Chemoprevention of lung cancer
- Robert L Keith, MD
Robert L Keith, MD
- Professor of Medicine and Cancer Biology
- Associate Chief of Staff
- Research, Division of Pulmonary Sciences and Critical Care Medicine
- Denver Veterans Affairs Medical Center
- University of Colorado Cancer Center
- University of Colorado School of Medicine
- York E Miller, MD
York E Miller, MD
- Thomas L Petty Chair of Lung Research
- Division of Pulmonary Sciences and Critical Care Medicine
- Co-Leader, Lung, Head and Neck Cancer Program
- University of Colorado Cancer Center
- Staff Physician
- Denver Veterans Affairs Medical Center
- University of Colorado School of Medicine
- Section Editors
- Rogerio C Lilenbaum, MD, FACP
Rogerio C Lilenbaum, MD, FACP
- Section Editor — Lung Cancer
- Yale Cancer Center
- David E Midthun, MD
David E Midthun, MD
- Mayo Clinic College of Medicine
Lung cancer is the leading cause of cancer deaths worldwide, with an estimated 1.8 million new cases and 1.3 million deaths in 2012 . Tobacco smoking is responsible for most cases of lung cancer (approximately 90 percent for men and 70 to 85 percent for women).
Never smoking or smoking cessation for smokers is the only proven means to decrease the risk of developing lung cancer. Former smokers continue to have an elevated risk of developing lung cancer for at least 30 years after stopping smoking, making these individuals an important target group for further efforts at mortality reduction [2,3]. (See "Overview of smoking cessation management in adults" and "Screening for lung cancer".)
Chemoprevention is the use of dietary or pharmacologic agents to prevent or slow the progression of cancer . Currently, however, there is no convincing evidence that any approach (other than smoking cessation) can decrease the risk of lung cancer.
Multiple agents have been studied to decrease the incidence of lung cancer, particularly in those at high risk for the development of this disease. The rationale for various approaches to chemoprevention (beyond never smoking and smoking cessation), observational data and its implications for epidemiologic studies, and results of chemoprevention trials that have been conducted are discussed in this topic.
Patient population — For chemoprevention to be feasible, a high-risk population must be identified and an effective chemopreventive agent with minimal side effects must be available. Current or former smokers with an annual risk of up to 2 percent are identifiable using a combination of clinically available risk factors including smoking history, age, gender, airflow obstruction or emphysema, environmental/occupational exposure, and family history of lung cancer [5,6].
- Brambilla E, Travis WD. Lung cancer. In: World Cancer Report, Stewart BW, Wild CP (Eds), World Health Organization, Lyon 2014.
- Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst 1993; 85:457.
- Anthonisen NR, Skeans MA, Wise RA, et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 2005; 142:233.
- Sporn MB. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 1976; 36:2699.
- Prindiville SA, Byers T, Hirsch FR, et al. Sputum cytological atypia as a predictor of incident lung cancer in a cohort of heavy smokers with airflow obstruction. Cancer Epidemiol Biomarkers Prev 2003; 12:987.
- Spitz MR, Hong WK, Amos CI, et al. A risk model for prediction of lung cancer. J Natl Cancer Inst 2007; 99:715.
- Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489:519.
- Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med 2008; 178:738.
- Moghaddam SJ, Li H, Cho SN, et al. Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model. Am J Respir Cell Mol Biol 2009; 40:443.
- Karoor V, Le M, Merrick D, et al. Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism. Cancer Prev Res (Phila) 2012; 5:1061.
- Wistuba II, Gazdar AF. Lung cancer preneoplasia. Annu Rev Pathol 2006; 1:331.
- SLAUGHTER DP, SOUTHWICK HW, SMEJKAL W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6:963.
- Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 2003; 63:1727.
- Nicholson AG, Perry LJ, Cury PM, et al. Reproducibility of the WHO/IASLC grading system for pre-invasive squamous lesions of the bronchus: a study of inter-observer and intra-observer variation. Histopathology 2001; 38:202.
- Jonsson S, Varella-Garcia M, Miller YE, et al. Chromosomal aneusomy in bronchial high-grade lesions is associated with invasive lung cancer. Am J Respir Crit Care Med 2008; 177:342.
- van Boerdonk RA, Sutedja TG, Snijders PJ, et al. DNA copy number alterations in endobronchial squamous metaplastic lesions predict lung cancer. Am J Respir Crit Care Med 2011; 184:948.
- Hirsch FR, Prindiville SA, Miller YE, et al. Fluorescence versus white-light bronchoscopy for detection of preneoplastic lesions: a randomized study. J Natl Cancer Inst 2001; 93:1385.
- Banerjee AK. Preinvasive lesions of the bronchus. J Thorac Oncol 2009; 4:545.
- Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6:244.
- Austin JH, Garg K, Aberle D, et al. Radiologic implications of the 2011 classification of adenocarcinoma of the lung. Radiology 2013; 266:62.
- Kim CF, Jackson EL, Kirsch DG, et al. Mouse models of human non-small-cell lung cancer: raising the bar. Cold Spring Harb Symp Quant Biol 2005; 70:241.
- Malkinson AM. Primary lung tumors in mice as an aid for understanding, preventing, and treating human adenocarcinoma of the lung. Lung Cancer 2001; 32:265.
- Witschi H. Tobacco smoke-induced lung cancer in animals--a challenge to toxicology (?). Int J Toxicol 2007; 26:339.
- Hudish TM, Opincariu LI, Mozer AB, et al. N-nitroso-tris-chloroethylurea induces premalignant squamous dysplasia in mice. Cancer Prev Res (Phila) 2012; 5:283.
- Meuwissen R, Linn SC, Linnoila RI, et al. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 2003; 4:181.
- Nemenoff R, Meyer AM, Hudish TM, et al. Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of peroxisomal proliferator--activated receptor gamma. Cancer Prev Res (Phila) 2008; 1:349.
- Wang Y, James M, Wen W, et al. Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice. Mol Cancer Ther 2010; 9:3074.
- Kisley LR, Barrett BS, Dwyer-Nield LD, et al. Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice. Carcinogenesis 2002; 23:1653.
- Keith RL, Karoor V, Mozer AB, et al. Chemoprevention of murine lung cancer by gefitinib in combination with prostacyclin synthase overexpression. Lung Cancer 2010; 70:37.
- Ito Y, Wakai K, Suzuki K, et al. Lung cancer mortality and serum levels of carotenoids, retinol, tocopherols, and folic acid in men and women: a case-control study nested in the JACC Study. J Epidemiol 2005; 15 Suppl 2:S140.
- Wattenberg LW, Wiedmann TS, Estensen RD, et al. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis 2000; 21:179.
- Parimon T, Chien JW, Bryson CL, et al. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175:712.
- Rothwell PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377:31.
- Rothwell PM, Wilson M, Price JF, et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379:1591.
- Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013; 10:334.
- Kelly K, Kittelson J, Franklin WA, et al. A randomized phase II chemoprevention trial of 13-CIS retinoic acid with or without alpha tocopherol or observation in subjects at high risk for lung cancer. Cancer Prev Res (Phila) 2009; 2:440.
- Lee JS, Lippman SM, Benner SE, et al. Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J Clin Oncol 1994; 12:937.
- Kurie JM, Lee JS, Khuri FR, et al. N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium. Clin Cancer Res 2000; 6:2973.
- Arnold AM, Browman GP, Levine MN, et al. The effect of the synthetic retinoid etretinate on sputum cytology: results from a randomised trial. Br J Cancer 1992; 65:737.
- McLarty JW, Holiday DB, Girard WM, et al. Beta-Carotene, vitamin A, and lung cancer chemoprevention: results of an intermediate endpoint study. Am J Clin Nutr 1995; 62:1431S.
- Heimburger DC, Alexander CB, Birch R, et al. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. JAMA 1988; 259:1525.
- van den Berg RM, Teertstra HJ, van Zandwijk N, et al. CT detected indeterminate pulmonary nodules in a chemoprevention trial of fluticasone. Lung Cancer 2008; 60:57.
- Veronesi G, Szabo E, Decensi A, et al. Randomized phase II trial of inhaled budesonide versus placebo in high-risk individuals with CT screen-detected lung nodules. Cancer Prev Res (Phila) 2011; 4:34.
- Lam S, MacAulay C, Le Riche JC, et al. A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. J Natl Cancer Inst 2002; 94:1001.
- Keith RL, Blatchford PJ, Kittelson J, et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res (Phila) 2011; 4:793.
- Kim ES, Hong WK, Lee JJ, et al. Biological activity of celecoxib in the bronchial epithelium of current and former smokers. Cancer Prev Res (Phila) 2010; 3:148.
- Lam S, leRiche JC, McWilliams A, et al. A randomized phase IIb trial of pulmicort turbuhaler (budesonide) in people with dysplasia of the bronchial epithelium. Clin Cancer Res 2004; 10:6502.
- Gustafson AM, Soldi R, Anderlind C, et al. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Transl Med 2010; 2:26ra25.
- Kelly RJ, Lopez-Chavez A, Szabo E. Criteria of evidence to move potential chemopreventive agents into late phase clinical trials. Curr Drug Targets 2011; 12:1983.
- Omenn GS, Goodman G, Thornquist M, et al. Chemoprevention of lung cancer: the beta-Carotene and Retinol Efficacy Trial (CARET) in high-risk smokers and asbestos-exposed workers. IARC Sci Publ 1996; 67.
- The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330:1029.
- Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996; 334:1145.
- Kamangar F, Qiao YL, Yu B, et al. Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China. Cancer Epidemiol Biomarkers Prev 2006; 15:1562.
- van Zandwijk N, Dalesio O, Pastorino U, et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 2000; 92:977.
- Lippman SM, Lee JJ, Karp DD, et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 2001; 93:605.
- Karp DD, Lee SJ, Keller SM, et al. Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597. J Clin Oncol 2013; 31:4179.
- Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005; 294:47.