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

Abstract and Introduction

Abstract

Background Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs).
Methods A double-blind placebo-controlled randomized trial involving 240 subjects aged 37–87 years with 10–40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ2 or Fisher exact tests. All statistical tests were two-sided.
Results There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups.
Conclusions Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.

Introduction

Cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), classified together as nonmelanoma skin cancers, are the most common malignancies in the United States.[1] Although it is uncommon for these cancers to metastasize, they are responsible for considerable morbidity and represent a substantial economic burden to the health-care system. The direct cost of treatment for nonmelanoma skin cancers in the United States has been estimated to exceed $1.4 billion annually.[2] The incidence of nonmelanoma skin cancers, unlike that of many other malignancies, has been increasing,[3,4] and these cancers are beginning to occur more frequently in younger people.[5]

Because most cutaneous SCCs and BCCs are thought to be caused by excessive exposure to ultraviolet (UV) radiation,[6–8] there has been a concerted effort by various health-care organizations to educate the public about the hazards of overexposure to the sun and artificial UV light sources. Actions that have been advocated include the use of protective clothing and hats, avoidance of outdoor activities during peak hours of sun exposure, construction of permanent shade structures in outdoor areas, and the liberal and frequent application of sunscreens.[9,10] However, sunscreens may not completely protect against SCCs, and there is limited evidence that they reduce the incidence of BCCs.[11] Thus, attempts have been made to identify alternative forms of chemoprevention for sunlight-induced skin cancers.

A number of chemopreventive agents for nonmelanoma skin cancer have been examined, including retinoids,[12] oral difluoromethylornithine,[13] topically applied DNA repair enzymes,[14] and low-fat diets.[15,16] In addition, evidence from experimental and epidemiological studies suggests that cyclooxygenase 2, an enzyme involved in prostaglandin synthesis, may be involved in the pathogenesis of nonmelanoma skin cancers.[17–24] On the basis of evidence that cyclooxygenase 2 may be involved in UV-induced nonmelanoma skin cancers,[17–22] we conducted a clinical trial to examine whether oral administration of celecoxib, a nonsteroidal anti-inflammatory drug (NSAID) that is an inhibitor of cyclooxygenase 2, would be an effective chemopreventive agent in individuals who had evidence of substantial UV damage and therefore were at increased risk for development of additional actinic keratoses and/or nonmelanoma skin cancers. Based on the evidence from animal models that treatment with celecoxib inhibits the development of UV-induced premalignant skin papillomas, which are thought to correspond to actinic keratoses in humans, and results of immunohistochemical studies in humans indicating that COX-2 is expressed in actinic keratoses,[17–22] the primary endpoint of the trial was the number of new actinic keratoses at month 9 after randomization as a percentage of those at randomization. Patients were treated with celecoxib or placebo for 9 months and followed up for an additional 2 months. In exploratory analyses, we also evaluated the number of nonmelanoma skin cancers over the same period.

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