Recent advances in the medical therapy of high-grade gliomas

Abstract

Malignant glial neoplasms, including glioblastoma, are amongst the most devastating and intractable of solid tumors. Until recently the standard of care for newly diagnosed glioblastoma was surgical resection to the extent feasible followed by conventional fractionated radiotherapy. When administered for disease progression, chemotherapy had modest benefit and its use in the adjuvant setting was controversial. Temozolomide, an oral alkylating chemotherapeutic agent, has now been demonstrated to increase survival time in patients with newly diagnosed glioblastoma when used concurrently with radiotherapy and as adjuvant or maintenance treatment for six cycles thereafter. Correlative molecular studies suggested that the benefit of temozolomide is largely restricted to patients whose tumor has silenced the gene for methylguanine methyltransferase, a repair enzyme implicated in resistance to alkylator chemotherapy. Use of temozolomide chemotherapy upfront in the management of glioblastoma is now considered the standard of care. This significant advance has also stimulated development of therapeutic strategies that incorporate temozolomide, and other agents, in the initial management of most high-grade gliomas. Furthermore, our increased understanding of the molecular derangements that underlie gliomagenesis has identified a number of putative molecular targets against which novel therapeutics have been tested with encouraging preliminary results. Finally, the challenges presented by the blood–brain barrier to adequate drug delivery have stimulated the development of unique locoregional delivery techniques that are currently undergoing clinical evaluation. This review summarizes these recent advances, and speculates on how the field is likely to evolve in the near future.