There is substantial laboratory and clinical evidence that repopulation of tumor clonogens during a typical 7 week course of radiation therapy for carcinomas of the cervix contributes to poor tumor control. Pelvic failure rates for cervical carcinoma after radiation therapy range from 30-90% for intermediate to advanced tumors, with repopulation likely contributing to this poor outcome. There is clearly a need for innovative treatment approaches in this disease affecting women that is often poorly controlled. This proposed clinical study will test the clinical feasibility of targeting repopulation in cervical carcinoma by delivering antiproliferative therapy during multi-fractionated radiation therapy, with the goal of improving pelvic control. The concept of modulating tumor proliferation during radiotherapy is a novel approach which has not been prospectively tested previously in a clinical setting. The pre-clinical data indicate that hydroxyurea (HU), when present chronically in low, clinically achievable concentrations, significantly inhibits tumor cell growth. Transit through S phase is prolonged, while producing little cell lethality or readiosensitization at the relatively low concentrations of 100- 150Ym required. Use of this agent as a antiproliferative agent during radiation therapy is proposed. Hydroxyurea is specifically selected because of its effectiveness as an antiproliferative agent, its suitability for oral administration, and its well known pharmacologic profile derived from various medical uses. The phase I clinical study proposed will determine the dose of orally administered hydroxyurea given TID required to produce a defined degree of reduction in tumor proliferation rate and will determine whether that level has acceptable toxicity when delivered concurrently for the duration of radiation therapy. The study will utilize drug-induced proliferative changes in each patient's tumor as an intermediate endpoint to determine the antiproliferative efficacy of the drug serum level attained, and will determine toxicities and tumor response when these drug levels are subsequently maintained during a full course of radiotherapy.
