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

BACKGROUND:: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interactsbiochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU) PATIENTS AND METHODS:: IUdR was added to the previously studied regimen of continuousinfusion 5-FU at 300 mg/ m²/day for 5 days, HU 500 mg every12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days,all administered for 7 consecutive weeks to patients with malignantglioma. IUdR was administered as 5-day continuous intravenousinfusion during weeks 1 and 4. The IUdR dose was changed incohorts of patients. IUdR plasma concentrations were determinedduring weeks 1 and 4, and IUdR incorporation into the DNA ofgranulocytes was measured on weeks 2 and 5. RESULTS:: Two patients treated at the initial IUdR dose of 500 mg/m²/daydeveloped grade 3 or 4 myelosuppression and mucositis. Additionaldose levels of IUdR tested were 250 mg/m²/day and 125 mg/m²/day;at the latter dose, severe or life-threatening toxicity wasseen in only 3 of 8 patients treated. IUdR incorporation intoDNA of granulocytes was 10.5(± 2.3)% at an IUdR doseof 500 mg/mVday but decreased to 0.76(± 0.3)% at 125mg/m²/day. Similarly, lUdR plasma concentrations decreased from436 (± 114) ng/ml to 99(±29)ng/ml. CONCLUSIONS:: The addition of IUdR to 5-FU and HU results in significant systemictoxicity necessitating limitation of the IUdR dose to 125 mg/m²/day. There is a significant biochemical interaction betweenIUdR, 5-FU and HU leading to increased IUdR incorporation intoDNA and to substantial clinical toxicity. Further clinical studiesto exploit this interaction at more feasible schedules may beuseful. malignant gliomas, concomitant chemoradiotherapy, IUdR, fluorouracil, hydroxyurea