A promising new approach to treating the more than 170,000 cancer patients in the U.S. whose cancer spreads from another part of their body to their brain each year may increase tumor response rates and reduce progression of the disease, according to a study published in this week's Journal of Clinical Oncology.
The multi-center Phase Ib/II clinical trial of the investigational agent,
motexafin gadolinium (Xcytrin® Injection,
Pharmacyclics, Inc.;, administered in
combination with standard whole brain radiation therapy, showed the treatment
increased local tumor control, as evidenced by a high tumor response rate
(i.e., significant tumor shrinkage) and low rate of death due to tumor
progression in the brain.
"We are particularly pleased to see the high tumor response rate, which is
nearly double what we have observed in the literature with radiation alone,"
said Minesh Mehta, M.D., associate professor and interim chair, Department of
Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison,
one of the study's lead investigators. "Based on these encouraging results,
we conducted a large multi-center international Phase III study designed to
measure survival and time to neurologic progression in a similar patient
population. Enrollment in this 428-patient trial has been completed, and we
expect to report results by the end of this year."
Motexafin gadolinium is the first of a new class of drugs called
texaphyrins. It selectively accumulates in cancer cells and disrupts cellular
metabolism by a unique mechanism of action. By interfering with the flow of
energy in cancer cells, motexafin gadolinium makes the tumor more responsive
to the effects of radiation and chemotherapy without increasing damage to
Key Study Findings
Sixty-one patients with brain metastases were enrolled in the combined
Phase Ib/II trial. For 10 days, daily intravenous injections of motexafin
gadolinium were administered, followed by whole brain radiation treatment each
day. Thirty-nine patients were enrolled in the Phase Ib portion of the trial
intended to determine optimal dosing and tumor localization using magnetic
resonance imaging (MRI), and 22 patients were enrolled in the Phase II portion
of the trial designed to assess tumor response and side effect profile.
Eighteen Phase II patients were evaluable for tumor response based on
follow-up MRI scans. After a two-month follow-up, tumor response, defined as
greater than 50 percent reduction in tumor volume, was seen in 13 of
18 patients (72 percent), significantly higher than the 43 percent reported in
previous studies of patients treated with standard whole brain radiation
therapy alone. Death due to tumor progression in the brain was just
12 percent, compared to a rate of about 50 percent reported in previous
studies of patients treated with radiation alone. MRI scanning showed visual
enhancement of the brain metastases for 56 days following administration of
motexafin gadolinium, demonstrating how the drug localizes selectively and is
retained in the tumors.
The treatment was well tolerated. The most common side effects observed
were discoloration of the skin, urine and eyes due to the dark green color of
the drug. The discoloration developed gradually after repeated drug dosing,
and cleared three to four days after the last dose.
"This is the first treatment of its kind that appears to enhance the
beneficial effects of radiation therapy in a clinical setting," said Dr.
Patrice Carde, Chef de Service, Department of Medicine, Institut Gustave
Roussy, Villejuif, France, lead author of the study.
Brain Metastases: An Increasing Clinical Problem
Approximately 170,000 patients are diagnosed with brain metastases each
year in the United States. This number is increasing as cancer patients live
longer due to new treatment advances made in the last several years. However,
there are few treatment options for patients whose cancer has advanced and
spread to the brain.
Metastases in the brain are one of the most devastating consequences of
cancer, affecting up to 40 percent of all cancer patients. The majority of
brain metastases originate in breast and lung cancers. Brain metastases occur
when cancer cells from the primary site migrate (often through the blood
stream) and travel to the brain, where they remain and grow. Patients with
brain metastases may suffer devastating complications from uncontrolled
progression of tumor growth in the brain; these complications include
headaches, seizures, paralysis, blindness, neurocognitive deterioration and
death. The goal of whole brain radiation therapy is to reverse or prevent
neurological deterioration and prevent death due to tumor progression in the