Hormone Therapy and Chemotherapy:

Androgen Deprivation Therapy (Hormone Therapy)

Male hormones (called androgens), particularly testosterone and dihydrotestosterone, determine male secondary sex characteristics and stimulate prostate cell growth. When prostate cells, both healthy and cancerous, are deprived of androgens, they no longer proliferate and eventually die.

Androgen deprivation therapy (also called androgen suppression therapy or hormone therapy) uses drugs or surgery to suppress or block male hormones, particularly testosterone and dihydrotestosterone, that stimulate the growth of prostate cells. Androgen deprivation therapy is not a cure for prostate cancer, but it can help control symptoms and disease progression.

Androgen deprivation therapy is used for advanced and metastatic cancer and may be used if treatment for localized prostate cancer has failed and cancer recurs (as indicated by rising PSA levels).

There has been some debate about when to start androgen deprivation therapy. In 2007, the American Society of Clinical Oncology (ASCO) published clinical guidelines for androgen deprivation therapy in patients with recurrent, progressive, or advanced prostate cancer. The guidelines recommend that hormone therapy should, in general, be delayed until patients begin to experience symptoms from their cancer. However, when therapy is deferred, patients should regularly visit their doctors every 3 - 6 months for careful monitoring of their condition.

ASCO recommends either removal of both testicles (bilateral orchiectomy) or injections with luteinizing hormone-releasing hormone (LHRH) as initial androgen deprivation treatments. Combining antiandrogen drug therapy with orchiectomy or LHRH may also be considered.

When prescribing hormone therapy drugs, some doctors recommend periodically stopping and restarting treatment (intermittent therapy). This approach may help men avoid the loss of sexual function. More research needs to be conducted to determine the effectiveness of intermittent therapy.

Orchiectomy

Orchiectomy is the surgical removal of the testicles (surgical castration). It is the single most effective method of reducing androgen hormones, but because it is permanent it is not suitable for intermittent or temporary androgen deprivation. Orchiectomy plus radical prostatectomy may delay progression in patients with cancers that have spread only to the pelvic lymph nodes.

Men who have orchiectomy have reduced sexual function and desire. Patients do not experience a reversal of sex characteristics and the voice does not change. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis.

LHRH Agonists

The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormones (LHRH) agonists. LHRH drugs block the pituitary gland from producing hormones that stimulate testosterone production. They include leuprolide (Lupron, Leuprogel), goserelin (Zoladex), and buserelin.

Treatment with LHRH agonists produces a testosterone surge in the first week, which may actually intensify symptoms. After this phase, testosterone levels drop to near zero. LHRH agonists can also cause PSA levels to rise temporarily.

Side Effects. Side effects include hot flashes and occasionally nipple and breast tenderness.

Anti-Androgens

Anti-androgens are drugs used to block the effects of testosterone. They are generally used in combination with LHRH agonists or orchiectomy to completely block androgen hormones. This combination approach is called combined androgen blockade (CAB) in the U.S., and maximal androgen blockade (MAB) in Europe.

The main anti-androgen drugs include flutamide (Eulexin, Drogenil), nilutamide (Nilandron), and bicalutamide (Casodex). Diarrhea is the most common side effect.

Other Drugs Used in Hormone Therapy

If patients do not respond to standard hormonal medications, other drugs may be tried. They include estrogen therapy and ketoconazole (Nizoral), an anti-fungal drug that blocks testosterone production.

In 2008, the FDA approved degarelix as a hormonal drug treatment for advanced prostate cancer. Degarelix belongs to a class of drugs called gonadotropin releasing hormone (GnRH) receptor inhibitors. It works by suppressing testosterone and thereby slowing the growth and progression of prostate cancer. Degarelix is given by injection. It is the first new drug approved in several years for treatment of prostate cancer.

Combining Hormonal Therapy with Radiation or Surgery

Androgen Deprivation Therapy Before or With Radiation. Hormonal drugs combined with radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these drugs long-term to improve outcomes. Hormonal drugs before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used.

Androgen Deprivation Therapy Before or After Surgery. Some studies suggest benefits from using hormone therapy before surgery (neoadjuvant therapy) to reduce the tumor size, but this approach does not appear to increase survival.

Complications of Androgen Deprivation Therapy

Men often experience fatigue, loss of energy, and emotional distress from androgen suppression treatment. Hormonal therapy may significantly impair quality of life, particularly in men who had no symptoms beforehand and whose cancer has not metastasized. Common side effects of androgen suppression drugs include:

• Hot flashes, which may go away over time
• Osteoporosis, the loss of bone density. A number of medications, especially bisphosphonates, are available to help prevent or reduce bone loss.
• Decrease in HDL (“good” cholesterol) levels
• Loss of muscle mass
• Weight gain
• Decreased mental alertness
• Fatigue and depression
• Swelling and tenderness of the breasts (gynecomastia)
• Anemia (low red blood cell count)
• Sexual dysfunction and loss of sexual drive

In addition, there is growing evidence that androgen deprivation therapy increases the risks for heart attack, stroke, and diabetes.

Chemotherapy for Hormone-Resistant Cancer

Prostate cancer that does not respond to hormonal treatment is called hormone-resistant, or hormone-refractory, cancer. Chemotherapy may be used to treat hormone-resistant cancer.

Chemotherapy drugs for prostate cancer include docetaxel (Taxotere), mitoxantrone (Novantrone), estramustine (Emcyt), and various platinum-based drugs, such as carboplatin. These drugs are often combined with other cancer drugs (such as 5-fluorouacil) or corticosteroids (such as prednisone).

Docetaxel-based drug regimens are emerging as the main chemotherapy treatment for hormone-refractory prostate cancer. In 2004, the FDA approved docetaxel injection in combination with prednisone for treatment of patients with hormone-resistant prostate cancer. Patients who received this drug combination survived on average 2.5 months longer than patients who received mitoxantrone and prednisone. Side effects can be serious and may include gastrointestinal problems (nausea, vomiting, or diarrhea), fatigue, low blood cell counts, and increased risk for blood clots.

Researchers are continuing to investigate docetaxel combinations and compare them to other chemotherapy regimens.