Chemoprevention of lung cancer

Victor Cohena and Fadlo R. Khurib

Purpose of review

Lung cancer is one of the major causes of cancer-relateddeaths. Grim mortality figures argue powerfully for newapproaches to control this disease. Chemoprevention is theuse of specific natural or synthetic chemical agents to reverse,suppress, or prevent carcinogenic progression to invasivecancer. The current article focuses on the field of lung cancerchemoprevention and recent advances. Lung cancer biologyand general principles of prevention strategies are alsodescribed.Recent findings

Trials in lung cancer chemoprevention have so far producedeither neutral or harmful primary end point results whether inthe primary, secondary and tertiary settings. The data suggestthat lung cancer was not prevented by beta-carotene,alpha-tocopherol, retinal, retinyl palmitate, N-acetylcysteine, orisotretinoin in smokers. The results from the recentlycompleted Canadian study of anethole dithiolethione insmokers with bronchial dysplasia as well secondary analysesof the phase III trials involving selenium and data from the USIntergroup NCI-91-0001 supporting treatment with isotretinoinin never and former smokers are hopeful and may help definenew avenues of chemopreventive treatment after scientistsand clinicians analyze the information generated.Summary

The concept of chemoprevention in lung cancer is still in itsinfancy but one day may have a significant impact on theincidence and mortality of this leading cancer threat. Animproved understanding of carcinogenesis and cancerprevention mechanisms will no doubt aid in the design offuture clinical trials and in the validation of candidate agents aswell as the development of new targets. Planned or ongoingtrials currently are targeting important molecular markers oflung carcinogenesis and progression includingcyclooxygenase-2, the ras-signaling pathway through farnesyltransferase inhibitors and the tyrosine kinase/epidermal growthfactor receptor pathway. Until such studies are completedhowever, no drug or drug combination should be used for lungcancer 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.

aSir Mortimer B. Davis–Jewish General Hospital, McGill University School ofMedicine, Department of Oncology, Montreal, Quebec, Canada, and b WinshipCancer 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-1E2Tel: 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 & Wilkins1070-5287

IntroductionLung 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 antic-

ipated by 2004 [1]. Despite some improvements in treat-

ment results during the past decade due to improved

surgical techniques, increased utilization of combined-

modality treatments for locally advanced lung cancer,

and the introduction of novel agents, the overall progno-

sis 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 ar-

gues powerfully for new, emerging approaches to control

this disease. Chemoprevention is one of these new ap-

proaches.

Chemoprevention is “the use of specific natural or syn-

thetic 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 chemopreven-

tion and prevention research. He was the first to put

forward the notion that the goals and objectives of clini-

cal 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 skep-

ticism, this approach has led to proven, significant ad-

vances in cancer prevention. Clinical validation for the

cancer prevention concept was provided by a random-

ized 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 re-

duction 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 evi-

dence 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 tar-

geted agents there has been a push to consider molecu-

279

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 che-

moprevention and recent advances. Lung cancer biology

and general principles of prevention strategies are also

described.

Lung cancer biology and first principles

of chemopreventionLung 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 imbal-

ances between cellular proliferation, apoptosis, and shed-

ding. Imbalance in cellular population kinetics promotes

a buildup of cells that if sufficiently abnormal has ma-

lignant capability. Numerous systems including repair,

replacement, or recruitment, replication and redundancy

mechanisms become operational to help restore struc-

tural and functional integrity. In some instances, how-

ever these mechanisms fail or are overwhelmed and un-

repaired 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 carcino-

genesis” and lateral intraepithelial spread of genetically

related preinvasive clones. Field carcinogenesis denotes

diffuse epithelial tissue injury resulting from carcino-

genic exposure in an entire epithelial field or region

where tissue changes can be detected at the gross, mi-

croscopic, 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 illus-

trated in aerodigestive cancers for which both synchro-

nous and metachronous second primary tumors are

common. These two basic concepts of multistep carci-

nogenesis and the diffuse field-wide carcinogenic pro-

cess 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 propa-

gation of aberrant cells by blocking DNA damage, re-

tarding 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 in-

tended 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 treat-

ments 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 ma-

lignancy is a good example of tertiary prevention.

Randomized lung cancer

chemoprevention trialsPrimary 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 combina-

tion with retinol have resulted in increased risk of de-

veloping lung cancer in individuals receiving these

agents. Statistically significant increases in lung cancer

incidence in smokers receiving beta-carotene supple-

ments were shown in the Beta-Carotene and Retinol Ef-

ficacy Trial (CARET) and the Alpha-Tocopherol, Beta-

Carotene (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 beta-

carotene and reduced lung cancer risk [15–18]. Possible

explanations for this effect include an inhibition of ab-

sorption of other nutrients by large doses of beta-

carotene 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 pre-

malignancy, one trial randomized former smokers to 13-

cis-retinoic acid plus alpha-tocopherol versus 9-cis-

retinoid 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

280 Neoplasms of the lung

RAR-beta (retinoic acid receptor-beta) in bronchial epi-

thelium [25•]. While 9-cis-retinoic acid was more effec-

tive than placebo in up-regulating RAR-beta, data impli-

cating 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 bron-

chial dysplasia. ADT belongs to the dithiolethione class

of organosulfur compounds, which have antioxidant, che-

motherapeutic, 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 statis-

tically significantly lower with treatment. This interest-

ing 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 preven-

tion 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 In-

tergroup study showed no benefit intervening with ret-

inoids [28–30]. In fact, these trials continue to suggest

that individuals who maintained their smoking behavior

and were given supplementation with vitamin A deriva-

tives might have an enhancement of their risk of devel-

oping lung cancer. These discouraging data were bal-

anced 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 ret-

inoid in the US Intergroup study.

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 Inter-

group trial of low-dose, long-term isotretinoin in stage I,

II head and neck squamous cell carcinoma patients de-

finitively treated with radiation therapy or surgery. Re-

sults of this trial were presented at the 2003 American

Society of Clinical Oncology meeting [32•]. One thou-

sand 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 ex-

plained 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 popu-

lation of patients with early stage disease and good prog-

nosis). A way forward may be the study of retinoid com-

Table 1. Major trials of chemoprevention in lung cancer

Intervention EndpointPatients(n) Outcome

Primary

ATBC [13]Beta-caroteneAlpha-tocopherol Lung cancer 29,133 Negative/harmful

CARET [14]Beta-caroteneRetinol Lung cancer 18,314 Negative/harmful

Physician’s Health Study Beta-carotene Lung cancer 22,071 NegativeSecondary

Lee et al. [20] Isotretinoin Metaplasia 40 NegativeKurie et al. [21] Fenretinide Metaplasia 82 NegativeArnold et al. [22] Etretinate Metaplasia 150 Negative

McLarty et al. [23]Beta-caroteneRetinol Sputum atypia 1067 Negative

Heimburger et al. [24]Vitamin B12Folic acid Sputum atypia 73 Positive

Lam et al. [27•] ADT Dysplasia 112 PositiveTertiary

Pastorino et al. [28] Retinyl palmitate SPT 307 PositiveEUROSCAN [29] Retinyl palmitate SPT 2592 NegativeLippman et al. [30] 13cRA SPT 1304 NegativeMayne et al. [31] Beta-carotene SPT 264 NegativeKhuri et al. [32] Isotretinoin SPT 1190 Negative

Chemoprevention of lung cancer Cohen and Khuri 281

binations such as a retinoid and an interferon, which

currently are being tested in ongoing clinical and mecha-

nistic studies.

In addition to the completed SPT trials, there is an on-

going Intergroup trial of selenium for reducing the inci-

dence of lung cancer-associated SPT. The basis for this

study includes observational studies showing lower se-

rum 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 por-

tended a poorer survival in early stage disease has en-

hanced interest in examining selective COX-2 inhibitors

in the chemoprevention of lung cancer [35]. Clinical tri-

als 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 path-

ways. Further studies of prostacyclin inhibitors are being

conducted through the Lung Cancer Biomarker Chemo-

prevention Consortium (LCBCC), which comprises sev-

eral leading lung cancer research institutions in North

America. Randomized trials of iloprost, a long-acting

prostacyclin analogue, have been initiated at the Uni-

versity of Colorado Cancer Center by Dr. Paul Bunn

and are being expanded to several other investigational

centers.

Also through the LCBCC, two chemoprevention pro-

jects 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 stud-

ies designed to evaluate the efficacy of tipifarnib, a far-

nesyl transferase inhibitor (STOP-FTI) and geftinib, an

epidermal growth factor receptor tyrosine kinase inhibi-

tor (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 label-

ing index and to assess intermediate serological and tis-

sue markers as preliminary predictors for efficacy. These

studies have been stalled largely because of the over-

whelming negative results observed in various lung can-

cer therapy trials (recently Schering-Plough Research In-

stitute 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.

ConclusionAll 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 beta-

carotene, alpha-tocopherol, retinal, retinyl palmitate, N-

acetylcysteine, 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

1 Lung cancer: In: BW Stewart and P Kleihues (eds). World Cancer Report.Lyon, France: IARC Press, 2003:182–187.

2 Ginsberg RI, Vokes EE, Rosenzweig K: Cancer of the lung. Non-small celllung cancer. In: VT DeVita, S Hellman, SA Rosenberg (eds). Cancer: Prin-ciples and Practice of Oncology, 6th edition. Philadelphia: Lippincott-Raven,2001:925–983.

3 Sporn MB, Dunlop NM, Newton DL, et al.: Prevention of chemical carcino-genesis by vitamin A and its synthetic analogues. Fed Proc 1976, 35:1332–1338.

4 Gail M, Brinton L, Byar D, et al.: Projecting individualized probabilities of de-veloping breast cancer for white females who are being examined annually. JNatl Cancer Inst 1989, 81:1879–1886.

5 Fisher B, Constantino JP, Wickerham DL, et al.: Tamoxifen for prevention ofbreast cancer: report of the National Surgical Adjuvant Breast and BowelProject P-1 study. J Natl Cancer Inst 1998, 90:1371–1388.

6 Steinbach G, Lynch PM, Phillips RK, et al.: The effects of celecoxib, a cyclo-oxygenase inhibitor, in familial adenomatous polyposis. N Engl J Med 2000,342:1946–1952.

7 Hong WK, Endicott J, Itri LM, et al.: 13-cis-Retinoic acid in the treatment oforal leukoplakia. N Engl J Med 1986, 315:1501–1505.

8 Hong WK, Lippman SM, Itri LM, et al.: Prevention of second primary tumorswith isotretinoin in squamous cell carcinoma of the head and neck. N Engl JMed 1990, 323:795–801.

9 Auerbach O, Stout AP, Hammond EC, et al.: Changes in bronchial epitheliumin relation to cigarette smoking and in relation to lung cancer. N Engl J Med1961, 265:253–267.

10 Mao L, Lee JS, Kurie JM, et al.: Clonal genetic alterations in the lungs ofcurrent and former smokers. J Natl Cancer Inst 1997, 89:857–862.

11 Wistuba II, Lam S, Behrens C, et al.: Molecular damage in the bronchial epi-thelium of current and former smokers. J Natl Cancer Inst 1997, 89:1366–1373.

12 Hong WK, Sporn MB: Recent advances in chemoprevention of cancer. Sci-ence 1997, 278:1073–1077.

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

282 Neoplasms of the lung

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

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

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

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

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

•19 Greenwald P: Beta-carotene and lung cancer: A lesson for future chemopre-

vention investigations? J Natl Cancer Inst 2003, 95:E1.An excellent and comprehensive review of the issues surrounding the ATBC andCARET studies. It offers a number of possible reasons why the results of thesetrials differed from the many epidemiologic observations showing an associationbetween reduced lung cancer risk and higher fruit and vegetable intake and higherserum beta-carotene.

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

21 Kurie JM, Lee JS, Khuri FR, et al.: N-(4-hydroxyphenyl)retinamide in the che-moprevention of squamous metaplasia and dysplasia of the bronchial epithe-lium. Clin Cancer Res 2000, 6:2973–2979.

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

23 McLarty JW, Holiday DB, Girard WM, et al.: Beta-carotene, vitamin A, andlung cancer chemoprevention: results of an intermediate endpoint study. AmJ Clin Nutr 1995, 62:1431S–1438S.

24 Heimbuger DC, Alexander CB, Birch, et al.: Improvement in bronchial squa-mous metaplasia in smokers treated with folate and vitamin B12. Report of apreliminary 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 thereversal of biomarkers of bronchial preneoplasia in former smokers (unpub-lished data).

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

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

•27 Lam S, MacAulay C, Le Riche JC, et al.: A randomized phase IIb trial of an-

ethole dithiolethione in smokers with bronchial dysplasia. J Natl Cancer Inst2002, 94:1001–1009.

The results of this study suggest that in smokers, ADT is a potential efficaciouschemoprevention agent for lung cancer.

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

29 van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomizedtrial of vitamin A and N-acetylcysteine in patients with head and neck canceror lung cancer. For the European Organization for Research and Treatment ofCancer Head and Neck and Lung Cancer Cooperative Groups. J Natl CancerInst 2000, 92:977–986.

30 Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial ofisotretinoin to prevent second primary tumors in stage I non-small-cell lungcancer. J Natl Cancer Inst 2001, 93:605–618.

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

•32 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 orII head and neck squamous cell carcinoma following definitive treatment with ra-diation therapy or surgery, isotretinoin does not reduce head and neck cancerrecurrence or second primary tumors (oral cavity, pharynx, larynx, and lung).

33 Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplemen-tation for cancer prevention in patients with carcinoma of the skin. JAMA1996, 276:1957–1963.

34 Blot WJ, Li JY, Taylor RR, et al.: Linxian nutrition intervention trials: Supple-mentation with specific vitamin/mineral combinations, cancer incidence, anddisease-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 markerof poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res2001, 7:861–867.

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

Chemoprevention of lung cancer Cohen and Khuri 283