A randomized double-blind study of the biological effects of celecoxib as a chemopreventive agent in current and former smokers.

1501 Background: Cyclooxygenase-2 (COX-2) is overexpressed in bronchial premalignancy and promotes tumor cell proliferation and survival. Bronchial premalignant lesions have enhanced cellular proliferation as measured by nuclear Ki-67 expression. In histologically normal bronchial epithelium, Ki-67 is detectable in basal and parabasal layers. Celecoxib (COX-2 inhibitor) may have activity in the bronchial epithelium of current and former smokers and this was tested by measuring Ki-67 in bronchial biopsy samples.,Patients (pts) with or without a prior cancer history were required to have at least a 20 pack-year smoking history and be disease-free for at least 6 months (mos). Pts were randomized into one of 4 treatments (3-mo intervals): celecoxib then placebo; celecoxib then celecoxib; placebo then celecoxib; placebo then placebo. Pts underwent bronchoscopy with biopsies at baseline, 3 and 6 mos. Celecoxib was administered at 200 mg bid (low dose, 81 pts), then changed to high-dose (400 mg bid, 123 pts). The study design had 80% power to detect a 1.2% difference in Ki-67 (celecoxib vs placebo) with 2 sided 5% level of significance. The primary endpoint was change in Ki-67 (baseline to 3 mos).,From 11/01 to 9/06, 204 of 212 registered pts were randomized (median age 53 years, 106 males, 175 Caucasian, 162 current smokers, and 182 with no prior cancer history). 127 pts completed 3 mos and 104 completed 6 mos of treatment. 3 pts experienced one grade 3 toxicity. No cardiac toxicities were observed. Baseline Ki-67 expression in basal and parabasal layers was higher in current smokers than in former smokers (p=.001 and p=.005, respectively). Multicovariable analyses revealed that basal layer Ki-67 expression decreased in current and former smokers treated with high-dose (p=0.003) but not low-dose (p=0.88) celecoxib (vs placebo).,This study is the first reported randomized trial of celecoxib in lung chemoprevention and demonstrates the possible importance of COX-2 inhibition in the prevention of lung cancer. Celecoxib was safe and tolerable and may have an effect of downregulating proliferation in the bronchial epithelium of current smokers. Supported by grant 1P01 CA 091844, DOD W81XWH-04-0142, CA 16672 No significant financial relationships to disclose.