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Receptor tyrosine kinase signaling causes profound neo-angiogenesis in high-grade gliomas (HGG). The KIT, PDGFR-α, and VEGFR2 genes are frequently amplified and expressed in HGG and are molecular targets for therapeutic inhibition by the small-molecule kinase inhibitor sunitinib malate. Twenty-one patients with progressive HGG after prior radiotherapy and chemotherapy received a daily dose of 37.5 mg sunitinib until progression or unacceptable toxicity. Magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC)-enhanced perfusion measurements were performed before and during therapy. Cerebral blood volume (CBV) and cerebral blood flow (CBF) lesion-to-normal-white matter ratios were measured to evaluate the antiangiogenic effects of sunitinib. The most frequent grade ≥3 adverse events were skin toxicity, neutropenia, thrombocytopenia, and lymphocytopenia. None of the patients achieved an objective response, whereas a decrease in CBV and CBF within the lesion compared with the normal brain was documented in four out of 14 (29%) patients evaluable for DSC-enhanced perfusion measurements. All patients experienced progression of their disease before or after eight weeks of therapy. Median time-to-progression and overall survival were 1.6 (95%CI 0.8-2.5) and 3.8 (95% CI 2.2-5.3) months, respectively. No correlation could be established between VEGFR2, PDGFR-α, and KIT gene copy numbers or protein expression and the effects of sunitinib. Single-agent sunitinib at 37.5 mg/day had insufficient activity to warrant further investigation of this monotherapy regimen in recurrent HGG.

Low-grade gliomas (LGG) are a group of uncommon neuroglial tumors of the central nervous system. They are characterized by a grade I or II according to the WHO classification. Grade I tumors are non-invasive and amenable to surgical resection with curative intent. Diffuse infiltrating LGG (WHO grade II) are tumors with a highly variable prognosis. Curative resection can only rarely be achieved and progression is characterized by transformation into a high-grade glioma (WHO grade III-IV). There are only limited evidence-based treatment recommendations for the management of progressive LGG because of a lack of data from prospective randomized trials. Most often radiotherapy is offered to patients with symptomatic and/or progressive disease. Three randomized trials have failed to demonstrate a survival improvement with either early versus delayed radiation or with a higher dose of radiation. The potential role of chemotherapy for the treatment of LGG has only been addressed in phase II trials. The PCV-chemotherapy regimen is associated with considerable toxicity that limits its applicability. The results with temozolomide (TMZ) chemotherapy have been more promising. Patients with chemosensitive LGG as predicted by heterozygotic loss of chromosomal arms Ip and 19q or methylation of the promoter of the MGMT-gene in the genome of the glioma cells respond to TMZ. Radiotherapy will be compared to chemotherapy asfirst line treatment for LGG in two phase III studies that are planned for by the brain tumor group of the European Organization for Research and Treatment of Cancer (BTG-EORTC) and Radiation Therapy Oncology Group (RTOG).

Gliomas are the most frequent primary brain tumors. They are derived from glial cells of astrocytic, oligodendroglial and ependymal origin. According to the WHO classification of brain tumors gliomas are divided in low-grade (grades I and II) and high-grade (grades III and IV) tumors. Low-grade tumors are well-differentiated, slow-growing lesions. Grade I tumors are well-circumscribed and often surgically curable, whereas grade II tumors are diffuse, infiltrating lesions with a marked potential over time for progression towards a high-grade malignant tumor. The optimal management of low-grade gliomas is still debated. Important prognostic factors such as histology, grade and location of the tumor, age and functional status of the patient, must be taken into consideration to select the most appropriate treatment. Major advances in the molecular genetic assessment of brain tumors and of gliomas in particular have lead to the identification of several molecular markers playing a crucial role in the development of gliomas and in their malignant transformation. Some of those markers were found very useful to assist in the histological diagnosis and to predict survival and response to therapy. A combined deletion of chromosomes arms 1p and 19q can be found in more than 50% of Grade II and III oligodendrogliomas and has been associated with chemosensitivity and a better prognosis. Once limited to the field of research, molecular biology has now entered the daily neuropathological practice and will undoubtedly play an increasing role in future classification and treatment of brain tumors.