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Study of cancer trials finds significant
safety improvement
Risk of dying from experimental cancer
treatment drops by 90 percent over 12 years
BOSTON - November 2, 2004 - The chance that patients participating
in early-stage cancer research studies will die from the experimental
treatments has dropped dramatically over the past decade, according
to a study from the Massachusetts General Hospital (MGH) Cancer
Center and the Massachusetts Institute of Technology (MIT). In an
analysis of more than 200 Phase 1 research trials from 1991 through
2002, the researchers found that treatment-related deaths decreased
by 90 percent during the study period. The report appears in the
November 3 Journal of the American Medical Association.
"We undertook this study because there has been so much concern
in recent years about the safety of clinical trials. We wanted to
see if the increased attention to patient safety had made a difference
and if the addition of targeted therapies, which tend to be less
toxic, had also helped," says Thomas Roberts Jr., MD, of the
MGH
Cancer Center, the paper's lead author. "Now we can tell
patients with cancer that, compared with 10 years ago, they can
expect a higher level of safety when they enroll in early-stage
clinical trials."
Representing the first time potential new drugs are tested in humans,
Phase 1 trials have a goal of assuring drug safety and determining
the best dosage. While most of these early-stage studies enroll
healthy volunteers, cancer studies have several important differences.
Phase 1 cancer studies are usually restricted to patients with cancer
who have exhausted established therapeutic options. While identifying
toxic effects is the primary goal of most Phase 1 studies, cancer
trials also have a secondary goal of evaluating anti-tumor effects.
Since there had been no comprehensive analysis of Phase 1 trials
since the mid-1980s, the researchers compiled a database of Phase
1 trial results reported at the annual meeting of the American Society
for Clinical Oncology from 1991 through 2002. In order to insure
that the studies were comparable, the investigators focused on published
studies of single agents that had not yet received FDA approval
and excluded those involving radiation therapy or treatment of leukemia
or lymphoma. This strategy narrowed the study group down to 213
trials, enrolling aproximately 6,500 patients. For these studies,
the researchers analyzed how often participants died from drug toxicity,
cancer-related deaths, other toxic treatment effects, and whether
or not the treatment caused the tumor to shrink, as measured by
CT scanning.
The most significant change during the study period was the more
than 90 percent drop in the risk of drug-related deaths - from a
risk of about 1 percent in the first four years of the study to
.06 percent in the last four years. The chance that the tested drug
would have a measurable anti-tumor effect also dropped during the
study period but by only 50 percent, suggesting a possible improvement
in the overall risk/benefit ratio.
The researchers cite several possible reasons for the improvements
in safety, including increased attention to patient safety regulations,
the use of less-toxic targeted therapies, and improvements in supportive
care, such as new treatments for chemotherapy-induced anemia and
neutropenia. While they were surprised and concerned about the reduced
chance of a therapeutic benefit, Roberts explains several potential
underlying reasons.
"We have gotten more systematic in the determination of response
rates, so the later results may be more accurate," he says.
"In addition, some of the newer agents like angiogenesis inhibitors,
could be stopping cancer progression without actually shrinking
the tumor. We may need to find new ways to measure treatment success."
Roberts continues, "Many investigators feel frustrated about
the regulatory hurdles they have to go through to initiate and conduct
clinical trials. There will always be a balance between optimizing
patient safety and conducting research efficiently. We need to be
aware of that balance and to find ways to monitor patient safety
in real time." Roberts is an instructor in Medicine at Harvard
Medical School and visiting scientist at MIT.
Roberts' co-authors are Bernardo Goulart, MD, Bruce Chabner, MD,
and Jeffrey Clark, MD of the MGH Cancer Center; Elkan Halpern, PhD,
and G. Scott Gazelle, MD, MPH, PhD, of the MGH Institute of Technology
Assessment; and Sarah Stallings, PhD, Stan Finkelstein, MD, and
Lee Squitieri of Massachusetts Institute of Technology. The study
was supported by grants from the Alfred P. Sloan Foundation and
the National Cancer Institute.
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 more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
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