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Chemoradiotherapy in Malignant Glioma: Standard of Care and Future Directions

Roger Stupp, Monika E. Hegi, Mark R. Gilbert, Arnab Chakravarti

From the Multidisciplinary Oncology Center; Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne; National Center of Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research, Epalinges, Switzerland; Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Laboratory of Molecular and Cellular Radiation Neuro-Oncology, Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, MA

Address reprint requests to: Roger Stupp, MD, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 46, Lausanne, Switzerland CH-1011; e-mail: roger.stupp{at}chuv.ch

Glioma has been considered resistant to chemotherapy and radiation. Recently, concomitant and adjuvant chemoradiotherapy with temozolomide has become the standard treatment for newly diagnosed glioblastoma. Conversely (neo-)adjuvant PCV (procarbazine, lomustine, vincristine) failed to improve survival in the more chemoresponsive tumor entities of anaplastic oligoastrocytoma and oligodendroglioma. Preclinical investigations suggest synergism or additivity of radiotherapy and temozolomide in glioma cell lines. Although the relative contribution of the concomitant and the adjuvant chemotherapy, respectively, cannot be assessed, the early introduction of chemotherapy and the simultaneous administration with radiotherapy appear to be key for the improvement of outcome. Epigenetic inactivation of the DNA repair enzyme methylguanine methyltransferase (MGMT) seems to be the strongest predictive marker for outcome in patients treated with alkylating agent chemotherapy. Patients whose tumors do not have MGMT promoter methylation are less likely to benefit from the addition of temozolomide chemotherapy and require alternative treatment strategies. The predictive value of MGMT gene promoter methylation is being validated in ongoing trials aiming at overcoming this resistance by a dose-dense continuous temozolomide administration or in combination with MGMT inhibitors. Understanding of molecular mechanisms allows for rational targeting of specific pathways of repair, signaling, and angiogenesis. The addition of tyrosine kinase inhibitors vatalanib (PTK787) and vandetinib (ZD6474), the integrin inhibitor cilengitide, the monoclonal antibodies bevacizumab and cetuximab, the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and the protein kinase C inhibitor enzastaurin, among other agents, are in clinical investigation, building on the established chemoradiotherapy regimen for newly diagnosed glioblastoma.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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