GnRH Receptor Antagonist-Another Chemical Way to Control the Production of Testosterone

Degarelix (Firmagon) works immediately, binding to gonadatropin-releasing hormone (GnRH) receptors in the pituitary gland. This induces a fast and profound reduction in testosterone without a PSA flare. This also means that you do not need to use an anti-androgen such as Casodex .

The most serious of its possible side effects are:

  • Difficulty breathing
  • Swelling of the face, lips, tongue or throat
  • Dizziness, fainting or pounding heartbeat
  • Pain or burning during urination
  • Swelling in your hands, ankles, or feet
  • Injection site reactions
  • Dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats or seizures

If you experience any of these symptoms, immediately see your doctor or go to an emergency room.

Anti-Androgen Medications – Blocking Testosterone from Accessing the Cancer Cells

Many doctors choose to add another drug to the GnRH agonist/antagonist drug, whose function is to block the androgen receptors, which are located on every cancer cell, from accessing any testosterone that might still be produced in your body. These drugs are called anti-­androgens. When used in combination with the GnRH drugs that restrict the testosterone production, the treatment is called “combined hormonal therapy,” or in shorthand, ADT2.  ADT2 provides a more complete form of hormone therapy.

As discussed above, when first starting GnRH agonist medications (e.g. Lupron) the testes respond to the termination of the signals from the pituitary gland and over-produce testosterone that can be detrimental, especially for a man with serious disease, indicated by PSA flare.  To prevent this, ask your doctor if the anti-androgen drugs should be started at least ten days prior to the first administration of a GnRH agonist in order to prevent this damaging situation.  (A GnRH antagonist such as Firmagon does not require the earlier anti-androgen since it does not produce a testosterone flood.)

The commonly used antiandrogen drugs are:

  • Casodex (bicalutamide)
  • Eulexin (flutamide)
  • Nilandron (Nilutamide)
  • Androcur (cyprotertone acetate)

Anti-androgens also have their own side effects, which will vary from man to man. These drugs may:

  • Negatively affect the liver
  • Cause hot flashes
  • Cause breast tenderness or growth (gynecomastia)
  • Cause a loss of libido

 

Ask your doctor and pharmacist about the side effects of all of your medications.

A Long Simmering Controversy — The Use of a 5-alpha-reductase Inhibitors

An enzyme called 5-alpha-reductase is responsible for the conversion of testosterone to 5a-dihydrotestosterone (5a-DHT). 5a-DHT is three times more potent than testosterone in causing prostate cancer cells to grow because of its greater affinity for androgen receptors. (Citation: Wright, A. S., L. N. Thomas, etal. (1996) and Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat. J Clin Invest 98(11): 2558-63.)

Nevertheless, some doctors will recommend that their patients use 5a-reductase inhibitors (5-AR1s) such as finasteride (Proscar, Propecia) or dutasteride (Avodart) because 5-ARIs are thought to be a better testosterone blockade, as well as being able to extend the “off” periods during intermittent hormone therapy (IHT). We struggle to find evidence to supports this recommendation.

As with any other drug, the 5a-reductase inhibitors have side effects. The most common side effects include gynecomastia (breast enlargement) and loss of ejaculate. The 5-ARIs are metabolized in the liver and should be used with great caution by anyone with any sort of liver disease.

Anti-Androgens as ADT Mono-Therapy

Some doctors will start you out on only an antiandrogen drug, as a ADT “mono-therapy.”  As we’ve seen, anti-androgen drugs block testosterone from interacting with the androgen receptors on the prostate cancer cells, thus depriving the cancer cells of testosterone. However, it’s important to note that this protocol does not prevent the production of testosterone. Therefore, side effects from anti-androgen mono-therapy are not as significant as when ADT is coupled with a GnRH drug or orchiectomy, so mono-therapy may be a good choice for someone concerned with quality of life.

Although it is rare that a doctor in the United States will offer antiandrogen mono-therapy, the 2007 guidelines from The American Society of Clinical Oncologists (ASCO) for initial ADT states, “non-steroidal antiandrogen mono-therapy merits discussion as an alternative to combined androgen blockage (CAB) (50 mg Casodex with a GnRH agonists).”  Translated, an anti-androgen along with the GnRH agonist or antagonist may be more effective than the GnRH drug by itself. So, if the doctor does not offer you an anti-androgen ask about it.

Casodex (150 mg daily) mono-therapy has become the established alternative treatment in Europe. In men with biochemical recurrences only, this dosage of Casodex may provide comparable outcomes, while preserving bone mineral density and muscle strength, as well as other quality of life advantages. In men with demonstrated metastases, mono-therapy is not as effective as combined androgen blockage.  A doctor might prescribe Casodex (150mg daily) mono-therapy for a month or two before undergoing a radical prostatectomy (primary treatment) since it can help shrink the prostate gland, simplifying the surgical procedure.  (http://www.nejm.org/doi/pdf/10.1056/NEJM198908173210702)

Timing of Hormone Therapy — When to Start and How to Structure It

Data from the National Cancer Institute (NCI) Intergroup Trial showed longer survival times with combined therapy (CAB) for men with metastatic disease. This observation and other studies suggest the benefits of using ADT early. It is possible that early treatment with CAB in men with metastatic disease will improve survival time compared to waiting until symptomatic metastasis occurs. There appears to be a recent trend to treat men earlier using CAB, before metastatic symptoms develop. (http://www.nejm.org/doi/pdf/10.1056/NEJM198908173210702)

However, in a recent study involving men who have a PSA only (bio-chemical) recurrence starting hormone therapy immediately doesn’t provide any additional survival benefit over delaying the start of hormone therapy (http://advancedprostatecancer.net/?p=4602).  So, if you have PSA only recurrence you should discuss with your doctor the possibility of delaying the start of hormone therapy.  Delaying the therapy will allow you to put off having to deal with the side effects of the therapy.

Timing of Hormone Therapy- Intermittent (IHT) vs. Continuous Therapy

Traditionally, ADT has almost always been administered on a continuous basis; once on ADT a man stayed on it indefinitely. Unfortunately, ADT itself poses significant risks to a man’s life as well as to his quality of life (Q0L).

Many doctors now suggest using intermittent hormone therapy (IHT), except for those patients with very aggressive prostate cancer. Instead of keeping a man on therapy continually and indefinitely, they start and stop ADT by monitoring PSA levels.  Most survivors refer to the off ADT period as being “on vacation.”  For the most part, research has shown that intermittent ADT is not inferior to continuous therapy (or stated in lay terms, “just is as good”).  A recent exception to this was a study done by Dr. Maha Hussain from the University of Michigan (http://abstract.asco.org/AbstView_114_92516.html) concluding that intermittent ADT was inferior to continuous therapy.  This was a very large study performed over many years, but it may have enough design flaws to render its conclusions invalid.  (A complete explanation of the author’s conclusions about this study may be viewed at: http://advancedprostatecancer.net/?p=3274).

 

With respect to IHT, here are excerpts from the Advanced Prostate Cancer Blog:

An intermittent androgen blockade appears to delay the progression from treatable androgen-dependent cancer to untreatable androgen-independent disease (castrate resistant prostate cancer).

From: “A Report from The Impact Conference On Intermittent Androgen Blockade” at: http://advancedprostatecancer.net/?p=55.  

“Side-effects were more pronounced in those on continuous ADT. Men on intermittent therapy reported better sexual function.”

The conclusions of the researchers was that IHT should be considered for use in routine practice because it is associated with no reduction in survival, no clinically meaningful impairment, better sexual activity, and considerable economic benefit to the individual and the community at: http://advancedprostatecancer.net/?p=539.

“Comparing Intermittent To Continuous Androgen Deprivation For Advanced Prostate Cancer”, http://advancedprostatecancer.net/?p=386 concluded that IAD appears feasible for patients with locally advanced, hormone sensitive prostate cancer.

“Intermittent Hormone Blockade is Safe & Effective”; http://advancedprostatecancer.net/?p=73  The study showed that IAS is safe. The men on IAS experienced a 40% “off time” while also

experiencing an increase in a positive “quality of life.

“Intermittent Androgen Deprivation (IAD) provides similar outcomes to continuous therapy with the potential for fewer side effects and less disruption to quality of life.- No Longer Considered Experimental for Treating Men with Advanced Prostate Cancer” http://advancedprostatecancernet/?p=2729

Managing the Side Effects of ADT

The potential side effects of ADT can be both bothersome and serious. These side effects include:

  • Hot Flashes and “the sweats”
  • Loss of Libido and erectile dysfunction
  • Fatigue and weakness accompanied with loss of muscle mass
  • Weight gain
  • Breast tenderness and growth
  • Memory loss and confusion
  • Increase risk for metabolic and cardio problems
  • Mood swings and depression
  • Bone thinning (osteoporosis)

 

You should work closely with your doctor on developing strategies to maintain or even improve the quality of your life (QoL) by keeping you as free as possible of undesirable side effects. The advanced prostate cancer blog has a number of posts specific to managing these side effects:

“How to Manage the Side Effects of Hormone Therapy MDT in the Treatment of Prostate Cancer” http://advancedprostatecancer.net/?p=803

“Long-Term Effects of Intermittent Androgen Suppression on Testosterone Recovery and Bone Mineral Density: Results of a 33-Month Observational Study” reported that the bone mineral density partially recovered in men who recovered their testosterone levels during a vacation or “off period” at: http://advancedprostatecancer.net/?p=547

Although not the side effect that puts a man at risk, hot flashes seems to be the most reported side effect as being bothersome.  To counter them members of the Malecare Advanced Prostate Cancer On-line Support Group have reported good results using a 400 mg intramuscular injection of of Depo‐Provera.

Recent evidence suggests that the use of estrogen, either to mitigate hot flashes or as a second line ADT, can pose additional risks for men who have breast cancer in their families as well as men who are at a higher risk of developing Melanoma. (www.advancedprostatecancer.net/?p=2996)

Another common treatment for hot flashes is the drug Gabapentin. Research shows, however, that Gabapentin offers only a moderate benefit. (Citation: Ann Oncol. 2009 Jan 6. Epub ahead of print. doi:10.1093/annonc/mdn644, PMID:19129205)

Some advanced prostate cancer support group members report success with acupuncture, weight loss, hypnosis, reducing alcohol consumption, smoking cessation, biofeedback and also drinking a tea of Pueraria root (Chinese name Ge Gen). Talk to your doctor about all of these, before you try them yourself.

Hot flashes that we experience from ADT are similar to the hot flashes experienced by postmenopausal women.  These women have pioneered ways to deal with the flashes, so ask someone you know what they find helpful.

Other tricks you might want to consider are avoiding stress, caffeine, spicy foods and alcohol.  Dress in layers so that you can shed some cloths as needed. Carry a personal fan, use cooling pads, a bag of frozen peas on your pillow as well as on your neck, head and wrists.  These are all simple, inexpensive tricks that do not come with any side effects of their own.