Bevacizumab in temozolomide refractory high-grade gliomas: single-centre experience and review of the literature

Abstract

Background:Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV’s efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience.Methods:We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany.Results:Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients.Conclusions:The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV.

Reduction of intratumoral brain perfusion by noninvasive transcranial electrical stimulation

“…From a molecular point of view, vascular endothelial growth factor A (VEGF-A) seems to be the principal mediator of the pathological neoangiogenesis in GBM, correlating also with clinical outcomes ( 23 ). Considering the importance of inhibiting this specific GBM feature, antibodies targeting the VEGF pathway [i.e., bevacizumab (BEV)] were developed and tested.…”

“…Considering the importance of inhibiting this specific GBM feature, antibodies targeting the VEGF pathway [i.e., bevacizumab (BEV)] were developed and tested. However, controlled phase 3 trials failed to show a significant effect of BEV on OS in primary GBM ( 23 ). Other new therapies for GBM include the Optune device (NovoTTF-100A system; Novocure Ltd., Haifa, Israel), recently cleared by the Food and Drug Administration for the treatment of newly diagnosed and recurrent GBM.…”

Arterial Spin Labeling (ASL) in Neuroradiological Diagnostics – Methodological Overview and Use Cases

“…Regarding monitoring of treatment response, the main purpose of perfusion imaging in glioma is to differentiate true tumor relapse or progression from treatment-induced alterations. Specifically, in HGG, pseudoprogression can typically appear as early changes within a few months after treatment (particularly after radiotherapy and/or temozolomide), while pseudoresponse can take effect after the administration of anti-angiogenic agents (such as bevacizumab) [99][100][101][102]. In this context, it has been demonstrated that ASL-based perfusion imaging can distinguish predominant recurrent HGG from radiation necrosis with a sensitivity of more than 80 %, which was comparable to findings from DSC-MRI and fluorodeoxyglucose PET (FDG-PET) [103].…”

Bevacizumab is associated with cerebral microstructural alterations: a DTI study in high-grade glioma

“…To date, there is no widely accepted standard care for patients with recurrent GBM, and treatment options in this condition are re-resection, re-irradiation, and re-exposure to alkylating agents ( 2 ). Another frequently used agent in recurrent high-grade glioma, especially GBM, is bevacizumab, a humanized monoclonal anti-vascular endothelial growth factor (VEGF) antibody ( 4 ). VEGF expression is highly increased in high-grade glioma, leading to increased microvascular proliferation and thus facilitating tumor growth and invasion ( 5 ).…”

“…Nevertheless, there is a widely accepted benefit of PFS ( 6 – 8 ). Several studies demonstrated that a subgroup may show long-term responses to bevacizumab of more than 1 year ( 9 – 11 ) with a corticosteroid-sparing effect ( 4 ).…”