title: Why phase II trials in cervical chemoprevention are negative: what have we learned?
abstract: Cervical cancer is an important cause of mortality in women worldwide, and the cervix is a well-established clinical, cytologic, and histopathologic model of carcinogenesis. The cervix is easily accessible for examination and biopsy, and colposcopy improves visualization. Identifying chemopreventives in cervical cancer requires rigorous study design: dose de-escalating phase I, IIa trials; placebo-controlled phase IIb trials; and multicenter phase III trials. Reduction in disease incidence and surrogate endpoint biomarkers (SEB) may be trial endpoints. The goal of chemoprevention studies is to prevent or delay the development of cancer. Each agent requires a phase I or IIa trial for each organ site. Phase I, IIa studies of micronutrients, retinoids, alpha-difluoromethylornithine, and indole-3-carbinol have demonstrated response rates of up to 70%, but results of placebo-controlled phase IIb studies have been disappointing and their findings confounded by the high regression rates in placebo-treated patients. Enhancement of research methods, including sufficient enrollment guided by power calculations, uniform biopsy at study entry and exit, and strict progression through trial design phases would ensure valid and reliable results. Because human papillomavirus (HPV) is the major etiologic agent, pretrial laboratory and animal studies should have demonstrated the efficacy of the chemopreventive agent to decrease HPV viral protein expression or HPV tumor induction. SEB modulation must be characterized in any trial's earliest phases before use in phases IIb and III. Lessons learned in chemoprevention will serve as a basis for immunoprevention and vaccine trials.
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. mfollen@mdanderson.org
authors.forename: Michele
authors.initials: M
authors.lastname: Follen
authors.forename: Anne-Thérèse
authors.initials: AT
authors.lastname: Vlastos
authors.forename: Frank L
authors.initials: FL
authors.lastname: Meyskens
authors.forename: E Neely
authors.initials: EN
authors.lastname: Atkinson
authors.forename: David
authors.initials: D
authors.lastname: Schottenfeld
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000453:epidemiology; D018890:Chemoprevention; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D015994:Incidence; D027383:Papillomaviridae; D016133:Polymerase Chain Reaction; D016032:Randomized Controlled Trials as Topic; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control* / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000453:epidemiology