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Inhaled Corticosteroids and Lung Cancer
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
(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
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Inhaled corticosteroids and risk of lung cancer among patients with
risk individuals (beyond smoking cessation) will be as standard
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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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Denver Veterans Affairs Medical Center
and DOI: 10.1164/rccm.200701-087ED