ACS (PC) 14-Jun-07

From Kidney Cancer Resource

To Go To Androgen Deprivation

Hormone Androgen Deprivation Therapy

Hormone therapy is also called androgen deprivation therapy (ADT) or androgen suppression therapy. The goal is to reduce levels of the male hormones, called androgens, in the body. The main androgens are testosterone and dihydrotestosterone (DHT). Androgens, produced mainly in the testicles, stimulate prostate cancer cells to grow. Lowering androgen levels often makes prostate cancers shrink or grow more slowly. However, hormone therapy does not cure prostate cancer.

Hormone therapy may be used in several situations:

• if you are not able to have surgery or radiation or can't be cured by these treatments because the cancer has already spread beyond the prostate gland
• if your cancer remains or comes back after treatment with surgery or radiation therapy
• as an addition to radiation therapy as initial treatment if you are at high risk for cancer recurrence
• before surgery or radiation to try and shrink the cancer to make other treatments more effective

Types of Hormone Therapy

There are several types of hormone therapy used to treat prostate cancer.

Orchiectomy (surgical castration):

Even though this is a type of surgery, its main effect is as a form of hormone therapy. In this operation, the surgeon removes the testicles, where more than 90% of the androgens, mostly testosterone, are made. With this source removed, most prostate cancers stop growing or shrink for a time.

This is done as a simple outpatient procedure. It is probably the least expensive and simplest way to reduce androgen levels in the body. But unlike some of the other methods of lowering androgen levels, it is permanent, and many men have trouble accepting the removal of their testicles. Some men having the procedure are concerned about how it will look. If wanted, artificial silicone sacs filled with saline (salt water) can be inserted into the scrotum. These look and feel like testicles.

Possible side effects of orchiectomy are generally related to changing levels of hormones in the body. About 90% of men who have had this operation have reduced or absent libido (sexual desire) and impotence. Some men also experience:

• hot flashes (these may go away with time)
• breast tenderness and growth of breast tissue
• osteoporosis (bone thinning) which can lead to broken bones
• anemia (low red blood cell counts)
• decreased mental acuity (sharpness)
• loss of muscle mass
• weight gain
• fatigue
• decrease in HDL ("good") cholesterol
• depression

Many of these side effects can be prevented or treated. For example, sometimes the hot flashes will be helped by treatment with antidepressants. Brief radiation treatment to the breasts before surgery can help prevent their enlargement.

Men getting this treatment should be watched and treated for osteoporosis to help prevent broken bones. There are several different drugs available. Exercise is a good way to reduce fatigue, weight gain, and the chance of loss of bone and muscle mass. If anemia occurs, it is often very mild and usually doesn't cause symptoms. Depression can be treated by antidepressants and/or counseling.

Luteinizing hormone-releasing hormone (LHRH) analogs:

Even though LHRH analogs (also called LHRH agonists) cost more and require more frequent doctor visits, most men choose this method over orchiectomy. These drugs lower testosterone levels just as well as orchiectomy by lowering the levels of androgens (mainly testosterone) made by your testicles.

LHRH analogs are injected or placed as small implants under the skin. They are given either monthly or every 3, 4, 6, or 12 months. The LHRH analogs available in the United States include leuprolide (Lupron, Viadur, Eligard), goserelin (Zoladex), and triptorelin (Trelstar).

Possible side effects of LHRH analogs such as hot flashes, osteoporosis, and others are similar to those of orchiectomy (see above), and are largely due to low testosterone levels.

When LHRH analogs are first given, testosterone production increases briefly before falling to very low levels. This effect is called flare and results from the complex way in which LHRH analogs work. Men whose cancer has spread to the bones may experience bone pain. If the cancer has spread to the spine, even a short-term increase in growth could compress the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-androgens for a few weeks when starting treatment with LHRH analogs. (For more on anti-androgens, see below.)

Luteinizing hormone-releasing hormone (LHRH) antagonists:

A newer drug, abarelix (Plenaxis), is an LHRH antagonist. It is thought to work like LHRH agonists, but it appears to reduce testosterone levels more quickly and does not cause tumor flare like the LHRH agonists do.

A small percentage of men (fewer than 5%) have serious allergic reactions to the drug. Because of this, it is only approved for use in men who have serious symptoms from advanced prostate cancer and who cannot or refuse to take other forms of hormone therapy.

The possible side effects are similar to those with orchiectomy (see above) or LHRH agonists.

Abarelix is given only in qualified doctors' offices. It is injected into the buttocks every 2 weeks for the first month, then every 4 weeks. You will be asked to remain in the office for 30 minutes after the injection to make sure you are not having an allergic reaction.

Anti-androgens:

Anti-androgens block the body's ability to use any androgens. Even after orchiectomy or during treatment with LHRH analogs, a small amount of androgens is still made by the adrenal glands.

Drugs of this type, such as flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron), are taken daily as pills.

Anti-androgens are not often used by themselves (see below). An anti-androgen may be added if treatment with orchiectomy or an LHRH analog is no longer working by itself.

Anti-androgen treatment may be combined with orchiectomy or LHRH analogs as first-line hormone therapy. This is called combined androgen blockade (CAB). There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH analog alone. If there is a benefit, it appears to be small.

Some doctors are testing the use of anti-androgens instead of orchiectomy or LHRH analogs. Several recent studies have compared the effectiveness of anti-androgens alone with that of LHRH agonists. Most found no difference in survival rates, but a few found anti-androgens to be slightly less effective.

If hormone therapy including an anti-androgen stops working, some men seem to benefit for a short time from simply stopping the anti-androgen. Doctors call this the "anti-androgen withdrawal" effect, although they are not sure why it happens.

Side effects of anti-androgens in patients already being treated by orchiectomy or with LHRH agonists are usually not serious. Diarrhea is the major side effect, although nausea, liver problems, and tiredness can also occur.

The major difference from LHRH agonists and orchiectomy is that anti-androgens may have fewer sexual side effects. When these drugs are used alone libido and potency can often be maintained.

Other androgen-suppressing drugs:

Estrogens were once the main alternative to orchiectomy for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been largely replaced by LHRH analogs and anti-androgens. Still, estrogens may be tried if androgen deprivation is no longer working.

Ketoconazole (Nizoral), first used for treating fungal infections, blocks production of androgens and is sometimes used.

Current Controversies in Hormone Therapy

There are many issues around hormone therapy that not all doctors agree on, such as the best time to start and stop it and the best way to give it. Studies looking at these issues are now under way. A few of the issues are discussed here.

Early vs. delayed treatment:

Some doctors think that hormone therapy works better if it is started as soon as possible if the cancer has reached an advanced stage (for example, when it has spread to lymph nodes), if it is large (T3) or has a high Gleason score, or if the PSA starts rising after initial therapy, even though the patient feels well. Some studies have shown that hormone treatment may slow down the disease and perhaps even lengthen patient survival. But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the likely side effects and the chance that the cancer could become resistant to therapy sooner, treatment should not be started until symptoms from the disease appear. Studies addressing these questions are now under way.

Intermittent vs. continuous hormone therapy:

Nearly all prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression may not be needed, so they advise intermittent (on-again, off-again) treatment.

In one form of intermittent therapy, androgen suppression is stopped once the blood PSA level drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy involves using androgen suppression for fixed periods of time -- for example, 6 months on followed by 6 months off.

Clinical trials of intermittent hormonal therapy are still in progress. It is too early to say whether this new approach is better or worse than continuous hormonal therapy. However, one advantage of intermittent treatment is that for a while some men are able to avoid the side effects of hormonal therapy such as impotence, hot flashes, and loss of sex drive.

Combined androgen blockade (CAB):

Some doctors treat patients with both androgen deprivation (orchiectomy or an LHRH agonist) and an anti-androgen. But most doctors are not convinced there's enough evidence that this combined therapy is better than one drug alone.

Triple androgen blockade (TAB):

Some doctors have suggested taking combined therapy one step further, by adding a drug called a 5-alpha reductase inhibitor -- either finasteride (Proscar, Propecia) or dutasteride (Avodart) -- to the combined androgen blockade. There is very little evidence to support the use of this "triple androgen blockade" at this time.

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