Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib: A Randomized, Double-blind, Placebo-Controlled Trial

Craig A. Elmets; Jaye L. Viner; Alice P. Pentland; Wendy Cantrell; Hui-Yi Lin; Howard Bailey; Sewon Kang; Kenneth G. Linden; Michael Heffernan; Madeleine Duvic; Ellen Richmond; Boni E. Elewski; Asad Umar; Walter Bell; Gary B. Gordon

Disclosures

J Natl Cancer Inst. 2010;24(15):1835-1844. 

In This Article

Participants and Methods

Study Design

We conducted a randomized, double-blind, placebo-controlled phase II–III clinical trial to assess whether oral administration of celecoxib reduces the incidence of actinic keratoses, BCCs, and cutaneous SCCs in individuals who were at high risk for these lesions.[25,26] Patients were considered to be at high risk based on the reports from other studies which showed that individuals with large numbers of actinic keratoses and Fitzpatrick sun reactive skin types I, II, or III are at increased risk of developing nonmelanoma skin cancers. The clinical trial was registered at clinicaltrials.gov (NCT0027976). Eight study sites in the United States participated: the University of Alabama at Birmingham (Birmingham, AL); the University of Rochester School of Medicine and Dentistry (Rochester, NY); the University of Wisconsin–Madison (Madison, WI); the University of Michigan (Ann Arbor, MI); the University of California, Irvine (Irvine, CA); Washington University School of Medicine (St Louis, MO); the University of Texas M.D. Anderson Cancer Center (Houston, TX); and Northwestern University (Chicago, IL). The study began on January 18, 2001, and completed on November 3, 2006, at which time the Food and Drug Administration (FDA) requested termination of this trial after preliminary data from another trial[27] showed an association between another cyclooxygenase 2 inhibitor and cardiovascular adverse events. The protocol was approved by the institutional review board at each participating site, and all participants gave written informed consent. The trial was a cooperative effort of the participating sites, the National Cancer Institute (NCI), and Pfizer, Inc (New York, NY) (the manufacturer of celecoxib [Celebrex]) through a clinical trials agreement with the NCI's Division of Cancer Prevention.

Study Population

Individuals were eligible to participate if they were at least 18 years old and had a Fitzpatrick sun reactive skin type of I, II, or III. All subjects were required to have 10–40 actinic keratoses on the upper extremities, neck, face, and scalp at the time of entry into the study, and a previous histological diagnosis of at least one actinic keratosis and/or nonmelanoma skin cancer. On the basis of these inclusion criteria, subjects were considered to be at high risk for nonmelanoma skin cancers.[25,26] Individuals with more than 40 actinic keratoses were excluded because of technical difficulties involved in mapping that many lesions. Subjects were not allowed to take NSAIDs or doses of aspirin more than 81 mg/day at any time during the study and in the 30 days before randomization or use any topical medications during the study with the exception of emollients and sunscreens, which were allowed and recommended.

Exclusion criteria included having a known photosensitivity disorder; use of topical corticosteroids, alpha-hydroxyacids, or retinoids within 14 days before random assignment; use of oral or intravenous corticosteroids for more than two consecutive weeks during the 6 months before randomization; use of inhaled corticosteroids for more than 4 weeks during the 6 months before randomization and/or the use of nasally inhaled corticosteroids in the month before randomization; use of psoralens, cryotherapy to target skin lesions, immunotherapy, retinoids, or radiation therapy within 30 days of randomization; or laser resurfacing, dermabrasion, or chemical peels within 60 days before randomization. Subjects were excluded if they had been treated with topical 5-fluorouracil within 3 months of randomization or with other forms of topical chemotherapy or local radiotherapy to the areas being studied within 6 months of randomization.

Study Treatment

Participants were screened for inclusion and exclusion criteria and the number of actinic keratoses. Two weeks later, they were randomly assigned to receive 200 mg of celecoxib or placebo orally twice daily. Randomization was performed by a block randomization procedure that was stratified for each center in blocks of four treatment assignments. Study medications were administered through month 9 after randomization, at which time they were discontinued, and the subjects were followed up for two additional months. Subjects were evaluated for chemopreventive efficacy and safety at months 3, 6, 9, and 11 after randomization. At each visit, actinic keratoses were counted on the upper extremities, neck, face, and scalp. A clear plastic template was placed over each anatomical site on which actinic keratoses were counted and the location of each actinic keratosis was recorded by a study investigator on the plastic template. Separate plastic templates were used at each visit, and the person who recorded the lesions had no knowledge of or access to earlier results for that subject. At the end of the study, we compared the location of actinic keratoses on the plastic template map from months 3, 6, 9, and 11 with the one prepared at randomization to identify the number of new, persistent, and regressed actinic keratoses. On clinical examination, lesions that appeared as discrete scaling or keratotic patches, often with erythema and a sandpaper-like scale, were considered actinic keratoses. Lesions that did not have these clinical characteristics of an actinic keratosis were not recorded on the plastic maps. At randomization, 32 lesions suspected of being actinic keratoses were biopsied and analyzed histologically, of which 28 (88%) were confirmed to be actinic keratoses, an accuracy rate that is consistent with other reports in the literature.[28–32] Actinic keratoses were not treated at baseline or during the entire duration of the study. Lesions suspected of being BCC or SCC were biopsied, examined histologically, and, if found to be skin cancers by histopathologic examination, were managed by surgical removal. Adverse events were graded according to the NCI Common Toxicity Criteria.[33]

Statistical Analysis

The sample size calculation was based on information from previous studies that examined the effects of sunscreens on the incidence of actinic keratoses;[28,34] those studies used Poisson models to model the number of new actinic keratoses as the percentage of the number at randomization for both users and nonusers of sunscreen. With 120 subjects per treatment arm and assuming a 20% dropout rate, a simulation modeling based on 1000 replications showed that this study had approximately 95% power at a two-sided statistical significance level of .05 to detect a 40% relative reduction in the number of new actinic keratoses at the final visit (month 9 visit) as the percentage of randomization in the celecoxib-treated group compared with the placebo group.

Analyses were performed on the per-protocol and the intention-to-treat populations for all subjects who were randomly assigned to a study arm and who had at least one follow-up visit after baseline. Compliance with study medications was monitored by pill counts at each visit. Subjects who had taken more than 80% of their pills were considered to be compliant, a compliance figure that is consistent with that used in another clinical chemoprevention trial of NSAIDs in BCC.[35] In addition, subjects who failed to present for clinic follow-up on two consecutive visits were withdrawn from the study. Patients' baseline characteristics were compared for the two treatment arms (celecoxib vs placebo) using the t test for continuous variables and the χ2 or Fisher exact test for categorical variables. We used the same univariate analytical methods to compare the baseline characteristics for subjects who completed and withdrew from the study, stratified by treatment arm.

The two treatment arms were compared for the mean values of the following measures using t tests: the total number of actinic keratoses at randomization, the total number of actinic keratoses at the completion of therapy (ie, month 9), the number of new actinic keratoses at the completion of therapy, the ratio of new actinic keratoses at the completion of therapy to the number of actinic keratoses at randomization, and the ratio of the total number of actinic keratoses at the completion of therapy to the number at randomization. The effect of celecoxib on the ratio of new actinic keratoses at the completion of therapy to the number of actinic keratoses at randomization was also evaluated using a Poisson regression model that controlled for age, sex (male/female), sunscreen use (yes/no), and Fitzpatrick skin type (I, II, or III).[25,26]

The mean cumulative number of nonmelanoma skin cancers, BCCs, and SCCs per patient at months 3, 6, 9, and 11 (or at the time of withdrawal) and their 95% confidence intervals (CIs) were calculated based on the Poisson distribution. The difference between study arms in the mean cumulative number of tumors at each visit (or at the time of withdrawal) was evaluated using Poisson regression, adjusting for patient on-study time. The celecoxib treatment effect was also evaluated after adjusting for age, sex (male/female), Fitzpatrick skin type (I, II, or III), actinic keratosis history at randomization (yes/no), skin cancer history at baseline (yes/no), and time on study.

The safety analysis included all randomly assigned patients who took at least one dose of study medicine. The numbers of adverse events in the two treatments arms were compared using χ2 or Fisher exact tests. All statistical analyses (including univariate tests and Poisson regressions) were performed using SAS version 9.0 software (SAS Institute, Cary, NC). A P value less than .05 was considered statistically significant. All statistical tests were two-sided.

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