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.
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