title: Final report of the phase I trial of continuous infusion etanidazole (SR 2508): a Radiation Therapy Oncology Group study.
abstract: Seventy-eight patients have been treated on a Phase I trial using continuous infusion etanidazole while undergoing brachytherapy for locally advanced tumors. There were two sequential schemata, the first treated 63 patients with doses ranging from 8-23 g/m2 over 48 hr and the second treated 15 patients with doses ranging from 20-23 g/m2 over 96 hr. The tumor sites were: brain (n = 42), cervix (n = 22), and breast (n = 14). Patients received a loading dose of etanidazole of 2 g/m2 followed by a continuous infusion for a total of 48 or 96 hr while radioactive implants were in place. Of the 63 patients in the 48-hr study, 52 were entered at doses of less than or equal to 21 g/m2 and there were no definite neuropathies but two patients with the cramping/arthralgia syndrome. Of the 11 patients entered at 22-23 g/m2, 1 patient had symptoms of peripheral neuropathy (Grade II) and 6 had the cramping/arthralgia syndrome. This is a new syndrome, distinct from the peripheral neuropathy, characterized by transient alterations in sensations consisting of cramping, arthralgias, or tingling that resolved completely at intervals varying from a few hours to about 1 week post-treatment. The cramping/arthralgia syndrome limited dose escalation; therefore, the maximum tolerated dose over 48 hr was determined to be 20-21 g/m2. The 96-hr infusion was limited to patients with recurrent gliomas undergoing stereotactic implantation. To date, 15 patients have been treated with doses of 20-23 g/m2. No toxicity was encountered at doses less than or equal to 22 g/m2. At 23 g/m2, one patient developed Grade III neuropathy and three patients had mild cramping/arthralgia syndrome, for whom the drug was discontinued. Therefore, it appears the maximum tolerated dose at 96 hr will be approximately 23 g/m2, which is 10-15% higher than for the 48-hr infusion.
authors.affiliation: Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA 02115.
authors.forename: C N
authors.initials: CN
authors.lastname: Coleman
authors.forename: L
authors.initials: L
authors.lastname: Noll
authors.forename: N
authors.initials: N
authors.lastname: Riese
authors.forename: L
authors.initials: L
authors.lastname: Buswell
authors.forename: A E
authors.initials: AE
authors.lastname: Howes
authors.forename: J S
authors.initials: JS
authors.lastname: Loeffler
authors.forename: E
authors.initials: E
authors.lastname: Alexander
authors.forename: P
authors.initials: P
authors.lastname: Wen
authors.forename: J R
authors.initials: JR
authors.lastname: Harris
authors.forename: R A
authors.initials: RA
authors.lastname: Kramer
mesh_terms: D001918:Brachytherapy; D003131:Combined Modality Therapy; D004341:Drug Evaluation; D017341:Etanidazole; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole