Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

• Published in: BMC cancer 2009-03, Vol.9 (1), p.101-101, Article 101
• Main Authors: Fabi, Alessandra, Metro, Giulio, Russillo, Michelangelo, Vidiri, Antonello, Carapella, Carmine Maria, Maschio, Marta, Cognetti, Francesco, Jandolo, Bruno, Mirri, Maria Alessandra, Sperduti, Isabella, Telera, Stefano, Carosi, Mariantonia, Pace, Andrea
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alkylating agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; DNA damage; DNA Methylation; Dosage and administration; Dose-Response Relationship, Drug; Drug therapy; Follow-Up Studies; Genetic aspects; Glioma - drug therapy; Glioma - genetics; Glioma - pathology; Gliomas; Humans; Karnofsky Performance Status; Middle Aged; Multivariate Analysis; Nausea - chemically induced; Neoplasm Recurrence, Local; Neutropenia - chemically induced; Nitrosourea Compounds - administration & dosage; Nitrosourea Compounds - adverse effects; Nitrosourea Compounds - therapeutic use; O-Methylguanine-DNA Methyltransferase - genetics; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - adverse effects; Organophosphorus Compounds - therapeutic use; Patient outcomes; Physiological aspects; Promoter Regions, Genetic - genetics; Promoters (Genetics); Retrospective Studies; Survival Analysis; Thrombocytopenia - chemically induced; Treatment Outcome; Vomiting - chemically induced
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-9-101

In recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m(2) weekly for 3 consecutive weeks followed by triweekly administration after a 5-week rest period). Also, the impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status on fotemustine activity has never been explored in the clinical setting. 40 patients with recurrent pretreated MG were identified as being treated with fotemustine at doses ranging from 65 mg/m(2) to 100 mg/m(2). Patients were classified into 3 groups according to the dose of fotemustine received, from the lowest dosage received in group A, to the highest in group C. Analysis of MGMT promoter methylation in tumor tissue was successfully performed in 19 patients. Overall, 20% of patients responded to treatment, for a disease control rate (DCR, responses plus stabilizations) of 47.5%. Groups A and B experienced a response rate of 40% and 26.5% respectively, while the corresponding value for group C was 10%. Out of 19 patients, MGMT promoter was found methylated in 12 cases among which a DCR of 66.5% was observed. All 7 patients with unmethylated MGMT promoter were progressive to fotemustine. Low-dose fotemustine at 65-75 mg/m(2) (induction phase) followed by 75-85 mg/m(2) (maintenance phase) has an activity comparable to that of the conventional schedule. By determination of the MGMT promoter methylation status patients might be identified who are more likely to benefit from fotemustine chemotherapy.