Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study.
OBJECTIVE
To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma.


METHODS
Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used.


RESULTS
Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM).


CONCLUSIONS
In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.
Schulz
Craig A
CA
Department of Human Oncology, University of Wisconsin Medical School, 600 Highland Avenue, Madison, WI 53792, USA.
Mehta
Minesh P
MP
Badie
Benham
B
McGinn
Cornelius J
CJ
Robins
H Ian
HI
Hayes
Lori
L
Chappell
Rick
R
Volkman
Jen
J
Binger
Kim
K
Arzoomanian
Rhoda
R
Simon
Kris
K
Alberti
Dona
D
Feierabend
Christine
C
Tutsch
Kendra D
KD
Kunugi
Keith A
KA
Wilding
George
G
Kinsella
Timothy J
TJ
D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000378:metabolism / Q000532:radiotherapy*; D001932:Brain Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D007065:Idoxuridine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D017567:Karnofsky Performance Status; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D011838:Radiation-Sensitizing Agents; D007065:Idoxuridine