Biological activity of celecoxib in the bronchial epithelium of current and former smokers

Abstract

Non-small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium. No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers-a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non-small cell lung cancer chemoprevention may be warranted.

Figure 1

CONSORT flow diagram of subject accrual into the trial. Patients were randomized to receive the following daily for 3-month intervals: placebo then placebo (PCB + PCB); placebo then celecoxib (PCB + CCX); celecoxib then placebo (CCX + PCB); or celecoxib then celecoxib (CCX + CCX). Number of patients (n) who completed baseline (B), 3-month (B+3), and 6-month (B+6) evaluations are listed. Reasons for leaving the study are also listed.

Figure 2

Cotinine levels by smoking status over time in both former smokers and current smokers. Each black line represents one participant’s data. The red line represents the average. The Y axis is the measured cotinine level.

Figure 3

Baseline squamous metaplasia. Current smokers had a higher percentage of squamous metaplasia than former smokers. Each dot represents one participant’s information in relation to metaplasia index.

Figure 4

Mean Ki-67 over time in all layers. A. Baseline and 3-month time points show decreasing expression of Ki-67 with high-dose celecoxib over time in both current and former smokers who had both baseline and 3-month Ki-67 measurements. Total evaluable patients are 28 in former smokers group and 97 in current smoker group. Y-axis represents Ki-67 index. B. Baseline and 3- and 6-month time periods show a similar trend for Ki-67 expression with high-dose celecoxib in both current and former smokers who had baseline, 3-month and 6-month Ki-67 measurements. Total evaluable patients are 10 in former smokers group and 37 in current smoker group. Placebo and low-dose celecoxib follow similar patterns, especially in current smokers. Y-axis represents Ki-67 index.