Systemic Recurrence

Androgen Deprivation Therapy (ADT)

Androgen deprivation therapy(ADT), is the first line of treatment for metastatic prostate cancer. This type of treatment is aimed at reducing the levels of male hormones (androgens) in the body, or blocking  them from affecting prostate cancer cells. The main androgens are testosterone and dihydrotestosterone; they act like growth factors, encouraging prostate cancer to grow. (Most androgens are made by the testes, but a small amount is made by the adrenal glands, which are two paired glands that are located above the kidneys and produce a number of important hormones including androgens.) Without androgens, prostate cancer goes into remission, and the man can live for for many years without signs and symptoms of cancer. 

There are several medications to achieve ADT

Gonadotropin Releasing Hormones (GnRH) agonists. 

These drugs lower the amount of testosterone made by the testicles. They work in the area of the brain that produce release hormones to signal the testes to make testosterone. Because they are synthetic and not made by the body they eventually cause the testes  to stop making testosterone.The one disadvantage is that they cause an initial surge of testosterone production. They are given as injections or implants placed  under the skin. GnRH agonists available in the United States include triptorelin (Trelstar), leuprolide  (Lupron), goserelin (Zoladex)and others.

Antiandrogens

After blocking the releasing hormones from the brain, the testes do not produce testosterone. However metastatic  prostate cancer may  still grow due to androgens released from adrenals and because certain mechanisms in cancer cells try to overcome the GnRH blockade. To prevent this certain medications called anti androgens are given. The antiandrogens prevent testosterone  and other androgens in the blood from attaching to tumor cell receptors and making cancer cells grow. Available antiandrogens include flutamide (Eulexin ), bicalutamide (Casodex ),  and nilutamide (Nilandron). These medications are taken daily as pills.

GnRH antagonists. 

Degarelix (Firmagon) and Abarelix  are GnRH antagonists.These medications block gonadatrophin releasing hormone receptors in the pituitary gland in the brain. The pituitary gland then stops producing luteinising hormone. Luteinising hormone triggers the testes to make testosterone. With this medication, the testes no longer receive “instructions” from the brain to make androgens, and production of the hormones is shut down. Unlike GnRH agonists, GnRH antagonists do not cause a surge of testosterone.  These drugs lower testosterone more quickly than do GnRH agonists. They have a faster effect on lowering testosterone, faster suppression of prostate-specific antigen, no risk for testosterone surge or clinical flare, and improved prostate-specific antigen progression-free survival, suggesting a delay in castration resistance. Degarelix is given as an injection.

Side Effects of Antiandrogens

Anti androgens are detoxified by the liver and  liver function must be checked with periodic blood tests. Side effects include nausea, vomiting, stomach pain, extreme tiredness, loss of appetite, flu-like symptoms, dark yellow or brown urine, and/or yellowing of the skin or eyes. Excessive amounts of alcohol should be avoided, as they can prevent the liver from breaking down antiandrogens.

Side Effects of GnRH agonists and antagonists

Common side effects of the GnRH agonists and antagonists include symptoms of hypogonadism such as hot flashes, gynecomastia, fatigue, weight gain, fluid retention, erectile dysfunction and decreased libido.  Long term therapy can result in metabolic abnormalities, weight gain, worsening of diabetes and osteoporosis. There is also sarcopenea and insulin resistance. Rare, but potentially serious adverse events include transient worsening of prostate cancer due to surge in testosterone with initial injection of GnRH agonists and pituitary apoplexy in patients with pituitary adenoma.  Single instances of clinically apparent liver injury have been reported with some GnRH agonists (histrelin, goserelin), but the reports were not very convincing.  There is no evidence to indicate that there is cross sensitivity to liver injury among the various GnRH analogues.

 

Bilateral Orchiectomy 

Another way to stop the testicles from producing male hormones is orchiectomy, a surgical procedure in which the testicles are removed.The removal of the testicles causes most prostate cancers to stop growing. Orchiectomy is a form of hormonal therapy with the least side effects. The scrotal sac is left intact and in most men a form of subtotal orchiectomy is done to give the appearance of some testicular content. However unlike GnRH therapy where the treatment can be given intermittently, orchiectomy is permanent.

An orchiectomy is done as an outpatient procedure. While it is probably the simplest form of antiandrogen hormone therapy, most men cannot accept it psychologically as well the change to their anatomy. For some men who accept it, testicular implants are possible.

Hormone Resistant Prostate Cancer/Castrate Resistant Prostate Cancer

Metastatic prostate cancer usually responds to hormonal therapy and goes into remission, but cancer cells can sometimes resist treatments. Prostate cancer cells can “learn” how to grow, even without male hormones. Doctors call this condition hormone-resistant prostate cancer. In some cases of hormone-resistant prostate cancer, simply stopping antiandrogen treatment causes a man’s PSA level to go down and his prostate cancer to shrink or disappear.

 

Combination of ADT with chemotherapy 

In some men the  chemotherapy drug docetaxel (Taxotere) may be given in conjunction with hormone therapy as a first line approach. Studies have shown that it may be possible to slow the growth of cancer cells by combining docetaxel with ADT (rather than prescribing it sequentially).

Chemo Therapy and Newer Agents

Chemo Therapy

These drugs are used when ADT fails and may be used in combination with ADT in some patients. They are given in cycles, usually once a month and there are periods of rest between cycles allowing the body to recover. Because they attack dividing cells, they do have side effects in other parts of the body such as in the lining of the mouth and intestines, hair follicles, and may also cause bruising and easy bleeding. 

 

Docetaxel (Taxotere)

This agent is the first FDA-approved chemotherapy for advanced prostate cancer. This medication is in class of medications called taxanes. It works by blocking cell division which results in cancer cell death. The medication is well tolerated in patients, about 3% of men will experience fever with low white cell count. This can be prevented with a medication that helps white cells grow (neulesta) when patients have low white count, they have a risk for infection. 50% of men will experience fatigue. About 1/3 of men will esxperience neuropathy in the fingers or toes. this usually improves over time. There are other side effects, but these are mild.​ 

 

Cabazitaxel (Jevtana)

This agent is another taxane which is administered in combination with prednisone and is one of the newer chemotherapy agents approved by the FDA. The most common side effects seen with this agent is diarrhea in 50% of patients which can be controlled with medications such as lomotil. Other side effects include fatigue 37%, neuropathy 13%, hair loss 10%, abdominal pain 17%.

 

Sipuleucel-T (Provenge). 

This medication works by using the body’s own immune system using types of white blood cells, to destroy prostate cancer cells. Sipuleucel-T, an immunotherapy, is given as a series of three infusions into a vein, with about two weeks between each infusion. A few days before each treatment, some of the patient’s white blood cells are removed from the blood. The white blood cells are exposed to a protein that attaches antibodies onto them to target and destroy prostate cancer cells. These  treated white blood cells from the mans own body becomes a  an activated form of immune therapy which is then transfused back to the man’s bloodstream to fight the cancer.

 

Abiraterone (Zytiga) 

LHRH antagonists can stop the production of androgens by the testes, but adrenal cells in the body can still produce small amounts of androgens . Abiraterone blocks an enzyme called CYP17, helping to stop the production of androgens by adrenal cells. Used with prednisone, this hormone therapy can be given before or after chemotherapy. Abiraterone is a tablet, usually taken once a day.

 

Enzalutamide (Xtandi) 

This drug blocks male hormones from attaching to prostate cancer cells and helping them grow. As a result, enzalutamide slows the growth of prostate tumors and destroys them. this drug is approved for use in men who have previously received chemotherapy docetaxel.

 

Radium Ra 223 (Xofigo)

Radium Ra 223 is a drug that contains a small amount of radiation and is injected into the bloodstream. The radiation seeks out prostate cancer cells that have spread to the bone and that may cause pain. Radium Ra 223 was approved by the FDA for men whose cancer has spread to bones but not to other organs, and has not responded to other treatments.

DR NARAYAN AT    NFLUA.HIFU@GMAIL.COM

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