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Management of Metastatic Disease |
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Prostate Cancer Update 2005 (3)
DR E DAVID CRAWFORD: The SWOG-S9346
study of intermittent therapy,
which has been ongoing for a number of
years, has accrued over 2,000 patients.
Men with newly diagnosed, untreated
metastatic disease receive combined
androgen ablation. At nine months, if
their PSA drops below 4 ng/mL, they
are randomly assigned to continuous or
intermittent therapy.
With intermittent therapy, the
patient resumes hormonal therapy when
his PSA goes up to a predetermined level
— usually half of the baseline level or
10 ng/mL.
The whole idea is to provide a hormonal
therapy holiday to reduce toxicity
and cost. Integrated in that trial is
the use of bisphosphonates, particularly
zoledronic acid, to evaluate its effect on
bone disease.
We have enough data suggesting
that intermittent therapy is probably
not going to make the patient’s scenario
worse — at least that’s what has been
reported. Whether it’s going to be better
is unknown. If it’s the same as continuous
therapy, it’s a no-brainer that intermittent
therapy would be the choice, as
patients can have a drug holiday with
fewer side effects and less expense.
Prostate Cancer Update —
Think Tank Issue 1, 2006
DR KLOTZ: Dave Crawford is leading a
trial of intermittent therapy in metastatic
disease, and we are leading one in Canada
in biochemical failure after radiation
therapy. These trials are not yet mature,
but we have data from a Portuguese trial
that has just been reported. Click on the image to enlarge
In the Portuguese trial, 630 patients
with locally advanced or metastatic disease
were randomly assigned to intermittent
versus continuous therapy with
an LHRH analog and cyproterone acetate,
following three months of induction
therapy. The Europeans tend to use three
months of induction therapy, whereas in
the United States and Canada it tends to
be more like eight months to a year.
Although a lot of studies have reported
preliminary results showing no difference
in mortality, the event rate is low.
However, in this trial the majority of
patients have died, and prostate cancer
was thought to be the cause in approximately
two thirds of the deaths in both
arms.
Despite stratification by PSA at randomization
or metastatic status, there
was no difference between therapies and
absolutely no difference in survival. I
believe this is excellent support for the
concept that the time to androgen-independent
progression and prostate cancer
survival are not significantly different
between the two approaches.
Prostate Cancer Update — Think Tank Issue 1, 2006
DR SCHELLHAMMER: In 2000, the
Prostate Cancer Trialists’ Collaborative
Group conducted a meta-analysis and
found a 2.9 percent five-year survival
benefit for patients receiving maximal
androgen blockade with flutamide and nilutamide. In a trial with more than
800 patients with metastatic disease that
compared two different CAB constructs
— bicalutamide versus flutamide — a
trend to benefit in survival was evident
for patients on the bicalutamide arm. Click on the image to enlarge
Click on the image to enlarge
Currently, a trial in Japan is comparing
an LHRH agonist with or without
bicalutamide. The preliminary data
show an advantage in PSA progression
and progression to hormone-refractory
disease for adding bicalutamide.
An analysis by Dave Penson of maximal
androgen blockade with bicalutamide
shows an overall quality-adjusted
and overall per-year-of-life gain that is
reasonable with bicalutamide for MAB.
It’s within the construct of what we
accept from renal dialysis in patients
with renal failure.
Prostate Cancer Update —
Think Tank Issue 1, 2006
DR CRAWFORD: I believe maximal
androgen blockade is the gold standard.
Plenty of data from large randomized
Phase III trials support it. None of the
studies were negative, and I believe there
is a reason to administer it to patients
with metastatic disease.
Prostate Cancer Update—
Think Tank Issue 1, 2006
DR THOMAS E KEANE: The older studies
dealt with patients with more advanced
disease. In the Dijkman and Janknegt
studies, patients with heavy-volume
metastatic disease whose PSA levels
reached nadir as low as 0.5 had a seven-month
statistically significant survival
advantage.
We probably underestimated the
effect of maximal androgen blockade
and mistreated most of the patients. If
you have a patient whom you plan to
treat with an LHRH agonist, I recommend
maximal androgen blockade.
Interview, December 2006
DR PETRYLAK: My general approach to a
patient with metastases to the vertebrae,
if he’s symptomatic, is radiation therapy.
If he’s asymptomatic, however, I recommend
maximal androgen blockade with
bicalutamide 50 mg.
Interview, November 2006
DR EISENBERGER: I don’t recommend
maximum androgen blockade because
I participated in a key study that was
negative. In the overview analysis of the
prostate cancer trials, there was maybe a
two percent improvement in survival at
two years. However, that doesn’t mean
that a secondary and a tertiary hormonal
therapy are not valuable, so if a patient
fails gonadal suppression, then we can
attempt another form of hormonal therapy
and maybe that will be effective.
I do use intermittent androgen
suppression. My approach is to treat the
patient until the PSA reaches a nadir, and
I maintain it with two consecutive determinations
at least three months apart,
and then I stop it. Then I follow the patient with serum testosterone and measure
PSA levels every two or three months. Click on the image to enlarge
On average, approximately 12 to 18
months later the patient will need re-treatment
if we use a threshold of 10
to get started. We base our decision of
when to get started on our own experience
here at Johns Hopkins. Depending
on the doubling time, at that point the
development of bone metastases becomes
more of a threat.
Interview, October 2006
DR SMITH: Hormone therapy is my
approach to patients who present with
metastases. In the presence of bone
metastases, we will continue it forever. I
don’t routinely use intermittent therapy
for patients with bone metastases.
In very selected cases, I add chemotherapy.
One thing we can be fairly
cavalier about with hormone therapy is
that the response rate, even in metastatic
disease, is nearly 100 percent.
However, a few rare patients do present
with such burden of disease or in
unusual situations that I don’t feel comfortable
that they will respond — for
example, patients with PSA-negative
tumors who present with poorly differentiated
cancers and who are symptomatic
with bone pain and weight loss.
These are rare situations.
Those are selected patients whom
I have, in the past and present, elected
to treat with concurrent chemotherapy
from the beginning because we had little
basis on which to be certain they would
respond. We also didn’t have the luxury
of PSA to monitor their disease, meaning
we’d know they were failing by symptomatic
progression.
In the survey I said, “I would be
very likely to receive chemotherapy for
asymptomatic bone metastases after failing
hormone therapy.” Docetaxel is reasonably
well tolerated, and it has a survival
advantage.
Except for a patient who is not a candidate
for chemotherapy because of disability
or severe comorbid disease, it’s not
a question of will they receive it, but it’s a
matter of when.
I don’t think you have to wait until
patients have symptomatic bone metastases.
In some settings it might be reasonable,
but for myself I would choose to
be treated before I became symptomatic.
Interview, November 2006
DR EISENBERGER: We recently
published a paper in the July 2006
issue of Oncology on the evolving role of
cytotoxic chemotherapy in the treatment
of prostate cancer over the past 20 years.
A number of things have changed:
First of all, the patient population has
changed. We don’t see patients with
end-stage disease anymore because of the
lead effect we get from the routine use
of PSA. Our patients live longer and are
healthier today than they were before, so
they’re better candidates for treatment.
The second change is that we have
better treatments than before and there
are several choices, although only one
— docetaxel — has been shown to
prolong survival. There are approximately
six large, ongoing randomized trials
for patients with hormone-refractory
disease, and that is a bigger difference
from what we had before.
The third key issue is that cancer
treatment in general has become much
better. We try to target our therapies to
patients with less advanced disease, and
we can evaluate adjuvant therapy, which
is such an important issue.
I believe we will see the role of chemotherapy
move forward as it has in the
treatment of breast cancer. We took a
first step forward with docetaxel.
Now we are evaluating combinations like docetaxel/bevacizumab, docetaxel/calcitriol, docetaxel with a radiopharmaceutical,
and docetaxel/atrasentan. Click on the image to enlarge
Click on the image to enlarge
Maybe one of these regimens will take
us another step forward. Then we have
all the targeted compounds, and some
of them have shown synergism with taxanes.
I’m hopeful that over the next five
years or so we’ll have a new standard that
is better than docetaxel.
Prostate Cancer Update —
Think Tank Issue 1, 2006
DR PETRYLAK: Two randomized trials
published in 2004 established docetaxel-based
therapy as the standard of care for
hormone-refractory metastatic prostate
cancer.
In SWOG-S9916, a combination of
docetaxel and estramustine was compared
to mitoxantrone and prednisone.
The other study (TAX-327) compared
either weekly or every three-week
docetaxel with prednisone to mitoxantrone
and prednisone. Click on the image to enlarge
The consistency of the data in terms
of survival is remarkable. SWOG-S9916 demonstrated a two-month difference in
median overall survival and a 20 percent
reduction in the rate of death in favor of
the docetaxel-containing regimen.
TAX-327 demonstrated a 24 percent
reduction in the risk of death and a two-month
difference in median survival in
favor of the patients treated with every
three-week docetaxel.
Prostate Cancer Update 2005 (3)
DR EISENBERGER: The results from
those two trials are similar. In SWOG-S9916,
survival for the patients treated
with docetaxel and estramustine was
17.5 months compared to 15.6 months
for those on mitoxantrone and prednisone.
A PSA response occurred in 50
percent of the patients on docetaxel and
estramustine, compared to 27 percent of
those on mitoxantrone and prednisone.
The difference between the two trials
was in the toxicities. Although no head-to-head comparison was conducted,
estramustine with docetaxel was more
toxic than docetaxel with prednisone.
The most significant toxicities were
cardiovascular or thrombotic. Halfway
through SWOG-S9916, the protocol
was amended to include prophylactic
anticoagulation (ie, warfarin and aspirin)
for the patients treated with estramustine.
The patients that enrolled in the
TAX-327 trial had hormone-refractory
metastatic prostate cancer and a
testosterone level in the castrate range.
Patients were allowed to have received
only one prior chemotherapy treatment
with estramustine and were withdrawn
from anti-androgen therapy. The trial’s
endpoint was survival. We wanted to
detect a hazard ratio of 0.75 for survival
in favor of docetaxel.
The three treatment arms included:
(1) docetaxel 75 mg/m2 every three
weeks plus prednisone, (2) docetaxel
30 mg/m2 weekly for five out of six weeks
plus prednisone and (3) mitoxantrone
12 mg/m2 every three weeks plus prednisone.
We enrolled 1,006 patients over
two years, and the analysis occurred
about three and a half years after the first
patient was enrolled. Each treatment
arm had more than 300 patients.
With a median follow-up of about
20.7 months, the median survival
for patients treated with every three-week
docetaxel and prednisone was
18.9 months, compared to a median
survival of 16.5 months for those treated
with mitoxantrone and prednisone.
Forty-five percent and 48 percent of
patients treated with every three-week
and weekly docetaxel had a 50 percent
decline in their PSA that lasted for at
least three weeks, and 32 percent of the
patients treated with mitoxantrone and
prednisone had a 50 percent decline
in their PSA, which was significantly
different (p < 0.001).
About 30 percent of the patients in
the docetaxel arms had a reduction in
pain, compared to about 20 percent of
the patients treated with mitoxantrone
and prednisone.
The difference in the reduction in
pain between mitoxantrone with prednisone
and every three-week docetaxel
with prednisone was also significant
(p = 0.01). Few objective responses in
soft tissue metastases were reported in
all three arms.
The toxicity was as predicted with
these compounds, mostly myelosuppression.
Thirty-two percent of the patients
treated with every three-week docetaxel
and prednisone had myelosuppression
(Grade III/IV neutropenia), but less
than three percent had neutropenic fever,
documented sepsis or death. Only 1.5
percent of the patients receiving weekly
docetaxel and prednisone had myelosuppression
(Grade III/IV neutropenia),
compared to about 20 percent of the
patients on mitoxantrone and prednisone.
The incidence of febrile complications
was low and similar in all three treatment
arms.
The other toxicities were minor
(≤Grade II) and not dose limiting. There
was some neuropathy, fatigue and edema in the patients treated with docetaxel,
which is more toxic than mitoxantrone
and prednisone, but the toxicities were
reasonable. We had few episodes of significant
nausea and vomiting and some
changes in liver function tests. Alopecia
was reported more frequently with every
three-week docetaxel, and changes in the
nails and eyes were reported more with
weekly docetaxel. Click on the image to enlarge
About 16 percent of the patients on
weekly docetaxel discontinued treatment
because of an adverse drug reaction,
compared to only 11 percent on every
three-week docetaxel.
Prostate Cancer Update 2005 (3)
DR KLOTZ: In patients with metastatic
prostate cancer, two trials have shown a
survival benefit with docetaxel — TAX-327 and SWOG-S9916. This was widely
acknowledged to be a huge step forward
because, up to that point, chemotherapy
provided just a quality-of-life benefit. A
survival benefit is a major event.
Of course, the size of that benefit
was somewhere around two and a half
months. The trials compared docetaxel
to other chemotherapy regimens. Hence,
it’s definitely a significant event in the
history of the management of prostate
cancer.
Clearly, the standard of care is now
docetaxel, and it should be offered to
patients who have hormone-refractory
metastatic prostate cancer. The controversy
involves whether it should be
offered earlier, and those studies are
being conducted.
If a patient has a rapidly rising PSA
with hormone-refractory metastatic disease
— whether he’s symptomatic or not
— I believe it’s reasonable to treat him
with docetaxel. I use the PSA doubling
time as a surrogate marker for symptomatic
progression, because I know that the
patient is going to have symptoms soon.
If he has hormone-refractory disease
without evidence of recurrence, I don’t
treat him. Click on the image to enlarge
Click on the image to enlarge
Prostate Cancer Update 2006 (3)
DR FREEDLAND: The two large studies
that were published in The New England
Journal of Medicine showed that, relative
to treatment with mitoxantrone
and prednisone — which was the FDA-approved
standard of care for men with
hormone-refractory metastatic prostate
cancer — treatment with docetaxel and
prednisone every three weeks resulted in
a two-month survival advantage, from
about 16 months to 18 months.
How important is a two-month survival
benefit? Rather than ask that question,
the way to consider this is that we
have an agent that we know works in the
latest of late stages — hormone-refractory
metastatic disease, a year and a half
to live — and we see benefit.
A study that was published in the
Journal of Clinical Oncology showed that
for men with PSA recurrence, docetaxel
by itself is active, so we have an active
agent that improves survival in the late
to latest stages.
Now the key question is, if we use this earlier, can we achieve a similar 15
percent survival benefit? Click on the image to enlarge
Click on the image to enlarge
If we treat when the patient has five
years left to live, can we see nearly a year
— eight, nine months — improvement
in survival? Docetaxel has made the
medical oncologist interested in clinical
trials for prostate cancer, and previously
we weren’t seeing a lot of those.
Prostate Cancer Update 2005 (2)
DR GOMELLA: The data showing a
survival advantage with docetaxel-based
chemotherapy in patients with hormone-refractory
prostate cancer are provocative.
The two large trials reported at
ASCO in 2004 have made early chemotherapy
a more viable option. The tolerability
of docetaxel is also significantly
better than the estramustine-based therapies
that caused so much toxicity in the
1990s.
We are also seeing an emphasis on
a multidisciplinary team approach and
consulting with the medical oncologist
earlier in the management of prostate
cancer.
Previously, we didn’t have effective
chemotherapy regimens to offer patients
— nothing demonstrated a statistically
significant advantage in large prospective
randomized trials until mid-2004, when
the two positive docetaxel studies were
reported.
I believe we will see an intrinsic change
in the treatment of these patients as a
result of these data. In addition, other
compounds will be available in the next
couple of years that may further redefine
how patients with PSA recurrence or
progressive prostate cancer are treated.
Interview, October 2006
DR SLOVIN: Currently not many choices
exist for chemotherapy in the treatment
of metastatic prostate cancer. The clinical
trial indicated that docetaxel was
more efficacious than mitoxantrone-based
therapy for hormone-refractory
metastatic prostate cancer, with a two-month
survival benefit and a decline in
PSA.
In addition to docetaxel, I have had
a lot of success using doxorubicin, and
I’ve been impressed with vinorelbine
lately. Some Phase II clinical trials of
vinorelbine have been suggesting anywhere
from a 25 to a 75 percent reduction
in the PSA level.
I’ve used it and have seen some patients
who improved their performance status
and had their lesions stabilize and their
PSA decrease in the third-line setting.
Chemotherapy today is more effective
than it was 10 years ago, and it’s
better tolerated. Ten years ago we didn’t
have a standard of care. We were using
paclitaxel, under the investigational
umbrella, and it was becoming widespread.
We were limited by the neuropathy,
and it was replaced by docetaxel. In
the 25- to 30-year period before that, we
had nothing that was FDA approved.
Prostate Cancer Update 2006 (1)
DR FERRARI: I have extensive clinical
experience with docetaxel for the treatment
of prostate cancer. We have been
using docetaxel or taxane-based chemotherapies
since the late 1990s. Overall,
my experience with this agent has been
extremely positive.
I have seen many patients who are
highly symptomatic, either with bone
pain or obstructive symptoms. Some of
them come into the office in a wheelchair
or are hardly able to walk, and over the
course of two to three months, you see
remarkable changes both in their symptoms
and in their overall sense of well-being
and quality of life.
At times, as oncologists, we may be
reluctant to start treatments for these
patients because they are impaired in
terms of their quality of life or their ability
to move around, and we believe that
the weakness or fatigue associated with
chemotherapy could worsen their quality
of life. But, not surprisingly, because
of the response rates that docetaxel elicits
in the control of pain — not control
of PSA progression — these patients’
conditions reverse remarkably.
I could provide you with many anecdotal
stories, but I believe the most
significant aspect has been the overall
experience and what the major studies
ultimately showed.
Furthermore, it’s not simply a PSA
response or a 25 percent reduction in the
size of the metastases. More than anything,
it’s an improvement in their quality
of life and the ability in many cases to
return to their normal activities.
The side effects of docetaxel depend
on the schedule you administer. If we use
the standard every three-week schedule
— which is the schedule that has been
approved by the FDA in combination
with prednisone or estramustine — the
higher doses cause hair loss. Generally
it’s not full baldness, but hair thinning
and partial hair loss definitely occur.
Another symptom that we see is
fatigue. Generally, most men describe
fatigue within 72 hours or so after treatment.
If I treat someone on a Wednesday
or a Thursday, he might feel a bit more
fatigued on Saturday or Sunday but not
enough for that to carry over so he would
not be able to go to work on Monday.
Perhaps the most common side effect is
neutropenia. A decrease in the white cell
count generally tends to occur anywhere
between seven and 10 days post-treatment.
Prostate Cancer Update —
Think Tank Issue 1, 2006
DR KEANE: I have five or six patients
who have received chemotherapy. It
is remarkable how much better the
patients seemed after receiving a course
of docetaxel. A lot of people in the
community still live by the old paradigm
that chemotherapy is the last resort and
can’t be used until you have tried everything
else. I don’t think that holds true
anymore, and I think we need to bring
medical oncologists into the treatment of
prostate cancer earlier and earlier.
Prostate Cancer Update 2005 (2)
DR D’AMICO: Patients whose performance
status is good — such as men
under 65 years of age — tolerate docetaxel
well. They come in, receive the infusion,
go home, have a couple days with symptoms
and then go back to their routine.
Toxic deaths are rare, and few patients
require hospitalization for complications.
Growth factors can be used to bring
up blood counts if need be, and these
patients must have their counts monitored.
This is a new arena, not for medical oncologists but for the urologists
and radiation oncologists who deal with
patients with prostate cancer.
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