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.
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.
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.
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. The finding of one neoplasm in the exposed area provides evidence for the presence of multiple premalignant lesions of independent origin. In this setting, lesion-specific therapy is insufficient; interventions that prevent the promotion and progression of unrecognized lesions are needed.
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 womans 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.
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]