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Lung Cancer Chemoprevention: An Integrated Approach

From the Departments of Clinical Cancer Prevention, Thoracic/Head and Neck Medical Oncology, and Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Scott M. Lippman, MD, M.D. Anderson Cancer Center, Department of Clinical Cancer Prevention, Box 236, 1515 Holcombe Blvd, Houston, TX 77030; email: slippman{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION CHEMOPREVENTION REFERENCES

 
ABSTRACT: Lung cancer is the leading cause of cancer deaths in the United States and the world, with grim incidence and mortality figures underscoring the need for new approaches, such as chemoprevention, for controlling this disease. There have been definitive, randomized, controlled lung-cancer chemoprevention trials in the three chemoprevention trial settings: primary (healthy high-risk [eg, smokers]), secondary (premalignant lesions), and tertiary (prevention of second primary tumors in previously treated patients), all of which produced negative (either neutral or harmful) primary end point results. These trials established that lung cancer was not prevented by alpha-tocopherol, beta-carotene, retinol, retinyl palmitate, N-acetylcysteine, or isotretinoin in smokers. Provocative leads of the definitive trials include the possible activity of isotretinoin in never and former smokers and that of alpha-tocopherol in prostate cancer prevention. A major area of lung cancer research is molecular epidemiologic study of highest smoking-related risk based on the interactions between tobacco carcinogens, genetic polymorphisms involved in activating and detoxifying these carcinogens, and host-cell efficiency in monitoring and repairing tobacco carcinogen-DNA damage. The future of lung cancer chemoprevention will rely heavily on molecular studies of carcinogenesis and drug mechanisms to develop novel chemopreventive targets and drugs, risk markers, and surrogate end point biomarkers; new preclinical drug-testing models; novel imaging techniques for monitoring agent activity; and molecular epidemiologic risk models for identifying the highest-risk current and former smokers.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION CHEMOPREVENTION REFERENCES

 
LUNG CANCER IS the leading cause of cancer death of men and women in the United States despite intensive efforts to control lung-cancer mortality with standard surgery, radiation, and chemotherapy. It is projected that the United States will experience 157,400 lung cancer deaths in 2001.¹ The 7% 5-year lung cancer patient survival rate of 1970 has improved to only 14% at present. Over 1,000,000 new cases of lung cancer are diagnosed worldwide each year.² This grim overview indicates the urgent need for new, emerging approaches, such as chemoprevention, for controlling lung cancer.

	CHEMOPREVENTION

TOP ABSTRACT INTRODUCTION CHEMOPREVENTION REFERENCES

 
Chemoprevention is the use of natural or synthetic agents to reverse, prevent, or delay carcinogenic progression to invasive cancer. The two fundamental concepts of chemoprevention are multistep and multifocal carcinogenesis.³ According to the multistep carcinogenesis concept, cancer develops in a stepwise fashion, with an accumulation of molecular alterations progressing through preinvasive steps to invasive disease. Suppressing one or more of the preinvasive steps may impede the development of cancer. The accumulated molecular alterations contribute to lesion heterogeneity and drug resistance, especially in advanced premalignant lesions. According to multifocal carcinogenesis, cancer can develop from multiple genetically distinct clones (field carcinogenesis) and lateral (intraepithelial) spread of genetically related preinvasive clones.⁴ Field carcinogenesis denotes diffuse tissue damage resulting from carcinogenic exposure (eg, cigarette smoke) in an entire epithelial field or region such as the lung, where the wide range of histologic changes associated with chronic smoking and cancer include the loss of cilia, cellular atypia, reserve cell hyperplasia, squamous metaplasia and dysplasia, and carcinoma-in-situ.⁵ Genetic changes and premalignant and malignant lesions in one area of the exposed field imply increased risks of developing cancer in other sites within the field.

MOLECULAR EPIDEMIOLOGY
The efficiency of randomized controlled chemoprevention trials for lung cancer would be enhanced by enrolling the highest-risk subgroups of smokers or former smokers. However, individuals are known to differ in their susceptibility to tobacco exposures. Over 80% of lung cancers are attributed to tobacco, yet only a fraction of smokers will develop lung cancer in their lifetimes. The cumulative risk of lung cancer through age 75 is estimated to be 15.9% for men and 9.5% for women.⁶ It is also noteworthy that about half of all newly diagnosed lung cancer patients are former smokers (quit at least 1 year before lung cancer diagnosis).⁷ The challenge for epidemiologists is to incorporate measures of genetic susceptibility into the quantitative risk assessment process.

The molecular epidemiology approach, with the confluence of sophisticated advances in molecular biology and field-tested epidemiologic methodology, has advanced our knowledge of tobacco carcinogenesis and susceptibility. However, indirect indicators of host susceptibility to tobacco carcinogenesis are identifiable even from classical epidemiologic studies.

Whether women are more susceptible than men to the carcinogenic effects of cigarettes remains controversial. Several case-control studies have suggested that the association between smoking and lung cancer was considerably stronger for women than for men,^8-10 although prospective population-based research has not confirmed these previous reports.¹¹

The relationship between diet and lung cancer has been extensively explored in ecologic, case-control, and prospective studies. More recently, interest has been focused on diet-exposure and diet-gene interactions.¹² Sinha et al¹³ recently reported that specific heterocyclic amines in the diet were associated with significantly increased risk of lung cancer in nonsmokers and light-to-moderate smokers. A Dutch cohort study of 939 male lung cancer patients suggested that folate, vitamin C, and beta-cryptoxanthin had protective effects, mainly in current smokers.¹⁴

Familial aggregation studies of lung cancer provide indirect evidence for the role of genetic predisposition. Tokuhata and Lilienfeld¹⁵ and Ooi et al¹⁶ found increased risks for lung cancer in both smoking and nonsmoking relatives of lung cancer patients. In men but not women, the effect from smoking seemed to be stronger than the familial effect. Smoking was found to interact synergistically with a family history of lung cancer.¹⁷ These inheritance-pattern studies suggest that a small proportion of lung cancer is a result of lung cancer genes that are likely to be of low frequency but high penetrance. However, low penetrance/high frequency genes are likely to be valuable in elucidating the causal pathways for the vast majority of lung cancers.

There are multiple genetically determined factors that are thought to abrogate the effects of environmental carcinogens and thus explain differences in susceptibility. Risk is dependent on the dose of tobacco carcinogens, which is modulated in turn by genetic polymorphisms in the enzymes responsible for activation and detoxification of these carcinogens and by the efficiency of the host cells in monitoring and repairing tobacco carcinogen-DNA damage.

Defective repair of genetic damage should be factored into risk assessment. Maintenance of genomic integrity requires intact DNA repair and cell cycle control systems, and a defect in either of these systems will lead to genomic instability. Assays that measure cellular DNA repair are now being applied in population studies to investigate the association between DNA repair and susceptibility to cancer. Wei et al^18,19 investigated whether differences in DNA repair capacity (DRC) for repairing tobacco carcinogen–induced DNA damage are associated with differential susceptibility to lung cancer. In both the initial pilot study¹⁸ (51 patients and 56 frequency-matched controls) and a subsequent large hospital-based case-control study¹⁹ (316 each of lung cancer patients and controls), statistically significantly lower DRC was observed in lung cancer patients compared with controls and was associated with a greater than two-fold increased risk of lung cancer. Compared with the highest DRC quartile in the controls, suboptimal DRC was associated with adjusted risks for lung cancer of 1.8, 2.0, and 4.3 for the second, third, and fourth quartiles of DRC, respectively (P_trend < .001). Within the subgroups of patients who were younger at diagnosis (< 60 years old), female, lighter smokers, or had a family history of cancer, the patients with the lowest DRC had the highest lung-cancer risk, suggesting that suboptimal DRC is particularly relevant within these subgroups to lung-cancer susceptibility.¹⁹

The mutagen sensitivity assay, in which in vitro mutagen-induced breaks are quantitated as a measure of carcinogen sensitivity, can also identify significant risk factors for lung cancer. In a series of 242 previously untreated lung cancer patients and 262 controls, the adjusted risk estimate for bleomycin sensitivity was 2.87 (95% confidence interval [CI], 1.96 to 4.2) (unpublished data). Higher risk estimates were evident for current compared with former and lighter smokers (< 1 pack per day) and for the lighter smokers compared with heavier smokers. In assays using two different test mutagens (bleomycin and benzo[a]pyrene), higher adjusted odds ratios (ORs) were evident in the higher quartiles of induced chromatid breaks.²⁰ Individuals exhibiting both suboptimal DRC on the host-cell reactivation assay and the mutagen-sensitive phenotype had a risk estimate of 5.33 (95% CI, 3.05 to 9.32). This pattern was evident for current, former, and never smokers.

The roles of phase 1 activating enzymes (eg, cytochrome p450, myeloperoxidase) and phase 2 detoxifying enzymes (eg, glutathione S-transferases, epoxide hydrolase) and their regulating genes in the risk of lung cancer have been reported extensively.²¹ There is also extensive screening for sequence variations, or polymorphisms, in DNA repair genes to understand interindividual differences in DRC.²² The functional impact of these polymorphisms in DRC is only now beginning to be explored. Most of the amino acid substitutions are at highly conserved residues important in maintaining normal protein structure and function. These sequence conservations suggest a functional role for these residues and that amino acid substitutions could result in proteins with reduced function in either repair capacity or fidelity. For example, XPD (originally named excision repair cross-complementing group 2) is one of the seven genetic complementation groups encoding for proteins involved in the nucleotide excision repair pathway. XPD functions dually in nucleotide excision repair and in basal transcription. It functions as an evolutionary conserved adenosine triphosphate–dependent helicase within the multisubunit transcription repair factor complex TFIIH. We recently showed that XPD polymorphisms at Lys751Gln and Asp312Asn have a modulating effect on DRC, as measured by the host-cell reactivation assay.²³

Multiple susceptibility factors, including serum markers such as insulin-like growth factors,^24,25 most likely must be accounted for to represent the true dimensions of gene-environment interactions. Functional assays that require viable lymphocytes are not currently suitable for large-scale population-based epidemiologic studies of cancer susceptibility. Therefore, it is important to identify genotypes (eg, that predict DRC) that are amenable to high-throughput analysis. It will be necessary to capitalize on technologic advances in high throughput, automated approaches for rapid, large-scale genotyping to identify and evaluate biologic markers more selectively predictive of cancer risk in current and former long-term smokers.

RANDOMIZED, CONTROLLED TRIALS
Randomized controlled trials (RCTs) provide the highest level of evidence of agent activity. RCTs have been conducted in the three lung cancer chemoprevention settings: primary (healthy high-risk, eg, smokers), secondary (premalignant lesions), and tertiary (prevention of second primary tumors in previously treated patients) (Table 1).^26-35 This section will focus on the results of lung cancer–chemoprevention RCTs with premalignant (phase IIb) and cancer (phase III) end points.

Five phase IIb chemoprevention trials^28-32 have been conducted in smokers with metaplasia or sputum atypia, and all have been negative (Table 1). Two trials used a systematic bronchoscopic approach to sample the epithelium throughout the bronchial tree. The first of these trials tested isotretinoin versus placebo for the reversal of metaplasia in bronchial biopsy specimens and found a substantial reduction in metaplasia in (and no statistical difference between) both arms.²⁹ Smoking cessation correlated with a significant reduction in squamous metaplasia and cell proliferation,³⁸ and isotretinoin plus smoking cessation further reduced metaplasia. A randomized, placebo-controlled trial of beta-carotene (50 mg/d) plus retinol (25,000 IU every other day) in 755 asbestos workers was the largest reported phase IIb lung chemoprevention trial.³² No significant changes (reduction or progression) in sputum atypia occurred after a mean follow-up of 58 months.

Imaging techniques are a major area of concern for developing phase IIb trials in the lung. The sampling techniques of fluorescent localization and standard white-light bronchoscopy have been roughly equivalent in their ability to identify premalignant lesions.³⁹ New imaging techniques (eg, molecular imaging) are needed to advance this area of phase IIb cancer chemoprevention study. Metaplastic and dysplastic lung lesions are associated with a high rate of spontaneous regression and a wide spectrum of cancer risks. Their actual cancer risk, and therefore potential for valid phase-IIb end points, are being refined by surrogate end point biomarkers,^3,37 such as molecular markers of clonality (eg, loss of heterozygosity and DNA content).⁴

Phase III Lung Cancer Prevention Trials Fifteen definitive³⁶ phase III cancer chemoprevention trials (that involved 22 different primary interventions/end points) have been completed, four of which (that involved six different primary interventions/end points) were lung cancer prevention trials (Fig 1).^{26,27,34-36,40-50} There have been three positive/beneficial phase III trials, two of which involved tamoxifen in breast cancer prevention/risk reduction,^49-51 and two negative/harmful phase III trials, both of which involved lung cancer prevention (with beta-carotene alone or with retinol). There are also four negative/neutral results of phase III lung cancer prevention trials (Table 1, Fig 1). Two completed phase III lung cancer chemoprevention trials, the Alpha-Tocopherol, Beta-Carotene (ATBC) Study²⁶ and the Beta-Carotene and Retinol Efficacy Trial (CARET),²⁷ involved primary prevention, and two, Euroscan and the recent United States Lung Intergroup Trial (both testing retinoids), involved tertiary prevention.

View larger version (34K): [in this window] [in a new window]   Fig 1. Risk ratio estimates and 95% CIs (vertical bars) for outcomes of the definitive phase III cancer chemoprevention trials (the lung trials are indicated by the light-blue CI bars). Modified from a figure originally published in the Journal of the National Cancer Institute36 (reproduced with permission of Oxford University Press).

The CARET²⁷ was a multicenter lung cancer prevention trial of beta-carotene (30 mg/d) plus retinol (25,000 IU/d) versus placebo in 18,314 asbestos workers and smokers. This trial was terminated when the results of interim analyses were consistent with the ATBC beta-carotene/lung cancer findings. A significant 28% increase in lung cancer incidence occurred in the supplemented subjects, and total mortality increased by 17%. The statistical significance of the treatment-associated increase in lung cancer incidence was due to the increase in current smokers.

On the basis of these data, it is prudent to recommend that heavy smokers avoid high-dose beta-carotene supplementation. Recent preclinical data are beginning to provide biologic plausibility for the adverse interaction of cigarette smoke and beta-carotene that occurred in the ATBC and CARET.^36,52,54-56 It is possible that lung carcinogenesis is enhanced when high tissue concentrations of beta-carotene interact with strongly oxidative tobacco smoke. Wang et al⁵⁴ reported that smoke and high doses of beta-carotene are associated with retinoic acid receptor (RAR)–beta suppression and activator protein-1 (AP-1) overexpression in the lungs of ferrets. Therefore, oxidative metabolites of beta-carotene may inhibit retinoid signaling and thus increase tumorigenesis. Beta-carotene or its oxidation products may have co-carcinogenic effects involving cytochrome p450 changes under certain conditions.⁵⁶

Tertiary phase III trials. Lung cancer–associated second primary tumors (SPTs) have etiologic, regional, and biologic traits in common with SPTs associated with head and neck squamous cell cancer.⁵⁷ Therefore, the consistent positive results of retinoid/retinoic acid (RA) studies in head and neck chemoprevention^58-62 contributed substantially to the rationale for testing retinoids in lung SPT prevention.

Euroscan³⁴ was an open-label multicenter trial of retinyl palmitate and N-acetylcysteine (NAC) for 2 years in a 2 x 2 factorial design involving 2,592 patients, approximately 1,000 of whom had lung cancer. The rationale for retinyl palmitate came largely from a smaller RCT (307 stage I non–small-cell lung cancer [NSCLC] patients) indicating that the time to tobacco-related SPT development was significantly shorter in the control than in the retinyl palmitate arm (P = .045) (although the two groups did not differ significantly with respect to overall SPT rates).³³ The Euroscan end point was SPT prevention after definitive therapy of early-stage head and neck cancer (larynx, T_is, T_1-3, N_0-1; oral cavity, T_1-2, N_0-1) and NSCLC (pT_1-2, N_0-1, and T₃N₀). At a median follow-up of 49 months, retinyl palmitate and/or NAC produced no improvement in event-free survival, overall survival, or incidence of SPTs.

Led by the M.D. Anderson Cancer Center Community Clinical Oncology Program Research Base,⁶³ the phase III Lung Intergroup Trial (National Cancer Institute [NCI] I91-0001) was recently completed and reported in detail.³⁵ The Intergroup effort was a double-blind trial of low-dose isotretinoin (30 mg/d) versus placebo to prevent SPTs in patients 6 weeks to 3 years from their definitive resections of pathologic stage I NSCLC. Registering over 1,400 patients (into the placebo run-in period) in less than 4 1/2 years, this was the largest prospective study of stage I NSCLC and demonstrated the remarkable success of the NCI Intergroup mechanism in accruing these patients (see Table 2 for accrual by cooperative group). There were 1,166 randomized and eligible patients, who were stratified by T-stage, histology, and smoking status. The trial was definitively neutral in its primary end point, SPT prevention (including neutral with respect to tobacco-related SPTs), and prespecified secondary end points, recurrence and death. Median follow-up was 3 1/2 years. The SPT rate was 3.9% per year ( 1/2 in the lung) and was exceeded by the recurrence rate (6.2%), even in T₁N₀ patients. Univariate analyses of the stratification factors indicated that stage T₂ NSCLC was associated significantly with recurrence and mortality and that histology (squamous cell carcinoma) and smoking correlated with mortality. The significant associations between stage and histology remained in the multivariate stratification-factor analyses, but smoking was no longer associated with mortality. This led to a post hoc analysis of a potential treatment-smoking interaction, which found a significant harm associated with treatment-by-current smoking, significant benefit associated with treatment-by-never smoking and nonsignificant trend of benefit over time associated with treatment-by-former smoking. This was the first report of differential retinoid treatment-smoking interactions, which as results of post hoc secondary analyses are subject to statistical error. Plans for continuing and future studies based on this seminal Intergroup trial include longer clinical follow-up (eg, to assess former smoker trends) and biologic study of the retinoid-smoking interactions with respect to lung carcinogenesis.

A body of basic data involving the potential molecular RA targets RAR-beta/methylation, AP-1, gastrin-releasing peptides, gastrin-releasing peptide receptors, and NF-kappa-B activation^64-68 relates to the phase III Intergroup SPT findings in the lung. Retinoids regulate the growth and differentiation of normal lung epithelial cells by interacting with nuclear retinoid receptors (RARs and retinoid X receptors [RXRs]), which function as transcription factors. Several receptors (particularly RAR-beta) are suppressed in a substantial percentage of metaplastic lesions and NSCLCs.⁶⁹ The downregulation of RAR-beta expression by promoter methylation and allelic loss may partly explain RA resistance in vitro and in vivo in lung cancers.⁶⁴ Suppression of RA signaling via RAR-beta could enhance mitogenic activities (eg, increased activity of the transcription factor AP-1, a complex of the proto-oncogenes c-fos and c-jun). RA leads to a modest increase in the expression of RAR-beta in the lungs of smokers who do not have lung cancer.^69,70 Although this indicates that the lung epithelium of smokers retains some ability to respond to retinoid signaling, this ability is far less than that of oral premalignant lesions.⁶¹ Therefore, it is possible that the lack of beneficial RA activity in smokers in these trials is a result of defects in the genes that are regulated by RA via RAR-beta. This theory is supported by a study using an in vitro model of human lung carcinogenesis.⁷¹ An unexpected finding, that increased (not lost) RAR-beta expression was associated with poor prognosis in stage I NSCLC,⁷² further complicates the understanding of the role of RAR-beta in lung carcinogenesis.

FUTURE DIRECTIONS
All the definitive phase II and III lung cancer chemoprevention trials have produced negative (either neutral or harmful) primary end point results, whether in the primary, secondary or tertiary chemoprevention trial settings (as illustrated in Table 1 and Fig 1). These trials provided definitive answers to the questions they were designed to answer: lung cancer was not prevented by alpha-tocopherol, beta-carotene, retinol, retinyl palmitate, NAC, or isotretinoin in smokers. They also provided provocative leads: isotretinoin may prevent lung cancer in never and former smokers, and alpha-tocopherol may prevent prostate and, as discussed above, even lung cancer (probably at higher doses and longer durations than those tested in the ATBC).

There are several current directions of lung cancer chemoprevention that show promise for developing effective agents in the future. Molecular targets, such as RA receptors (RAR-beta and possibly RAR-gamma and RXR-beta), aberrant methylation, p53, p16, telomerase, Ras association domain family 1A gene (RASSF1), loss of heterozygosity (eg, at 3p, 8p, and 9p), fragile histidine triad (FHIT), K-ras, cyclooxygenase-2, lipoxygenases, and AP-1,^36,64-81 are used in the development of promising new drugs, such as those listed in Table 3. Molecular-targeting study is developing more clinically relevant in vitro and in vivo drug-screening assays, such as tissue-specific transgenic and gene-knockout models. Better preclinical models are being developed to help in identifying potential human surrogate end point biomarkers. The molecular study of carcinogenesis and drug mechanisms is helping to develop chemoprevention combination regimens, eg, RA combined with demethylating agents to reverse smoking-related RAR-beta–promoter methylation or combined with agents that can help overcome single-agent RA resistance associated with tumor heterogeneity.^64,82

Molecular epidemiologic study is attempting to improve the efficiency of randomized controlled lung cancer chemoprevention trials by identifying the highest-risk subgroups of smokers or former smokers, whose high anticipated event rates would allow for smaller trial sample sizes and durations.³⁶ Identifying these subgroups is complicated, however, by individual differences in susceptibility to tobacco exposures. Individual risks are determined by the dose of tobacco carcinogens, genetic polymorphisms in the enzymes responsible for activation and detoxification of these carcinogens, and DRC. The relatively recent identification of nicotine-addiction genes^83,84 may lead to developing agents that can target these genes to achieve smoking cessation. This novel approach that combines molecular epidemiology and chemoprevention would attack the major cause of lung cancer, tobacco-carcinogen exposure.

Other promising areas of study include advances in imaging techniques, such as molecular imaging, which will allow better short-term monitoring of chemopreventive drug activity in phase II trials. New developments in the local delivery of high concentrations of pharmacologic agents to lung tissue (eg, aerosolized steroids) might lead to enhanced agent activity and reduced systemic toxicity.^79,85 New statistical models are needed to analyze multiple biomarkers in phase IIb trials and important secondary outcomes of phase III lung chemoprevention trials.^36,86 One such potential secondary outcome, which is supported by exciting animal data showing RA reversal of emphysema,⁸⁷ would be improved lung function in possible future phase III trials of RA in former smokers.

Considering the negative results of all the definitive lung-cancer prevention RCTs, lung cancer is perhaps chemoprevention’s greatest challenge. Considering the unabated worldwide consequences of this major cancer, chemoprevention must continue its effort to help control lung cancer, aided by the clinical, mechanistic, and molecular studies outlined above.

	ACKNOWLEDGMENTS

 
Supported in part by Public Health Service grant nos. CA45809, CA 16672, CA55769, and CA86390 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

	NOTES

 
S.M.L. holds the Margaret and Ben Love Professorship in Clinical Cancer Care. M.R.S. holds the Olga Keith Wiess Chair.

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