A randomized phase III study, supported in part by the National Cancer Institute and Genentech, finds no overall survival improvement from the addition of bevacizumab (Avastin?, Genentech/Roche) to standard first-line chemoradiation for glioblastoma. Patients who received bevacizumab also experienced more side effects compared to those treated with chemoradiation alone. The findings suggest that it should not be a part of first-line therapy for these patients with glioblastoma.

Glioblastoma is the most common and most aggressive form of primary brain tumor. Bevacizumab, an antibody that blocks the growth of tumor blood vessels, is currently approved by the U.S. Food and Drug Administration (FDA) for patients with recurrent glioblastoma. Despite a lack of clear evidence, bevacizumab has been used off-label as first-line therapy in certain patients, in hopes of increasing the benefit to the patient.

?Unless we can identify a group of patients that clearly benefits from early use of bevacizumab, it appears that it should not be used in the first-line setting,? said Mark R. Gilbert, MD, a professor of neurooncology at the University of Texas MD Anderson Cancer Centerin Houston, Texas. ?Bevacizumab remains an important part of our armory against glioblastoma, but in most situations it should be reserved
as a salvage regimen.?

Patients treated with bevacizumab + temozolomide had more side effects than those treated with temozolomide alone, with no improvement in overall survival.

In this multi-institutional clinical trial, 637 patients with newly diagnosed glioblastoma were randomly assigned to treatment with chemoradiation ? temozolomide (Temodar?, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.) and radiation ? plus placebo or chemoradiation plus bevacizumab. All patients had undergone surgery before starting chemoradiation.

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Patients were allowed to cross over to the placebo group or continue bevacizumab at the time of progression. The median overall survival was not statistically different between the two groups (16.1 months with placebo vs. 15.7 months with bevacizumab). The median progression-free survival was longer in the bevacizumab group relative to the placebo group (10.7 months vs. 7.3 months), but the difference did not reach the pre-set level of significance prescribed for this study.

A subgroup analysis based on molecular markers (MGMT methylation status and a nine-gene expression signature) found no subgroup withimproved survival using bevacizumab. Overall, there were more side effects in the bevacizumab group, particularly low platelet counts, blood clots and high blood pressure. However, Gilbert said that toxicity differences alone would not have precluded the decision to use bevacizumab had the trial found a survival benefit.

?Bevacizumab received FDA approval for recurrent glioblastoma based on dramatic radiographic activity in several phase II trials. Now, two separate multinational randomized phase III trials demonstrate thatbevacizumab modestly increases progression-free survival but not overall survival for newly diagnosed patients. Although bevacizumab will clearly continue to have an important role in the treatment of
patients with glioblastoma, the timing of its use, the specific subpopulation of patients that benefit the most, and the biological and clinical consequences of chronic VEGF inhibition on glioma and normal cells within the central nervous system need to be clarified,? said Howard Fine, MD,CNS tumors expert and ASCO spokesperson.

Researchers also assessed patients? quality of life, symptom burden and neurocognitive function, which also favored the group of patients who received chemoradiation alone; the findings from those analyses
will be presented in separate oral presentations at the Annual Meeting. This study component revealed that patients in the bevacizumab arm had a greater increase of symptom burden and more decline of neurocognitive function over time compared to patients in the placebo arm. Molecular profiles of tumor samples collected on this study, as well as imaging scans, are being examined to determine if there is any group of patients that could still benefit from bevacizumab in the first-line setting.

For more information:
Abstract #1: RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM).
Plenary Session
Study Author: Mark R. Gilbert, MD, University of Texas MD Anderson Cancer Center
Date: Sunday, June 2, 2013, 1:50 ? 2:05 PM CDT
Location: Room: N Hall B1 Houston, TX.

Photo: Mark R. Gilbert, MD., a professor of neurooncology at the University of Texas MD Anderson Cancer Center in Houston, Texas.Photo Courtesy:? ASCO/Silas Crews.

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