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Chemoprevention of lung cancer Victor Cohena and Fadlo R. Khurib

Purpose of review Lung cancer is one of the major causes of cancer-related deaths. Grim mortality figures argue powerfully for new approaches to control this disease. Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The current article focuses on the field of lung cancer chemoprevention and recent advances. Lung cancer biology and general principles of prevention strategies are also described. Recent findings Trials in lung cancer chemoprevention have so far produced either neutral or harmful primary end point results whether in the primary, secondary and tertiary settings. The data suggest that lung cancer was not prevented by beta-carotene, alpha-tocopherol, retinal, retinyl palmitate, N-acetylcysteine, or isotretinoin in smokers. The results from the recently completed Canadian study of anethole dithiolethione in smokers with bronchial dysplasia as well secondary analyses of the phase III trials involving selenium and data from the US Intergroup NCI-91-0001 supporting treatment with isotretinoin in never and former smokers are hopeful and may help define new avenues of chemopreventive treatment after scientists and clinicians analyze the information generated. Summary The concept of chemoprevention in lung cancer is still in its infancy but one day may have a significant impact on the incidence and mortality of this leading cancer threat. An improved understanding of carcinogenesis and cancer prevention mechanisms will no doubt aid in the design of future clinical trials and in the validation of candidate agents as well as the development of new targets. Planned or ongoing trials currently are targeting important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors and the tyrosine kinase/epidermal growth factor receptor pathway. Until such studies are completed however, no drug or drug combination should be used for lung cancer prevention outside of a clinical study.

Keywords lung cancer, multistep carcinogenesis, field carcinogenesis, chemoprevention, retinoids Curr Opin Pulm Med 10:279–283. © 2004 Lippincott Williams & Wilkins.

a Sir Mortimer B. Davis–Jewish General Hospital, McGill University School of Medicine, Department of Oncology, Montreal, Quebec, Canada, and b Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA

Correspondence to Victor Cohen, Sir Mortimer B. Davis–Jewish General Hospital, McGill University School of Medicine, Department of Oncology, 3755 Cote Ste., Catherine Road, Suite E-177, Montreal, Quebec, Canada H3T-1E2 Tel: 514 340 8222 x5527; fax: 514 340 8302; e-mail: vcohen@onc.jgh.mcgill.ca Current Opinion in Pulmonary Medicine 2004, 10:279–283 © 2004 Lippincott Williams & Wilkins 1070-5287

Introduction Lung cancer remains the most common cause of death from cancer worldwide with approximately 1,240,000 cases diagnosed in 2001 and more than 1,500,000 anticipated by 2004 [1]. Despite some improvements in treatment results during the past decade due to improved surgical techniques, increased utilization of combinedmodality treatments for locally advanced lung cancer, and the introduction of novel agents, the overall prognosis is still very poor: 5-year survival rates in the United States including all stages is 16.8% with 5-year survivals in Great Britain around 7% [2]. This grim overview argues powerfully for new, emerging approaches to control this disease. Chemoprevention is one of these new approaches. Chemoprevention is “the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer.” The term was coined by Michael Sporn who is widely credited with launching the modern era of cancer chemoprevention and prevention research. He was the first to put forward the notion that the goals and objectives of clinical efforts in the treatment of some types of cancers should be the process of carcinogenesis rather than the state of cancer [3]. Although at first regarded with skepticism, this approach has led to proven, significant advances in cancer prevention. Clinical validation for the cancer prevention concept was provided by a randomized trial using the selective estrogen receptor modulator tamoxifen in women who are at high risk for breast cancer development based on age, ductal carcinoma in situ, or the Gail model. In women who received tamoxifen, there was a highly statistically significant reduction in the risk of both invasive and noninvasive breast cancers [4,5]. Studies in colon and head and neck cancers have also provided clear and compelling evidence of the efficacy of the chemopreventive approach [6–8]. In the case of lung cancer, results have been somewhat disappointing. With the advent of novel targeted agents there has been a push to consider molecu279


280 Neoplasms of the lung

larly targeted approaches to non-small cell lung cancer. The success of these agents remains open to question at this time. This review will focus on the field of lung cancer chemoprevention and recent advances. Lung cancer biology and general principles of prevention strategies are also described.

Lung cancer biology and first principles of chemoprevention Lung carcinoma appears to develop from a pluripotent stem cell involved in the generation of the bronchial epithelium and capable of differentiation along several pathways. The mutlistep process of carcinogenesis can be viewed as a process of progressive disorganization characterized by the occurrence of initiation, promotion, and progression events happening over latent periods over a decade or more and resulting from exposure to a variety of environmental insults. These events produce an accumulation of genetic and epigenetic alterations of at least three groups of genes: proto-oncogenes, tumor suppressor genes, and mutator genes resulting in imbalances between cellular proliferation, apoptosis, and shedding. Imbalance in cellular population kinetics promotes a buildup of cells that if sufficiently abnormal has malignant capability. Numerous systems including repair, replacement, or recruitment, replication and redundancy mechanisms become operational to help restore structural and functional integrity. In some instances, however these mechanisms fail or are overwhelmed and unrepaired injury not only occurs but is also proliferated resulting in the liberation of cells from normal growth restrictions and progression through preinvasive stages culminating in a fully transformed invasive cancer. Malignant lesions can develop from multiple genetically distinct clones in diverse areas so-called “field carcinogenesis” and lateral intraepithelial spread of genetically related preinvasive clones. Field carcinogenesis denotes diffuse epithelial tissue injury resulting from carcinogenic exposure in an entire epithelial field or region where tissue changes can be detected at the gross, microscopic, and molecular levels [9]. Recent observations detecting intense genetic alterations in histologically normal-appearing tissue from high-risk individuals have provided strong support for this notion [10–12]. The clinical importance of this phenomenon is best illustrated in aerodigestive cancers for which both synchronous and metachronous second primary tumors are common. These two basic concepts of multistep carcinogenesis and the diffuse field-wide carcinogenic process have provided an excellent model for prevention study and have guided the development of lung cancer chemoprevention efforts. The essence of chemoprevention is intervention within the multistep carcinogenic process and throughout a

wide field. Using pharmacologic or natural compounds, chemoprevention is meant to interrupt this clonal propagation of aberrant cells by blocking DNA damage, retarding or reversing malignant phenotype, or inducing apoptosis in the damaged cells of premalignant lesions. Chemoprevention strategies can be considered at three different major levels: primary, secondary, and tertiary. Primary prevention is defined as an intervention intended to delay the development of cancer or hinder its progression. Normal healthy individuals represent the population at which primary prevention is directed. Such approaches as smoking prevention and cessation treatments or the use of chemoprevention drugs in a group of asymptomatic smokers are examples of this strategy. Secondary chemoprevention is aimed at persons with evidence of early disease, but without frank cancer and tertiary prevention involves decreasing the morbidity of established disease. Chemoprevention of second primary tumors in patients treated for or cured of an initial malignancy is a good example of tertiary prevention.

Randomized lung cancer chemoprevention trials Primary prevention interventions

Table 1 lists the major trials of chemoprevention in lung cancer. Among these, several large good-quality clinical studies randomizing high-risk individuals in the primary prevention setting to beta-carotene alone or in combination with retinol have resulted in increased risk of developing lung cancer in individuals receiving these agents. Statistically significant increases in lung cancer incidence in smokers receiving beta-carotene supplements were shown in the Beta-Carotene and Retinol Efficacy Trial (CARET) and the Alpha-Tocopherol, BetaCarotene (ATBC) Lung Cancer Prevention Study [13,14]. These results were in sharp contrast with prior epidemiologic data showing an association between higher fruit and vegetable intake and higher serum betacarotene and reduced lung cancer risk [15–18]. Possible explanations for this effect include an inhibition of absorption of other nutrients by large doses of betacarotene and the autocatalytic pro-oxidant activity of beta-carotene under high oxygen tension such as occur in the lungs of smokers [19•]. Secondary prevention interventions

Secondary prevention trials have generally attempted to reverse premalignant lesions [20–25•]. Most of these studies with various retinoids including isotretinoin, fenretinide, etretinate, or retinol have been negative (neutral). Among recent studies targeting reversal of premalignancy, one trial randomized former smokers to 13cis-retinoic acid plus alpha-tocopherol versus 9-cisretinoid acid, a pan-retinoid agonist, versus placebo in an attempt to reverse pre-malignancy in former smokers with the desired biomarker being the up-regulation of


Chemoprevention of lung cancer Cohen and Khuri 281 Table 1. Major trials of chemoprevention in lung cancer Intervention

Endpoint

Patients (n)

Outcome

Lung cancer

29,133

Negative/harmful

Lung cancer Lung cancer

18,314 22,071

Negative/harmful Negative

Primary ATBC [13] CARET [14] Physician’s Health Study Secondary Lee et al. [20] Kurie et al. [21] Arnold et al. [22] McLarty et al. [23] Heimburger et al. [24] Lam et al. [27•] Tertiary Pastorino et al. [28] EUROSCAN [29] Lippman et al. [30] Mayne et al. [31] Khuri et al. [32]

Beta-carotene Alpha-tocopherol Beta-carotene Retinol Beta-carotene Isotretinoin Fenretinide Etretinate Beta-carotene Retinol Vitamin B12 Folic acid ADT Retinyl palmitate Retinyl palmitate 13cRA Beta-carotene Isotretinoin

SPT SPT SPT SPT SPT

RAR-beta (retinoic acid receptor-beta) in bronchial epithelium [25•]. While 9-cis-retinoic acid was more effective than placebo in up-regulating RAR-beta, data implicating maintenance of RAR-beta intratumorly in stage I lung cancers in individuals with a poorer prognosis [26], cast these results in a less than optimal light. A second trial reported by Lam et al. [27•] investigated the effects of anethole dithiolethione (ADT) in smokers with bronchial dysplasia. ADT belongs to the dithiolethione class of organosulfur compounds, which have antioxidant, chemotherapeutic, radioprotective, and chemopreventive properties. The study concluded that the progression rate of preexisting dysplastic lesions by two or more grades and/or the appearance of new lesions were statistically significantly lower with treatment. This interesting finding merits further exploration. Tertiary prevention interventions

Finally, large randomized tertiary prevention trials in former cancer patients have also been mostly negative. While the initial trial of retinyl palmitate in the prevention of second primary lung cancers in individuals who had a prior history of stage I non-small cell lung cancer had a positive result, subsequent studies including the European Study on Chemoprevention with Vitamin A and N-acetylcystein (EUROSCAN) trial and the US Intergroup study showed no benefit intervening with retinoids [28–30]. In fact, these trials continue to suggest that individuals who maintained their smoking behavior and were given supplementation with vitamin A derivatives might have an enhancement of their risk of developing lung cancer. These discouraging data were balanced by the fact that there were supportive trends for decreases in primary tumor recurrence in individuals who were never smokers and were randomized to a retinoid in the US Intergroup study.

Metaplasia Metaplasia Metaplasia

40 82 150

Negative Negative Negative

Sputum atypia

1067

Negative

Sputum atypia Dysplasia

73 112

Positive Positive

307 2592 1304 264 1190

Positive Negative Negative Negative Negative

More recently, Mayne et al. [31] reported the results of a randomized trial evaluating the efficacy of supplemental beta-carotene on reducing failure attributable to second primary tumors (head and neck, esophagus and lung) and local recurrences in individuals curatively treated for early stage cancers of the head and neck. The trial was stopped early after the results of the ATBC and CARET studies were available. Similar to the primary prevention trials of beta-carotene, this trial showed a nonsignificant trend toward increased lung cancer incidence in patients who were treated with beta-carotene. Subsequent results in this area with retinoids have also been disappointing. In 1991, University of Texas MD Anderson Cancer investigators launched a large Intergroup trial of low-dose, long-term isotretinoin in stage I, II head and neck squamous cell carcinoma patients definitively treated with radiation therapy or surgery. Results of this trial were presented at the 2003 American Society of Clinical Oncology meeting [32•]. One thousand three hundred eighty-four patients were registered and 1190 were eligible and randomized to receive either isotretinoin or placebo for 3 years with a subsequent 4 years of follow-up. No significant difference was found between the two groups with respect to overall survival, SPT-free survival, or recurrence-free survival (P = 0.79, 0.99, and 0.18 respectively). The annual SPT rate was 4.7% for both arms. The most common secondary tumor site in both groups was lung followed by the oral cavity, larynx, and pharynx. These negative results may be explained by the fact that the dose chosen may have been too low. A higher dose however, although potentially more effective, would have likely resulted in increased toxicity (toxicity that would be unacceptable for a population of patients with early stage disease and good prognosis). A way forward may be the study of retinoid com-


282 Neoplasms of the lung

binations such as a retinoid and an interferon, which currently are being tested in ongoing clinical and mechanistic studies. In addition to the completed SPT trials, there is an ongoing Intergroup trial of selenium for reducing the incidence of lung cancer-associated SPT. The basis for this study includes observational studies showing lower serum levels of selenium in lung cancer patients compared with control subjects and encouraging secondary lung cancer findings of two NCI phase III trials involving selenium [33,34]. Novel agents and future studies

The data showing that expression of COX-2 mRNA portended a poorer survival in early stage disease has enhanced interest in examining selective COX-2 inhibitors in the chemoprevention of lung cancer [35]. Clinical trials of celecoxib and rofecoxib are ongoing at UCLA and the University of Texas MD Anderson Cancer Center seeking to evaluate whether premalignant lesions in the lung cancer be reversed utilizing these compounds to down-regulate COX-2 dependent cell signaling pathways. Further studies of prostacyclin inhibitors are being conducted through the Lung Cancer Biomarker Chemoprevention Consortium (LCBCC), which comprises several leading lung cancer research institutions in North America. Randomized trials of iloprost, a long-acting prostacyclin analogue, have been initiated at the University of Colorado Cancer Center by Dr. Paul Bunn and are being expanded to several other investigational centers. Also through the LCBCC, two chemoprevention projects called SPORE (Specialized Programs of Research Excellence) Trials of Lung Cancer Prevention or STOP are being developed testing novel signal transduction inhibitors [36]. The trials are randomized phase IIb studies designed to evaluate the efficacy of tipifarnib, a farnesyl transferase inhibitor (STOP-FTI) and geftinib, an epidermal growth factor receptor tyrosine kinase inhibitor (STOP-TKI) in former and current smokers with a previous specified smoking-related cancer (non-small cell lung, head and neck squamous cell, small cell lung, bladder, or esophageal cancer). The major objectives are to evaluate the effectiveness of these compounds in the response of histology and modulation of the Ki-67 labeling index and to assess intermediate serological and tissue markers as preliminary predictors for efficacy. These studies have been stalled largely because of the overwhelming negative results observed in various lung cancer therapy trials (recently Schering-Plough Research Institute voluntarily stopped its phase 3 clinical study of the FTI lonafarnib in non-small cell lung cancer after analysis of the interim data led to the conclusion that the study will not provide sufficient evidence of efficacy to warrant further enrollment) and concerns over the rela-

tive safety profile of these agents. However, discussions are ongoing between the Food and Drug Administration, the National Cancer Institute, and SPORE investigators with the hope that both will eventually be activated in the United States and possibly Europe.

Conclusion All the prospective randomized controlled trials in lung cancer chemoprevention have so far produced either neutral or harmful primary end point results whether in the primary, secondary, and tertiary settings. The data suggest that lung cancer was not prevented by betacarotene, alpha-tocopherol, retinal, retinyl palmitate, Nacetylcysteine, or isotretinoin in smokers. An improved understanding of carcinogenesis and cancer prevention mechanisms should aid in the design of future clinical trials and in the validation of candidate agents as well as the development of new targets. Until such studies are completed however, no drug or drug combination should be used for lung cancer prevention outside of a clinical study.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: •

Of special interest

••

Of outstanding interest

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Alpha-tocopherol: Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. New Engl J Med 1994, 330:1029–1035.


Chemoprevention of lung cancer Cohen and Khuri 283 14

Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta-carotene and vitamin A and cardiovascular disease. N Engl J Med 1996, 334:1150–1155.

A randomized placebo-controlled trial showing that 9-cis-retinoid acid can restore RAR-beta expression in the bronchial epithelium raising the possibility that this retinoid has potential chemopreventive properties in former smokers.

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Block G, Patterson B, Subar A: Fruit, vegetables and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992, 18:1–29.

26

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van Poppel G, Goldbohm RA: Epidemiologic evidence for beta-carotene and cancer prevention. Am J Clin Nutr 1995, 62:1393S–1402S.

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Menkes MS, Comstock GW, Vuilleumier JP, et al.: Serum beta-carotene, vitamins A and E, selenium and the risk of lung cancer. N Engl J Med 1986, 315:1250–1254.

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Stryker WS, Kaplan LA, Stein EA, et al.: The relation of diet, cigarette smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels. Am J Epidemiol 1988, 127:283–296.

19 Greenwald P: Beta-carotene and lung cancer: A lesson for future chemoprevention investigations? J Natl Cancer Inst 2003, 95:E1. • An excellent and comprehensive review of the issues surrounding the ATBC and CARET studies. It offers a number of possible reasons why the results of these trials differed from the many epidemiologic observations showing an association between reduced lung cancer risk and higher fruit and vegetable intake and higher serum beta-carotene. 20

Lee JS, Lippman SM, Benner SE, et al.: Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J Clin Oncol 1994, 12:937–945.

21

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, 6:2973–2979.

22

Arnold AM, Browman GP, Levine MN, et al.: The effect of the synthetic retinoid etredinate on sputum cytology: results from a randomized trial. Br J Cancer 1992, 65:737–743.

23

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–1438S.

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Heimbuger DC, Alexander CB, Birch, 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, 259:1525–1530.

25 •

Kurie JM, Lotan R, Lee JS, et al.: Randomized, placebo-controlled tiral of 9-cis-retinoic acid versus 13-cis-retinoic acid plus alpha-tocopherol in the reversal of biomarkers of bronchial preneoplasia in former smokers (unpublished data).

Khuri FR, Lotan R, Kemp B, et al.: Retinoic acid receptor-beta as a prognostic indicator in stage I non-small cell lung cancer. J Clin Oncol 2000, 18:2798– 2804.

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, 94:1001–1009. The results of this study suggest that in smokers, ADT is a potential efficacious chemoprevention agent for lung cancer. 27 •

28

Pastorino U, Infante M, Maioli M, et al.: Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993, 11:1216–1222.

29

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, 92:977–986.

30

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, 93:605–618.

31

Mayne ST, Cartmel B, Baum M, et al.: Randomized trial of supplemental betacarotene to prevent second head and neck cancer. Cancer Res 2001, 61:1457–1463.

Khuri FR, Lee JJ, Lippman SM, et al.: Isotretinoin effects on head and neck cancer recurrence and second primary tumors. Proc Am Soc Clin Oncol. 2003, 22:90 (abstr 359). The results of this multicenter, phase III trial suggest that in patients with stage I or II head and neck squamous cell carcinoma following definitive treatment with radiation therapy or surgery, isotretinoin does not reduce head and neck cancer recurrence or second primary tumors (oral cavity, pharynx, larynx, and lung). 32 •

33

Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. JAMA 1996, 276:1957–1963.

34

Blot WJ, Li JY, Taylor RR, et al.: Linxian nutrition intervention trials: Supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993, 85:1483–1492.

35

Khuri FR, Wu H, Lee JJ, et al.: Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001, 7:861–867.

36

Cohen V, Khuri FR: Chemoprevention of lung cancer: current status and future prospects. Cancer Metastasis Rev 2002, 21:349–362.


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