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Phase II Cancer Prevention Clinical Trials

Eva Szabo

The development of agents to prevent cancer requires an iterative process of target identification,preclinical testing, and early and late phase clinical trials to establish efficacy and safety. Since phaseIII definitive efficacy trials with cancer endpoints require a lengthy timeframe and considerableresources for completion, it is critical to first optimize agent delivery and trial design and todetermine preliminary efficacy via the conduct of phase II trials. Phase II trials vary considerably intheir endpoints, cohorts, and designs due to differences in the process of carcinogenesis and abilityto sample tissues across different target organs. However, the goal of all such trials is to provideevidence of interference with the development of cancer and to identify safety signals that wouldlimit the benefit from interventions.Semin Oncol 37:359-366. Published by Elsevier Inc.

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bundant evidence indicates that invasive cancercan be prevented, or at least significantly de-layed, if addressed early enough. Clinical suc-

esses include US Food and Drug Administration (FDA)-pproved approaches such as breast cancer riskeduction with tamoxifen or raloxifene, cervical cancerrevention with vaccines against human papillomavi-us, and reduction in colorectal polyp number in famil-al adenomatous polyposis.1–5 However, with an everncreasing understanding of the molecular events lead-ng to cancer at a variety of target organ sites and an in-reasing number of potential targets for intervention, its essential to prioritize agents for drug development.he convincing demonstration of prevention of a dis-ase that occurs only in a portion of the study popula-ion requires large clinical trials of lengthy duration. Forxample, the Study of Tamoxifen and RaloxifeneSTAR) and Alpha-Tocopherol Beta Carotene (ATBC)reast and lung cancer phase III trials required 5�ears of treatment of more than 19,000 and 29,000ndividuals, respectively, to demonstrate 163 and 876ew cases of breast and lung cancer.2,6 It is thereforeecessary to ensure that maximal efficacy and safety

nformation is known prior to committing the consid-rable resources that are required for phase III cancerrevention trials. Phase II preliminary efficacy clinical

ung and Upper Aerodigestive Cancer Research Group, National CancerInstitute, National Institutes of Health, Bethesda, MD.

ddress correspondence to Eva Szabo, MD, Lung and Upper Aerodi-gestive Cancer Research Group, Division of Cancer Prevention, NCI,NIH, 6130 Executive Blvd, Room 2132, Bethesda, MD 20892. E-mail:szaboe@mail.nih.gov

270-9295/ - see front matterublished by Elsevier Inc.

ooi:10.1053/j.seminoncol.2010.06.015

eminars in Oncology, Vol 37, No 4, August 2010, pp 359-366

rials provide critical human data to inform the “go–noo” drug development decision. This review will pro-ide an overview of phase II cancer prevention trialesign, including issues inherent to the choice of tar-ets, optimization of risk–benefit ratios, cohort selec-ion, and intermediate endpoint assessment.

ARGET SELECTION FORANCER PREVENTION TRIALS

The selection of appropriate targets for interventions the most critical component of the drug develop-

ent process. Appropriate target selection is based onfficacy assessment as well as the potential negativeffects of impacting the target (as discussed below).ndications of effectiveness fall into several major cat-gories: knowledge of mechanisms, in vitro and animaln vivo experimental data, epidemiological case–con-rol and cohort studies, and data from clinical trials,ither early-phase prevention trials or secondary end-oint analyses from trials performed for other indica-ions.7 During each stage of drug development, butarticularly at the juncture between preclinical andarly clinical trials and then again at the juncture be-ween early phase and definitive phase III clinical trials,t is necessary to review all the available data and toxamine it for consistency. The quality and consistencyf the available data help determine whether additionalata need to be obtained prior to clinical trials, or ifufficient knowledge is available to make the “go–noo” decision.

Understanding the mechanisms responsible for car-inogenesis at specific target organs is critical to de-igning the appropriate clinical intervention trials.owever, despite the recent logarithmic increases in

ur knowledge, the detailed mechanisms giving rise to

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360 E. Szabo

ost human cancers are not well worked out. It isecoming clear that cancer represents a multitude ofolecular processes with different pathogenetic mech-

nisms even within the same target organ. For exam-le, breast cancer classification has moved beyond theimple estrogen receptor–positive and estrogen recep-or–negative categories, while a variety of molecularlterations, several of which can be specifically tar-eted for therapy, are known to lead to lung adenocar-inoma.8,9 This molecular complexity suggests thatultiple strategies may well be needed to prevent

ifferent types of cancers and thus it becomes evenore important to identify the individuals at high risk

or specific molecular types of cancer.The more dependent a cell is on a particular path-

ay for its growth and survival, the more likely that anntervention blocking the pathway will be effective.his is best illustrated by the tyrosine kinase inhibitor

matinib, which inhibits p210BCR-ABL, which causeshronic myelogenous leukemia (CML) and also inhibits-Kit, which is involved in gastrointestinal stromal tu-ors (GIST) and small cell lung cancer (SCLC).10–12 InML, p210BCR-ABL is necessary and sufficient to cause

he disease, and imatinib has striking efficacy, espe-ially in the early chronic phase. In fact, chronic CMLan be considered a premalignant phase of the leuke-ic process. However, imatinib’s efficacy decreasesarkedly with advancing disease, such as acceleratedhase and blast crisis, both of which are characterizedy the accumulation of additional mutations. Similarly,

n GIST, c-Kit is mutated and imatinib is again veryffective in the tumors with the appropriate mutations.owever, in SCLC, although c-Kit is frequently ex-ressed, activating mutations in c-kit exon 11 are not

ound while a multitude of other mutations in otherenes do exist, and imatinib is inactive.13 Efficacy inlocking a single pathway only occurs when the cell isritically dependent on that pathway.

Thus, the better one understands the process ofarcinogenesis and the molecular basis for the evolu-ion of the neoplastic phenotype, the more likely willne be able to develop interventions to prevent andossibly even reverse neoplastic progression. The effi-acy of an agent in preventing cancer will depend onow critical its target is to carcinogenesis (as exempli-ed by the role of imatinib in CML), whether the agentan be delivered at the time that its target drives thearcinogenic process, and the potency of the interven-ion. Because different aspects of carcinogenic progres-ion may depend on different molecular abnormalitiesr signaling pathways, it is important to determinehen specific abnormalities should be targeted. For

xample, targeting the initial DNA damage from carcin-gen exposure in tobacco smoke by blocking carcino-en metabolism may be very effective prior to thecquisition of much DNA damage but is not likely to be

ffective once the damage already exists and cells have t

cquired multiple genetic lesions (eg, after years ofmoking). A priori, there is no reason to theorize thatnterventions that are effective during some phases ofarcinogenesis will be effective during other stages,nless the target has a critical biological role duringultiple stages of carcinogenesis. Finally, it is impor-

ant to remember that phase III cancer prevention trialsith tumor incidence endpoints generally test inter-

entions for only a small number of years, so theserials are, by design, testing intervention efficacy onelatively advanced stages of premalignancy (Figure 1).onsequently, an intervention that blocks early events

n carcinogenesis, such as initiating DNA damagevents, is highly unlikely to prevent cancer in a trialhere the duration of the intervention is 3 to 5 years.

n selecting targets for cancer prevention, the ability toesign the appropriate clinical trials to demonstratefficacy must be considered—if one cannot demon-trate preventive ability within the context of our cur-ently available clinical trials resources (eg, if the inter-ention must be delivered prior to all carcinogenxposure), the drug development process is likely toail.

HE RISK–BENEFIT BALANCE

The side effect profile of a putative chemopreven-ive agent is as important as its efficacy, although safetylone is insufficient to justify clinical trials. The mainssues to consider regarding the side effect profile ofotential chemopreventive drugs are the common mi-or side effects that are not consequential to generalealth but may significantly impact quality of life orompliance and uncommon major side effects thathreaten an individual’s short-term or long-term well-eing and thus potentially substitute another seriousisease for cancer.

To be acceptable for cancer prevention, a drug haso be tolerable so that people will be willing to take itor extended periods of time. The level of discomforthat is tolerable varies considerably, depending on thelinical context. For example, in a chemoprevention

igure 1. Timing of clinical trials during the process ofarcinogenesis.

rial of anethole dithiolethione (ADT) for the reversion

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f bronchial dysplasia, National Cancer Institute Com-on Toxicity Criteria (CTC) grade 2 side effects

mainly gastrointestinal) resulted in protocol-mandatedose reductions in 45% of participants taking ADTersus 25% taking placebo.14 While this level of toxicitys quite mild compared with the more severe (grades 3nd 4) toxicities frequently encountered during treat-ent for metastatic cancer with any of a variety of

gents, the clinical context (low short-term risk ofeath and anticipation of lengthy duration of treatmentor chemoprevention) is quite different. Even mild tox-cities may be bothersome enough to affect quality ofife and compliance in the setting of cancer preventionnd thus may limit the utility of effective agents.

Although tolerability and impact on quality of lifeay limit the potential utility of chemopreventive in-

erventions, the rare but serious short- and long-termide effects are of even greater concern. Several phaseII cancer prevention trials, in part due to their placebo-ontrolled design and long careful follow-up, haveemonstrated adverse effects that have limited the up-ake of efficacious agents into common medical prac-ice. The National Surgical Adjuvant Breast and Bowelroject (NSABP) P-1 study of tamoxifen for breast can-er prevention showed an increased risk for the devel-pment of endometrial cancer (relative risk [RR] �.53; 95% confidence interval [CI], 1.35–4.97) and an

ncrease in the incidence of stroke, pulmonary embo-ism, and deep vein thrombosis, all in the context of anmpressive 49% decrease in invasive breast cancer.1

hese adverse events were more frequent in womenver age 50, with no endometrial cancer occurring inomen under 50 years of age. Nevertheless, despite no

ignificant differences in important adverse events be-ween tamoxifen and placebo in women under 50ears of age, the perception of tamoxifen as being toooxic for prevention persists, and use has been limitedven in this age group.

A different clinical situation arose from the identifi-ation of significant cardiotoxicity during rofecoxibreatment for the prevention of recurrence of colorec-al adenomas. Although associated with a 24% decreasen colorectal adenoma recurrence, extended use ofofecoxib was found to increase the relative risk ofhrombotic events such as cardiac events (hazard ratioHR] � 2.80; 95% CI, 1.44–5.45) and cerebrovascularvents (HR � 2.32; 95% CI, 0.89–6.74).15,16 Rofecoxibas subsequently withdrawn from the market. The

nitial report indicated that cardiovascular risk did notncrease until approximately 18 months after drug use,aising the intriguing dilemma of how to identify in-reased risk of common diseases such as cardiovascularvents in the elderly that do not occur until later timeoints and thus are unlikely to be identified in theriginal drug registration trials of relatively short dura-

ion. t

It thus becomes clear that the appropriateness of angent for prevention is dependent not only on tolera-ility and side effect profile but also on the cancer riskf the intended cohort and the duration of the inter-ention. The acceptable level of toxicity and the risk ofhe cohort for serious disease are directly related—theigher the risk of immediate serious disease, the higherhe toxicity that is acceptable for interventions. Sincelmost all interventions are likely to have some sideffects, it is critical to identify the most appropriateigh-risk cohorts that stand to benefit the most from

nterventions. Similarly, tailoring therapies towardhose who are most likely to respond to specific inter-entions due to individual pharmacogenetic profilesill help shift the balance toward maximal benefit.The alternative strategy to affect the risk–benefit

alance is to lower the risk of the interventions, eithery excluding individuals at risk for toxicity or throughegional rather than systemic drug delivery or combi-ation therapy. Lam et al demonstrated minimal toxic-

ty in a phase IIb lung chemoprevention trial of inhaledudesonide, a corticosteroid used for asthma, evenhough systemic treatment with corticosteroids woulde considered unacceptably toxic.17 Regional deliveryo the oral cavity, lung, or colon (via delivery of agentshat act locally and are not absorbed systemically) isarticularly appealing. Similarly, agent combinationssing lower doses than required for single-agent treat-ent have the potential to increase efficacy while de-

reasing toxicity, although possible additive or unex-ected toxicities from the combination require carefultudy. Meyskens et al showed that the combination oflow dose of the nonsteroidal anti-inflammatory drug

NSAID) sulindac with the polyamine inhibitor difluo-omethylornithine (DFMO) resulted in a superior clin-cal outcome and apparently less toxicity than woulde expected from the use of NSAIDs alone.18 This trialhowed an impressive 70% reduction in total adenomaurden and a greater than 90% reduction in advancedr multiple adenomas, the highest efficacy reported toate. Finally, alternative drug delivery schedules, suchs periodic pulsatile treatment, may lower drug-associ-ted toxicities, although this has not yet been ade-uately studied in animals or humans. Lubet et al re-ently described excellent efficacy from intermittentelivery of gefitinib in a carcinogen-induced rat mam-ary cancer model system, suggesting that intermittent

elivery, with its attendant decreased toxicity and thusncreased tolerability, should be considered for futurelinical trials.19

HASE II CLINICAL TRIALS

A number of different prevention phase II clinicalrial designs exist due to the heterogeneity of the dis-ase processes and the inherent difficulties in sampling

issues from different target organs. The challenges to

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362 E. Szabo

esigning phase II trials that are truly informative re-arding the prevention of cancer are multiple. Identifi-ation of the appropriately high risk cohorts is difficultith our current limited understanding of cancer risk

cross multiple target organs. Furthermore, since pre-ention trials are performed before the development ofmeasurable cancer, it is difficult to measure the effectf an intervention on the process of carcinogenesis ando identify endpoints that are truly predictive of aancer preventive effect. As a result, phase II cancerrevention trial design is a work in evolution. Some ofhe more common designs and relevant considerationsave been summarized by the American Associationor Cancer Research (AACR) Cancer Prevention Taskorce.20

ohort Selection

Optimizing the risk–benefit ratio requires the iden-ification of high-risk cohorts that stand to gain theost from interventions. However, current risk assess-ent tools are very imprecise for most cancer types.

or example, even though the link between tobaccoxposure and lung cancer is among the strongest in allf cancer biology, only a minority of smokers develop

ung cancer during their lifetime. Peto et al estimatedhat the cumulative risk of lung cancer at age 75 to be5.9% for men and 9.5% for women.21 Even identifyinghe smokers who are most likely to develop cancer hasroven to be quite challenging.

To date, the most useful model predicting cancerisk has been the Gail model for breast cancer riskssessment, which was successfully used to identifyandidates for the NSABP P-1 study of tamoxifen.22

imilar attempts were made by Bach et al to develop anssessment tool to identify lung cancer risk in currentnd former smokers, based on the information availablerom the Carotene and Retinol Efficacy Trial (CARET)ung cancer prevention trial of more than 18,000 par-icipants.23,24 While this tool is useful for individualsho fit the enrollment criteria for CARET, it is not

pplicable to individuals with different characteristicseg, those younger than 50 years or with less smokingxposure). Spitz et al have further expanded on lungancer risk assessment to incorporate multiple expo-ures and family history as well as to assess risk inever-smokers.25 However, all of these models rely pri-arily on demographic information rather than on the

pecific molecular characteristics of a given individualnd consequently have substantial limitations. Never-heless, it should be noted that attempts to improve onhe Gail model for breast cancer risk assessment bydding information on common genetic variants led toery minimal prognostic improvement.26 It thereforeeems likely that identification of the actual somatic

olecular changes occurring during carcinogenesis in m

particular individual may be needed to improve theerformance of risk assessment models.

The power of molecular prognostication is exempli-ed by the case of oral leukoplakia, which is a precur-or to oral cancer with a very heterogeneous progres-ion rate to cancer. While the rate of progression ofysplastic oral leukoplakia to cancer is typically de-cribed as 36% over 8 years, genetic damage in the formf loss of heterozygosity (LOH) at one or more specifichromosomal loci can identify subgroups of individualsith rates as high as 25% to 50% over 5 years.27,28 The

isk–benefit balance and, consequently, the acceptableoxicity of interventions differ substantially in suchigh-risk individuals compared with those individualsith lower risk molecular phenotypes. This informa-

ion is being used as the basis for a phase III trial testingrlotinib in subjects with high-risk oral leukoplakia, therlotinib Prevention of Oral Cancer (EPOC) trial.29

iven the extraordinarily high risk of the cohort, thisrial is the first oral leukoplakia trial that was able to beesigned to have a definitive cancer incidence end-oint rather than relying on the effect of the interven-ion on the cancer precursor, namely, oral leukoplakia.he development of improved risk assessment tools to

dentify the truly high-risk individuals who stand to gainhe most benefit from preventive interventions remainspriority for cancer prevention research.

ntermediate Endpoints

Identification of appropriate (and informative) studyndpoints is a critical aspect of any drug developmentrogram. Phase III cancer prevention trials are thegold standard” in demonstrating preventive efficacyy assessing cancer incidence. Phase II preliminaryfficacy cancer prevention trials, on the other hand,ely on short-term, or intermediate, endpoints that areheoretically predictive of patient outcomes such asancer incidence. In contrast to phase II cancer treat-ent trials that rely on tumor measurements to assess

gent efficacy, phase II cancer prevention trials do notave easily measured primary trial endpoints for indi-ating preventive efficacy. Instead, early-phase cancerrevention trials generally assess surrogate efficacyeasures such as histologic preneoplasia or prolifera-

ive indices that are even more distantly related to theefinitive endpoint of cancer incidence than tumorhrinkage is related to survival.

To be useful, an intermediate marker should satisfyeveral criteria.30–32 The marker should be integrallynvolved in the process of carcinogenesis and its ex-ression should correlate with the disease course. Thexpression of the marker should differ between normalnd at-risk epithelium, and it should be easily andeproducibly measurable in specimens likely to be ob-ained in clinical trials. Last, the expression of the

arker should be modulated by effective interventions,

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Phase II cancer prevention clinical trials 363

nd there should be minimal spontaneous fluctuationsnd no modulation by ineffective agents. A marker thatatisfies these criteria then needs to be validated inrospective clinical trials.32

No intermediate endpoint marker has passed theseequired rigorous validation measurements thus far.owever, it is becoming clear that the complex molec-lar mechanisms that regulate tumor development in-olve a number of molecules and regulatory pathwaysontrolling various cellular processes, including prolif-ration, differentiation, apoptosis, invasion through theasement membrane, and angiogenesis.33 Classes ofolecules found to be altered in epithelial cancers andreneoplastic lesions include oncogenes, tumor-sup-ressor genes, growth factors or their receptors, andolecules regulating cellular immortality, immune de-

ense, and tumor-associated angiogenesis. These aber-antly expressed molecules provide an opportunity toevelop biomarkers for risk assessment, as well as foronitoring response to chemopreventive or therapeu-

ic interventions. For example, it was recently reportedhat the phosphoinositide 3-kinase (PI3K) pathway ispregulated early during lung carcinogenesis and thatn intervention with the drug myo-inositol that resultedn regression of bronchial dysplasia also inhibited PI3Kctivation in the bronchial epithelium.34 These datauggest that upregulated PI3K signaling could poten-ially identify smokers at increased risk for lung cancernd that pathway inhibition could serve as an endpointor assessing treatment effect—a hypothesis thatlearly requires further testing.

Nevertheless, even in the absence of validation, in-ermediate endpoints can significantly inform earlyhase drug development by demonstrating that the

nterventions affect the target epithelium. The mostommonly used intermediate endpoints in phase IIancer prevention are histologic precursors to invasiveancer, generally referred to as “intraepithelial neopla-ia.”35 The natural history of such lesions can varyignificantly, depending on the target organ and theeverity of the abnormality. For example, in the lung,pproximately 3.5% of low or moderate dysplasiasrogress to severe dysplasia, 37% of severe dysplasiasemain or progress, and approximately 50% of carcino-as in situ progress to invasive carcinoma within a 2- to

-year follow-up period.36,37 Since one cannot predicthich dysplasias will persist or progress, this argues forrandomized placebo controlled trial design whereby

he “spontaneous” reversion rate in the placebo arman be used as a comparison to account for the effectsf the biopsies and for true biologic reversion. A num-er of phase II trials have used this approach in aariety of target organs. Fabian et al studied DFMO inomen with breast cytologic atypia diagnosed via ran-om periareolar fine needle aspiration.38 Lam et al stud-

ed the inhaled steroid budesonide in smokers with

ronchial dysplasia diagnosed by autofluorescence l

ronchoscopy,17 and Heath et al studied celecoxib inubjects with Barrett’s esophagus with dysplasia iden-ified via endoscopy.39 All three of these studies wereegative, suggesting either that all three agents wereruly negative or that only a highly effective agent coulde identified with an intraepithelial neoplasia endpoint.

A variety of other biomarkers, such as the Ki-67roliferation index, also have been used as primarytudy endpoints, although the direct correlation be-ween such biomarkers and cancer incidence is evenore remote than the relationship between intraepi-

helial neoplasia and cancer.31 Prevention trials gener-lly assess proliferation in preneoplastic or histologi-ally normal epithelium in high-risk individuals, aetting where proliferation is elevated but to a far lesseregree than in overt malignancy. Fabian et al showedhat 6 months of treatment with letrozole in postmeno-ausal women at high risk for breast cancer who wereaking stable doses of hormone replacement resulted instriking 66% decrease in the Ki-67 proliferation index

n breast epithelial cells, in the absence of a discernibleffect on cytology.40 Similarly, Kim et al demonstratedstatistically significant decrease in Ki-67 in the his-

ologically normal bronchial epithelium in smokersreated with celecoxib.41 Thus, proliferation appears toe more sensitive to modulation than histology; unfor-unately, in the absence of data linking changes inroliferation with the definitive endpoint of cancer

ncidence, it is difficult to know how predictive thisndpoint truly is.

An alternative to using single markers such as Ki-67s to examine a panel of markers or even a gene ex-ression profile. The effect of 12 months of treatmentith celecoxib on gene expression in the normal co-

onic mucosa in subjects with hereditary nonpolyposisolon cancer was studied recently.42 These investiga-ors found changes in expression in more than 1,400enes, albeit with a magnitude of change of less thanwofold in the majority. The main biologic processeshat were found to be affected were immune response,ell signaling and adhesion, response to stress, trans-orming growth factor-� signaling, and regulation ofpoptosis. This approach is similar to that of Gustafsonnd colleagues described above, who examined theffect of myo-inositol on gene expression in the normalronchial epithelium and were able to show that inhi-ition of PI3K activation correlated with regression ofysplasia.34 The use of gene expression analysis totudy a small number of subjects treated with an inter-ention offers a faster and more efficient way to eval-ate mechanisms of action of the intervention and torovide evidence of efficacy. Such an approach mayventually replace the relatively large phase IIb trialshat study 100 or more participants with interventions

asting 3 to 6 months or longer.

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arly-Phase Clinical Trial Designs

The design of clinical prevention trials has to ac-ount for different target organ biology and tissue ac-essibility, leading to a variety of trial designs currentlyn use for phase II trials. Depending on the nature ofhe endpoint being assessed, trials range from multi-onth treatments with the aim of regressing intraepi-

helial neoplasia to short-term treatments with the aimf demonstrating an effect on a pharmacodynamic end-oint.20 Several potential phase II trial designs are sum-arized in Table 1. Longer treatment is thought to beecessary to reverse premalignant lesions, whereasharmacodynamic endpoints or processes such as pro-

iferation and a wide variety of alterations in gene orrotein expression can be modulated within a few dayso weeks. The amount of information learned differsubstantially between the different designs.

As cancer treatment strategies become more tar-eted and less toxic and as our understanding of theiology of preneoplasia matures to reveal relevant mo-

ecular targets for early intervention, the same agentsay become appropriate for both prevention and treat-ent. This provides unprecedented opportunities to

ssess chemopreventive efficacy during the use ofgents for cancer treatment or in the presurgical set-ing. “Prevention-relevant endpoints,” such as biomar-ers of proliferation or pharmacodynamic effects, cane assessed in short-term presurgical settings or longererm neoadjuvant settings while the patient is awaitingefinitive surgical treatment. This has already been

Table 1. Early-Phase Clinical Trial Designs

Trial Type

Prevention trial with IEN endpoint High-riskPrevention trial with molecular

endpoint(s)High-risk

needeAdvanced cancer trial with nested

“prevention endpoint”Cancer

Adjuvant trial with nested “preventionendpoint”

Curativepatien

Presurgical or neoadjuvant model Cancerdefinit

IEN � intraepithelial neoplasia.

articularly well modeled using endocrine therapies in c

he setting of breast cancer.43 Since acquisition of tissueccurs within the context of “standard of care” andresumably large amounts of tissue (at least tumorissue) become available at the time of definitive re-ection, these approaches have clear benefits. The neg-tive of a presurgical or neoadjuvant approach is thatreatment duration is limited and thus may be too briefo demonstrate effects on intraepithelial neoplasia. Inddition, it is the effect on intraepithelial neoplasia thats of most interest for assessing preventive agents, yethe amount of premalignant tissue at the time of resec-ion is still likely to be quite limited.

Similar to the presurgical approach, assessment ofrevention-relevant endpoints also can be nested inancer treatment trials that use agents that have poten-ial for cancer prevention. If agents have an appropri-tely benign toxicity profile, this allows simultaneousarly development for prevention and treatment indi-ations. For example, bronchoscopies or colonosco-ies to assess agent effects on bronchial dysplasia andberrant crypt foci, respectively, can be performedretreatment and at defined times during treatment inatients with an excellent performance status who arearticipating in phase II cancer treatment trials, sincehese premalignant lesions occur with high frequencyn these patient populations. The obvious limitation ofhis trial design is the high progressive disease rate fordvanced cancer populations, which may prevent theost-treatment evaluation. The variable need for addi-ional invasive procedures such as bronchoscopies and

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informatives, � IEN Potentially high drop-out rate

due to progressive disease;agent must be appropriate forprevention; additional (“non–standard of care”) tissueacquisition required

ted cancerN

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Limited duration of treatment,primarily biomarkermodulation; tissue acquisitionas part of “standard of care”

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ifficulty of this approach. Nesting of prevention-rele-ant endpoints into adjuvant therapy trials increaseshe likelihood of being able to perform the post-treat-ent assessment after appropriately long treatment

uration, although these trials are fewer in number andurrently are much more likely to include cytotoxichemotherapy as part of the treatment regimen. How-ver, simultaneous assessment of prevention-relevantndpoints would considerably speed up new preven-ion agent development by giving an early indication offfectiveness, which may or may not need to be fol-owed by dose titration to establish the optimal doseor true prevention indications.

ONCLUSIONS

The recent explosion of knowledge regarding theevelopment of cancer offers hope for and challengeso the development of strategies to prevent cancer. Asancers arising at a variety of target organs are showno be considerably more complex and molecularly het-rogeneous than originally thought, prevention haslso proven to be more complicated and elusive thannitially anticipated. Rational selection of targets forntervention requires a greater understanding of theiology of the carcinogenic process. Since carcinogen-sis occurs over time, potentially with different mech-nisms assuming primary importance during differenttages of cancer development, it is particularly impor-ant to understand the temporal progression of molec-lar abnormalities. Equally important is the identifica-ion of the appropriate high-risk cohort that should beargeted for intervention. The proper risk–benefit bal-nce can only be reached when the cohort’s cancerisk is high enough to justify the potential toxicitiesrom the intervention. Finally, there is a tremendouseed to develop new models of clinical trials that canfficiently identify promising agents for cancer preven-ion. This requires identification of biomarkers thateflect clinical benefit, and, eventually, validation ofhese markers if they are to be used as surrogates.ovel technologies, including imaging modalities asell as molecular analyses of tissues and body fluids,ill be needed to reach these goals.

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