What is the role of Bevacizumab (Bevacizumab) in treating recurrent Glioblastoma Multiforme (GBM)?

Bevacizumab in Recurrent GBM

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

Evidence Against Survival Benefit

The most recent and highest-quality guideline evidence from the Congress of Neurological Surgeons (2022) provides a Level III recommendation that bevacizumab does not provide increased overall survival when used for treatment of patients with progressive glioblastoma 1. This represents a critical update from earlier guidelines and supersedes the 2009 FDA accelerated approval, which was based solely on imaging response rates rather than survival outcomes 1.

The 2021 EANO guidelines similarly state that bevacizumab does not prolong progression-free survival nor overall survival in patients with recurrent glioma 1. This consensus across multiple high-quality guidelines from 2021-2022 establishes that survival benefit is not an expected outcome.

FDA-Approved Indication and Dosing

Bevacizumab received FDA accelerated approval in 2009 for recurrent glioblastoma based on two phase II studies showing MRI-defined objective response rates of 28-38%, with median survival around 9 months 1. The FDA-approved dose is 10 mg/kg every 2 weeks administered as an intravenous infusion until disease progression or unacceptable toxicity 2.

When to Consider Bevacizumab

Use bevacizumab selectively for:

• Quality of life improvement in patients aged 55 years or older with recurrent disease 1, 3
• Steroid-sparing effect to reduce corticosteroid requirements and associated side effects 1, 4
• Symptomatic relief from tumor-associated edema and mass effect 1
• Improved progression-free survival at 6 months (PFS6 rates of 37.5% reported), though this does not translate to overall survival benefit 1, 5

The 2012 NCCN guidelines note that bevacizumab "likely improves quality of life (and possibly overall survival) in patients aged 55 y or older" 1, though the survival component has been refuted by more recent evidence.

Combination Therapy Considerations

Bevacizumab plus lomustine (CCNU) may provide modest additional benefit over bevacizumab monotherapy 3, 6. A 2016 study demonstrated that BEV/CCNU resulted in:

• Median PFS of 6.11 months versus 4.1 months with bevacizumab alone 6, 5
• Median OS of 6.59 months versus 6.4 months with bevacizumab alone 6, 5
• This represents approximately 2 months additional survival benefit 6

However, the 2022 CNS guidelines state there is insufficient or conflicting data regarding the benefit of bevacizumab in combination with other agents 1.

Serious Adverse Events

Bevacizumab carries significant toxicity risks that must be weighed against limited benefits 1, 2:

• Hypertension (8-11% Grade 3-4) 2
• Thromboembolic events (5-9% venous, up to 5% arterial) 2
• Hemorrhage (up to 5% serious bleeding, including CNS hemorrhage) 2
• Gastrointestinal perforation (0.3-3%, potentially fatal) 2
• Wound healing complications (5% in GBM patients, 15% in colorectal cancer) 2
• Proteinuria (3-7% Grade 3-4) 2

In clinical studies, 54% of patients experienced bevacizumab-related adverse effects, with 16.6% experiencing Grade 3-4 toxicity 5. The FDA label notes that 22% of patients discontinued treatment due to adverse reactions when bevacizumab was combined with lomustine 2.

Alternative Treatment Options

Before considering bevacizumab, prioritize 3, 7:

1. Repeat cytoreductive surgery if feasible for symptomatic progressive disease with good performance status 1, 3, 8
2. Lomustine (CCNU) monotherapy as an approved chemotherapeutic option 3, 7
3. Temozolomide rechallenge particularly in patients with MGMT promoter methylation 3, 7
4. Reirradiation to provide improved local tumor control and maintain neurological status 1, 8

Critical Pitfalls

• Do not use bevacizumab expecting survival prolongation - the evidence clearly demonstrates no overall survival benefit 1
• Imaging response does not equal clinical benefit - bevacizumab reduces vascular permeability, creating the appearance of response on MRI without true tumor control 1
• Pseudoprogression versus true progression - apparent tumor growth within 2-9 months after radiotherapy may represent treatment effect rather than progression; do not prematurely start bevacizumab 8, 7
• Contraindications - avoid in patients with recent hemoptysis (≥1/2 teaspoon red blood), recent surgery (<28 days), or active bleeding 2

Practical Administration

• First infusion: 90 minutes 2
• Second infusion: 60 minutes if first tolerated 2
• Subsequent infusions: 30 minutes if second infusion tolerated 2
• Continue until: disease progression or unacceptable toxicity 2
• Withhold: at least 28 days before elective surgery and until adequate wound healing 2

Bottom Line Algorithm

For recurrent GBM, consider bevacizumab only when:

1. Patient has good performance status (KPS ≥60) AND
2. Primary goal is symptom control or steroid reduction (not survival) AND
3. Patient has been counseled about lack of survival benefit AND
4. No contraindications to therapy exist AND
5. Other options (surgery, lomustine, temozolomide rechallenge) have been exhausted or are inappropriate

Bevacizumab with lomustine is preferred over bevacizumab monotherapy if combination therapy is tolerated, providing approximately 2 additional months of progression-free survival 6.