© 2007 American Thoracic Society doi: 10.1164/rccm.200701-087ED
Inhaled Corticosteroids and Lung Cancer ChemopreventionDenver Veterans Affairs Medical Center and University of Colorado Cancer Center, University of Colorado at Denver and Health Sciences Center, Denver, Colorado Pulmonologists manage many current and ex-smokers with varying degrees of airflow obstruction. Lung cancer, rather than cardiovascular disease, was the leading cause of mortality in the Lung Health Study, which enrolled middle-aged volunteers with asymptomatic airflow obstruction (1). In some cohorts of smokers and ex-smokers with airflow obstruction, the risk for development of lung cancer approaches two cases per 100 patient-years (2). Smoking cessation decreases lung cancer risk. This has recently been validated within the context of a randomized clinical trial (3). However, due to large numbers of ex-smokers, lung cancer in the United States is now diagnosed in approximately equal numbers of smokers and ex-smokers, leading to the challenge of lowering lung cancer risk in former smokers (4). Early detection by computed tomography screening holds great potential but likely will remain controversial until validated by a randomized trial, such as the ongoing National Cancer Institute (NCI)–sponsored National Lung Screening Trial or several smaller European trials (5, 6).
The term "chemoprevention" was coined by Sporn and colleagues in 1976 to describe either pharmacologic or dietary interventions that would interfere in the carcinogenic process, resulting in a decrease in cancer risk (7). Chemoprevention has been applied with some early success to individuals at high risk for breast, prostate, and colon cancer, but there is no currently available chemoprevention for lung cancer. Retinoids have received the most attention in the past as potential lung cancer chemopreventive agents (8). A large body of epidemiologic, genetic, and cell biology data suggested that supplementation with At present, there are four major approaches to choosing promising agents for study in lung cancer chemoprevention trials: observational studies, analysis of the effects of drugs or targeted agents on cancer or dysplastic cell biology, preclinical animal models of lung carcinogenesis, and intermediate endpoint trials in humans. Since we have no validated lung cancer chemoprevention agents, none of these strategies is a reliable predictor. A number of preclinical studies have demonstrated that corticosteroids, either administered systemically or by inhalation, can decrease chemical carcinogen–induced pulmonary adenoma formation in mice (11). The mouse model has many similarities to human adenocarcinoma in terms of histology, mutations, and gene expression patterns (12). In this issue of the Journal (pp. 712–719), Parimon and colleagues describe a cohort study performed in patients being treated in the ambulatory care clinics of the Department of Veterans Affairs (13). Over 10,000 patients were assessed. Interestingly, 20% of the cohort had received inhaled corticosteroids, but only 5% (517) achieved the 80% compliance benchmark set by the investigators for inclusion in the analysis. Compared with control subjects, those receiving high-dose inhaled corticosteroids (219 subjects) had a decreased risk for lung cancer (hazard ratio = 0.39; 95% confidence interval, 0.16–0.96). One advantage of this study is the information on compliance; a weakness is the relatively small number of subjects and incident cases of lung cancer (5) in the group that apparently accrued benefit. A number of large clinical trials have examined the benefits of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). Recently, a meta-analysis of seven such randomized trials (n = 5,085 subjects) was published (14). Inhaled corticosteroids were associated with a decrease in all-cause mortality. No specific mortality causes were significantly reduced, but lung cancer mortality showed a trend (hazard ratio = 0.47; 95% confidence interval, 0.22–1.00) toward decreased risk in the inhaled corticosteroid group (personal communication, D. Sin). These trials were not designed to study lung cancer chemoprevention and are only somewhat suggestive of benefit due to a mean follow-up time of only 26 months (short for a lung cancer outcome), only 33 lung cancer cases in the population, and cancer death, rather than incidence, as an endpoint. An alternative approach for choosing chemopreventive agents for trials with cancer incidence as an endpoint is to determine whether they affect intermediate endpoints of cancer risk. One such trial of inhaled corticosteroids in high-risk current and former smokers with endobronchial dysplasia has been reported (15). The primary endpoint was dysplasia and no effect of inhaled budesonide compared with placebo was observed. The problem with intermediate endpoint biomarker trials is that we do not know if a biomarker response will predict a decrease in lung cancer. Endobronchial dysplasia may be a better biomarker for central squamous cell lung carcinoma than peripheral adenocarcinoma, the cell type that inhaled corticosteroids prevent in mice. Better intermediate endpoint biomarkers for all forms of lung cancer, particularly peripheral adenocarcinoma, are needed. An improved understanding of the natural history of bronchial dysplasia is also required. Although the data at present are certainly not definitive, inhaled corticosteroids deserve further consideration for lung cancer chemoprevention. Adequately powered, prospective, controlled trials with prolonged follow-up to capture effects on a carcinogenic process that progresses over years will ultimately be needed to determine efficacy. If these could be designed to capturetr outcomes of interest relevant to both lung cancer and COPD, joint funding by the NCI and NHLBI would then be desirable. The risk reductions suggested by the studies discussed would be a clinically significant achievement (13, 14), particularly in light of the continued lung cancer epidemic. Many additional agents are undergoing evaluation for lung cancer chemoprevention, including micronutrients, tyrosine kinase inhibitors, and blockers or agonists of signaling pathways, as reviewed (16). It is hoped, within the next decade, that chemoprevention of lung cancer in high-risk individuals (beyond smoking cessation) will be as standard in pulmonary and primary care settings as is influenza vaccination or cardiac risk factor modification. The potential for benefit is just as great. FOOTNOTES Conflict of Interest Statement: Y.E.M. was site principal investigator for a multicenter trial sponsored by Xillix, Inc. ($39,000), in 2003, Peceptronix, Inc. ($87,000), in 2004, and a single-site trial sponsored by SomaLogic ($60,000) in 2004. R.L.K. and Y.E.M. are collaborators on a patent application for the use of prostacyclin analogs for the chemoprevention of cancer. REFERENCES
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-carotene would be protective, although preclinical animal studies were not very supportive. No one would have predicted that the two large trials (the ATBC [Alpha-Tocopherol, Beta Carotene] and CARET [
