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The Prostate Cancer InfoLink


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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