Glioblastoma is the most common primary malignant brain tumor in adults and, despite treatment advances in recent years, the average survival of patients enrolled in clinical trials is less than 16 months and few patients live beyond five years.
Glioblastoma is characterized by angiogenesis, the formation of new blood vessels that support tumor growth stimulated by the GBM-produced vascular endothelial growth factor A ( VEGF-A ).
Bevacizumab ( Avastin ) is a monoclonal antibody that targets VEGF-A production to block the growth of tumor-derived blood vessels. Clinical trials evaluating the addition of Bevacizumab to standard treatment for recurrent glioblastoma demonstrated clinical benefit and led to the drug's FDA approval for this indication.

Additionally, compelling preclinical data suggest that anti-angiogenic targeted therapies may normalize the tumor's rapidly forming and underdeveloped blood vessels, resulting in improved oxygen and chemotherapy delivery to the tumor and potentially enhancing radiotherapy and chemotherapy treatment. The RTOG 0825 study tested this hypothesis.

Six hundred and thirty-seven adult study participants were enrolled in the multicenter trial and randomized into one of two study arms, with treating physicians blinded to treatment assignment. All participants were treated with standard radiotherapy ( 60 Gy ) and daily Temozolomide. Bevacizumab ( experimental arm ) or a placebo ( standard treatment arm ) was administered starting at week 4 of radiotherapy and continued every 2 weeks until 1) disease progression, or 2) severe treatment-related toxicity, or 3) completion of adjuvant therapy. At the time of disease progression, the treatment arm was unblinded allowing for follow on treatment with or without Bevacizumab.

Mark Gilbert, at The University of Texas MD Anderson Cancer Center, Houston, Texas, reported data undertaken at 18 months after completion of study participant enrollment in May 2011, which revealed no statistical difference in overall survival between the two study arms ( median 16.1 months for the standard-treatment arm vs. 15.7 months for the Bevacizumab arm ). Although there was a difference in progression-free survival ( 7.3 months for the placebo arm vs 10.7 months for the Bevacizumab arm ), the established level of benefit for progression-free survival was not reached.
The relevant result is that the upfront use of Bevacizumab is not indicated.

Study participants were stratified equally across study arms by prognostic molecular markers of tumor O6-methylguanine–DNA methyltransferase ( MGMT ) methylation status and a tumor-based 9-gene assay. Investigators, however, did not find a subgroup of patients based on the molecular marker analysis who survived longer from first-line Bevacizumab administration.
Researchers postulated that patients with worse prognosis, determined by their tumor markers, would do better if they received Bevacizumab as first-line treatment because they may not survive to take advantage of, or do well enough to be considered for, second-line treatment, but we didn't find that result.

Because Bevacizumab is known to confound magnetic resonance imaging ( MRI ) examination results used to assess glioblastoma tumor progression, RTOG 0825 investigators incorporated a net clinical benefit component in the trial design to determine if quality of life, symptom burden and neurocognitive functioning test results corroborate MRI-reported stable or improved disease status. More than 80% of study participants agreed to take part in the net clinical benefits component, which demonstrated a greater decline of cognitive function for patients in the Bevacizumab arm compared with those in the placebo arm.

While researchers found a difference in progression-free survival in the Bevacizumab arm, there was an overall increase in symptom burden and decline in neurocognitive function and some measures of quality of life comparing the patients receiving Bevacizumab with those on placebo.

Source: American College of Radiology, 2013

XagenaMedicine2013