New chemotherapy options for the treatment of malignant gliomas

This review focuses on the recent advances in chemotherapy of malignant gliomas, with special emphasis on the most common primary brain tumor in adults, glioblastoma. The demonstration of the superiority of concomitant and adjuvant temozolomide with standard radiotherapy over radiotherapy alone in patients with newly diagnosed glioblastomas by means of phase III international trial has been the major advance in the care of these patients so far. Moreover, patients whose tumors display the hypermethylation of the promoter of the gene for the repairing enzyme O-methylguanine-DMA methyltransferase are most likely to benefit from the combination regimen. The advantage of a postsurgical local administration of carmustine by slow-release polymers ('gliadel wafers') is more modest, and the efficacy and safety of a sequence of carmustine wafers followed by temozolomide combined with radiotherapy remain to be defined. Different DNA repair modulation strategies are being investigated to further improve the results: dose-dense regimens of temozolomide, combination of temozolomide with specific inhibitors of O-methylguanine-DMA methyltransferase and combination of temozolomide with specific inhibitors of base excision repair [poly(ADP-ribose) polymerase inhibitors]. Other developments include the combination of cytotoxic, cytostatic and targeted therapies. Multitargeted compounds that simultaneously affect multiple signaling pathways, such as those involving epidermal growth factor receptor, platelet-derived growth factor receptor and vascular endothelial growth factor receptor, are increasingly employed. In the future, innovative trial designs (factorial and adaptative designs), pretreatment molecular profiling of individual tumors and the adoption of biological end-points (changes in serum tumor markers, measures of target inhibition), in addition to the traditional clinical and radiographic end-points, will be needed to achieve further advances.