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Prostate cancer

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of prostate cancer.

Other Treatments

Androgen Suppression Guidelines

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.

Hormonal treatment in prostate cancer uses drugs or surgery (orchiectomy) to suppress or block male hormones (androgen), particularly testosterone and dihydrotestosterone. Hormone 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). Side effects can include decreased bone density, decreased muscle mass, hot flashes, and enlargement of breasts.

Therapies that suppress male hormones (called androgens) are the mainstay treatment for advanced and metastasized cancer (Stage IV). Such therapies may be in the form of hormonal drugs, orchiectomy (surgical removal of the testicles) surgery, or both. Cure is possible in late-stage prostate cancer, but it is rare. Even without cure, however, treatments can produce striking subjective or objective responses in most patients.

Androgen-suppression treatments include:

Hormonal Drugs . The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormone (LH-RH) agonists.

Orchiectomy . Orchiectomy is the surgical removal of the testicles. It is the single most effective method of reducing androgen hormones, but it is considered an extreme procedure. Studies do not indicate that it significantly improves survival rates. Orchiectomy plus radical prostatectomy may delay progression in patients with cancers that have spread only to the pelvic lymph nodes. Combining orchiectomy with antiandrogen drug therapy adds a modest benefit.

The median survival rate after the operation is about 55% over a 40-month period. An estimated 25% of patients survive 5 years or more. Nevertheless, orchiectomy, although irreversible, may produce fewer adverse effects than hormonal drugs, and interestingly, patients report significantly higher quality of life after orchiectomy than patients who opt for hormonal treatment, particularly total androgen ablation. Because orchiectomy is irreversible, about 75% of patients with advanced prostate cancer choose hormonal therapy to block androgens. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis.

Many men can still achieve erection after orchiectomy, but there is almost always a decline in sexual drive. Men who cannot achieve erection may be candidates for a penile implant. Patients do not experience a reversal of sex characteristics; the voice does not change and body hair is not affected.

Disease Progression and Androgen-Independent Cancer

Unfortunately, in advanced disease, prostate cancer usually returns within about 18 months after antiandrogen treatments. In such cases, the condition is referred to as androgen-independent, and the tumors are not responsive to antiandrogen therapy. The reason for this is still unknown. One theory is that once androgen-sensitive cells have been blocked, cells that are resistant to androgen are stimulated to grow, and the cancer returns. Some studies have detected overexpression of genetic mutations in patients with androgen-independent tumors that signals the cancer cells to grow in response to other hormones even in the absence of androgen. Researchers are continually searching for drugs to treat relapses and act against these androgen-independent tumors.

Choosing Hormonal Treatments

Hormonal therapies may be appropriate for men with locally advanced prostate cancer before they have radiation therapy (neoadjuvant therapy). These men call also receive hormonal therapy following radiation therapy (adjuvant therapy). Studies suggest that these therapies improve survival in men at high-risk for cancer progression. Men with metastatic cancer (cancer that has spread beyond the prostate gland) also receive hormonal treatments. Doctors vary widely on their opinions of androgen suppression therapy. A 2006 study found that the decision to use hormonal therapy depends more on a patient’s urologist than on the patient’s tumor or other factors.

Hormonal Treatment Before or After Surgery . Some studies suggest benefits from using hormone therapy before surgery (neoadjuvant therapy) to reduce the tumor size, although it is not clear yet if this approach has survival benefits. Hormonal treatment may be useful after surgery in men who have high-grade tumors or tumors that have invaded the semen-carrying vessels or lymph nodes. Such men have a risk for failure after surgery of 50 - 80%.

Hormonal 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. An important study published in 2004 in the Journal of the American Medical Association found that for men with localized prostate cancer, a 6-month course of hormone therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be administered for 3 years; the JAMA study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

LH-RH Agonists

The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormones (LH-RH) agonists. They include:

• Leuprolide (Lupron, Leuprogel). Studies report that disease progression is prevented in 72% of men taking daily leuprolide and up to 89% of those taking monthly injections. Certain men, however, may not respond to injections. Drug delivery using implants is under investigation.
• Goserelin (Zoladex). Partial responses of 60 - 80% have been reported. A controlled release formulation has been developed that increases the time between injections from 4 weeks to 3 months.
• Buserelin.

LH-RH drugs block the pituitary gland from producing hormones that stimulate testosterone production. Patients must have injections of LH-RH agonists for the rest of their lives.

Testosterone and PSA Surges. Treatment with LH-RH agonists produces a testosterone surge in the first week, which may actually intensify symptoms. After this phase, testosterone levels drop to near zero. Leuprogel, a newer leuprolide, may pose a lower risk for this effect. Researchers are investigating other drugs, such as GnRH antagonists, that do not produce this surge.

LH-RH agonists can also cause PSA levels to rise temporarily. Administering flutamide, a drug known as an antiandrogen, for 2 weeks prior to LH-RH agonists may not only prevent PSA surge but also induce early declines in PSA levels.

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

Antiandrogens

Antiandrogens are powerful drugs produced in the adrenal gland. They are used alone or in maximal androgen blockage (MAB), in which they are combined with LH-RH agonists or orchiectomy to completely block androgen hormones. Antiandrogens are either steroidal or nonsteroidal.

Nonsteroidal Antiandrogens. The nonsteroidal antiandrogen drugs include:

• Flutamide (Eulexin, Drogenil). Flutamide has produced extended response in some patients. Side effects may include diarrhea and liver damage, which has been fatal in rare cases; liver function must be monitored closely.
• Nilutamide (Nilandron). Nilutamide is associated with reversible interstitial pneumonitis, nausea, alcohol intolerance, and visual disturbances.
• Bicalutamide (Casodex). Bicalutamide is effective and appears to have fewer severe side effects than other antiandrogens, including loss of sexual interest, osteoporosis, visual disturbance, and interstitial pneumonia. This drug is proving to have survival rates equal to those of maximal androgen blockage.

An interesting 2002 study suggested that flutamide may actually trigger a pathway that causes cell proliferation, which could be the reason why complete androgen blockage ultimately fails to prevent cancer progression.

Steroidal Antiandrogens. The steroidal antiandrogens act like female hormones and include:

• Megestrol Acetate. Megestrol acetate suppresses androgen production, but incompletely, and is generally not used as initial therapy.
• Cyproterone Acetate. Cyproterone combined with estrogen may prevent the testosterone surge that occurs with LH-RH agonists.

Gonadotropin-Releasing Hormone (GnRH) Antagonists

Gonadotropin-releasing hormone (GnRH) stimulate the pituitary gland to release luteinizing hormone-releasing hormones (LH-RH). Drugs known as GnRH antagonists, such as abarelix (Plenaxis) and histrelin, block this action. They have two advantages over LH-RH agonists:

• They do not cause the same testosterone surge that can temporarily worsen cancer symptoms
• They seem to reduce testosterone levels more quickly

In one study, histrelin was administered as an implant and was effective for up to 30 months. This offers an advantage over existing drugs, which must be administered at 1- to 3-month intervals.

Estrogens

Estrogens, usually diethylstilbestrol (DES), may also be used. When given in high doses, however, certain types of these female hormones may worsen heart conditions and their use has declined. Other estrogens, such as fosfestrol, may prove to be effective without posing such high risks. An estrogen drug, estramustine phosphate, which is also used in chemotherapy, is showing promise.

Techniques for Improving Androgen Deprivation Therapies

Maximal Androgen Blockage (MAB). Even after using standard hormonal drugs, residual testosterone is usually present. In such cases, doctors may try drugs or techniques to produce a complete shut-down of all male hormones. This approach, known as maximal androgen blockage (MAB), uses antiandrogens combined with LH-RH agonists or orchiectomy. MAB, however, has considerable adverse effects on quality of life, and studies suggest that survival benefits are very modest compared to androgen suppression with single drugs or orchiectomy.

Intermittent Androgen Suppression. Oddly, stopping antiandrogens sometimes causes PSA levels to drop again, a phenomenon called antiandrogen withdrawal syndrome. This has led to investigation of therapy that uses intermittent androgen suppression, which involves alternating cycles of therapy and rest. First, antiandrogen drugs are given for at least 6 months until PSA levels are at their lowest and remain there. The drugs are then stopped until PSA levels rise again to greater than 10 ng/mL, at which point treatment resumes. This cyclic therapy appears to delay tumor progression, and in any case, offers a drug-free period in which the patients experience renewed sexual function and a greater sense of well-being.

Sequential Androgen Blockage. Sequential androgen blockage, like intermittent androgen suppression, is designed to effectively reduce the effects of testosterone while offering the patient some relief from side effects. It uses drugs known as 5 alpha-reductase inhibitors, such as finasteride, to block conversion of testosterone to dihydrotestosterone along with an antiandrogen to mop up any residual male hormones. This treatment allows some testosterone to remain in circulation and helps prevent some of the distressing side effects of total androgen ablation.

Complications of Androgen Deprivation

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:

• Osteoporosis, the loss of bone density. This risk is higher with orchiectomy than with androgen suppressants. Some androgen suppressants, such as bicalutamide, may cause less bone loss. The use of estrogens may actually be bone protective . A number of medications, especially bisphosphonates, are available to help prevent or reduce bone loss.
• Diarrhea
• Loss of muscle mass
• Psychological disturbances
• Fatigue
• Loss of sexual drive and sexual dysfunction
• Swelling of the breasts (gynecomastia)
• Nausea and vomiting
• Hair loss
• Anemia

Needless to say, these side effects can cause severe emotional problems.

Therapies for Hormone-Resistant Cancer

Prostate cancer that does not respond to hormonal treatment is called hormone-resistant, or hormone-refractory, cancer. There are various drug treatments for hormone-resistant cancer:

Docetaxel and Other Chemotherapy. 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. Another 2004 clinical trial found that a docetaxel and estramustine combination worked better than mitoxantrone and prednisone for advanced resistant prostate cancer. 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. A large 2006 study reported that docetaxel and prednisone worked better than mitoxantrone plus prednisone in improving quality of life, pain relief, and survival. Docetaxel is also being investigated in combination with vitamin D-related drugs. A 2006 trial found that men with advanced prostate cancer who took docetaxel plus high-dose vitamin D (calcitriol) lived about 8 months longer than men who received docetaxel and placebo. Calcitriol also appeared to protect against docetaxel’s side effects, especially gastrointestinal problems and blood clots.

Doctors are also studying other ways to help patients cope with docetaxel’s side effects. Research presented at the 2006 Prostate Cancer Symposium suggested that patients may be able to take periodic breaks from docetaxel treatment instead of having continuous therapy. In the study, patients with advanced prostate cancer were given the option of suspending docetaxel treatment if their PSA levels improved within a certain range. Researchers found that patients were able to take 16-week breaks and still show improvement once they resumed treatment. This approach may work best for patients who experienced a good initial response to docetaxel.

Ketoconazole . Ketoconazole is an antifungal drug that blocks an enzyme that stimulates production of testosterone. It is effective in high doses but can have severe gastrointestinal effects, mainly nausea and anorexia. Long-term use can result in impotence, itchy skin, nail changes, and suppression of stress hormones. One center reported a consistent PSA response in more than 60% of patients who had failed other androgen suppression treatments.

Aromatase Blockers. Aminoglutethimide (Cytadren) and similar drugs block aromatase, an enzyme important in estrogen production. Because the female hormone estrogen plays such a major role in the development of breast cancer, some experts think that blocking the small amount of estrogen found in men may also affect prostate cancer. Side effects include drowsiness and skin rash.

Investigational Drugs

Bisphosphonates. These drugs prevent bone loss and reduce bone pain in metastasized cancers. They are of particular interest because they may even inhibit prostate cancer cell growth in the bone. The bisphosphonates showing most promise in prostate cancer are newer drugs called nitrogen-containing bisphosphonates (pamidronate, zoledronic acid).

Immunotherapies. The prostate organ offers special possibilities for genetic therapies because it contains highly specific antigens (factors that the immune system can target.) There are a number of approaches currently under investigation including:

• Genetically designed vaccines (Provenge, Gvaz, JBT 1001) inject factors into prostate cancer cells that trick the immune system into attacking the cancer cells.
• Antisense therapy for prostate cancer blocks expression of a protein called BCL-2, which tends to be genetically overexpressed in some patients with androgen-independent prostate cancer. This protein prevents apoptosis (a natural process by which all cells, including cancer cells, self-destruct).
• Monoclonal antibodies (MAbs) are genetically designed immune factors that target foreign compounds called antigens for attack by the immune system. Monoclonal antibodies are being designed to target prostate-specific antigens.

Angiogenesis Inhibitors. Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis ). The spread of new blood vessels is controlled by compounds called growth factors, which may be important in cancer cell proliferation. Researchers are interested in drugs that turn off these growth factors or their receptors, such as epidermal growth factor receptor (EGFR). In doing so, the drugs may be able to cut off cancer's life blood. Gefitinib (Iressa) and erlotinib (Tarceva) are angiogenesis inhibitors that target receptors of an epidermal growth factors called tyrosine kinase. They are being used in lung cancer and are being investigated in a number of other cancers, include prostate cancer. Various drugs that inhibit angiogenesis in other ways (thalidomide, endostatin) are also under investigation.

Atrasentan. Atrasentan is known as an ET(A)-receptor antagonist. It is showing promise in reducing bone loss and delaying progression of prostate cancer in men with advanced disease that no longer responds to hormone therapy. Side effects are relatively mild.

• Review Date: 7/9/2006
• Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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