Localised and Locally Advanced Prostate Cancer: Who to Treat and How?

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1 european urology supplements 6 (2007) available at journal homepage: Localised and Locally Advanced Prostate Cancer: Who to Treat and How? David Gillatt a, *, Laurence Klotz b, Colleen Lawton c, Kurt Miller d, Heather Payne e a Department of Urology, Southmead Hospital, Bristol, United Kingdom b Department of Urology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, Canada c Radiation Oncology Clinic, Medical College of Wisconsin, Milwaukee, WI, United States d Department of Urology, Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany e Department of Urology, University College London Hospitals NHS Foundation Trust, London, United Kingdom Article info Keywords: Casodex TM (bicalutamide) Localised prostate cancer Locally advanced prostate cancer Radiotherapy Abstract Prostate cancer is the third most common cause of male death in Europe. In 2004, prostate cancer accounted for 85,200 deaths, equating to 8.9% of all male cancer deaths. In recent years, heightened awareness of the disease and increased prostate-specific antigen screening have resulted in an overall rise in the incidence of prostate cancer detection, with more young men presenting with earlier stage (ie, localised or locally advanced) disease. For many patients diagnosed with prostate cancer, especially for those who wish to maintain an active life, quality of life is of paramount importance. The challenge, therefore, is to identify which patients will benefit most from the different treatment options available. In this article we present two clinical scenarios to facilitate discussion of the treatment options available for two patients one with localised disease and another with asymptomatic locally advanced disease who are both anxious to avoid death from prostate cancer. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Southmead Hospital, Bristol, BS10 5NB, United Kingdom. Tel. +44 (0) ; Fax: +44 (0) address: davidgillatt@aol.com (D. Gillatt). 1. Introduction In Europe in 2004, prostate cancer was the second most frequent type of cancer in men, with 237,800 new cases estimated that year (15.5% of all cases of cancer) [1]. Prostate cancer was also the third most common cause of male death in Europe in 2004, accounting for 85,200 deaths (8.9% of all cancer deaths in men) [1]. At present, the overall incidence of prostate cancer is rising (albeit at a slower rate than in previous years) due to increased awareness of the disease and earlier detection by prostatespecific antigen (PSA) screening [2]. As a consequence, more men are now presenting with an earlier stage of disease (localised and locally advanced prostate cancer) and at a younger age. An increasing problem with the early detection of prostate cancer, particularly for those patients with localised disease whose tumours are confined to the prostate, is overstaging and overdiagnosis. It has been estimated that among patients with detectable prostate cancer that would prove lethal by the age of /$ see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 european urology supplements 6 (2007) yr, only 16% would actually die from the disease (most dying of other causes) [3]. Therefore, for patients with localised disease who have a low risk of prostate cancer death, deferring radical treatment until early disease progression may have quality-oflife benefits, because any tolerability issues associated with active treatment will be delayed [4,5]. However, for those patients who are more likely to die from prostate cancer, a policy of waiting until metastatic disease develops may deny the patient treatment of curative intent (radical prostatectomy or radiotherapy). In contrast to patients with localised disease, patients with locally advanced disease whose tumours have extended through the prostatic capsule have an increased risk of positive surgical margins, lymph node metastases, distant relapse and, consequently, death from prostate cancer [6]. These patients, therefore, may benefit from immediate and more aggressive treatment than those with localised disease, to reduce the risk of disease progression and the probability of prostate cancer death [7]. When choosing a treatment for localised or locally advanced prostate cancer, quality of life is an important issue, especially for men who wish to maintain an active life. Physicians should consider each patient on an individual basis and discuss the advantages and disadvantages of all the available treatment options, to ensure they provide a treatment regime that is appropriate to the patient s lifestyle. Here we present two clinical scenarios describing patients who are anxious to undergo treatment of curative intent and discuss the optimal treatments for these types of patients. In the first scenario, the patient has localised disease, and in the second scenario, the patient has asymptomatic locally advanced disease. 2. Clinical scenario I: a patient with localised prostate cancer In the first clinical scenario, our patient opted to have a PSA test after three of his friends had been diagnosed with prostate cancer and one had died of the disease. The initial presentation of this patient is shown in Box Treatment options According to data for survival and cumulative mortality from prostate cancer, a patient yr of age with a Gleason score of 6 has an approximate 1 in 4 chance of dying of prostate cancer 20 yr after Box 1. Presentation of patient in clinical scenario I 63-yr-old married man Prostate-specific antigen level 11.8 ng/ml Digital rectal examination was normal Biopsy showed Gleason score 6 (3+3) with 25% of cancer on right-hand side of the prostate (3/6 cores on right-hand side; 0/6 cores on left-hand side) The patient is continent, potent, and anxious to avoid prostate cancer death his diagnosis when managed with observation or androgen withdrawal alone [8]. Given this relatively low risk of prostate cancer death after 20 yr, a policy of active surveillance until early disease progression would be an option for our patient. Our patient, however, is anxious to avoid prostate cancer death; therefore, radical prostatectomy or radiation therapy (external beam or brachytherapy) may be more appropriate because they are primary curative procedures for the treatment of localised prostate cancer. Staging algorithms, such as the Partin tables, combine preoperative serum PSA level, clinical stage (TNM classification), and biopsy Gleason score to predict the likelihood of various final pathologic stages after surgery [6,9]. According to these tables, the patient discussed here would have a 62% chance of his cancer remaining organ-confined after radical prostatectomy [9]. The tables also predict that he would have a 33% chance of extraprostatic extension and a minimal risk (2 4%) of positive seminal vesicles and positive lymph nodes (Table 1) [9]. Radical prostatectomy would, therefore, be a viable option for the patient given the high chance of the cancer remaining organ confined, as indicated by the Partin tables. The efficacy of radical prostatectomy has also been demonstrated in a randomised controlled trial (n = 695) comparing radical prostatectomy with no treatment (watchful waiting). At a median follow-up of 8.2 yr, radical prostatectomy significantly reduced the risk of death by 44% compared with watchful Table 1 Partin prediction of pathologic stage after surgery for a patient with a T1c, nonpalpable tumour, a PSA level >10 ng/ml and a Gleason score of 5 6 [9] Case notes % risk (95% confidence interval) Organ-confined disease 62 (58 64) Extraprostatic extension 33 (30 36) Positive seminal vesicles 4 (3 5) Positive lymph nodes 2 (1 3) PSA = prostate-specific antigen.

3 336 european urology supplements 6 (2007) waiting (hazard ratio 0.56; 95% confidence interval [CI] ; p = 0.01) [10]. In addition, the greatest reduction in prostate cancer deaths was in the subset of patients who were <65 yr of age [10]. External-beam radiotherapy (EBRT) is also a curative procedure for the treatment of localised prostate cancer. It is known that increased radiation dose is associated with increased cancer cell death, but due to concerns over normal tissue toxicities, conventional doses have been limited to 70 Gy. New technologic advances have improved the precision of EBRT and, therefore, permitted the delivery of higher doses of radiation than was previously possible. The use of three-dimensional conformal radiotherapy (3D-CRT) has allowed doses >70 Gy to be delivered to the whole prostate, by reducing doses to the surrounding normal tissue with the intention of improving outcomes. This has been demonstrated in a randomised dose-escalation trial where an increase in radiation dose from 70 Gy to 78 Gy improved freedom from failure in patients with stage T1-3 prostate cancer (64% vs. 70%, respectively, p = 0.03) [11]. However, treatment of >25% of the rectal volume with 70 Gy of radiation was associated with increased rectal complications [11]. Dose escalation, therefore, appears to improve patient outcome but, because higher radiation doses can increase the risk of rectal gastrointestinal toxicity, 3D-CRT or intensity-modulated radiotherapy should be used. Brachytherapy is also a curative option; patients who undergo brachytherapy for the management of localised prostate cancer have been reported to have a 10-yr disease-specific survival rate of 98% [12] and a 3-yr biochemical failure rate of 3 5% [13]. Newer treatments such as cryotherapy and high-intensity focused ultrasound (HIFU) should, however, still be considered exploratory because they lack long-term efficacy data and both have high morbidity rates in terms of impotence and urinary incontinence [14 16]. Hormonal therapy alone is not usually recommended in localised disease. In the Early Prostate Cancer (EPC) programme, the addition of the nonsteroidal antiandrogen Casodex TM (bicalutamide) 150 mg to standard care (radical prostatectomy, radiotherapy, or watchful waiting) in patients with T1-2, N0/Nx prostate cancer showed no benefit in terms of progression-free survival (PFS) and overall survival compared with standard care alone [17]. Interestingly, adjuvant combined androgen blockade (CAB) following 3D-CRT can confer a survival benefit in some patients with high-grade (Gleason score 7 or PSA 10 ng/ml), clinically localised disease. In a study by D Amico et al [18] comparing 3D-CRT alone with 3D-CRT plus 6 mo of CAB (luteinising hormone-releasing hormone [LHRH] agonist plus nonsteroidal antiandrogen), there was a significant overall survival advantage at 4.52 yr of follow-up for patients who received CAB ( p = 0.04). In addition, there were significant advantages in terms of PSA failure ( p < 0.001), PFS ( p < 0.004), and prostate cancer-specific death ( p = 0.02). Therefore, for some patients with highgrade localised disease, 6 mo of adjuvant CAB may offer benefits over radiotherapy alone. To help clarify the optimal treatment for patients with localised disease, trials such as Surveillance Therapy Against Radical Treatment (START) and Prostate Testing for Cancer and Treatment (Pro- TeCT) are currently ongoing. START is comparing active surveillance with radical prostatectomy and radiotherapy (brachytherapy or EBRT) in patients with T1b-2b, Gleason score <6, PSA level <10 ng/ml prostate cancer. ProTeCT is comparing radical prostatectomy with radiotherapy and active surveillance in patients with T1-2, any Gleason score, and PSA level <20 ng/ml prostate cancer Summary The standard treatment options for a patient with localised disease would be active monitoring, radical prostatectomy, brachytherapy, or EBRT. In our clinical scenario, the patient is anxious to avoid prostate cancer death, so radical prostatectomy or radiotherapy may be more appropriate than active monitoring. Newer treatments such as cryotherapy and HIFU lack long-term efficacy data and so should still be considered experimental. Hormonal therapy alone would not be recommended in this patient. In a poll of 746 specialists, >70% of respondent urologists and oncologists (clinical, medical, and radiation) said they would recommend curative treatment with radical prostatectomy for this patient [19]. The high percentage of respondents recommending surgery probably reflects the high proportion of urologists in the audience compared with oncologists (74% vs. 8%). Among the radiation oncologists polled, opinions were divided between EBRT (34% of radiation oncologists), brachytherapy (33% of radiation oncologists), and radical prostatectomy (20% of radiation oncologists). The poll data reflect that most of the specialists polled would offer treatment of curative intent. However, when discussing the treatment options with a patient with localised disease, it is important that they are informed of the possible overall survival advantage with immediate active treatment as well as the

4 european urology supplements 6 (2007) potential quality-of-life benefits with deferred treatment, so that treatment options can be matched to their individual needs and lifestyle. 3. Clinical scenario II: a patient with locally advanced prostate cancer The initial presentation of the patient in our second clinical scenario is shown in Box Treatment options The patient was diagnosed as having ct3 prostate cancer. Although the results of the digital rectal examination (DRE) were normal, the patient was diagnosed with locally advanced prostate cancer on the basis of transrectal ultrasound-guided biopsy (TRUS). This finding highlights the importance of using a combination of DRE and TRUS in diagnosis [20]. Based on the initial presentation described for our clinical scenario (Box 2), the Partin tables predict that there is only a 6% likelihood of the patient s cancer being organ-confined after surgery [6]. His risk of developing extraprostatic extension, positive seminal vesicles, and positive lymph nodes after surgery is also high (26 40%; Table 2) [6]. Surgery alone, therefore, may be insufficient as a local control and the patient is likely to need additional radiotherapy. As with surgery, radiotherapy alone is unable to eradicate micrometastatic disease. There are data to support the use of combination therapies, such as brachytherapy plus EBRT and the addition of adjuvant radiotherapy to radical prostatectomy in patients with locally advanced disease (Table 3) [21,23,25,26]. Most evidence, however, supports the addition of hormonal therapy to radiotherapy, with Casodex 150 mg and the LHRH agonist Zoladex TM (goserelin acetate) being the most widely studied agents (Table 3) [7,17,28,30,31,33 35]. Key data that show the advantages of adding hormonal therapy to Box 2. Presentation of patient in clinical scenario II 50-yr-old married man Prostate-specific antigen level 12 ng/ml Digital rectal examination was normal Transrectal ultrasound-guided biopsy revealed Gleason score 7 (4+3) with cancer on both sides of the prostate (2/5 cores on right-hand side; 3/5 cores on left-hand side) Clinical suspicion of infiltration of the capsule ct3 disease The patient has asymptomatic disease Table 2 Partin prediction of pathologic stage after surgery for a patient with ct3 disease, a PSA level ng/ml, and a Gleason score of 7 [6] Case notes % risk (95% confidence interval) Organ-confined disease 6 (3 10) Extraprostatic extension 40 (30 50) Positive seminal vesicles 28 (18 39) Positive lymph nodes 26 (16 38) PSA = prostate-specific antigen. radiotherapy or radical prostatectomy are described in the following sections Radical prostatectomy plus hormonal therapy In the Eastern Cooperative Oncology Group (ECOG) 7887 trial at a median follow-up of 11.9 yr, patients who underwent radical prostatectomy and pelvic lymphadenectomy and were found to have nodepositive disease were randomised to receive either immediate (adjuvant) castration (70% received Zoladex, 28% orchiectomy, 2% refused treatment) or observation until they developed distant metastases or symptomatic recurrences [28]. Although this study closed because of a lack of accrual (n = 100 of a planned 220), those patients who received immediate castration showed a significant reduction in the risk of disease progression ( p < ) and death ( p = 0.04) compared with radical prostatectomy alone (Fig. 1A) [28]. Casodex 150 mg has also been shown to have clinical benefits adjuvant to radical prostatectomy in patients with locally advanced disease (Fig. 1B). In the EPC programme at a median follow-up of 7.6 yr, Casodex 150 mg adjuvant to radical prostatectomy significantly reduced the risk of objective progression compared with radical prostatectomy alone ( p = 0.004) [36] Radiotherapy plus hormonal therapy The addition of hormonal therapy to radiotherapy has been shown to improve overall survival in several large studies. For example, Bolla et al demonstrated that Zoladex given adjuvant to radiotherapy significantly improved overall survival compared with radiotherapy alone ( p < 0.001), reducing the risk of death by 49% [30]. Two recent trials, the Radiation Therapy Oncology Group (RTOG) trial and the EPC programme, with similar median follow-up times (7.6 and 7.2 yr, respectively) and study designs (hormonal therapy was administered as adjuvant treatment in both trials) have published long-term data on the efficacy of hormonal therapy adjuvant to radiotherapy in patients with locally advanced disease [17,31]. In the RTOG trial, Zoladex adjuvant to radiotherapy for 3 yr signifi-

5 338 european urology supplements 6 (2007) Table 3 Frequently used treatments for patients with locally advanced prostate cancer and a summary of the evidence available to support their use Treatment LDR brachytherapy plus EBRT HDR brachytherapy plus EBRT RP as primary treatment with or without adjuvant RT RP as primary treatment with adjuvant HT RT with or without adjuvant HT HT alone Evidence to support use of treatment No prospective randomised trials to support use [21]. Increased genitourinary and gastrointestinal complications have been reported [22]. Data from patients treated at 3 institutions (n = 1260) have shown that at 4.4 yr median follow-up, the 8-yr bned of patients treated with HDR brachytherapy plus EBRT was 81% [23]. The rectal dose from HDR brachytherapy may have a significant impact on the incidence of grade 2 rectal bleeding [24]. In the EORTC trial at 5 yr of median follow-up, RP as primary treatment with adjuvant RT significantly reduced the risk of biochemical progression by 52% (HR 0.48; 98% CI ; p < ) and clinical progression by 39% (HR 0.61; 98% CI ; p = ) vs. RP alone. There was no significant difference in OS. Grade 2 or 3 late effects were greater in the adjuvant RT group ( p = ) but grade 3 toxicity was rare [25]. In the SWOG 8794 trial at 9.7 yr of follow-up, RP with adjuvant RT improved 10-yr relapse-free survival (HR 0.59; p = 0.001) and 10-yr bned (HR 0.71; p < 0.001) vs. observation alone. An improvement in OS and metastasis-free survival was observed but did not reach significance [26]. A 25.2% significant advantage for DFS in favour of Zoladex adjuvant to RP vs. RP alone (5-yr median follow-up; p value not reported) has been published [27]. In the ECOG 7887 trial at 11.9 yr median follow-up, immediate castration * adjuvant to RP significantly reduced the risk of progression by 71% (HR 0.29; 95% CI ; p < 0.001) and significantly reduced the risk of death by 46% (HR 0.54; 95% CI ; p = 0.04) vs. deferred treatment in patients with node-positive disease [28]. In the EPC programme at 7.6 yr median follow-up, Casodex adjuvant to RP significantly reduced the risk of objective progression by 25% vs. RP alone (HR 0.75; 95% CI ; p = 0.004). There was no difference in OS (HR 1.09; 95% CI ; p = 0.51) [17]. In a prospective, randomised trial at 6.1 yr median follow-up, flutamide 750 mg adjuvant to radical RP significantly reduced the risk of progression by 49% vs. RP alone in patients with lymph node-negative prostate cancer (HR 0.51; 95% CI ; p = 0.004). There was no difference in OS (HR 1.04; 95% CI ; p = 0.92) [29]. In the EORTC trial at 5.5 yr median follow-up, Zoladex concomitant and adjuvant to RT significantly reduced the risk of death by 49% vs. RT alone (HR 0.51; 95% CI ; p < 0.001) [30]. In the RTOG trial at 7.6 yr median follow-up, Zoladex adjuvant to RT significantly reduced the risk of death by 23% vs. RT alone (HR 0.77; p = 0.001) [31]. In the EPC programme at 7.2 yr median follow-up, Casodex 150 mg adjuvant to RT significantly reduced the risk of objective progression by 44% (HR 0.56; 95% CI ; p < 0.001) and significantly reduced the risk of death by 35% (HR 0.65; 95% CI : p = 0.03) compared with RT alone [17]. In the EPC programme at 7.4 yr median follow-up, Casodex 150 mg significantly reduced the risk of objective progression by 40% (HR 0.60; 95% CI ; p < 0.001) and showed a trend towards improved OS vs. WW patients (HR 0.81; 95% CI ; p = 0.06) [17]. In the SPCG-6 study (also known as Trial 25 of the EPC programme) at 7.1 yr median follow-up, Casodex 150 mg significantly reduced the risk of objective progression by 53% vs. WW patients (HR 0.47; 95% CI ; p < 0.001). This significant objective PFS benefit observed with Casodex 150 mg was accompanied by a significant reduction in the risk of death by 33% vs. WW patients (HR 0.67; 95% CI ; p = 0.007) [32]. bned = biochemical no evidence of disease (<0.4 ng/ml); CI = confidence interval; DFS = disease-free survival; EBRT = external-beam radiotherapy; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organisation for Research and Treatment of Cancer; EPC = Early Prostate Cancer; HDR = high-dose rate (usually done with high-activity iridium-192 [10-Ci sources]; cobalt sources were previously used; radiation doses delivered over several minutes); HR = hazard ratio; HT = hormone therapy; LDR = low-dose rate (iodine-125 or palladium-103 with half-lives of 60 and 17 d, respectively, and radiation doses delivered over several months); OS = overall survival; PFS = progression-free survival; RP = radical prostatectomy; RT = radiotherapy; RTOG = Radiation Therapy Oncology Group; SWOG = Southwest Oncology Group; WW = watchful waiting. * 70% of patients received Zoladex, 28% received orchiectomy, and 2% refused treatment. cantly reduced the risk of local and distant failure ( p < ) as well as the risk of death ( p = 0.001) compared with radiotherapy alone (Table 3) [31]. This difference in mortality was due to a lower risk of prostate cancer-related deaths (Fig. 2A). Likewise, in the EPC programme, Casodex 150 mg adjuvant to radiotherapy significantly reduced the risk of objective progression ( p < 0.001) and the risk of death ( p = 0.03) compared with radiotherapy alone (Table 3) [17]. This difference in mortality between Casodex 150 mg adjuvant to radiotherapy and radiotherapy alone was again due to a lower risk of prostate cancer-related deaths (Fig. 2B) [17,31]. It appears, therefore, that adjuvant to radiotherapy, Casodex 150 mg has comparable survival to Zoladex [17]. This is consistent with a phase 3 study at a

6 european urology supplements 6 (2007) yr median follow-up that showed no significant difference in overall survival between castration (orchiectomy or Zoladex) and Casodex 150 mg in patients with locally advanced disease [33]. In addition, Zoladex has been associated with improved survival in patients receiving neoadjuvant hormonal therapy. In the RTOG trial, there was a significant overall survival benefit for patients with Gleason score 2 6 disease who received radiotherapy plus neoadjuvant Zoladex followed by adjuvant antiandrogen therapy compared with those who received radiotherapy alone ( p = 0.015) [37]. Furthermore, in the RTOG study, where patients who received radiotherapy with neoadjuvant hormonal therapy were randomised to receive Zoladex (for 2 yr) or no further androgen deprivation, there was a significant improvement in all end points except overall survival with adjuvant Zoladex at 5- and 10-yr follow-up [38,39]. However, in patients who had prostate cancer with a Gleason score of 8 10, Zoladex was associated with a significant improvement in overall survival at the 5-yr follow-up ( p = 0.044). Ten-year follow-up data for patients with a Gleason score of 8 10 are not yet published; however, full publication of these study data is expected in Fig. 1 Clinical benefits of adding hormonal therapy to radical prostatectomy in patients with locally advanced disease. (A) Overall survival of Zoladex adjuvant to radical prostatectomy at 11.9 yr median follow-up (n = 98) [28] (Reprinted from Messing EM, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7:472 9, copyright 2006 with permission from Elsevier Inc). (B) Objective progression-free survival of Casodex 150 mg adjuvant to radical prostatectomy at 7.6 yr median follow-up (n = 1719) [36] Hormonal therapy in patients who would have otherwise undergone watchful waiting In the EPC programme at a 7.4-yr median follow-up in patients with locally advanced disease, Casodex 150 mg significantly improved objective PFS ( p < 0.001) and showed a trend towards improved overall survival ( p = 0.06) compared with those who underwent watchful waiting (Table 3) [17]. Recent data from the Scandinavian Prostate Cancer Group (SPCG-6), one of the three trials within the EPC programme, at 7.1-yr median follow-up showed that the significant objective PFS benefit with Casodex 150 mg compared with watchful waiting ( p < 0.001) was accompanied by a significant overall survival benefit ( p = 0.007; Fig. 3) [34]. It is clear that hormonal therapy plays an integral role in the treatment of locally advanced prostate cancer. Clinical data confirm that it provides significant clinical benefits, particularly when given with radiotherapy, in patients with locally advanced disease. However, the two most widely studied hormonal therapies, Casodex 150 mg and Zoladex, appear to have similar clinical benefits when given adjuvant to radiotherapy, raising the question: Which hormonal therapy should be used? 3.2. Which hormonal therapy? In addition to efficacy, and given the similar overall survival benefits observed with Casodex and Zoladex in locally advanced prostate cancer, quality-oflife benefits are likely to be important considerations when choosing a long-term hormonal therapy. Castration-based therapies are associated with a number of shared effects, namely, hot flushes, a loss of bone mineral density and bone mass, increased bone fracture risk, impotence, and decreased libido

7 340 european urology supplements 6 (2007) Fig. 2 In patients with locally advanced disease, the overall survival benefits observed with (A) Zoladex adjuvant to radiotherapy in RTOG at 7.6 yr median follow-up (n = 977) [31] (Reprinted from Pilepich MV, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma long term results of phase III RTOG Int J Radiat Oncol Biol Phys 2005;61: , copyright 2005 with permission from Elsevier Inc) and (B) Casodex 150 mg adjuvant to radiotherapy in EPC programme at 7.2 yr median follow-up (n = 305) [35] (Reprinted with kind permission of Springer Science and Business Media) were driven by a lower number of prostate cancer deaths. Fig. 3 In patients with locally advanced disease, a significant overall survival benefit was observed with Casodex 150 mg versus watchful waiting patients in the SPCG-6 study (also known as Trial 25 of the EPC programme) at 7.1 yr median follow-up (n = 359) [34] (Reproduced with kind permission of Taylor & Francis). and vitality [7,40 43]. Although the adverse events associated with castration are manageable, in a prospective, multicentre, open-label study, Casodex 150 mg has been shown to maintain bone mineral density, whereas castration was associated with a progressive loss of bone mineral density ( p < at week 96) [40]. In this same study, Casodex 150 mg also showed no deterioration of lean muscle mass, whereas patients undergoing medical castration experienced a trend towards a greater progressive loss over 24 to 48 to 72 weeks ( p = 0.54) [40]. In addition, in two open-label multicentre studies of identical design, Casodex has been shown to offer advantages over castration in terms of maintaining sexual interest and physical capacity [33]. Nonsteroidal antiandrogens, such as Casodex, have a higher incidence of gynaecomastia and breast pain than castration-based therapies [7,33]. In the EPC programme, >90% of men who received Casodex 150 mg experienced mild to moderate gynaecomastia and breast pain; however, these adverse events led to withdrawal of therapy in only 16.8% (676 of 4022) of men [17]. Occurrences of

8 european urology supplements 6 (2007) gynaecomastia and breast pain can be managed effectively with either radiotherapy (therapeutic or prophylactic) or tamoxifen [44 46] Summary Hormone therapy has become the mainstay of treatment of patients with locally advanced prostate cancer. The most widely studied hormonal therapies are Casodex 150 mg and Zoladex, and the published data suggest that both should be considered viable treatment options for this particular patient. In particular, data confirm that Casodex 150 mg or Zoladex adjuvant to radiotherapy offer significant overall survival advantages compared with radiotherapy alone. In a poll of 746 specialists, 48% of respondents recommended radiotherapy with or without hormonal therapy for the patient in our clinical scenario. When this poll result was analysed by speciality, there was some difference in response, with >60% of respondent oncologists (clinical, medical, and radiation) and 43% of respondent urologists recommending radiotherapy [19]. Inthe same poll, approximately 50% of respondent oncologists said they would recommend Zoladex and 51% of respondent urologists recommended Casodex as an adjuvant hormonal treatment for this patient. Most respondents (70%) agreed that hormonal therapy should be initiated immediately, 29% said they would delay hormonal therapy until clinical or disease progression, and the remaining 1% were undecided. Interestingly, when the poll results were analysed by speciality, 100% of medical and clinical oncologists who responded recommended immediate hormonal therapy compared with 65% of urologists and 85% of radiation oncologists. At the meeting where the poll was conducted, the audience members were polled both before and after presentation of the relevant trial data. Interestingly, whereas only 39% of the total number of respondents would have offered radiotherapy (with or without adjuvant therapy) before the data were presented, 48% selected radiotherapy as the best approach to treatment at the end of the session. Overall, these poll results reflect differences in the way in which surgical oncologists and radiation oncologists approach treatment, but also highlight how clear and balanced discussion of data may influence future treatment choices. However, physicians should consider each patient on an individual basis and discuss both the efficacy benefits and treatment-related adverse events of all the available therapeutic options with the patient so that he can make an informed decision about which treatment is best suited to him and his lifestyle. 4. Conclusions The overall incidence of prostate cancer is continuing to rise and more young men are now presenting with localised and locally advanced disease. Quality of life is of paramount importance for most patients, especially those who wish to maintain an active life. Therefore, when making a decision as to which treatment regime should be used, both the advantages and disadvantages of all the available therapies should be discussed with the patient so he can choose a treatment that is appropriate for his lifestyle. Conflicts of interest Mr David Gillatt has worked as a paid consultant and attended advisory boards for AstraZeneca. Professor Laurence Klotz has received honoraria from AstraZeneca, Abbott and Sanofi-Aventis. Professor Colleen Lawton is a paid speaker for AstraZeneca. Professor Kurt Miller has worked as a paid consultant and attended advisory boards for AstraZeneca. Dr Heather Payne has attended advisory boards for AstraZeneca but does not have any commercial interests in the company. Acknowledgements We thank Dr Sarah Goodger, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. References [1] Boyle P, Ferlay J. Cancer incidence and mortality in Europe, Ann Oncol 2005;16: [2] Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2006;56: [3] McGregor M, Hanley JA, Boivin JF, McLean RG. Screening for prostate cancer: estimating the magnitude of overdetection. CMAJ 1998;159: [4] Johansson JE, Andren O, Andersson SO, et al. Natural history of early, localized prostate cancer. JAMA 2004; 291: [5] Klotz L. Active surveillance for prostate cancer: for whom? J Clin Oncol 2005;23: [6] Partin AW, Kattan MW, Subong ENP, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277:

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