context: Prostate cancer occurs when a tumor develops in the prostate gland, which makes the liquid portion of semen. Cancer that spreads outside the prostate gland to the lymph nodes, bones, or other areas is called metastatic prostate cancer. Currently, no treatments can cure advanced prostate cancer. However, there are ways to help control its spread and related symptoms. Treatments that slow the spread of advanced prostate cancer and relieve symptoms often cause side effects. Some patients, often those who are older, decide that the risk of side effects outweighs the benefits of treatment. These patients may choose not to treat their advanced prostate cancer. It's important to remember that researchers are always searching for new and better treatments that will cause fewer side effects, better disease control, and longer survival rates. Male hormones, specifically testosterone, fuel the growth of prostate cancer. By reducing the amount and activity of testosterone, the growth of advanced prostate cancer is slowed. Hormone (endocrine) therapy, known as androgen ablation or androgen suppression therapy, is the main treatment for advanced prostate cancer. It is the first line of treatment for metastatic prostate cancer. In many patients, endocrine therapy provides temporary relief of symptoms of advanced prostate cancer. Endocrine therapy may reduce tumor size and levels of prostate specific antigen ( PSA) in most men. PSA is a substance produced by the prostate gland that, when present in excess amounts, signals the presence of prostate cancer. However, hormone therapy is not without side effects. Some of the more serious side effects include loss of sex drive, impotence, weakened bones (osteoporosis), and heart problems. Eventually, most patients with advanced prostate cancer stop responding to hormone therapy. Doctors call this castrate-resistant prostate cancer. Patients who no longer respond to hormone therapy have another option. The chemotherapy drug docetaxel ( Taxotere) taken with or without prednisone (a steroid) is the standard chemotherapy regimen for patients who no longer respond to hormone therapy. Docetaxel works by preventing cancer cells from dividing and growing. Patients receive docetaxel, along with prednisone, through an injection. Side effects of docetaxel are similar to most chemotherapy drugs and include nausea, hair loss, and bone marrow suppression (the decline or halt of blood cell formation). Patients may also experience neuropathy (nerve damage causing tingling, numbness, or pain in the fingers or toes) and fluid retention. Docetaxel, when used with or without prednisone, was the first chemotherapy drug proven to help patients live longer with advanced prostate cancer. The average survival was improved by about 2.5 months when compared to mitoxantrone with or without prednisone. Docetaxel has the best results when given every three weeks as compared to weekly dosing. Cabazitaxel ( Jevtana) is another chemotherapy drug, used in combination with the steroid prednisone, to treat men with prostate cancer. Cabazitaxel ( Jevtana) is used in men with advanced prostate cancer that has progressed during, or after, treatment with docetaxel ( Taxotere). The safety of cabazitaxel ( Jevtana) and its effectiveness were established in a single, 755-patient study. All study participants had previously received docetaxel ( Taxotere). The study was designed to measure overall survival (the length of time before death) in men who received cabazitaxel ( Jevtana) in combination with prednisone as compared to those who received the chemotherapy drug mitoxantrone in combination with prednisone. The median overall survival for patients receiving the cabazitaxel ( Jevtana) was 15.1 months compared with 12.7 months for those who received the mitoxantrone regimen. Side effects in those treated with cabazitaxel ( Jevtana) included significant decrease in infection-fighting white blood cells (neutropenia), anemia, low level of platelets in the blood (thrombocytopenia), diarrhea, fatigue, nausea, vomiting, constipation, weakness, and renal failure. Sipuleucel- T ( Provenge) is a "vaccine" for advanced prostate cancer that helps prolong survival. Provenge isn't your everyday vaccine. It's an immune therapy created by harvesting immune cells from a patient, genetically engineering them to fight prostate cancer, and then infusing them back into the patient. It's approved only for treatment of patients with few or no prostate cancer symptoms whose cancer has spread outside the prostate gland and is no longer responding to hormone therapy. Once a cancer grows beyond a certain point, the immune system has a hard time fighting it. One reason is that cancer cells look a lot to the immune system like normal cells. Another reason is that tumors may give off signals that manipulate the immune system into leaving them alone. Provenge bypasses these problems. The treatment first removes a quantity of dendritic cells from a patient's blood. Dendritic cells show pieces of tumor to immune cells, priming them to attack cells that carry those pieces. The patient's doctor ships the cells to Provenge's manufacturer, Dendreon, which then exposes them to Provenge. Provenge is a molecule made inside genetically engineered insect cells. Once these cells have been exposed to Provenge, they're shipped back to the doctor who infuses them back into the patient. This is done three times in one month. The first infusion primes the immune system. The second and third doses spur an anticancer immune response. The most common side effect is chills, which occurs in more than half of the men that receive Provenge. Other common side effects include fatigue, fever, back pain, and nausea. Provenge has been remarkably safe. However, clinical trials suggest that the treatment might be linked to a slightly increased risk of stroke. Drugs work as well as prostate cancer surgery (orchiectomy -- removal of the testicles) to reduce the level of hormones in the body. Most men opt for drug therapy rather than surgery. The three types of hormone-related drugs approved to treat advanced prostate cancer include luteinizing hormone-releasing hormone ( LHRH) analogs, luteinizing hormone-releasing hormone ( LHRH) antagonists, and antiandrogens. Most patients who receive hormonal therapy choose LHRH analogs. These drugs work by decreasing testosterone production to very low levels by depleting the pituitary gland of the hormone needed to produce testosterone. However, before this decrease in testosterone occurs, patients experience a brief and temporary increase in testosterone production and tumor growth. This is due to a transient increase in release of LHRH from the pituitary gland with a resulting stimulation of testosterone production. This phenomenon, called tumor flare, can cause increased symptoms from the prostate cancer that didn't exist before the patient received the therapy. Some doctors prescribe antiandrogens (described below) to combat the symptoms caused by tumor flare. LHRH analogs are administered via injection or small implants placed under the skin. The most commonly used LHRH analogs in the U. S. are leuprolide ( Eligard, Lupron), histrelin ( Vantas), triptorelin ( Trelstar), and goserelin ( Zoladex). They cause side effects similar to those from the surgical orchiectomy. These drugs carry a risk of triggering diabetes, heart disease, osteoporosis, and/or stroke. Before starting one of these drugs, patients should tell their doctor if they have a history of diabetes, heart disease, stroke, heart attack, high blood pressure, high cholesterol, or cigarette smoking. These drugs have been approved for use as hormone therapy in patients with advanced prostate cancer. LHRH antagonists lower testosterone levels more quickly than LHRH analogs. In addition, they don't cause a tumor flare (temporary rise in testosterone levels) as do LHRH analogs. Degarelix ( Firmagon) is a LHRH antagonist used to treat advanced prostate cancer. It has been shown to decrease the progression of disease, but further trials are needed to look at long-term outcomes. It is fairly well tolerated with common side effects being local injection site problems and increased liver enzymes. These prostate cancer drugs work by blocking the effect of testosterone in the body. Antiandrogens are sometimes used in addition to orchiectomy or LHRH analogs. This is due to the fact that the other forms of hormone therapy remove about 90% of testosterone circulating in the body. Antiandrogens may help block the remaining 10% of circulating testosterone. Using antiandrogens with another form of hormone therapy is called combined androgen blockade ( CAB), or total androgen ablation. Antiandrogens may also be used to combat the symptoms of flare (temporary rise in testosterone that occurs with the use of LHRH agonists). Some doctors prescribe antiandrogens alone rather than with orchiectomy or LHRH analogs. Available antiandrogens include abiraterone acetate ( Zytiga), biclutamide ( Casodex), enzalutamide ( Xtandi),flutamide ( Eulexin), and nilutamide ( Nilandron). Patients take antiandrogens as pills. Diarrhea is the primary side effect when antiandrogens are used as part of combination therapy. Less likely side effects include nausea, liver problems, and fatigue. When antiandrogens are used alone they may cause a reduction in sex drive and impotence. Sometimes, patients receive hormone therapy in combination with external beam radiation therapy for the treatment of prostate cancer. This treatment uses a high-energy X-ray machine to direct radiation to the prostate tumor. For patients with intermediate or high risk prostate cancer, studies show this combination is more effective at slowing the disease than endocrine therapy or radiation therapy alone. Radiation can also come in the form of a monthly intravenous drug called Xofigo. Xofigo is approved for use in men who have advanced prostate cancer that has spread only to the bones. Candidates should have also received therapy designed to lower testosterone. The drug works by binding to minerals within bones to deliver radiation directly to bone tumors. A study of 809 men showed that those taking Xofigo lived an average of 3 months longer than those taking a placebo. Two other similar drugs arestrontium-89 ( Metastron) and samarium-153 ( Quadramet). At some point, PSA levels begin to rise despite treatment with hormone therapy. This signals that hormone therapy is no longer working to reduce testosterone levels in the body. When this happens, doctors may decide to make changes to the hormone therapy. This is called secondary hormone therapy. It can be done in a number of ways. For instance, if you have had surgery to remove your testicles, your doctor may suggest that you begin taking an antiandrogen. If you have been using combination therapy that involves an antiandrogen and LHRH analogs, your doctor may stop the use of the antiandrogen. This is known as anti-androgen withdrawal. Another option is to change the type of hormone drug. However, the use of an LHRH drug must be continued to prevent a testosterone rebound from stimulating the growth of prostate cancer cells. Ketoconazole, an antifungal agent, inhibits adrenal and testicular synthesis of testosterone when used at high doses. Response rates in a second line setting are 20%-40% with significant side effects. Doses range from 200 mg 3 times a day to 400 mg three times a day. The drug must be given with hydrocortisone to prevent adrenal insufficiency. Most doctors agree that hormone therapy is the most effective treatment available for patients with advanced prostate cancer. However, there is disagreement on exactly how and when hormone therapy should be used. Here are a few issues regarding standards of care: Timing of Cancer Treatment The disagreement is due to conflicting beliefs. One is that hormone therapy should begin only after symptoms from the metastases, like bone pain, occur. The counter belief is that hormone therapy should start before symptoms occur. Earlier treatment of prostate cancer is associated with a lower incidence of spinal cord compression, obstructive urinary problems, and skeletal fractures. However, survival is not different whether treatment is started early, or deferred. The only exception to the above, is in lymph node-positive, post-prostatectomy patients, given androgen deprivation as an adjuvant immediately after surgery. In this situation, immediate therapy resulted in a significant improvement in progression free survival, prostate cancer specific survival, and overall survival. Length of Cancer Treatment The disagreement in this situation is between continuous androgen deprivation (hormone therapy) and intermittent androgen deprivation. In early 2012, it was discovered that intermittent androgen deprivation is equal in long-term survival to continuous androgen deprivation. A new paradigm of treatment, in which androgen deprivation was given for 8-9 months and then discontinued if the PSA normalized, was published. Re-treatment is recommended only when the PSA level becomes greater than 10 with monitoring every two months. Combination vs. Single- Drug Therapy There is also disagreement about whether using a combination of hormone therapies or just a single anti-androgen drug works best to treat prostate cancer. The studies are inconclusive. However, patients who receive combination therapy are more likely to experience treatment-related side effects than patients receiving a single form of hormone therapy. In some cases of advanced or recurrent prostate cancer, surgeons may remove the entire prostate gland in a surgery known as "salvage" prostatectomy. They usually do not perform the nerve-sparing form of prostatectomy. Often, surgeons will remove the pelvic lymph nodes at the same time. Cyrosurgery (also called cryotherapy) may be used in cases of recurrent prostate cancer if the cancer has not spread beyond the prostate. Cryosurgery is the use of extreme cold to destroy cancer cells. To reduce testosterone levels in the body, doctors may sometimes recommend removing the testicles, a surgery called orchiectomy. After this surgery, some men choose to get prosthetics (artificial body parts) that resemble the shape of testicles. Doctors may also remove part of the prostate gland with one of two procedures, either a transurethral resection of the prostate ( TURP) or a transurethral incision of the prostate ( TUIP). This relieves blockage caused by the prostate tumor, so urine can flow normally. This is a palliative measure, which means it is done to increase the patient's comfort level, not to treat the prostate cancer itself. Researchers are pursuing several new ways to treat advanced prostate cancer. Vaccines that alter the body's immune system and use genetically modified viruses show the most promise. One vaccine technique works by manipulating blood cells from the patient's immune system and causing them to attack the prostate cancer. Blood is drawn from the patient. From the blood sample, cells that are part of the immune system (called dendritic cells) are exposed to cells that make up prostate cancer. Then the blood cells are placed back in the body, with the hope that they will cause other immune system cells to attack the prostate cancer. In a more traditional type of vaccine, the patient is injected with a virus that contains PSA. When the body is exposed to the virus, it becomes sensitized to cells in the body that contain PSA and his immune system attacks them. Immune or genetic therapy have the potential to deliver more targeted, less invasive treatments for advanced prostate cancer. This would result in fewer side effects and better control of the prostate cancer.