Chemoradiotherapy in Malignant Glioma: Standard of Care and Future Directions

Abstract

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.

Uncertainty, mood states, and symptom distress in patients with primary brain tumors

“…1 Once diagnosed, the overall prognosis for patients remains poor, and their clinical course is complicated and unpredictable because of significant morbidity from both tumor-related neurologic and cognitive symptoms as well as treatment-related toxicity. 2 Uncertainty, defined as an individual's lack of ability to determine the meaning of illness-related events, 3 may pervade the whole illness trajectory of PBTs. One of our studies demonstrated that patients' uncertainty during active treatment was as high as in the newly diagnosed period.…”

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

“…Although surgery followed by chemotherapy is the normal treatment regimen for gliomas, most malignant gliomas are resistant to chemotherapeutic agents. Because the blood-brain barrier (BBB) restricts and regulates the delivery of chemotherapy agents, the prognosis for glioma is poor (Stupp et al, 2007;Villano et al, 2009). Therefore, it is necessary to develop highly permeable agents that cross the BBB for the chemotherapeutic treatment of patients with malignant glioma.…”

The Role of Myosin II in Glioma Invasion of the Brain

“…Malignant gliomas are a group of primary brain tumors that have remained resistant to therapy and that have a dismal prognosis (Buckner et al, 2007;Stupp et al, 2007). Part of the reason for this state of affairs is that although gliomas rarely metastasize outside the CNS, they are capable of spreading long distances within the brain (Sherer, 1940;Burger and Kleihues, 1989;Hoelzinger et al, 2007).…”