Antiangiogenic Agent Shows Promise against Glioblastoma
An experimental antiangiogenesis drug may improve the treatment of the most common and deadly type of adult brain cancer, researchers from Massachusetts General Hospital and Harvard Medical School reported this week at the American Association for Cancer Research (AACR) annual meeting in Los Angeles.
The promising clinical results were buttressed by imaging and biomarker analyses that support a theory that the value of antiangiogenic agents may not be limited to halting the development of blood vessels that feed tumors, but that the drugs also can "normalize" them to the point where the delivery of standard treatments to the tumor may be improved.
The research team presented updated data from a phase II clinical trial involving 31 patients with glioblastoma that had recurred after standard treatment of chemotherapy and radiation. Daily use of the experimental agent, AZD2171, an inhibitor of vascular endothelial growth factor (VEGF) receptors, improved progression-free survival compared with what is historically seen in patients with recurrent glioblastoma, 111 days vs. 63 days. The drug had a more modest improvement in overall survival compared with historical controls, 211 days vs. 179 days. In addition, 9 of the first 16 patients achieved partial responses as measured by at least a 50-percent reduction in tumor contrast enhancement by imaging.
"The results are encouraging," said the study's lead investigator, Dr. Tracy Batchelor, chief of neuro-oncology at Massachusetts General Hospital Cancer Center. "All of the arrows are pointing in the right direction."
Even so, Dr. Batchelor warned, this was a small number of patients in a nonrandomized trial, so the results should be interpreted with an abundance of caution.
According to Dr. Percy Ivy of NCI's Cancer Therapy Evaluation Program, the study also reached another important metric: 27.6 percent of patients were alive and with no signs of disease progression at 6 months, compared with a historic benchmark of approximately 15 percent with standard therapy. That suggests further studies are warranted.
"This is exciting because, as a single agent, [AZD2171] has shown some evidence of activity in a disease that is uniformly fatal," Dr. Ivy said. "And the evidence is sufficient to start exploring combinations and determining if this represents a new advance in treatment."
In addition to the improved survival results, in some patients the use of AZD2171 remedied a significant problem associated with glioblastoma: swelling in the brain caused by fluid retention, known as edema. As a result, many of the patients were able to reduce or halt altogether the use of steroids to treat the edema, which carry their own debilitating side effects.
Evidence for normalization was acquired through a novel application of imaging studies that allowed a careful comparison of blood vessels on the unaffected side of the brain with vessels in and around the tumor. Molecular biomarker analyses, meanwhile, showed that the expression of two proteins, bFGF and SDF1α, correlated with tumor progression and reversion of vessel diameter to an abnormal, enlarged state during treatment.
These findings, Dr. Jain continued, suggest that bFGF and SDF1α are pro-angiogenic reinforcements called to action to help tumors escape anti-VEGF treatment. Although animal model studies had indicated bFGF was likely involved in angiogenesis, SDF1α's involvement is a new finding.
Based on these results, NCI has approved an early-phase clinical trial to evaluate AZD2171 in combination with standard therapy of radiation and temozolomide in newly diagnosed glioblastoma patients. And Dr. Batchelor will lead a randomized phase III trial supported by AstraZeneca that will test AZD2171 in combination with chemotherapy in patients with recurrent glioblastoma. That trial has been submitted to the FDA for approval, Dr. Batchelor said, with the hope of enrolling patients by the end of the year.
By Carmen Phillips