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The Prostate Cancer InfoLink

Antiandrogen Withdrawal in the Treatment of
Hormone-Refractory Prostate Cancer

Last Revised January 6, 1996
[Newer findings may change this information. For education only.]

Introduction | The flutamide withdrawal syndrome | Withdrawal of other antiandrogens | The theoretical basis of the antiandrogen withdrawal effect | Clinical recommendations for antiandrogen withdrawal

Introduction

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+ a nonsteroidal antiandrogen there is an odd effect which can occur if the nonsteroidal antiandrogen is stopped or "withdrawn" when the combined hormonal therapy begins to stop working.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 tissue metastases.

This effect has now been documented in up to half of the patients who have flutamide withdrawn when their PSA starts to rise.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 effect

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 withdrawal

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.


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The content in this section of the Phoenix 5 site was originally developed by CoMed Communications (a Vox Medica company) as part of The Prostate Cancer InfoLink. It is reproduced here with the permission of Vox Medica.

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