Following surgery, radiation and chemotherapy with a drug that hinders formation of tumor-supporting blood vessels does not increase the survival of glioblastoma patients, according to a phase III clinical trial.
Results of the first randomized, double-blind clinical trial of the drug bevacizumab (Avastin) for newly diagnosed glioblastoma patients were presented at the American Society of Clinical Oncology 2013 Annual Meeting in Chicago by Mark Gilbert, M.D., professor in MD Anderson's Department of Neuro-Oncology.
Glioblastoma is the most common and lethal form of brain cancer. More than 12,000 people will be diagnosed with the disease in 2013, with an average survival rate of less than 18 months, Gilbert says.
Bevacizumab is a monoclonal antibody that blocks vascular endothelial growth factor-A (VEGF-A), which is produced by glioblastoma to stimulate blood vessel growth.
"Glioblastoma is a cancer with too few effective therapies," said Gilbert, who also holds the Blanche Bender Professorship in Cancer Research.
"When we launched this study, those in the field of brain cancer - both the scientific and patient communities -- were excited. Bevacizumab recently received approval in the second-line (recurrent disease) setting, and we knew some physicians were already giving the drug as a frontline therapy -- even with virtually no data to support that decision. It was important from a patient care and regulatory standpoint that we conduct this trial."
The drug showed promise when used for approved compassionate use and in numerous early stage institutional studies: a 35-40 percent objective response rate, or tumor shrinkage of more than 50 percent, and a six-month progression-free survival rate in the mid-30 percent, Gilbert says. In May 2009, the FDA granted an accelerated registration of bevacizumab for second-line therapy, use after glioblastoma progresses or reoccurs.
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The study enrolled 637 newly diagnosed glioblastoma patients. Participants underwent surgery to remove some or most of the tumor, received the standard of care of chemoradiation with temozolomide, and were then randomized to receive either bevacizumab or placebo.
Two distinguishing factors of the study design include crossover to bevacizumab in the placebo arm at the time of progression, and longitudinal assessment of cognitive function and quality of life.
"With the crossover, we could determine the possible overall, or progression free survival benefits that could distinguish the potential benefits of early versus later use of bevacizumab," Gilbert says. "Also, there may be some alternative advantages for delaying progression in the disease. In order to interpret that possible delay in progression, it was important to understand the quality of survival during that possible progression-free survival interval."
The researchers found no difference in overall survival between the bevacizumab and placebo arms, 15.7 and 16.1 months, respectively. Progression-free survival did not reach the pre-set level of statistical significance - although it was longer ®_®_in those taking bevacizumab upfront (10.7 months), compared to in those receiving placebo (7.3 months).
Bevacizumab was associated with a higher rate of toxicities, including hypertension, bleeding, deep vein thrombosis and pulmonary embolism, and gastrointestinal perforation. Those on the therapy also experienced increased symptom burden and cognitive decline, as well decreased quality of life, compared to those on placebo.
"Ultimately, our study showed that bevacizumab has the same benefit whether given early or late and because of the risk of extra toxicity upfront, its use can be reserved as a later treatment for most patients," Gilbert notes.
MD Anderson News Release
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