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New drugs, smarter drugs, safer drugs, just plain
better drugs. The world of chemotherapy for prostate cancer is
experiencing an earthquake, and Hopkins is at the epicenter —with
a wealth of clinical trials, many of compounds and drug regimens
developed at the Kimmel Cancer Center by Mario Eisenberger, M.D.,
Michael A. Carducci, M.D., Ted DeWeese, M.D., Roberto Pili, M.D.,
and Samuel Denmeade, M.D.—aimed at an unprecedented spectrum of
men.
Gone are the days of last-ditch efforts— waiting
to start conventional chemotherapy until everything else had failed,
often when men were too sick to tolerate the drugs’ harsh side
effects, and the cancer had become too aggressive and widespread.
Over the last several years, these oncologists, building on a
solid basic science foundation of molecular insights into how
prostate cancer works, have transformed the “traditional” chemotherapy
mindset. They’re attacking the disease earlier, and developing
an elite cadre of selective drugs aimed at controlling—if not
necessarily curing—prostate cancer, and prolonging life for years.
“We’re using ‘smart’ drugs,” says Eisenberger. “They work at very
specific molecular steps of cancer cell growth. Some of these
drugs interfere with those steps; many of them will not cause
a response in a traditional way—that is, the PSA may not always
drop immediately; it will just remain stable.” Because the drugs
work differently, their effects must be measured differently,
and the newest clinical trials are designed for long-term follow-up.
“We’re taking advantage of the current patterns
of prostate cancer patients coming to the clinic,” Eisenberger
continues. “We’re seeing more men with early disease, and we believe
these are the men who are most likely to benefit from our new
compounds. Say a man has a probable lifetime survival, without
further treatment, of eight to 10 years. If we could double this
time, that man may never die of prostate cancer. So we may not
be able to cure the disease, but we may be able to stabilize it—delay
the progression in a big way. Because these smart compounds either
don’t have side effects, or have far fewer side effects than conventional
chemotherapy and hormone therapy, they’re perfect for men with
early disease, and we’ll have achieved a benefit that is comparable
to a cure.”
Clinical trials are available for patients at
every stage of prostate cancer. The ever-evolving range of clinical
trials is so big that we can only hit a few highlights here. You
can find out more about these and other trials by calling (410)
955-8964, or on our website at
http://urology.jhu.edu/research/trials.php
For
men with locally confined cancer awaiting radical prostatectomy:
Most men have a “limbo” period between the time their cancer is
diagnosed by biopsy, and the time surgery is scheduled. Although
it can seem like an interminable stretch of time, in the world
of clinical trials, it’s actually quite brief. Could taking a
drug or dietary supplement for a few weeks make a difference in
the prostate, on the cancer cells and their rate of growth, and
on the growth of nearby blood vessels? Two trials aim to find
out. One of them involves the anti-inflammatory drug celecoxib.
The other will study the effects of the antioxidant vitamin E
and a drug called Sulindac, alone and in combination. For men
after radical prostatectomy, whose cancer is likely to recur:
These are men who have no evidence of disease, but a risk (based
on Gleason score and pathological stage) that the prostate cancer
may come back. In one multicenter study, led by Hopkins, men receive
adjuvant chemotherapy with docetaxel (Taxotere) —a drug in the
taxol family, used for women with breast cancer. Treatment, given
weekly, starts at two months after surgery, three out of every
four weeks for six months. In prostate cancer, some cells are
driven by male hormones, and some are impervious to them. (This
is why hormonal therapy is very effective at killing some prostate
cancer cells, but it can’t kill all of them.) “The idea is that
the docetaxel would potentially kill both the hormone-independent
and the hormone-dependent cells.” There are a few mild, reversible
side effects, including fatigue, a risk of a lowered blood count,
a risk of tingling or numbness, some swelling in the legs and
ankles, and modest hair loss. “This is an aggressive treatment,”
says Eisenberger. “We’re trying to see whether we can prolong
the time to PSA relapse,” a point when the blood’s PSA level starts
to climb. “Our objective is to double that time.”
Eisenberger and colleagues have just finished
taking part in a massive, 40-country study of docetaxel in men
with “hormone-refractory” cancer—men with metastatic disease after
months or years of being on hormonal therapy. “This study is going
to define a new standard for chemotherapy treatments for prostate
cancer,” says Eisenberger. “Over the last five years, docetaxel
has shown reproducible evidence of cancer- fighting activity.
In at least 50 percent of our patients, we get a remission.” Building
on this study, the Hopkins oncologists are launching new studies
to test docetaxel in combination with other drugs, including exisulind,
which is related to the antiinflammatory drug sulindac.
For
men with a rising PSA after surgery or radiation:
One trial for these men features the drug Gleevec. Although the
trial is currently full, if early results are successful, “we
will build on it,” Eisenberger promises. “Gleevec is a smart drug.
It blocks the signal for overproduction of a growth factor called
PDGF. About 60 percent of the patients in our prior trials appear
to overproduce PDGF.” In laboratory studies, Eisenberger and colleagues
have found that Gleevec appears to stunt the growth of prostate
cancer. The drug is already approved by the Food and Drug Administration
for use in a form of leukemia, and in a rare intestinal tumor.
“With these two diseases, the majority of patients can enter a
very remarkable, very impressive remission,” Eisenberger says.
In another trial, he is also studying Gleevec’s effectiveness
in men with a rising PSA who are taking hormonal therapy.
Another
trial for men with a rising PSA, who have not begun hormonal therapy,
features the drug atrasentan, which was developed at Hopkins several
years ago by urologist Joel Nelson and Carducci. It blocks a chemical
called endothelin, made by the endothelial cells that line blood
vessels. Endothelin is linked to both the excruciating, debilitating
pain that comes when cancer invades the bone, and the unique bone
damage found in some men with prostate cancer, in which the bone
becomes unnaturally thick and rock-hard. But it also may have
something to do with the progression of prostate cancer—and blocking
it, in addition to preventing or easing bone pain and damage,
may also slow or halt progression of the disease.
In this trial, led by Carducci, men with a PSA
of 0.6 to 5 are given either atrasentan or a placebo. “The goal
is to see whether atrasentan delays the progression of PSA’s rise,”
Eisenberger explains. Carducci’s research, conducted on men with
more advanced cancer, suggests that it can. “In studies of men
with metastatic bone disease, without symptoms, who had a rising
PSA after hormonal therapy, we found that the men who were treated
with atrasentan had a significant delay in the time to progression.
What we also showed fairly dramatically, was that the drug seemed
to target bone tissue and be protective against damage and pain,
while the men in the placebo group continued to progress.” That
work has led to an expanded Phase III study, under way in the
U.S. and Europe.
There are many more drugs being studied, including
one that has no name yet— for men with advanced cancer. This drug,
called MLN-2704, is genetically engineered to target cells that
make PMSA (prostate-membrane specific antigen, an enzyme that’s
made on the surface of prostate cells). “A monoclonal antibody
is hooked up to a chemotherapeutic agent that kills cells,” explains
Eisenberger, “so it’s a smart bomb.”
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