5-fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: A clinical and pharmacologic analysis

Abstract

Background: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU). Patients and methods: IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/ m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4. The IUdR dose was changed in cohorts of patients. IUdR plasma concentrations were determined during weeks 1 and 4, and IUdR incorporation into the DNA of granulocytes was measured on weeks 2 and 5. Results: Two patients treated at the initial IUdR dose of 500 mg/m2/day developed grade 3 or 4 myelosuppression and mucositis. Additional dose levels of IUdR tested were 250 mg/m2/day and 125 mg/m2/day; at the latter dose, severe or life-threatening toxicity was seen in only 3 of 8 patients treated. IUdR incorporation into DNA of granulocytes was 10.5(± 2.3)% at an IUdR dose of 500 mg/mVday but decreased to 0.76(± 0.3)% at 125 mg/m2/day. Similarly, lUdR plasma concentrations decreased from 436 (± 114) ng/ml to 99(±29)ng/ml. Conclusions: The addition of IUdR to 5-FU and HU results in significant systemic toxicity necessitating limitation of the IUdR dose to 125 mg/m2/ day. There is a significant biochemical interaction between IUdR, 5-FU and HU leading to increased IUdR incorporation into DNA and to substantial clinical toxicity. Further clinical studies to exploit this interaction at more feasible schedules may be useful. © 1993 Kluwer Academic Publishers.