Chemoprevention of Lung Cancer

Introduction

Lung cancer is the most common and deadly malignancy in the United States and throughout the world. It is the leading cancer killer of both men and women in the United States, and is expected to be responsible for approximately 31% of all cancer deaths in men and 25% of cancer deaths in women in 1999. Overall, the 5-year survival rate for lung cancer is only 15%.[1]

Since 90% of lung cancers are tobacco related, primary prevention of lung cancer by smoking prevention and cessation is one of the highest priorities for United States health policy. In the United States today, 50 million individuals are current smokers, and another 50 million are former smokers. In fact, 50% of newly diagnosed lung cancers occur in former smokers, perhaps due to persistent genetic changes in the bronchial epithelium from tobacco carcinogens.[2,3] Chemoprevention is defined as the use of specific natural or pharmacologic agents to reverse, suppress, or prevent the carcinogenic process to the development of invasive cancer.[4]

Biologic Concepts

The basic idea behind lung cancer chemoprevention is the concept that diffuse injury of the respiratory epithelium results from chronic carcinogen exposure. This is known as “field cancerization,” which describes the diffuse mucosal changes observed in patients with head and neck cancers. These changes, identified from resected surgical specimens of carcinoma of the oral cavity, were of three primary histologic abnormalities surrounding the primary tumor: Hyperplasia (an increase in the number of rows in the epithelium), hyperkeratinization, and dyskariosis (atypia). When the entire surgical specimen was further sectioned, separate foci of in situ and invasive carcinoma were frequent findings. Basically, the entire upper aerodigestive tract is exposed to long-term carcinogenic insult (in this instance, cigarette smoke), and is therefore at increased risk of developing cancer.[1-4]

The evidence for multistep carcinogenesis in this setting also includes genetic damage to lung tissue, demonstrated by the linear relationship between genetic instability (eg, polysomy of chromosomes 3, 9, and 17) in human lung tissue and cigarette smoking, and the increased frequency of proliferative markers in high-risk tissues and premalignant lesions (Figure 1).[5-9]

Auerbach et al sectioned the entire tracheobronchial trees of chronic smokers and patients who died of lung cancer. They recorded three major types of epithelial changes: an increase in the number of cell rows, loss of cilia, and the presence of atypical cells. The most striking finding was the frequency of carcinoma in situ, a lesion composed entirely of atypical cells without cilia in an average thickness of 5 or more cell rows; this finding was observed in 15% of the sections from those who died of lung cancer. These lesions were found in 4.3% of sections from men who smoked one to two packs of cigarettes per day, and 11.4% of sections from those who smoked two or more packs per day.[5,6,10,11] These lesions were never found in pathologic specimens of nonsmokers, and few were found in the bronchial trees of light smokers.

Rationale for Chemoprevention

The field of chemoprevention grew in large part out of the epidemiologic data demonstrating the existence of dietary inhibitors of carcinogenesis. The rationale for chemoprevention arose from a combination of sources: epidemiologic data demonstrating the existence of dietary inhibitors of carcinogenesis, basic studies of epithelial carcinogenesis, and laboratory evidence from animal models.[5,12-15] Despite these data, difficulty has persisted in determining which specific compounds within complex foods provide anticarcinogenic (or carcinogenic) effects.

The term “chemoprevention” was coined by Michael B. Sporn to define the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer.[3,4] In 1981, Peto et al examined the impact of dietary b-carotene on the reduction of human cancer rates. Several groups had previously demonstrated an inverse correlation between human cancer risk, blood retinol(Drug information on retinol), and dietary b-carotene.[16] They reviewed the literature on whether supplemental b-carotene or vitamin A could materially retard the carcinogenic process. The cancer-preventive data from epidemiologic studies led to in vitro and in vivo (animal) laboratory studies evaluating the specific components of complex foods. Whereas these studies discovered many agents with laboratory anticarcinogenic activity and suggested potential toxicity profiles of these agents, translational clinical chemopreventive trials to substantiate their efficacy in humans were lacking at the time.[6,17,18]

Much of this work has been conducted by investigators from M. D. Anderson Cancer Center (Houston) in carefully designed, double-blind, placebo-controlled clinical chemoprevention trials.[3,17,18] These studies focused on vitamin A and its synthetic analogs, collectively referred to as retinoids. The retinoids appear to act by binding to a specific set of retinoic acid receptors (RAR) and retinoid-X-receptors (RXR). The binding of retinoids to these receptors results in binding to specific nuclear sites and the transcriptional activation of multiple downstream genes. Retinoids function by inducing differentiation in cells that have lost normal regulatory mechanisms. Whereas retinol and the synthetic retinoids produce significant toxic effects if given in high doses, different synthetic retinoids with different receptor-specific ties are being developed, several of which have undergone extensive clinical testing. Synthetic retinoids that have demonstrated activity in various clinical trials to date include 13-cis-retinoic acid (13cRA) in head and neck cancers, myelodysplasia, childhood neuroblastoma, and juvenile chronic myelogenous leukemia; all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL); etretinate in cervical and skin cancers; and retinyl palmitate in lung cancer. Also, 9-cis-retinoic acid (9cRA), an RXR-specific ligand, 4-N-(4-hydroxyphenyl) retinamide (4-HPR), and other new vitamin A derivatives are under active clinical investigation.[2,3,9,12]

The ability of retinoids to suppress lung carcinogenesis in animal models was believed to result from changes in the expression of their nuclear retinoid receptors, because these receptors play a proximal role in the retinoid signaling pathway. Retinoids exert their actions through activation of the nuclear retinoid receptors that act as transcription factors for genes that influence cell growth and differentiation. Therefore, changes in their expression may cause aberrations in cells’ response to retinoids and alterations in growth and differentiation regulation. It was found that RAR-b expression is suppressed in many lung cancer cell lines, a finding that implies a selective suppression of RAR-b in malignant transformation. Selective suppression of RAR-b in the early stages of carcinogenesis in the oral cavity and marked upregulation of RAR-b after retinoid treatment associated with clinical response have been confirmed, thus giving RAR-b excellent potential as an intermediate biomarker.[2-4,19] A pilot study of RAR-b expression in specimens from a previous chemoprevention trial in bronchial metaplasia revealed that only 55% of patients expressed RAR-b before treatment, with some upregulation of RAR-b expression taking place after retinoid treatment.

Retinoid receptor expression was compared in specimens from normal and malignant lung tissues. All receptors were expressed in at least 89% of control normal bronchial tissue specimens from patients without a primary lung cancer and in distant normal bronchus specimens from patients with non–small-cell lung cancer. RAR-a, RXR-a, and RAR-g were expressed in more than 95% of the 79 non–small-cell lung cancer specimens, in contrast to RAR-b, RAR-g, and RXR-b expression, which were detected in only 42%, 72%, and 76% of non–small-cell lung cancer specimens, respectively. These findings provide further evidence for implication of RAR-b, and possibly RAR-g and RXR-b, in lung carcinogenesis.[19]

Chemoprevention Trials in Bronchial Premalignant Lesions

Bronchial metaplasia, dysplasia, and sputum atypia are associated with lung cancer and a history of smoking. Sputum atypia was examined in a multi-center lung cancer screening, and was not found to predict lung cancer development. Chemoprevention trials have investigated the effect of different agents on bronchial metaplasia and dysplasia and sputum atypia (Table 1). In a small uncontrolled pilot trial of participants with at least a 15–pack-year smoking history, Mathe et al observed a reduction in bronchial metaplasia following treatment with etretinate, a synthetic retinoid.[28] In smokers with at least a 15–pack-year history, Arnold et al examined the effect of 6 months of treatment with etretinate or placebo on sputum atypia and found no effect.[21] In a population with a heavier smoking history and exposure to asbestos, McLarty et al observed no effect of b-carotene and retinol on sputum atypia.[22] In participants with at least a 20–pack-year smoking history, Lee et al found no effect on 13cRA on bronchial metaplasia, but bronchial metaplasia was reduced by smoking cessation, suggesting that bronchial metaplasia is an acute reaction to cigarette smoke exposure in active smokers.[17]

The previously mentioned trials have relied on white-light bronchoscopy for the detection of bronchial metaplasia and dysplasia. A new technique using a laser incorporated into a bronchoscope was reported to be 50% more sensitive in the detection of bronchial dysplasia than standard white-light bronchoscopy. This technique is based on the principle that light of specific wavelengths can stimulate intrinsic cellular florophors, such as flavins, riboflavins, nucleic acids, and proteins, to fluoresce, thereby emitting a spectral pattern of light typical of that particular tissue. Epithelial carcinogenesis is associated with altered levels of these fluoroflors; by using fluorescence spectroscopy, normal, dysplastic, and neoplastic tissues can be distinguished on the basis of their spectral patterns. This new bronchoscopic technique is under evaluation in chemoprevention trials as a method of enhancing the detection of bronchial premalignancy in smokers and former smokers.[29-31]