Anti-Angiogenic Therapies in the Management of Glioblastoma

Jessica D. Schulte; Manish K. Aghi; Jennie W. Taylor


Chin Clin Oncol. 2021;10(4):37 

In This Article

Evolving use of Anti-angiogenic Therapy

Though anti-angiogenic therapies to date have failed to extend survival in new or recurrent GBM, their contribution to PFS suggests some degree of benefit, possibly through alleviation of peritumoral edema.[116] Corticosteroids are first line therapy for peritumoral edema, but have a broad and high-frequency side effect profile particularly in the setting of prolonged use, including myopathy, hyperglycemia, weight gain, hypertension, osteoporosis, insomnia, anxiety, and rarely avascular necrosis among other toxicities.[117] Bevacizumab carries a distinct range of side effects, including hypertension and poor wound healing, but also rare risks of thromboembolism, hemorrhage, gastrointestinal perforation and nephrotic syndrome.[118] Several clinical trials suggested that bevacizumab can reduce reliance on corticosteroids in GBM patients. These observations emerged from the AVF3708g trial, EORTC26101 trial, and other observational studies.[38,39,119] Likewise, use of cediranib and cabozantinib (which inhibits VEGF2, MET, AXL tyrosine kinase, and ret protooncogene RET) also correlated with reduced corticosteroid use over time.[60,94] In regards to quality-of-life and symptom control, there is conflicting evidence as to whether bevacizumab is beneficial. The AVAglio trial in newly diagnosed GBM noted delayed deterioration of quality-of-life metrics (including global health status, cognitive, emotional, and social functioning, and ability to communicate) with bevacizumab compared to control, and stable Mini Mental Status Examination.[43] However, the RTOG0825 study reported decreased quality-of-life measures (symptom control and neurocognitive function) with bevacizumab compared to placebo.[42]

Bevacizumab is also used to treat the clinical and radiographic changes associated with radiation necrosis in the brain. Radiation may underlie short- and long-term changes to the vasculature including increased vascular permeability, vasculopathy, ischemia, necrosis, and resultant edema.[120] These pathological changes underlie MRI findings including increased contrast enhancement and edema that are often difficult to distinguish from tumor progression. Radiation necrosis can be symptomatic with focal deficits including weakness and aphasia, headaches, and seizures. Recent studies demonstrated bevacizumab to be a powerful tool for managing radiation-associated edema.[121,122] There is an ongoing phase II clinical trial comparing corticosteroids plus bevacizumab versus placebo for the treatment of radiation necrosis in brain metastasis (NCT02490878).

In addition to symptomatic treatment, there is still hope that anti-VEGF agents may be helpful in combination with other therapies, including cytotoxic chemotherapy, TKIs, and immunotherapy, in improving survival in GBM. Many of these combinatorial strategies rely on the recent mechanistic understanding that anti-VEGF therapies may act to normalize the blood vasculature, improving spatial and temporal delivery of therapeutic agents across the tumor.[34,123] Improved efficacy of combinatory treatment may require specific timing of anti-VEGF agents with cytotoxic/cytostatic agents. For example, a phase II trial looking at cediranib demonstrated vascular normalization occurs day 1 to 28 after drug dosage.[94] Experiments looking at the time frame for vascular normalization after bevacizumab have yet to be been done in GBM, but mouse models suggest it starts as early as 1 day after infusion and clinical trials in rectal carcinoma suggest half of the tumor vasculature is normalized by day 12.[124] The dosing of bevacizumab may influence response as well, with some studies suggesting that a reduced dose may be more efficacious.[125,126]

The interaction of VEGF signaling and the immune system is of particular interest given the impact of immunotherapies in several cancers. VEGF signaling inhibits differentiation of circulating hemopoietic progenitor cells, dendritic cells, and T cells through nuclear factor kappa B (NFκB) signalling.[127,128] Aflibercept also increases the mature dendritic cell population in solid tumors.[129] In a study of colorectal cancer, bevacizumab increased CD4+ and CD8+ T cells, as well as CD20+ B cells in peripheral blood.[130] However, these studies suggesting that VEGF inhibition may alleviate VEGF-mediated immunosuppression was countered by a study in which VEGF inhibition was tied to impaired lymphocyte recruitment.[131] A better understanding of the role of VEGF in regulating the brain immune niche and GBM tumor microenvironment is clearly needed.