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.