DescriptionAn in-depth report on the causes, diagnosis, treatment, and prevention of prostate cancer.
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.
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.
Hormonal therapies are also being investigated in locally advanced prostate cancer following radiation therapy or surgery (called adjuvant therapy) or when used before radiotherapy (neoadjuvant therapy). Studies are suggesting that they improve survival in men at high-risk for progression. The most positive evidence to date is reported with adjuvant hormonal therapy after radiotherapy. Such agents are also being investigated as an alternative to watchful waiting, surgery, and radiation therapy in localized cancer. In a 2003 Japanese study, for example, five-year survival rates in patients using androgen-blocking agents was equal to those in the general population. They have significant side effects and possible long-term complications, however.
Specific Treatments Used to Block Androgen. Androgen-suppression treatments include the following:
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.
The primary agents used for suppressing androgens are called luteinizing hormone-releasing hormones (LH-RH) agonists. They include:
LH-RH agents 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 two 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 are powerful agents 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 drugs are as follows:
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 the following:
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:
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 one to three -month intervals.
Estrogens, usually diethylstilbestrol (DES), may also be used. Certain types of these female hormones may exacerbate heart conditions in high doses, however, and their use has declined. Other estrogens, such as fosfestrole, may prove to be effective without posing such high risks. An estrogen agent, estramustine phosphate, which is also used in chemotherapy, is showing promise.
Orchiectomy is surgical removal of the testicles. It is the single most effective method of reducing androgen hormones, but it is considered an extreme procedure. The operation can be done on an outpatient basis, through a tiny incision in the scrotum, and is relatively pain-free.
Sexual Effects. 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.
Quality of Life. Interestingly, patients who choose this option report significantly higher quality of life afterward than those who opt for hormonal treatment, particularly total androgen ablation. Although the operation impairs sexuality, it causes less fatigue, physical dysfunction, and psychological distress than other treatments for advanced cancer, excluding no treatment at all. These studies, however, did not compare orchiectomy to intermittent hormonal therapy, which may prove to have psychological benefits.
Osteoporosis. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis, a loss of bone density that increases the risk for fracture. In fact, the risk for osteoporosis may be higher with surgery than hormonal drugs.
Techniques for Improving Androgen Deprivation Therapies
Maximal Androgen Blockage (MAb). Even after using standard hormonal agents, residual testosterone is usually present. In such cases, physicians 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 agents 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 six 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, it 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. 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 the following:
Needless to say, these side effects can cause severe emotional problems.
Therapies for Androgen-Independent Tumors
Cancer nearly always returns after androgen suppression fails, which is referred to as androgen-independent cancer. Researchers are investigating the use of chemotherapy and other agents that affect hormonal triggers of prostate cancer. Some studies indicate that when tumors recur after antiandrogen treatments, they may actually be sensitive to testosterone. If so, administering androgens at the point of relapse might suppress tumor growth in some situations. More research is needed for this interesting finding.
Secondary Hormonal Therapies. A number of hormonal agents are being used or tested for relapsed androgen-independent cancer.
Ketoconazole. Ketoconazole, usually used to fight fungal infections, is a nonhormonal drug that inhibits 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 postulate that blocking the small amount of estrogen found in men may also affect prostate cancer. Side effects include drowsiness and skin rash.
Corticosteroids. Corticosteroids, such as prednisone, are important for reducing pain and improving quality of life. Some experts believe they should be the first choice for progressive prostate cancer that is resistant to hormonal treatments. Corticosteroids may be particularly effective in relieving pain and delay disease progression when used in combination with chemotherapy drugs, particularly mitoxantrone. There is evidence that corticosteroids can reduce PSA levels and boost survival in some patients.
Chemotherapy. Chemotherapy for prostate cancer improves symptoms but standard agents have not improved survival rates. A number of drugs are being investigated, both alone and in combinations, for cancer that is unresponsive to hormone treatments. Among the drugs that have shown some promising results are mitoxantrone combined with corticosteroids, estramustine in combinations with drugs such as vinblastine, paclitaxel, or docetaxel, and platinum-based agents in combinations with 5-fluoroouracil. Other combinations are being explored.
Other Agents Investigated for Metastasized Cancer
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 agents called nitrogen-containing bisphosphonates (e.g., 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 the following:
Vitamin-D Derived Treatments. Some studies are reporting that vitamin-D derived agents, such as calcitriol (Zemplar), may eventually be beneficial for prostate cancer patients. Calcitriol is derived from the active compound in vitamin D. It is being studied in combination with other chemotherapies. A 2003 study suggested that it may also enhance the treatment effects of radiation therapy without increase its adverse effects.
Angiogenesis Inhibitors. Much research is focusing 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, then, are interested in agents that literally turn off these growth factors or their receptors, such as epidermal growth factor receptor (EGFR). In so doing, the agents 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 investigated in a number of others, include prostate cancer. Various agents that inhibit angiogenesis in other ways (e.g., thalidomide, endostatin, and others) are also under investigation.
Doxazosin. Doxazosin (Cardura), a drug commonly used to treat benign prostatic hyperplasia, has been shown to kill prostate cancer cells in lab experiments. The effects are amplified when doxazosin is combined with adriamycin or etoposide, chemotherapy drugs. More research is needed to determine if this effect has significance for patients.
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.