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Strategies for Identification and Clinical Evaluation of Promising Chemopreventive Agents

Strategies for Identification and Clinical Evaluation of Promising Chemopreventive Agents

ABSTRACT: Strategies for chemopreventative drug development are based on the use of well-characterized agents, intermediate biomarkers correlating to cancer incidence, and suitable cohorts for efficacy studies. Since chemoprevention is applied over the long-term, chemopreventive drugs must have low toxicity. Strategies for enhancing chemopreventive drug efficacy and minimizing toxicity include combinations of drugs with complementary mechanisms and/or synergistic activity; coadministration of drugs to counter the toxicity of the chemopreventive agents; and pursuit of related compounds that retain efficacy with reduced side effects. Because of its slow development, cancer is not a feasible end point for clinical evaluation of chemoprevention, and so intermediate biomarkers that can serve as surrogate end points are crucial. Particularly important biomarkers are the morphometric and cytometric changes defining intraepithelial neoplasia (IEN). Cohorts for chemoprevention trials should have high incidences of the cancer or intermediate biomarker(s) under study within the trial duration. [ONCOLOGY 10(10):1471-1488, 1996]


Cancer chemoprevention is defined as the use of specific chemical
compounds to prevent, inhibit, or reverse carcinogenesis. As shown
in Figure 1, cancer development in humans requires an average
of 20 to 40 years,[1-6] and the scope of chemoprevention encompasses
all phases of this process--from healthy subjects at normal risk;
to populations at intermediate risk from environmental and lifestyle
factors, genetic predisposition, and precancerous lesions; to
previous cancer patients at high risk for second primary malignancies.

Chemoprevention is a relatively new medical science. It is only
during the past 5 years that results of clinical intervention
trials with chemopreventive drugs have begun to appear in the
literature. For example, a 1990 seminal trial by Hong and colleagues
demonstrated that 13-cis-retinoic acid (iso-retinoin [Accutane])
prevented second primary cancers in patients with previous squamous-cell
carcinoma of the head and neck.[7] Second primaries were seen
in 24% (12 patients) of the placebo group but in only 4% (2 patients)
of the treatment group.

Of course, such clinical trials represent only a fraction of current
knowledge about human chemoprevention. Epidemiologic studies,
ranging from descriptive assessment of dietary influences to prospective
case-control analyses with specific micronutrients and drugs,
have provided and continue to furnish leads for definitive intervention
trials. For example, the protective effects of aspirin in the
colon were substantiated by such studies.[8-10]

Chemoprevention is not the same as cancer chemotherapy. These
two treatment modalities are compared and contrasted in Table
. A primary distinction is the timing and duration of intervention.
Chemoprevention is applied throughout the long process of carcinogenesis
depicted in Figure 1, before invasive disease develops. Chemopreventive
treatment is intended to be long term, conceivably up to a lifetime
in high-risk subjects. A consequence of this long duration of
treatment in relatively healthy subjects is a requirement for
agents with very low toxicity. In contrast, chemotherapeutic agents
are administered after invasive disease is detected. Many such
agents are given to cancer patients for short periods or in discrete
cycles under conditions in which side effects are expected and
carefully monitored and palliative treatment can be administered
to lessen their immediate impact.

A second fundamental distinction relates to the goals of the two
treatment modalities relative to cancer. Chemotherapy seeks to
increase survival and remission of invasive disease and to prevent
metastases, whereas chemoprevention tries to prevent or prolong
the time to the onset of cancer. Because of these differences,
the developmental paths for chemotherapeu- tic[11] and chemopreventive
agents[12] are divergent. In particular, cancer incidence generally
is not a feasible end point for the evaluation of chemopreventive
drugs because of the long time needed for carcinogenesis and the
relatively low incidences of cancers, even in high-risk populations.

Despite the differences between chemoprevention and chemotherapy,
there are areas of conceptual and practical overlap between the
two modalities. For instance, chemopreventive agents can be used
as adjuvant therapies to prevent recurrences or new primary tumors
in patients who have already been treated for cancer. This use
was defined by Hong et al[7] in the trial with isotretinoin cited

Also, some of the mechanisms of chemopreventive and chemotherapeutic
action are similar. Cytotoxicity was the primary mechanism of
early chemotherapeutic agents. Many newer chemotherapeutic agents
are cytostatic and have mechanisms similar to those of some chemopreventive
agents; ie, they slow the growth and progression of dysplastic
cells (eg, by inducing terminal differentiation or apoptosis).
A significant feature of chemoprevention is that it intervenes
at the early stages of carcinogenesis when normal cell order and
function are partially preserved. Chemoprevention strategies can
be designed to target these preserved pathways before they are
lost during the accelerating disorder that ends in the uncontrolled
cell growth of cancer.

As suggested above, a significant aspect of chemoprevention is
the end points selected for intervention trials. Numerous chemoprevention
studies have used well-recognized precancerous lesions as end
points. For example, patients with familial adenomatous polyposis
(FAP) develop large numbers of colorectal adenomas beginning in
their teens and, if untreated, have a 90% chance of progressing
to colorectal cancer by 50 years of age.[13] In a small phase
II trial in patients with FAP, Giardiello et al[14] showed that
9 months of sulindac (150 mg bid) caused a mean decrease in polyp
number to 44% of baseline (p = .014) and a mean reduction in polyp
diameter to 35% of baseline (P less than .001), although no patient
had complete resolution of all polyps. During the 3-month follow-up,
polyp size and incidence increased but remained significantly
lower than baseline. Also, Meyskens et al[15] showed that all-trans-retinoic
acid (Vesanoid) was effective in causing regression of cervical
intraepithelial neoplasia (CIN), a precursor to cervical carcinoma.

These studies represent the vanguard effort in clinical trial
design and evaluation of precancerous lesions and earlier biomarkers
as surrogate end points for chemoprevention. Hong and Lippman[16,17]
and Lipkin[13,18,19] were early contributors to the conceptualization
of intermediate biomarkers as end points for chemoprevention.
Our group and others have continued to expand this approach and
formalize its application to chemopreventive drug development.[12,20-26]
In the comparison between chemoprevention and chemotherapy above,
we noted the importance of the safety of chemopreventive drugs
during long-term administration. Approaches to eliminate toxicities
that would preclude the use of highly efficacious agents is another
significant component of chemopreventive drug development. The
objective of this paper is to describe these current strategies
and current progress in the development of chemopreventive drugs.

Bases for Successful Chemoprevention Strategies

We have previously presented a multidisciplinary approach to the
development of chemopreventive drugs[12,23-27] and have collaborated
with the FDA to provide guidance for applying this approach.[12]
The strategy considers experimental and epidemiologic evidence
that defines cancer risk at major target sites, as well as the
underlying molecular, cellular, and tissue level mechanisms that
contribute to the development and progression of human cancers.
As previously described,[27] we have identified three critical
components to the successful development of chemopreventive drugs:

  1. Well-characterized agents with the potential for inhibiting
    the target cancer;
  2. Biomarkers correlating with cancer incidence for measuring
    chemopreventive effect; and
  3. Suitable cohorts for clinical efficacy studies.


The most important criterion for a chemopreventive agent is evidence
of chemopreventive efficacy, in particular, a high likelihood
that the agent will be active in preventing cancer at the target
site. We have already discussed the requirement for low toxicity,
and thus, evidence of a high margin of safety is also necessary
to warrant consideration of an agent for clinical evaluation.
This second criterion implies that sufficient prior clinical use
or preclinical efficacy, toxicity, and pharmacodynamics data are
available to allow estimation of an efficacy/safety ratio. Often,
studies to determine the optimal dose and dosing regimen are performed
as part of early clinical efficacy trials.

A third criterion is that there is a logical, presumed mechanism
of chemopreventive activity of the agent. Such mechanisms guide
the selection of both cohorts and end points for clinical trials.
For example, an antiproliferative agent such as 2-difluoromethylornithine
(DFMO [Eflornithine]) may be most effective against cancers with
a pronounced proliferative component, such as the development
of colon cancers from hyperproliferative tissue and adenomas.
An antimutagenic agent such as oltipraz may be more effectively
evaluated in a cohort such as smokers, who are constantly exposed
to the DNA-damaging effects of carcinogens. Likewise, indicators
of proliferation, such as S-phase fraction and proliferating cell
nuclear antigen (PCNA), may prove to be more reliable and easily
quantified measures of the effects of antiproliferative agents
than would be the identification of specific mutations.


Generally, biomarkers causally related to subsequent cancer are
more easily validated as end points than biomarkers for which
the relationship to cancer is indirect. Carcinogenesis is progressive,
and therefore, biomarkers appearing close in time to the cancer
and those exhibiting increasing or decreasing incidence or potency
during carcinogenesis are likely to be the most reliable surrogate
end points for cancer.

We have previously identified intraepithelial neoplasia (IEN)
as the intermediate biomarker that most closely meets these requirements,[12,20-22,24,27]
and histopathologic changes associated with the progression of
IEN should prove to be reliable end points for chemoprevention
trials. Including colorectal adenomas and CIN, which were cited
above, IEN lesions that have been and are currently being evaluated
in chemoprevention trials are listed in Table 2. Furthermore,
within IEN, other types of biomarkers--direct measures of proliferation
and differentiation, mutations, changes in expression and activity
of cell growth regulators, and, possibly, less direct biochemical
indicators of growth and proliferation (eg, hormone levels)--may
be evaluated as potential end points.

As has been elegantly described by Fearon and Vogelstein for the
development of colorectal cancer,[28] carcinogenesis is a multipath,
stochastic process.[22] Except for IEN, which essentially comprises
all the varying changes that occur, this multiplicity of pathways
complicates the validation of single intermediate biomarkers as
surrogate end points, since they may appear on only one or a few
of the many possible causal pathways. Consequently, panels of
biomarkers, particularly those representing the range of carcinogenesis
pathways, may prove more useful as surrogate end points.

Used alone, biomarkers representing isolated events that may or
may not be on the causal pathway or otherwise associated with
carcinogenesis are unlikely to be reliable. These include markers
of normal cellular processes that may be increased or expressed
during carcinogenesis. Examples are expression of receptors and
growth factors and activities of such enzymes as glutathione S-transferase
(GST) and ornithine decarboxylase (ODC). However, while these
biomarkers have the disadvantage of nonspecificity for cancer,
they may be useful as part of a panel of biomarkers and provide
important mechanistic measurements for identifying new chemopreventive
drugs. We have previously described a strategy for selecting and
prioritizing biomarkers to evaluate in chemoprevention trials;[27]
this strategy is summarized in Table 3.

Clearly, it must be possible to change the expression of an intermediate
biomarker/surrogate end point with chemopreventive agents. Intraepithelial
neoplasia can be modulated, as demonstrated by the chemoprevention
trials cited above that used colorectal adenomas and CIN as end
points. While they will more often be risk biomarkers used primarily
for identifying cohorts for chemoprevention studies, genetic lesions
or their encoded products can also provide biomarkers that can
be modulated in certain circumstances. Although acquired genetic
lesions would not be excised by a chemopreventive agent, one can
assume that some agents will confer a selective advantage for
cells not carrying the lesion over those that do. In this instance,
the biomarker would be the quantitative reduction in genetically
altered cells at the tissue level.

The surrogate end point should have short latency compared with
cancer incidence--ideally, months or a few years, compared with
the 20- to 40-year period that may be required for cancer development.
Intraepithelial neoplasia, even in its early stages, would appear
to occur too late for effective chemoprevention studies in asymptomatic
subjects. However, as will be discussed below, some cohorts with
previous IEN are at high risk for recurrence or new lesions within
the time frame of a chemoprevention study.

Some cohorts chosen for chemoprevention trials may be available
for too short a period to allow modulation of the lesions most
closely related to cancer. For example, we are carrying out trials
in patients scheduled for surgery for early-stage prostate cancer
and for breast lesions. The biopsy samples in these trials may
be most useful for exploring changes in proliferation indices
and other early biomarkers rather than actual progression of histologic
lesions. Despite the brief duration of the associated trials (1
or 2 months), studies in these cohorts may provide valuable information
on modulation of selected biomarkers that are known to be associated
with cancer risk.


In early stages of chemopreventive drug evaluation, clinical research
efforts focus primarily on short-term phase II trials to measure
efficacy and to identify and standardize intermediate biomarker
end points. The chemopreventive agents must be able to affect
the disease or risk of disease within the relatively short treatment
duration of such trials (many span 6 months or less; some may
last up to 3 years). There are cohorts at high risk for cancer
who are not good candidates for phase II chemoprevention trials,
even though they will be targets for chemopreventive intervention.
An example is patients at risk because of germ-line mutations
(eg, BRCA1) or other family history who do not also have premalignant

From a practical standpoint, the chemopreventive effect should
also be easily measured in the subject population. Tissues that
are more accessible and that can be monitored in a relatively
noninvasive manner provide better sites for definitive efficacy
trials than do less accessible tissues. This does not mean that
chemopreventive agents will be ineffective in the more difficult
settings, but rather, that initial demonstration of activity may
be best carried out in situations where fewer obstacles to measurement

Often, the cohorts in these phase II chemoprevention clinical
trials are cancer patients or patients with previous high-risk
lesions who have undergone prior treatment. These patients are
constantly monitored for possible recurrences and new lesions.
It is important that chemoprevention trials work within the constraints
of standard treatment so that patients are not at unusual risk.
For example, in trials in patients with small colon adenomas (0.5
to 1.0 cm), this may result in frequent monitoring and removal
of any adenomas larger than 0.5 to 1.0 cm.[29] As suggested above,
in early phase II trials where the primary goal is identification
and standardization of biomarkers as end points, normal treatment
may also lead to very short-term trials prior to surgery in patients
who are scheduled for excision of cancers or high-risk tissue,
eg, prostate carcinoma or ductal carcinoma in situ (DCIS) of the

In larger phase II trials and pivotal phase III trials, the eMPHasis
is on efficacy evaluation with the standardized and validated
biomarkers. These trials are generally of longer duration and
are carried out in cohorts that do not initially present IEN severe
enough to warrant surgery but are at high risk for progression
within a 1- to 5-year time frame. Examples are individuals with
atypical breast hyperplasia and multiple biomarker abnormalities,
such as estrogen (ER) and epidermal growth factor receptor (EGFR)
overexpression, p53 mutations, HER-2/neu, and aneu-ploidy;[30]
patients with prostatic intraepithelial neoplasia (PIN);[31] and
patients with previous colorectal adenomas[13] or superficial
bladder cancers.[32] Cohorts currently being studied in chemoprevention
trials that provide the characteristics for biomarker standardization
and efficacy evaluation have been discussed elsewhere[24,26,27]
and are listed in Table 2.


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