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Lung cancer chemoprevention with celecoxib in former smokers.

ABSTRACT: Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2-selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ? 45, ? 30 pack-years of smoking, ? 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI) after 6 months of treatment. Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t test). In participants who crossed over to the other study arm at 6 months (all of whom had received 6 months of celecoxib at the end of a 12 months treatment period), the decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in bronchoalveolar lavage (BAL) samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in BAL cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease.

SUBMITTER: Mao JT

PROVIDER: S-EPMC3153413 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Lung cancer chemoprevention with celecoxib in former smokers.

Mao Jenny T JT Roth Michael D MD Fishbein Michael C MC Aberle Denise R DR Zhang Zuo-Feng ZF Rao Jian Yu JY Tashkin Donald P DP Goodglick Lee L Holmes E Carmack EC Cameron Robert B RB Dubinett Steven M SM Elashoff Robert R Szabo Eva E Elashoff David D

Cancer prevention research (Philadelphia, Pa.) 20110701 7

Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2-selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥ 45, ≥ 30 pack-years of smoking, ≥ 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular ...[more]

PMID: 21733822

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Project description:Although obesity has been directly linked to the development of many cancers, many epidemiological studies have found that body mass index (BMI)--a surrogate marker of obesity--is inversely associated with the risk of lung cancer. These studies are difficult to interpret because of potential confounding by cigarette smoking, a major risk factor for lung cancer that is associated with lower BMI.We prospectively examined the association between BMI and the risk of lung cancer among 448?732 men and women aged 50-71 years who were recruited during 1995-1996 for the National Institutes of Health-AARP Diet and Health Study. BMI was calculated based on the participant's self-reported height and weight on the baseline questionnaire. We identified 9437 incident lung carcinomas (including 415 in never smokers) during a mean follow-up of 9.7 years through 2006. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for lung cancer risk factors, including smoking status. To address potential bias due to preexisting undiagnosed disease, we excluded potentially unhealthy participants in sensitivity analyses. All statistical tests were two-sided.The crude incidence rate of lung cancer over the study follow-up period was 233 per 100?000 person-years among men and 192 per 100?000 person-years among women. BMI was inversely associated with the risk of lung cancer among both men and women (BMI ?35 vs 22.5-24.99 kg/m(2): HR = 0.81, 95% CI = 0.70 to 0.94 and HR = 0.73, 95% CI = 0.61 to 0.87, respectively). The inverse association was restricted to current and former smokers and was stronger after adjustment for smoking. Among smokers, the inverse association persisted even after finely stratifying on smoking status, time since quitting smoking, and number of cigarettes smoked per day. Sensitivity analyses did not support the possibility that the inverse association was due to prevalent undiagnosed disease.Our results suggest that a higher BMI is associated with a reduced risk of lung cancer in current and former smokers. Our inability to attribute the inverse association between BMI and the risk of lung cancer to residual confounding by smoking or to bias suggests the need for considering other explanations.

Dataset Information

Lung cancer chemoprevention with celecoxib in former smokers.

Publications

Lung cancer chemoprevention with celecoxib in former smokers.

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