in the Treatment of
Last Revised January 6, 1996
Hormone-Refractory Prostate Cancer
[Newer findings may change this information. For education only.]
The flutamide withdrawal syndrome |
Withdrawal of other antiandrogens |
The theoretical basis of the antiandrogen withdrawal effect |
Clinical recommendations for antiandrogen withdrawal
We still do not have an absolute understanding of why this happens,
but it is now clear that for many patients who receive combined
hormonal therapy with either an orchiectomy + a nonsteroidal antiandrogen
or an LHRH agonist + a nonsteroidal antiandrogen there is an odd effect which
can occur if the nonsteroidal antiandrogen is stopped or "withdrawn" when
the combined hormonal therapy begins to stop working.
The clear sign that combined hormonal therapy has stopped working is a
gradual rise in the patient's PSA (usually from undetectable levels into single
or double digits) over a matter of a few months.
The flutamide withdrawal syndrome
The antiandrogen withdrawal effect was first noted in patients who had received
the nonsteroidal antiandrogen flutamide (Eulexin) as part of their combined
hormonal therapy. As a consequence it was initially known as the "flutamide
withdrawal syndrome." When the PSA level rose to about 20 ng/ml and it was
clear that combined hormonal therapy was failing, some physicians would stop
the patients' flutamide on the ground that there was no point to continuing
this form of therapy. Then they noted that over the next month the patients'
PSA level could drop back to nearly undetectable levels for a matter of weeks or
months. In some patients, it has even been indicated that this decline in PSA
level can be associated with clinical responses in patients with soft
This effect has now been documented in up to half of the patients who have
flutamide withdrawn when their PSA starts to rise. However, we still do not
know precisely why it occurs.
Withdrawal of other antiandrogens
Until very recently it was uncertain whether this effect was exclusive to
flutamide or whether it was an effect which was common to all antiandrogens.
Recent information makes it clear that this effect is also seen on withdrawal
of bicalutamide (Casodex). However, there do appear to be distinctions between
the effects observed on withdrawal of flutamide and on withdrawal of
bicalutamide. Presumably these distinctions are related to the detailed
mechanisms of action of the two drugs.
On a very preliminary basis, it
seems that withdrawal of bicalutamide results in a slower but more long-lasting
effect than withdrawal of flutamide. Whether this is of any clinical importance
is not currently known. However, physicians and patients should be aware
that withdrawal of bicalutamide does not result in an immediate
decline in PSA levels. The response may not be observed for several weeks or
even a couple of months
after drug withdrawal. Since bicalutamide has a significantly longer
"half-life" (a measure of the period for which a pharmaceutical is active)
than flutamide, this difference in effects is perhaps to be expected.
The Prostate Cancer InfoLink is not currently aware of any information on
the existence of an antiandrogen withdrawal effect following withdrawal
of nilutamide (Anandron) or any of the steroidal antiandrogens. It is likely
that a similar effect will be observed as a consequence of nilutamide
withdrawal. However, it may be that this effect is exclusive to the
nonsteroidal antiandrogens and will not be seen on withdrawal of any of the
steroidal antiandrogens such as cyproterone acetate (Andocur).
The theoretical basis of the antiandrogen withdrawal
The possibility exists that the nonsteroidal antiandrogens -- while blocking
the effects of dihydrotestosterone-receptor complexes on the synthesis of
new protein in prostate cancer cells -- may also have a stimulatory effect
on mutated androgen receptors in prostate cancer cells. Since it is
believed that hormone-refractory prostate cancer results from the growth
over time of mutated prostate cancer cells which do not respond to the normal
forms of hormonal manipulation, this particular suggestion would certainly
account for the clinical effects that are observed in some patients.
The Prostate Cancer InfoLink will attempt to offer a better explanation for this
effect once one becomes available.
Clinical recommendations for antiandrogen
It is now widely recommended by experts in the treatment of advanced prostate cancer
that in patients who have been receiving complete hormonal therapy and
who show clear signs of disease refractory to this form of therapy that
the first manipulation to be carried out should be withdrawal of the
antiandrogen component of the complete hormonal therapy. However, patients
who are receiving LHRH agonist analogs for suppression of their testosterone
should be maintained on this form of treatment.
Patients need to understand that the effect of antiandrogen withdrawal is
always palliative and temporary. However, it can prolong the period
of effective therapy with orchiectomy or LHRH agonists by many weeks or months
before the patient's PSA level begins to rise again.