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

• Published in: Annals of oncology 1993-08, Vol.4 (7), p.591-595
• Main Authors: Vokes, E. E., Dolan, M. E., Krishnasamy, S., Mick, R., Ratain, M. J., Berezin, F., Brachman, D., Whitman, G., Schilsky, R. L., Charette, J., Weichselbaum, R. R., Dohrmann, G. J., Hekmatpanah, J.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Astrocytoma - drug therapy; Astrocytoma - metabolism; Astrocytoma - radiotherapy; Biological and medical sciences; Chemotherapy, Adjuvant; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); concomitant chemoradiotherapy; Drug Administration Schedule; Female; fluorouracil; Fluorouracil - administration & dosage; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - radiotherapy; Humans; hydroxyurea; Hydroxyurea - administration & dosage; Idoxuridine - administration & dosage; Idoxuridine - metabolism; IUdR; Male; malignant gliomas; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Remission Induction
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/oxfordjournals.annonc.a058594

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.