Researchers from the Massachusetts General Hospital (MGH) Cancer Center have found that AZD2171 (RECENTIN(tm)), a new angiogenesis inhibitor, can significantly reduce the size of the deadly brain tumors called glioblastomas and has the potential of improving the effectiveness of other therapeutic techniques. The Phase 2 clinical trial also finds that AZD2171 treatment can alleviate brain swelling (edema), a debilitating symptom in many brain cancer patients that currently can be treated only with steroid drugs. Appearing in the January 2007 issue of Cancer Cell, the study is too preliminary to determine whether this new drug may have an impact on overall patient survival.
"Patients with recurrent glioblastomas desperately need new, effective treatment alternatives," says Tracy Batchelor, MD, chief of Neuro-Oncology in the MGH Cancer Center, the study's lead author. "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."
Glioblastoma is the most malignant form of brain tumor and has a very poor prognosis. Standard treatments -- including surgery, chemotherapy and radiation therapy -- may delay tumor growth, but patients usually survive for little more than a year. There are currently no effective options for patients whose tumors recur, the vast majority of whom die within 6 months.
Angiogenesis inhibitors suppress the growth of blood vessels supplying a tumor and have received a lot of attention as potential cancer-fighting agents. While the earliest clinical trials did not meet expectations that these drugs would 'starve' tumors, the agents did improve patient survival when combined with traditional anticancer therapies. Three such drugs have received FDA approval for the treatment of certain tumors, and several others are under investigation. An oral medication, AZD2171 is a potent inhibitor of the three primary receptors for the powerful angiogenesis factor VEGF, known be present on glioblastoma blood vessels. Manufactured by AstraZeneca, AZD2171 is currently available only to participants in clinical trials.
The MGH trial, sponsored by the National Cancer Institute, was designed to assess whether AZD2171 could benefit patients with recurrent glioblastomas and also if the drug might normalize tumor vasculature. Blood vessels that develop around and within tumors are leaky and disorganized, potentially blocking the delivery of chemotherapy drugs or the effectiveness of radiation therapy, which requires an adequate supply of oxygen to the tumor. The fact that combining angiogenesis inhibitors with other therapies improved survival for some patients supports a theory developed by Rakesh Jain, PhD, director of the Steele Laboratory in the MGH Department of Radiation Oncology, that the agents temporarily 'normalize' blood vessels, creating a period during which chemotherapy and radiation treatment can be more effective. Jain is the senior author of the Cancer Cell article.
The paper reports on the first 16 patients to enter the clinical trial, which began in January 2006. All had glioblastomas that had resumed growing despite prior radiation or chemotherapy. Participants took a daily oral dose of AZD2171, which started at 45 mg and could be reduced in those experiencing negative side effects, including fatigue, diarrhea and hypertension. Participants were followed with regular physical, neurological, and MR imaging exams during the 6-month study period.
Imaging studies showed that tumors began to shrink in most participants within 28 days of the initial AZD2171 dose. Overall, the tumors shrank by at least 25 percent in three-quarters of the study participants and by 50 percent or more in half of the patients. Factors indicating a normalization of the tumors' blood vessels -- including reduction in size and a decrease in permeability or 'leakiness' -- were seen almost immediately in most participants and continued for at least 28 days, with some features persisting up to four months. These results are the first to define how long the period of vascular normalization might last, which may establish a window of time during which applying additional therapies would be most effective.
The highly advanced MR imaging techniques used in this report, developed at MGH, showed the vascular normalization to be very rapid, beginning after the first dose in some patients. Other MGH-pioneered MRI techniques showed that AZD2171 treatment led to a rapid decrease in brain edema, an effect that continued as long as the medication was taken. Edema produces many of the symptoms experienced by brain tumor patients and can only be treated with steroids, which have negative side effects of their own. The alleviation of edema allowed several study participants to reduce or even discontinue steroid treatment.
Analysis of potential biomarkers -- molecular and cellular factors that can be measured in the blood -- identified several that may indicate when the period of vascular normalization is ending or which patients' tumors are most likely to become resistant to AZD2171 treatment. These findings suggest that the imaging and biomarker studies will be important scientific tools for future assessment of therapy with AZD2171 and other drugs.
"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," says Jain. He is the Cook Professor of Radiation Oncology at Harvard Medical School, where Batchelor is an associate professor of Neurology. The researchers expect that the complete results of this trial, which enrolled a total of 31 patients, will be available later this year. They also are exploring additional trials to further define the role of AZD2171 in glioblastoma treatment and hope to study the drug in combination with traditional therapies and in newly diagnosed patients.
A. Gregory Sorensen, MD, codirector of the Martinos Center for Biomedical Imaging at MGH, is the co-lead author of the Cancer Cell report. Additional co-authors are Emmanuelle Di Tomaso, PhD, Wei-Ting Zhang, MD, Dan Duda, DMD, PhD, Kenneth Cohen, MD, Kevin Kozak, MD, PhD, Daniel Cahill, MD, Poe-Jou Chen, Mingwang Zhu, Marek Ancukiewicz, PhD, Maciej Mrugala, MD, PhD, Scott Plotkin, MD, PhD, David N. Louis, MD, David T. Scadden, MD, Thomas Benner, PhD, and Jay Loeffler, MD, of the MGH; Jan Drappatz, MD, and Patrick Y. Wen, MD, Dana-Farber Cancer Institute; and Percy Ivy, MD, National Cancer Institute. The study was supported by grants from the National Cancer Institute, the Simches Endowment for Brain Tumor Research, the Montesi Family Fund, the National Center for Research Resources, the MIND Institute and an AACR-Genentech BioOncology Career Development Award.
An integral part of one of the world's most distinguished medical centers, the Massachusetts General Hospital Cancer Center is chosen by more cancer patients than any other hospital in New England. Known for providing individualized, compassionate care to both adults and children, the MGH Cancer Center is comprised of 16 fully integrated, multidisciplinary clinical programs and a vast network of support and educational services. Scientific investigations are conducted as part of the largest hospital-based research program in the United States, and a powerful synergy between physicians and laboratory scientists fosters innovation in basic, translational and clinical research. The MGH is consistently ranked as one of the best cancer treatment centers and among the top three neurological centers by US News and World Report; and MGH nurses were the first in the state to achieve Magnet status for exceptional nursing care.
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