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How did bevacizumab become the standard of care in adult brainstem glioma?

Brainstem gliomas are rare and heterogeneous tumor entities that mostly affect the brainstem. It accounts for only 2% of all adult brain tumors. Adult brainstem gliomas have a diverse clinical course based on clinicopathological and radiological features, and they are a poorly described cohort with a variable prognosis [1].


Current treatment options for brainstem glioma


Brainstem glioma treatment options are restricted, primarily consisting of radiotherapy with an uncertain role for chemotherapy and no standard of care for patients with recurring brainstem tumors. The available standard treatment options for brainstem glioma are:

  • Radiotherapy

  • Chemotherapy

  • Biological treatment

  • Surgery

How did bevacizumab become the standard of care in adult brainstem glioma?

Radiotherapy is regarded as the cornerstone of adult brainstem gliomas, but only a small percentage of patients presented with clinical and radiographic improvement after radiotherapy. The role of chemotherapeutic and biological therapies has received little attention. However, because gliomas are located in the brainstem, surgical resection is not usually considered a safe treatment choice. Thus, a biopsy is the only means of pathological investigation. However, because brainstem glioma is uncommon in adults, there are very few studies reported and as a result, standard therapeutic approaches remain controversial [1].


Why is bevacizumab in the limelight?


Novel therapies are required to prevent clinical symptoms from worsening and to extend survival in brainstem glioma adult patients. Bevacizumab, an antiangiogenic therapy, has recently been identified as an effective salvage therapy for progressing brainstem gliomas. Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody that has been extensively explored in recurrent glioblastoma [1,2].


Bevacizumab may have a palliative effect in addition to its anti-neoplastic activity. Bevacizumab exerts its antiangiogenic activity and results in symptom alleviation as it:

  • Reduces vasogenic cerebral edema

  • Acts as a vasoconstrictor

  • Reduces vascular permeability

  • Typically allows patients to taper their steroid dose, which can have downstream benefits.

Furthermore, bevacizumab treatment has been reported to have shown an improvement in clinical conditions, as well as adequate radiological responses and progression-free survival of up to 2 years [1,2].


Why antiangiogenic therapy?


Angiogenesis is widely known to play a role in tumor growth and metastasis. Angiogenesis is important in the growth, invasion, and metastasis of gliomas. Antiangiogenic agents are thus a viable treatment option for glioma patients. Antiangiogenic drugs decrease angiogenesis by targeting vascular endothelial growth factor (VEGF) and/or its tyrosine kinase receptor (VEGFR family) and can cross the blood-brain barrier. The interaction of VEGF and its tyrosine kinase receptor (VEGFR family) drives angiogenesis processes [1,2].


Anti-angiogenic drugs are approved for use in a variety of solid tumors. Drugs targeting circulating VEGF and tyrosine kinase inhibitors directing angiogenic receptors have been developed. The mechanism by which these drugs exert an anti-tumor impact remains controversial. One proposed hypothesis is that of vascular normalization, as opposed to the initial notion of inhibiting new blood vessel creation and starving the tumor of vital nutrition and oxygen. Tumor-associated blood vessels are poorly formed, big in size, and leaky due to insufficient pericyte covering. Normalization results in the stabilization of these blood vessels and enhanced more uniform perfusion, allowing for significant improvements in cerebral edema and better drug delivery. Angiogenesis inhibition likely disturbs the fragile cancer-stem-cell vascular niche, thereby rendering these cells more sensitive to environmental perturbations. Tumors are likely to be affected by a combination of these potential pathways [3].


On this ground, antiangiogenic therapy paired with chemotherapy may give significant benefits as antiangiogenic therapy can normalize the form and function of tumor vasculature, resulting in improved drug delivery and a normalized tumor microenvironment. As a result, combined management with radiotherapy, chemotherapy, and antiangiogenic therapy for patients with brainstem gliomas will add tremendous therapeutic value [1].


A positive future outlook


Despite the presence of unfavorable prognostic variables such as worsening performance status, age, tumor location, histology, and the limited efficacy of radiotherapy or chemotherapy, treating brainstem glioma patients with a multimodal approach may result in a considerable benefit. Experiences with combining various regimens may help clinicians expand a better knowledge of this rare condition and also find more effective treatments for these patients.


References


1. Yu, D. et al. 'Treatment of adult brainstem glioma with combined antiangiogenic therapy: a case report and literature review'. Onco Targets Ther. (2019) 12, 1333–1339. DOI: 10.2147/OTT.S195783.

2. Moriya, S. et al. 'A retrospective study of bevacizumab for treatment of brainstem glioma with malignant features'. J Clin Neurosci. (2018) 47, 228–233. DOI: 10.1016/j.jocn.2017.10.002.

3. Taylor, J. et al. 'Anti-angiogenic Therapy in High-Grade Glioma (Treatment and Toxicity)'. Curr Treat Options Neurol. (2013) 15(3), 328–337. DOI: 10.1007/s11940-013-0224-y.

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