Prostate cells are physiologically dependent on androgens to stimulate growth, function and proliferation. Deprived of androgenic stimulation, prostate cells undergo apoptosis. Any treatment that results ultimately in suppression of androgen activity is referred to as androgen deprivation therapy (ADT).31(p.96)
Androgen suppressing strategies are central to the management of advanced prostate cancer. They are also being used as neoadjuvant / concomitant /adjuvant therapy in combination with radiation in localised or locally advanced prostate cancers.31, 63 The role of ADT in individuals with rising PSA level and no symptomatic or clinical evidence of cancer presents therapeutic dilemma, because the benefit of ADT as monotherapy in this circumstance is not clear. There are no current Australian guidelines to advise recommended treatment approaches.
ADT can be achieved by: 31(p.96)
- suppressing the secretion of testicular androgens
- inhibiting the action of circulating androgens at the level of their receptor using competing compounds known as anti-androgens
- combination of suppression and inhibition to achieve complete (or maximal or total) androgen blockade (CAB).
Testosterone lowering therapy (castration)31
- Surgical castration using bilateral orchiectomy:
- performed under local anaesthesia
- less than 12 hours to achieve decline in testosterone level and induce a hypogonadal status
- associated with negative psychological effects
- does not allow for intermittent treatment.
- Mechanisms of action in management of prostate cancer include:
- down regulation of LHRH secretion
- androgen inactivation
- direct suppression of Leydig cell function.
- Good response rates associated with oestrogen use in castrate-refractory prostate cancer.
- Precluded as standard first-line treatment due to cardiotoxicity.
Luteinizing hormone-releasing hormone (LHRH) agonists31
- Synthetic analogues of LHRH.
- Chronic exposure to LHRH agnoists results in the down-regulation of LHRH-receptors, suppressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion and therefore testosterone production. The castration level is usually obtained within 2-4 weeks. 31(p.97)
- A ‘testosterone surge’ or ‘flare up’ phenomenon may occur after the first dose and might lead to detrimental effects such as increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and fatal cardiovascular events due to hypercoagulation status.
Luteinizing hormone-releasing hormone (LHRH) antagonists31
- LHRH antagonists bind immediately and competitively to LHRH receptors in the pituitary gland leading to rapid decrease in LH, FSH and testosterone levels without any flare.
- Use limited by lack of long-acting formulation.
- Compete with androgens at the receptor level
- Oral compounds classified as:
- steroidal, e.g. cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate
- non-steroidal or pure, e.g. nilutimide, flutamide and bicalutamide.
Individualised assessment, based on other prognostic indicators, personal concerns of the person affected by cancer, and consideration of short and long-term effects of ADT, is required to decide therapeutic options.40 In general, adverse effects of ADT include:63
- hot flashes
- hot flushes
- vasomotor instability
- greater incidence of clinical fractures
- insulin resistance
- alterations in lipids, and
- greater risk for diabetes and cardiovascular disease.
Management of these effects will involve a combination of supportive care strategies including information provision, counselling, pharmacological intervention and lifestyle changes.
Explain the rationale for hormonal manipulation in prostate cancer.
Access a current pharmaceutical database (e.g. MIMS) and the NCCN Clinical practice guidelines in oncology - prostate cancer 63 (a free resource, but you must register and then click 'Remember me' to bypass the login page in future) and identify the indications, method of administration, and adverse effects of the following drugs:
- goserelin acetate
- leuprorelin acetate
- cyproterone acetate
Explain the mechanisms underpinning the following risks associated with ADT:
- Metabolic syndrome
- Cardiovascular disease
- Mood changes.
Choose three of the above adverse effects, and for each, outline how you would educate a man about signs and symptoms of the adverse effects and management strategies.
Describe the supportive care needs of a man who is to have surgical castration (orchiectomy) for the management of prostate cancer.