Investigational Drug Normalizes Blood Vessels in Brain Tumors

January 16, 2007

BOSTON -- An investigational drug aimed at making recurrent glioblastomas more vulnerable to chemotherapy and radiation seems to restore a normal vasculature to the tumor, at least temporarily, show preliminary results of a Phase II trial.

BOSTON, Jan. 16 -- An investigational drug aimed at making recurrent glioblastomas more vulnerable to chemotherapy and radiation seems to restore a normal vasculature to the tumor, at least temporarily, show preliminary results of a Phase II trial.

The angiogenesis inhibitor Recentin (cediranib or AZD2171) also reduces swelling in patients, an important clinical benefit, according to Tracy Batchelor, M.D., of the Massachusetts General Hospital here.

Many patients treated with a daily dose of the drug continually also saw their tumors shrink, Dr. Batchelor and colleagues reported in the Jan. 16 issue of Cancer Cell.

The effects, evaluated by magnetic resonance imaging, begin within 24 hours of administration and lasted as long as 28 days, the researchers said.

"While these are preliminary results of an initial trial, it's looking like these agents may play an increasingly important role in the treatment of patients whose tumors have recurred and perhaps in newly diagnosed patients as well," Dr. Batchelor said.

Recentin is an oral tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptors. It is being developed by AstraZeneca Pharmaceuticals.

The data reported were for 16 of the patients in the 31-patient study. The researchers expect that complete results will be available later this year.

The study found that the size of tumor blood vessels significantly decreased (at P

At the same time, the vasogenic edema associated with the glioblastoma was reduced sharply, alleviating the need for corticosteroids. Of the 11 patients who received corticosteroids during therapy, eight had their dose reduced and three had them stopped.

The authors wrote that "toxicity was modest," and median progression-free survival in the small cohort was 111 days, which compares favorably with that reported from an historical database.

Similar to other antiangiogenic therapies that target only tumor endothelium, monotherapy with Recentin may not improve overall survival, the authors added, suggesting the need to combine cytotoxic therapies with the investigational agent. In the 16 patients, median overall survival was 211 days, compared with a median overall survival of 175 days from an historical database.

The use of anti-angiogenic medications in brain cancer has been slowed by the fear of hemorrhage, according to Shahin Rafii, M.D., of the Memorial Sloan-Kettering Cancer Center in New York, writing in an accompanying editorial.

Dr. Rafii said the discovery that Recentin normalizes the tumor vasculature has "rekindled the hope that judicious introduction of anti-angiogenic agents may circumvent fatal hemorrhagic complications."

On the other hand, he said, simply restoring a normal vasculature to the tumor may not be enough. Anti-angiogenic therapy may need to target the stable blood vessels as well in order to increase survival.

"This small group of patients needs to be followed for a longer period of time, but we are cautiously optimistic that this trial and future studies will lead to positive long-term outcomes for some patients," said Rakesh Jain, Ph.D., also of Massachusetts General Hospital, the study's senior author.