Phase I clinical trial of parenteral hydroxyurea in combination with pelvic and para-aortic external radiation and brachytherapy for patients with advanced squamous cell cancer of the uterine cervix

Purpose: Oral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix. Methods: This Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity. Results: At dose level 1 (0.25 mg/m²/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m²/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m²/min), 4 of 5 patients failed to complete therapy without a gt;7-day interruption in HU. Conclusions: The maximal tolerated dose of parenteral HU was 0.375 mg/m²/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.