Androgen deprivation treatment in prostate cancerBMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.e8555 (Published 09 January 2013) Cite this as: BMJ 2013;346:e8555
- Benjamin C Thomas, senior clinical fellow12,
- David E Neal, honorary consultant urological surgeon 1, professor of surgical oncology2
- 1Department of Urology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
- 2Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, UK
- Correspondence to: BC Thomas
A 65 year old man presents with lower back pain and acute urinary retention. He has tenderness over his lumbar spine, a palpable urinary bladder, and a firm, irregularly enlarged prostate on digital rectal examination. His prostate specific antigen (PSA) level was 75 ng/mL (75 µg/L) (normal range <4.0 ng/mL). A transrectal ultrasound guided biopsy of the prostate confirms prostate cancer. A bone scan shows increased uptake in the pelvis and lumbar spine suggestive of metastases. His urinary retention is treated. After discussion of the diagnosis and treatment options with the patient, a decision is made to start androgen deprivation treatment.
What is androgen deprivation treatment?
Androgen deprivation treatment refers to treatments that act by reducing the effects of testosterone and other androgens, thus inhibiting the progression of prostate cancer.1 Surgical castration was the first form of such treatment, but the main treatments now are luteinising hormone releasing hormone (LHRH) agonists and anti-androgens.
LHRH agonists such as goserelin, leuprorelin, and triptorelin induce castrate levels of testosterone by binding to their associated receptors in the anterior pituitary. This results in down regulation of the receptors, reducing luteinising hormone release from the pituitary and decreasing testosterone production by testicular Leydig cells. The initial stimulation of the receptors may lead to an initial flare-up of testosterone level, lasting up to 10 days. Castrate levels of testosterone (<1.74 nmol/L (< 50 ng/dL)) are reached within four weeks.
This is a broad category of drugs that act mainly by inhibiting signalling through the androgen receptor, sometimes by competing with testosterone and dihydrotestosterone for receptor binding. Diminished signalling through the androgen receptor leads to apoptosis and inhibition of prostate cancer growth. There are two classes of anti-androgens: steroidal (cyproterone acetate) and non-steroidal (bicalutamide, nilutamide, and flutamide).
Other forms of androgen deprivation treatment include LHRH antagonists, such as degarelix, which binds competitively to pituitary LHRH receptors, rapidly reducing luteinising hormone and testosterone levels without the initial testosterone flare. Prostate cancer may regrow after androgen deprivation treatment, despite castrate levels of testosterone. This phase is known as castration resistant prostate cancer. Newer drugs used in this phase include abiraterone (which inhibits enzymes needed for androgen biosynthesis) and enzalutamide (which inhibits androgen receptor transfer to the nucleus).
How well does androgen deprivation treatment work?
In advanced prostate cancer, androgen deprivation treatment delays progression and prevents potentially catastrophic complications.2 3 4 However, its use may not prolong survival.3 4 A randomised controlled trial of 934 patients receiving immediate or deferred androgen deprivation treatment found a significant reduction in extraskeletal metastases (number needed to treat 25), spinal cord compression (33), and ureteric obstruction (20) in those receiving the immediate treatment.3 Overall, survival was significantly improved in patients with non-metastatic disease but not with metastatic disease.
Similar overall survival results were seen in the landmark Veterans Administration Co-operative Research Group studies, which randomised 2052 men to receive either androgen deprivation treatment or a placebo (with this group later being allowed androgen deprivation treatment on clinical progression).4 The researchers found no significant difference in five year overall survival (54% v 56% respectively for locally advanced disease and 32% v 20% for metastatic disease).
A meta-analysis of 10 randomised controlled trials of 1908 patients with advanced prostate cancer found no significant difference in overall survival between LHRH agonists and surgical castration (hazard ratio 1.12, 95% confidence interval 0.915 to 1.386).5
Neither steroidal nor non-steroidal anti-androgens as monotherapy have been shown to be equivalent to LHRH agonists or surgical castration in metastatic disease and are not licensed as monotherapy in metastatic disease. Patients taking cyproterone acetate had poorer median survival than those taking LHRH agonists in a randomised trial.6 Two large randomised trials compared bicalutamide with medical and surgical castration7 8; while pooled analysis showed improved overall survival in the castration arm (albeit by only six weeks), there was no significant difference for those with locally advanced disease.9
Combined with LHRH agonist
Several systematic reviews have examined combined LHRH agonist and anti-androgen treatment. The most recent meta-analysis of 21 randomised controlled trials of 6871 patients showed a small survival advantage starting at follow-up after five years (hazard ratio 0.871, 95% confidence interval 0.805 to 0.942), although this may be of minimal clinical significance.10 Anti-androgens are also often later added to an LHRH agonist after PSA progression (rising PSA level on treatment) is noted, with 80% of men with locally advanced disease and 54% with metastatic disease then having a 50% reduction in their PSA level; however, this treatment approach has not been shown to correlate with overall survival benefit.11
A phase III trial of 504 patients with 12 month follow-up found that degarelix was superior to LHRH agonists for survival without PSA progression.12 In a crossover extension trial with 27 months of follow-up, patients who switched to degarelix from LHRH agonists after 12 months had a decrease in their hazard rate for PSA progression from 0.20 events a year to 0.08 events a year. However, PSA progression is a surrogate outcome with debatable clinical significance.
In a phase III trial of 1195 patients with metastatic castration resistant prostate cancer who had previously had docetaxel chemotherapy, abiraterone with prednisolone was compared with placebo with prednisolone. At a median follow-up of 20.2 months, median overall survival was 15.8 months (95% confidence interval 14.8 to 17.0 months) in the abiraterone group and 11.2 months (10.4 to 13.1 months) in the placebo group.13
In a randomised controlled trial of enzalutamide versus placebo in 1199 patients with castration resistant prostate cancer that is refractory to chemotherapy, median overall survival significantly improved with enzalutamide (18.4 months, 95% confidence interval 17.3 months to “not yet reached”) compared with placebo (13.6 months, 11.3 to 15.8 months).14
Guidelines from the European Association of Urology and the National Institute for Health and Clinical Excellence (NICE) recommend androgen deprivation treatment for metastatic prostate cancer.9 15 In locally advanced prostate cancer, the guidelines recommend it as adjuvant treatment with radiotherapy (but not with surgery) and also when the patient is unfit for radical local treatment. They also recommend LHRH agonists or antagonists as initial treatment, but they recommend that anti-androgen monotherapy is not used in this way. Anti-androgens are indicated to overcome the initial surge in testosterone that occurs when LHRH agonists are started and also after PSA progression occurs while the patient is taking LHRH agonists or antagonists.
NICE now recommends abiraterone with prednisolone as an option for castration resistant prostate cancer after docetaxel treatment.16 The European Association of Urology’s guidelines recommend further study of enzalutamide and degarelix before mainstream use.
How safe is androgen deprivation treatment?
LHRH agonists and anti-androgens
Testosterone flare-up phenomenon—This can occur with the initial testosterone surge with LHRH agonists if given without anti-androgen cover. The flare-up can result in spinal cord compression, severe bone pain, bladder outlet obstruction, obstructive renal failure, and cardiovascular events owing to a hypercoagulation state. Flare-up occurs in about 10% of men with metastatic disease.17
Hot flushes—These are usually described as a subjective feeling of warmth over the chest and head followed by perspiration. They are common, occurring in 50-80% of patients. Treatment options include cyproterone acetate.
Metabolic syndrome (with loss of muscle mass and increase in body fat mass)—This is present in more than 50% of men receiving androgen deprivation treatment.18 Diabetes develops in 11% of men taking androgen deprivation treatment.19 The risk of metabolic syndrome and diabetes can be minimised with lifestyle modifications such as reduced smoking and alcohol consumption, and resistance exercises.
Cardiovascular events—Androgen deprivation treatment significantly increases the risk of a cardiovascular event, from 19% for men not receiving this treatment to 24% for men who are.20
Osteopenia and osteoporosis—Duration of treatment increases the risk of developing fractures. At five years of androgen deprivation treatment, 19% of men experienced fractures (number need to harm 16).21 Calcium supplementation, vitamin D, and bisphosphonates can minimise these effects.
Erectile dysfunction and loss of libido—These are quite profound and relate to duration of treatment. Only 10-17% of men having androgen deprivation treatment will maintain adequate erectile function for intercourse. Erectile dysfunction can be managed with phosphodiesterase-5 inhibitors and injections of intracavernosal prostaglandin. Libido is also compromised, with only 5% of men maintaining a high level of sexual interest.22
Anaemia (usually normochromic and normocytic)—Although this is common, as red cell mass is partly determined by testosterone levels, only 13% of men will have symptoms.23
Gynaecomastia—This occurs in about 60% of patients taking non-steroidal anti-androgens owing to the peripheral aromatisation of testosterone to estradiol.
Hepatotoxicity—This can be caused by anti-androgens, so liver function tests are needed after they are started.
Aside from the side effects noted above, the most common adverse effects observed with degarelix resulted from reactions at the injection site (40%, number needed to harm 2.6).24 Mineralocorticoid effects of abiraterone resulted in a peripheral oedema rate of 31% (11) and hypokalaemia rate of 17% (11), which were significantly different from the those of the placebo group. Cardiac arrhythmias occurred in 2-3% of patients in this trial but were not significantly different between groups.25
The phase III trial of enzalutamide found that adverse effects were significantly more common with the drug than with placebo: fatigue (34%, number needed to harm 20), diarrhoea (21%, 25), hot flushes (20%, 10), musculoskeletal pain (14%, 25), and headache (12%, 16). Seizures occurred in about 1% of patients, although patients at risk of seizures were excluded from this trial.14
What are the precautions?
For those with impending spinal cord compression, LHRH agonists as monotherapy are contraindicated. The options for treatment in this case would be LHRH agonists with a covering anti-androgen started before LHRH agonists; LHRH antagonists; or surgical castration.
Abiraterone should be used with caution in patients with hepatic impairment. Enzalutamide should be used with caution in men at risk of seizures as these men were excluded from the trial and so its safety in this setting is not known.
How cost effective is androgen deprivation treatment?
A meta-analysis evaluated cost effectiveness of androgen deprivation treatment including combination treatments but excluding degarelix, abiraterone, and enzalutamide.26 Based on an index case of a 65 year old man with locally advanced prostate cancer treated for 20 years, surgical castration was found to be the most cost effective, and combined androgen blockade with an LHRH agonist and anti-androgen was found to be the least cost effective. This analysis did not include degarelix, abiraterone, or enzalutamide.
The financial cost of androgen deprivation treatment remains a substantial burden on the NHS, which is one reason why radical treatments (which cure the cancer and reduce the risk of needing long term androgen deprivation treatment) are cost effective. Current annual costs based on list prices are £1159 (€1425; $1889) for goserelin, £3129 for bicalutamide, £1724 for degarelix, and £35 160 for abiraterone. The cost of enzalutamide is not yet available.
From NICE’s analysis of incremental cost effectiveness ratios, LHRH agonists cost £17 500 per quality adjusted life year (QALY) gained compared with surgical castration.15 Degarelix costs £59 000 per QALY gained compared with combined androgen blockade with an LHRH agonist and an anti-androgen.27 Abiraterone plus prednisolone costs £63 233 per QALY gained compared with prednisolone.16 Cost analysis for enzalutamide has not yet been conducted.
How is androgen deprivation treatment taken and monitored?
LHRH agonists and antagonists are administered as a subcutaneous depot injection, commonly into the anterior abdominal wall below the navel, at intervals between one and six months. Anti-androgens, abiraterone, and enzalutamide are all oral medications.
Guidelines for monitoring androgen deprivation treatment effects are relatively flexible. The following regimen is modelled on the European Association of Urology’s guidelines9:
Serum PSA and testosterone levels one month after start of androgen deprivation treatment to assess PSA response and whether testosterone reaches castrate levels
Serum PSA levels at intervals of three to six months to monitor for disease progression and determine whether castrate refractory status develops
Serum haemoglobin and creatinine, checking for anaemia and renal failure either from disease or from adverse effects of drugs
Consider dual energy x ray absorptiometry (DEXA scanning) in men at high risk of developing osteoporosis before androgen ablation (the individual risk of osteoporosis may be estimated using the FRAX score (www.sheffield.ac.uk/FRAX/). Consider further bone mineral density testing every one to two years depending on t scores from their initial test
Haemoglobin A1c, fasting glucose, and lipid profile at baseline and every three months to monitor for metabolic syndrome, diabetes, and hypercholesterolaemia
Liver function tests for patients taking anti-androgens and abiraterone, checking for hepatic toxicity. This should be done every two weeks for the first three months for abiraterone
Blood pressure and urea and electrolytes monthly for patients on abiraterone owing to mineralocorticoid effects.
How does androgen deprivation treatment compare with other treatments for inhibiting the progression of prostate cancer?
At present, LHRH agonists have been shown to be similar in effectiveness to the established treatment, surgical castration. They are equivalent to oestrogens, which now have limited use owing to their high cardiovascular risk. Anti-androgens as monotherapy are not as suitable, and their main role is in combination with LHRH agonists. Degarelix has been shown to be superior to LHRH agonists in some trials. The newer drugs such as abiraterone and enzalutamide have so far been compared with placebo only in the setting of castration resistant prostate cancer in men who have previously had docetaxel chemotherapy.
Androgen deprivation treatment improves overall survival when combined with radiotherapy in men with high risk localised prostate cancer and in men with pelvic nodal metastases, compared with radiotherapy alone.28 29
Tips for patients
The growth of prostate cancer depends on the male sex hormone, testosterone. To reduce testosterone levels we use drugs called hormone therapy or androgen deprivation treatment. These drugs slow the growth of prostate cancer and reduce symptoms and are given as an injection and tablets:
-The injections are given every three to six months. They switch off the production of testosterone by lowering the level of a hormone produced by the pituitary gland. Examples of the drugs used are goserelin, leuprorelin, and triptorelin
-After the first injection there may be a surge in testosterone (“tumour flare”), which can worsen the symptoms of prostate cancer. To prevent this, tablets called anti-androgens are given for about two weeks. These block testosterone receptors in cancer cells
Hormone therapy does have potential side effects:
-Hot flushes: these can be treated with other drugs if severe
-Loss of sexual interest (libido) and erectile dysfunction (impotence): this can sometimes be treated with Viagra-like drugs or injections into the penis to produce an erection
-Weight gain: blood tests to monitor blood glucose and cholesterol levels will be performed as these levels may rise as a result of the weight gain
-Breast swelling and tenderness: sometimes a drug called tamoxifen is given to ease this, or radiotherapy can be given to treat it
-Bone fragility (osteoporosis): in people at high risk of this, we may monitor with bone density scans. Calcium, vitamin D, and a drug called a bisphosphonate may be given to lower the risk of developing fractures
The effects of hormone therapy on your prostate cancer will be monitored by regular blood tests for PSA (prostate specific antigen) and testosterone
Cite this as: BMJ 2013;346:e8555
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This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Albert Ferro, professor of cardiovascular clinical pharmacology, King’s College London. To suggest a topic for this series, please email us at.
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