title: Fotemustine combined with procarbazine in recurrent malignant gliomas: a phase I study with evaluation of lymphocyte 06-alkylguanine-DNA alkyltransferase activity.
abstract: The aims of this phase I study in patients with recurrent malignant gliomas were to determine the maximum tolerated dose (MTD) and toxicity profile of fotemustine when combined with a fixed dose of procarbazine (PCZ), and to evaluate the extent of O6-alkylguanine-DNA alkyltransferase (ATase) depletion in circulating lymphocytes during treatment. Sixteen patients received an induction cycle consisting of 100 mg/day oral PCZ for 12 consecutive days and a 1-h intravenous infusion of fotemustine given 4 h after PCZ on days 5 and 12 at escalated doses (50, 75, 100 and 125 mg/m2/day). After a 6-week rest period, a maximum of 4 maintenance cycles (PCZ 300 mg/day, 4 days; fotemustine, day 4) was given every 4 weeks. ATase activity was measured on days 1, 5 and 12 over 4 h after PCZ intake. Fifteen patients had previously received at least one nitrosourea-based chemotherapy, associated with PCZ in 12 cases. The MTD of fotemustine was 125 mg/m2 (days 5 and 12) with myelosuppression as the dose limiting toxicity (DLT). At this dose level, half of patients experienced grade 3 anemia, neutropenia or thrombopenia. No extra-hematological DLT was observed. No significant depletion of ATase activity by PCZ was evidenced. One partial response and 7 stable diseases were obtained leading to a disease control rate of 50%. The median times to progression and survival were 2.6 and 9.7 months, respectively. This combined regimen of PCZ and fotemustine was well tolerated with a good disease control rate in heavily pretreated glioma patients and merits further investigation in phase II studies.
authors.affiliation: Istituto Carlo Besta, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Boiardi
authors.forename: A
authors.initials: A
authors.lastname: Silvani
authors.forename: E
authors.initials: E
authors.lastname: Ciusani
authors.forename: A
authors.initials: A
authors.lastname: Watson
authors.forename: G
authors.initials: G
authors.lastname: Margison
authors.forename: E
authors.initials: E
authors.lastname: Berger
authors.forename: C
authors.initials: C
authors.lastname: Lucas
authors.forename: B
authors.initials: B
authors.lastname: Giroux
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009607:Nitrosourea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011344:Procarbazine / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D011344:Procarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C054368:fotemustine