The Use of Nonsteroidal Antiandrogens in Treatment of Advanced Disease
Introduction | What are nonsteroidal antiandrogens, and how do they work? | The clinical effectiveness of nonsteroidal antiandrogens in prostate cancer | The side effects of nonsteroidal antiandrogen therapy
Introduction
The nonsteroidal antiandrogens were for years a class of drugs looking
for a disease. It was the work of Ferdinand Labrie in Canada, who first
used these drugs in combination with the LHRH agonists, which first
showed the true potential of these agents in treatment of prostate
cancer.
Even today, the two nonsteroidal antiandrogens (flutamide and
bicalutamide)currently available in the US are exclusively approved by
the Food and Drug Administration for use in combination with an LHRH
agonist for the treatment of advanced forms of prostate cancer. They
are only rarely used on their own. For this reason, a great deal of
relevant information on the use of the nonsteroidal antiandrogens in the
treatment of advanced prostate cancer will be found in the section on combined hormonal therapy
What are nonsteroidal antiandrogens, and how do they work?
Nonsteroidal antiandrogens are agents which act on the male hormones
(androgens) but have no steroidal effects. In other words they are
"pure" antiandrogens. Their methods of action appear to vary in detail
from drug to drug. However, both flutamide and bicalutamide have the
effect of blocking the action of dihydrotestosterone in stimulating the
synthesis of new protein in prostate and prostate cancer cells.
In the prostate the male hormone testosterone is converted into a
structurally similar biochemical called dihydrotestosterone or DHT.
DHT is the "active" molecule in the prostate which acts on the prostate
and prostate cancer cells to stimulate new growth. The precise details
of this mechanism of action are complex and are still not completely
understood. However, both flutamide and bicalutamide are able to
interfere with the way in which DHT stimulates prostate cell growth when
it is combined with other molecules in the cell. The effect is to
drastically slow the growth of new prostate and prostate cancer
cells.
The clinical effectiveness of nonsteroidal antiandrogens in prostate
cancer
The clinical effectiveness of the nonsteroidal antiandrogens in the
treatment of advanced prostate cancer has been tested in various ways.
Both flutamide and bicalutamide have been tested for their clinical
effect as single agents in the treatment of stage D2 prostate cancer at
various doses. There is no evidence to suggest that they have any
particular effect on the progression of stage D2 disease when used as
single agents.
On the other hand, bicalutamide, flutamide, and nilutamide have all
been tested for their value in so-called "combined hormonal therapy"
(CHT) or "maximal androgen deprivation" (MAD). It is in this setting
that these nonsteroidal antiandrogens have shown their greatest utility
to date.
The side effects of nonsteroidal antiandrogen therapy
The major long-term side effects of nonsteroidal antiandrogens in the
treatment of prostate cancer are as follows:
- Gynecomastia or nipple tenderness in which there is mild
swelling or at least tenderness of the man's breasts are frequent,
although not as frequent as in DES therapy.
- Diarrhea is observed in a significant percentage of patients.
A significant proportion of patients discontinue treatment with
nonsteroidal antiandrogens because of this problem. There is data from
one trial which suggests that this side effect is much less prevalent in
patients receiving bicalutamide than it is in patients receiving
flutamide. Confirmation of this data would be helpful.
- Hepatotoxicity or toxic effects on the liver have been
observed in very small numbers of patients but can be very serious.
Other side effects which have been observed include nausea and vomiting,
headaches, and other less serious adverse reactions.
An important side effect which is not observed in patients
receiving monotherapy with nonsteroidal antiandrogens is impotence.
Studies are known to be continuing on the potential use of antiandrogens
as single agents for treatment of prostate cancer because, if these
drugs could be shown effective at appropriate doses as single agents,
they would make it possible for patients to continue to have normal
sexual function.
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