The role of cytotoxic drugs in the treatment of central nervous system gliomas.

Gliomas are the mostfrequent subtype of primary brain tumors. They are lethal tumors, characterized by diffuse infiltration of the brain and a high resistance to conventional cancer therapies. Following maximal neurosurgical resection, bound to the limits of acceptable neurological sequelae, immediate post-operative radiotherapy is indicated in the majority of patients. Chemotherapy with the alkylating agent temozolomide, administered daily concomitantly to radiotherapy, and followed by six adjuvant monthly cycles, significantly improves the survival of newly diagnosed glioblastoma patients and has become the standard of care. Temozolomide is also the most often used chemotherapeutic treatment for recurrent low-grade and anaplastic gliomas after initial surgery and irradiation. The potential role of postoperative temozolomide in the first line treatment for low-grade and anaplastic glioma is currently under investigation in phase III trials. After failure of temozolomide, there is only limited activity of any other cytotoxic agent and the benefit of such second line therapy seems to be limited to a small subgroup of patients with the most chemosensitive gliomas. Abnormal hypermethylation of the promoter of the MGMT gene has been correlated with the response of glioma to alkylating chemotherapy. The loss of chromosomal arms 1p and 19q are genetic markers characteristic for gliomas with oligodendroglial differentiation which are also most sensitive to treatment. The predictive and prognostic value of these molecular markers is currently being determined prospectively in phase III studies. Anti-angiogenic agents and targeted receptor tyrosine kinase inhibitors are new pharmacological classes with activity against malignant gliomas. Phase III clinical studies evaluating combinations of these new agents with classical cytotoxic agents in first and in second line have recently been initiated.