Secondary Forms of Hormonal Manipulation
in the Treatment of Hormone-Refractory Prostate Cancer
Last Revised January 6, 1996
[Note: Developments in hormone therapy since this was written may change this information. For education only.]
Introduction |
Re-suppression of testicular androgens |
Suppression of adrenal androgen production |
Androgen receptor blockade |
Somastatin analogs |
Estrogens and progestins |
Final comments
Introduction
The nature of the forms of secondary hormonal manipulation that are available to any
individual patient will depend upon the form of primary hormonal manipulation which
that patient has previously received. With an increasing number of patients
now receiving
combined hormonal therapy or maximal androgen deprivation
as their primary form of hormonal therapy, there are fewer opportunities now available
than their used to be to attempt secondary hormonal manipulation. However,
as new pharmaceuticals become available, secondary forms of hormonal manipulation will
continue to have an important place in the management of patients who
fail first-line hormonal therapies.
For the purposes of this section only, we are going to assume that the
majority of patients in North America will now receive some form of
combined hormonal therapy as their first-line hormonal therapy. This will
certainly not necessarily be the case in other parts of the world,
so non-North American users of The Prostate Cancer InfoLink
should use this information with caution.
Re-suppression of testicular androgens
For some patients, suppression of testosterone with LHRH agonists may not
be as effective as it is for other patients. These patients may be
appropriate candidates for cessation of their LHRH agonist and its
replacement by an orchiectomy (with or without continuation of antiandrogen
therapy as considered appropriate by their physician).
The use of an orchiectomy to replace LHRH agonist therapy is commonly
attempted and can offer a period of additional clinical benefit to the patient.
However, there are no data to indicate that there is any absolute survival
benefit associated with this form of treatment and it is not considered to
be absolutely indicated for all patients whose PSA starts to rise after
effective treatment with combined hormonal therapy.
The Prostate Cancer InfoLink has heard of a number of cases in which patients
who are failing combined hormonal therapy are given an orchiectomy and
maintained on LHRH agonist therapy as well as their antiandrogen.
We are uncertain why any patient
should receive treatment of this type. On a theoretical basis there should be
no potential benefit whatsoever to surgical orchiectomy in combination with
medical orchiectomy using an LHRH agonist.
Suppression of adrenal androgen production
We have addressed the principle of androgen receptor blockade in other
places within The Prostate Cancer InfoLink (see
Antiandrogens and
Secondary androgen receptor blockade). However, a
different option available to the patient failing primary hormonal
manipulation is suppression of the production of the adrenal androgens.
The first attempts to suppress production of the adrenal antiandrogens date
back to the work of Huggins and his colleagues, who introduced occasional
surgical removal of the adrenal glands (adrenalectomy) in attempts to
prevent the production of the adrenal androgens in patients who had previously
received orchiectomies. However, this form of total adrenal androgen suppression
is no longer practiced solely as a form of treatment for prostate cancer.
Adrenal androgen suppression is currently carried out using a small number
of pharmaceuticals:
Information on the use of each of these classes of pharmaceutical or the
specific drug in question is given below.
Corticosteroids
Corticosteroids have been used for more than 40 years in the treatment
of prostate cancer. They can suppress the production of a hormone known as
adrenocorticotropic hormone or ACTH. Suppression of ACTH production results
in a significant reduction in the production of the adrenal androgens.
The most commonly used corticosteroids are hydrocortisone, prednisone, and
dexamethasone. All three products can induce significant reductions in PSA
levels and subjective responses in which the patient reports improvements
in his disease even though there may be no objective way to measure this
improvement.
The length of time for which patients can show subjective improvements as
a consequence of corticosteroid therapy appears to be extremely variable. In
at least once case a response lasting 38 months has been reported to treatment
with oral prednisone. However, only a small minority of patients will
respond will to corticosteroid therapy. In general responses are of short
duration (3 to 9 months) and occur in only 20-30% of patients. These patients
can show reductions in their PSA levels of 50% or more.
Ketoconazole
Originally developed for the treatment of fungal infections, ketoconazole
(Nizoral/Janssen Pharmaceutica) at doses of 200-400 mg three times daily has been shown to affect the
production of testicular and adrenal androgens.
Our appreciation of the actual value of ketoconazole in the treatment of hormone-refractory
prostate cancer has, however, been complicated by the fact that in many
clinical trials it has been used in combination with
corticosteroids.
Ketoconazole is assumed to work by inhibition of one specific step in the
normal pathway for steroid synthesis in men. In those trials in which
this pharmaceutical has been give on its own to patients with advanced
prostate cancer, there has been a 20-30% response rate which includes subjective
and objective responses. The addition of corticosteroids does not appear to
make any significant difference to these results, and in the majority of those
patients who do show a response, the nature of that response is stabilization
of their disease rather than any actual improvement in their condition.
The availability of the PSA test has, in recent years, allowed researchers
to attempt to assess the value of ketoconazole in a more objective fashion
than previously. It is now clear that ketoconazole treatment can result in
significant long-term reductions in PSA levels. However, it is not
clear that this reduction in PSA level is necessarily associated with any
noticeable clinical benefit for the majority of patients.
Information on the adverse effects commonly induced by ketoconazole can be
found in the section on
pharmaceuticals in the treatment of prostate cancer.
Liarozole
Liarozole is a new form of azole (which is the same class of pharmaceutical
as ketoconazole). This is an experimental pharmaceutical which is currently
being evaluated for the treatment of patients who have failed primary
hormonal therapy for prostate cancer.
At this time there is very little information available on the use of
liarozole. However, patients may be offered the opportunity to receive
this drug in clinical trials. Supposedly this agent has a greater degree
of safety and a higher degree of efficacy than ketoconazole. Limited
information about liarozole can be
found on
Gary Huckaby's Prostate Pointers web site;
The Prostate Cancer InfoLink wishes patients to be clear that this
information does not establish the effectiveness or safety of liarozole,
which has not yet been approved for clinical use anywhere in the world
outside organized clinical trials.
Aminoglutethimide
Aminoglutethimide (Cytadren/Ciba-Geneva), like ketoconazole, affects the
normal biosynthesis of steroids in man. Also, all of the clinical trials of
aminoglutethimide have combined its use with the use of
corticosteroids, so it is difficult to know
precisely how effective this drug is in the management of late stage
prostate cancer.
In one large series of patients who were failing combined hormonal therapy
with orchiectomy and flutamide, aminoglutethimide + low-dose hydrocortisone
gave a 14% response rate. More recent studies have once again shown that
aminoglutethimide can clearly induce a significant reduction in PSA levels.
However, as with forms of secondary hormonal manipulation, there is
considerable doubt as to whether these reductions in PSA level are of any
clinical significance when it comes to progression of the patient's disease.
Information on the adverse effects commonly induced by aminoglutethimide can be
found in the section on
pharmaceuticals in the treatment of prostate cancer.
Androgen receptor blockade
Two classes of androgen receptor blockers have been investigated and used clinically in the treatment
of patients failing primary hormonal therapy: the steroidal antiandrogens
(most specifically cyproterone acetate or Androcur) and the nonsteroidal antiandrogens
(flutamide, bicalutamide, and nilutamide).
Since one of the nonsteroidal antiandrogens is now customarily a component
of primary hormonal therapy using combined hormonal therapy, the critical
question which may arise now that other nonsteroidal antiandrogens have
become available is going to be can a patient who has received flutamide
(for example) as part of his primary hormonal therapy gain any benefit from
switching to bicalutamide or nilutamide once his primary therapy starts to
fail? The same question will be true for patients who initially receive
nilutamide or bicalutamide. It should be emphasize that at present there is
no evidence to suggest a significant clinical benefit from this type of
treatment. However, The Prostate Cancer InfoLink certainly expects this
method of lengthening the period of combined hormonal therapy to be
tried in the near future (if it has not already been tried). There
appears to be just sufficient difference between the mechanisms of action
of some of the nonsteroidal antiandrogens to believe in a potential value
from this strategy.
Conversely, there appears to be little or no clinical benefit available to
patients who receive antiandrogen therapy after LHRH agonist therapy or
orchiectomy starts to fail. Although antiandrogen therapy at this stage
may induce short-term reductions in patients' PSA levels, the disease
appears to progress without any significant period of stabilization.
Use of the steroidal antiandrogen cyproterone acetate appears to be
controversial. This pharmaceutical has never been approved for treatment of
any disease in the US. However, in some European countries it has been
(and continues to be) extensively used alone and in combination with
LHRH agonists and orchiectomy for the treatment of advanced prostate cancer.
The Prostate Cancer InfoLink, being primarily directed to US prostate cancer
patients and health care professionals, can not at this time see any
significant role of the use of cyproterone acetate given the expanding
availability of the nonsteroidal antiandrogens.
Somastatin analogs
Somastatin is a naturally occurring hormone that affects the levels of certain
other hormones in men and women (including growth hormone). There is
some evidence to suggest that somastatin analogs such as octreotide acetate
(Sandostatin/Sandoz) may
be able to affect the growth of prostate cancer, and this has certainly
been demonstrated in the laboratory. Pilot studies have indicated a
response rate of up to 20% in patients with hormone-refractory disease.
At this time the use of somastatin analogs for the treatment of patients with
any stage of prostate cancer is clearly experimental. However, patients may
be invited to participate in clinical trials of these agents. They should
ensure that they appreciate the nature of these trials and the potential
risks involved in using experimental pharmaceuticals. It should be noted that
in experimental therapy to date these analogs appear to be well tolerated.
Reported side effects include some mild abdominal and gastrointestinal effects.
Estrogens and progestins
As discussed elsewhere, there was a time
when estrogens such as diethylstilbestrol (DES) were extensively used for the treatment of prostate cancer.
Similarly, stilphostrol, a modified estrogen, was commonly used in the treatment of
patients who had failed primary hormonal therapy. This form of therapy is now very
rare. By comparison, the use of progestins is not unusual.
There are three progestins which have been used in the treatment of patients
failing primary hormonal therapy for prostate cancer: cyproterone acetate,
medroxyprogesterone acetate, and megestrol acetate. Cyproterone acetate has
been discussed previously in the section on androgen receptor blockade.
Megestrol acetate (Megace/Bristol-Myers Squibb) is certainly the progestin
which is most widely used in the management of hormone-refractory prostate cancer.
However, its true benefits are still being evaluated. The justification for the use of this
form of therapy appears to have more to do with its relatively low level of side effects
and the fact that it acts as an appetite stimulant, which thus assists
patients who may be debilitated in maintaining their weight and strength,
than it does with any direct benefit of the drug on the prostate cancer itself.
There
has been a recent trend towards the use of high-dose megestrol acetate at
doses of 640 mg/d as opposed to the lower traditional doses of 120-160 mg/d.
Whether this form of therapy will have a real impact in the treatment of
hormone-refractory prostate cancer awaits the results of recent clinical trials.
Medroxyprogesterone acetate (MPA)at doses of 500-1200 mg/d appears to have a low level of
activity in the treatment of hormone-refractory prostate cancer. Since the
adverse reactions to this drug are generally not as favorable as those to
megestrol acetate, MPA has very limited use in the treatment of prostate cancer and
is referred to here largely for purposes of completeness.
Final comments
It should be clear from the information provided above that all of the
currently available pharmaceuticals used in the secondary hormonal manipulation
of prostate cancer once primary hormonal manipulation starts to fail
have significantly limited value on the basis of research to date.
Patients should clearly recognize that in many cases, while these agents
may be able to offer reductions in PSA levels and subjective responses
(i.e., the drugs may make you feel somewhat better in the short term), their
long-term effect on progression of prostate cancer is liable to be minimal.
Patients may consider that they would be better advised to become involved in
clinical trials of new forms of therapy than to use older agents that are known to
have limited value. However, there are certainly some patients for whom older
drugs can offer improvement in quality of life in the short term which may
be of greater importance (and less risk) than newer drugs whose benefits are
utterly unknown.
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