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.

• Authors: Jenny T Mao, Michael D Roth, Michael C Fishbein, Denise R Aberle, Zuo-Feng Zhang, Jian Yu Rao, Donald P Tashkin, Lee Goodglick, E Carmack Holmes, Robert B Cameron, Steven M Dubinett, Robert Elashoff, Eva Szabo, David Elashoff
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 7 Pg. 984-93 (Jul 2011) ISSN: 1940-6215 [Electronic] United States
• PMID: 21733822 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers, Tumor
• Cyclooxygenase 2 Inhibitors
• Interleukin-6
• Ki-67 Antigen
• Pyrazoles
• Sulfonamides
• C-Reactive Protein
• Celecoxib

Topics

• Biomarkers, Tumor (metabolism)
• Bronchi (cytology, metabolism)
• Bronchoalveolar Lavage
• C-Reactive Protein (metabolism)
• Celecoxib
• Cross-Over Studies
• Cyclooxygenase 2 Inhibitors (therapeutic use)
• Double-Blind Method
• Enzyme-Linked Immunosorbent Assay
• Female
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Interleukin-6 (metabolism)
• Ki-67 Antigen (metabolism)
• Lung Neoplasms (etiology, metabolism, prevention & control)
• Male
• Middle Aged
• Pyrazoles (therapeutic use)
• Smoking (adverse effects)
• Sulfonamides (therapeutic use)
• Survival Rate
• Tomography, X-Ray Computed
• Treatment Outcome