What about bevacizumab (Avastin) as a repurposed medication for brain tumors?

Bevacizumab for Brain Tumors: A Repurposed Agent with Limited Survival Benefit

Bevacizumab does not improve overall survival in recurrent glioblastoma and should be used primarily for symptom control and quality of life improvement, not as a survival-extending therapy. 1

Primary Brain Tumors (Glioblastoma)

Evidence Against Survival Benefit

The most critical finding from recent guidelines is that bevacizumab provides no overall survival benefit in recurrent glioblastoma, despite its FDA approval in 2009. 1 This represents a major shift from earlier optimism about this agent. The Congress of Neurological Surgeons explicitly states that bevacizumab does not provide increased overall survival when used for progressive glioblastoma. 1 The European Association of Neuro-Oncology (EANO) concurs, noting that bevacizumab does not prolong progression-free survival nor overall survival in recurrent glioma. 2, 1

When Bevacizumab May Be Considered

Despite the lack of survival benefit, bevacizumab has specific palliative roles:

• Steroid-sparing effect: Use bevacizumab to reduce corticosteroid requirements and their associated side effects (weight gain, hyperglycemia, immunosuppression, myopathy). 1
• Symptomatic relief: Consider for tumor-associated edema and mass effect causing neurological symptoms. 1
• Quality of life: May improve quality of life in patients aged 55 years or older with recurrent disease, though this should not be confused with survival prolongation. 1

FDA-Approved Dosing

The FDA-approved dose is 10 mg/kg every 2 weeks administered as an intravenous infusion until disease progression or unacceptable toxicity. 1 This approval was based on two phase II studies showing MRI-defined objective response rates of 28-38%, with median survival around 9 months. 1

Critical Pitfall: Imaging Response ≠ Clinical Benefit

A major pitfall is interpreting MRI improvement as therapeutic success. Bevacizumab reduces vascular permeability, creating the appearance of response on MRI without true tumor control—this is a radiographic artifact, not genuine disease control. 1 Clinicians must not be misled by impressive imaging changes into believing the patient is experiencing meaningful disease modification.

Combination Therapy

There is insufficient or conflicting data regarding the benefit of bevacizumab in combination with other agents, including lomustine. 1 Research shows that patients who progress on a bevacizumab-containing regimen rarely respond to a second bevacizumab-containing regimen (6-month PFS of only 2% on second regimen versus 33% on first regimen). 3 Therefore, continuing bevacizumab after progression is futile.

Preferred Alternatives for Recurrent Glioblastoma

When managing recurrent glioblastoma, prioritize these evidence-based options over bevacizumab:

1. Repeat cytoreductive surgery: For symptomatic progressive disease with good performance status and possibility of gross total resection. 4, 1
2. Reirradiation: Provides improved local tumor control and maintains neurological status. 4, 1
3. Lomustine monotherapy: An approved chemotherapeutic option. 4, 1
4. Temozolomide rechallenge: Particularly in patients with MGMT promoter methylation. 4, 1

Serious Adverse Events

Bevacizumab carries significant toxicity risks that must be weighed against its limited palliative benefits:

• Hypertension
• Thromboembolic events
• Hemorrhage (including intracranial hemorrhage)
• Gastrointestinal perforation
• Wound healing complications
• Proteinuria

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Population-based data confirms these risks, with documented cases of cerebral hemorrhage, cardiac arrhythmia, intestinal perforation, and treatment-related death. 5

Brain Metastases from Lung Cancer

The evidence for bevacizumab in brain metastases is distinctly different and more favorable than for primary brain tumors.

Non-Small Cell Lung Cancer with Brain Metastases

In patients with stage IV non-squamous NSCLC and treated, stable brain metastases who are otherwise candidates for bevacizumab therapy, the addition of bevacizumab to first-line, platinum-based chemotherapy is a safe therapeutic option. 2

Safety Requirements

Patients must meet these criteria:

• Previously treated brain metastases with whole-brain radiation therapy, radiosurgery, and/or neurosurgery (with at least 3 months elapsed since neurosurgery). 2
• No evidence of progression or hemorrhage at baseline, confirmed by MRI or CT scan within 1 week of treatment. 2
• ECOG performance status of 0 or 1. 2

Safety Data

The PASSPORT study prospectively evaluated 115 patients with previously treated brain metastases receiving bevacizumab. There were no reported grade 1 to 5 CNS hemorrhages. 2 This finding was corroborated by multiple large retrospective analyses showing CNS hemorrhage rates of approximately 3.3% in bevacizumab-treated patients versus 1% in controls—not statistically different. 2

A comprehensive review of 57 trials including 10,598 patients found no episodes of intracranial hemorrhage in 121 patients with brain metastases treated with anti-VEGF therapy. 2

Anticoagulation Considerations

Full-dose anticoagulation was permitted in the PASSPORT study, with 17% of patients on anticoagulants for more than 1 week (enoxaparin, warfarin, or aspirin). 2 However, no recommendation can be given about the use of bevacizumab in patients receiving therapeutic anticoagulation or with an ECOG PS of 2 due to insufficient data. 2

Efficacy in NSCLC with Brain Metastases

For the primary lung cancer indication (not the brain metastases themselves), bevacizumab improves survival when combined with carboplatin and paclitaxel in clinically selected patients with non-squamous histology, lack of hemoptysis, and good performance status. 2 The presence of treated, stable brain metastases does not negate this survival benefit.

Brain Metastases from Breast Cancer

Limited data exist for bevacizumab in breast cancer patients with brain metastases. The EANO-ESMO guidelines note that more data are needed on the efficacy of bevacizumab in combination with various chemotherapies in leptomeningeal metastasis patients. 2 In HER2-positive tumors with leptomeningeal metastasis, anti-HER2 treatment in combination with chemotherapy should be prioritized over bevacizumab. 2

Pediatric Brain Tumors

Bevacizumab-related acute toxicity appears low in children, even in combination with irinotecan. 6 However, efficacy data are limited: tumor reduction was observed in 6 of 7 patients with low-grade gliomas, but no efficacy could be documented in patients with high-grade glioma, PNET, or ependymoma. 6 Further prospective trials are required to confirm hypothetical efficacy and assess long-term toxicity risks, especially in young children. 6

Discouraged Uses

The EANO guidelines explicitly discourage:

• Continuing bevacizumab beyond confirmed progression on that same treatment, as clinical benefit has not been established. 2
• Use of repurposed drug cocktails (such as CUSP9) that have never been tested in appropriate randomized controlled trials. 2