An Historical Appreciation of Treatment
The discovery of hormonal therapy |
The VACURG studies |
The development of LHRH agonists |
The work of Ferdinand Labrie |
Did combined hormonal therapy really work? |
for Advanced Prostate Cancer
Many people find it useful to understand the way in which treatments for
advanced prostate cancer have evolved over recent decades. So this is a
brief introduction to that evolution.
The discovery of hormonal therapy
In the late 1930s and early 1940s there were no effective treatments for
advanced prostate cancer other than pain management. We understood little
about the evolution of this disease and little about the endocrine
mechanisms which caused the spread of the disease initially within the
prostate and later throughout the body. Our appreciation of the nature
of prostate cancer was limited.
Then, in the early 1940s Dr Charles Huggins and his colleagues at the
University of Chicago started to investigate the biochemical mechanisms
which led to the spread of prostate cancer. They quickly recognized the
critical role of the male sex hormone, testosterone, in stimulating the
growth of prostate and prostate cancer cells. As a consequence, they
became the first group of physicians to treat a patient with advanced
prostate cancer with so-called "hormonal" therapy: they gave patients an
An orchiectomy or surgical castration removes the primary source of
testosterone in man. As a consequence, the amount of testosterone in
the body is reduced to about 5-10% of its original level. Huggins and
his colleagues discovered not only that they could reduce the painful
symptoms of prostate cancer, they also appeared to be able to slow the
progression of the disease. Several years later Huggins was awarded the
Nobel Prize for medicine for these and related discoveries.
Throughout the 1940s and 1950s, the work started by the Chicago group was
continued in Chicago and in various other centers across America. Among
the most interesting developments were an increasing appreciation of the
role of the so-called hypothalamic-pituitary-adrenal axis (made up of
three of the key endocrine glands) in the growth and development of the
prostate and prostate cancer. This led to the discovery that other forms
of hormone therapy could be used instead of surgical castration in order to
counteract the effects of testosterone. By far the most important of
these was the use of female sex hormones or estrogens such as
diethylstilbestrol (DES). For over 30 years the two standard forms of
treatment for patients with advanced prostate cancer were castration or
However, a number of other developments in the management of advanced
prostate cancer can also be traced back to the early work of Huggins and
his colleagues. Among the more important of these developments was the
recognition that the adrenal androgens had a role in the growth of
prostate cancer. Bilateral adrenalectomy or removal of the adrenal glands
was a relatively rare but accepted procedure in attempts to slow the
progression of prostate cancer in patients who were failing standard
hormone therapy. Some would consider that this form of therapy was the
earliest type of combined hormone therapy.
The Veterans Administration Cooperative Urology Research Group studies
The mid 1960s saw the first attempts to expand and formalize the treatment
of advanced prostate cancer through the use of randomized clinical trials.
The largest such trials comprised two studies planned and carried out by
the Veterans Administration Cooperative Urological Research Group (VACURG),
a relatively informal group of physicians working in VA hospitals. The
studies carried out by this group were, for their time, highly significant,
despite later suggestions of major flaws in their design.
The VACURG group was interested in two primary questions. (1) Was
orchiectomy + 5 mg of DES as good or better for the treatment of advanced
prostate cancer than orchiectomy alone or 5 mg of DES alone? (2) What was
the best dose of DES for treatment of advanced prostate cancer. However,
it is important to realize that an additional result of the VACURG studies
was the careful review and classification of tissue from over 2000
prostates which led to the Gleason grading
It is unnecessary for us to go in detail into the complexities of the
VACURG studies. Suffice it to say that they definitively documented that
DES treatment at high doses (5 mg/d) is associated with severe
cardiovascular side effects which could lead to death in a relatively
large number of men at risk for cardiovascular disease. In addition, they
argued that their studies showed that there was no benefit to early
hormonal therapy for prostate cancer. The latter claim has now been
partially discredited, leading to newer trials designed to reassess the
putative value of early hormonal therapy. The first trial which may be
large enough and well enough designed to answer this question will report
its results in 1996.
The development of LHRH agonists
The association of DES with important cardiovascular side effects was a
stimulus to research on new agents which could replace DES for the
hormonal treatment of prostate cancer. These agents needed to have
different effects on the endocrine cascade. However, the end result had to
be the same: they had to block the effects of testosterone on the prostate
which could stimulate the growth of prostate cancer cells.
The new agents which met these criteria were the
luteinizing hormone releasing hormone (LHRH) agonists.
These synthetic biochemicals mimic the effects of a hormone called
luteinizing hormone releasing hormone. This natural hormone is
made by the pituitary and acts on the hypothalamus to stimulate the
release of a second hormone called luteinizing hormone (LH).
Luteinizing hormone then stimulates the production of testosterone. By
flooding the body with synthetic LHRH agonist molecules, one stops the
body from producing the natural LHRH molecule. As a result, there is no
stimulation of LH release and so no stimulation of testosterone production.
The clinical use of LHRH agonists is a classic example of using a
biochemical "feedback" system to block the production of the normal end
product of a specific biochemical pathway.
In a major clinical trial conducted in the early 1980s, it was shown that
a daily injection of one of these LHRH agonists (leuprolide acetate) could
produce the same effects on patients with advanced prostate cancer as
3 mg/d of DES -- but without the risk of cardiovascular side effects.
Several other LHRH agonists have now been developed by different
pharmaceutical companies. Two of them are in relatively common use for
the treatment of prostate cancer in the US. Others are available in other
parts if the world.
The work of Ferdinand Labrie
With the availability of the LHRH agonists, researchers and clinicians
turned their attention to ways in which they could offer improved methods
for the treatment of advanced prostate cancer. One of these researchers
was a Canadian physician named Ferdinand Labrie.
Dr Labrie returned to some of the earlier work of Huggins and his
colleagues and came to the conclusion that, once one had successfully
blocked the effects of testosterone on prostate cancer, there were still
the adrenal androgens available which could be converted into testosterone
with the same impact. Although the adrenal androgens comprise only 5-10%
of the normal complement of male hormones, there was sufficient
experimental data to support Dr Labrie's beliefs. Luckily for Dr Labrie,
there was also another new pharmaceutical available which appeared to have
the effect that he sought, at least in animal models. That pharmaceutical
was flutamide -- the first nonsteroidal antiandrogen.
Flutamide and the other nonsteroidal antiandrogens work by blocking the
effects of DHT directly on the synthesis of new protein in the prostate
cell. As explained above, DHT is formed from testosterone and the adrenal
androgens. Labrie therefore argued that by giving an LHRH to block
testosterone production and a nonsteroidal antiandrogen to block the
effect of any DHT on the synthesis of
prostatic proteins, he had developed a potentially superior form of
treatment for advanced prostate cancer. He carried out clinical trials of
this new combination therapy and published results which have been debated
to this day. According to Labrie, in those first clinical trials, he was
able to show a significant survival benefit in some 80% of his patients.
Although these trials were not randomized nor were they blinded, the result
was a small flood of patients across the border from America to Montreal
to be treated by Dr Labrie's new method. American prostate cancer
specialists were not happy about this turn of events.
Did combined hormone therapy really work?
As told by at least one leading urologist involved in the clinical studies,
the American prostate cancer establishment set out to prove Labrie wrong.
In 1984 they initiated what came to be known as National Cancer Institute
Intergroup trial 0036, and this trial demonstrated exactly the opposite of
their expectation. This trial is discussed in more detail in a section on
combined hormonal therapy. However, the
trial clearly showed that patients who received an LHRH agonist and
flutamide had a median survival advantage over those who received only the
Several other studies have since been carried out on the use of so-called
combined hormonal therapy (CHT) or maximal
androgen deprivation (MAD) in the treatment of patients with advanced
prostate cancer. We still do not have final and conclusive evidence of
its clinical value, although the amount of data supporting this form of
therapy continues to accumulate.