Testosterone is a male hormone produced mainly by the testicles. Many organs in the body are composed of cells that respond to or are regulated by exposure to testosterone. Cells in the prostate have testosterone receptors and when exposed to testosterone, are stimulated to grow. When cells that have testosterone receptors become cancerous, the growth of these cancer cells can be increased by exposure to testosterone. The basis of hormone therapy as a treatment for prostate cancer is to block or prevent the cancer cells from being exposed to testosterone. Hormone therapy is primarily cytostatic (it prevents cancer cells from growing) not cytotoxic (kills cancer cells). Chemotherapy and radiation therapy are cytotoxic treatments. There are two methods of delivering hormone therapy: 1) surgical orchiectomy and 2) medical hormone therapy.
Bilateral orchiectomy (castration) is surgical operation to remove the testicles. By removing the testicles, the main source of male hormones is removed and hormone levels decrease. Orchiectomy is a common treatment for patients with metastatic (stage IV) prostate cancer who will likely require hormone therapy for life. Patients may experience a benefit in symptoms in a matter of days following surgery.
Orchiectomy can cause side effects such as loss of sexual desire, impotence, hot flashes, and weight gain. The operation itself is relatively safe and not associated with severe complications. Orchiectomy is a convenient and less costly method of hormone therapy; however, it is irreversible.
Medical Hormone Therapy
The second method of hormone therapy is to take medicines that produce the same effect as an orchiectomy. The medicines that reduce male hormone levels are called LHRH analogues and antiandrogens. Female hormones such as estrogens can also reduce male hormone levels, but can also cause serious side effects and are therefore rarely used.
LHRH Analogues: Drugs that act like luteinizing hormone releasing hormone (LHRH) are known as LHRH analogues. These drugs turn off the signal for testosterone production by the testicles. By turning off the signal, hormone levels are reduced and cancer cells are not exposed to male hormones. LHRH analogues are given as a small injection under the skin of the abdomen every month or every three months. These drugs work just as effectively against prostate cancer as bilateral orchiectomy.
LHRH analogues can cause side effects such as loss of sexual desire, impotence, hot flashes and the development of osteoporosis, which increases the risk of bone fractures. Because these drugs require an injection every 1 or 3 months, LHRH analogues may not be as convenient as an orchiectomy. Unlike orchiectomy, these drugs can be discontinued, and male hormone levels gradually return to normal.
Bisphosphonates are a group of agents that have demonstrated the ability to reduce bone loss in cancer patients with hypercalcemia, bone metastases, Paget’s disease or osteoporosis. This prompted researchers to conduct a clinical trial evaluating the bisphosphonate Aredia® (pamidronate) in patients with prostate cancer undergoing hormonal therapy with a GnRH agonist.
In this clinical trial, 41 patients had either advanced or recurrent prostate cancer, with no spread of cancer to the bones. All patients were receiving treatment with leuprolide, a GnRH agonist, and half of the patients also received Aredia® during treatment. Measurements of bone density of the lumbar spine, trochanter (top of the femur) and hip were taken prior to initiation of the trial and approximately one year following treatment. Patients who were treated with leuprolide alone had a significant decrease of bone density in all measured areas. Conversely, patients who received the combination of leuprolide plus the bisphosphonate experienced no significant density change in any measured area.
LHRH analogues may be used to treat patients with any stage of prostate cancer. When first taken, these drugs may increase prostate cancer growth and make a patient’s symptoms worse. This temporary problem is called “tumor flare.” Gradually, these drugs cause hormone deprivation, shrinkage of prostate cancer, and improvement in symptoms. This “tumor flare” can be prevented by taking an antiandrogen medication before LHRH analogues. Antiandrogens are discussed below.
Antiandrogens: Not all male hormones are made by the testicles. A small amount of male hormone is made by the adrenal glands, and may not be affected by bilateral orchiectomy or LHRH analogues. An antiandrogen is a medication that can block the effect of the remaining male hormone on prostate cancer cells. Antiandrogens are pills often given to patients in addition to orchiectomy or LHRH agonists. This combination of treatment is known as total or combined androgen blockade.
Several clinical studies have directly compared total androgen blockade with a single form of hormone therapy (LHRH analogue or orchiectomy) for patients with metastatic prostate cancer. Two large studies conducted in the U.S. and Europe have shown improvement in disease control and survival with total androgen blockade. In one study involving 603 patients, half the patients treated with a LHRH analogue were alive at 28 months and half the patients treated with combined androgen blockade were alive at 35 months. Most doctors feel combined androgen blockage controls disease and improves survival better than either an LHRH analogue or orchiectomy alone.
Antiandrogens can cause side effects such as loss of sexual desire, diarrhea, enlargement of the breasts and occasional impotence. When used alone, these drugs appear to cause impotence much less often than other forms of hormone therapy. On rare occasion, these drugs can cause liver abnormalities, and blood tests can help detect these problems before serious side effects occur. These drugs can also be discontinued, and male hormone levels gradually return to normal.
When to Start Hormonal Therapy
There is general agreement that men experiencing symptoms from prostate cancer should begin treatment immediately. There has been some disagreement, however, regarding the best time to start hormonal therapy in asymptomatic patients. Researchers from London recently conducted a clinical trial comparing the timing of hormone therapy. Almost 1,000 men participated in the clinical study. Half received immediate hormonal therapy and half had hormonal therapy deferred until they developed symptoms. Patients treated with immediate hormonal therapy lived longer without cancer progression and were less likely to develop significant complications from cancer.
Strategies to Improve Treatment
The progress that has been made in the treatment of prostate cancer has resulted from improved development of radiation treatments, surgical techniques, development of hormonal therapies, and participation in clinical trials. Future progress in the treatment of prostate cancer will result from continued participation in appropriate clinical trials.
Intermittent Therapy: Some doctors believe that using medical hormonal therapy intermittently can decrease the cost and reduce the side effects of treatment. When treatment is withheld for a period of time, sexual function and quality of life may improve. It is currently unknown whether intermittent hormonal therapy will provide the same survival benefit as early continuous hormonal therapy.
Combination Therapy: Recently, researchers in England conducted a clinical trial evaluating treatment consisting of hormone therapy plus the chemotherapy agent mitozantrone versus hormone therapy alone for patients with locally advanced prostate cancer. Hormone therapy in this trial consisted of injections of an agent that reduced the production of androgens (particularly testosterone) in the body. Ninety-five percent of patients who received the combination treatment experienced a complete or partial disappearance of their cancer, compared to only 53% of patients who received only hormone therapy. Importantly, the average duration of survival following therapy was significantly higher in patients who received both Novantrone® and hormone therapy, nearly 7.5 years, compared to 3 years for patients receiving only hormone therapy.
1 Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. Journal of the National Cancer Institute. 2010;102:39-46.
2 Klotz L, Boccon-Gibod L, Shore ND et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102:1531-8.