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Pharmaceuticals Used to Treat Prostate Cancer

Last Revised July 27, 1996

[Note: Although the pharmaceutical market has changed since this was written, it still contains basic information that may be of value. For education only.]

Introduction | The names of pharmaceuticals | Different names in different countries | LHRH agonists |
Antiandrogens | Miscellaneous hormonally active agents | Chemotherapeutic agents


Introduction

The pharmaceuticals which will be discussed here are all prescription drugs. They should only be taken under the guidance of a physician, and preferably a physician with demonstrated experience in the management of prostate cancer. Many of these pharmaceuticals are indicated by the US Food and Drug Administration (FDA) for specific uses, but are also used by physicians outside those limited indications. We will attempt to be clear about the differences between the indicated uses of these products and the other uses which are either common or clearly experimental.

Brief references will also be found in this section to experimental pharmaceuticals which are currently not available in the US outside of clinical trials. We wish to emphasize that knowledge of the appropriate use of such pharmaceuticals is limited. A full understanding of the effectiveness and safety of any pharmaceutical will only become apparent after it is widely prescribed outside of the cautious parameters set in clinical trials. Patients who elect to receive experimental pharmaceuticals in clinical trials should recognize that there can be considerable risks involved in participation in such trials. They should be absolutely sure that they understand those risks prior to signing any form of agreement to participate.

The names of pharmaceuticals

Pharmaceuticals generally have at least three names, of which two are important from a clinical point of view. They have a "generic" name, which is the general name of the drug, regardless of who makes it and what color, shape, or form it comes in. For example, aspirin is aspirin regardless of who makes it or what bottle it comes in. A pharmaceutical very often also has a "brand" or "trade" name. This is the name given to it by the individual manufacturer of that particular form of the pharmaceutical (e.g., Bayer is a brand of aspirin or Tylenol is a brand of acetaminophen). Finally, a pharmaceutical always has a highly detailed chemical name which gives a precise description of the structure of the pharmaceutical.

In the following materials we have always given the generic name of the pharmaceutical first (e.g., flutamide) followed by the brand name in the United States and the name of the manufacturer (e.g., Eulexin/Schering Laboratories). We haven't worried about the chemical names. If you want to know these, you can usually find them in the prescribing information which is given to physicians and pharmacists and which is published in books like the Physician's Desk Reference.

Different names in different countries

It is most important for non-US readers of this information to understand that pharmaceuticals frequently have differing "brand" or "trade" names in different countries and may also be sold by different companies. However, the generic name is almost always unchanged.

Luteinizing hormone releasing hormone (LHRH) agonists

Three LHRH agonists are available in the US, of which two are widely used in the treatment of patients with prostate cancer. They are both synthetic analogs of a hormone known as luteinizing hormone releasing hormone. These two pharmaceuticals are leuprolide acetate (Lupron/TAP Pharmaceuticals) and goserelin acetate (Zoladex/Zeneca Pharmaceuticals). To all intents and purposes, from the point of view of the patient, the differences between these two pharmaceuticals are minor and it probably does not matter which of these two products your physician prescribes for you once the decision has been taken to give you this form of hormonal therapy.

Patients who receive an LHRH agonist as their hormonal therapy for the palliative treatment of advanced prostate cancer will normally continue on such drugs until they either have an orchiectomy or their prostate cancer becomes completely hormone refractory. The major side effect of treatment with LHRH agonists is hot flashes, most particularly those associated with an initial rise in a man's testosterone level during the first couple of weeks of treatment with these LHRH agonists. This initial rise in testosterone levels is rapidly followed by a subsequent fall in testosterone concentration to castrate levels.

Goserelin acetate (Zoladex/Zeneca Pharmaceuticals)

Goserelin acetate or Zoladex is indicated in its approved prescribing information for the palliative treatment of patients with advanced prostate cancer, and offers an alternative to the use of orchiectomy or estrogen therapy. Treatment with goserelin acetate suppresses the synthesis of testosterone as a consequence of its effect on the secretion of gonadotropin. Goserelin acetate is provided in the form of a once-monthly depot injection which is normally implanted under the supervision of a physician.

Goserelin acetate (like all LHRH agonists) initially raises the amount of testosterone in a patient's bloodstream. However, within about two weeks it has the effect of reducing the amount of testosterone to castrate levels, which effectively prevents the growth and division of prostate cancer cells and therefore lowers the amounts of PSA and PAP circulating in the patient's bloodstream. After initially placing a patient on goserelin acetate, the physician will normally give regular PSA tests to monitor the patient's PSA level. In the majority of patients, treatment with an LHRH agonist will reduce a patient's PSA value to an undetectable or very low level within two to four weeks.

Like other LHRH agonists, goserelin acetate is associated with a range of side effects which are common when this class of pharmaceuticals are used to treat men for prostate cancer. However, it is rare for these side effects to cause a patient to stop goserelin acetate therapy. The most common of these side effects are hot flashes, which occur in about two-thirds of all patients. Impotence and other forms of sexual dysfunction can occur, as can breast or nipple tenderness (gynecomastia).

Goserelin acetate is commonly used in the treatment of patients with stage T3 prostate cancer and later stages (N+ or M+) when the cancer is known to have escaped from the prostate and definitive therapy with surgery or radiation is no longer carried out with curative intent. In addition, goserelin acetate is now commonly used by some physicians either prior to surgery or radiation in some patients with localized prostate cancer (so-called neoadjuvant therapy) or immediately following surgery or radiation therapy (so-called adjuvant therapy). Some published data appear to support the clinical benefit of these adjuvant and neoadjuvant uses of LHRH agonists either alone or in combination with nonsteroidal antiandrogen therapy; however, they are not indicated for these uses by the FDA.

Approval to market a three-month implant formulation of goserelin acetate has been received by the manufacturer. It is expected that three-month formulations of LHRH agonists will, in time, become the common method of administration of these agents.

Leuprolide acetate (Lupron/TAP Pharmaceuticals)

Leuprolide acetate or Lupron is the pharmaceutical with which the largest number of US prostate cancer patients are perhaps familiar. It is indicated in its approved prescribing information for the palliative treatment of patients with advanced prostate cancer, and offers an alternative to the use of orchiectomy or estrogen therapy which is intended to suppress the synthesis of testosterone as a consequence of its effect on the secretion of gonadotropin. Leuprolide acetate first became available as a daily injection. However, it is now most commonly used in the form of a once-monthly depot injection which must be administered under the supervision of a physician.

Leuprolide acetate (like all LHRH agonists) initially raises the amount of testosterone in a patient's bloodstream. However, within about two weeks it has the effect of reducing the amount of testosterone to castrate levels, which effectively prevents the growth and division of prostate cancer cells and therefore lowers the amounts of PSA and PAP circulating in the patient's bloodstream. After initially placing a patient on leuprolide acetate, the physician will normally give regular PSA tests to monitor the patient's PSA level. In the majority of patients, treatment with an LHRH agonist will reduce a patient's PSA value to an undetectable or very low level within two to four weeks.

Leuprolide acetate is associated with a range of side effects which are common to LHRH agonists when used to treat men for prostate cancer. However, it is rare for these side effects to cause a patient to stop leuprolide acetate therapy. The most common of these side effects are hot flashes, which occur in about two-thirds of all patients. Impotence and other forms of sexual dysfunction can occur, as can breast or nipple tenderness (gynecomastia).

Leuprolide acetate is often used in the treatment of patients with stage T3 prostate cancer and later stages (N+ or M+) when the cancer is known to have escaped from the prostate and definitive therapy with surgery or radiation is no longer carried out with curative intent. In addition, leuprolide acetate is now commonly used by some physicians either prior to surgery or radiation in some patients with localized prostate cancer (so-called neoadjuvant therapy) or immediately following surgery or radiation therapy (so-called adjuvant therapy). Some published data appear to support the clinical benefit of these adjuvant and neoadjuvant uses of LHRH agonists either alone or in combination with nonsteroidal antiandrogen therapy; however, they are not indicated for these uses by the FDA.

Approval to market a three-month depot formulation of leuprolide acetate has been received by the manufacturer. It is expected that three-month formulations of LHRH agonists will, in time, become the common method of administration of these agents.

Antiandrogens

Antiandrogens have been used as single agents, but are most commonly used in conjunction with some form of castration (either orchiectomy or an LHRH agonist) to provide the patient what is believed to be the most complete form of androgen deprivation available at this time. You will find this form of therapy referred to by many names. Among the most common are combined hormonal therapy (CHT), maximal androgen deprivation (MAD), total androgen blockade (TAB), combined androgen blockade (CAB), and others. For more information about this form of therapy, please review the information in the section on treatment of advanced prostate cancer.

Bicalutamide (Casodex/Zeneca Pharmaceuticals)

Bicalutamide or Casodex is a nonsteroidal antiandrogen which was approved for clinical use in the US in October 1995 for the treatment of advanced prostate cancer in combination with an LHRH agonist. It has been available since early 1995 in some European countries.

Published clinical data on the use of bicalutamide support earlier suggestions that this antiandrogen has fewer side effects than either flutamide or nilutamide. In particular, bicalutamide does not appear to induce diarrhea, night blindness, or alcohol intolerance. Bicalutamide, like flutamide and nilutamide, is associated with effects on liver enzymes, which suggests that rare cases of hepatotoxicity may be seen with broader use of this compound.

The currently published data indicate that, in a direct comparison between bicalutamide + an LHRH agonist and flutamide + an LHRH agonist, the former was associated with a lower level of diarrhea and a potentially beneficial effect on overall time to treatment failure. However, there are as yet no data to support any survival benefit for bicalutamide compared to flutamide.

Bicalutamide has been investigated at a variety of dose levels. However, the initial recommended dose is 50 milligrams once a day in combination with an LHRH agonist. It has been suggested that the lower level of side effects (compared to flutamide and nilutamide) and the availability of a single daily dose may make bicalutamide the more appropriate first line antiandrogen for treatment of prostate cancer. However, it will be some time before we can attempt to assess physician and patient acceptance of bicalutamide following its approval.

Cyproterone acetate

Cyproterone acetate is a steroidal antiandrogen which is not available in the US. As far as The Prostate Cancer InfoLink is currently aware, there are no plans on the part of any pharmaceutical company to seek approval to market this product in the US. It is available in several other countries in the world, where it has been used alone or in combination with other agents in the palliative treatment of advanced prostate cancer. Careful students of the prostate cancer literature will find many references to this pharmaceutical.

In general, by comparison with the nonsteroidal antiandrogens, a steroidal antiandrogen such as cyproterone acetate has unwanted additional side effects which would make this product unacceptable to large numbers of physicians and their patients.

Flutamide (Eulexin/Schering Laboratories)

Flutamide or Eulexin was the first nonsteroidal antiandrogen to become available for the treatment of advanced prostate cancer in the US. It is still one of only two such products which physicians can offer their patients outside a clinical trial. Flutamide was initially indicated for the palliative treatment of metastatic prostate cancer (stage D2 or M1 disease) in combination with an LHRH agonist (i.e., leuprolide acetate or goserelin acetate). Recently, the manufacturer has also received clearance to market flutamide in combination with an LHRH agonist and radiation therapy for the management of stage B2 (T2b) and stage C (T3) adenocarcinoma of the prostate.

For many years most physicians did not consider that the addition of flutamide to other forms of hormonal therapy had any clinical value. However, two large clinical trials in recent years clearly demonstrated that there is a small but significant survival benefit of about 7 months associated with the addition of flutamide to LHRH therapy. Both of those trials were actually begun with the belief that they would prove that the addition of flutamide would, in fact, not show any benefit!

What we still do not know is exactly which patients are most likely to gain the most benefit from combination treatment with flutamide and an LHRH agonist. There is some evidence to support the idea that the prostate cancer patients who are most likely to benefit are those who are otherwise in good health and have "minimal disease," which is normally defined as metastatic prostate cancer which has only involved a small number of selected sites outside the prostate (so-called M0 or D1 disease). It should be noted that flutamide is not indicated in the US for treatment of this stage of advanced prostate cancer, although many physicians do, in fact, prescribe it for this stage of the disease. A second unanswered question is whether flutamide can be used in combination with orchiectomy instead of an LHRH agonist and have the same effect. A major clinical trial is currently investigating this possibility.

In discussing the LHRH agonists, we mentioned that they were being used outside of their accepted indication in neoadjuvant and adjuvant treatment of prostate cancer in association with definitive therapy for earlier stage disease. In many of these investigative procedures, the actual form of hormonal therapy which is being used is a combination of an LHRH agonist plus flutamide. As stated above, flutamide is now indicated for this application at least in selected patients with stage T2b and T3 disease in combination with radiotherapy.

Flutamide is prescribed as a 125 milligram tablet. The indicated dose is two such tablets to be taken every 8 hours. However, there is relatively little evidence to support this particular dose of flutamide. Some physicians will suggest lower doses of flutamide for some patients because of the side effects or the cost of this pharmaceutical.

When used in combination with an LHRH agonist, flutamide is associated with only one common side effect which does not occur on treatment with the LHRH agonist on its own. This side effect is diarrhea, which seems to occur in about 10 percent of patients or more and can be severe and prolonged. Customarily, physicians will initially try lowering the dose of flutamide in patients for whom diarrhea is a serious problem -- often to one tablet every eight hours instead of two tablets. However, there are some patients who are simply unable to tolerate flutamide. It was believed at one time that the diarrhea might be associated with lactose used to manufacture the flutamide tablet. However, there is no evidence to support this theory and significant information to suggest that the flutamide itself is the cause of the problem in individuals unable to tolerate this drug. A rare, but very important side effect of flutamide is a toxic effect on the liver (hepatotoxicity). A very small number of individuals worldwide have died following hepatotoxicity problems related to flutamide treatment. For this reason it is now recommended that patients be regularly and carefully monitored for liver problems if they are receiving flutamide.

Nilutamide (Nilandron/Hoechst Marion Roussel)

Nilutamide or Nilandron is the third oral nonsteroidal antiandrogen to be approved for clinical use in the USA by the Food and Drug Administration (FDA). (This product appears to have many trade names. For example, in Canada it is known as Anandron.)

Published clinical trial data on the use of nilutamide support the concept that nonsteroidal antiandrogens do, in fact, work as well in combination with orchiectomy as they do with LHRH agonists. However, nilutamide is associated with certain side effects which suggest that it may not be as useful as flutamide or other nonsteroidal antiandrogens currently in development. There appears to be no relationship between treatment with nilutamide and consequent diarrhea. By contrast, nilutamide has been associated with a significant incidence of impairment of adaptation to the dark (so-called night blindness), a slightly increased risk of nausea and other digestive disorders, and also with alcohol intolerance in some patients. While there are no known cases of hepatotoxicity leading to death as a consequence of treatment with nilutamide, this agent does have clear impact on liver enzymes, suggesting that rare cases of hepatotoxicity cannot be ruled out.

The known potential benefits of nilutamide compared to flutamide are that patients need to take this antiandrogen only once or twice a day as compared to three times a day for flutamide, and also that nilutamide has proven its value in combination with orchiectomy. Nilutamide should be taken as three 50 mg tablets twice a day (300 mg/d) for the first month and three 50 mg tablets once a day (150 mg/d) thereafter.

Miscellaneous hormonally active agents

Aminoglutethimide (Cytadren/Ciba Pharmaceutical Co.)

Aminoglutethimide has been used for many years to treat selected patients with advanced prostate cancer. Most experts would consider aminoglutethimide to be a "second line" hormonal intervention appropriate for selected patients who had failed initial hormone therapy (e.g., orchiectomy, LHRH therapy, or maximal androgen deprivation). This drug suppresses the synthesis of adrenal androgens and is frequently given in combination with hydrocortisone. Responses to this form of therapy have been varied. However, at best it offers a further palliation of disease progression and can effect a significant reduction in PSA levels.

Aminoglutethimide has not been approved in the US for the treatment of advanced prostate cancer, but clinical trials of this drug in this condition have included more that 500 patients. Doses used have ranged from 1000 to 1750 mg/d. The drug is associated with a broad range of very common side effects which can include lethargy, nausea, and skin rashes. Rarer side effects which a physician needs to watch for include peripheral edema (swelling of the extremities), hypothyroidism (an overactive thyroid gland), and abnormal liver function.

Diethylstilbestrol

Diethylstilbestrol (commonly abbreviated to DES) is a synthetic analog of the female hormone estrogen. For many years before the development of the LHRH agonists, DES was the only widely available option to surgical castration (orchiectomy) which could lower a man's testosterone levels and therefore reduce the risk of cancer progression.

DES can have some very serious side effects, particularly in patients who have a history of cardiovascular disease. DES has been associated with an increased incidence of heart attacks, strokes, and other circulatory problems, particularly at doses of 5 milligrams a day, which used to be a common dose for patients with advanced prostate cancer. The general consensus of most physicians is now that DES should not be prescribed to patients who have a history of or are at risk for cardiovascular disease. However, there is a belief on the part of a significant number of prostate cancer specialists that at low doses (say 1 or 2 milligrams per day) DES may be a very suitable form of hormone therapy for many men with advanced prostate cancer if they are appropriately monitored for cardiovascular problems. Certainly, there are prostate cancer patients who have been successfully treated with DES for years and who have done very well with no side effects.

The exact way in which DES acts to lower testosterone levels in men with prostate cancer is still unknown. Estrogens have complex effects on the male hormonal system. It normally takes about 30 to 60 days from the start of DES therapy for a man's testosterone to reach its minimum level. DES is associated with mild to moderate breast tenderness or enlargement in about two-thirds of all male patients. This may be unacceptable for some.

DES does have certain advantages for certain patients. In particular, it is easy to manage because the patient need only take one dose of DES each day. Furthermore, it is very low in cost when compared to LHRH agonists (with or without an antiandrogen).

Some physicians have suggested that new clinical trials should be conducted to compare the clinical value of low doses of DES to LHRH agonists. There is also the question whether combination therapy with DES and a nonsteroidal antiandrogen would be safe and as effective as the combination of an LHRH and an antiandrogen.

Finasteride (Proscar/Merck & Co.)

Finasteride or Proscar is the first of a class of pharmaceuticals known as 5a-reductase inhibitors. Finasteride is indicated by the FDA for the treatment of symptomatic benign prostatic hyperplasia (BPH). It appears to have an extremely low incidence of side effects and is very well tolerated by almost all patients.

Finasteride is not currently indicated for the treatment of prostate cancer. However, it has been widely suggested that this pharmaceutical may have potential value in the prevention of prostate cancer (as discussed in the section on prostate cancer prevention). In addition, clinical trials have been carried out to investigate the possible value of finasteride as adjuvant therapy for carefully selected patients following radical prostatectomy. The preliminary results of one trial showed that patients receiving finasteride in such an adjuvant setting had a significant delay in resurgence of symptoms of prostate cancer, as indicated by rising PSA levels, as compared to patients who received a placebo. As yet there is no information to suggest that this delay in recurrence of rising PSA levels has any survival benefit in this group of patients.

The normal dose of finasteride for treatment of BPH is 5 milligrams once a day. If finasteride has any possible value in the treatment of prostate cancer, the appropriate dose of this pharmaceutical for such a use is still to be determined.

Ketoconazole (Nizoral/Janssen Pharmaceutica)

Ketoconazole or Nizoral has been available for many years as an antifungal agent for the treatment of certain types of fungal infections. However, it has also been known for some time that ketoconazole can have effects similar to antiandrogens because of its effects on androgen synthesis. (It blocks androgen synthesis by inhibiting the steps which depend on an enzyme known as cytochrome P-450.)

Ketoconazole is, however, a potentially dangerous pharmaceutical. It is not indicated by the FDA for the treatment of prostate cancer. Most physicians would reserve the use of this product until other forms of hormonal therapy had failed. When used as an agent to lower the levels of androgens, ketoconazole is often used at a dose of 400 milligrams three times a day, and patients are followed with care for any signs or symptoms of liver dysfunction. Patients are normally advised to watch for and report any unusual fatigue, anorexia, nausea and/or vomiting, jaundice, darkness of the urine, or pale stools. Loss of libido and impotence are also known to be associated with the use of ketoconazole.

Megestrol acetate (Megace/Bristol-Myers Squibb)

Megestrol acetate is a progestational and antineoplastic agent which has been used for the treatment of late stage prostate cancer. It has several concurrent effects which combine to suppress the effects of androgens and therefore the growth and spread of prostate cancer cells. It is not indicated for treatment of prostate cancer by the FDA. Megestrol acetate, like ketoconazole, would only be used by most physicians in patients who have failed to respond to LHRH agonist treatment, with or without and antiandrogen.

Patients who are treated with megestrol acetate should be advised to use this pharmaceutical only as directed by their physician and to report any side effects or adverse reactions which they may note while being treated with this agent. The dose of megestrol acetate which is customarily given to patients with late stage prostate cancer is 40 milligrams four times a day. The adverse effects which have been specifically associated with megestrol acetate in the treatment of late stage prostate cancer include weight gain, thromboembolic effects, nausea and vomiting, and a range of other problems.

Chemotherapeutic agents

Suramin

Suramin is a very old pharmaceutical which was used for the treatment of certain types of parasitic disease (usually confined to patients who caught these infections in tropical countries).

In recent years, as researchers looked for new agents to treat patients with very late stage prostate cancer, it was discovered that Suramin appeared to have some activity against hormone-refractory disease. Clinical trials of Suramin have now continued for several years with mixed results.

Suramin can be highly toxic if inappropriately used. It is still unknown whether its potential benefits will outweigh the potential risks associated with treatment with this pharmaceutical. At the present time, patients should only receive Suramin in the setting of a properly conducted clinical trial carried out under the close supervision of a physician experienced in clinical research and who has significant experience of the use and side effects of this pharmaceutical.

At least some patients who have received Suramin within the context of appropriately conducted clinical trials appear to have demonstrated normalization or significant reductions in their PSA values. However, The Prostate Cancer InfoLink is not aware of any published information which shows a survival benefit or a benefit in terms of time to treatment failure which can be specifically linked to Suramin therapy. By contrast, the adverse effects of Suramin are considerable.

Estramustine phosphate sodium (Emcyt/Pharmacia)

Estramustine phosphate or Emcyt is the only chemotherapeutic agent which has ever been approved by the FDA for the palliative treatment of advanced prostate cancer. Since estramustine phosphate is a combination of an estrogen with a nitrogen mustard compound, it has many of the same side effects as DES. Few physicians would recommend this product in patients until they had failed treatment with more conventional therapies -- such as an LHRH agonist with or without an antiandrogen.

The customary regimen of estramustine phosphate is 14 milligrams per kilogram of the patient's body weight per day, given in three or four divided doses. It must be taken at least one hour before or two hours after meals with water. Milk, milk products, and calcium containing foods or drugs must be avoided. Treatment usually lasts for a minimum of 60 days before effectiveness can be properly evaluated.

The use of estramustine is not recommended in patients with active thrombophlebitis or thromboembolic disorders. In general, as with DES, estramustine phosphate poses particular risks for patients with any form of cardiovascular disorder because of its estrogenic activity.


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