Bromodeoxyuridine alternating with radiation for advanced uterine cervix cancer: A phase I and drug incorporation study

Purpose: Preclinical studies show a significant increase in the ratio of th e radiosensitizer bromodeoxyuridine (BUdR) in tumors versus the intestinal mucosa during the drug elimination period, compared with the ratio during d rug infusion. We constructed a phase I study in patients with locally advan ced cervix cancer, using alternating cycles of BUdR and radiation therapy ( RT). Patients and Methods: Eighteen patients with stage IIB to IVA cervix cancer participated. A treatment cycle consisted of a 4-day BUdR infusion followe d by a week of pelvic RT, 15 Gy twice daily in 1.5-Gy fractions. After thre e cycles, additional BUdR was infused, followed by brachytherapy. The fract ion of thymidine replaced by BUdR and the fraction of cells incorporating B UdR were determined in rectal mucosa and tumor biopsies at the end of the f irst BUdR infusion (day 5), at the middle of the first Ri week (day 10), an d at the time of brachytherapy. Results: Dose-limiting toxicity was observed in one of 16 patients receivin g 1,000 mg/m(2)/d x 4 days and in both patients receiving 1,333 mg/m(2)/d x 4 days each cycle. After a median follow-up of 39 months, 12 patients (66% ) were free of pelvic disease and nine (50%) were alive and disease free. T he ratio of tumor to rectum BUdR incorporation averaged 1.5 to 1.8 and did nor differ significantly between day 5 and day 10. A trend toward reduced r atio was observed at brachytherapy Drug-containing cells in rectal biopsies migrated from the crypts to the mucosal surface. Conclusion: In this sched ule, 1,000 mg/m2/d is the maximum-tolerated dose of BUdR, BUdR incorporatio n levels in tumors were consistent with clinically significant radiosensiti zation. The migration of BUdR-containing rectal mucosa cells from the crypt s to the surface at the time of RT suggests that this regimen may offer a r elative sparing of the mucosa from radiosensitization. J Clin Oncol 17:31-40, (C) 1999 by American Society of Clinical Oncology.