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Inhaled Corticosteroids and Lung Cancer Chemoprevention

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					636                                                          AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 175 2007

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Inhaled Corticosteroids and Lung Cancer
Chemoprevention
Pulmonologists manage many current and ex-smokers with vary-                      20% associated with -carotene supplementation (particularly
ing degrees of airflow obstruction. Lung cancer, rather than cardio-               in current smokers) (9, 10). While this was a disappointing result,
vascular disease, was the leading cause of mortality in the Lung                  it would have been worse if -carotene supplementation had
Health Study, which enrolled middle-aged volunteers with asymp-                   been applied on a large scale without the foresight of a clinical
tomatic airflow obstruction (1). In some cohorts of smokers and                    trial.
ex-smokers with airflow obstruction, the risk for development                          At present, there are four major approaches to choosing
of lung cancer approaches two cases per 100 patient-years (2).                    promising agents for study in lung cancer chemoprevention trials:
    Smoking cessation decreases lung cancer risk. This has re-                    observational studies, analysis of the effects of drugs or targeted
cently been validated within the context of a randomized clinical                 agents on cancer or dysplastic cell biology, preclinical animal
trial (3). However, due to large numbers of ex-smokers, lung                      models of lung carcinogenesis, and intermediate endpoint trials
cancer in the United States is now diagnosed in approximately                     in humans. Since we have no validated lung cancer chemopreven-
equal numbers of smokers and ex-smokers, leading to the chal-                     tion agents, none of these strategies is a reliable predictor. A
lenge of lowering lung cancer risk in former smokers (4). Early                   number of preclinical studies have demonstrated that cortico-
detection by computed tomography screening holds great po-                        steroids, either administered systemically or by inhalation, can
tential but likely will remain controversial until validated by a                 decrease chemical carcinogen–induced pulmonary adenoma for-
randomized trial, such as the ongoing National Cancer Institute                   mation in mice (11). The mouse model has many similarities to
(NCI)–sponsored National Lung Screening Trial or several                          human adenocarcinoma in terms of histology, mutations, and
smaller European trials (5, 6).                                                   gene expression patterns (12).
    The term “chemoprevention” was coined by Sporn and col-                           In this issue of the Journal (pp. 712–719), Parimon and col-
leagues in 1976 to describe either pharmacologic or dietary inter-                leagues describe a cohort study performed in patients being treated
ventions that would interfere in the carcinogenic process, re-                    in the ambulatory care clinics of the Department of Veterans Af-
sulting in a decrease in cancer risk (7). Chemoprevention has                     fairs (13). Over 10,000 patients were assessed. Interestingly, 20%
been applied with some early success to individuals at high risk                  of the cohort had received inhaled corticosteroids, but only 5%
for breast, prostate, and colon cancer, but there is no currently                 (517) achieved the 80% compliance benchmark set by the investi-
available chemoprevention for lung cancer. Retinoids have re-                     gators for inclusion in the analysis. Compared with control sub-
ceived the most attention in the past as potential lung cancer                    jects, those receiving high-dose inhaled corticosteroids (219 sub-
chemopreventive agents (8). A large body of epidemiologic,                        jects) had a decreased risk for lung cancer (hazard ratio 0.39;
genetic, and cell biology data suggested that supplementation                     95% confidence interval, 0.16–0.96). One advantage of this study
with -carotene would be protective, although preclinical animal                   is the information on compliance; a weakness is the relatively
studies were not very supportive. No one would have predicted                     small number of subjects and incident cases of lung cancer (5)
that the two large trials (the ATBC [Alpha-Tocopherol, Beta                       in the group that apparently accrued benefit. A number of large
Carotene] and CARET [ -Carotene and Retinol Efficacy Trial]                        clinical trials have examined the benefits of inhaled corticoste-
trials) conducted in the 1990s would each show a statistically                    roids in chronic obstructive pulmonary disease (COPD).
significant increase in lung cancer incidence of approximately                     Recently, a meta-analysis of seven such randomized trials
Editorials                                                                                                                                                         637

(n 5,085 subjects) was published (14). Inhaled corticosteroids                                                        University of Colorado Cancer Center
were associated with a decrease in all-cause mortality. No specific                                                    University of Colorado at Denver
mortality causes were significantly reduced, but lung cancer                                                            and Health Sciences Center
mortality showed a trend (hazard ratio 0.47; 95% confidence                                                            Denver, Colorado
interval, 0.22–1.00) toward decreased risk in the inhaled corti-
costeroid group (personal communication, D. Sin). These trials                            References
were not designed to study lung cancer chemoprevention and
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                                                                                          10. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR,
trials with prolonged follow-up to capture effects on a carcinogenic                             Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, et al. Effects
process that progresses over years will ultimately be needed to                                  of a combination of beta carotene and vitamin A on lung cancer
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of interest relevant to both lung cancer and COPD, joint funding                          11. Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CL, Steele
by the NCI and NHLBI would then be desirable. The risk reduc-                                    VE, Kelloff GJ. Chemoprevention of pulmonary carcinogenesis by
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                                                                                          12. Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA
tinued lung cancer epidemic. Many additional agents are under-                                   Jr, Johnson GL, Hirsch FR, Merrick DT, Franklin WA, et al. Analysis
going evaluation for lung cancer chemoprevention, including                                      of orthologous gene expression between human pulmonary adeno-
micronutrients, tyrosine kinase inhibitors, and blockers or ago-                                 carcinoma and a carcinogen-induced murine model. Am J Pathol
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                                                                                                 Inhaled corticosteroids and risk of lung cancer among patients with
risk individuals (beyond smoking cessation) will be as standard
                                                                                                 chronic obstructive pulmonary disease. Am J Respir Crit Care Med
in pulmonary and primary care settings as is influenza vaccina-                                   2007;175:712–719.
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is just as great.                                                                                Calverley PM, Connett JE, Lindmark B, Pauwels RA, et al. Inhaled
                                                                                                 corticosteroids and mortality in chronic obstructive pulmonary disease.
Conflict of Interest Statement : Y.E.M. was site principal investigator for a multicen-          Thorax 2005;60:992–997.
ter trial sponsored by Xillix, Inc. ($39,000), in 2003, Peceptronix, Inc. ($87,000),      15. Lam S, leRiche JC, McWilliams A, MacAulay C, Dyachkova Y, Szabo
in 2004, and a single-site trial sponsored by SomaLogic ($60,000) in 2004. R.L.K.                E, Mayo J, Schellenberg R, Coldman A, Hawk E, et al. A randomized
and Y.E.M. are collaborators on a patent application for the use of prostacyclin
                                                                                                 phase IIb trial of pulmicort turbuhaler (budesonide) in people with
analogs for the chemoprevention of cancer.
                                                                                                 dysplasia of the bronchial epithelium. Clin Cancer Res 2004;10:6502–
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                                                                                          16. Keith RL, Miller YE. Lung cancer: genetics of risk and advances in
                               Robert L. Keith, M.D.                                             chemoprevention. Curr Opin Pulm Med 2005;11:265–271.
                               Denver Veterans Affairs Medical Center
                               and                                                        DOI: 10.1164/rccm.200701-087ED

				
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