Part of the “Enhancing Prostate Cancer Care” MOOC

Catherine HolbornSenior Lecturer in Radiotherapy & Oncology

Sheffield Hallam University

IntroductionThis 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

Principles of ADTProstate cells (normal and malignant) are physiologically dependent

on androgens to grow, function and proliferateTestosterone 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

Main testosterone productionVery 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.

Stopping the production of testosteroneAs a general rule, this is the most common first line

approach to hormone therapy for prostate cancerSurgically, 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,

triptorelineLHRH antagonists e.g. abarelix, degarelix

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 ¹This 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

Bilateral orchidectomy

OestrogensMechanisms of action:

Down regulate LHRH secretion (and ultimately testosterone production)

Androgen inactivationDirect suppression of leydig cell functionDirect 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 eventsHence it is not recommended as a first line optionOestrogen skin patches ( as an alternative administration method) are

being researched to see if these reduce this cardiovascular risk

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

PSA flareThe 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

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

LHRH antagonists

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 resultsDegarelix 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

Recent promising evidence

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. cyproteroneNon-steroidal

E.g. flutamide, bicalutamide

Anti-androgens

Non-steroidal anti-androgensDon’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

Steroidal anti-androgensCyproterone acetate is the most common. The most

effective dose is still under investigationIn 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

Key effects of testosteroneReviewing the key roles of testosterone within the body,

helps to explain the side effects that are observed when this is removed: Growth of muscle massBone growth, increased bone density and strengthMaturation of sex organs and secondary sexual

characteristics e.g. body hairSexual arousal / libidoPositive effect on cognitive functions such as attention,

memory and spatial ability

An overview of key side effectsHot 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

Effects more likely with longer term useOsteoporosis; bone mineral density is reducedIncreasing 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

The impact of ADT on general wellbeing and quality of life will be explored more ion week 4 of the MOOC.