CHEMOPREVENTION TRIALS AND SURROGATE END-POINT BIOMARKERS IN THE CERVIX

Cervical cancer is the second most common malignancy in women worldwid e and remains a significant health problem for women, especially minor ity and underserved women. Despite an understanding of the epidemiolog ic risks, the screening Papanicolaou smear, and morbid and costly trea tment, overall survival remains 40%. New strategies, based on the clin ical and molecular aspects of cervical carcinogenesis, are desperately needed. Chemoprevention refers to the use of chemical agents to preve nt or delay the development of cancer in healthy populations. Chemopre vention studies have several unique features that distinguish them fro m classic chemotherapeutic trials; these features touch on several dis ciplines and weave knowledge of the biology of carcinogenesis into the trial design. In the design of chemoprevention trials, four factors a re important: high risk cohorts must be identified; suitable medicatio ns must be selected; study designs should include Phases I, II, and II I; and studies should include the use, of surrogate end point biomarke rs. Surrogate end point biomarkers are sought because the cancer devel ops over a long period of time, and studies of chemopreventives would require a huge number of subjects followed for many years. Surrogate e nd point biomarkers serve as alternative end points for examination of the efficacy of chemopreventives in tissue. High risk cohorts include women with cervical intraepithelial neoplasia (CIN) or squamous intra epithelial lesions (SIL). Nutritional studies have helped define micro nutrients of interest (folate, carotenoids, vitamin C, vitamin E). Oth er medications of interest include retinoids (4-hydroxyphenylretinamid e [4-HPR], retinyl acetate gel, topical all-trans-retinoic acid), poly amine synthesis inhibitors (alpha-difluoromethylornithine [DFMO]), and nonsteroidal antiinflammatory drugs (ibuprofen). Phase I chemoprevent ion studies of the cervix have tested retinyl acetate gel and all-tran s-retinoic acid. Phase II trials of all-trans-retinoic acid, beta-caro tene, and folic acid have been and are being carried out, whereas Phas e III trials of all-trans-retinoic acid have been completed and have s hown significant regression of CIN 2 but not CIN 3. Phase I studies of DFMO and Phase II studies of DFMO and 4-HPR are underway. Surrogate e nd point biomarkers under study include (1) quantitative cytology and histopathology; (2) human papillomavirus type testing; (3) biologic me asures of proliferation, regulation, differentiation, and genomic inst ability; and 4) fluorescence spectroscopic emission. Clinical trials w ith biologic end points will contribute to our understanding of the ne oplastic process and hence aid us in developing new preventive and the rapeutic strategies.