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Androgen Deprivation Therapy and Prostate Cancer

An overview of the principles of ADT for prostate cancer and the various drug types used.

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Androgen Deprivation Therapy and Prostate Cancer

  1. 1. Part of the “Enhancing Prostate Cancer Care” MOOC Catherine Holborn Senior Lecturer in Radiotherapy & Oncology Sheffield Hallam University
  2. 2. Introduction This presentation aims to provide an overview of Androgen Deprivation Therapy (ADT), also referred to as Hormone therapy, for prostate cancer. It covers the basic principles and methods and provides an insight into the side effects It does not cover the use of these methods (when and how they are used) in the management of the different stages of prostate cancer
  3. 3. Principles of ADT Prostate cells (normal and malignant) are physiologically dependent on androgens to grow, function and proliferate Testosterone is the primary male androgen. The testes are the major source of testosterone  The adrenal glands also produce 'weak' androgens. These can be converted into more potent testosterone. Overall though, their effect is negligible in comparison to testosterone production in the testes. Dihydrotestosterone (DHT) is a metabolite of testosterone and is a more potent androgen Testosterone doesn’t ‘cause’ prostate cancer but promotes and encourages growth. Androgen deprivation can help to induce apoptosis (cell death) or at the very least prevent further growth. It can be achieved in two main ways:  Surgical or medical ‘castration’; stops the production of testosterone  Anti-androgen therapy; inhibits the action of testosterone preventing its interaction with the receptors on the prostate cancer cells
  4. 4. Main testosterone production Very broadly, the hypothalamus and pituitary will send signals to the testes which cause them to produce testosterone. The hypothalamus, releases a hormone called either 'gonadotropin releasing hormone ' (GnRH) or 'luteinizing hormone releasing hormone' (LHRH). This is passed to the pituitary which responds to produce two gonadotropins. These are called Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). In males, LH binds with the Leydig cells in the testes and promotes the synthesis of testosterone. FSH binds with Sertoli cells in the seminiferous tubules and promotes spermatogenesis.
  5. 5. Stopping the production of testosterone As a general rule, this is the most common first line approach to hormone therapy for prostate cancer Surgically, this would involve a bilateral orchidectomy (removal of the testes) Medically, there are a number of ways in which the production of testosterone can be stopped/reduced; Oestrogens e.g. Diethylstilboestrol (DES) LHRH agonists e.g. busereline, gosereline, leuproreline, triptoreline LHRH antagonists e.g. abarelix, degarelix
  6. 6. Bilateral orchidectomy In terms of testosterone reduction, this method of surgical castration is considered the gold standard of androgen deprivation therapy (ADT) against which the effectiveness of other therapies are measured Current definition of castration is <20ng/dl ¹ This is less favoured though given the psychological impact. It is also permanent. Nevertheless, men should be offered this as an option if appropriate. 1. Schulman CC, Irani J, Morote J, Schalken JA, Montorsi F, Chlosta PL, Heidenreich A. Androgen-Deprivation Therapy in Prostate Cancer: A European Expert Panel Review. European Urology Supplements. 2010; 9:675- 691
  7. 7. Oestrogens Mechanisms of action: Down regulate LHRH secretion (and ultimately testosterone production) Androgen inactivation Direct suppression of leydig cell function Direct cytotoxicity (tested in-vitro) DES is the most commonly used oestrogen (doses of 1mg, possibly 3mg) However, it has fallen out of favour due to the associated risks of cardiac toxicity and adverse cardiovascular events Hence it is not recommended as a first line option Oestrogen skin patches ( as an alternative administration method) are being researched to see if these reduce this cardiovascular risk
  8. 8. LHRH agonists (LHRHa) The preferred method of first line ADT for prostate cancer. Note the term ‘agonist’ not ‘antagonist’. LHRH agonists stimulate the pituitary to produce more Leutenising Hormone (LH) which causes an initial elevation in testosterone production within the testes. However, prolonged exposure eventually causes the pituitary receptors to ‘down regulate’ and testosterone is ultimately reduced/stopped
  9. 9. PSA flare The initial rise in testosterone can cause the PSA levels to rise slightly (as prostate growth is encouraged). This is called the ‘flare’ phenomenon. It is important that patients are aware. It begins 2-3 days after the first injection and lasts approximately 1 week It can have detrimental effects in those with advanced disease e.g. bone pain, bladder outlet obstruction, obstructive renal failure and cord compression. If the latter is a risk then the use of LHRH agonists should be avoided Anti-androgens e.g. Cyproterone, started on the same day and lasting for two weeks, can be used to counteract this flare
  10. 10. LHRH antagonists These drugs compete for and bind to the LHRH pituitary receptors preventing the normal signals for testosterone production, reaching the testes This causes a rapid decrease in testosterone production and there is no prostate flare with these drugs HOWEVER, they are associated with histamine-mediated side effects (allergic reactions), which in many cases have been serious e.g. anaphylactic shock (particularly so with abarelix, degarelix lessens the risk) Their benefits over the more traditional LHRH agonists are yet to be proven in light of these side effects
  11. 11. Recent promising evidence A met-analysis by Klotz et al (2014)² pooled individual patient data from 5 comparative randomised clinical trials of degarelix vs. LHRHa. Efficacy and safety were assessed. Key results Degarelix was found to increase PSA progression free survival; especially for those with an initial PSA <20ng/ml. Those with >20ng/ml correlated with a increased risk of progression. Degarelix was also associated with increased overall survival; interestingly, due to a decreased risk of cardiovascular disease – a promising benefit! Decreased joint, musculoskeletal and urinary tract events were also observed with degarelix 2. Klotz L, et al. Disease Control Outcomes from Analysis of Pooled Individual Patient Data from Five Comparative Randomised Clinical Trials of Degarelix Versus Luteinising Hormone-releasing Hormone Agonists. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2013.12.063
  12. 12. Anti-androgens These have a similar structure to testosterone and bind with the testosterone receptors on the prostate cells, blocking the effects of testosterone. There are two main groups of anti-androgens: Steroidal E.g. cyproterone Non-steroidal E.g. flutamide, bicalutamide
  13. 13. Non-steroidal anti-androgens Don’t lower testosterone levels therefore libido, overall physical performance and bone mineral density, are more likely to be preserved They are not without side effects though e.g. gynaecomastia, breast pain and hot flashes. Liver toxicity is also a problem and liver function must be checked regularly Bicalutamide shows a more favourable safety and tolerability profile
  14. 14. Steroidal anti-androgens Cyproterone acetate is the most common. The most effective dose is still under investigation In contrast to non-steroidal anti-androgens they also have progestational properties which help to ‘lower’ testosterone levels; so loss of libido may still be an issue
  15. 15. Key effects of testosterone Reviewing the key roles of testosterone within the body, helps to explain the side effects that are observed when this is removed: Growth of muscle mass Bone growth, increased bone density and strength Maturation of sex organs and secondary sexual characteristics e.g. body hair Sexual arousal / libido Positive effect on cognitive functions such as attention, memory and spatial ability
  16. 16. An overview of key side effects Hot flashes (flushes); can be significant, very bothersome and distressful. Can disrupt daily activities and plans. Fatigue; a common symptom and multi-faceted. Can be related to a reduction in testosterone but may also be related to other treatments, physical and psycho-social factors Cognitive decline; forgetfulness, lack of concentration and mood changes Sexual dysfunction and loss of libido; drugs that block testosterone action rather than decrease its levels may be used if a man is concerned about this, but they may not be as effective in terms of disease control
  17. 17. Effects more likely with longer term use Osteoporosis; bone mineral density is reduced Increasing risk of weight gain and obesity; lean muscle mass reduces and fat mass increases, especially around the tummy area Increases the risk of sarcopenia; a term used to describe the erosion of skeletal muscle and general frailty/feeling weak; can increase the risk of falls and further increase the risk of fractures Hormone therapy also increase serum cholesterol and triglyceride levels and so can increase the risk of cardiovascular complications
  18. 18. The impact of ADT on general wellbeing and quality of life will be explored more ion week 4 of the MOOC.

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An overview of the principles of ADT for prostate cancer and the various drug types used.

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