June 3, 2013
Addition Of Bevacizumab To Initial Treatment For Brain Tumors Does Not Extend Patients’ Lives
Results of a randomized phase III clinical trial conducted by the Radiation Therapy Oncology Group (RTOG) determined that adding bevacizumab to initial treatment for glioblastoma (GBM) did not improve patient overall survival or progression-free survival. Results were reported June 2 during the plenary session of the American Society of Clinical Oncology 2013 Annual Meeting.
GBM 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. GBM 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 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," says Mark Gilbert, MD, RTOG 0825 Principal Investigator and professor of neuro-oncology at The University of Texas MD Anderson Cancer Center, Houston, Texas. "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," explains Gilbert. 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 (RT) (60 Gy) and daily temozolomide. Bevacizumab (experimental arm) or a placebo (standard treatment arm) was administered starting at week 4 of RT 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.
At today's ASCO plenary session, Gilbert 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 (PFS) (7.3 months for the placebo arm vs. 10.7 months for the bevacizumab arm), the established level of benefit for PFS was not reached. "The relevant result is that the upfront use of bevacizumab is not indicated," says Gilbert. "It's important to emphasize that the question we sought to answer was whether administering bevacizumab as first line treatment improved survival; the cross-over component allowed comparison of risk and benefit of early versus late treatment We now know by giving it late you delay the risk of toxicity, and that may be relevant."
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. "We 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" says Gilbert.
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 functioning test results corroborate MRI-reported stable or improved disease status. More than 80 percent 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 we 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," says Gilbert.
"Study participants' consent allowing the collection of tumor tissue and blood samples, as well as imaging examination, longitudinal symptom, QOL, and neurocognitive function data provides RTOG investigators a rich archive of data to support ongoing investigations of potential molecular markers to identify subgroups of patients who may benefit from early bevacizumab," says Minesh Mehta, MD Study Co-Principal Investigator and Chair of the Brain Committee of RTOG.
ASCO 2013 will feature three additional presentations of RTOG 0825 study results to include molecular predictors of outcome and response to bevacizumab, patient-reported QOL and patients' neurocognitive function.
"I congratulate the entire RTOG 0825 team on the design of an innovative trial that has provided important insight about the use of anti-angiogenic therapies with standard front-line treatment and on the unprecedented collection of specimens and associated outcome data that will continue to provide significant future information. I also thank our ECOG and NCCTG colleagues for their trial support," says Walter J. Curran, RTOG Chair and Executive Director of the Winship Cancer Center at Emory University in Atlanta.
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