort of high risk subjects, there were

naire. For BCC, the ORs for frequent use of NSAIDs did not sug- only inconsistent, weak suggestions of an inverse association of

gest significant associations in any of the exposure periods consid- use of aspirin and other NSAIDs with the incidence of NMSC in

ered (Table IV). For SCC, there was an inverse association of spo- years following use. At most, our data suggest a weak chemopre-

radic use with risk. For example, the adjusted OR for NSAID use in ventive effect of NSAID use on SCC in the year prior to diagnosis,

the same or the previous year was 0.45 (95% CI: 0.28–0.87). How- and on the number of BCCs and SCCs.

ever, ORs for frequent use were much closer to the null (Table IV). The chemopreventive attributes of NSAIDs against carcinogen-

Again, results for all BCC were very similar to those for all NMSC esis have been widely recognized.30–32 In relation to the skin, the

(data not shown). effect of NSAIDs, particularly aspirin, on carcinogenesis has been

To evaluate the effect of NSAIDs on the number of recurrences, investigated in a few in vitro studies7,33 and in many animal stud-

we used 2 approaches. First, we studied the relationship between ies; the majority have reported an anticarcinogenic effect of

NSAID use reported at the intake questionnaire and the number of NSAIDs.1–6,33–36 Uncontrolled human studies have reported a

cancers diagnosed during the trial (Table V). For BCC, baseline decrease in the number of new skin tumors or regression of exist-

NSAID use conferred a significant reduction of risk in the crude ing ones with the use of topical or oral NSAIDs, supporting the an-

analysis (unadjusted ratio of the average number of tumors 0.86, tineoplastic properties of these drugs.8–10,37

95% CI: 0.66–0.95). Adjustment lowered this point estimate, but In spite of this, little human epidemiological research has been

statistical significance was lost (adjusted ratio 5 0.78, 95% CI: done to explore this association. Two population-based studies21,22

0.66–1.12). We obtained similar estimates for all NMSC. Results that used administrative databases assessed the risk of various can-

for SCC were also not striking. cers, including NMSC, in relation to use of NSAIDs, with null

EFFECT OF NSAIDS ON THE RECURRENCE OF NONMELANOMA SKIN CANCER 685

TABLE V – ASSOCIATION OF NSAID USE ON THE AVERAGE NUMBER OF NONMELANOMA SKIN CANCERS DIAGNOSED

Basal-cell carcinomas Squamous-cell carcinomas

NSAID use

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 study

None 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)

4

Sporadic 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)

1

Avg. # NMSC 5 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 positive

for NSAID use), sporadic use (less or half of questionnaires positive for NSAID use) and frequent use (more than half of the questionnaires positive).





results. However, a randomized trial has provided good evidence tive bias in our estimates. Finally, confounding seems to be an im-

of the therapeutic properties of NSAIDs, showing the efficacy of portant factor in the analysis, since our estimates were often closer

topical diclofenac against actinic keratoses, proliferative lesions to the null and in the full multivariate models.

that are thought to be precursors of SCCs.25 Another single-arm, Nonetheless, our analysis has several strengths. To our knowl-

open-label study of topical diclofenac and actinic keratosis reached edge, our study is the first to address the association between use of

similar positive conclusions.26 aspirin and other NSAIDs and the risk of NMSC in a closely moni-

The best-known mechanism of action of NSAIDs is the inhibi- tored cohort of high risk patients. We used data from a carefully

tion of COX-2, the inducible isoform of the cyclooxygenase controlled cohort of patients that were part of a randomized clinical

enzyme, implicated in inflammation and promotion of neoplastic trial. Study dermatologists performed annual exams and removed

tumors.30,31,38–40 Overexpression of COX-2 seems to be a factor all suspicious lesions. Biopsy specimens were read locally and uni-

in almost all types of neoplasia, and in various stages of carcino- formly by the coordinating center pathologist and the level of agree-

genesis.3,30–32,41,42 In the skin, experimental studies have shown ment was 96%. We used several statistical approaches to analyze

that acute UVB exposure can cause COX-2 overexpression in mu- the data, exploring different exposure periods, and various case–

rine and human skin and high levels of the enzyme are present in control definitions within the cohort design. We also explored the

neoplastic lesions following UV irradiation.33,39–41 Furthermore, possibility of separate associations for BCC and SCC, acknowl-

many in vitro and animal studies provide strong evidence for a role edging the many indications that BCC and SCC are biologically

of COX-2 as an endogenous promoter of skin neoplasia.3,34,41,43–45 distinct: essential differences in histogenesis,46–49 molecular path-

However, our data only show inconsistent suggestions of effects of ways50,51 and vascularization patterns.52,53 The major limitation

NSAIDs on BCC and SCC. of our study is the lack of data regarding the doses and duration of

One potential explanation for our mixed findings could be that NSAID use in our subjects.

the NSAID use we observed was too short to have affected the Thus, despite the role of COX-2 in skin carcinogenesis, our study

occurrence of NMSC. For colorectal cancer, for example, 10–20 provides only weak suggestions of chemopreventive effect of NSAIDs

years of consistent use may be required for a protective effect.30 on BCC and SCC. Of course, these results must be interpreted in the

Unfortunately, our data do not permit us to assess the association context of the limitations of our data. At this point, more observatio-

of risk with the duration of use. Also, we observed a limited num- nal and randomized studies would be very valuable, especially stud-

ber of SCCs, and had only limited statistical power to detect sig- ies that can assess more closely the duration of NSAID use.

nificant associations for this endpoint. Another plausible reason

could be inaccuracies in the assessment of NSAID use, since our Acknowledgements

questionnaires did not collect information about dose or frequency

of use and this measurement error could have biased our findings. We are indebted to the subjects of the Beta Carotene Skin Cancer

Moreover, patients were not asked specifically about use of aspirin Trial, as well as to Nicholas Lowe, J. Corwin Vance, Peter Elias and

or other NSAIDs, possibly leading to underreporting. If this af- Steven K. Spencer, all of whose enthusiasm and cooperation were

fected cases and controls equally, the result would be a conserva- essential for the successful completion of the study.



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