Endocrine prevention and treatment of prostate cancer

Molecular and Cellular Endocrinology xxx (2012) xxx–xxx

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Endocrine prevention and treatment of prostate cancer Teuvo L.J. Tammela ⇑ Department of Surgery, Tampere University Hospital, Teiskontie 35, P.O. Box 2000, FIN-33521 Tampere, Finland

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Article history: Available online xxxx Keywords: 5a-Reductase inhibitors GnRH agonists GnRH antagonists Antiandrogens Oestrogens Adverse effects

a b s t r a c t The major androgen within the prostate is dihydrotestosterone (DHT). DHT and 5a-reductase are highly associated with prostate cancer. It has been hypothesised that inhibition of 5a-reductase activity might reduce the risk of prostate cancer development, slow tumour progression and even treat the existing disease. The basis for endocrine treatment of prostate cancer is to deprive the cancer cells of androgens. Every type of endocrine treatment carries adverse events which influence quality of life in different ways. 5a-Reductase inhibitors (5-ARI) reduce risk of being diagnosed with prostate cancer but they do not eliminate it. By suppressing PSA from BPH and indolent prostate cancers 5-ARI enhances the ability of a rising PSA to define a group of men at increased risk of clinically significant prostate cancer. Also fewer high-grade cancers are missed because biopsy is more accurate in smaller prostates. Androgen deprivation is an effective treatment for patients with advanced prostate cancer. However, it is not curative, and creates a spectrum of unwanted effects that influence quality of life. Castration remains the frontline treatment for metastatic prostate cancer, where orchiectomy, oestrogen agonists, GnRH agonists and antagonists produce equivalent clinical responses. MAB is not significantly more effective than single agent GnRH agonist or orchiectomy. Nonsteroidal antiandrogen monotherapy is as effective as castration in treatment of locally advanced prostate cancer offering quality of life benefits. Neoadjuvant endocrine treatment has its place mainly in the external beam radiotherapy setting. Increasing data suggest IAD is as effective as continuous ADT. The decision regarding the type of androgen deprivation should be made individually after informing the patient of all available treatment options, including watchful waiting, and on the basis of potential benefits and adverse effects. There are new promising secondary or tertiary forms of endocrine therapies under evaluation, like CTP17A1 inhibitors and more potent antiandrogens including MDV3100, which give new hope for patients developing castration resistant prostate cancer. Ó 2012 Published by Elsevier Ireland Ltd.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine prevention of prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine treatment of prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Elimination of testosterone production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. GnRH agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. GnRH antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Maximum androgen blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Oestrogen agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5. Adverse effects of ADT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Intermittent androgen deprivation therapy (IAD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Androgen deprivation therapy in combination with surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Neoadjuvant treatment before radical prostatectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Adjuvant treatment after radical prostatectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Androgen deprivation therapy in combination with radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⇑ Fax: +358 3 31164371. E-mail address: teuvo.tammela@uta.fi 0303-7207/$ - see front matter Ó 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.mce.2012.03.002

Please cite this article in press as: Tammela, T.L.J. Endocrine prevention and treatment of prostate cancer. Molecular and Cellular Endocrinology (2012), http://dx.doi.org/10.1016/j.mce.2012.03.002

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4. 5.

3.6. Timing of therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Sequential therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Although androgen deprivation as a treatment for patients with prostate cancer was described more than 60 years ago its optimal use remains controversial (Huggins and Hodges, 1941). After that androgen deprivation therapy (ADT) has been the mainstay of treatment for locally advanced and metastatic disease. Despite the long pedigree for this treatment, the optimal use of ADT remains controversial. Although testosterone is the primary circulating androgen in men, within the prostate it is converted to a more potent dihydrotestosterone (DHT) by the action of intracellular 5a-reductase enzymes including type 1 and type 2 isoforms (Zhu and Sun, 2003). Circulating DHT levels are low (1:10) when compared with testosterone, whereas in the prostate, this ratio is reversed, making DHT the primary androgen in the prostate. DHT has stronger affinity of binding to androgen receptor (AR) and slower dissociation rate. DHT is also more potent at stimulating prostatic growth than testosterone. DHT and 5a-reductase are highly associated with prostate cancer. Expression of type 1 5a-reductase in the prostate is elevated in the different stages of prostate cancer (PIN, localised, recurrent and metastases) when compared with benign prostatic hyperplasia (BPH), while type 2-reductase, normally the most prevalent isoform within the prostate, is elevated in BPH (Thomas et al., 2003, 2005, 2008). It has been hypothesised that inhibition of 5a-reductase activity might reduce the risk of prostate cancer development, slow tumour progression and even treat the existing disease. Specific inhibition of DHT production maintains the levels of testosterone and avoids the androgen depletion associated adverse effects (Andriole et al., 2005). The basis for endocrine treatment of prostate cancer is to deprive the cancer cells of androgens. Apoptotic regression of an androgen-dependent tumour can be induced by any procedure that reduces intracellular concentration of dihydrotestosterone by 80% or more (Kyprianou and Isaacs, 1987). This can be done by elimination of the testosterone production of the testes. Alternatively the androgen receptors (AR) of the prostate cancer can be blocked. Only 6% of all the cancers do not respond to androgen deprivation (Palmberg et al., 1999). Every type of endocrine treatment carries adverse events which influence quality of life in different ways. Debates continue regarding the proper use and timing of endocrine therapy with orchiectomy, oestrogen agonists, gonadotropin hormone-releasing (GnRH) agonists, GnRH antagonists, and androgen antagonists (antiandrogens). In spite of initial response to ADT advanced prostate cancer progresses eventually to castration resistant prostate cancer (CRPC). However, CRPC often remains responsive to other hormonal therapies (Scher and Sawyers, 2005; Attard et al., 2008; Shafiri, 2010) in large part due to the intratumoural regeneration of androgens (Montgomery et al., 2008). Therefore these patients are often treated with secondary hormonal therapies which further delete androgen concentrations or directly bind and inhibit AR (Ryan and Smith, 2005). Monitoring the level of prostate specific antigen (PSA) has created a dramatic shift in the population of patients in whom the endocrine treatment is initiated. Patients with recurrent prostate carcinoma after the failure of local therapy are now diagnosed with

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recurrence on basis of a rising PSA level. These patients have a median life expectancy of 10–15 year, which is in sharp contrast to patients who present with metastatic disease having that of 3 years (Klotz, 2000). They are treated with ADT when their PSA level begins to rise. However, there is substantial uncertainty with regard to the benefit of initiating treatment this early. Whether treatment needs to be continuous, which has been the traditional practice, is open to question. The impact of long-term ADT on quality of life is much greater for the patient who is facing 15 years treatment than for the patient whose treatment duration will be short due to the progression of metastatic bone disease.

2. Endocrine prevention of prostate cancer There are currently available two 5a-reductase inhibitors (5ARI). finasteride specifically inhibits type 2 5a-reductase and at the therapeutic dose (5 mg daily) reduces circulating DHT by 70% and intraprostatic by 68–86%. Dutasteride inhibits both type 1 and type 2 5a-reductase and at the therapeutic dose (0.5 mg daily) reduces circulating DHT levels by 95% and intraprostatic levels by 94% (Rittmaster, 2005). Large-scale clinical trials in BPH patients have shown ARIs to be safe and generally well tolerated over long-term treatment. Both 5-ARIs have been studied in large-scale trials as possible protective agents to reduce the developing of prostate cancer. The Prostate Cancer Prevention Trial (PCPT) tested finasteride. This study enrolled approximately 18,000 healthy men aged more than 55 years. All of them were at low risk for prostate cancer determined by a normal digital rectal examination (DRE) and a prostate specific antigen (PSA) value <3 ng/ml. These men were randomised into two groups receiving either 5 mg finasteride daily or placebo for 7 years. Annual DREs and PSA values were recorded. Biopsy was recommended for an abnormal DRE or PSA >4 ng/ml. At baseline no biopsy was required, but at the end of the study the biopsy was requested of all participants who had not yet received one to assess the presence of prostate cancer (Thompson et al., 2003). The finasteride-treated men had a significantly lower rate of prostate cancer (18.4%) than the placebo arm (24.4%), resulting a 24.8% relative reduction in cancer prevalence over the 7-year period. In addition, there was a significant reduction in the rate of acute urinary retention, BPH, transurethral resection of the prostate and urinary tract infection. There was, however, an increase in the detection of high-grade prostate cancer (HGPC) in the finasteride treated population compared with the placebo group (6.4% vs. 5.1%). This is probably mostly explained by decrease in prostate volume allowing a greater proportion of the prostate to be sampled by biopsy and so increased chances to detect prostate cancer (Thompson et al., 2007; Lucia et al., 2007). The PCPT data suggest that finasteride does not reduce the volume of HGPC as effectively as in low-grade disease. As type 1 5a-reductase is more highly expressed in prostate cancer, it is probable that inhibition of both type 1 and 2 5areductase would be more effective than inhibition of type 2 only. Dutasteride inhibits both types and could therefore be more ideal for chemoprevention of prostate cancer. A retrospective analysis of three phase 3 trials involving BPH patients revealed that the cumulative incidence of prostate cancer as an adverse event

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was approximately 50% lower in the dutasteride arm than in patients in the placebo arm (1.2% vs. 2.5%) (Rosenberg et al., 2010). In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study the subjects were randomised to receive either dutasteride of placebo for 4 years (Andriole et al., 2010). The study recruited men who were at high risk of prostate cancer having PSA between 2.5 and 10 ng/ml but had a previous negative prostate biopsy within 6 months of randomisation. Eight thousand men aged between 55 and 75 years were included in the study. Rebiopsies were performed after 2 and 4 years of followup. Dutasteride significantly reduced the rate of biopsy-detectable prostate cancers compared with placebo representing a relative risk reduction with dutasteride of 22.8%. There were 220 (6.7%) tumours with Gleason score of 7–10 among 3299 men the dutasteride group and 233 among 3407 men in the placebo group (6.8%). Like finasteride in PCPT dutasteride also improved the outcomes related to BPH. By suppressing PSA from BPH and indolent prostate cancers 5ARI seems to enhance the ability of a rising PSA to define a group of men at increased risk of clinically significant prostate cancer. Also fewer high-grade cancers are missed because biopsy is more accurate in smaller prostates. It can be concluded that 5-ARIs reduce risk of being diagnosed with prostate cancer but they do not eliminate it. At the moment there is not enough information of the effect of 5-ARIs on prostate cancer and all-cause mortality. Although sexual and erectile dysfunctions are relatively uncommon 5-ARIs however increase them (Wilt et al., 2010).

3. Endocrine treatment of prostate cancer 3.1. Elimination of testosterone production Castration was previously defined by induction of a serum testosterone level of <50 ng/ml. However, recent literature redefines this upper limit to <20 ng/ml (Scherr et al., 2003). The first method of permanent castration was bilateral orchiectomy, and the first reversible method was diethylstilbestrol (DES) (Huggins and Hodges, 1941). Medical castration may be obtained with oestrogen agonists, GnRH agonists and GnRH antagonists.

3.1.1. GnRH agonists GnRH is a small hormone, composed of ten amino acids, which is synthesized in hypothalamic neurones and secreted directly into the hypophyseal-portal blood circulation in a pulsatile manner. GnRH interacts with high-affinity receptors on the gonadotropic cells in the anterior pituitary, stimulating the synthesis and release of the gonadotropins, LH and FSH. Short pulses of GnRH increase pituitary sensitivity, presumably by increasing GnRH-receptor number and LH/FSH levels. The episodic release of endogenous GnRH prevents receptor desensitisation and is mandatory for continuing androgen production. Continuous stimulation of the pituitary with high concentrations of GnRH agonist induces regulatory changes, possibly down regulation of the GnRH-receptors (Conn and Crowley, 1994; Tieva et al., 2003). This results in receptor desensitisation and inhibition of LH release which further inhibits the production of testosterone by the testicle. Endogenously produced GnRH has a very short half-life because of peptidase degradation. By altering the basic amino acid structure of synthetically produced analogues, compounds with a prolonged half-life time and increased resistance to peptidase degradation have been developed for systemic administration. Depot GnRH agonists are administered by subcutaneous injection at intervals of 1–12 months. Studies demonstrate that only about 5% of patients being treated with GnRH agonist therapy fail to

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achieve testosterone suppression <50 ng/ml (Seidenfeld et al., 2000). GnRH agonists initially impose an increase in LH production, and, therefore, an increase in plasma testosterone levels lasting 1–2 weeks (Bubley, 2001). In prostate cancer this is responsible for the tumour flare effect. This represents androgen-induced stimulation of tumour growth as a result of the testosterone surge. In particular, increased activity in bone metastases can cause severe pain and spinal cord compression. Therefore, co-treatment with antiandrogen should be used during the commencement of GnRH agonist for 2–3 weeks. This kind of therapy is now a standard especially in patients with bone metastases and, therefore, spinal cord compression and increased bone pain is rarely seen in contemporary urological practice. The equivalence of orchiectomy, oestrogen agonists and GnRH agonists has been well demonstrated in several studies as well as in a meta-analysis (Seidenfeld et al., 2000). GnRH agonists have largely replaced orchiectomy as the castrative treatment of prostate carcinoma. There are several GnRH agonists available, including goserelin, leuprorelin, buserelin and tritorelin. Although there are no proven differences in the efficacy of each preparation, no prospective, randomised, controlled trials have been undertaken to compare their efficacy and side effect profiles directly. 3.1.2. GnRH antagonists GnRH antagonists (blockers) bind directly to the GnRH receptor in the pituitary, rapidly and competitively blocking the release of both LH and FSH. This results in a major and rapid reduction in serum testosterone level, after only 1 day of treatment, which is similar to that caused by surgical castration. This offers potential benefit compared to GnRH agonists because the LH and tumour testosterone surges as well as microsurges in association with reinjections are avoided, and therefore there is no requirement for concomitant antiandrogen flare protection (Van Poppel, 2010). The recent phase III study demonstrated that degarelix was as effective and well tolerated as GnRH agonists (Klotz et al., 2008). Compared to the first GnRH antagonist abarelix, degarelix is not associated with immediate-onset systemic allergic reactions resulting from histamine release. However, there was a higher incidence of injection site reactions and chills with subcutaneous injection of degarelix than with leuprolide, while the incidence of disease-related adverse events such as arthralgia and urinary tract infection was significantly higher with leuprolide. 3.1.3. Maximum androgen blockade Castration blocks testicular testosterone production. However, testosterone is also produced from the adrenal glands under independent control. This accounts around 5% of serum testosterone concentration. An important quantity of total androgen (40–50%) is produced in the peripheral tissues, including the prostate, from inactive precursors dihydroxyepiandrosterone (DHEA) and its sulphide (DHEA-S) of adrenal origin (Labrie, 1991). Many investigators have been convinced that development of CRPC was caused by the adrenal androgen source. Therefore, GnRH agonists have been used in conjunction with specific antiandrogens. Terms complete androgen blockade (CAB), combined androgen blockade (CAB) or maximum androgen blockade (MAB) describe the use of two forms of androgen blockade, first, to inhibit the production of testosterone using castration, and second, by blocking the androgen receptor to inhibit the effects of adrenal and locallyproduced androgens using steroidal or nonsteroidal antiandrogens. Conclusive evidence for superiority of MAB over castration alone as primary treatment of metastatic prostate cancer has not been provided, despite of a large number of randomised trials. A recent meta-analysis showed only a marginally significant improvement in 5-year survival in patients receiving MAB, but this

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benefit was confined to the subgroup of the patients with best prognosis (Samson et al., 2002), while a large randomised trial (Eisenberger et al., 1998) showed no significant difference in survival between patients receiving MAB and those undergoing orchiectomy without concomitant antiandrogen therapy. 3.1.4. Oestrogen agonists Oral oestrogen treatment with DES, once the most common method for hormone manipulation of prostate cancer, was largely abandoned in the 1970s due to its significant thromboembolic and cardiovascular toxicity (Veterans Administration Co-operative Research Group, 1967). In the mid 1980s, interest in oestrogen therapy was renewed when it was found that oestrogen administered parenterally did not induce these side effects. The significant changes in liver metabolism and grave deviations in blood levels of coagulation factors seen after oral therapy were reported to be absent or only marginally present after parenteral therapy (Herinkson et al., 1990). Anticancer efficacy of parenteral polyestradiol phosphate (PEP) was found to be equal to orchiectomy or MAB in terms of time to biochemical and clinical progression and overall and disease-specific survival (Mikkola et al., 1998; Hedlund et al., 2002). No significant increase in cardiovascular mortality with PEP was observed. There was, however, a significant increase in non-fatal ischaemic heart disease and heart decompensation. In addition, prominent breast enlargement and feminisation as a rule are unwanted side effects. 3.1.5. Adverse effects of ADT Adverse effects of ADT do not only include loss of libido and erectile function, and hot flushes, but also anaemia, obesity, metabolic syndrome, decrease in muscular strength, fatigue, decline in physical activity and general vitality, mood changes and depression. Although ADT results in development of multiple risk factors for cardiovascular disease, including increases in serum cholesterol and triglycerides, insulin resistance, body mass index and fat body mass along with decreases in lean body mass (Shafiri et al., 2005), effects on cardiovascular mortality are still uncertain (Shafiri et al., 2010). In addition, castration induces osteoporosis in long-term. These effects should be concerned when planning to start a castrative treatment in patients who will need it for a long time. Hot flushes develop in 50–75% of patients after castration while they have been registered in 17–30% of patients treated with oestrogen (Hedlund, 2000). Contrary to what is generally thought, hot flushes do not vanish quickly, but persist in a practically unchanged intensity in more than half of patients who get them (Karling et al., 1994; Spetz et al., 2001). Treatment with small doses of oestrogen, cyproterone acetate or medroxyprogesterone can decrease or completely abolish hot flushes, probably by increasing endogenous betaendorphins (Hedlund, 2000). Androgens are important activators of erythropoiesis by stimulating haematopoietic stem cells and the production of erythropoietin. Patients on ADT develop a decrease in haemoglobin and haematocrit within 3–6 months (Strum et al., 1997). This is typically normocytic, normochromic anaemia with a 10–25% reduction of haemoglobin. It is more prominent when MAB is used. If necessary, this anaemia can be treated successfully by recombinant human erythropoietin (Hedlund, 2000). Endocrine treatment of prostate cancer with GnRH agonists or orchiectomy has been shown to have negative effects on bone mass (Clarke et al., 1991; Daniell, 1997; Morote et al., 2003). Accordingly the risk of osteoporotic fractures is greatly increased in men undergoing androgen suppression therapy for prostate cancer (Daniell, 1997; Townsend et al., 1997; Morote et al., 2003). Both prevalence of osteoporosis and relative risk of hip fracture increase according to the length of androgen suppression. After 5 years of treatment the prevalence of osteoporosis was 50% while the

relative risk of hip fracture had doubled during the same time (Morote et al., 2003). Exercise and calcium supplementation are recommended for men receiving hormonal treatment, as these are often beneficial (Smith, 2002). As therapeutic approaches to treat and avoid the loss of bone mass have been studied mainly treatments with bisphosphonates and most recently denosumab with encouraging results (Smith et al., 2003, 2009). In addition, replacement of oestrogenic function with SERMs may favourably affect bone density (Smith et al., 2008, 2010). Also in patients treated with intermittent androgen blockade mineral density has stabilised or increased during off periods (Higano et al., 1999).

3.2. Antiandrogens Antiandrogens, steroidal and non-steroidal, can be used as monotherapy or in combination with castration. Cyproterone acetate, a steroidal anti-androgen, competitively inhibits the binding of dihydrotestosterone (DHT) and testosterone to AR. Due to combined androgenic and progestogenic action it binds to progesterone receptors in the pituitary, inhibiting also the release of LH and production of testosterone by the testicles (Varenhorst et al., 1982). The adverse effects of cyproterone acetate are more or less the same as those of castration therapy (de Voogt, 1992). In addition, thromboembolic complications are possible due to the progestogenic action of the compound (Hedlund, 2000). Nonsteroidal antiandrogens such as bicalutamide, flutamide and nilutamide inhibit the activity of androgens by blocking competitively the interaction of testosterone and DHT with the androgen receptor. They still cross the blood–brain barrier raising LH secretions and, therefore, testosterone secretion in the testes. Treatment with nonsteroidal antiandrogens is the only established way to avoid castration in the endocrine treatment of prostate cancer. Nausea, diarrhoea and some liver toxicity are commonly observed in patients treated with flutamide whereas in those treated with bicalutimide they are uncommon (Boccon-Gibod, 1998). Currently, bicalutamide is the best tolerated agent in this group (Boccardo et al., 1999; Iversen et al., 2000; See et al., 2002). These nonsteroidal AR antagonists may have AR agonist activity especially in association with CRPC (Chen et al., 2004). There has been an increased interest in nonsteroidal antiandrogens as monotherapy, partly because of the side effects of castration. Bicalutamide has been evaluated as monotherapy for advanced prostate cancer in a number of studies. When it was compared (150 mg/day) to MAB with either flutamide or nilutamide as antiandrogen (Boccardo et al., 1999), no significant differences in regard to progression-free or overall survival were observed. When compared with castration this was also true in patients with nonmetastatic cases but there was a small survival advantage for castration in the M1 subgroup (Tyrrell et al., 1998). In the multinational Early Prostate Cancer Trial (with 8115 patients enrolled) bicalutamide has been assessed as adjuvant or primary treatment for early (localised to locally advanced) prostate cancer. At a median follow-up of 7.3 years, progression free survival (PFS) was significantly improved in men who received bicalutamide (objective progression 30.7% vs. 27.4%) compared with those who received standard care alone, but with no significant difference in overall survival. There was no PFS benefit in patients with in patients with localised cancer, but instead, a trend toward decreased survival in patients receiving bicalutamide. In the subset of patients with locally advanced disease, bicalutamide significantly improved PFS regardless of the type of standard care, whereas bicalutamide improved overall survival only in patients who hade received radiotherapy, with a 35% reduction in the risk of death (See and Tyrrell, 2006; Iversen et al., 2006; Wirth et al., 2008).

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Bicalutamide offers quality of life benefits in terms of sexual interest, physical capacity and potentially, preservation of bone mineral density (Iversen et al., 2000). Therefore, bicalutamide monotherapy may be a preferred option to castration for younger, sexually active men with locally advanced prostate cancer who wish to optimise their physical activity. Also hot flushes occur less frequently than after castration. However, gynaecomastia and breast pain are common adverse events and develop to most patients. The main pathogenesis for this is that the antiandrogen blocks AR in the breast tissue while aromatisation of increased testosterone results in higher concentrations of estradiol which further induces development of gynaecomastia. There are, however, prophylactic and treatment measures, such as radiotherapy, surgery and possibly some medical treatments, may offer relief or prevention (Tyrrell, 1999a). MDV3100 is a member of the new class of diarylthiohydantoin AR antagonists. It binds AR with a 4- to 8-fold higher affinity than bicalutamide, inhibits AR nuclear translocation, and has reduced agonist activity, distinguishing it from the nonsteroidal antiandrogens used in current clinical practice (Tran et al., 2009). The preliminary results from phase 1–2 studies have been very encouraging in CRPC (Scher et al., 2010). Phase 3 studies are under way to further investigate the efficacy and safety of MDV3100 in larger patient populations. 3.3. Intermittent androgen deprivation therapy (IAD) Intermittent androgen deprivation became feasible when medical castration became available. Serial serum PSA determinations make it possible by providing an easy method for early determination of tumour growth during periods of no treatment. There are several potential advantages. Libido and potency could be recovered during off-treatments in previously potent patients, and also other side effects of long-term androgen deprivation may be avoided, which would improve quality of life. In addition, IAD might improve outcome by delaying the onset of hormonal resistance, but currently there are no clinical data available to verify this hypothesis. Although several studies are currently still in progress to determine the impact of IAD on survival and quality of life, and to compare intermittent therapy with continuous ADT there are increasing data suggesting that IAD is as effective as continuous (Miller et al., 2007; Gulley et al., 2008; Calais da Silva et al., 2009). This is especially true in non-metastatic cases like in patients with locally advanced disease with or without lymph node involvement and those experiencing relapse following curative treatment (Abrahamsson, 2010). However, patients with large tumour burden like those with more than five spots on bone scan and/or non-lymphatic soft tissue metastases should be excluded as only one third of these could start three or more cycles (Albrecht et al., 2003). 3.4. Androgen deprivation therapy in combination with surgery 3.4.1. Neoadjuvant treatment before radical prostatectomy Although neoadjuvant ADT of three months before radical prostatectomy has been reported to reduce prostate size by 30–50% and incidence of positive margins by 18–37% in patients with clinically localised tumour (T1/T2), the outcome of the neoadjuvant treatments has been disappointing (Scolieri et al., 2000; Wirth and Froehner, 2003). Although the 5-year results of a study comparing radical prostatectomy alone or preceded by three months of treatment with MAB in patients having clinical T2b tumours showed a significant reduction in the rate of positive margins with neoadjuvant hormonal treatment there was no difference in the recurrence rate (Soloway et al., 2002). For the neoadjuvant

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treatment of locally advanced T3 stages before radical prostatectomy, only a few studies, with a limited number of cases, are available (Wirth and Froehner, 2003). They do not offer any valid evidence for the beneficial role of neoadjuvant ADT before surgery. Since a PSA decrease can be observed for up to 8 months, it has been speculated that neoadjuvant treatment of more than 3 months’ duration might have a better effect (Gleave et al., 2000). It can be concluded that no advantage of neoadjuvant ADT before radical prostatectomy has been consistently and convincingly demonstrated so far (Tyrrell, 1999b; Wirth and Froehner, 2003; Scolieri et al., 2000). In addition, no study has demonstrated that neoadjuvant treatment reduces the complications of radical prostatectomy (Scolieri et al., 2000). 3.4.2. Adjuvant treatment after radical prostatectomy When studies in patients with seminal vesicle involvement or lymph node metastases are excluded, no conclusive data from randomised studies on the efficacy of adjuvant endocrine treatment after radical prostatectomy are available (Tyrrell, 1999b; Zincke et al., 2001; Wirth and Froehner, 2003). However, patients who do not achieve an undetectable PSA after radical prostatectomy although the surgical margins were negative are at high risk of unrecognised metastatic disease (Trapasso et al., 1994) which might favour the use of adjuvant ADT in these cases. The advantage for adjuvant treatment has been shown in patients who undergo radical prostatectomy and have lymph node metastases (Messing et al., 2006). The rationale for adjuvant hormonal therapy in patients with PSA progression after radical prostatectomy is based on the finding that most cases of PSA recurrence are not localised (Pound et al., 1997). Especially patients with early time to PSA recurrence, rapid PSA doubling time and adverse pathologic features (Gleason score 8–10, positive lymph nodes, seminal vesicle invasion) are suggestive of metastatic disease (Scherr et al., 2003). 3.5. Androgen deprivation therapy in combination with radiotherapy The combination is aiming at decreasing the volume of the prostate, reducing the risk of local relapse within the irradiated volume by inhibiting repopulation during irradiation, decreasing the occurrence of distant metastases, and improving the effectiveness of radiation by an additive or supra-additive effect (Bolla and Laramas, 2010). Neoadjuvant ADT is capable of reducing the volume of the prostate by 30–50%. This allows reduction of field size and dose of radiotherapy for prostate cancer, thus decreasing radiation exposure of the bladder, rectum and other adjacent organs and significantly reducing radiation-related adverse effects and complications (Zelefsky and Harrison, 1997; Tyrrell, 1999b). Similar effects of neoadjuvant treatment before brachytherapy for prostate cancer have been reported (Blank et al., 1999). In this setting, ADT serves to downsize the prostate to overcome anatomical limitations, including larger gland volume and pubic arch interference (Kucway et al., 2002). Large randomised trials, having locally advanced (T3–T4) or large T2 tumours, have shown significant improvements in overall or disease-specific survival, or both, in patients receiving adjuvant hormonal therapy with a GnRH agonists in addition to external beam radiotherapy, compared with those receiving radiotherapy alone (Bolla et al., 1997, 2010; Lawton et al., 2001; Pilepich et al., 2001). In the EORTC study in patients with locally advanced prostate cancer GnRH analogue therapy was continued for 3 years. The 5-year overall survival was 78%, and the proportion of surviving patients who were free from disease was 74% in patients receiving adjuvant GnRH agonist therapy, compared with 62% and 40%, respectively, in those receiving radiotherapy alone (Bolla et al.,

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1997). At 10 years the survival was in the combination group 58.1% and the radiotherapy alone 39.8% (Bolla et al., 2010). The available data suggest that short-term (less than 6 months) adjuvant therapy significantly improves survival in patients with Gleason score 2–6 disease (Pilepich et al., 2001), whereas a longer duration of treatment is necessary in patients with Gleason score 8–10 disease (Lawton et al., 2001; Bolla and Laramas, 2010). However, the optimal duration of adjuvant hormone therapy has not been determined. The SPCG-7/SFUO-3 trial showed that androgen suppression alone was inferior to long-term androgen suppression combined with radiation therapy (Widmark et al., 2009). In the study 78% of cancers were T3 tumours and patients were randomised to receive endocrine treatment alone (3 months of MAB followed by flutamide permanently), or to same endocrine treatment combined with radiotherapy. The cumulative incidence at 10 years for prostate cancer-specific mortality was 23.9% in the endocrine treatment alone group and 11.9% in the combination group for a relative risk of 0.44. 3.6. Timing of therapy While there are potential benefits of adjuvant hormonal therapy after local treatment in locally advanced prostate cancer, a number of questions remain concerning the timing of the treatment, and it is unclear how early treatment should be given. Delayed therapy has been advocated, because hormonal therapy is not curative and is associated with adverse effects, and because there is usually a long delay between PSA relapse and the development of metastatic disease (Walsh et al., 2001). Several studies in different patient populations, including patients with locally advanced, lymph node-positive and metastatic disease, have suggested that early hormonal therapy improves overall or disease-specific survival (Medical Research Council Prostate Cancer Working Group, 1997; Granfors et al., 1998; Pilepich et al., 2001; Messing et al., 2006; Bolla et al., 2010). The effect of early versus delayed hormonal therapy was investigated in a randomised study of 938 patients with locally advanced or metastatic prostate cancer (Medical Research Council Prostate Cancer Working Group, 1997). The time to progression from M0 and M1 disease was significantly longer in patients receiving immediate therapy than those receiving deferred therapy, and significantly fewer patients in the immediate treatment group required transurethral resection for local progression. Complications like pathological fractures, spinal cord compression, ureteric obstruction and development of extraskeletal metastases, were twice as common in the deferred therapy group. The incidence of death from prostate cancer was significantly lower in patients receiving immediate therapy than in the deferred group (62% vs. 71%), particularly among patients with M0 disease (54% vs. 70%, respectively) but not in M1 patients. Another randomised trial (n = 98, median follow-up 11.9 years) comparing immediate hormonal treatment with observation in prostate cancer patients with minimal lymph node disease treated by radical prostatectomy and pelvic lymph node dissection showed a significant improvement in overall survival, prostate cancer specific survival, and progressionfree survival (Messing et al., 2006). In the Early Prostate Cancer Programme testing immediate hormonal treatment with bicalutamide, significant reductions in the risk of disease progression, including the development of bone metastases, were seen not only in patients who received immediate bicalutamide treatment as the primary treatment but also in those had received before that after therapy of curative intent (radical prostatectomy or radiotherapy) (See et al., 2002). However, bicalutamide improved overall survival only in men with locally advanced cancer and had received radiotherapy, while no

difference in survival was seen in patients who had undergone radical prostatectomy (Wirth et al., 2008). The benefits of early endocrine therapy must be counterbalanced with significant impairments in quality of life and increased risks of cardiovascular and osteoporotic disease. Taken together, the data available support early initiation of androgen deprivation therapy not only in M1 patients but also in those with locally advanced, high volume, high grade or lymph node positive prostate cancer. 3.7. Sequential therapy Although initially effective in most patients, ADT is not curative and the prostate cancer eventually starts to progress. Resistance to castration is thought to be result of a variety of mechanisms, including amplification of AR gene leading to hypersensitivity to low levels of testosterone, missense mutations leading to AR promiscuity for weaker androgen agonists, trans-activation of coactivators, and direct activation of other proliferative pathways (Visakorpi et al., 1995; Hsieh and Ryan, 2008), while AR signalling pathway remains activated. Local overexpression of androgens by the tumour itself or within the tumour microenvironment is also thought to be of importance (Mostaghel and Nelson, 2008). Patients who fail initial ADT and demonstrate evidence of disease progression may be treated with sequential therapy with other agents. In men who had initial ADT from either orchiectomy or GnRH agonist monotherapy, the addition of non-steroidal antiandrogen therapy may be considered, as around one third of patients respond for it at least short periods (Palmberg et al., 2000; Kucuk et al., 2001). Also secondary responses with one antiandrogen in patients who have progressed on another antiandrogen are seen between 25% and 50% of cases (Koivisto et al., 1997). If the initial therapy consisted of MAB, the nonsteroidal antiandrogen should be withdrawn, as around one third of patients will respond with a decrease in PSA lasting 4–6 months (Small and Vogelzang, 1997). The simultaneous reduction of adrenal androgens by taking ketoconazole and hydrocortisone can enhance this response observed as an increase in the PSA response in comparison to androgen withdrawal alone (Small and Carrol, 1994). Corticosteroids cannot only induce PSA responses but also produce regression of soft tissue disease in some patients (Scherr et al., 2003). Ketoconazole inhibits cytochrome P450 enzymes, including 17a-hydroxylase/17,20-lyase (CYP17A1), in the adrenal and probably also in the cancer tissue, which is required for androgen synthesis. This leads to frequent PSA declines in CRPC (Figg et al., 2005), but no survival advantage for CRPC has ever been demonstrated with any of these standard secondary hormonal therapies (Shafiri et al., 2010). Abiraterone acetate is a new, more specific and potent inhibitor of CYP17A1 showing promising results in the recent clinical trials. Because it shunts the steroidogenic pathway to mineralocorticoids low-dose glucocorticoid therapy is also needed (Attard et al., 2008, 2009). MDV3100, a new kind of potent antiandrogen, is also a promising new modality in the treatment of CRPC (Tran et al., 2009; Scher et al., 2010). 4. Conclusions It can be concluded that 5-ARIs reduce risk of being diagnosed with prostate cancer but they do not eliminate it. At the moment there is not enough information of the effect of 5-ARIs on prostate cancer and all-cause mortality. By suppressing PSA from BPH and indolent prostate cancers 5-ARIs enhance the ability of a rising PSA to define a group of men at increased risk of clinically significant prostate cancer. Also fewer high-grade cancers are missed because biopsy is more accurate in smaller prostates.

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ADT is an effective treatment for patients with advanced prostate cancer. However, although it improves survival, it is not curative, and creates a spectrum of unwanted effects that influence quality of life, particularly when its use is prolonged. Castration remains the frontline treatment for metastatic prostate cancer, where orchiectomy, oestrogen agonists, GnRH agonists and antagonists produce equivalent clinical responses. MAB is not significantly more effective than single agent GnRH agonist or orchiectomy. Antiandrogen monotherapy with bicalutamide is as effective as castration in palliative treatment of locally advanced prostate cancer, offering quality of life benefits. Adjuvant endocrine treatment is able to delay disease progression at any stage. There is, however, controversy of the possible survival benefit of such treatment that has also to be balanced against its side effects and costs. Whether onset of androgen deprivation at PSA relapse in patients who have undergone definitive local treatment for prostate cancer produces survival benefit may be a topic of further studies. Neoadjuvant endocrine treatment has its place mainly in the external beam radiotherapy setting. IAD is as effective as continuous ADT in nonmetastatic, locally advanced disease with or without lymph node involvement and those experiencing relapse following curative treatment. Hormonal agents for treating advanced prostate cancer represent a wide range of treatment options. The decision regarding the type of androgen deprivation should be made individually after informing the patient of all available treatment options, including watchful waiting, and on the basis of potential benefits and adverse effects. The decision should be based on factors such as staging extent of the disease, the patient’s performance status and the patient’s requirements in terms of quality of life and survival. 5. Future perspectives Several large studies are under way to investigate the role of adjuvant endocrine treatment in the field of early prostate cancer and that of IAD in the treatment of prostate cancer. However, the real challenge is to develop better means to avert CRPC and better treatments for patients with CRPC when it occurs. At the moment it looks like, we are very close to take into clinical use really more potent drugs with reasonable side effects in these patients. References Abrahamsson, P.-A., 2010. Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. Eur. Urol. 57, 49–59. Albrecht, W., Collette, L., Fava, C., et al., 2003. Intermittent maximal androgen blockade in patients with metastatic prostatic cancer: an EORTC feasibility study. Eur. Urol. 44, 505–511. Andriole, G., Bostwick, D., Civantos, F., et al., 2005. The effects of 5a-reductase inhibitors on the natural history, detection and grading of prostate cancer: current state of knowledge. J. Urol. 174, 2098–2104. Andriole, G., Bostwick, D., Brawley, O., et al., 2010. Effect of dutasteride on the risk of prostate cancer. N. Engl. J. Med. 362, 1192–1202. Attard, G., Reid, A.H., Yap, T.A., et al., 2008. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J. Clin. Oncol. 26, 4563– 4571. Attard, G., Reid, A.H., A’Hern, R., et al., 2009. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration resistant prostate cancer. J. Clin. Oncol. 27, 3742–3748. Blank, K.R., Whittington, R., Arjomandy, B., et al., 1999. Adjuvant androgen deprivation prior to transperineal prostate brachytherapy: smaller volumes, less morbidity. Cancer J. Sci. Am. 5, 370–373. Boccardo, F., Rubagotti, A., Barichello, M., et al., 1999. Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: results of Italian Prostate Cancer Project study. J. Clin. Oncol. 17, 2027–2938. Boccon-Gibod, L., 1998. Are non-steroidal anti-androgens appropriate as monotherapy in advanced prostate cancer? Eur. Urol. 33, 159–164. Bolla, M., Laramas, M., 2010. Combined hormonal therapy and radiation therapy for locally advanced prostate cancer. Crit. Rev. Oncol./Hematol. 12. doi:http:// dx.doi.org/1016/j.critrevone:2010.11.003.

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Please cite this article in press as: Tammela, T.L.J. Endocrine prevention and treatment of prostate cancer. Molecular and Cellular Endocrinology (2012), http://dx.doi.org/10.1016/j.mce.2012.03.002