Art & science oncology

Pharmacological treatment of patients with advanced prostate cancer Turner B, Drudge-Coates L (2014) Pharmacological treatment of patients with advanced prostate cancer. Nursing Standard. 28, 23, 44-48 . Date of submission: April 29 2013: date of acceptance: August 15 2013.

Abstract Prostate cancer is linked to the male sex hormone testosterone. In advanced disease, blocking the production of testosterone using androgen deprivation therapy causes regression of prostate cancer and minimises or prevents symptoms associated with the disease. Luteinising hormone-releasing hormone agonists are commonly used in the management of prostate cancer, however less is known about the role of the newer gonadotrophin-releasing hormone (GnRH) antagonists. This article focuses on the differences between the two treatments and provides nurses with the knowledge to explain the use of GnRH antagonists to patients and administer this therapy effectively.

Authors Bruce Turner Uro-oncology nurse practitioner, Homerton University Hospital, London and Barts Health Hospitals, London. Lawrence Drudge-Coates Urology oncology clinical nurse specialist and honorary lecturer, King’s College Hospital, London. Correspondence to: [email protected]

Keywords Androgen deprivation therapy, gonadotrophin-releasing hormone antagonists, luteinising hormone-releasing hormone agonists, prostate cancer

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IN THE UK, prostate cancer affects about 40,000 men annually and accounts for approximately 10,000 deaths (Cancer Research UK 2013). Although the disease is more prevalent in men over the age of 65, younger men can be affected. Prostate cancer can be localised to the prostate, locally advanced where it grows immediately outside the prostate, or advanced where distant metastases affect soft tissue or the skeleton. Men usually present after having a prostate-specific antigen (PSA) blood test, which may be elevated, or the prostate may feel abnormal on digital rectal examination. Some men may experience symptoms such as changes in urinary flow, but these are commonly associated with benign enlargement of the prostate, which may occur simultaneously. Because prostate cancer tends to develop slowly, some men, especially those who are older, or who have other major health problems, such as cardiovascular disease, may never need treatment for prostate cancer as they are likely to die of other conditions. For example, men in their eighties do not need to be investigated for prostate cancer unless they have symptoms that require palliation (National Institute for Health and Care Excellence (NICE) 2005). However, some men will have cancer that is more aggressive or considered high-risk, requiring treatment to help prevent or delay the disease spreading outside the prostate gland (Prostate Cancer UK 2013). There is no cure for metastatic prostate cancer. Bone is the most common site of metastases in prostate cancer and affects more than 85% of men with advanced disease (Hatoum et al 2008). Bone metastases can cause complications for the patient such as bone pain and skeletal-related events such as pathological fracture, the need for radiotherapy or surgery to bone, malignant spinal cord compression and hypercalcaemia (Mundy 2006). In addition to bone, prostate cancer may metastasise to any organ; the most commonly affected being the lymph nodes, liver, lung, brain and skin (Drudge-Coates and Turner 2012). Prostate cancer is, at least initially, androgen-dependent (Turner et al 2011). Androgens are mainly responsible for the growth

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of both the normal prostate and prostate cancer, and it is widely recognised that prostate cancer is sensitive to testosterone deprivation (Princivalle et al 2007). Advanced prostate cancer is incurable and treatment involves reducing symptoms and delaying the time to disease progression and death. The aim of androgen deprivation therapy (ADT) is to achieve castration (serum testosterone levels ≤0.5ng/mL) (Klotz et al 2008) and deprive the prostate cancer cells of the testosterone that they initially require for growth and proliferation, thereby increasing life expectancy and reducing the burden of any symptoms (Miller et al 2009). After initiating ADT, prostate cancer is stabilised in over 80% of men (d’Ancona and Debruyne 2005). After an average of two years, however, because of numerous molecular mechanisms, ADT may no longer be effective in controlling prostate cancer and the disease may progress in the presence of a small amount of testosterone (Berthold et al 2008). At this stage, further treatment is usually required. There are several ways to reduce testosterone and cause castration using ADT (Table 1), but the most common way is using luteinising hormone-releasing hormone (LHRH) agonists, also termed gonadotrophin-releasing hormone (GnRH) agonists. LHRH agonists cause continuous stimulation of luteinising hormone (LH) and subsequent down-regulation of pituitary LHRH receptors, and a reduction in LH and ultimately testosterone production. Before this occurs, however, there is a transient increase in levels of LH and follicle-stimulating hormone (FSH) and a surge in testosterone (Van Poppel and Klotz 2012), necessitating anti-androgen medication to be given for around one week before and one week after administration of the LHRH agonist to prevent tumour flare (increased tumour activity). LHRH agonists can take up to one month to cause castrate levels of testosterone and in symptomatic men, it may take a significant time for symptoms to be relieved. In contrast, GnRH antagonists bind directly to GnRH receptors and cause an immediate reduction in testosterone without an initial surge in testosterone (Van Poppel and Klotz 2012). Symptomatic patients are usually asymptomatic within seven days of commencing treatment. Removal of the testicular tissue (bilateral subcapsular orchidectomy) is a surgical alternative to pharmacological ADT and is effective in reducing levels of testosterone (Anderson et al 2008). Bilateral subcapsular orchidectomy should be offered to all men with advanced prostate cancer (NICE 2008), but many patients prefer to avoid surgery and choose medical castration with pharmacological therapy. It is unclear why patients or clinicians opt for

pharmacological therapy over orchidectomy, but one explanation for the avoidance of surgical castration might be the expectation of psychological consequences as a result of loss of the testicles (Sharifi et al 2005). Patients may also prefer not to undergo a surgical procedure or there may be a perception that arranging an orchidectomy takes up time and valuable theatre space, however this method is as effective as medical castration (Chang et al 2009).

Testosterone production Gonadotrophins such as FSH and LH are hormones secreted by the anterior pituitary gland that act on the gonads (Germann and Stanfield 2002). The primary function of FSH in men is to stimulate the Sertoli cells to produce sperm. The primary function of LH is to stimulate the secretion of testosterone by the Leydig cells in the testes (Germann and Stanfield 2002). Up to 95% of testosterone is produced by the Leydig cells in the testicles, and the remaining 5% is produced by the adrenal glands (Labrie 2004). Secretion of testosterone from the testes is controlled by the hypothalamic-pituitary-gonadal axis (Figure 1). Hypothalamic LHRH, also termed GnRH, stimulates the anterior pituitary to release LH, which subsequently stimulates the testes to release testosterone. However, it is the negative feedback loop that regulates hypothalamic GnRH and pituitary LH secretion.

Luteinising hormone-releasing hormone agonists LHRH agonists, also known as GnRH agonists, should not be confused with GnRH antagonists.

TABLE 1 Androgen deprivation therapy Class of drug

Name of drug used

Oestrogen

Diethylstilbestrol

Luteinising hormone-releasing hormone agonists

Goserelin, leuprorelin acetate, triptorelin, histrelin

Gonadotrophin-releasing hormone antagonists

Degarelix

Anti-androgens

Bicalutamide, flutamide, cyproterone acetate

Non-specific cytochrome P450 enzyme inhibitors

Ketoconazole

Specific CYP17 inhibitors

Abiraterone acetate

Glucocorticoids

Prednisolone, dexamethasone

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Art & science oncology Many nurses will be familiar with some or all of the three LHRH agonists widely available: leuprorelin, triptorelin and goserelin. LHRH agonists are widely used and there is much evidence demonstrating their benefit in patients with advanced prostate cancer (Labrie et al 2005). When administered they cause a transient release of FSH and LH followed by a marked inhibition of the release of these gonadotropins, and ultimately suppress testosterone production after two to four weeks (Chu and Sartorelli 2007). The initial physiological response to LHRH agonists results in initial stimulation and secretion of LH and FSH, which can cause stimulation and growth of prostate cancer cells (tumour flare) and lead to an exacerbation of clinical symptoms (Turner and Drudge-Coates 2009), such as spinal cord compression, bone pain and uretreal obstruction (Waxman et al 1985).

Gonadotrophin-releasing hormone antagonists GnRH antagonists (blockers) bind directly to GnRH receptors and block the effect of GnRH on the pituitary gland, producing immediate suppression of LH, FSH and testosterone (Van Poppel and Klotz 2012). They differ from LHRH agonists in that they do not result in an initial increase in gonadotrophins and there is no risk of tumour flare (Figure 2).

FIGURE 1 Testosterone production and the hypothalamic-pituitary-gonadal axis Testes Negative feedback control

Pulsatile release of GnRH every 90-120 minutes

LH

ACTH Hypothalamus

Testosterone (95%)

Prostate

Pituitary

Negative feedback control

Adrenal androgens (5%)

(Drudge-Coates 2009)

PETER LAMB

Adrenal glands ACTH = adrenocorticotrophic hormone GnRH = gonadotrophin-releasing hormone LH = luteinising hormone

The initial GnRH compounds investigated for use in prostate cancer were found to result in histamine release and there was a risk of anaphylactic reactions (Amling and Moul 2005). However, degarelix is a new generation of GnRH antagonist that does not cause significant histamine release and is not associated with an increased risk of anaphylaxis (Koechling et al 2010). Degarelix is faster acting than the LHRH agonists. A pivotal study by Klotz et al (2008) demonstrated that castrate levels of testosterone (testosterone ≤0.5ng/mL) were achieved within three days of administration in over 95% of men – none of the patients who received the LHRH agonist had achieved castration at this point. In addition, more than 70% of patients were castrate within 24 hours of administration (Klotz et al 2008). This is particularly important for patients who have symptoms associated with metastatic prostate cancer or those at risk of complications, such as spinal cord compression, who benefit from immediate treatment. PSA levels (serum markers which can help demonstrate a response to treatment) were lower at two and four weeks in the patients taking degarelix than in those taking the LHRH agonist (P

Pharmacological treatment of patients with advanced prostate cancer.

Prostate cancer is linked to the male sex hormone testosterone. In advanced disease, blocking the production of testosterone using androgen deprivatio...
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