Combined Hormonal Therapy in the Treatment of Advanced Disease
Combined hormonal therapy: an introduction |
CHT: a general overview |
The initial NCI trial: NCI 0036 |
The Janknegt trial |
Other important trials of CHT for the treatment of advanced prostate cancer |
Making sense of meta-analysis |
Unanswered questions about the use of CHT |
What is intermittent hormone therapy?
Combined hormonal therapy: an introduction
Combined hormonal therapy for the treatment of advanced prostate cancer
is not a new idea. It dates back at least to the 1940s, when
Charles Huggins and his colleagues first attempted to carry out
bilateral adrenalectomies on patients who had already received a
bilateral orchiectomy. However, this form of combined hormonal therapy
using surgical means was dangerous for the patient and proved to have
little long-term value. It was only with the availability of new forms
of pharmaceutical in the 1980s that this form of therapy for advanced
prostate cancer again became a practical possibility. It remains
controversial even today.
Modern combined hormonal therapy (CHT) or maximal androgen deprivation
(MAD) is based on the concept that if one could stop all of the
male hormones or androgens from being able to have impact on the
prostate cells, then one would completely stop the development of new
prostate or prostate cancer cells, thereby completely arresting the
progression of prostate cancer. Theoretically, this is an
appealing concept. However, it should be pointed out immediately that
the ability to completely shut down the development of prostate
cancer in this way is probably unrealistic; the question is, how close
can we get?
Elsewhere, we have already indicated that it was a Canadian physician,
Ferdinand Labrie, who initially suggested that by combining treatment
with an LHRH agonist (leuprolide acetate) and treatment with a
nonsteroidal antiandrogen (flutamide), it might be possible to achieve
better clinical effects than by using either drug on its own. While the
details of much of Labrie's work have come into question, there is now
little doubt that the principle which he suggested has had major impact
in the ways in which physicians and patients in many parts of the world
think about the treatment of advanced prostate cancer.
CHT is still not absolutely established as the "gold standard" for the
treatment of advanced prostate cancer, and in any case CHT can be
implemented a variety of differing methods. In these pages we will
offer a summary review of all of the major clinical trials which have
advanced our understanding of the appropriate use of CHT in the
treatment of metastatic prostate cancer. In addition, we will attempt
to provide some guidance for patients on the areas which are clearly
CHT: a general overview
Well over 20 different randomized trials have now been carried out with
the stated purpose of evaluating CHT and comparing it to other forms of
hormonal therapy for the treatment of advanced prostate cancer. Despite
all this effort, we still do not have any consensus in the urology
community. A skeptic could easily come to the conclusion that the
"right" trial still had not been carried out!
The first problem that patients need to appreciate is that many of these
trials are certainly not good trials. They had more to do with
getting drugs approved in different countries around the world than they
did with gaining a true appreciation of the clinical value of CHT. The
second problem is that at least five more trials used a steroidal
antiandrogen (as opposed to a nonsteroidal antiandrogen) in combination
with the method of testosterone ablation (e.g., the LHRH agonist).
There are serious questions about the value of steroidal antiandrogens
in the treatment of prostate cancer, and particularly about their value
At the present time The Prostate Cancer InfoLink would suggest that the
only forms of CHT which should be seriously considered for the treatment
of advanced prostate cancer are the following:
Certainly these two forms of CHT are those which have been most widely
evaluated in the best constructed clinical trials to date, and even then
there are outstanding questions.
- (a) An LHRH agonist + a nonsteroidal antiandrogen
Orchiectomy + a nonsteroidal antiandrogen.
It would appear that it is possible to draw the following very general
conclusions from the large, well constructed clinical trials which seem
to meet most of the criteria necessary for a meaningful evaluation:
The outstanding questions about CHT will be addressed below or in the
pages on intermittent CHT, which is an
experimental form of CHT currently under clinical evaluation.
- First, CHT appears to extend overall patient survival in
patients with stage D2 (or M1) disease by about 7 months, regardless of
the ultimate cause of death.
- Second, there is some evidence to suggest (but not to conclude) that
patients with stage D2 (or M1) disease who "only" had low levels of bone
metastasis and were otherwise in a relatively good state of health
respond far better than patients with later stages of the disease. The
only trial followed for long enough to actually establish a difference
in survival for such "early stage" patients appears to show a survival
benefit of 19 months for patients receiving CHT as compared to patients
receiving an LHRH agonist alone.
- There is little reason to believe that CHT using orchiectomy + a
nonsteroidal antiandrogen is either better or worse than CHT
administered by using an LHRH agonist + a nonsteroidal antiandrogen.
- We still do not know whether the survival benefit which appears to
result from long-term CHT would in fact be evident if the patients
received only short-term CHT to overcome the so-called "flare" reaction
which results from initial LHRH therapy. However, since there is no
"flare" response to orchiectomy, and at least one trial has now clearly
shown that CHT with an orchiectomy + a nonsteroidal antiandrogen had a
7-month cancer-specific survival benefit, it now seems less likely that
short-term antiandrogen therapy to prevent flare is as valid as
The initial NCI trial: NCI 0036
The first major clinical trial ever initiated to evaluate CHT was
organized by the National Cancer Institute and became known as NCI 0036
or the "Intergroup" trial. It was initiated in 1984, and there is
little doubt that many participated in this trial with the clear belief
that it would prove that CHT did not offer any benefit to
patients as compared with older forms of hormonal therapy.
According to a story told by one of the principle investigators, they
were so keen to proved that CHT didn't work that they tried to publish
the results at least twice before the trial reached a point when half of
the patients had died (and therefore before the true value of CHT would
have been known.)
Over 600 patients were enrolled into this trial, all of whom had stage
D2 prostate cancer. Half received an LHRH agonist (leuprolide acetate)
+ the nonsteroidal antiandrogen flutamide. The other half received the
same LHRH agonist and a placebo (a sugar pill that looked like the
nonsteroidal antiandrogen flutamide, but actually wasn't.) This type of
trial, in which neither the patients nor the investigators know which
patient is receiving which form of therapy is known as a
double-blind trial. This is important, because many trials are
not double blind, which means that the investigators or the patients can
affect the results of the trial because of their knowledge.
When half of the patient had died, and the results were analyzed in
1989, it was clear that the patients in the CHT arm of the trial -- on
average -- were living longer than the patients in the LHRH only arm of
the trial, by about 7 months overall. The US Food and Drug
Administration promptly approved flutamide (Eulexin/Schering) as the
first nonsteroidal antiandrogen for the treatment of stage D2 prostate
cancer patients in combination with an LHRH agonist.
As time progressed, and the data were more carefully analyzed, it became
evident that there was a small subgroup of patients in this trial that
were going to have a survival benefit that was far better than just 7
Because of the way in which this trial was set up there were equal
numbers of patients in each arm of this trial who had so-called "good
performance status." As compared to the average patient in this trial,
these "good performance status" patients had lower levels of disease
burden, with lesser levels of bone metastasis and a generally better
quality of life at the time that the trial began. There were 41 such
patients in each arm or the trial. By 1992, eight years after the trial
had begun, half of each of these two groups of patients had died, and
there was a clear survival benefit of 19 months for the patients who had
Some physicians have never considered that this trial (or indeed any
other) has effectively demonstrated the value of maximal androgen
deprivation. It is certainly fair to say that there were many
physicians who believed that until the results of this trial were
substantiated, it was difficult to justify changing their treatment for
advanced prostate cancer on the basis of this one trial. However, as
more evidence has come to the fore, the majority of the prostate cancer
treatment community now seems to consider that CHT is the preferred form
of therapy for patients with clear signs and symptoms of advanced
The Janknegt trial
For over 40 years prior to 1990, orchiectomy had been considered the
"gold standard" for the treatment of advanced prostate cancer. Despite
the availability of LHRH agonists and all of the other innovations, it
still remains the "gold standard" for the world's urologists because as
yet we have not proven that combined hormonal therapy is truly a better
choice under all circumstances.
Only two large trials have so far been carried out with the intention of
clearly evaluating the benefit of CHT using orchiectomy + a nonsteroidal
antiandrogen as compared to orchiectomy + a placebo. The first of these
two trials was an international trial carried out by Dr Janknegt and his
colleagues. This trial will be discussed here in detail. The second
such trial is known as the Southwest Oncology Group trial 8894 (SWOG
8894) or the NCI Intergroup trial 0105; this trial is expected to report
its results some time in 1996.
The Janknegt trial enrolled just over 450 patients with stage M1 (stage
D2) prostate cancer, and was generally similar to the initial NCI trial
discussed earlier. The major differences were as follows:
Because the Janknegt trial enrolled a smaller number of patients than
the original NCI trial, the results of the trial are not quite as
definitive. However, the key results from this trial are as follows:
- First, patients were randomized to receive either an
orchiectomy and a nonsteroidal antiandrogen (nilutamide) or an
orchiectomy and a placebo. In other words, this trial replaced the LHRH
agonist used in the NCI trial with orchiectomy and used a different
nonsteroidal antiandrogen. Otherwise there were few meaningful
differences between these two trials.
- Second, the PSA test was now available to carefully monitor patient
progression. At the time of the original NCI trial the PSA test was
still in development and so was not available for carefully monitoring
The investigators concluded that the combination of orchiectomy and
nilutamide was superior to orchiectomy alone in the first line treatment
of patients with metastatic prostate cancer. Others were not completely
- (a) Patients receiving CHT showed signs of disease progression
an average of 6 months later than those who received orchiectomy
- (b) Patients receiving CHT and who died from prostate
cancer survived for an average of 37 months, whereas patients who
received only an orchiectomy and who died from prostate cancer survived
for an average of 30 months.
- (c) Patients who received CHT were
more likely to achieve normal PSA values (and to achieve them faster)
than patients who received only an orchiectomy.
Other important trials of CHT for the treatment of advanced prostate cancer
As we have mentioned, there have been many other clinical trials which
have attempted to add to our knowledge regarding the potential benefit
of CHT in advanced prostate cancer as compared to various forms of
The problems with these trials is that some included a variety of
different patient categories in an unstratified manner, others simply
did not include enough patients to allow for differences in the results
between the patient groups to become evident, and still others were not
double-blinded, which means that patient or investigator knowledge may
have prejudiced the trial results. This is critical in evaluating the
large trials which have been used to suggest that there is no benefit to
The European Organization for Research and Treatment of Cancer (EORTC)
compared bilateral orchiectomy alone to CHT with an LHRH agonist and a
nonsteroidal antiandrogen in patients with stage M1 disease. This trial
included 320 patients on whom there was sufficient data to assess
survival. After a median follow-up of 5 years, the authors reported a 7
month survival advantage in favor of the group receiving CHT. This
result is very similar to the overall result of the original NCI trial,
despite the fact that both the patients and their physicians clearly
knew exactly which form of therapy that each patient had received.
The Danish Prostatic Cancer Group conducted a very similar trial to the
EORTC. Patients were also randomized to receive bilateral orchiectomy
or an LHRH agonist and a nonsteroidal antiandrogen. However, no all of
the 262 patients entered into this trial had stage M1 disease. A small
number had only locally advanced disease. In this trial there was no
overall or cancer-specific survival benefit for CHT compared to
Finally, two other relatively large trials claim to show no benefit for
CHT over an LHRH agonist alone. However, both of these two trials
included patients with locally advanced and advanced disease; neither
trial was double blind; and there are other technical reasons to
consider that these trials might be flawed.
Making sense of meta-analysis
There has been a recent trend in medical science to use data from many
different trials to carry out what is known as "meta-analysis."
Basically, this is a statistical method of putting all the data from
several trials together in order to try and make final decisions about
the value of a specific type of therapy. Such meta-analysis has been
used in attempts to demonstrate the value of adjuvant hormonal therapy
in breast cancer, of CHT in advanced prostate cancer, and of other
treatments in other diseases.
In mid-1995 a paper in a major English medical journal, The
Lancet purported to demonstrate that CHT was not, in fact,
clinically superior to hormonal therapy with bilateral orchiectomy or
other forms of single hormone therapy. It is the opinion of The
Prostate Cancer InfoLink, and of several reputable authorities, that
this meta-analysis of the available CHT data was flawed by the inclusion
of improperly constructed trials and trials which had used steroidal (as
opposed to nonsteroidal) antiandrogens. The Prostate Cancer InfoLink
recognizes that there are several unanswered questions about the value
of CHT in the treatment of advanced prostate cancer. However,
attempting to mix data from very different types of clinical trial does
not help to clarify the situation.
Unanswered questions about the use of CHT
[Reminder: This was written in 1995.]
There are a significant number of unanswered questions about the use of
CHT in the treatment of advanced prostate cancer (quite apart from its
other potential uses which are dealt with elsewhere in The Prostate
The first and most important question is, "When should a patient start
to receive CHT (or indeed any other form of hormone therapy)?" Bluntly,
we still don't know the answer to this question. There are a series of
These are difficult issues. So far there is only one large clinical
trial in place which is attempting to answer these questions as they
affect the use of CHT in advanced prostate cancer. That trial (SWOG
8894, also known as NCI Intergroup trial 0105) is expected to report its
findings at some point in 1996. It is an important trial, constructed by
many of the same individuals who constructed the original NCI trial of
CHT. Its results are eagerly awaited.
- A patient could start to receive CHT as soon as he is
diagnosed as having metastatic prostate cancer. The problem with this
is that it is very difficult to tell exactly when a patient starts to
have metastases. There is no problem when a patient clearly has signs
of metastases on a bone scan, and some physicians have suggested that
the majority of patients with a PSA of 20 ng/ml or more very likely will
have metastases, but as yet there is no definite way to tell that a
patient has a microscopic metastatic site of prostate cancer outside the
prostate until it becomes apparent on a bone scan.
- A patient could start to receive CHT once he has clearly
failed definitive treatments such as surgery or radiation and his PSA
starts to rise. However, we do not know whether this is a good idea.
It may be better to delay therapy until the first clear symptoms of
metastatic prostate cancer (e.g., bone pain) start to appear.
- A patient could delay starting CHT until the first clear symptoms of
metastatic prostate cancer start to appear. However, is it possible
that in this case we will fail to gain the greatest possible benefit
from CHT in terms of patient survival?
What are some of the other questions to which we would like answers?
Well, they include the following:
- What is the "best" form of CHT? Is one LHRH agonist better
than another? Is one nonsteroidal antiandrogen better than another?
- Might it be possible to carry out "intermittent" CHT with a similar
degree of effectiveness as continuous CHT?
- Can we develop other
forms of hormonal therapy which will be better than the presently
available forms of CHT?
What is intermittent hormone therapy?
Intermittent hormone therapy is an
investigational form of CHT which may offer new benefits to patients and
is currently undergoing careful evaluation in clinical trials. It will
be some years before we are able to know its true value as compared to
other forms of hormonal therapy.