Glioblastoma: Bevacizumab added to initial treatment doesn't improve overall survival
Glioblastoma ( GBM ) is the most common primary malignant adult brain tumor and, despite treatment advances in recent years, the average survival of patients enrolled in clinical trials is less than 16 months with few patients living beyond five years. GBM tumors are 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 have demonstrated clinical benefit and led to the drug's FDA ( Food and Drug Administration ) 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 enhanced radiotherapy and chemotherapy treatment.
The Radiation Therapy Oncology Group ( RTOG ) 0825 study tested this hypothesis.
Six hundred and twenty-one adult study participants included in the study's final analysis 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-of-care ( 60 Gy RT and daily Temozolomide chemotherapy ).
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.
The authors have reported data at a median follow-up time of 20.5 months, 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 pre-established level of benefit for progression-free survival was not reached.
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 GBM 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 function 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 over time comparing the patients receiving Bevacizumab with those on placebo.
Source: American College of Radiology, 2014
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