Lung Cancer Chemoprevention: ACCP Evidence-Based Clinical ...€¦ · Background: Lung cancer is the most common cause of cancer death in the United States. Cigarette smoking is the

DOI 10.1378/chest.07-1348 2007;132;56-68 Chest

Kurie and Gerold Bepler Jhanelle Gray, Jenny T. Mao, Eva Szabo, Michael Kelley, Jonathan

(2nd Edition)Evidence-Based Clinical Practice Guidelines Lung Cancer Chemoprevention: ACCP

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Lung Cancer Chemoprevention*ACCP Evidence-Based Clinical Practice Guidelines(2nd Edition)

Jhanelle Gray, MD; Jenny T. Mao, MD, FCCP; Eva Szabo, MD;Michael Kelley, MD; Jonathan Kurie, MD; and Gerold Bepler, MD, PhD

Background: Lung cancer is the most common cause of cancer death in the United States.Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk forlung cancer compared with lifetime never-smokers. Chemoprevention is the use of specificagents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews themajor agents that have been studied for chemoprevention.Methods: Articles of primary, secondary, and tertiary prevention trials were reviewed andsummarized to obtain recommendations.Results: None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid,�-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducibleresults. For facilitating the evaluation of promising agents and for lessening the need for a largesample size, extensive time commitment, and expense, focus is now turning toward the assessment ofsurrogate end point biomarkers for lung carcinogenesis. With the understanding of importantcellular signaling pathways, various inhibitors that may prevent or reverse lung carcinogenesis arebeing developed.Conclusions: By integrating biological knowledge, more trials can be performed in a reasonable timeframe. The future of lung cancer chemoprevention should entail the evaluation of single agents orcombinations that target various pathways while working toward identification and validation ofintermediate end points. (CHEST 2007; 132:56S–68S)

Key words: acetyl salicylic acid; apoptosis; biomarkers; chemoprevention; cyclooxygenase-2 inhibitors; lung cancer;proliferation; protein kinase C; selenium; signal transduction pathways; tyrosine kinase inhibitors; vitamin A; vitamin E

Abbreviations: ADT � anethole dithiolethione; ATBC � � Tocopherol �-Carotene; CARET � Beta-Carotene and RetinolEfficacy Trial; CI � confidence interval; COX � cyclooxygenase; HOPE � Heart Outcomes Prevention Evaluation;HR � hazard ratio; LOX � lipoxygenase; MCM2 � minichromosome maintenance factor 2; PG � prostaglandin;PGI � prostacyclin; PKC � protein kinase C; RR � relative risk; SEB � surrogate end point biomarker

T he number of newly diagnosed cases of lungcancer in the United States in 2007 is estimated

to be 213,380. Lung cancer causes more death(160,390) than colorectal cancer (52,180), breastcancer (40,910), and prostate cancer (27,050) com-

bined.1 The annual worldwide incidence of lungcancer is � 3,000,000 and continues to rise. Thesingle most important risk factor is smoking. Approx-imately 20% of the US adult population continues tosmoke. In those who smoke, the risk for lung cancer

*From the H. Lee Moffitt Cancer Center and Research Institute(Drs. Gray and Bepler), Program and Division of Thoracic Oncol-ogy, Tampa, FL; Jonsson Comprehensive Cancer Center (Dr. Mao),University of California, Los Angeles, CA; National Cancer Institute(Dr. Szabo), Bethesda, MD; Duke Comprehensive Cancer Center(Dr. Kelley), Duke University Medical Center, Durham, NC; andMD Anderson Cancer Center (Dr. Kurie), Houston, TX.The authors have reported to the ACCP that no significant conflictsof interest exist with any companies/organizations whose products orservices may be discussed in this article.

Manuscript received May 30, 2007; revision accepted June 5,2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Gerold Bepler, MD, PhD, Division of Tho-racic Oncology, H. Lee Moffitt Cancer Center and ResearchInstitute, 12902 Magnolia Dr, MRC-4W, Room 4046, Tampa, FL33612; e-mail: [email protected]: 10.1378/chest.07-1348

SupplementDIAGNOSIS AND MANAGEMENT OF LUNG CANCER: ACCP GUIDELINES

56S Diagnosis and Management of Lung Cancer: ACCP Guidelines



is on average 10-fold higher than in lifetime never-smokers (defined as a person who has smoked � 100cigarettes in their lifetime). There were 45.4 millionformer smokers in the United States in 2003.2Although smoking prevention and cessation remainessential in the overall strategy for lung cancerprevention, former smokers continue to have anelevated risk for lung cancer for years after quitting.3In fact, more than one half of lung cancers occur inthose who have stopped smoking.

At the time of diagnosis, the majority of patientshave stage IIIB to IV disease, which carries a 5-yearsurvival of � 5%. Efforts to improve this dismaloutcome have more recently been directed at che-moprevention to reduce the incidence and mortalityof lung cancer.

The rationale for chemoprevention is based on twomain concepts, multistep carcinogenesis and “fieldcancerization,” which can be used to explain theprocess of lung carcinogenesis as it occurs over timeand throughout the entire bronchoalveolar epithe-lium. Multistep carcinogenesis is based on the theorythat the progression of normal bronchoepithelialcells to a malignant lesion entails a multistep processinvolving numerous morphologic and molecularmodifications. A series of alterations that lead tomalignant transformation with unregulated clonalexpansion and cellular proliferation occur over time.The morphologic correlate of multistep carcinogen-esis is the progression of bronchial epithelium fromhyperplasia to metaplasia to increasing grades ofdysplasia and carcinoma in situ onward to invasivecarcinoma. Specific genetic abnormalities that cor-relate with the morphologic steps that are involved inthe evolution to malignancy have been described.

Physiologically, proliferation of bronchoepithelialcells is required to replace cells lost at the lumen andto repair epithelial damage caused by environmentalinfluences. To control proliferation in response totissue damage, a complex system of intercellularcommunication that includes epithelial cells, stroma,and inflammatory cells has evolved.4 The vehicles ofcommunication are growth factors, cytokines, pep-tides, and lipid metabolites and their respectivecellular receptors. Their functions include inductionand suppression of not only proliferation but alsomigration, contact inhibition, angiogenesis, apopto-sis, and antitumor immunity. Reactive oxygen spe-cies that are generated during inflammation canresult in DNA damage and may thus trigger oraccelerate carcinogenesis.

In 1953, it was first established that many areas ofthe aerodigestive tract are simultaneously at risk forcancer formation as a result of exposure to carcino-gens.5 This concept is known as field cancerizationand serves to explain the synchronous presence of

various premalignant and malignant lesions at differ-ent locations in the aerodigestive tract of the sameperson. The high rate of second primary cancers inindividuals who underwent curative treatment for anaerodigestive malignancy provides further evidencefor field cancerization.

Tobacco exposure is among the most preventablecauses of morbidity and mortality in the UnitedStates. It includes smokeless tobacco and pipe andcigar use. The most important of these is cigarettesmoke. It has been estimated that the majority oflung cancer is associated with cigarette smoking.6,7

Given the harm associated with tobacco use, it isimportant not only to promote the cessation oftobacco use but also to prevent the initiation.

For reducing the incidence of smoking, tobaccoprevention is also an imperative public health focus.The key is to provide early information about theharms of tobacco exposure to middle and high schoolstudents. Policies and programs exist and continue tobe developed to educate youth on the harms oftobacco use given its potential for dependency andassociated morbidity and mortality.

Advocacy efforts have been increasingly successfulat limiting tobacco use and public exposures toenvironmental tobacco smoke. Some of these meth-ods include strict regulation of tobacco advertise-ments, increases in tobacco taxes, and comprehen-sive smoking bans for indoor and public outdoorareas.

Another major public health focus in the UnitedStates is tobacco cessation. Numerous cessation pro-grams are available for those who would like to quit.These range from behavioral therapy to pharmaco-logic interventions. As an essential aspect of allprimary care practices, all patients should be askedabout smoking status, and counseling and adviceshould be provided when needed. This has beenassociated with an increase in smoking cessation.8 Byproviding mutual support, behavior modifications,and coping skills, group therapy has been found to bean effective method.9 The use of pharmacologicinterventions such as all forms of nicotine replace-ment (including nicotine spray, gum, and patches),bupropion, and varenicline (partial agonists of nico-tinic acetylcholine receptors) have been effective inincreasing smoking cessation rates.10–16 Other tech-niques, such as acupuncture and hypnosis, to date,have not been effective.17

Smoking cessation results in a decrease in precan-cerous lesions from 27 to 7%.18 For those who havequit smoking for 10 years (15 years), the risk for lungcancer may be 30 to 50% (80 to 90%) less than thatof current smokers.3,18

Many options are available to help with smokingcessation. Physicians are strongly encouraged to

www.chestjournal.org CHEST / 132 / 3 / SEPTEMBER, 2007 SUPPLEMENT 57S



discuss these options with their patients to developindividualized cessation plans. Still, half of lungcancers occur in those who have stopped smoking.To help reduce the incidence of lung cancer, recentefforts have been directed to chemoprevention. Che-moprevention is defined as the use of specific agentsto reverse, suppress, or prevent the process ofcarcinogenesis.19 The first and most powerful step inlung cancer chemoprevention is avoidance of contin-ued carcinogen exposure, for instance, through smok-ing cessation. However, people who have smoked inthe past and have successfully quit have a substan-tially higher risk for lung cancer development thanpeople who are lifetime never-smokers.19 Chemo-prevention as a means of reducing cancer incidencehas been successful for breast cancer and prostatecancer.20,21 For lung cancer, chemoprevention is anarea that needs further exploration for proper rec-ommendations to be formed. This article discussesthe methods used to obtain articles and grade rec-ommendations. It is organized into sections: (1)high-risk populations, (2) various chemopreventiveinterventions investigated to date, (3) arachidonicacid pathway studies, (4) studies using other path-ways, and (5) future studies.

Materials and Methods

In 2005 to 2006, a panel of experts corresponded to update theprevious recommendations on the use of lung cancer chemopre-vention agents. The panel consisted of investigators who wereexperienced in the formulation, design, and execution of chemo-prevention clinical trials. Deliberations were resolved to establishguidelines for practitioners to use for patients at high risk for lungcancer.

For obtaining various lung cancer chemoprevention guidelines,a systematic review of the literature was performed (see “Meth-ods and Grading” chapter). These guidelines were focused onprimary, secondary, and tertiary lung cancer chemopreventionstudies that were mostly funded by the National Cancer Institute.Additional information was obtained by performing a literaturesearch of the PubMed and Medline databases and review of theThoracic Oncology NetWork reference lists. For establishingstudy quality, recommendations were organized by the panel ofexperts on the writing committee and then graded by thestandardized American College of Chest Physicians methods (see“Methodology for Lung Cancer Evidence Review and GuidelinesDevelopment” chapter). Before final approval, this chapter wasreviewed by all panel members, which included a multidisci-plinary team that consisted of thoracic surgeons, medical oncolo-gists, radiation oncologists, and pulmonologists, followed byreview by the Thoracic Oncology NetWork, Health and SciencePolicy Committee, and the Board of Regents of the AmericanCollege of Chest Physicians. Following are key considerations indesigning chemoprevention trials for lung cancer.

Identification of Candidate Agents

The selection of chemoprevention agents involves a carefulprocess. First, sufficient in vitro and animal model data should

exist to support the use of a specific agent. The use of specificagents should not be based solely on epidemiologic data. Recentadvances in tumor biology have resulted in the development ofagents that target specific cellular pathways that are thought to becrucial for tumor development and progression. Therapies cannow be directed at various steps that are involved in carcinogen-esis. Agents that target DNA repair may prevent or reverse theinitial development of mutations that frequently are found inbronchial atypia. Rather than prevent the initiation process,other agents may inhibit promotion or progression. As moreevidence and data are obtained regarding the molecularpathways that are involved in these processes, these agentsmay serve as realistic targets for future drug development andtherapeutic interventions.

Other issues must be considered when selecting agents forchemoprevention trials. A favorable safety profile must be asso-ciated with the chosen drug because it may be used for prolongedperiods of time in a putatively healthy, albeit high-risk, popula-tion to prevent disease. Agents should be easy to administer suchthat compliance will be high. In addition, the agent should bereadily available and affordable.

Populations at Risk for Lung Cancer

Chemoprevention trials can be divided into three types: pri-mary prevention, secondary prevention, and tertiary prevention.In primary prevention trials, participants have no evidence oflung cancer. Such trials are targeted at high-risk individuals, forinstance, those with a significant smoking history. Secondaryprevention studies involve the use of participants who haveevidence of premalignacy, such as sputum atypia or dysplasia onbronchial sampling. Individuals who have a history of being curedfrom their primary lung cancer are the focus of tertiary preven-tion trials (second primary tumor prevention). The practicalrationale for selecting high-risk individuals is to reduce thesample size and duration of therapy. However, it is important torecognize that individuals who are at high risk, such as activesmokers with ongoing smoke exposure, may have a differentbiology of disease than former smokers. As a result, the outcomeof a trial may be adverse in one group (smokers) yet beneficial inanother (former smokers). In the end, the ultimate goal of lungcancer chemoprevention is to reduce disease incidence andmortality. Within each trial category, guidelines are needed forenrollment criteria.

Smoking and Risk for Lung Cancer

Chemoprevention trials typically focus on high-risk popula-tions. The main criteria for selection of patients to lung cancerchemoprevention trials are based on smoking history. In addition,airway obstruction and environmental factors, such as asbestosexposure, family history, and obstructive disease, have well-established hazard ratios (HRs) for lung cancer risk and havebeen used as factors for identifying special cohorts (see “Epide-miology of Lung Cancer” chapter).22 Case-control studies23–25

linking smoking to lung cancer became available in the 1950s.These were confirmed by prospective cohort studies26–29 thatsupported the conclusion that smoking causes lung cancer. Manystudies30 have demonstrated that a longer smoking duration,younger age of initiation, and a higher number of packs per dayincrease the risk for lung cancer. The 12-year follow-up data ofthe American Cancer Society’s Cancer Prevention Studies fol-lowed � 1 million individuals and included smokers, nonsmok-ers, and former smokers. An individual with a history of smok-ing � 40 cigarettes a day for 35 to 39 years has a mortality riskfrom lung cancer of 19.45 compared with an individual who has




a history of 1 to 9 cigarettes daily for 20 to 24 years, whose lungcancer-related mortality risk is 1.26.31 When evaluating numer-ous trials, individuals with a � 30–pack-year smoking historyhave higher rates of lung cancer.30 There seems to be a contin-uum between risk and 10, 20, and 30 pack-years of smoking; still,no one level has been accepted as a definitive threshold for whatis considered high risk. What is known is that the risk for lungcancer for nonsmokers is significantly less than the risk forsmokers.

Dysplasia and Risk for Lung Cancer

The progression from a benign to a malignant lesion in thebronchial epithelium involves a multistep process. Changes occurin concert at both the molecular and the cellular levels, enhanc-ing the ability of a cell to proliferate, evade cell death, and invadethe basement membrane. Before becoming invasive, morpho-logic descriptions include hyperplasia, metaplasia, dysplasia, andcarcinoma in situ. In general, hyperplasia and metaplasia are notnecessarily premalignant, because these lesions can spontane-ously regress and can be found after trauma or along with chronicinflammation. Dysplasia and carcinoma in situ are considered theprincipal premalignant lesions, although these, too, can sponta-neously regress, albeit at a lower frequency than hyperplasia andmetaplasia.32 Specific genetic alterations are associated with thesteps involved. Wistuba et al33 demonstrated an increase inmolecular abnormalities, including loss of heterozygosity, whenlesions progressed from normal to carcinoma in situ. Molecularcharacteristics of dysplastic lesions that seem to be associatedwith progression to carcinoma in situ are high telomerase activity,increased Ki-67 labeling index, and p53 positivity.34 These maycorrelate with an increased risk for subsequent carcinoma,although this has not been clearly demonstrated.

Saccomanno et al35 demonstrated that sputum atypia could beseen 4 to 5 years before the development of lung cancer. Apopulation with sputum atypia is at increased risk for lung cancerdevelopment.36,37

On the basis of these observations, the National CancerInstitute sponsored three lung cancer screening trials in the1970s using chest radiograph and sputum cytology as screeningtools. One of these trials, conducted at Johns Hopkins University(“the JHU cohort”), addressed the utility of sputum cytology as ascreening tool. The study showed that 10% of participants withmoderate atypia on sputum cytology and no overt evidence forlung cancer developed lung cancer up to 9 years later. Of thosewith severe atypia, lung cancer developed in � 40% during thesame time period.38

Second Primary Lung Cancer

The development of second primary tumors is common inpatients with previously treated lung cancer. After resection of alung cancer, there is a 1 to 2% risk for a second lung cancer perpatient per year.39 Those who do have a second lung cancer havea median survival of 1 to 2 years and a 5-year survival ofapproximately 20%.39 As such, chemoprevention in this popula-tion is an important area of research.

Results

Vitamins as Chemoprevention Agents With LungCancer as an End Point

Beta Carotene Use in Former and Current Smok-ers and Those With Asbestos Exposure: A diet rich

in fruits and vegetables (at least three servingsper day) is associated with a lower cancer inci-dence as based on epidemiologic data. The �Tocopherol �-Carotene (ATBC) study40 randomlyassigned 29,133 people to receive beta carotene, �tocopherol, both, or placebo. Study participants av-eraged 57.2 years of age, 20.4 cigarettes per day, and35.9 years of smoking. They were followed up for 5to 8 years. The incidence of lung cancer in the studygroup was 18% higher than in the placebo group(p � 0.01). When this trial was completed, a secondtrial to evaluate beta carotene was under way. TheBeta-Carotene and Retinol Efficacy Trial (CARET)evaluated high-risk current and former smokers witha � 20–pack-year history of smoking (n � 14,254) orwith asbestos exposure and a 15-pack-year smokinghistory (n � 4,060). Forty percent of the � 20–pack-year smoking history group were women. The par-ticipants were randomly assigned to receive either acombination of beta carotene and vitamin A orplacebo. An early analysis was performed because ofthe finding of the ATBC trial. The relative risk (RR)for lung cancer in the active treatment group was1.28 (95% confidence interval [CI], 1.04 to 1.57;p � 0.02). In a subgroup analysis, the RR for lungcancer in current smokers was 1.40 (95% CI, 1.07 to1.87), whereas the RR in participants who were nolonger smoking at the time of randomization was0.80 (95% CI, 0.48 to 1.31). As a result of thesefindings, the CARET was terminated 21 monthsearly. Both of these trials demonstrated a higherincidence of lung cancer in those who had receivedthe beta carotene.

In the United States, the Physicians Health Studyevaluated 22,071 physicians who ranged in age from40 to 84 years41; 11% were current smokers, and39% were former smokers. The participants wererandomly assigned to beta carotene or placebo.There was no difference in lung cancer rates in thosewho received the beta carotene (82 lung cancers inthe beta carotene group vs 88 in the placebo group).

The Women’s Health Study explored the use of 50mg of beta carotene every other day vs placebo in39,876 women who were � 45 years old. Thirteenpercent of the women were smokers. The study wasterminated early, and the median treatment durationwas 2.1 years. There was no significant difference inthe development of any site-specific cancer includinglung cancer (30 cases vs 21 cases, respectively).42

Recommendation

1. For individuals with a smoking history > 20pack-years or a history of lung cancer, the useof beta carotene supplementation is not recom-




mended for primary, secondary, or tertiary che-moprevention of lung cancer. Grade of recom-mendation, 1A

Vitamin E Use in Men With a Smoking History:Epidemiologic data support that vitamin E (� to-copherol) has antitumor properties such that individ-uals with high levels of vitamin E are less likely tohave cancer. The ATBC study40 was published in theNew England Journal of Medicine in 1994. It in-volved 14 study sites, mainly based in Finland. Morethan 29,000 high-risk participants were randomlyassigned to � tocopherol, beta carotene, both, orplacebo. The participants were men who ranged inage from 50 to 60 years and had smoked at least fivecigarettes per day. The primary end point was diagnosisof lung cancer, and the secondary end point wasdiagnosis of any cancer. Participants were followed upfor 5 to 8 years. There was a nonsignificant reduction inthe incidence of lung cancer by 2%.

The Heart Outcomes Prevention Evaluation(HOPE) trial was an international, randomized, dou-ble blind, placebo-controlled trial that evaluatedparticipants who were � 55 years of age and hadvascular disease or diabetes from 1993 to 1999. Thetrial was extended to 2003 and was known as theHOPE TOO trial. A total of 9,541 participantsenrolled in the HOPE trial, and 7,030 continued onthe HOPE TOO trial. The participants were treatedwith 400 IU/d vitamin E or placebo. The trialincluded 174 centers, and follow-up was for a me-dian duration of 7 years. Lung cancer incidence didnot differ between the vitamin E and placebo treat-ment arms either in the primary analysis of theHOPE trial (69 cases [1.4%] vs 92 cases [2%];p � 0.04) or in the HOPE TOO trial (58 cases[1.6%] vs 74 cases [2.1%]; p � 0.16).43 Participantsin the vitamin E arm were found to have a higherrate of heart failure (p � 0.03).

The Women’s Health Study explored the use of600 IU of vitamin E every other day vs placebo in39,876 women who were � 45 years of age and werefollowed up for 10.1 years. There was no significantdifference in lung cancer incidence between thetreatment and placebo arms (RR, 1.09; 95% CI, 0.83to 1.44).44

Vitamin A in Current or Former Smokers: Epide-miologic data supported the idea that fruits andvegetables that are high in vitamin A lower theincidence lung cancer. In 1996, the results of theCARET were published.45 This study evaluated18,314 high-risk patients with either � 20 years ofsmoking or � 15 years of smoking and a history ofasbestos exposure. Participants were randomly as-signed to vitamin A and beta carotene or placebo.

Participants were either current smokers or smokerswho had quit in the previous 6 years. This studyfound a RR of 1.28 (p � 0.02) for lung cancer in thetreatment arm compared with placebo.

13-Cis-Retinoic Acid in Patients With Stage ILung Cancer: Preclinical and early clinical studieshave suggested that retinoids have chemopreventiveeffects. A large randomized trial46 of 1,166 partici-pants who had stage I lung cancer that was treatedwith curative intent were randomly assigned to re-ceived placebo or isotretinoin. HRs were 1.08 (95%CI, 0.78 to 1.49) for time to second primary tumor,0.99 (95% CI, 0.76 to 1.29) for recurrence, and 1.07(95% CI, 0.84 to 1.35) for mortality. Isotretinoin didnot decrease the incidence of second primary tu-mors. In a subgroup analysis, current smokers whowere treated with isotretinoin had increased mortal-ity compared with former smokers and nonsmokers(HR, 1.56; 95% CI, 1.09 to 2.24; p � 0.01).

N-Acetylcysteine: Preclinical data have demon-strated that N-acetylcysteine has antitumor proper-ties. A large clinical study47 evaluated this agent in1,023 patients who had non-small cell lung cancer(pT1-T3, N0-1, or T3, N0) that was treated withcurative intent. Patients were randomly assigned toN-acetylcysteine, retinyl palmitate (vitamin A), both,or no intervention. The primary end points wererecurrence, death, or second lung cancer. No signif-icant differences were noted between the groups.

Other Agents for Chemoprevention

Acetylsalicylic Acid: There is literature supportinga protective role of aspirin and nonsteroidal antiin-flammatory drugs on development of cancer. Threemajor trials have been conducted, which evaluatedthe use of acetylsalicylic acid in lung cancer preven-tion. The UK Physicians’ Health Study was a 6-year,randomized trial that evaluated 5,139 healthy maledoctors who were receiving 500 mg/d aspirin.48

Eleven percent were current smokers, and 39% wereformer smokers. The lung cancer death rate in theaspirin group was 7.4/10,000 person-years vs 11.6/10,000 person-years in the placebo group. Thisdifference was not statistically significant. In 1989,the results of the United States Physicians Healthstudy49 was published. This study evaluated 22,071physicians and did not demonstrate a decreasedrate of lung cancer in participants who had takenaspirin.

More recently, the results of the Women’s HealthStudy50 were published; this was a randomized trialof 39,876 US women who were treated with either100 mg of aspirin or placebo every other day.




Approximately 13% were current smokers, and 35.8%were former smokers. There was an average of 10.1years of follow-up. Lung cancer was a secondary endpoint. Lung cancer developed in a total of 205 partic-ipants. The RR for lung cancer in the aspirin group was0.78, which did not reach statistical significance.

Recommendation

2. For individuals who are at risk for lungcancer and patients with a history of lung can-cer, the use of vitamin E, retinoids, N-acetylcys-teine, and aspirin is not recommended for pri-mary, secondary, or tertiary prevention of lungcancer. Grade of recommendation, 1A

Surrogate End Point Biomarkers UnderDevelopment

Double-blind, randomized, phase III trials areconsidered the “gold standard” for proof of superi-ority of a novel therapy over current standard of care.Lung cancer incidence should be the primary endpoint. Because of the large number of requiredparticipants and long intervention/follow-up time,such trials pose a formidable challenge to conductsuccessfully from a logistical as well as a financialperspective.

To allow for testing of an increased number ofpromising agents over a short period of time, the useof surrogate end point biomarkers (SEBs) is beingexplored as an alternative to cancer incidence. How-ever, because such trials do not use a definitiveclinical end point (eg, cancer incidence), promisingresults obtained require confirmation in a phase IIIdesign.

The identification of SEBs that are reliablyassociated with cancer incidence is of paramountimportance. Examples of SEBs currently usedinclude premalignancy by morphologic criteriaand proliferative markers by immunohistochemis-try, specifically Ki-67 and minichromosome main-tenance factor 2 (MCM2). Other potential SEBsare molecules targeted by the specific agentsunder investigation.

Biomarkers that are under study include dysplasia,Ki-67, MCM2, and others. However, no surrogatemarker has been validated; therefore, use of suchmarkers is limited to phase II efficacy trials thatrequire subsequent confirmation in a phase III trialusing cancer incidence and/or mortality as the endpoint.

Dysplasia has long been used as a SEB for lungcancer in many chemoprevention trials. Carcinogen-esis involves a progression from a precancerouslesion to invasive disease. Not all dysplasia will

progress to cancer. There are data to suggest that58% of dysplastic lesions will regress spontaneous-ly.51 A statistically significant change must occur inthe bronchoepithelium for chemopreventive agentsto have a noticeable impact. On histopathologicreview, a complete or near-complete regression ofdysplasia in the treatment vs control arm should bedemonstrated.

Given the importance of dysregulated prolifera-tion to the carcinogenesis process, several prolifera-tion indexes have been studied as potential SEBs.Ki-67 is an epitope of a nuclear protein recognizedby the MIB-1 monoclonal antibody. The protein isfrequently expressed throughout the cell cycle ofproliferating cells and has not been detected innonproliferating cells. During interphase, Ki-67 islocated primarily in nucleolar and perinucleolar re-gions in association with condensed chromatin.52 Thefunction of the Ki-67 protein is still unknown,53 al-though it seems to be required for cell progressionthrough the cell cycle.54,55 MCM2 is a new proliferationmarker and one of six members of the MCM proteinfamily. These serve as components of “licensing factor,”which is essential for initiation of DNA replication andfor limiting replication to one round per cell cycle.56,57

The MCM proteins are also associated with replicationforks and are likely to stimulate the unwinding of theparental DNA strands at these forks.58

Other markers under investigation include molec-ular end points such as epidermal growth factorreceptor, human epidermal growth factor 2 receptor,p53, Bcl2/Bax, and telomerase, among others. Pro-teomics and GeneChip arrays are platforms underinvestigation for SEB development. However, markervalidation remains a major challenge to ensure repro-ducibility and clinical relevance for any of the SEBsin lung cancer chemoprevention trials.

For instance, it has been reported that plasmalevels of folate are lower in smokers with bronchialmetaplasia than in those with normal mucosa.59 In1988, a randomized, controlled, prospective inter-vention trial in smokers with bronchial metaplasiawas published.60 Seventy-three men with at least a20 –pack-year history of smoking were stratifiedaccording to smoking level and randomly assignedto placebo or folate, 10 mg, and hydroxocobal-amin, 500 �g. Therapy was administered for 4months, and patients were followed up by directcytologic comparison. The supplemental group didshow significantly greater reduction in atypia(p � 0.02). However, results from this study arelimited by the rate of spontaneous variation in thesputum samples, the small sample size, and theshort duration of therapy.




Arachidonic Pathway and Lung CancerChemoprevention

Arachidonic acid is metabolized to prostaglandins(PGs) and prostacyclin (PGI) by the cyclooxygenase(COX) pathway, whereas leukotrienes are formed viathe lipoxygenase (LOX) pathway. Their end productsare thought to be involved in carcinogenesis.

Two isoforms of COX exist: COX-1 and COX-2.COX-1 exists in most cells and is constitutivelyactive. In contrast, COX-2 is induced by inflamma-tory and mitogenic stimuli that lead to increased PGformation in inflamed and neoplastic tissues.61,62

Despite having similar structures, COX-2 can beselectively inhibited.

Evidence exists to support arachidonic pathwaymodulation for inhibition of carcinogenesis. Cortico-steroids are known modulators of the ecosanoid-signaling pathway. Synthesized glucocorticoids havebeen demonstrated to block the development ofcancer in A/J mice with induced pulmonary adeno-mas. COX-2 expression has been demonstrated inpremalignant and malignant bronchial cells.63

Higher levels are associated with a poor prognosis inthose with non-small cell lung cancer.64,65 It hasbeen demonstrated in mouse models that by inhib-iting COX-2 with celecoxib, the rate of growth oflung cancer and number and size of metastasis couldbe decreased.66 The expression of COX-2 has beenshown to enhance tumorigenesis by regulation ofangiogenesis via CXCL 5 and 867–69 and epidermalgrowth factor receptor,70,71 invasion via CD4472–74

and matrix metalloproteinases,72,74–77 apoptosis viasurvivin78,79 and insulin-like growth factor,80–82 andantitumor immunity via interleukin-10 and -12.83–88

However, not all preclinical carcinogenesis modelshave shown chemopreventive efficacy.89

5-LOX is an enzyme involved in the conversion ofarachidonic acid to leukotrienes. Leukotrienes areproinflammatory and enhance cell adhesion.90 Leu-kotrienes seem to affect the development and pro-gression of lung cancer. This is based on datademonstrating that 5-LOX is expressed in lung can-cers,91 5-LOX inhibitors reduced the multiplicity andincidence of lung tumors in mice,92 and 5-LOXmetabolites may play a role in angiogenesis.93

Lung Cancer Chemoprevention Trials WithArachidonic Acid Pathway Modulators

Several studies have been completed and areongoing to evaluate the use of arachidonic acidpathway modulators for lung cancer chemopreven-tion. The following is an overview of these trials.

Budesonide: Lam et al94 evaluated the use ofinhaled budesonide, a corticosteroid that is used for

the treatment of asthma, in 112 smokers with bron-chial dysplasia and found no effect on bronchialdysplastic lesion or on the prevention of new lesions.A modest decrease in p53 and Bcl2 protein expres-sion in bronchial samples was noted as well as aslightly higher rate of resolution of lung noduleson CT.

Celecoxib for Primary Chemoprevention of LungCancer in High-Risk Smokers: Several clinical trialsto address the use of celecoxib for lung cancerprevention are underway. The results of a pilot,phase IIa trial90,95,96 in high-risk smokers performedat University of California, Los Angeles suggestedthat celecoxib may reduce PGE2 production, inhibitimmunosuppression, and modulate SEBs. A follow-up, larger phase IIb trial focusing on heavy formersmokers is evaluating the effect of celecoxib oncellular and molecular events associated with lungcarcinogenesis. Another phase IIb trial of celecoxibin current and former smokers is being conducted atMD Anderson Cancer Center.

Other Arachidonic Pathway Metabolites: A clinicaltrial of the 5-LOX inhibitor zileuton is under way atthe Karmanos Cancer Institute to address the effectof zileuton on bronchial dysplasia (primary endpoint) and multiple molecular markers (secondaryend points) in at-risk smokers or patients with cura-tively treated aerodigestive cancers. Another metab-olite of arachidonic acid is PGI. It has been demon-strated that up-regulation of PGI resulted in decreasedtumorigenicity in mice that were exposed to carcin-ogens.30 The University of Colorado is enrollingparticipants in a phase II, randomized clinical trial toevaluate the effectiveness of iloprost, a PGI analog.End points include the comparison of phenotypicmodulation of bronchial epithelium between the twogroups, as well as evaluation of multiple molecularmarkers.

Recommendation

3. For individuals who are at risk for lungcancer or have a history of lung cancer, budes-onide, COX-2 inhibitors, 5-LOX inhibitors, andPGI analogs are not recommended for use forprimary, secondary, or tertiary lung cancer che-moprevention outside the setting of a well-designed clinical trial. Grade of recommendation,2C

Impact of Information Regarding CardiovascularRisk Associated With COX-2 Inhibitors: In late 2004,unfavorable news was released regarding an in-




creased cardiovascular risk with the use of COX-2inhibitors rofecoxib and celecoxib. The Vioxx GIOutcomes Research Study97 evaluated 8,076 patientswho had rheumatoid arthritis and received rofecoxibvs naproxen; the RR for a cardiac event associatedwith rofecoxib was 2.38 (p � 0.002). The CelecoxibLong-term Arthritis Safety Study98 involved 8,059patients with both osteoarthritis and rheumatoidarthritis and compared celecoxib with nonsteroidalantiinflammatory drugs; in this trial, no significantdifference in cardiovascular events was demon-strated between the two groups.

In 2001, Merck started the Adenomatous PolypPrevention on Vioxx trial,99 which was stopped earlybecause of the finding of an increased risk foradverse thrombotic cardiovascular events after 18months of therapy over placebo during an interimanalysis. One study100 in chemoprevention of colo-rectal cancer also reported an increased cardiovas-cular risk with prolonged use of celecoxib. Thefinding led to the suspension of the aforementionedclinical trials in lung chemoprevention in late De-cember 2004. In February 2005, after careful con-sideration, the Food and Drug Administration con-cluded that the benefits of celecoxib outweigh thepotential risks in properly selected and informedpatients. Advisors to the Food and Drug Adminis-tration also recommended that COX-2 inhibitorscontinue to be studied in the treatment and preven-tion of cancer. With the addition of new monitoringguidelines as well as exclusion criteria to safeguardthe well-being of study participants, it is believedthat the potential benefits from the studies outweighthe risks.

Future Directions for Chemoprevention

Selenium: Epidemiologic data have demonstratedan association between high selenium exposure and areduction in lung cancer risk.101 The mechanism ofaction is thought to be related to oxidative stresspathways, modification of gene expression throughDNA methylation, and suppression of COX-2 and5-LOX expression.102–104

The Nutritional Prevention of Cancer trial105 wasdesigned to evaluate the role of selenium in reducingthe incidence of nonmelanomatous skin cancer. Thetrial did not demonstrate a decrease in skin cancerbut did show a 26% decrease in lung cancer risk. Aphase IIA chemoprevention trial using selenium wascompleted at the Moffitt Cancer Center to evaluatetoxicity and modulation of biomarkers in current andformer smokers. Although selenium was very welltolerated, analysis of samples from the 14 individualswho completed the trial showed no alterations in thebiomarkers that were assessed (p53 by immunohis-

tochemistry in sputum, proliferating cell nuclearantigen and p16 by immunohistochemistry in bron-chial biopsies, and apoptosis by terminal deoxynu-cleotidyl transferase-mediated digoxigenin-deoxyuri-dine nick-end labeling in bronchial biopsies.

Easter Cooperative Oncology Group protocolE5597 is a phase III, double-blind, placebo-controlled study of selenium (200 �g of L-selenome-thionine) in the prevention of second primary lungcancers in patients who have had a complete resec-tion of a pathologically staged T1/2N0M0 non-smallcell lung cancer. The primary end point of the trial isthe incidence of second lung cancers. Intermediatebiomarkers are also studied as potential surrogatesfor lung cancer. This is a national, multiinstitutional,cooperative group trial with an accrual goal of 1,960patients. The study is powered to detect a 40%relative decrease in the 2.0% annual incidence rateof second lung cancers in this cohort of patients andis still in the accrual stage.

Organosulfurs: The organosulfur compounds olti-praz and anethole dithiolethione (ADT) belong tothe dithiolethione class. They have antitumor activityas a result of their antioxidant, chemopreventive,chemotherapeutic, and radiopreventive proper-ties.106 Furthermore, oltipraz was thought to inhibitmacromolecule adducts of carcinogens by inducingphase II detoxifying enzymes.107 For further inves-tigation of this in relation to tobacco, a phase Ichemoprevention trial using oltipraz was initiated.Participants received 0, 200, or 400 mg/wk oltipraz for12 weeks and were followed up with bronchoscopies at1 and 12 weeks. No significant difference was foundbetween the two groups, but the oltipraz group didhave substantial toxicity. In an earlier trial,107,108 olti-praz was combined with N-acetylcysteine. This trialwas stopped early as a result of hepatotoxicity.

ADT is available in Europe and Canada for thetreatment of xerostomia as a result of radiation. In2002, data from a randomized phase II study109 thatevaluated ADT vs placebo for secondary chemopre-vention of lung cancer was published. Althoughthere was no statistical difference in histologic re-gression of bronchial dysplasia, there was a statisticaldifference in the progression rate: 8% vs 17%.109

Recommendations

4. For individuals at risk for lung cancer orhave a history of lung cancer, the use of oltiprazas a primary, secondary, or tertiary chemopre-ventive agent of lung cancer is not recom-mended. Grade of recommendation, 1B

5. For individuals at risk for lung cancer or




have a history of lung cancer, the use of sele-nium and ADT for primary, secondary, ortertiary lung cancer chemoprevention is notrecommended outside the setting of a well-designed clinical trial. Grade of recommenda-tion, 1B

Looking Forward, New Targets

Many other targeted therapeutic agents have po-tential as chemopreventive agents. Table 1 listspotential targets for lung cancer chemoprevention.

Protein kinase C (PKC) is involved in cellularproliferation, apoptosis, and mobility.110 Enzastaurin, aPKC-� inhibitor, is being studied in patients withglioblastoma, lung cancer, and non-Hodgkin lym-phoma. The role of PKC in carcinogenesis is complex.Since there are 12 known isoforms with distinct andat times opposing effects. The � isoform is activatedby growth factors. Enzastaurin competes with theadenosine triphosphate-binding site of PKC-�. Morespecific, in lung cancer cells, enzastaurin demon-strates inhibitory activity on intracellular signalingproteins.111,112 Because of its molecular mechanismof action and low adverse effect profile, this drug isa possible candidate for chemoprevention in high-risk individuals. As demonstrated by the COX-2inhibitor experience, extensive data on safety andefficacy are needed before novel agents can beapplied to the realm of chemoprevention.

Ras is an oncogene that is important for cancer cellsurvival. Farnesyltransferase inhibitors block ras far-nesylation. They have been tested extensively in A/Jmice and transgenic mice and are strong chemopre-ventive agents.113–115 This prompted further investi-gation in patients with lung cancer. The adverseeffects experienced by participants in these trialsincluded myelosuppression, nausea, diarrhea, ab-dominal pain, and fatigue. The clinical toxicity limitsthis drug as a candidate for chemoprevention despitethe impressive preclinical data.

Recommendation

6. For individuals at risk for lung cancer orhave a history of lung cancer, there are not yetsufficient data to recommend the use of anyagent either alone or in combination for pri-mary, secondary, or tertiary lung cancer che-moprevention outside a clinical trial. Grade ofrecommendation, 1B

Conclusion

Chemoprevention is a developing area of re-search. The main goal of lung cancer chemopre-vention is to find an effective agent with a favor-able toxicity profile for patients who are at highrisk for primary or secondary lung cancer. Anumber of compounds have been tested, butresults of trials to date have been either negativeor, in the case of those evaluating beta caroteneand retinoids in active smokers, deleterious. Table2 summarizes the large phase III trials that havebeen conducted. In addition, several smaller,phase II chemoprevention trials have been per-formed that used morphologic parameters, such asmetaplasia and dysplasia in bronchoepithelial bi-opsy specimens or cellular atypia in cytol-ogic sputum specimens, as intermediate endpoints. Agents that have been investigated includevarious retinoids,116 –120 folate and vitamin B12,60

and budesonide,94 but none has demonstratedimprovement.

Some of the phase III trials, although largelydisappointing, nonetheless provided useful lessonsthat continue to shape the design of ongoing chemo-prevention trials, including the importance of takinginto consideration environmental as well as hostfactors when conducting chemoprevention trials inlung cancer. These large trials have underscored thatsmall increases in adverse effects cannot be appre-ciated without large and lengthy clinical trials; how-ever, small increases may have a large public healthimpact given the number of people at risk. Finally,these trials have reinforced the lesson that nutri-tional supplements, just like other pharmacologicinterventions, can have significant adverse effects;therefore, these agents must also be tested in rigor-ous clinical trials.

With the understanding of important cellularsignaling pathways, various inhibitors that mayprevent or reverse lung carcinogenesis are beingdeveloped. Many trials are under way to evaluateagents such as selenium and COX-2 inhibitors. Forhelping to lessen the need for a large sample size,extensive time commitment, and expense, focushas turned toward assessment of SEBs for lung

Table 1—Potential Target Molecules for Lung CancerChemoprevention Trials

COX-2PGI-2HistonedeacetylaseInsulin-like growth factor binding protein 3Mammalian target of rapamycinEpidermal growth factor receptorPKCSignal transduction and activator of transcription-35-, 12-LOXVEGFFarnesyltransferaseProtein kinase B




carcinogenesis. By integrating biological knowl-edge, more pilot trials can be performed in ashorter time frame. For individuals who are athigh risk for lung cancer or have a history of lungcancer, it is strongly recommended to encouragethem to participate in lung cancer chemopreven-tion trials.

The future of lung cancer chemopreventionshould entail the evaluation of single or drug com-binations that will target multiple pathways whileworking toward identification and validation of inter-mediate end points. Despite this promising future,no one agent is recommended for use in the chemo-prevention of lung cancer.

Summary of Recommendations

1. For individuals with a smoking history>20 pack-years or with a history of lungcancer, the use of beta carotene supplemen-tation is not recommended for primary,secondary, or tertiary chemoprevention oflung cancer. Grade of recommendation, 1A

2. For individuals at risk for lung cancerand for patients with a history of lung can-cer, the use of vitamin E, retinoids, N-ace-tylcysteine, and aspirin is not recommendedfor primary, secondary, or tertiary preven-tion of lung cancer. Grade of recommenda-tion, 1A

3. For individuals at risk for lung canceror have a history of lung cancer, budes-onide, COX-2 inhibitors, 5-LOX inhibitors,and PGI analogs are not recommended forprimary, secondary, or tertiary lung cancerchemoprevention outside the setting of awell-designed clinical trial. Grade of recom-mendation, 2C

4. For individuals at risk for lung canceror have a history of lung cancer, the use ofoltipraz as a primary, secondary, or tertiarychemopreventive agent of lung cancer isnot recommended. Grade of recommendation,1B

5. For individuals at risk for lung canceror have a history of lung cancer, the use ofselenium and ADT for primary, secondary,or tertiary lung cancer chemoprevention isnot recommended outside the setting of awell-designed clinical trial. Grade of recom-mendation, 1B

6. For individuals at risk for lung canceror have a history of lung cancer, there arenot yet sufficient data to recommend theuse of any agent either alone or in combi-nation for primary, secondary, or tertiarylung cancer chemoprevention outside aclinical trial. Grade of recommendation, 1B

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DOI 10.1378/chest.07-1348 2007;132;56-68 Chest

and Gerold Bepler Jhanelle Gray, Jenny T. Mao, Eva Szabo, Michael Kelley, Jonathan Kurie

Practice Guidelines (2nd Edition)Lung Cancer Chemoprevention: ACCP Evidence-Based Clinical

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Lung Cancer Chemoprevention: ACCP Evidence-Based Clinical ...€¦ · Background: Lung cancer is the most common cause of cancer death in the United States. Cigarette smoking is the