Fotemustine: a third-generation nitrosourea for the treatment of recurrent malignant gliomas

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas.