Antiandrogens in the Treatment of Prostate Cancer

european urology 51 (2007) 306 314 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review Prostate Cancer Antiandrogens in the Treatment of Prostate Cancer Manfred P. Wirth *, Oliver W. Hakenberg, Michael Froehner Department of Urology, University Hospital Carl Gustav Carus, Technical University of Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany Article info Article history: Accepted August 22, 2006 Published online ahead of print on September 11, 2006 Keywords: Prostate cancer Hormonal treatment Antiandrogens Bicalutamide Flutamide Nilutamide Cyproterone acetate Abstract Objectives: To give an overview on the contemporary role of antiandrogens in prostate cancer treatment. Methods: A review of the literature was performed concerning pharmacologic properties, possible indications and side effects of antiandrogens in the treatment of early and advanced prostate cancer. Results: One steroidal and three non-steroidal antiandrogens are in common use for the treatment of prostate cancer. Monotherapy with non-steroidal antiandrogens may prevent osteoporosis, loss of musculature and may preserve sexual activity in a proportion of patients and therefore has advantages in quality of life compared to castration. In patients with localized disease managed by watchful waiting or in an adjuvant setting, there are no studies showing an advantage in early versus delayed treatment with antiandrogens regarding clinical progression. In locally advanced non-metastatic prostate cancer, antiandrogen monotherapy seems to be an alternative to castration treatment if treatment is required. In patients with metastatic disease and a high tumor burden, antiandrogen monotherapy is inferior to castration. In advanced disease, combined androgen blockade can provide a small survival advantage, which, however, has to be balanced against increased side effects and costs. Conclusions: Antiandrogens are a treatment option in some patients with prostate cancer. However, it has to be taken into account that the hormonal effect is inferior to castration. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Tel. +49 351 4582447; Fax: +49 351 4584333. E-mail address: Manfred.Wirth@uniklinikum-dresden.de (M.P. Wirth). 1. Introduction Since the discovery of the beneficial effect of androgen deprivation by orchiectomy on prostate cancer disease, the stage-corrected survival rates of prostate cancer patients treated by androgen ablation have not been further improved [1,2]. Regardless of the obvious symptomatic benefit in advanced disease, definite evidence for any prolongation of survival by endocrine treatment not combined with curative local treatment (radical prostatectomy or external beam radiotherapy) is still lacking. Early 0302-2838/$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.08.043

european urology 51 (2007) 306 314 307 Table 1 Pros and cons of different modalities of hormonal treatment for prostate cancer Treatment modality Pro Con Orchiectomy low long-term costs high short-term costs definitive androgen ablation surgical complications possible no problems with compliance psychological side effects, cognitive decline long term side effects (anaemia and osteoporosis) loss of libido and potency loss of physical activity loss of muscle mass, weight gain hot flushes irreversible measure LHRH analogues preservation of body integrity side effects comparable with surgical castration temporary treatment possible flare-up phenomenon treatment reversible high long-term costs regular contact with physician LHRH antagonists no flare-up phenomenon anaphylaxis Nonsteroidal antiandrogens Steroidal antiandrogens Maximal (combined) androgen blockade temporary adjuvant or intermittent therapy possible preservation of sexual function possible oral applicability, partially once daily favourable tolerability profile osteoporosis probably less frequent step-up treatment possible treatment reversible temporary adjuvant or intermittent therapy possible oral applicability step-up treatment possible treatment reversible blockade of both testicular and adrenal androgens possible small survival advantage treatment reversible high long-term costs (bicalutamide) gynecomastia and breast pain frequent hepatotoxicity and diarrhoea (especially flutamide) non-compliance less effective in high tumor burden (metastatic disease) limited approval side effects comparable with surgical castration inferior to castration in terms of time to progression hepatotoxicity with long term use limited approval combined side effects of castration and oral antiandrogens high long-term costs Estrogens treatment reversible cardiovascular toxicity low costs oral applicability studies demonstrated a survival advantage, but these studies do not meet contemporary requirements for comparative clinical trials any more and can therefore not be regarded as conclusive [1]. Surgical or chemical castration is accompanied by adverse effects and results in a decrease in quality of life if undertaken early in the course of the disease (Table 1). Most patients with metastatic prostate cancer will develop hormone-refractory disease within 12 to 18 months. Longer response periods may be expected when hormonal treatment is started at earlier stages [3,4]. Long-term androgen deprivation, however, increases the risk of adverse effects such as osteoporosis and pathologic fractures [5]. Prostate cancer today is diagnosed with increasing frequency in physically and sexually active younger men and although prostate cancer is increasingly detected in localized and potentially curable tumor stages [6], a considerable proportion of patients will experience treatment failure and will become candidates for hormonal treatment [1]. Therefore, considerable effort has been undertaken to assess the effect of early, adjuvant or neoadjuvant hormonal manipulations and to decrease the side effects of this treatment modality [3]. This article summarizes the current role of antiandrogens in the treatment of prostate cancer. 2. Properties and side effects of currently available antiandrogens Nonsteroidal antiandrogens (bicalutamide, flutamide, nilutamide) competitively inhibit the binding of androgens to the androgen receptor. As a consequence, the serum testosterone levels are

308 european urology 51 (2007) 306 314 Table 2 Properties and side effects of the currently available antiandrogens Bicalutamide Flutamide Nilutamide Cyproterone acetate Half-life: 7 days 5 6 hours 2 days 30 40 hours Dosage: 150 mg daily * 3 250 mg daily 3 100 mg daily y 3 100 mg daily Side effects: hepatotoxicity (rarely) hot flushes breast tenderness gynaecomastia (70%) nausea diarrhoea impotence (20%) diarrhoea hepatotoxicity (more frequent than other antiandrogens, may be fatal) impotence (20%) gynaecomastia visual disturbances (delayed adaptation to darkness, 33%) z alcohol intolerance (20%) z nausea hepatotoxicity (rarely, may be fatal) interstitial pneumonitis8 impotence (50%), lower testosterone levels loss of libido impotence (80%) rarely gynaecomastia cardiovascular toxicity (4 40% ) hepatotoxicity (may be fatal) * Monotherapy, 50 mg daily when combined with LHRH agonists. y Not licenced for monotherapy. z Not seen with other non-steroidal antiandrogens. Hypotension, tachycardia, heart failure, syncope, myocardial infarct, haemorrhage, cerebrovascular accident, cardiovascular disorder, retinal vascular disorder, embolus, pulmonary embolism, superficial and deep thrombophlebitis, thrombosis, retinal vein thrombosis, phlebitis, vascular headache, shock. not suppressed and may even increase. In contrast, the only available steroidal antiandrogen cyproterone acetate in addition to antiandrogenic also has progestational and antigonadotrophic properties. Its application via a feedback suppression of pituitary LHRH release thus leads to a reduction of serum testosterone levels. Cyproterone aceteate medication in contrast to the use of non-steroidal antiandrogens, thus results in the suppression of libido and erectile function and causes side effects similar to castration [7]. Bicalutamide is the most extensively studied nonsteroidal antiandrogen [7]. Compared to LHRH agonist treatment bicalutamide monotherapy results in reduced fat accumulation, increased bone density and fewer bothersome adverse effects both in animal studies [8] as well as clinically [9,10]. However, gynecomastia and breast pain are frequent side effects of bicalutamide monotherapy and occur in 70 80% of patients [11 13]. This can partially be prevented by local radiotherapy or tamoxifen treatment. In randomised studies, tamoxifen prevented gynecomastia effectively (odds ratio 0.1, p = 0.0009), whereas prophylactic breast irradiation reduced the incidence of gynecomastia by about 50% (odds ratio 0.51, p = 0.008),[14,15]. Tamoxifen did not add meaningful toxicity to bicalutamide monotherapy [15].It is, however, still unclear what effect the estrogenantagonist tamoxifen has on prostate cancer. Therefore, the routine use of tamoxifen to prevent gynecomastia cannot be recommended at present while the use of prophylactic or therapeutic breast irradiation is established. After the development of bicalutamide-induced gynecomastia and/or breast pain, about one third of patients may be expected to benefit from breast irradiation (two fractions of 6 Gy) [16]. Another problem of non-steroidal antiandrogens is the interaction with other drugs due to interference with plasma protein binding. The use of antiandrogens in patients taking drugs with high plasma protein binding such as warfarin, phenytoin or theophylline will increase the free drug serum concentration of these substances which may result in increased effects or side effects of these drugs [17]. Table 2 summarizes the properties and side effects of the four antiandrogens in clinical use. There are relatively few data available for nilutamide. Although direct comparisons are not available, compared to the other antiandrogens bicalutamide seems to have some advantages in terms of the side effect profile. Hepatotoxicity, the most serious side effect of nilutamide, flutamide and cyproterone acetate is relatively uncommon with bicalutamide. This relative advantage of bicalutamide is partially outweighed by the high rate of gynecomastia. Taken together, the side effect profile of non-steroidal antiandrogens compares favourably with castration, nevertheless, uncritical long-term use is inappropriate and harbours the risk of adverse events and even decreased survival [18]. Intermittent LHRH analogue treatment is an alternative to antiandrogens to reduce side effects caused by castration. Osteoporosis can also be prevented by bisphosphonate treatment. 3. Antiandrogen monotherapy 3.1. Locally advanced or metastatic disease In two combined randomised trials involving 480 patients with locally advanced non-metastatic

european urology 51 (2007) 306 314 309 disease (clinical stages T3-T4N0M0), bicalutamide monotherapy (150 mg daily) was compared with castration. After a median follow-up of 6.3 years, there was no detectable difference concerning time to progression or overall survival [19]. This study, however, was not able to demonstrate equivalence between both treatments since the upper 1-sided 95% confidence interval was greater than the value of 1.25 needed to reject the hypothesis that bicalutamide was at least 25% inferior to castration [19]. Thus, there was no unequivocal proof in this trial that bicalutamide monotherapy was equally effective as castration treatment. Advantages for bicalutamide monotherapy, however, were observed concerning sexual interest and physical capacity although detailed data on sexual potency were not reported [19]. Other studies suggest that approximately one third of patients receiving 150 mg bicalutamide daily maintain sexual function during long term treatment [20]. In a prospective randomised study including 220 patients with stage C or D prostate cancer, bicalutamide monotherapy (150 mg daily) was compared to combined androgen blockade. Patients in the bicalutamide arm underwent castration at disease progression. Again, there were no detectable differences concerning disease-specific or overall survival [21] while subgroup analysis suggested an unexplained increased overall mortality in patients with high-grade disease treated with bicalutamide only [21]. Tyrrell and co-workers compared bicalutamide monotherapy (150 mg daily) with castration as treatment for locally advanced non-metastatic or metastatic prostate cancer (n = 1453). Bicalutamide monotherapy was as effective as castration in nonmetastatic patients, but there was a small survival advantage for castration in the M1 subgroup. This difference was perhaps partially outweighed by a better tolerability profile and a higher quality of life in patients treated with bicalutamide monotherapy [22]. Thus, after adequate patient information, bicalutamide monotherapy is an option for younger and sexually active patients with locally advanced disease and in selected patients with metastatic prostate cancer. In men with a high disease burden (PSA values >400 ng/ml), castration definitely remains superior to antiandrogen monotherapy [23,24]. Schröder and co-workers reported the final results of a randomised EORTC trial comparing flutamide versus cyproterone acetate monotherapies in men with metastatic prostate cancer and favourable prognostic factors [25]. They found no significant difference between the two treatment arms concerning time to progression, diseasespecific or overall survival. The side effect analysis favoured cyproterone acetate regarding gynecomastia, diarrhoea and nausea [25]. In a phase III study of metastatic prostate cancer treatment with combined androgen blockade (goserelin acetate plus cyproterone acetate) versus goserelin acetate alone or cyproterone acetate alone with 525 patients, monotherapy with the antiandrogen cyproterone acetate was inferior to LHRH monotherapy in delaying time to progression (difference in the median delay of time to progression was 3 months, p < 0.02) [26]. Current recommendations of the American Society of Clinical Oncology therefore do not recommend the use of cyproterone acetate for monotherapy [27,28]. The supplementation of antiandrogen monotherapy with a 5a-reductase inhibitors is possible. It has been suggested that such a combination treatment may increase the antiandrogenic activity with low additional toxicity. About one third of patients treated in this way may be expected to maintain spontaneous erections [29]. No data on the longterm efficacy of such treatment regimens has been reported and this combination increases treatment costs considerably. 3.2. Adjuvant and primary antiandrogenic treatment in early prostate cancer Again, bicalutamide is the most extensively studied drug for this application. In the ongoing Early Prostate Cancer Program (EPC) bicalutamide is being evaluated as an adjuvant treatment for early prostate cancer (stages T1b-4N0-1M0), whereby antiandrogenic monotherapy together with watchful waiting as a primary treatment strategy is also defined as adjuvant. The program consists of three double-blind, parallel-group, placebo-controlled trials (North America, (trial 23, n = 3292), Europe/ rest of world (trial 24, n = 3603), Scandinavia (trial 25, n = 1218) [11,30]. While in the North American trial, all patients underwent curative treatment prior to study entry, watchful waiting was allowed as primary treatment besides radical prostatectomy or radiotherapy in trials 24 and 25 and in the Scandinavian trial comprised 82% of patients [11,30]. The study treatment was given for two years or until disease progression in trial 23 and until disease progression in trials 24 and 25. A maximum treatment duration of five years was recommended for patients receiving treatment adjuvant to curative measures [18,31]. Becauseof these differences in treatment schedules and in

310 european urology 51 (2007) 306 314 patient selection, the results of a combined analysis of the three studies have to be interpreted with caution. Time to objective clinical progression and survival were the primary study end points, time to treatment failure, PSA progression and toxicity as secondary end points. Side effects (gynecomastia/ breast pain) were the most common reason for discontinuation of treatment in the bicalutamide group and disease progression in the placebo group [11]. At the time of the most recently published analysis, at a median follow-up of 7.4 years, there was no benefit in progression-free survival for the bicalutamide group in the entire study population [18]. There was even a trend towards decreased overall survival for localized prostate cancer under watchful waiting when treated with bicalutamide (hazard ratio 1.16, 95% confidence interval 0.99 1.37, p = 0.07). In all patients with locally advanced disease, however, bicalutamide significantly improved progression-free survival irrespective of the primary treatment applied. Overall survival in patients with locally advanced disease was improved in the bicalutamide group only in patients treated by radiotherapy (hazard ratio 0.65, 95% confidence interval 0.44 0.95, p = 0.03) and these patients had a lower risk of prostate cancer-related mortality. In the bicalutamide group of patients with locally advanced disease under watchful waiting overall survival was not significantly improved (hazard ratio 0.81, 95% confidence interval 0.66 1.01, p = 0.06) nor was any survival difference seen in the radical prostatectomy subgroup [18]. Overall, the currently available data from the ongoing EPC studies suggest that early or adjuvant hormonal therapy is not beneficial in patients with localized disease while it seems of proven benefit in prolonging progression-free survival in patients with locally advanced disease irrespective of the primary treatment and in prolonging overall survival in patients undergoing primary radiotherapy [18,31]. 4. Combined androgen blockade The superiority of combined ( complete ) androgen blockade (i.e. the combination of an antiandrogen with orchiectomy or medical castration) as the primary treatment for advanced prostate cancer has not been proven conclusively up to date despite a large number of randomised trials [32,33]. A metaanalysis of 20 trials found no differences between combined androgen blockade and castration when 2-year overall survival was evaluated. Based on the 10 trials with available 5-year survival data, this same meta-analysis, however, did show a significant survival advantage for combined androgen blockade [32]. No evidence is available supporting a greater benefit of combined treatment in patients with favorable prognostic factors. Combined androgen blockade using a non-steroidal antiandrogen tends to be superior to those using cyproterone acetate in delaying progression [26,32,33]. The limited advantage of combined treatment over monotherapy must, however, be balanced against higher side effects and costs. The additional costs for one quality-adjusted life-year gained by using combined androgen blockade over orchiectomy alone has been estimated to be US$1 million [Prostate Cancer Trialists Collaborative Group 2000]. Combined androgen blockade is an option for patients with advanced or metastatic prostate cancer. It is, however, not the standard form of androgen ablative therapy for primary application [33]. 5. Adjuvant treatment after radiotherapy or radical prostatectomy A great body of data from prospective randomised trials supports the use of adjuvant hormonal treatment after external beam radiotherapy. High-risk patients with locally advanced disease or positive lymph nodes seem to benefit from immediate androgen deprivation after external beam radiotherapy whereas in earlier stages the differences tend to diminish [27]. The beneficial effect of adjuvant hormonal therapy in the external beam radiotherapy setting has been attributed to an elimination of occult metastases and to a potential additive effect by induction of apoptosis [34]. It is, however, still unknown to which degree the observed survival advantages may be attributed to hormonal therapy alone. Data from the Bicalutamide Early Prostate Cancer Program suggest that bicalutamide monotherapy may possibly be similarly effective as castration in the adjuvant setting after radiotherapy [18], randomised comparisons are, however, not available up to date. Conclusive evidence from randomised studies on the efficacy of adjuvant endocrine treatment and particularly of adjuvant antiandrogen treatment after radical prostatectomy is still lacking. In patients with positive lymph nodes, a small randomized study demonstrated a survival advantage for immediate hormonal therapy (castration) versus treatment at metastatic or symptomatic progression

european urology 51 (2007) 306 314 311 [35]. In a multicentric randomised trial of 352 patients with locally advanced, lymph node-negative prostate cancer after radical prostatectomy, adjuvant flutamide was compared to no adjuvant treatment. Tumor progression was significantly delayed in the flutamide arm ( p = 0.0041) but there was no difference in overall survival after a median follow-up of 6.1 years ( p =0.92)[36]. Similarly, the EPC studies on bicalutamide have so far only shown a delay in PSA-defined progression without any effect on overall survival in patients after radical prostatectomy (see above). 6. Neoadjuvant treatment prior to radiotherapy or radical prostatectomy Prior to radical prostatectomy, neoadjuvant hormonal treatment is not recommended for routine clinical use [23]. In patients with locally advanced prostate cancer selected for external beam radiotherapy, however, in one radomised trial, neoadjuvant combined androgen blockade (flutamide and goserelin) significantly improved local control, progression rate and overall survival in the Gleason score 2 6 subgroup [37]. Comparable evidence is not available for antiandrogenic monotherapy. Considering the prostate volume reduction, bicalutamide monotherapy seems to be less effective than LHRH analogues [38]. 7. Step-up hormonal treatment Because of the uncertainties surrounding the timing, side effects and costs of hormonal treatment, alternative treatments especially in patients with a low tumor burden have been considered. The socalled step-up treatment (stepwise escalation of androgen withdrawal, for instance starting with an antiandrogen and later adding a 5-a-reductase inhibitor) is frequently used in clinical practice. However, hardly any studies investigating this treatment option have been published. Oh and coworkers treated patients with PSA relapse after curative treatment or newly diagnosed metastatic disease initially with flutamide and finasteride. The authors suggested that such a strategy is feasible and effective in terms of PSA control. All patients who failed under the initial oral regimen experienced more than 50% decline in PSA when eventually androgen ablation treatment was undertaken [29]. Randomized studies comparing step-up hormonal treatment with early or deferred conventional androgen deprivation might be of considerable clinical interest. 8. Prevention of flare-up phenomenon in patients receiving LHRH agonists When given for the first time, long-acting LHRH agonists cause a transient testosterone increase by stimulating pituitary LHRH receptors. This so called flare-up phenomenon may cause fatal complications in patients with far advanced disease. Simultaneous antiandrogen application may decrease the incidence of initial disease progression. It has been recommended to start such treatment at the same day as the first LHRH analogue depot injection and maintain it for a two week period. In high risk patients (impending spinal cord compression), however, surgical castration should be preferred [23]. 9. Antiandrogen withdrawal syndrome and secondary hormonal manipulations Failure after initial hormonal treatment does not necessarily mean treatment refractory disease progression. Secondary hormonal manipulations are a safe and effective but short-term option in patients with failure after primary hormonal therapy [4]. Whenanantiandrogenispartofthe treatment regimen, discontinuation may result in the so-called antiandrogen withdrawal syndrome, described for the first time by Kelly and Scher [39]. The incidence of this effect has been reported to be 15 to 20% and it lasts for five months on average [4]. Replacement of an initially given antiandrogen by an alternative substance may also result in a PSA response [40]. Mutations in the androgen receptor gene are supposed to account for this phenomenon by enabling the antiandrogens to act as receptor agonists [41]. Similar observations were reported after replacement of bicalutamide or flutamide as part of a failing combined androgen blockade by nilutamide [42]. After initial antiandrogen monotherapy, orchiectomy at the time of failure of initial treatment may lead to a PSA response and to symptomatic improvement [43]. Second-line treatment with bicalutamide has been shown to improve symptoms and decrease pain in patients without prior antiandrogen therapy [4]. A 50% PSA decrease has been described after second line treatment with nonsteroidal antiandrogens in 14 50% of cases [4]. Responders to second-line hormonal treatment may be expected to survive significantly longer than non-responders [40]. Overall, however, it is still doubtful whether secondary hormonal manipulations do actually improve survival [4].

312 european urology 51 (2007) 306 314 However, the suppression of testicular androgens should be continued when the disease is hormone refractory, since a withdrawal of treatment may decrease survival [4]. 10. Conclusions Antiandrogens are an established treatment option in patients with prostate cancer either as monotherapy or in combination with LHRH analogues. In patients with a limited tumor burden, non-steroidal antiandrogen monotherapy seems as effective as castration. Antiandrogens which preserve testosterone levels can also preserve libido and sexual function in previously sexually active patients. Thus some side effects of castration may be avoided by antiandrogen monotherapy, but frequent gynecomastia (bicalutamide) and the risk of hepatotoxicity (cyproterone, nilutamide, flutamide) and a hitherto unexplained trend towards increased mortality when given to patients with localized prostate cancer prohibit their uncritical use. 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314 european urology 51 (2007) 306 314 Editorial Comment Steven P. Balk, Glenn J. Bubley, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States sbalk@bidmc.harvard.edu Mary-Ellen Taplin, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States This article is a timely review of androgen receptor antagonist (antiandrogen) clinical trials and the current role of these drugs in prostate cancer treatment. The nonsteroidal antiandrogens were widely used in the late 1970s and 1980s in combination with orchiectomy or luteinising hormone-releasing hormone (LHRH) agonist therapies (combined androgen blockade) to prevent androgen receptor activation by residual adrenal androgens, but randomised trials showed only a small survival advantage with increased toxicity. These results led to a marked decline in the initial use of antiandrogen combination therapies and the conclusion that complete androgen receptor blockade is not more effective than monotherapy. However, it now appears clear that the androgen receptor is reactivated and largely refractory to antiandrogens in prostate cancers that relapse subsequent to androgen-deprivation therapy, indicating that complete androgen receptor blockade is not achieved with currently available antiandrogens and that more potent antagonists (possibly functioning through alternative mechanisms such as androgen receptor degradation) may be more effective [1]. Antiandrogens (primarily bicalutamide) have also been examined as initial monotherapy and appear comparable to castration in some stages of disease, although high doses may be required. In contrast, bicalutamide monotherapy may be inferior to placebo in patients in watchful waiting therapy and inferior to castration in patients with greater disease burden (and may therefore be less effective in patients with short prostate-specific antigen doubling times). Nonetheless, as emphasised in the review, bicalutamide may be preferable in some patients due to a better side effect profile than castration (likely reflecting, in part, normal or increased levels of testosterone, which can be converted to estrogen by aromatase) [2]. However, it should be emphasised that these hormonal differences could also affect efficacy, including the apparent synergy between radiation and androgen deprivation [3]. Based on these observations, it is prudent to limit hormonal therapy (antiandrogen or castration) to patients who have been shown to benefit [4], to consider intermittent androgen-deprivation therapyasanalternative, andtouseantiandrogenmonotherapy cautiously in cases where its efficacy has not been directly compared to castration. References [1] Scher HI, Sawyers CL. Biology of progressive, castrationresistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005;23: 8253 61. [2] Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 2004;22:2546 53. [3] D Amico AV, Manola J, Loffredo M, Renshaw AA, Della- Croce A, Kantoff PW. 6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004;292:821 7. [4] Loblaw DA, Mendelson DS, Talcott JA, et al. American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol 2004;22:2927 41.