From OncoLog, June 2012, Vol. 57, No. 6

Bevacizumab for Glioblastoma: Symptom Relief Proven, Overall Survival Benefit Being Studied

By Stephanie Deming

The antiangiogenic agent bevacizumab has been shown to prolong progression-free survival and ameliorate symptoms in patients with recurrent glioblastoma. However, it remains unknown whether bevacizumab should be used to treat newly diagnosed glioblastoma and whether bevacizumab prolongs the overall survival of patients with glioblastoma.

The effect of bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF), on overall survival in glioblastoma patients is currently being studied in two multicenter clinical trials. At the same time, basic and translational researchers are trying to better understand bevacizumab’s mechanisms of action against glioblastoma and how to use bevacizumab to more effectively treat this disease. John de Groot, M.D., an associate professor in the Department of Neuro-Oncology at The University of Texas MD Anderson Cancer Center, divides his time between caring for patients in the clinic and studying glioblastoma in the laboratory. “There are many simple questions about treating glioblastoma with bevacizumab that we don’t know the answers to,” he said.

Bevacizumab for recurrent glioblastoma

Virginia Stark-Vance, M.D., an oncologist in private practice, was the first to report several partial responses in a small series of patients with recurrent glioblastoma treated with bevacizumab plus irinotecan. These data, presented in an abstract at the 2005 meeting of the European Association of Neuro-Oncology, opened the door to clinical trials of bevacizumab for the treatment of recurrent glioblastoma—a door that previously had been firmly shut because of concerns that the drug might cause bleeding in the brain.

The subsequent studies showed that bevacizumab produced dramatic radiographic responses: contrast-enhanced magnetic resonance imaging showed a reduction in contrast enhancement, which indicated a pruning of tumor vessels and a reduction in vascular permeability, in almost all patients after ad ministration of the drug. On the basis of two clinical trials in which patients with recurrent glioblastoma treated with bevacizumab alone or bevacizumab plus irinotecan had higher rates of 6-month progression-free survival than historical controls treated with irinotecan alone, bevacizumab received accelerated approval from the U.S. Food and Drug Administration in 2009 for use in the treatment of recurrent glioblastoma.

Bevacizumab can also dramatically improve quality of life for patients with recurrent glioblastoma, Dr. de Groot said. Glioblastomas have leaky blood vessels, which cause brain edema, and this edema pushes on different structures in the brain and causes a variety of debilitating symptoms. The edema is typically treated with steroids, but steroids themselves cause adverse effects, including diabetes, high blood pressure, and muscle weakness. Bevacizumab decreases the permeability of tumor blood vessels, which reduces edema and helps patients feel better, and the drug allows tapering or discontinuing the use of steroids in some patients.

Unfortunately, the mean duration of response to bevacizumab is only about 4 months in patients with recurrent glioblastoma, and once bevacizumab stops working, oncologists have few or no options left for slowing disease progression. “When these tumors become resistant to bevacizumab,” Dr. de Groot said, “they’re very hard to treat. No salvage therapy has ever been shown to help.” He is currently conducting a clinical trial to determine whether using a lower dose of bevacizumab in patients with recurrent disease may modulate or delay the development of resistance.

Bevacizumab for newly diagnosed glioblastoma

The standard therapy for newly diagnosed glioblastoma is surgery followed by a 6-week course of concurrent radiation therapy and temozolomide, followed by maintenance therapy with temozolomide for 1 year. Currently, two clinical trials are investigating whether adding bevacizumab to standard therapy will improve patient outcomes.

In the first trial, opened in 2008 by the Radiation Therapy Oncology Group (RTOG), more than 900 patients were randomly assigned to standard therapy plus either bevacizumab or placebo during chemoradiation and maintenance therapy. Mark Gilbert, M.D., a professor in the Department of Neuro-Oncology at MD Anderson, is the principal investigator. The study has completed patient accrual, and results will likely be available sometime in 2013.

In the RTOG trial, if patients randomly assigned to placebo experience disease progression, they can cross over and receive bevacizumab. Thus, according to Dr. de Groot, the trial may not show a survival difference between the two arms even if a survival difference would have been observed without crossover. “This trial is investigating whether giving bevacizumab at the time of progression will have the same survival benefit as giving it from the time of diagnosis,” he said. “And that’s an important question.”

The second trial, called AVAglio, is sponsored by Roche and is similar in design to the RTOG study. However, AVAglio is being conducted in Europe, where bevacizumab is not approved in all countries, and therefore it is expected that fewer patients who experience disease progression while receiving placebo will subsequently switch to bevacizumab. If this prediction is borne out, this trial will be better able to answer the question of whether bevacizumab treatment for newly diagnosed disease truly provides a survival benefit.

Dr. de Groot cautioned against the use of bevacizumab to treat newly diagnosed glioblastoma in the period before results from these two trials become available. There is some preliminary evidence, he said, that bevacizumab may promote tumor resistance to therapy. In addition, there is controversy in the literature about whether antiangiogenic therapy promotes tumor invasion.

Dr. de Groot noted that a significant portion of practicing physicians currently add bevacizumab to the standard treatment for newly diagnosed glioblastoma. However, he said, “Be cause we don’t have any evidence to suggest that adding bevacizumab up front improves outcomes compared with standard therapy, and be cause there are data suggesting that it could make matters worse, we don’t recommend adding antiangiogenic therapy to the standard of care for newly diagnosed patients outside of a clinical trial.”

Other clinical and laboratory studies

“Some glioblastoma patients respond to bevacizumab for long periods of time,” he said. “If we had a biomarker that identified those patients who were most likely to benefit, we could justify using the drug in that subgroup of patients—that’s sort of the holy grail of personalized medicine.” In collaboration with John Heymach, M.D., Ph.D., an associate professor in the Department of Thoracic/Head and Neck Medical Oncology, Dr. de Groot is trying to identify such a marker.

Dr. de Groot is also conducting preclinical studies of various combinations of bevacizumab plus new drugs as well as studying whether antiangiogenesis therapy promotes tumor invasion. “That’s something that you can reproduce in the laboratory,” he said, “but it’s not clear what effect these therapies have on tumor biology in patients.”

Dr. de Groot and his colleagues are also studying mechanisms of resistance to antiangiogenesis therapy. In a recent study, the researchers compared cells from xenografts of human glioblastoma in untreated mice and in mice with glioblastomas that had become resistant to a VEGF inhibitor. The treatment-resistant cells had increased expression of mesenchymal and proinflammatory genes and were more invasive in vitro. In collaboration with Amy Heimberger, M.D., an associate professor in the Department of Neurosurgery, Dr. de Groot recently found that the upregulation of the signal transducer and activator of transcription 3 (STAT3) protein plays a role in resistance to anti–VEGF therapy. They also found that, in a mouse model of glioblastoma, cotreatment with a VEGF inhibitor and a Janus kinase (JAK)/STAT3 inhibitor reduced tumor volume more than treatment with either agent alone did.

“I think we need to work harder to better understand how these drugs work,” Dr. de Groot said, “in order to use them more effectively.”

For more information, contact Dr. John de Groot at 713-792-7255.


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