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Copyright © 2010 by the Society for Endocrinology
An update on androgen deprivation therapy for prostate cancer
Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8852, USA (Correspondence should be addressed to N Sharifi; Email: nima.sharifi{at}utsouthwestern.edu)
Androgen deprivation therapy (ADT) with gonadal testosterone depletion is the frontline treatment for advanced prostate cancer. Other hormonal interventions have a role in the treatment of prostate cancer. We sought to examine systematically the evidence for hormonal interventions in prostate cancer, risks of ADT, and interventions that mitigate these risks. Search results for therapeutic studies were focused primarily on randomized controlled clinical trials, and the Jadad scale criteria were used to evaluate the quality of these studies. Four trials of the efficacy of intermittent ADT versus continuous ADT were included. One randomized study analysis and six postrandomization analyses were included on the effects of ADT on cardiovascular mortality. Seven randomized controlled trials of pharmacologic interventions were included for the treatment of metabolic effects due to ADT. One randomized trial of GnRH antagonist versus GnRH agonist was included. Six phase I/II clinical trials of secondary hormonal therapies with novel mechanisms of action were included. Randomized studies completed to date indicate that intermittent ADT might be equivalent to continuous ADT. Although adverse effects of ADT include risk factors for cardiovascular disease, effects on cardiovascular mortality are uncertain. Bone loss and increased risk of fracture may be effectively treated with pharmacologic interventions. Benefits of ADT must be balanced with a consideration of the risks.
In 2009 alone, there were an estimated 192 280 new cases of prostate cancer and 27 360 estimated deaths due to prostate cancer in the United States (Jemal et al. 2009). Depletion of gonadal testosterone through androgen deprivation therapy (ADT) is the frontline treatment for advanced prostate cancer and may be accomplished by medical or surgical castration. Of the 2 million men currently diagnosed with prostate cancer in the United States, over one-third have received treatment with ADT (Keating et al. 2006, Saylor & Smith 2010). Those treated comprise the vast majority of the 27 000 men who die annually from prostate cancer, including men who undergo ADT as primary therapy for localized disease, as an adjunct to radiation therapy for high-risk localized disease, and as treatment for biochemical relapse (prostate-specific antigen (PSA) rise only) after failure of localized therapy, often with uncertain benefits (Sharifi et al. 2005). Other hormonal interventions for prostate cancer include further depletion of androgens by inhibition of adrenal androgen synthesis, direct inhibition of the androgen receptor (AR), and inhibition of 5-reductase, which converts testosterone to the more potent dihydrotestosterone (DHT). New and more potent hormonal agents for the treatment of prostate cancer are in phase III clinical trials. The large number of men treated with hormonal therapy for prostate cancer has increased the urgency to understand and effectively treat adverse effects that accompany these therapies. This review is a critical evaluation of new hormonal therapies for prostate cancer, the adverse effects of ADT, treatments that may ameliorate adverse effects, and efficacy of continuous ADT versus intermittent ADT.
Electronic literature searches of PubMed and Web of Science were conducted for English language articles published between 1966 and February 2010, using the terms prostate cancer, ADT, and hormone treatment. To specifically identify studies on bone loss, cardiovascular endpoints, and intermittent hormonal therapy, the secondary search terms osteopenia, cardiovascular, and intermittent were used. Articles retrieved from clinical studies that were not based on randomized design were excluded. References from selected articles were reviewed manually, and supplemental searches of meeting abstracts from American Society of Clinical Oncology and American Urological Association annual meetings were performed to further identify relevant studies. Articles were further selected for agents with novel mechanisms of action based on randomized study design for clinical trials on ADT and any phase I/II clinical trial for secondary hormonal therapies. To extract these studies, the search terms GnRH antagonist, abiraterone acetate, and MDV3100 were used. The Jadad scale was used to evaluate the quality of randomized controlled clinical trials with emphasis placed on trials with scores 2. Finally, other manuscripts were selected to provide appropriate context and a contemporary perspective.
Study inclusion Emphasis was placed on the highest quality of data. Inclusion of data from trials of pharmacologic agents with novel mechanisms of action of ADT was based on randomized controlled trials for comparisons of medical castration (Table 1). Phase I/II clinical trial data for secondary hormonal therapies with novel mechanisms of action were included only if phase III placebo-controlled trials were ongoing, indicating the potential for eventual Food and Drug Administration approval. Only randomized studies were included to compare the effectiveness of intermittent ADT versus continuous ADT. Further selection of these studies was based on the size of the trial, and smaller studies were not included. Although some findings from prospective studies and population-based analyses were used to describe adverse effects of ADT, only data from randomized, placebo-controlled clinical trials were used to assess the effect of therapeutic interventions to prevent or reverse adverse effects. Not included were studies designed to assess changes in skeletal-related adverse events due to bony metastasis. Overall, 15 studies had a Jadad score 2.
Androgen deprivation therapy Gonadal testosterone is the main source of circulating androgens (Fig. 1). Although there are recognized limitations in measuring serum testosterone concentrations (Rosner et al. 2007), a total testosterone concentration >300 ng/dl (10.4 nmol/l) is generally considered normal (Bhasin et al. 2010). The upper limit of castration concentrations of serum testosterone is considered to be 50 ng/dl (1.7 nmol/l), although lower concentrations (20 ng/dl; 0.7 nmol/l) may be more desirable for optimal therapy (Bubley et al. 1999). Testosterone has AR agonist activity. In the prostate, testosterone is rapidly reduced by 5-reductases to DHT (Bruchovsky & Wilson 1968), a more potent AR agonist required for prostate development (Russell & Wilson 1994). For ADT to be effective against prostate cancer, the decline in serum testosterone must translate to a decrease in intraprostatic androgens. Despite the 94% decline in serum testosterone with ADT, however, intraprostatic concentrations of testosterone and DHT decline by only 70-80% (Page et al. 2006). The adrenal origin of the residual intraprostatic androgens is suggested by the correlation of serum dehydroepiandrosterone (DHEA) with intraprostatic testosterone and DHT (Page et al. 2006). These findings suggest that, despite the clinical effects of standard ADT, the potential exists to intensify the effects of ADT on prostate tissue.
ADT is achievable pharmacologically with medical castration or through surgical orchiectomy. Medical castration is generally favored by patients because of the psychological effects and irreversible nature of surgical orchiectomy (McLeod 2003). Bilateral orchiectomy, however, is significantly less expensive than medical castration (Chon et al. 2000). The common mechanism of the various means of medical castration is suppression of the release of LH from the anterior pituitary. GnRH is a peptide hormone that is synthesized in the hypothalamus and regulates pituitary LH release (Conn & Crowley 1994). The LH response depends on the nature of stimulation by GnRH, and LH is released only in response to pulsatile GnRH secretion (Conn & Crowley 1994). Although administration of estrogens, such as diethylstilbestrol (DES), suppresses pituitary release of LH and the resultant testosterone secretion from the Leydig cells of the testes (Cox & Crawford 1995), treatment with DES is also associated with cardiovascular deaths (Byar 1973) and is therefore no longer used. On the other hand, GnRH agonists are commonly used for medical castration. GnRH agonists are administered s.c. or i.m. for sustained release. Continuous pituitary stimulation by GnRH agonists overcomes endogenous pulsatile GnRH and suppresses LH release, resulting in low serum testosterone (Tolis et al. 1982). Synthetic GnRH agonists include leuprolide, buserelin, goserelin, and histrelin. A potential disadvantage of GnRH agonists is the initial rise in serum testosterone concentrations when beginning treatment and the potential to induce a consequent stimulation of prostate cancer growth. The effects of the initial testosterone surge can be blocked by AR antagonists (Kuhn et al. 1989). Alternatively, administration of GnRH antagonists, such as degarelix (Doehn et al. 2009), does not induce a testosterone surge. A three-armed, randomized phase III study compared a starting dose of 240 mg degarelix, followed by 80 or 160 mg monthly s.c. doses, with monthly 7.5 mg i.m. doses of leuprolide in 610 previously untreated patients (Klotz et al. 2008). Concomitant treatment with an AR antagonist in the leuprolide arm to prevent an initial testosterone surge and tumor flare was at the discretion of the investigator. By day 3, the median testosterone concentration rose from 384 ng/dl (13.1 nmol/l) to 630 ng/dl (21.4 nmol/l) in the leuprolide arm. In contrast, median testosterone concentrations were 24 ng/dl (0.82 nmol/l) and 26 ng/dl (0.88 nmol/l), and 96.1 and 95.5% of patients in the degarelix 240/80 and 240/160 mg arms respectively were below the testosterone castrate threshold of 50 ng/dl (1.7 nmol/l). The PSA decline at day 14 was significantly greater in the degarelix arms, reflecting the faster onset of testosterone decline, although this difference was no longer statistically significant at day 35. On the other hand, the PSA decline was similar between the degarelix arms and men who received leuprolide in addition to AR antagonist. Testosterone suppression to <50 ng/dl (1.7 nmol/l) for all monthly assessments up to 1 year was achieved in 97.2, 98.3, and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg, and leuprolide arms respectively. Although there were no allergic reactions, in contrast to other trials of GnRH antagonists, treatment in the degarelix arms was associated with a 40% chance of injection-site reactions. The benefits of ADT in advanced disease include fewer tumor-associated events, such as spinal cord compression, extraskeletal metastases, pathological fracture, and ureteral obstruction (Medical Research Council 1997). ADT adjuvant to radiation therapy increases survival in men with intermediate, high-risk, and locally advanced disease (D'Amico et al. 2004, Bolla et al. 2009, Souhami et al. 2009). Furthermore, there is a survival benefit for men treated with ADT after radical prostatectomy who also have lymph node involvement (Messing et al. 1999). Other hormonal interventions Although the majority of prostate tumors initially respond to ADT, metastatic disease almost invariably progresses eventually to castration-resistant prostate cancer (CRPC). Paradoxically, CRPC often remains responsive to other hormonal therapies (Scher & Sawyers 2005, McPhaul 2008, Sharifi 2010) in large part due to the intratumoral regeneration of androgens (Titus et al. 2005, Montgomery et al. 2008). Therefore, after the development of CRPC, patients are often treated with secondary hormonal therapies that further deplete androgen concentrations, or directly bind and inhibit AR (Ryan & Small 2005). Bicalutamide, nilutamide, and flutamide are nonsteroidal AR antagonists frequently used as secondary hormonal therapy in the United States (Ryan & Small 2005). Of these, bicalutamide binds AR with the highest affinity, has the longest half-life, and is generally the most favored (Gao et al. 2005). Importantly, these nonsteroidal AR antagonists may have AR agonist activity, particularly under certain circumstances associated with CRPC (Kelly & Scher 1993, Figg et al. 1995, Taplin et al. 2003, Chen et al. 2004). Ketoconazole is an antifungal imidazole that inhibits cytochrome P450 enzymes, including 17-hydroxylase/17,20-lyase (CYP17A1), in the adrenal, which is required for androgen synthesis (De Coster et al. 1996). Secondary hormonal therapy with ketoconazole inhibits the synthesis of adrenal androgens and leads to frequent PSA declines in CRPC (Figg et al. 2005). Treatment with ketoconazole can cause adrenal insufficiency due to declines in other adrenal steroids; patients are therefore supplemented with hydrocortisone (Khosla et al. 1989, Figg et al. 2005). Unfortunately, no survival advantage for CRPC has ever been definitely demonstrated with any of these standard secondary hormonal therapies. Two investigational hormonal therapies with novel mechanisms of action and promising activity in phase I/II clinical trials are currently in phase III placebo-controlled trials. Compared with ketoconazole, abiraterone acetate is a more specific and potent inhibitor of CYP17A1, with unique clinical activity and adverse effect profiles (Barrie et al. 1994, Haidar et al. 2003). Several phase I/II clinical trials of abiraterone acetate have been completed both in patients who have previously received and in those who have never been treated with ketoconazole and/or chemotherapy (Attard et al. 2008, 2009, Danila et al. 2010, Reid et al. 2010, Ryan et al. 2010). In two trials, serum testosterone was further suppressed from baseline after treatment with abiraterone acetate (median 7 ng/dl at baseline, <1 ng/dl at day 8 (Attard et al. 2008); mean 4 ng/dl at baseline, <1 ng/dl at day 28 (Ryan et al. 2010)). Serum DHEA and DHEA-sulfate (DHEA-S) concentrations also declined in these trials (median DHEA 282.4 ng/dl at baseline, 83.6 ng/dl at day 28 (Attard et al. 2008); median DHEA-S 39 µg/dl at baseline, <15 µg/dl at day 28 (Attard et al. 2008); mean DHEA-S 49 µg/dl at baseline, <15 µg/dl at day 28 (Ryan et al. 2010)). Inhibition of CYP17A1 activity with abiraterone acetate, which blocks the pathway to androgens and other 19-carbon steroids, shunts the steroidogenic pathway to mineralocorticoids. This results in 10- and 40-fold increases in deoxycorticosterone and corticosterone respectively (Attard et al. 2008). As might be predicted, the adverse effect profile includes hypertension, hypokalemia, and edema, which are manageable with the mineralocorticoid receptor antagonist eplerenone (Attard et al. 2008). These adverse effects may be ameliorated by low-dose glucocorticoids, which suppress ACTH and adrenal steroidogenesis (Attard et al. 2009). Two phase III randomized, placebo-controlled clinical trials are ongoing and will ultimately determine the role of abiraterone acetate for the treatment of CRPC. MDV3100 is a member of the new class of diarylthiohydantoin AR antagonists (Tran et al. 2009). This drug binds AR with a five- to eight-fold higher affinity than bicalutamide, inhibits AR nuclear translocation, and has reduced agonist activity, distinguishing it from the three nonsteroidal AR antagonists used in current clinical practice. A phase I/II clinical trial of MDV3100 demonstrated PSA declines of >50% in 57% of CRPC patients not previously treated with chemotherapy and 45% of patients who progressed on docetaxel chemotherapy (Tran et al. 2009, Scher et al. 2010). A phase III randomized placebo-controlled trial of MDV3100 is currently underway in patients with CRPC previously treated with chemotherapy, and a second trial will follow for chemotherapy-naïve patients. Continuous ADT versus intermittent ADT The antitumor effect of intermittent ADT versus continuous ADT has been debated since preclinical studies first suggested that intermittent ADT might allow for multiple cycles and delayed resistance to ADT (Akakura et al. 1993). Furthermore, given the adverse effects of ADT, there may be beneficial effects and potential cost savings in time off therapy with intermittent treatment, particularly if suppressive effects on prostate cancer are equivalent to continuous ADT (Seruga & Tannock 2008). A randomized trial of intermittent ADT versus continuous ADT in 335 patients with advanced (lymph node-positive or metastatic) prostate cancer demonstrated equivalent survival (51.4 vs 53.8 months, P=0.658; Miller et al. 2007). Patients in the intermittent arm were off treatment >40% of the time. It is important to note that testosterone recovery after discontinuation of GnRH agonist is often delayed and may depend on treatment duration, age, baseline testosterone, and ethnicity (Gulley et al. 2008). In a trial of intermittent ADT versus continuous ADT for advanced prostate cancer, 193 patients were randomized and, after a mean follow-up of 34 months, no difference in survival was observed (P value not stated; Langenhuijsen et al. 2008). A larger trial randomized 312 men to continuous ADT and 314 men to intermittent ADT (Calais da Silva et al. 2009). With a median follow-up of 51 months from randomization, there were fewer cancer deaths (84 vs 106), more cardiovascular deaths (52 vs 41), and an equivalent number of total deaths (169 vs 170) in the continuous versus intermittent arms respectively. Median time off ADT was 52 weeks for patients in the intermittent arm (Calais da Silva et al. 2009). It should be noted that the randomization criteria for all of these trials are a PSA decline of 80-90%, or to <4 ng/ml, on initial ADT. Furthermore, ADT for all of these trials included treatment with an AR antagonist (Miller et al. 2007, Langenhuijsen et al. 2008, Calais da Silva et al. 2009). Although current evidence suggests that intermittent ADT may be reasonable for some patients with hormone-sensitive prostate cancer (Seruga & Tannock 2008), there are still questions about patient selection, timing, and methodology of intermittent ADT (Keizman & Carducci 2009). SWOG 9346 is an ongoing randomized trial with an accrual goal of 1512 patients, with a primary objective to determine whether treatment of men with newly diagnosed, hormone-sensitive, metastatic prostate cancer with intermittent ADT and continuous ADT leads to equivalent survival (Hussain et al. 2009). This would be the largest randomized trial of continuous ADT versus intermittent ADT to date and is expected to yield more definitive results. Adverse effects of ADT Prostate cancer is generally a disease of older men, many of whom already have other significant comorbidities. In this population, the potential benefits of therapy must be tempered with a consideration of its adverse effects (Table 2). Prospective clinical trials of ADT for men with prostate cancer demonstrate the 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 (Sharifi et al. 2005, Levine et al. 2010). Population-based analyses further suggest that treatment with ADT is associated with an elevated risk for diabetes (Keating et al. 2006, Alibhai et al. 2009).
Cardiovascular risk Randomized study analyses and postrandomization analyses from several clinical trials have examined whether these longitudinal changes in cardiovascular risk factors translate to an increased risk of cardiovascular death. In a pooled analysis of 1372 men in three randomized trials of men receiving radiation for localized prostate cancer and 0 vs 3 vs 6 months, 3 vs 8 months, or 0 vs 6 months of ADT, men 65 years of age or older receiving 6 months of ADT had shorter times to fatal myocardial infarction compared with men not receiving ADT (P=0.017; D'Amico et al. 2007). No significant difference was observed in men younger than 65 years of age, or in men 65 years of age or older receiving 6-8 vs 3 months of ADT (D'Amico et al. 2007). In a randomized trial of 206 men receiving 6 months of ADT plus radiation versus radiation alone for localized prostate cancer, 13 deaths from myocardial infarction occurred in each group (D'Amico et al. 2008). In men receiving ADT, however, 11 deaths occurred in men with moderate to severe comorbidities, leading to a loss in overall survival benefit in these men. On the other hand, other studies from randomized clinical trials do not suggest that ADT confers an increased risk of cardiovascular events. In a randomized trial in 945 men with locally advanced prostate cancer receiving adjuvant ADT with radiation versus radiation and salvage ADT on disease recurrence (RTOG 85-31), the treatment arm was not significantly associated with risk of cardiovascular mortality after censoring for salvage ADT (Efstathiou et al. 2009). In a trial of 1554 men with locally advanced prostate cancer receiving radiation therapy and randomized to 4 vs 30 months of ADT (RTOG 92-02), duration of ADT was not significantly associated with 5-year risk of cardiovascular mortality (4.8 vs 5.9%; P=0.16; Efstathiou et al. 2008). The 10-year rate of fatal cardiac events in a randomized trial of short-term neoadjuvant ADT for locally advanced prostate cancer (RTOG 8610) was not significantly different in the arm receiving 2 months of ADT versus no ADT (12.5 vs 9.1%; P=0.32; Roach et al. 2008). A randomized trial of radiation plus 6 vs 30 months of ADT in 1113 men with locally advanced prostate cancer (EORTC 22961) showed no difference in the cumulative incidence of fatal cardiac events at 5 years (4.0 vs 3.0%; Bolla et al. 2009). A randomized trial of immediate versus deferred ADT in 985 men with localized prostate cancer not suitable for local treatment demonstrated no increase in cardiovascular mortality in the immediate ADT arm (17.9 vs 19.7%; Studer et al. 2006). It is presently unclear whether there is a causal relationship between ADT and cardiovascular mortality. The differences in outcome among studies that have examined this issue may be due to study design, characteristics of the study populations, or competing risks. ADT may affect cardiovascular mortality in a subset of these study populations. Alternatively, there may be no causal relationship. It may be prudent to carefully consider the potential risks and benefits before initiating ADT, particularly in patients with coronary artery disease. Patients with cardiac disease who initiate ADT should receive particular attention to secondary preventive interventions (Levine et al. 2010).
Intervention for hyperlipidemia Treatment of ADT adverse effects
Bone density and fracture risk Bisphosphonates decrease bone loss by inhibiting osteoclast function and bone resorption (Drake et al. 2008). Randomized, placebo-controlled clinical trials of several agents in this class, including pamidronate (Diamond et al. 2001, Smith et al. 2001), alendronate (Greenspan et al. 2007), and zoledronic acid (Smith et al. 2003, Michaelson et al. 2007), have demonstrated that bisphosphonates increase BMD in patients treated with ADT. None of these bisphosphonate studies was large enough to determine the impact on fractures due to ADT (Saylor & Smith 2010). Given that bone loss from ADT is due to a deficiency of estrogen (Guise et al. 2007), replacement of estrogenic function with SERMs may favorably affect bone density. In a phase III randomized study of placebo versus toremifene (80 mg daily), patients in the toremifene arm had significantly increased BMD in the hip and spine (Smith et al. 2008a). Furthermore, the 2-year incidence of new vertebral fractures was significantly lower in the toremifene arm (2.5%) than in the placebo arm (4.9%; P=0.05; Smith et al. 2010). The toremifene arm, however, had more than twice the number of venous thromboembolic events. The genesis, function, and survival of osteoclasts are critically dependent upon the receptor activator of nuclear factor-B ligand (RANKL; Lacey et al. 1998). Denosumab is a human monoclonal antibody against RANKL that inhibits osteoclast activity. A randomized, double-blind, placebo-controlled clinical trial compared denosumab (60 mg s.c.) with placebo, given every 6 months, in 1468 men on ADT for nonmetastatic, hormone-responsive prostate cancer (Smith et al. 2009). At 2 years, patients in the denosumab arm had significantly higher BMD than those in the placebo arm, with 4.8, 3.9, 5.5, and 4.0% increases (P<0.001) in total hip, femoral neck, distal third of radius, and whole body BMD values. The relative risk of vertebral fractures for men in the denosumab arm compared to placebo at 1, 2, and 3 years was 0.15, 0.31, and 0.38 (P0.006). Over 36 months, fractures at any site developed in 5.2 and 7.2% of patients in the denosumab and placebo groups respectively, although the difference was not statistically significant (P=0.10; Smith et al. 2009).
ADT with gonadal depletion of testosterone is widely used as the frontline therapy for advanced prostate cancer, and to treat localized disease in combination with other therapies. Other hormonal therapies that block adrenal steroidogenesis further reduce androgen synthesis, or directly and competitively inhibit the AR. Investigational agents in clinical trials appear to be more potent than those in current clinical use. The role of these investigational agents in earlier stage disease should also be investigated. Intermittent and continuous ADT may be equivalent, and selected patients may be candidates for intermittent therapy with reduced adverse effects. Nevertheless, more definitive results await completion of a larger clinical trial. Adverse effects of ADT include metabolic changes such as hyperlipidemia, increased fat mass, insulin resistance, and diabetes. Although many of the metabolic effects induced by ADT are risk factors for cardiovascular disease, the effects on cardiovascular risk are uncertain. Pharmacologic intervention may decrease bone loss and reverse increased risk of fracture due to ADT. Patient comorbidities and risk factors for the adverse effects of ADT, such as the history of osteoporosis or prior fractures, as well as the potential value of pharmacologic intervention should be taken into consideration prior to the initiation of ADT.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
This work was supported in part by a Howard Hughes Medical Institute Physician-Scientist Early Career Award, an award from the Prostate Cancer Foundation and from grant number PC80193 from the U.S. Army Medical Research and Materiel Command to N Sharifi and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.
Akakura K, Bruchovsky N, Goldenberg SL, Rennie PS, Buckley AR & Sullivan LD 1993 Effects of intermittent androgen suppression on androgen-dependent tumors. Apoptosis and serum prostate-specific antigen. Cancer 71 2782-2790, doi:10.1002/1097-0142(19930501)71:9<2782::AID-CNCR2820710916>3.0.CO;2-Z.[Medline] Alibhai SM, Duong-Hua M, Sutradhar R, Fleshner NE, Warde P, Cheung AM & Paszat LF 2009 Impact of androgen deprivation therapy on cardiovascular disease and diabetes. Journal of Clinical Oncology 27 3452-3458, doi:10.1200/JCO.2008.20.0923. D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A & Kantoff PW 2004 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. Journal of the American Medical Association 292 821-827, doi:10.1001/jama.292.7.821. D'Amico AV, Denham JW, Crook J, Chen MH, Goldhaber SZ, Lamb DS, Joseph D, Tai KH, Malone S, Ludgate C et al. 2007 Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. Journal of Clinical Oncology 25 2420-2425, doi:10.1200/JCO.2006.09.3369. D'Amico AV, Chen MH, Renshaw AA, Loffredo M & Kantoff PW 2008 Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. Journal of the American Medical Association 299 289-295, doi:10.1001/jama.299.3.289. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E 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. Journal of Clinical Oncology 26 4563-4571, doi:10.1200/JCO.2007.15.9749. Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E, Messiou C, Molife LR, Maier G, Thompson E et al. 2009 Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. Journal of Clinical Oncology 27 3742-3748, doi:10.1200/JCO.2008.20.0642. Barrie SE, Potter GA, Goddard PM, Haynes BP, Dowsett M & Jarman M 1994 Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). Journal of Steroid Biochemistry and Molecular Biology 50 267-273, doi:10.1016/0960-0760(94)90131-7.[CrossRef][Web of Science][Medline] Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS & Montori VM 2010 Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 95 2536-2559, doi:10.1210/jc.2009-2354. Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Oddens J, Poortmans PM, Gez E, Kil P, Akdas A, Soete G et al. 2009 Duration of androgen suppression in the treatment of prostate cancer. New England Journal of Medicine 360 2516-2527, doi:10.1056/NEJMoa0810095.[CrossRef][Medline] Bruchovsky N & Wilson JD 1968 The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro. Journal of Biological Chemistry 243 2012-2021. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G et al. 1999 Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Journal of Clinical Oncology 17 3461-3467. Byar DP 1973 Proceedings: the Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 32 1126-1130, doi:10.1002/1097-0142(197311)32:5<1126::AID-CNCR2820320518>3.0.CO;2-C.[Medline] Calais da Silva FE, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JA, Kirkali Z, Calais da Silva FM & Robertson C 2009 Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. European Urology 55 1269-1277, doi:10.1016/j.eururo.2009.02.016.[CrossRef][Web of Science][Medline] Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG & Sawyers CL 2004 Molecular determinants of resistance to antiandrogen therapy. Nature Medicine 10 33-39, doi:10.1038/nm972.[CrossRef][Web of Science][Medline] Chon JK, Jacobs SC & Naslund MJ 2000 The cost value of medical versus surgical hormonal therapy for metastatic prostate cancer. Journal of Urology 164 735-737, doi:10.1016/S0022-5347(05)67292-8.[CrossRef][Web of Science][Medline] Conn PM & Crowley WF Jr 1994 Gonadotropin-releasing hormone and its analogs. Annual Review of Medicine 45 391-405, doi:10.1146/annurev.med.45.1.391.[CrossRef][Web of Science][Medline] De Coster R, Wouters W & Bruynseels J 1996 P450-dependent enzymes as targets for prostate cancer therapy. Journal of Steroid Biochemistry and Molecular Biology 56 133-143, doi:10.1016/0960-0760(95)00230-8.[CrossRef][Web of Science][Medline] Cox RL & Crawford ED 1995 Estrogens in the treatment of prostate cancer. Journal of Urology 154 1991-1998, doi:10.1016/S0022-5347(01)66670-9.[CrossRef][Web of Science][Medline] Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, Taplin ME, Bubley GJ, Kheoh T, Haqq C et al. 2010 Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. Journal of Clinical Oncology 28 1496-1501, doi:10.1200/JCO.2009.25.9259. Diamond TH, Winters J, Smith A, De Souza P, Kersley JH, Lynch WJ & Bryant C 2001 The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study. Cancer 92 1444-1450, doi:10.1002/1097-0142(20010915)92:6<1444::AID-CNCR1468>3.0.CO;2-M.[CrossRef][Medline] Doehn C, Sommerauer M & Jocham D 2009 Degarelix for prostate cancer. Expert Opinion on Investigational Drugs 18 851-860, doi:10.1517/13543780902954713.[CrossRef][Web of Science][Medline] Drake MT, Clarke BL & Khosla S 2008 Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clinic Proceedings 83 1032-1045, doi:10.4065/83.9.1032. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM & Smith MR 2008 Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02. European Urology 54 816-823, doi:10.1016/j.eururo.2008.01.021.[CrossRef][Web of Science][Medline] Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM & Smith MR 2009 Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. Journal of Clinical Oncology 27 92-99, doi:10.1200/JCO.2007.12.3752. Figg WD, Sartor O, Cooper MR, Thibault A, Bergan RC, Dawson N, Reed E & Myers CE 1995 Prostate specific antigen decline following the discontinuation of flutamide in patients with stage D2 prostate cancer. American Journal of Medicine 98 412-414, doi:10.1016/S0002-9343(99)80323-4.[CrossRef][Web of Science][Medline] Figg WD, Liu Y, Arlen P, Gulley J, Steinberg SM, Liewehr DJ, Cox MC, Zhai S, Cremers S, Parr A et al. 2005 A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases. Journal of Urology 173 790-796, doi:10.1097/01.ju.0000147013.09157.8e.[CrossRef][Web of Science][Medline] Gao W, Bohl CE & Dalton JT 2005 Chemistry and structural biology of androgen receptor. Chemical Reviews 105 3352-3370, doi:10.1021/cr020456u.[CrossRef][Web of Science][Medline] Greenspan SL, Nelson JB, Trump DL & Resnick NM 2007 Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Annals of Internal Medicine 146 416-424. Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS & Smith MR 2007 Estrogenic side effects of androgen deprivation therapy. Reviews in Urology 9 163-180.[Medline] Gulley JL, Aragon-Ching JB, Steinberg SM, Hussain MH, Sartor O, Higano CS, Petrylak DP, Chatta GS, Arlen PM, Figg WD et al. 2008 Kinetics of serum androgen normalization and factors associated with testosterone reserve after limited androgen deprivation therapy for nonmetastatic prostate cancer. Journal of Urology 180 1432-1437, (discussion 1437), doi:10.1016/j.juro.2008.06.017.[CrossRef][Web of Science][Medline] Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C & Hartmann RW 2003 Effects of novel 17alpha-hydroxylase/C17,20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. Journal of Steroid Biochemistry and Molecular Biology 84 555-562, doi:10.1016/S0960-0760(03)00070-0.[Web of Science][Medline] Hussain M, Goldman B, Tangen C, Higano CS, Petrylak DP, Wilding G, Akdas AM, Small EJ, Donnelly BJ, Sundram SK et al. 2009 Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. Journal of Clinical Oncology 27 2450-2456, doi:10.1200/JCO.2008.19.9810. Jemal A, Siegel R, Ward E, Hao Y, Xu J & Thun MJ 2009 Cancer statistics, 2009. CA: A Cancer Journal for Clinicians 59 225-249, doi:10.3322/caac.20006. Keating NL, O'Malley AJ & Smith MR 2006 Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. Journal of Clinical Oncology 24 4448-4456, doi:10.1200/JCO.2006.06.2497. Keizman D & Carducci MA 2009 Intermittent androgen deprivation: questions remain. Nature Reviews. Urology 6 412-414, doi:10.1038/nrurol.2009.145.[CrossRef][Web of Science][Medline] Kelly WK & Scher HI 1993 Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. Journal of Urology 149 607-609.[Web of Science][Medline] Khosla S, Wolfson JS, Demerjian Z & Godine JE 1989 Adrenal crisis in the setting of high-dose ketoconazole therapy. Archives of Internal Medicine 149 802-804, doi:10.1001/archinte.149.4.802. Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK & Schroder FH 2008 The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU International 102 1531-1538, doi:10.1111/j.1464-410X.2008.08183.x.[CrossRef][Web of Science][Medline] Kuhn JM, Billebaud T, Navratil H, Moulonguet A, Fiet J, Grise P, Louis JF, Costa P, Husson JM, Dahan R et al. 1989 Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). New England Journal of Medicine 321 413-418, doi:10.1056/NEJM198908173210701.[Web of Science][Medline] Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S et al. 1998 Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93 165-176, doi:10.1016/S0092-8674(00)81569-X.[CrossRef][Web of Science][Medline] Langenhuijsen J, Schasfoort E, Heathcote P, Lock M, Zerbib M, Dijkema H, Vergunst H, Srougi M, Van de Beek C, Jimenez Rios M et al. 2008 Intermittent androgen suppression in patients with advanced prostate cancer: an update of the TULP survival data. European Urology 7 205, doi:10.1016/S1569-9056(08)60534-5. Levine GN, D'Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, Milani RV, Sagalowsky AI, Smith MR & Zakai N 2010 Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association. American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation 121 833-840, doi:10.1161/CIRCULATIONAHA.109.192695. McLeod DG 2003 Hormonal therapy: historical perspective to future directions. Urology 61 3-7, doi:10.1016/S0090-4295(02)02393-2.[CrossRef][Web of Science][Medline] McPhaul MJ 2008 Mechanisms of prostate cancer progression to androgen independence. Best Practice & Research. Clinical Endocrinology & Metabolism 22 373-388, doi:10.1016/j.beem.2008.02.006.[CrossRef][Web of Science][Medline] Medical Research Council Prostate Cancer Working Party Investigators Group, Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council TrialBritish Journal of Urology 79 1997 235-246.[CrossRef][Web of Science][Medline] Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED & Trump D 1999 Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. New England Journal of Medicine 341 1781-1788, doi:10.1056/NEJM199912093412401.[CrossRef][Web of Science][Medline] Michaelson MD, Kaufman DS, Lee H, McGovern FJ, Kantoff PW, Fallon MA, Finkelstein JS & Smith MR 2007 Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. Journal of Clinical Oncology 25 1038-1042, doi:10.1200/JCO.2006.07.3361. Miller K, Steiner U, Lingnau A, Keilholz U, Witzsch U, Haider A, Wachter U, Russel C & Altwein J 2007 Randomised prospective study of intermittent versus continuous androgen suppression in advanced prostate cancer. Journal of Clinical Oncology 25 5015. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD & Nelson PS 2008 Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Research 68 4447-4454, doi:10.1158/0008-5472.CAN-08-0249. Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, Nelson PS, Matsumoto AM & Bremner WJ 2006 Persistent intraprostatic androgen concentrations after medical castration in healthy men. Journal of Clinical Endocrinology and Metabolism 91 3850-3856, doi:10.1210/jc.2006-0968. Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, Molife LR, Hunt J, Messiou C, Parker C et al. 2010 Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. Journal of Clinical Oncology 28 1489-1495, doi:10.1200/JCO.2009.24.6819. Roach M III, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, Lawton C, Valicenti R, Grignon D & Pilepich MV 2008 Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. Journal of Clinical Oncology 26 585-591, doi:10.1200/JCO.2007.13.9881. Rosner W, Auchus RJ, Azziz R, Sluss PM & Raff H 2007 Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. Journal of Clinical Endocrinology and Metabolism 92 405-413, doi:10.1210/jc.2006-1864. Russell DW & Wilson JD 1994 Steroid 5 alpha-reductase: two genes/two enzymes. Annual Review of Biochemistry 63 25-61, doi:10.1146/annurev.biochem.63.1.25.[Web of Science][Medline] Ryan CJ & Small EJ 2005 Secondary hormonal manipulations in prostate cancer. Current Oncology Reports 7 228-233, doi:10.1007/s11912-005-0078-x.[CrossRef][Medline] Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F, Martins V, Lee G, Kheoh T, Kim J et al. 2010 Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. Journal of Clinical Oncology 28 1481-1488, doi:10.1200/JCO.2009.24.1281. Saylor PJ & Smith MR 2010 Adverse effects of androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer. Journal of the National Comprehensive Cancer Network 8 211-223.[Web of Science][Medline] Scher HI & Sawyers CL 2005 Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. Journal of Clinical Oncology 23 8253-8261, doi:10.1200/JCO.2005.03.4777. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J et al. 2010 Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 375 1437-1446, doi:10.1016/S0140-6736(10)60172-9.[CrossRef][Web of Science][Medline] Seruga B & Tannock IF 2008 Intermittent androgen blockade should be regarded as standard therapy in prostate cancer. Nature Clinical Practice. Oncology 5 574-576, doi:10.1038/ncponc1180.[CrossRef][Web of Science][Medline] Shahinian VB, Kuo YF, Freeman JL & Goodwin JS 2005 Risk of fracture after androgen deprivation for prostate cancer. New England Journal of Medicine 352 154-164, doi:10.1056/NEJMoa041943.[CrossRef][Web of Science][Medline] Sharifi N 2010 New agents and strategies for the hormonal treatment of castration-resistant prostate cancer. Expert Opinion on Investigational Drugs 19 837-846, doi:10.1517/13543784.2010.494178.[CrossRef][Web of Science][Medline] Sharifi N, Gulley JL & Dahut WL 2005 Androgen deprivation therapy for prostate cancer. Journal of the American Medical Association 294 238-244, doi:10.1001/jama.294.2.238. Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, Kantoff PW & Finkelstein JS 2001 Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. New England Journal of Medicine 345 948-955, doi:10.1056/NEJMoa010845.[CrossRef][Web of Science][Medline] Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S & Zinner N 2003 Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. Journal of Urology 169 2008-2012, doi:10.1097/01.ju.0000063820.94994.95.[CrossRef][Web of Science][Medline] Smith MR, Malkowicz SB, Chu F, Forrest J, Price D, Sieber P, Barnette KG, Rodriguez D & Steiner MS 2008a Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. Journal of Urology 179 152-155, doi:10.1016/j.juro.2007.08.137.[Web of Science][Medline] Smith MR, Malkowicz SB, Chu F, Forrest J, Sieber P, Barnette KG, Rodriquez D & Steiner MS 2008b Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study. Journal of Clinical Oncology 26 1824-1829, doi:10.1200/JCO.2007.13.5517. Smith MR, Egerdie B, Hernandez Toriz N, Feldman R, Tammela TL, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A et al. 2009 Denosumab in men receiving androgen-deprivation therapy for prostate cancer. New England Journal of Medicine 361 745-755, doi:10.1056/NEJMoa0809003.[CrossRef][Medline] Smith M, Morton R, Barnette G, Sieber P, Malkowicz S, Rodrigues D, Hancock M & Steiner M 2010 Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. Journal of Urology 184 1316-1321, doi:10.1016/j.juro.2010.06.022.[CrossRef][Web of Science][Medline] Souhami L, Bae K, Pilepich M & Sandler H 2009 Impact of the duration of adjuvant hormonal therapy in patients with locally advanced prostate cancer treated with radiotherapy: a secondary analysis of RTOG 85-31. Journal of Clinical Oncology 27 2137-2143, doi:10.1200/JCO.2008.17.4052. Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, Loidl W, Isorna S, Sundaram SK, Debois M et al. 2006 Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. Journal of Clinical Oncology 24 1868-1876, doi:10.1200/JCO.2005.04.7423. Taplin ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J, Stadler W, Hayes DF, Kantoff PW, Vogelzang NJ et al. 2003 Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. Journal of Clinical Oncology 21 2673-2678, doi:10.1200/JCO.2003.11.102. Titus MA, Schell MJ, Lih FB, Tomer KB & Mohler JL 2005 Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clinical Cancer Research 11 4653-4657, doi:10.1158/1078-0432.CCR-05-0525. Tolis G, Ackman D, Stellos A, Mehta A, Labrie F, Fazekas AT, Comaru-Schally AM & Schally AV 1982 Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. PNAS 79 1658-1662, doi:10.1073/pnas.79.5.1658. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A et al. 2009 Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324 787-790, doi:10.1126/science.1168175.
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Abstract
Introduction