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Treating prostate cancer,
Part VI: Androgen deprivation and beyond
Harvard Men's Health Watch | October 2008

Hormonal therapy for prostate cancer dates back to 1941 when Drs. Charles Huggins and C.V. Hodges reported that androgens (male hormones) fuel the growth of prostate cancers and that androgen-deprivation therapy could slow or halt that growth. It was a groundbreaking discovery, important enough to earn a 1966 Nobel Prize for Dr. Huggins, and it remains the basis for the treatment of advanced prostate cancer more than half a century later. Despite the seniority of androgen-deprivation therapy, however, it shares two features common to all prostate cancer treatments: uncertainty and debate. While doctors agree that hormonal therapy has an important place in treating advanced prostate cancer, they disagree on which of the available hormonal therapies is best, when it should be started, and what to do about side effects. As in all areas of prostate cancer treatment, the choice among options for hormonal therapy requires an individualized decision by the patient and his doctors.

Hormones and the prostate: A lengthy chain

Drs. Huggins and Hodges discovered that androgens stimulate the growth of prostate cells, both benign and malignant, but those brilliant scientists might be surprised to learn how complex the process has turned out to be.

It all begins in the brain, where the hypothalamus produces the hormone that starts things off; although itís a single protein, it has two names, gonadotropin-releasing hormone (GnRH) and luteinizing hormoneĖreleasing hormone (LHRH). Hormones are chemicals that are produced in one part of the body before traveling to another part, where they do their work. LHRH is a true hormone, but it doesnít have to travel very far to do its job; it acts on another part of the brain, the pituitary gland, where it stimulates the release of two additional hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

FSH and LH were named by scientists who discovered that the hormones stimulate the female ovary. But FSH and LH are just as important for men: they stimulate the Leydig cells in the testicles to produce testosterone, the primary androgen, or male hormone. About 95% of a manís androgens are produced by his testicles, the remainder by his adrenal glands, which are not under the control of LH and FSH.

After testosterone enters the blood, approximately 95% of the hormone is bound to proteins while the rest circulates freely. Itís the free testosterone that acts on the prostate by diffusing into the glandís epithelial cells. Other androgens from the adrenal gland also enter prostate cells, where they are converted to testosterone.

The testosterone is then converted to dihydrotestosterone (DHT), with the help of an enzyme called 5-alpha reductase. DHT is the final hormone in the long and complex chain that links the brain to the prostate. DHT binds to androgen receptors in the prostate cells. The DHT-receptor complex turns on the cellsí DNA, stimulating cellular growth.

Itís a complex series of events, but itís important to all men. Itís what starts the prostate growing in adolescence and what causes the additional enlargement of benign prostatic hyperplasia (BPH) in older men. And itís what stimulates the growth of malignant cells in men with prostate cancer.

Breaking the chain

The doctors who discovered that androgens drive the prostate also learned they could put the brakes on by removing the testicles (orchiectomy) or administering estrogens (female hormones). These original treatments are still in use, but they have been eclipsed by newer, more popular methods of androgen deprivation. All the methods work in the same way: when prostate cells are deprived of androgens, they commit suicide by the process of apoptosis, or programmed cell death. Androgen deprivation usually succeeds in shrinking prostate cancers and reducing symptoms. However, while the improvement is often prolonged, it cannot result in cure. Thatís because a small proportion of the prostate cancer cells do not require androgens to grow; these androgen-independent cells continue growing, slowly enlarging enough to produce symptoms that no longer respond to hormonal treatment. And research suggests that in some patients, prostate cancer cells can undergo mutations of their androgen receptors so they are actually stimulated by anti-androgen medications.

Major hormonal therapies for prostate cancer

Drug

Side effects

Comments

LHRH agonists

Leuprolide (Lupron, Viadur)

Goserelin (Zoladex)

Triptorelin (Trelstar)

Histrelin implant (Vantas)

Hot flashes, impotence, decreased libido, fatigue, weight gain, anemia, osteoporosis.

Injected or implanted. Expensive.

Anti-androgens

Bicalutamide (Casodex)

Flutamide (Eulexin, generic)

Nilutamide (Nilandron)

Hot flashes, breast tenderness and swelling, nausea, and diarrhea. Rarely, liver disorders.

Taken orally. Liver function should be checked periodically. Brand name drugs are expensive.

Treatment options

There are many links in the chain of hormones that stimulate the prostate, and there are many ways to break the chain. Each method has its advantages and its drawbacks. Because studies have not demonstrated the superiority of any method, doctors disagree as to which is best. At present, all appear to have similar effectiveness, and all share one side effect, the loss of libido and sexual potency. Despite these common features, there are important differences in cost and convenience as well as in certain other side effects. Here is a rundown of the major options:

  • Orchiectomy. Surgical removal of the testicles is the fastest way to deprive the prostate of androgens; testosterone levels plummet within hours, and they stay at very low levels permanently. The operation is fast and safe. Saline (salt water)-filled prosthetic testicles can be implanted to maintain the appearance of the scrotum. Side effects include breast enlargement, which is usually mild, and hot flashes. Like all forms of androgen-deprivation therapy, orchiectomy causes bones to lose calcium, which can lead to osteoporosis.

    Orchiectomy is a convenient, one-step, inexpensive treatment. Many doctors think itís the best method of androgen deprivation, but most men with advanced cancer opt to take medications instead, no doubt because of psychological reactions to the operation. Because itís permanent, orchiectomy is not suitable for men who need only short-term or intermittent androgen deprivation.

  • Estrogens. In women, natural estrogens help regulate the menstrual cycle by shutting down LHRH. In men, estrogens will also block the release of LHRH, thus reducing testosterone levels.

    Although many estrogens can be used to treat prostate cancer, the best-studied is diethylstilbestrol (DES). In the 1960s, pioneering studies by the Veterans Administration Cooperative Urological Research Group (VACURG) showed that DES worked as well as orchiectomy. But the first VACURG study also gave DES the bad name it retains today, since men treated with DES had an increased risk of death from heart attacks and blood clots. The first VACURG study used 5 milligrams (mg) of DES, but a second study found that a 1-mg dose was as effective, even though it didnít produce a full reduction of testosterone. At 1 mg per day, DES produced many fewer cardiovascular side effects.

    Estrogens do not cause hot flashes or bone calcium loss, but they do produce breast enlargement. Low-dose estrogens are a viable option for androgen-deprivation therapy, especially for men with healthy hearts. But viable or not, they are rarely prescribed by American doctors today. DES is no longer available in the United States, but new research is evaluating a different estrogen preparation, a low-dose estradiol skin patch.

  • LHRH agonists. These synthetic drugs resemble LHRH ó but unlike the real thing, they block the release of FSH and LH by the pituitary, thus reducing testosterone production. LHRH agonists are now the mainstay of androgen-deprivation therapy. They are equivalent to orchiectomy in their ability to reduce testosterone levels and produce a clinical response; their side effects (loss of libido, hot flashes, breast enlargement, and loss of bone calcium) are also similar. And men should know that the cosmetic effects of LHRH agonists resemble those of orchiectomy, since the testicles shrink substantially.

    The major LHRH agonists are listed in the table above. All can cause a brief flare in prostate cancer symptoms due to a surge in testosterone production that lasts two to three weeks; after that, testosterone levels remain extremely low. LHRH agonist drugs are very expensive; histrelin is administered as a yearly implant under the skin, while the others are injected every one to four months. Some doctors measure testosterone levels and delay doses until testosterone levels begin to creep up.

  • Anti-androgens. Unlike the other forms of hormonal therapy, anti-androgens do not reduce testosterone production; instead, they block the action of androgens on the cellular level. Anti-androgens act against testosterone and DHT, and they also block the effects of the weaker androgens produced by the adrenal glands that constitute about 5% of the bloodís normal androgen activity. Anti-androgens are less likely to cause hot flashes, or to reduce libido and potency than other forms of hormonal therapy, and they do not lead to osteoporosis. However, they may cause breast enlargement, diarrhea, and other side effects. The table lists the major preparations, including bicalutamide (Casodex), flutamide (Eulexin, generic), and nilutamide (Nilandron). All are taken orally, and all the brand name preparations are expensive.

    Doctors are still studying how to best use anti-androgens. Most often, they are prescribed during the first weeks of LHRH agonist therapy to protect against the early rise in testosterone and the temporary symptoms that would otherwise occur. They are sometimes prescribed after orchiectomy or with LHRH agonists to produce total androgen blockade, but studies suggest this approach adds little to LHRH therapy except expense. Anti-androgens are also being tested for use alone; some men who take them alone retain erectile function.

    At present, anti-androgens are considered alternatives to standard androgen-deprivation therapy with LHRH agonists or orchiectomy. Provocative research suggests that some prostate cancer cells may become paradoxically dependent on anti-androgens. This means that some patients with advanced prostate cancer that has progressed on anti-androgen therapy may actually improve after the treatment is discontinued.

  • GnRH antagonist. The newest medication for advanced prostate cancer is abarelix, which suppresses the production of LH and FSH, reducing testosterone levels. Unlike the older LHRH agonists, however, abarelix does not cause an early surge in testosterone levels, so anti-androgen tablets are not required. Abarelix is administered by injection; it is very expensive, and patients must be monitored for at least 30 minutes after each injection because it can cause serious allergic reactions. It is currently available in Europe but not in the U.S.

  • Ketoconazole. It is a popular antifungal drug that many people use for athleteís foot. In very high doses, though, ketoconazole blocks androgen production, both in the adrenals and the testicles. In these doses, ketoconazole can damage the liver, and it does not appear suitable for long-term use. Because it dramatically reduces androgen levels within 24 hours, however, it can be helpful when rapid, if temporary, action is important.

  • 5-alpha reductase inhibitors. Finasteride (Proscar) and dutasteride (Avodart) donít affect testosterone levels, but they do lower DHT levels in the prostate and blood. Although these drugs can be very useful for BPH, they do not have a defined role in treating prostate cancer. However, researchers are studying 5-alpha reductase inhibitors in combination with other hormonal agents.

Using androgen deprivation

Doctors have identified three important roles for androgen-deprivation therapy. It can be used as an adjunct to curative radiotherapy for patients with locally advanced disease (see Part V); it can be used to control early relapses identified by rising PSA levels after surgery or radiotherapy; and it can be used to help control advanced prostate cancer that has spread to bones or lymph nodes. In all three settings, though, the details of how best to use this therapy are still being worked out.

An important issue is when to start androgen deprivation in men who feel well but have rising PSA levels after surgery or radiation. Studies that compare early vs. delayed hormone therapy are in progress. Until the results are in, many doctors are delaying therapy in men who have slow PSA doubling times (the time it takes for the PSA level to double) and are without symptoms or evidence of widespread cancer. Treatment is started if the PSA rises rapidly, symptoms of cancer appear, or imaging studies reveal that the cancer has spread.

Another question involves intermittent or interrupted androgen deprivation. Intermittent therapy gives men a respite from the side effects of androgen deprivation, an advantage. But more research is needed to find out if intermittent therapy is as good as, or better than, continuous therapy for preserving the long-term quality of life and prolonging survival.

Side effects

A third issue relates to the side effects of androgen deprivation. Hot flashes and breast enlargement are well-known problems. Hot flashes can often be controlled by progestational drugs such as medroxyprogesterone (Provera) or megestrol (Megace), or by newer treatments such as the antidepressant venlafaxine (Effexor), the antiseizure drug gabapentin (Neurontin), or a low-dose estrogen patch. Painful breast enlargement can be managed with anti-estrogens such as tamoxifen or by irradiating or surgically removing breast tissue.

Another problem thatís attracting more attention of late is osteoporosis. Testosterone increases bone calcium and bone strength; deprived of testosterone, bones weaken and become fracture-prone. Concern is greatest for men on long-term androgen-deprivation therapy. Doctors can detect falling bone calcium by using a DXA scan to monitor patients. A good intake of calcium (1,200 mg daily) and vitamin D (800 IU per day) can help, as can resistance exercises. Medications can also increase bone calcium; examples include the oral and injectable bisphosphonates alendronate (Fosamax) and zoledronic acid (Zometa). Breakdown of the jaw bone (osteonecrosis) is an uncommon but worrisome side effect of bisphosphonate therapy. With or without such medication, diet and exercise can help preserve muscle mass and strength, which can be negatively affected by life without testosterone.

Evidence is mounting that androgen-deprivation therapy may lead to metabolic side effects, including insulin resistance, diabetes, elevated cholesterol levels, and the metabolic syndrome. Even more worrisome are studies suggesting that therapy increases the risk of heart attack and stroke. Although the best way to manage these problems has not yet been determined, it seems wise for doctors to use diet, exercise, weight control, and medication to control these risks. However, a 2007 report raises a cautionary note: even though low-dose aspirin can reduce the risk of heart attack, it increases the likelihood of liver abnormalities in men taking the anti-androgen flutamide.

Androgen-deprivation therapy has also been linked to fatigue, reduced overall quality of life, periodontal disease, and alteration of cognitive function. More research is needed to determine the impact of all these side effects and to learn how to best prevent and treat them. None of these problems detract from the enormous benefits of androgen-deprivation therapy for men with widespread prostate cancer, but they do argue for judicious use of therapy in men with less advanced disease. Caution is particularly important for men with cardiovascular disease or risk factors.

Beyond hormones

Androgen-deprivation therapy can help nearly all men with recurrent or advanced prostate cancer. In some cases, it produces very prolonged remissions. Still, men whose other organs hold up long enough will outlive the benefits of androgen-deprivation therapy as their tumors become androgen insensitive. Doctors are working on ways to prolong the effects of androgen deprivation; examples include delaying the start of therapy, using new combinations of drugs, prescribing intermittent androgen deprivation, and producing total androgen blockage. But researchers have also been developing additional ways to treat androgen-independent prostate cancers.

Chemotherapy is the best established method. The first-line drug is docetaxel, which is usually administered every three weeks in combination with prednisone, a corticosteroid. This regimen can prolong life, but it is not curative. Another useful drug is mitoxantrone, which is also given with prednisone every three weeks. Older chemotherapy drugs, such as cyclophosphamide and vincristine, may be helpful, and experimental agents such as satraplatin and ixabepilone are available in clinical trials.

Bone pain, a common symptom of metastatic prostate cancer, usually responds well to targeted radiotherapy, intravenous bisphosphonates such as zoledronic acid, or therapy with bone-seeking radioisotopes such as strontium or samarium. Pain relievers can also provide comfort.

Medical oncologists have other tricks up their sleeves. Examples include prednisone, estrogens, progestins, ketoconazole, and celecoxib (Celebrex). All of these drugs are widely prescribed for other purposes; none have demonstrated prolonged benefit for prostate cancer, but each may help an individual patient. And even as they investigate these agents, researchers are developing new, still-experimental approaches such as vaccines, monoclonal antibodies, and growth factor inhibitors.

Given the uncertainties and unmet needs, many men turn to alternative medicine. Itís a tricky business. The PC-SPES fiasco, in which a heavily promoted ďnaturalĒ remedy turned out to be adulterated with estrogens and other prescription drugs, reminds us that caution is the watchword. Still, a good diet (lots of fish, whole grains, broccoli, and cooked tomatoes, but little saturated fat and only modest amounts of calcium) makes good sense, and supplements of vitamin D, vitamin E, lycopene, selenium, and soy have attracted interest. Remember, though, that none of these is of proven benefit, and some may have the potential for harm. Above all, men should never abandon conventional therapy, and they should only use supplements with the knowledge and approval of their physicians.

Perspectives

Prostate cancer is a puzzling disease. Scientists have learned a great deal about the biology of the disease, and clinicians have made important gains in diagnosis and treatment. Itís heartening progress, but it has provided only a partial answer to the famous question posed years ago by Dr. Willett F. Whitmore, Jr., the pioneering urologist who died of prostate cancer himself: ďIs cure possible in those for whom it is necessary, and is cure necessary in those for whom it is possible?Ē

Doctors have learned that some men with prostate cancer do well without any treatment (ďcureĒ is not necessary), while others clearly need and benefit from therapy (ďcureĒ is possible). Still, much remains to be learned. New research in prevention, diagnosis, and treatment is well under way. It is hard work, and it is frustratingly slow, especially for men who need to make important decisions about tests and treatments now. Slow or not, it is the only way to make further progress toward a goal that is important to every man, the control of prostate cancer.

Copyright © 2000-2007 President and Fellows of Harvard College.

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