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

Abstract

BackgroundIn recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m2 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.Methods40 patients with recurrent pretreated MG were identified as being treated with fotemustine at doses ranging from 65 mg/m2 to 100 mg/m2. 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.ResultsOverall, 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.ConclusionLow-dose fotemustine at 65–75 mg/m2 (induction phase) followed by 75–85 mg/m2 (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.

An algorithm for chemotherapy treatment of recurrent glioma patients after temozolomide failure in the general oncology setting

“…Fotemustine, a third generation chloroethylnitrosourea given to recurrent glioma patients after TMZ failure showed very promising results and limited toxicity in three recent studies from Italy [49][50][51]. In addition, like other alkylating agents, fotemustine appears more effective in patients with O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation [49].…”

Fotemustine and recurrent glioblastoma: possible new opportunities for an old drug

“…These data are interesting if we consider that the majority of the patients had a poor performance status with a compromised hematological status ( Table 1). The results showed that the toxicity incidence rate of fotemustine has a peak in correspondence of the induction completion and, it increases with the number of completed cycles [6]. In the trial by Brandes et al patients with progressive GBM after radiotherapy plus concomitant and/or adjuvant temozolomide received 3-weekly doses (100-75 mg m 2 ) of fotemustine followed, after a 5-week rest, by fotemustine (100 mg m 2 ) every 3 weeks.…”

“…The clinical trial by Fabi et al did not suggest any correlation between MMGT methylation status and response [6]. However, this study enrolled also anaplastic tumors and the analysis of MMGT promoter was performed in less that 50% of cases.…”

“…For secondary GBM, inhibition of hypoxia-inducible factor (HIF)-1a, may be particularly relevant since many of these tumors harbor isocitrate dehydrogenase-1 mutations [17,18] which prevent the formation of isocitrate to a-ketoglutarate which is an essential co-factor for prolyl hydroxylase (PHD) activity, which in turn is essential for HIF-1a degradation [19]. Moreover, trials including these combinations should also take in account drug interactions with corticosteroids and/ Scoccianti et al [9] FTM 27 29.6 48 Fabi et al [6] FTM 40 20 47.5…”

“…On the other hand, on the side of cytotoxic drugs recent phase-II trials have demonstrated activity of nitrosoureas such as fotemustine in recurrent GBM [6][7][8][9]. Fotemustine is a third generation chloroethylnitrosourea containing a phosphoalanine carrier group grafted to the nitrosourea radical.…”