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Cancer Chemoprevention Part 1: Retinoids and Carotenoids and Other Classic Antioxidants

Cancer Chemoprevention Part 1: Retinoids and Carotenoids and Other Classic Antioxidants

ABSTRACT: Cancer chemoprevention is the use of specific natural or synthetic substances with the objective of reversing, suppressing, or preventing carcinogenic progression to invasive cancer. Currently, numerous chemopreventive agents are in various stages of development and testing. Part 1 of this two-part series provides an overview of issues unique to chemoprevention trials, including the use of surrogate biomarkers as end points. This is followed by a discussion of the retinoids, such as all-trans-retinoic acid (ATRA [Vesanoid]), 9-cis-retinoic acid (9cRA), and isotretinoin (Accutane), and the carotenoids (eg, beta-carotene and lycopene) and other "classic" antioxidants (eg, vitamins E and C and selenium). Research on these agents will be delineated by disease site when applicable. Part 2, which will appear in next month’s issue, will focus on hormonally mediated chemopreventive agents, such as tamoxifen (Nolvadex), finasteride (Proscar), oral contraceptives, and dehydroepiandrosterone (DHEA). Part 2 also will cover nonantioxidant natural agents, such as calcium, the polyphenols, the isothiocyanates, and genistein; nonsteroidal anti-inflammatory drugs (NSAIDS), such as celecoxib, sulindac sulfone, and aspirin; difluro-methylornithine (DFMO [Eflornithine]); oltipraz; and N-acetylcysteine. [ONCOLOGY(11):1643-1658, 1998]

Introduction

Cancer chemoprevention is defined as the use of
chemical agents to suppress or reverse carcinogenesis to prevent the
development of invasive cancer.[1,2] Two basic concepts underlie this
approach to cancer control: the multistep nature of cancer
development and field carcinogenesis.

The development of cancer occurs over years and involves multiple
genetic and phenotypic alterations that lead to invasive cancer.
Chemoprevention is based on the premise that intervention is possible
during the many steps of this process.[2]

Based on animal model studies, carcinogenesis has been broadly
divided into three phases: initiation, promotion, and progression. In
initiation, a carcinogen interacts with DNA, producing a fixed
mutation. The specific molecular change depends on the carcinogen and
can be influenced by a number of factors, including the rate and type
of carcinogenic metabolism and the response of the DNA repair function.

During promotion, the initiated cells proliferate. This stage occurs
over a long period and can be altered by agents that affect growth rates.[3]

Progression is the phase between a premalignant lesion and the
development of invasive cancer. During this stage, genetic and
phenotypic changes occur, with the rate of progression based on the
rate of genetic mutation and cell proliferation.[1-8] Studies of
molecular progression in colon cancer support this model of
carcinogenesis, which involves a series of acquired genetic changes.[9]

Field carcinogenesis is the concept that, in patients at risk,
extensive, multifocal, genetically distinct premalignant and
malignant lesions can occur within the whole carcinogen-exposed
region. The classic example is exposure of the upper aerodigestive
tract and lungs to the carcinogenic effects of tobacco.[10] The
finding of one neoplasm in the exposed area provides evidence for the
presence of multiple premalignant lesions of independent origin.[11]
In this setting, lesion-specific therapy is insufficient;
interventions that prevent the promotion and progression of
unrecognized lesions are needed.

Issues Relevant to Prevention Trials

Study Design

Chemopreventive strategies can be applied to the general population
or to high-risk groups.[11-13] For use as a chemopreventive agent
among the general population, a compound must have minimal or no
toxicity. Agents that show promise for this purpose include dietary
constituents or their analogs, as well as medicinals, such as
nonsteroidal anti-inflammatory drugs (NSAIDs).[11-13]

High-risk individuals include those who have a genetic predisposition
to cancer, prior cancer diagnosis, history of a significant exposure
to a carcinogen, or a histology that indicates an elevated likelihood
of developing cancer. Because of their increased risk, some toxicity
may be acceptable in these populations.

In addition, subjects at high risk are ideal subjects for clinical
trials of chemopreventive agents because their increased incidence
rates allow for smaller study sample sizes.[11,14,15] For example,
selection of participants for studies of breast cancer
chemoprevention generally relies on the identification of high-risk
proliferative breast histology or epidemiologic factors known to
increase a woman’s risk of developing breast cancer. In general,
women with a ³ 20% lifetime risk of
developing breast cancer are considered to be good candidates for
participation in chemoprevention trials.[16]

Chemoprevention trials administer specific natural or synthetic
substances with the objective of reversing, suppressing, or
preventing carcinogenic progression to invasive cancers. In
preclinical research, the efficacy and toxicity of a chemopreventive
agent are assessed via in vitro cell screening systems and in vivo
assays using animal models.[11-15]

Designs for phase I-III chemoprevention trials are based on similar
principles as chemotherapeutic trials. A number of issues unique to
chemoprevention exist, however. Whereas phase I chemotherapy trials
identify maximum tolerable doses in patients with refractory cancer,
phase I chemoprevention trials establish safe doses with minimal
toxicity for relatively healthy subjects.[11,14,15]

Study End Points: Surrogate End Point Biomarkers

After establishing the dose level with the optimal chemopreventive
toxicity profile, phase II clinical trials evaluate biological
efficacy in a larger group of patients at high risk for specific
cancers and provide data that characterize dose, safety, and toxicity
in the selected population. The primary end points of phase II trials
are biological indices of neoplasia, based on clinical, histologic,
genetic, biochemical, proliferative, or differentiation-related
properties, that can be used to estimate the potential for neoplastic
progression to cancer and to determine the effect of the
chemopreventive agent being tested on these indices.[11,14,15] These
biological indices are referred to as surrogate, or intermediate, end
point biomarkers.

Phase IIa trials are feasibility studies of surrogate end point
biomarkers and can include dose de-escalation studies to determine
the lowest, least toxic drug dose that retains biological activity.
In phase IIb trials, preliminary surrogate end point biomarkers are
confirmed by definitive randomized study of treatment and control arms.

After short-term activity is established, phase III trials are
conducted to establish long-term efficacy in reducing cancer
incidence. Phase III trials can require thousands of subjects and 5
to 10 years to complete. Innovative strategies, such as factorial
designs and the use of a vanguard cohort, have been developed to
maximize the use of limited resources.[11,14,15]

Cancer incidence is the obvious end point of a trial investigating a
chemopreventive agent. The low incidence of cancer, however, even in
high-risk populations, necessitates lengthy studies with thousands of
patients, entailing tremendous expense.

Identification and validation of surrogate end point biomarkers is
vital to prevention research; eventually, surrogate biomarkers may
replace cancer incidence as end points in large-scale clinical
trials. With the development of valid surrogate end point biomarkers,
fewer subjects will be required for the study to achieve the desired
level of statistical power, and interventions can be evaluated over a
shorter period than is possible when cancer is used as the end point.[11,14,15]

Characteristics of the Ideal Surrogate Biomarker--A valid
surrogate biomarker should be on the causal pathway of cancer, and
not simply an associated change. It should be expressed differently
in normal than in high-risk premalignant sites; change its pattern
and/or degree of expression in correlation with the stage of
carcinogenesis; have a low rate of spontaneous change; and be
technically and logistically feasible to measure.[11,14]

It should be possible to modulate a surrogate end point biomarker by
chem-opreventive agents in such as way as to lead to a decrease in
the incidence of cancer. Thus, surrogate end point biomarkers differ
from susceptibility markers, such as certain genetic polymorphisms
and mutagen sensitivity. Finally, surrogate biomarkers should have
known sensitivity, specificity, and positive predictive value for the
development of cancer.[11,14,16]

The best-studied biomarkers are nonspecific indicators of
genotoxicity and cell proliferation. Types of biomarkers include
clinical and histologic parameters, genetic markers, proliferation
markers, biochemical indicators, and differentiation markers.[4-6,11,14-17]

Surrogate End Point Biomarkers Under Study--Surrogate end
point biomarkers can include markers of certain site-specific
changes, such as the premalignant lesions listed below, or markers of
general cellular/molecular changes, such as altered differentiation
and proliferation, that can occur at many sites. Site-specific
surrogate end point biomarkers (premalignant changes) currently under
study include ductal carcinoma in situ (breast), prostatic
intraepithelial neoplasia (prostate), adenomas and aberrant crypts
(colon), papillomas (bladder), cervical intraepithelial neoplasia and
human papillomavirus (HPV; cervix), leukoplakia (oral cavity), and
squamous metaplasia (eg, larynx and lung). DNA ploidy, growth factor
receptors (eg, epidermal growth factor receptor [EGFR]), oncogene
expression, loss of heterozygosity, quantitative morphometric
features, and proliferation, differentiation, and apoptosis markers
are examples of general surrogate biomarkers (biomarkers of
cellular/molecular changes) currently under study.[11,14,16,17]

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