It has been known for more than 60 years that prostate tumours are dependent on testosterone for their growth and dramatically regress when circulating androgens are suppressed.1 Indeed hormonal therapy has long been established as the mainstay of treatment for metastatic prostate cancer2 and is increasingly being used earlier in the course of disease as adjuvant to some radical treatments in order to increase their curative potential.3
There are two main types of hormonal therapy:2
These two types of hormonal therapy are sometimes combined in an approach known as complete or maximal androgen blockade (CAB or MAB).2
ADT (castration)
Luteinising hormone-releasing hormone receptor (LHRH) agonists have been used for more than 15 years and are the usual standard of care in ADT today.2 Examples of LHRH agonists include leuprorelin, buserelin, triptorelin, goserelin and histrelin. More detail on these agents can be found in the LHRH agonists section.
Prior to the availability of LHRH agonists, androgen suppression was frequently achieved with surgical castration (bilateral orchidectomy) or administration of estrogens. Although orchidectomy achieves rapid testosterone reduction, it has the disadvantage of being irreversible.2 Surgical castration is still considered the "gold standard" although the use of bilateral orchiectomy has recently declined, probably as a result of earlier diagnosis and the introduction of effective pharmacological castration methods.2 Estrogens (e.g. diethylstilboestrol) are another older form of ADT. Despite decades of experience with these agents, estrogens are now rarely used in clinical practice due to serious concerns regarding cardiotoxicity, though there has been a recent renewed interest in oestrogen.2
LHRH antagonists (e.g. degarelix, abarelix) are the newest class of testosterone-lowering therapy. Like LHRH agonists, these agents block secretion of luteinising hormone and consequently inhibit testosterone secretion by the testes. They are presently available as monthly depot injections. LHRH antagonists avoid the testosterone surge associated with LHRH agonist use and so initial coadministration of an antiandrogen is not required.2
Indications for ADT
ADT is the mainstay of therapy for advanced prostate cancer.2 In patients with symptomatic disease, immediate ADT is recommended in order to relieve symptoms. In patients with asymptomatic metastatic or locally advanced disease, ADT does not significantly prolong survival, and hence is considered palliative. However, ADT is prescribed for these patients to delay symptom development and reduce the risk of serious complications such as spinal cord compression, pathological fracture and ureteric obstruction.2 Immediate ADT is not recommended in asymptomatic localised disease where it has no proven benefit.2 For each patient then, the physician should weigh the potential benefits of immediate treatment against side effects of therapy.4
ADT is also increasingly being used in conjunction with some radical therapy in earlier disease stages to improve the cure rate.3 Hormonal therapy may be used as a neoadjuvant treatment (administrated before local therapy) or an adjuvant treatment (administered after local therapy). Recent data indicate that adjuvant ADT can increase survival in certain settings in patients with aggressive disease. In association with external beam radiotherapy for high risk localised or locally advanced disease, 6 months to 3 years of adjuvant ADT increases overall survival. 5,6,7, Adjuvant ADT is also used following radical prostatectomy in patients found to have nodal metastases.8
In patients with asymptomatic localised disease that are unfit for radical treatment, there is no indication for ADT.2
Side effects of ADT
Testosterone has many important physiological actions in men and thus testosterone deprivation may have serious consequences. Acute side effects include hot flushes, loss of libido, emotional liability and sexual dysfunction.2 Long-term side-effects include weight gain, muscular atrophy (sarcopenic obesity), increased cardiovascular risk and osteoporosis.2 It is important that physicians are aware of these side effects and monitor and manage adverse events as appropriate.
The side effects of ADT may be reduced by intermittent androgen deprivation, in which an LHRH agonist is given for a fixed period (e.g. 6–9 months) or until a defined PSA level is reached. Treatment is then ceased and patients are monitored until PSA levels start to rise, at which point ADT is reintroduced.9
Anti-androgen therapy
Anti-androgens compete with testosterone and other androgens for the androgen receptor in target tissues such as the prostate gland.2 Steroidal anti-androgens, such as cyproterone acetate also lower the level of testosterone.2 Concomitant use with LHRH agonists can suppress the repercussions of the testosterone surge.
Non-steroidal anti-androgens (NSAAs), such as flutamide, bicalutamide, and nilutamide, do not lower testosterone levels and so may be associated with a lower incidence of sexual side effects compared with ADT.2 However, NSAAs are associated with gastrointestinal toxicity (flutamide and nilutamide) and bothersome gynaecomastia (bicalutamide).2,10 In patients with locally advanced non-metastatic prostate cancer, monotherapy with bicalutamide 150mg demonstrated similar overall survival to castration11 and is licensed for use in Europe within this indication in high risk patients.12 However, anti-androgens are contraindicated as primary therapy in localised disease owing to a trend towards poorer survival compared with conservative management.2,13
CAB
Several studies have evaluated the combination of ADT plus an anti-androgen, with conflicting results. At best, it appears that CAB offers a small survival advantage over ADT alone, which must be balanced against the increased risk of adverse events, the potential impact on quality of life and increased costs.2,14
References:
1. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen, and of androgen injection on serum phosphatises in metastatic carcinoma of the prostate. Cancer Res 1941;1:293-7.
2. European Association of Urology. Guidelines on prostate cancer, 2010.
3. Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615-24.
4. Isbarn H, Boccon-Gibod L, Carroll PR, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur Urol 2009;55:62-75.
5. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103-6.
6. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285-90.
7. D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004;292:821-7.
8. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7:472-9.
9. Tunn U. The current status of intermittent androgen deprivation (IAD) therapy for prostate cancer: putting IAD under the spotlight. BJU Int 2007;99(Suppl 1):19-22.
10. Wirth MP, Hakenberg OW, Froehner M. Antiandrogens in the treatment of prostate cancer. Eur Urol 2007;51:306-13.
11 . Iversen P, Tyrrell CJ, Kaisary AV, et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 2000;164:1579-82.
12. AstraZeneca. Bicalutamide Summary of Product Characteristics, June 2008.
13. McLeod DG, Iversen P, See WA, et al. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006;97:247-54.
14. Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002;95:361-76.