High-dose fotemustine in temozolomide-pretreated glioblastoma multiforme patients

Abstract

Background:Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively investigated in the setting of recurrent/progressive disease after initial treatment. Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks.Methods:In this phase I/II trial, we aimed to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100 mg/m2 dose approved per label indication in a population of patients with recurrent GBM. In this phase I/II trial, fotemustine was administered intravenously over 1 hour every 2 weeks at either 120 or 140 mg/m2 doses for up to 1 year, until disease progression, unacceptable toxicity, or patient's request to withdraw from the study. The phase I part of the trial was conducted following the classic 3+3 study design. The phase II part of the trial was a single-arm study. The primary efficacy endpoint was the percentage of patients who had not progressed after 24 weeks (PFS-24).Results:Thirty-seven patients were enrolled in this phase I/II trial from August 2006 to November 2011. Treatment was well tolerated in the overall population. Main severe toxicity was grades 3 and 4 thrombocytopenia, which occurred in 4 of 6 patients treated at the 140 mg/m2 dose level and in 3 of 31 patients treated at 120 mg/m2. Median PFS and overall survival were 12.1 (1–40.2) weeks and 19.7 (1–102) weeks, respectively.Conclusion:We conclude that fotemustine can be safely administered at 120 mg/m2 biweekly. The efficacy of such modified schedule and doses should be compared to the biweekly schedule at 80 mg2 and the standard weekly schedule at 80 to 100 mg/m2.

Biweekly fotemustine schedule for recurrent glioblastoma in the elderly: activity and toxicity assessment of a multicenter study

“…Several studies have demonstrated the efficacy of FTM against newly diagnosed or recurrent high-grade gliomas [32][33][34][35]. Previous trials investigating FTM reported an OS of 9-20 months, PFS of 4-9.1 months, PFS-6 of 27-48.5% and DCR of 47.5-62% [18][19][20][21][22][23][24][25].…”

“…According to the results of several studies, FTM represents a treatment option for recurrent GBM [18][19][20][21][22][23][24][25]. Despite its efficacy, the original FTM administration schedule, as first proposed by Khayat, is cumbersome and limited by the associated hematological toxicity.…”

Recurrent Glioblastoma Treatment: State of the Art and Future Perspectives in the Precision Medicine Era

“…Unfortunately, due to the lack of power of these studies, with the majority being single-armed or retrospective in nature, providing only Class III evidence, none of the examined publications showed robust evidence favoring alternative dosing of TMZ compared with conventional TMZ alone or in combination with other cytotoxic agents. Promising results have been reported favoring the administration of fotemustine in patients with progressive disease, showing positive outcomes and safety profiles, especially in the elderly population with MGMT-positive rGBM relapsed after TMZ schedules [ 155 , 156 , 157 , 158 , 159 ]. Commonly evaluated administration protocols included 120 mg/m 2 every two weeks for up to 1 year and 70–100 mg/m 2 weekly for 3 weeks and then every 3 weeks as maintenance therapy, with the most frequent adverse events represented by grade-3 and -4 thrombocytopenia and grade-3 and -4 neutropenia.…”

Localized Drug Delivery Systems in High‐Grade Glioma Therapy—From Construction to Application

“…[102] Certainly also due to these results, subsequent studies rather focused on systemic fotemustine-continuative studies using bucladesine-loaded pellets have not been performed yet. [103,104]…”