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New angiogenesis inhibitor has promise
for treating deadly brain tumor
Preliminary results show tumor shrinkage,
reduction in edema, normalization of blood vessels
BOSTON - January 16, 2007 - Researchers from the Massachusetts
General Hospital (MGH) Cancer Center have found that AZD2171
(RECENTIN™), 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.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. The MGH Cancer
Center is chosen by more cancer patients than any other hospital
in New England, and 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. MGH and Brigham and Women's
Hospital are founding members of Partners HealthCare HealthCare
System, a Boston-based integrated health care delivery system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
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