[CANCER RESEARCH (SUPPL.). 52, 2758s-2763s, May I, 1992]

Chemoprevention Strategies for Lung and Upper Aerodigestive Tract Cancer1

Steven E. Benner, Scott M. Lippman, and Waun Ki Hong2

Section of Head, Neck and Thoracic Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Abstract

The field cancerization hypothesis suggests that carcinogen exposureaffects the entire epithelial lining of the lungs and upper aerodigestivetract. The concept that common exposures place the entire epithelium atrisk for the development of invasive cancer is supported both by theoccurrence of premalignant lesions such as leukoplakia and squamousmetaplasia, and by the development of multiple primary tumors withinthe field. Chemoprevention trials in lung and upper aerodigestive tractcancer have included studies to reverse premalignant lesions and toprevent second primary tumors. Promising results have been reported inboth settings using the retinoid 13-cw-retinoid acid. Several clinical trials

are in progress which attempt both to reduce cancer incidence and todetermine the mechanisms and biological markers of successfulChemoprevention.

Introduction

The tremendous impact of lung and upper aerodigestive tractcancer on U.S. mortality is well known, with over 150,000deaths predicted in 1991 (1). The difficulties in battling thispublic health threat are also unfortunately familiar, with incidence rates for lung cancer in women continuing to climb (2).The problem is increasing despite the knowledge that tobaccoexposure is the dominant risk factor for both lung and upperaerodigestive tract cancer (3, 4). As the result of tobacco andother carcinogenic exposures, millions of Americans are atincreased risk for these cancers. Even with successful smokingcessation an increased risk would persist for over a decade.

The presence of this large population at increased risk forlung and upper aerodigestive tract cancer and the significantmorbidity and mortality associated with these diseases haveprompted efforts to develop prevention strategies in additionto smoking cessation. Chemoprevention, the administration ofdrugs before the diagnosis of cancer, in order to block thecarcinogenic process, may be an important contributor to futureprevention efforts. Epidemiological studies have helped identifypotential Chemoprevention agents, such as /î-caroteneand reti-nol (5, 6). Recently, the retinoids, natural and synthetic analogues of vitamin A, have become widely studied as chemopre-ventive agents for aerodigestive tract cancer, due in part to theireffects on epithelium (7).

Interest in systemic treatments for cancer prevention in theaerodigestive tract has resulted from the understanding that theentire epithelial lining of the tract shares both common carcinogenic exposures and an increased cancer risk. Identification ofthe entire epithelium as condemned mucosa was first describedby Slaughter et al. (8). They chose the term "field cancerization"

to describe the diffuse histológica! abnormalities and multifocalnature of squamous cell cancers of the head and neck. Evidencesupporting the field cancerization model includes the identification of intermediate markers, such as micronuclei, whichcorrelate with exposure to known risk factors and increasedcancer risk, development of premalignant changes within the

1Presented at the NCI Workshop "Investigational Strategies for Detectionand Intervention in Early Lung Cancer," April 21-24. 1991, Annapolis, MD.

2To whom requests for reprints should be addressed, at Section of Head. Neck

and Thoracic Medical Oncology, University of Texas M. D. Anderson CancerCenter, Box 80, 1515 Holcombe Blvd., Houston, TX 77030.

field, and the increased risk of SPTs3 for patients with lung or

head and neck cancers.Field cancerization provides a powerful model for aerodiges

tive tract carcinogenesis and a basis for Chemoprevention studies. This concept explains the diffuse nature of molecular,biochemical, and histological changes which occur in individuals with significant carcinogen exposure. In addition, patientsat high risk for cancer are identified, providing a populationlikely to benefit from Chemoprevention studies.

Chemoprevention Trial End Points

Chemoprevention trials differ significantly from cancer therapy trials and require attention to a distinct set of issues. Intherapy trials, study end points, such as survival and responserates, are often less controversial than the end points in che-moprevention studies. For Chemoprevention trials, a variety ofend points may be appropriate. Chemoprevention is designedto block carcinogenesis, so there is great interest in identifyingthe critical steps of carcinogenesis which may be effectivelyinterrupted. It would be ideal to directly measure the impact ofChemoprevention agents on carcinogenesis. This approachwould allow Chemoprevention trials to be much shorter induration, since researchers would not have to wait for thedevelopment of invasive cancers, which may take decades, toassess the impact of the intervention (9). Since the impact ofthe Chemoprevention agent on carcinogenesis could be assessedfor all patients, not just the minority who develop cancer, trialscould also rely on smaller sample sizes. The difficulty has beento identify reliable intermediate markers.

A variety of different biomarkers have been proposed asintermediate end points in aerodigestive tract carcinogenesis(10). Molecular markers have appeal, because they may represent the specific critical steps in the process. Such markerswould include the presence of oncogene amplification. Elevatedlevels of H-ras, K.-ras, and myc, for example, have been observedin head and neck tumor specimens (11). The protooncogeneint-2 has also been reported to be increased in squamous cellcarcinomas of the head and neck (12). Similarly, several onco-genes, including myc and ras, have been implicated in lungcancer pathogenesis (13, 14). While these abnormalities mayrepresent essential stages in carcinogenesis, there is not yetsufficient information to use these changes to assess the outcome of Chemoprevention trials.

A number of other intermediate markers are also beingstudied to assess their role as end points for Chemopreventionstudies. These potential end points include markers of squamous differentiation, such as transglutaminase, involucrin, andkeratins (15). Other markers have been chosen in an effort toassess cellular proliferation, including proliferating cell nuclearantigen, Ki-67, and DNA polymerase a. Not enough is knownabout the expression of these markers to use them as the endpoints for a Chemoprevention trial.

The most widely studied intermediate marker for the aero-digestive tract is the presence of micronuclei (16). Micronuclei

1The abbreviations used are: SPT, second primary tumor; CR, complete

response; PR, partial response.

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CHEMOPREVENTION STRATEGIES FOR LUNG AND AEROD1GESTIVE CANCER

are fragments of extranuclear DNA, which represent ongoingDNA damage. They represent a quantitative but nonspecificassessment of DNA damage. Micronuclei have been used as anend point for chemoprevention studies in bronchial, oral, andesophageal premalignancy (17-19). Although considerable variation is observed in the measurement of micronuclei, they havegenerally varied as expected with administration of chemoprevention agents.

The other major class of aerodigestive tract chemopreventiontrial end points is histológica! changes. These range from pre-malignant lesions, such as oral leukoplakia or bronchial metaplasia, to cancer. While histológica! changes may be easier toassess than other potential end points, they may develop afterthe essential steps of carcinogenesis. Although development ofinvasive cancer is the end point of greatest clinical interest, itsuse requires long periods of follow-up.

Cúemoprevention Trial Design

As with the choice of study end points, chemopreventiontrials present a series of design problems which must be successfully addressed (19). Single-arm studies have been reportedbut are weakened by uncertainty about the correct end point.Marked sputum atypia, a potential end point for lung chemoprevention trials, for example, may regress without interventionor the alteration of risk factors (20). There has also beenconsiderable variation in the reported success of single-armstudies using comparable interventions. Randomized trials remain the gold standard for chemoprevention studies, especiallygiven the uncertainty about end points and comparability ofstudy results. In some settings, the efficiency of the randomizedtrial may be improved using a factorial design or other modification (21, 22).

Large sample sizes and long follow-up periods are generallyrequired for chemoprevention studies designed to demonstratea reduction in diagnosed cancers. Even the calculation of necessary sample size for these trials is complicated by the longperiod during which dropout may occur (23). An approach tothese sample size and compliance problems in chemopreventiontrials has been to focus on patients with both a perceived andactual increased risk of cancer. Patients with significant smoking history, asbestos exposure, or a history of previous cancer,for example, may be more willing to comply with protocolrequirements based on their personal concern about cancer.These populations are also more likely to benefit than thepopulation as a whole from a successful chemoprevention approach. A recent feasibility study demonstrated that patientssuccessfully treated for head and neck cancer could be recruitedfor a SPT chemoprevention trial (24). Chemoprevention trialsstudying high-risk populations and using the development ofcancer as an end point often require randomization of over1,000 patients to have sufficient statistical power.

Chemoprevention trials also require a reappraisal of the risksand benefits for participants. Primary tumor chemopreventiontrials include many participants who would never develop cancer and so side effects must be almost nonexistent. In contrast,SPT chemoprevention trials may use regimens with greatertoxicities, given the greater risk for each participant of developing cancer. The risks and side effects of the chemopreventionagent will also affect recruitment and compliance in the trial.

Another important consideration in the design of chemoprevention trials is the impact of confounding variables. Trialsstudying the effect of supplementation with dietary components

such as ß-carotene,for example, must consider the diets of the

participants. An individual participant could drop in to thetreatment arm through a change in diet. Since tobacco is acritical risk factor for aerodigestive tract cancers, changes insmoking status must be assessed. Imbalance in smoking statusbetween treatment arms could bias the study results. Smokingcessation efforts for all participants must be a component ofthese trials, since the dangers of this exposure are welldocumented.

Chemoprevention Trials for Lung and Upper AerodigestiveTract Cancer

Bronchial Metaplasia. Exposures which are associated with amarked increase in lung cancer incidence, such as tobacco useor uranium mining, are also clearly associated with abnormalities in the bronchial epithelium (25-27). Epithelial changesobserved in exposed individuals have included the loss of cilia,basal cell hyperplasia, the presence of atypical nuclei, andsquamous cell metaplasia (28, 29). Squamous cell metaplasiarefers to replacement of the ciliated, columnar bronchial liningwith cells resembling a squamous cell epithelium. Because ofthe strong association of these bronchial epithelial changes withthe risk factors for lung cancer and because of the widespreadpresence of these changes in the lungs of lung cancer patients,squamous metaplasia has been considered a histológica! markerof carcinogenesis. Several chemoprevention studies have beenperformed in patients with bronchial metaplasia, in hopes thatsuccessful reversal of the metaplasia would correlate with areduction in lung cancer risk.

Saccomano et al. (30) reported the results of a study to reverseabnormal sputum cytology with the retinoid 13-m-retinoicacid. In this study, patients were treated with doses rangingfrom 0.5 to 2.5 mg/kg/day. Duration of treatment also varied,from as short a period as 1 day to 40 weeks. All of the 26patients studied had abnormal sputum cytology, and in somepatients this was the only apparent pathology, whereas 5 of thepatients were known to have invasive tumor. Smoking statuswas not reported. The study did not observe an improvementin sputum cytology with retinoid treatment. Subsequent studieshave benefitted from the use of bronchoscopy specimens, takenfrom standardized sites, for assessing treatment effects andadministration of a uniform regimen during the study. A studyof heavy smokers (>15 pack-years) reported by Gouveia et al.(31) described the effects of treatment with 25 mg etretinate/day for 6 months in patients with an initial index of metaplasia>15%. The index of metaplasia was calculated by dividing thenumber of histológica! sections with metaplasia by the totalnumber of sections examined, which was then multiplied by100 and expressed as a percentage. Thirty-four of the 70 smokers initially screened were eligible for treatment. The reportdescribed an improvement in the metaplasia index for 10 of 11patients who had completed the protocol (P < 0.01). The studydemonstrated the ability to use bronchoscopy specimens and aquantitative assessment of metaplasia, but the results wereweakened by the small sample size and single-arm design. Asubsequent paper by the same researchers described the resultsfor a larger series of patients treated with the same protocol. Inthis report, 144 smokers underwent initial bronchoscopy, and61 were found to have an index of metaplasia >15 (32). Amongthe 34 évaluablepatients who completed the protocol, themetaplasia index improved with retinoid therapy from 34.57%to 26.96% (P < 0.001 ). For the 4 patients who stopped smoking

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during the trial, the metaplasia index dropped to 0%.A clinical trial is under way at M. D. Anderson to study the

effects of retinoids, using bronchial metaplasia as a lung cancerchemoprevention model. Bronchoscopy specimens obtainedfrom heavy smokers are assessed for the index of metaplasia.Patients with a metaplasia index >15 or the presence of dyspla-sia are randomized to receive placebo or 1.0 mg 13-m-retinoicacid/kg/day for 6 months. In this double-blind trial, bronchos-copy is repeated at 6 months. For patients who do not demonstrate an improvement on follow-up bronchoscopy, the treatment code is broken, and patients initially treated with placebocross over to receive a 6-month course of 13-m-retinoic acidfollowed by bronchoscopy. Over 100 patients have undergoneinitial bronchoscopy, with 58 patients randomized. Results ofthe drug intervention are not yet available. This trial will alsoestablish the association between retinoid reversal of bronchialmetaplasia/dysplasia and intermediate markers of genetic alteration, dysregulated proliferation, and differentiation.

Oral Leukoplakia. Another histológica! marker of premalig-nancy is oral leukoplakia. Oral leukoplakia has been defined as"a white patch or plaque that cannot be characterized clinically

or pathologically as any other disease, and again it must beemphasized that this use of the term is unrelated to the absenceor presence of dysplasia" (33). Obviously, the term describes a

heterogeneous group of conditions, rather than a single entity.Within this category there presumably may exist a variable riskfor development of a subsequent oral cancer. These lesions arefrequently associated with prolonged oral carcinogen exposure,such as chewing tobacco, betel nut chewing, or the use of snuff(34-36). The association between the presence of these lesionsand oral cancer is supported by the finding of adjacent leukoplakia lesions in 36% of oral cavity cancers (37). The associationof oral leukoplakia and oral cancer has also been demonstratedby studies following these patients over time. Silverman et al.

(38) followed 257 oral leukoplakia patients for 7.2 years andobserved the development of 45 (17.5%) squamous carcinomas(38). Invasive cancers developed both in patients with benignhyperkeratosis and in those with dysplasia, although dysplasticlesions were more than twice as likely to progress to cancer.Other studies have also reported an increased cancer risk fororal leukoplakia patients (39).

Chemoprevention studies have demonstrated the ability of ß-carotene, retinol, and retinoids to produce clinical improvementin oral leukoplakia (35-37, 40-49). The characteristics of thesetrials are summarized in Table 1. Response rates have variedconsiderably in these trials, especially for /3-carotene. Toxicityhas also varied between trials and has generally been a muchmore significant problem for retinoid trials. A problem for allof the trials has been the high rates of recurrence when thechemoprevention agent has been stopped.

Several important aspects of oral leukoplakia chemoprevention were demonstrated in the randomized, double-blind trialcomparing a placebo to 13-m-retinoic acid (48). Both clinicaland histological responses were significantly higher among the13-m-retinoic acid-treated patients (P = 0.0002 and P < 0.01,respectively). Although only 2 patients dropped out due totoxicity of the retinoid, 47% of the 17 patients treated with 2mg/kg required a dose reduction. The observed toxicities wereself-limited and included dry skin, cheilitis, conjunctivitis, andhypertriglyceridemia. Unfortunately, when the retinoid wasstopped, 9 of 16 patients who had responded to therapy relapsedwithin 2 to 3 months.

The findings of this trial led to the design of a subsequenttrial which used 1.5 mg 13-m-retinoic acid/kg/day for 3months followed by a low dose of 13-m-retinoic acid (0.5 mg/kg/day) or ^-carotene (30 mg/day) for 9 months (49). Thisstudy confirmed the conclusion that 13-m-retinoic acid causedthe regression of the leukoplakia lesions by 62%. Unfortunately,

Table 1 Oral leukoplakia chemoprevention trials: studycharacteristicsAuthorGarewalTomaStichStichSilvermanSilvermanStichRaqueKochRef.404142344344353645Agentrf-Carotenerf-Carotenerf-Carotene

rf-Caroteneand vitamin A

Placeborf-CaroteneVitamin

AVitamin

AVitamin

APlacebo1

3cRA°13cRA

TretinoinEtretinateDose30

mg/day X 3mos90

mg/day x 3mos180

mg/wk x 6 mos180 mg/wk100.000 lU/wkx 6mos30

mg twice/wk x 10wks600,000-900.000

IU/day x 4-12wks600.000

IU/day x 4wks200,000

lU/wk x 6mos0.1%

(topical)70

mg/d x 8 wks70 mg/d x 8 wks70 mg/d x 8 wksEvaluable

patients17152751332416621

3352427

24Response

(%)(CR +PR)712614.827.5

30448351.7

3.010087

5991

Shah

Koch

Hong

Lippman

46

47

48

49

13cRA

EtretinateEtretinate

13cRAPlacebo

13cRA

3-10 mg/d x 6 mos (topical)

75 mg/d x 6 wks50 mg/d x 6 wks (p.o. and topical)

1-2 mg/kg/day x 3 mos

1.5 mg/kg/day x 3 mos

11

2124

2420

56

82

71.583.5

6710

62l3cRA, 13-ci'j-retinoic acid.

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the less toxic /3-carotene maintenance therapy did not effectivelyprevent relapse. The improvement of 13-a's-retinoic acid-

treated patients was also observed by reduction of micronuclei.The current M. D. Anderson oral leukoplakia trial will com

pare the combination of fJ-carotene and retinol versus 13-c/s-retinoic acid. Treatment allocation is randomized, and the studywill use 3 years of treatment followed by 2 years of follow-up.The combination of 30 mg ß-carotene/day and 25,000 IUretinol/day was chosen based on studies suggesting that theseagents may be synergistic in chemoprevention while havingminimal toxicity (42, 50). The 13-m-retinoic acid will be givenat a dose of 0.5 mg/kg/day for year 1, then at 0.25 mg/kg/dayfor years 2 and 3. This lower dose is intended to preserve theefficacy demonstrated in earlier trials, while producing lesstoxicity. An important component of the trial will be theincorporation of a number of intermediate marker studies,including micronuclei.

Primary Lung and Upper Aerodigestive Tract Chemoprevention

Primary chemoprevention trials generally require extremelylarge sample sizes and long follow-up periods in order todemonstrate an effect. Sample size may be decreased somewhatby studying patients at high risk for developing cancer, anapproach which has been adopted by most researchers. Thechemoprevention regimen must have little if any associatedtoxicity. These problems have prompted some authors to question the feasibility of these trials (51 ). Despite this concern,however, several primary chemoprevention trials are currentlyunder way for these cancers (Table 2). The trials have generallyused naturally occurring nutrients as the chemopreventionagents. Results from these primary tumor chemopreventiontrials are not yet available.

SPTs: A Model for Chemoprevention

Patients successfully treated for lung or head and neck cancerremain at significant risk for the development of a SPT. Thedistribution of SPTs supports the field cancerization hypothesis. This group of patients is ideally suited for chemopreventionstudies. The patients are at increased risk for development of aSPT and would greatly benefit from successful chemoprevention. Compliance and acceptable toxicity may be somewhatgreater, given the extent of the threat of cancer which thesepatients must face.

Head and Neck SPTs. The study of head and neck SPTsdepends on the careful diagnosis of these tumors. Studies inthis area have benefited from rigorous application of diagnosticcriteria, modified from a report by Warren and Gates (59): (a)a distinct lesion separated from the primary tumor by >2 cmof normal epithelium; (b) a new cancer with a different histol

ogy; (c) any cancer, regardless of site, occurring 3 or more yearsafter initial treatment; and (d) in the lung, new primary tumors,if squamous cell cancers occur within 3 years, must have his-

tological findings of dysplasia or carcinoma in situ in theadjacent epithelium.

Using these criteria, the incidence of SPTs in recent serieshas been >20% (60-62). With long periods of follow-up, SPTscontinue to occur, developing at an apparently constant rate of3.6%/year in one study (63). Even for patients presenting withlocally advanced disease, by 4 years after initial treatment, therisk of SPTs exceeds the risk of relapse (64). Ultimately, SPTspose the greatest threat to the health of these patients (65). Thepattern of SPTs is consistent with field cancerization, withroughly one-half found in the head and neck, one-third in thelung, and one-fifth in the esophagus (66). Patients who developSPTs have a poor prognosis; among laryngeal cancer patients,for example, 5-year survival for patients developing SPTs was16.8%, compared with 43.5% for patients with a single primarytumor (67).

Lung SPTs. Following potentially curative surgical resectionof primary lung cancer, patients remain at risk for the development of a SPT in the lung. Lung SPTs have been defined onthe basis of (a) a different histológica! type; (b) a location in adifferent lobe; (c) a location in the contralateral lung; and (</)occurrence >3 years after initial diagnosis. For early-stage non-small cell lung cancer patients treated by surgical resection andobserved for long periods of time, 10-25% of the patients havedeveloped SPTs (68-70). In lung cancer patients, SPTs frequently occur in the lung and head and neck (71). Unfortunately, as with SPTs arising among head and neck cancerpatients, the prognosis is poor for lung cancer patients whodevelop SPTs.

SPT Chemoprevention Trials

Head and Neck SPT Chemoprevention Trials. Based on theactivity of retinoids in reversing oral premalignant lesions andthe risks of both recurrent disease and SPTs among head andneck cancer patients, an adjuvant retinoid trial was performedas a randomized, double-blind study (72). Following therapyfor squamous cell cancer of the head and neck, patients weretreated for 1 year with 50-100 mg/irr/day 13-a's-retinoic acid

or placebo. The initial report described a striking reduction inthe number of SPTs among the patients receiving 13-cw-reti-noic acid (2 or 4%) compared with placebo (12 or 24%) (P =0.005). With the extension of the median follow-up from 32 to48 months, the difference has persisted, with one additionalSPT among the retinoid-treated patients and two SPTs in theplacebo group. Four patients, all in the placebo group, developed SPTs at multiple sites. In the placebo group, 12 of 14SPTs occurred in the head and neck, lung, or esophagus.

Table 2 Primary chemoprevention trials in lung and upper aerodigestive tract cancer"

TrialHarvard

PhysiciansFinlandU.

Texas-TylerU.Texas-TylerSeattle,

CARETstudySeattle.CARETstudyU.

PittsburghU.AlabamaChina(Vanagihara)NCI/Huixian

StudyRef.53545556575752525658Agent/i-Caroteneß-Carotene,

n-tocopherol(¡-Carotene,retinolEtretinateli-Carotene,

retinol(¡-Carotene,retinold-CaroteneFolie

acid.Bufi-CaroteneSelenium,

zinc, riboflavinStudy

PopulationPhysiciansSmokersAsbestos

exposureAsbestosexposureSmokersAsbestosisSmokersSmokersTin

minersHuixian,ChinaSiteAll

sitesLungLungLungLungLungLungLungLungEsophagus

1Modified from Ref. 52.

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consistent with the field cancerization hypothesis.A difficulty for the study was the toxicity associated with

high-dose retinoid therapy. The planned dose of 100 mg/m2had to be decreased to 50 mg/m2, because of the number of

patients requiring dose reductions. While mild side effects wereexperienced equally in the two treatment groups, more significant side effects were seen predominantly in the 13-c/s-retinoicacid-treated patients. Sixteen of 49 retinoid-treated patients,compared with 3 of 51 placebo patients, did not complete theyear of therapy due to toxicity. The toxicity observed in thestudy was self-limited and consistent with previous reports.

The design of this study, as an adjuvant trial, may have ledto an underestimate of the impact of 13-m-retinoic acid. Overone-half of the study participants presented with locally advanced disease and had the competing risks of local failure anddistant métastases.The trial enrolled patients during a shortinterval (<16 weeks) following therapy for their primary tumor.Following initial therapy, the risk of local relapse declines,whereas SPTs continue to develop at an apparently constantrate for at least 8 years.

The findings of this study led to the design of a head andneck SPT chemoprevention trial. This randomized, double-blind, placebo-controlled trial will study the efficacy of 30 mg13-cw-retinoic acid/day for 3 years to prevent SPTs. The studywill enroll not only recently treated early-stage squamous cellcancer patients but also patients who have been free of theirdisease for up to 3 years. The study will be completed throughthe Radiation Therapy Oncology Group, the M. D. AndersonCancer Center, and its affiliated Community Clinical OncologyProgram centers. An important aspect of this clinical trial isthe incorporation of basic science investigations into the study.Companion studies will examine the cytogenetic and molecularabnormalities associated with field cancerization, as well asinvestigate retinoid-responsive genes and receptors.

Lung SPT Chemoprevention Trials. Chemoprevention trialsto prevent SPTs following resection of non-small cell lungcancer are currently under way. Pastorino et al. (73) havepresented the interim results of an adjuvant trial using 300,000IU vitamin A/day for 12 months (73). The outcome for 150vitamin A-treated patients was compared with that of 157control patients. Only 4 of the vitamin A-treated patients hadto stop the drug due to toxicity. No difference has yet beendetected in the development of SPTs (8, or 5%, in the vitaminA group and 9, or 6%, among the controls). Relapse-freesurvival has favored the vitamin A-treated patients but has notreached statistical significance (P = 0.07).

The European Organization for Research and Treatment ofCancer is performing a trial based on this experience, called theEuroscan trial (56). The study will testfor the chemopreventionof SPTs in patients successfully treated for lung and head andneck cancer. The Euroscan trial uses a factorial design with thefollowing treatment groups: 300,00 IU retinyl palmitate for 1year, then 150,00 IU for the second year; 600 mg /V-acetyl-

cysteine for 2 years; both agents for 2 years; or placebo. Retinylpalmitate was chosen for this trial based on epidemiológica!studies that suggest there is a reduction in lung cancer associated with high dietary vitamin A intake. The low toxicity of theregimen and the researchers, previous experience with vitaminA therapy also contributed to the choice of this chemopreven-tive agent. The presumed mechanism of ./V-acetyl-cysteine as achemoprevention agent is its action as an antioxidant. The goalfor accrual is 2000 patients, which should be achieved byDecember 1992.

In the United States another trial is being developed whichwould evaluate the efficacy of 13-c/s-retinoic acid in preventinglung SPTs. The study will evaluate this intervention in patientssuccessfully treated for Stage I non-small cell lung cancer.

Summary

There is tremendous excitement over the prospects for theeffective chemoprevention of lung and upper aerodigestive tractcancer. Recently completed trials have demonstrated the potential for the retinoid 13-cw-retinoic acid to interrupt field cancerization by reversing premalignant lesions and decreasing theincidence of SPTs. These interesting initial results must beverified in large chemoprevention trials. These trials must notsimply address the effect of the intervention on tumor incidence,but must also investigate the molecular and biochemicalchanges which accompany multistep carcinogenesis. Understanding of the carcinogenic process should improve our abilityto develop effective chemoprevention strategies.

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