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Hormone therapy for prostate cancer
Hormone therapy is also called androgen deprivation therapy (ADT) or androgen suppression therapy. The goal is to reduce levels of male hormones, called androgens, in the body, or to stop them from affecting prostate cancer cells.
Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone (DHT). Most of the androgens are made by the testicles, but the adrenal glands (glands that sit above your kidneys) also make a small amount. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.
When is hormone therapy used?
Hormone therapy may be used:
Types of hormone therapy
Several types of hormone therapy can be used to treat prostate cancer.
Treatments to lower androgen levels
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 most of the androgens (testosterone and DHT) are made. This causes most prostate cancers to stop growing or shrink for a time.
This is done as an outpatient procedure. It is probably the least expensive and simplest form of hormone therapy. But unlike some of the other treatments, it is permanent, and many men have trouble accepting the removal of their testicles.
Some men having this surgery are concerned about how it will look afterward. If wanted, artificial testicles that look much like normal ones can be inserted into the scrotum.
LHRH agonists
Luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs orGnRH agonists) are drugs that lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called chemical castration or medical castrationbecause they lower androgen levels just as well as orchiectomy.
Even though LHRH agonists cost more than orchiectomy and require more frequent doctor visits, most men choose this method. These drugs allow the testicles to remain in place, but the testicles will shrink over time, and they may even become too small to feel.
LHRH agonists are injected or placed as small implants under the skin. Depending on the drug used, they are given anywhere from once a month up to once a year. The LHRH agonists available in the United States include:
When LHRH agonists are first given, testosterone levels go up briefly before falling to very low levels. This effect is called flare and results from the complex way in which these drugs work. Men whose cancer has spread to the bones may have bone pain. If the cancer has spread to the spine, even a short-term increase in tumor growth as a result of the flare could press on the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-androgens (discussed below) for a few weeks when starting treatment with LHRH agonists.
LHRH antagonist
Degarelix (Firmagon) is an LHRH antagonist. It works like the LHRH agonists, but it lowers testosterone levels more quickly and doesn’t cause tumor flare like the LHRH agonists do. Treatment with this drug can also be considered a form of medical castration.
This drug is used to treat advanced prostate cancer. It is given as a monthly injection under the skin. The most common side effects are problems at the injection site (pain, redness, and swelling) and increased levels of liver enzymes on lab tests. Other side effects are discussed in detail below.
CYP17 inhibitor
LHRH agonists and antagonists can stop the testicles from making androgens, but other cells in the body, including prostate cancer cells themselves, can still make small amounts, which can fuel cancer growth. Abiraterone (Zytiga) blocks an enzyme called CYP17, which helps stop these cells from making androgens.
Abiraterone can be used in men with advanced castrate-resistant prostate cancer (cancer that is still growing despite low testosterone levels from an LHRH agonist, LHRH antagonist, or orchiectomy).
This drug is taken as pills every day. It doesn’t stop the testicles from making testosterone, so men who haven’t had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone (a cortisone-like drug) needs to be taken during treatment as well to avoid certain side effects.
Drugs that stop androgens from working
Anti-androgens
Androgens have to bind to a protein in the prostate cell called an androgen receptor to work. Anti-androgens are drugs that bind to these receptors so the androgens can’t.
Drugs of this type include:
They are taken daily as pills.
Anti-androgens are not often used by themselves in the United States. An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself. An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started to prevent a tumor flare.
An anti-androgen can also be combined with orchiectomy or an LHRH agonist 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 agonist alone. If there is a benefit, it appears to be small.
In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. Doctors call this the anti-androgen withdrawal effect, although they are not sure why it happens.
Enzalutamide (Xtandi) is a newer type of anti-androgen. Normally when androgens bind to their receptor, the receptor sends a signal to the cell’s control center, telling it to grow and divide. Enzalutamide blocks this signal. It is taken as pills each day.
Enzalutamide can often be helpful in men with castrate-resistant prostate cancer. In most studies of this drug, men were also treated with an LHRH agonist, so it isn’t clear how helpful this drug would be in men with non-castrate levels of testosterone.
Other androgen-suppressing drugs
Estrogens (female hormones) 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 replaced by other types of hormone therapy. Still, estrogens may be tried if these other hormone treatments are no longer working.
Ketoconazole (Nizoral), first used for treating fungal infections, blocks production of certain hormones, including androgens, similarly to abiraterone. It is most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.
Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid (such as prednisone or hydrocortisone).
Possible side effects of hormone therapy
Orchiectomy and LHRH agonists and antagonists can all cause similar side effects from lower levels of hormones such as testosterone. These side effects can include:
Some research has suggested that the risk of high blood pressure, diabetes, strokes, heart attacks, and even death from heart disease is higher in men treated with hormone therapy, although not all studies have found this.
Anti-androgens have similar side effects. The major difference from LHRH agonists and antagonists and orchiectomy is that anti-androgens may have fewer sexual side effects. When these drugs are used alone, sexual desire and erections can often be maintained. When these drugs are given to men already being treated with LHRH agonists, diarrhea is the major side effect. Nausea, liver problems, and tiredness can also occur.
Abiraterone can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea.
Enzalutamide can cause diarrhea, fatigue, and worsening of hot flashes. This drug can also cause some nervous system side effects, including dizziness and, rarely, seizures. Men taking this drug are more likely to fall, which may lead to injuries.
Many side effects of hormone therapy can be prevented or treated. For example:
There is growing concern that hormone therapy for prostate cancer may lead to problems thinking, concentrating, and/or with memory, but this has not been studied thoroughly. Still, hormone therapy does seem to lead to memory problems in some men. These problems are rarely severe, and most often affect only some types of memory. More studies are being done to look at this issue.
Current issues 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 are now looking at these issues. A few of them are discussed here.
Treating early-stage cancer: Some doctors have used hormone therapy instead ofwatchful waiting or active surveillance in men with early stage prostate cancer who do not want surgery or radiation. Studies have not found that these men live any longer than those who don’t get any treatment until the cancer progresses or symptoms develop. Because of this, hormone treatment is not usually advised for early-stage prostate cancer.
Early versus delayed treatment: For men who need (or will eventually need) hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who don’t yet have symptoms, it’s not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if it’s started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.
But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldn’t be started until a man has symptoms from the cancer. This issue is being studied.
Intermittent versus continuous hormone therapy:Most 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 might not be needed, so they advise intermittent (on-again, off-again) treatment. The hope is that giving men a break from androgen suppression will also give them a break from side effects like decreased energy, sexual problems, and hot flashes.
In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time – for example, 6 months on followed by 6 months off.
At this time, it isn’t clear how this approach compares to continuous hormone therapy Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.
Combined androgen blockade (CAB): Some doctors treat patients with both androgen deprivation (orchiectomy or an LHRH agonist or antagonist) plus an anti-androgen. Some studies have suggested this may be more helpful than androgen deprivation alone, but others have not. Most doctors are not convinced there’s enough evidence that this combined therapy is better than starting with one drug alone when treating metastatic prostate cancer.
Triple androgen blockade (TAB): Some doctors have suggested taking combined therapy one step further, by adding a drug called a 5-alfa reductase inhibitor– either finasteride (Proscar) 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.
Castrate-resistant versus hormone-refractory prostate cancer: Both these terms are sometimes used to describe prostate cancers that are no longer responding to hormones, although there is a difference between the two.