How Should WeTreat Patients with Locally Advanced Prostate Cancer?

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1 European Urology Supplements European Urology Supplements 2 (2003) How Should WeTreat Patients with Locally Advanced Prostate Cancer? Malcolm Mason * Section of Oncology and Palliative Medicine, University of Wales College of Medicine, Velindre Hospital, Whitchurch, Cardiff, CF14 2TL, UK Abstract Men with locally advanced prostate cancer are generally offered active treatment (radiotherapy or hormone therapy alone or in combination) with the aim of extending progression-free and overall survival. There is now good evidence from recent studies to suggest that patients who are treated with radiotherapy benefit from the addition of neoadjuvant or adjuvant hormone therapy. However, the extent of the contribution of radiotherapy in patients receiving hormone therapy is unclear, as the trials evaluating this combination approach did not include a hormone therapy only arm. Two ongoing trials, an International Intergroup study involving the National Cancer Institute of Canada (NCIC), the Medical Research Council (MRC), and the National Cancer Institute (NCI) in the United States, and a Scandinavian Prostate Cancer Group (SPCG) trial, are addressing this issue. Results should be available in the latter part of the decade. The optimum nature and schedule of hormone therapy are also unresolved. When hormone therapy is used to treat locally advanced disease, either as adjuvant therapy or immediate monotherapy, patients have traditionally undergone medical (e.g. goserelin [ Zoladex 1 ]) or surgical castration. However, bicalutamide ( Casodex 1 )150mg monotherapy may offer important benefits over castration with respect to quality of life, particularly the maintenance of physical capacity and sexual interest, as well as preservation of bone mineral density and muscle mass, while achieving a similar survival outcome. Nonetheless, the benefits of bicalutamide 150 mg monotherapy must be balanced against the risk of developing gynecomastia and/or breast pain. Patients presenting with locally advanced prostate cancer should be given a clear explanation on all available treatment options and allowed to make an informed choice. # 2003 Elsevier B.V. All rights reserved. Keywords: Prostate cancer; Locally advanced; Hormone therapy; Radiotherapy; Adjuvant; Castration; Goserelin; Bicalutamide; Quality of life 1. Introduction Prostate cancer that is locally advanced, i.e. extends beyond the prostate capsule but without evidence of distant metastases (T3 4, any N, M0 or T1 2, Nþ, M0), is associated with a significant risk of disease progression and cancer-related death [1]. Consequently, patients with locally advanced disease are generally offered active treatment, although some may still prefer to defer treatment and undergo watchful waiting, particularly if they have low-grade disease * Tel. þ ; Fax: þ address: malcolm.mason@velindre-tr.wales.nhs.uk (M. Mason). 1 Zoladex and Casodex are trademarks of the AstraZeneca group of companies. and/or a relatively short life expectancy [2]. There is, however, no consensus on the most appropriate active treatment approach for locally advanced prostate cancer; common options are radiotherapy alone, radiotherapy in combination with hormone therapy (either neoadjuvant and/or adjuvant) and hormone therapy alone. Of these, the combination of radiotherapy with hormone therapy appears to be the most widely used within Europe. A smaller, although still substantial, proportion of patients receive hormone therapy alone. When hormone therapy is employed, there has been a tendency, both in trial and clinical settings, to use medical or surgical castration. The aim of this paper is to explore and cross-examine the evidence for the treatments in common use for locally advanced disease /$ see front matter # 2003 Elsevier B.V. All rights reserved. doi: /j.eursup

2 M. Mason / European Urology Supplements 2 (2003) Outcomes with radiotherapy External-beam radiotherapy has traditionally been the mainstay of treatment for locally advanced prostate cancer. However, the long-term outcome tends to be unsatisfactory when conventional radiotherapy techniques are used in this setting [3]. A meta-analysis of four studies initiated by the Radiation Therapy Oncology Group (RTOG) between 1977 and 1986 highlights that patients with T3 disease have a poorer survival outcome with conventional radiotherapy than those with clinically localized disease [4]; the risk ratios for overall and disease-specific mortality for T3 versus T1 2 disease were 1.52 and 1.74, respectively (both p ¼ 0:0001). Of the 926 patients with T3 disease included in this analysis, approximately 17% died of prostate cancer within 5 years of treatment, 40% within 10 years, and 45% within 15 years. Zagars and colleagues [3] have presented a detailed retrospective review of progression outcomes with conventional radiotherapy in a cohort of 260 men with T3 disease (32% T3a, 68% T3b). However, these patients were diagnosed in and therefore may not be representative of patients being treated today, as seminal vesicle invasion at diagnosis is becoming increasingly less common. Relatively few patients in this cohort had high (8) Gleason scores or high (>20 ng/ml) prostate-specific antigen (PSA) levels at diagnosis (17% and 27%, respectively), as patients with these disease characteristics tended to receive adjuvant hormone therapy. The radiation dose was generally 66 Gy prior to 1991, 68 Gy in , and 70 Gy thereafter. Biochemical progression (defined as 2 or more consecutive rising PSA values) was documented in 54% of patients, with median onset 36 months after radiotherapy. Actuarial rates of biochemical progression at 5 and 10 years were 65% and 76%, respectively. The PSA level at diagnosis was the principal disease characteristic associated with a poor biochemical outcome. Radiation dose also independently influenced outcome. Patients with a PSA level <10 ng/ml who received radiation doses 68 Gy had a 24% risk of biochemical progression within 5 years. However, the risk exceeded 50% for all other patients. High rates of clinical progression were also documented in this study [3]. The actuarial rates of local progression at 5 and 10 years were 31% and 59%, respectively. As with biochemical progression, pretreatment PSA level and radiation dose correlated with local disease recurrence. Corresponding rates of metastatic progression were 11% and 24%. Factors predictive of metastatic progression were the PSA level at diagnosis and the Gleason score; patients with a PSA Table 1 Disease characteristics correlated with the development of distant metastases in 256 patients with T3 disease receiving radiotherapy alone [3] PSA level (ng/ml) Gleason score < < > > level >21.4 ng/ml and a Gleason score 8 10 had a 47% risk of metastatic progression within 7 years (Table 1). Of the patients developing metastatic disease, 68% died of prostate cancer. Although radiotherapy techniques have developed since the above studies were conducted and higher doses are now used, few data are available from longterm studies on outcomes and morbidity in patients with locally advanced disease. Furthermore, irrespective of the improvement in local disease control, radiotherapy will not eradicate distant micrometastatic disease. 3. Outcomes of hormone therapy in combination with radiotherapy Patients developing metastases (%) As conventional radiotherapy alone appears to have limited curative potential in patients with locally advanced prostate cancer, several collaborative studies have evaluated the benefits of adding hormone therapy, both in a neoadjuvant or adjuvant manner Neoadjuvant hormone therapy The benefits of hormone therapy neoadjuvant to radiotherapy were investigated in a major collaborative trial (RTOG 86-10) involving 471 patients [5,6]. Patients in this trial had bulky (25 cm 3 )T2 4 disease with or without nodal involvement but with no evidence of distant metastases. Hormone therapy comprising goserelin ( Zoladex ) 3.6 mg every 4 weeks plus flutamide 250 mg three times daily was commenced 2 months before radiotherapy and continued during the course of radiotherapy (total dose Gy). Data have been reported after a median 6.7 years patient follow-up. Neoadjuvant hormone therapy significantly improved 8-year actuarial rates of local progression (30% versus 42%; p ¼ 0:016), distant progression (34% versus 45%; p ¼ 0:040), and disease-free survival (33% versus 21%; p ¼ 0:004). Although neoadjuvant hormone therapy also improved 8-year disease-specific survival (77% versus 69%; p ¼ 0:05), a significant difference in overall survival

3 16 M. Mason / European Urology Supplements 2 (2003) was not achieved (53% versus 44%; p ¼ 0:10). Analysis by the centrally reviewed Gleason score showed that in the subgroup with scores of 2 6 (n ¼ 129), neoadjuvant hormone therapy conferred significant benefits with respect to all endpoints including overall survival (8-year estimates: 70% versus 52%; p ¼ 0:015). However, patients with Gleason scores 7 or 8 10 only had significant improvements in the rate of biochemical progression Adjuvant hormone therapy Two collaborative trials, RTOG [7] and European Organization of Research and Treatment of Cancer (EORTC) [8,9] have evaluated hormone therapy as adjuvant to conventional radiotherapy. The two trials did however differ in terms of eligibility criteria and, although both used the luteinizing hormone-releasing hormone (LHRH) agonist goserelin as the hormone therapy, there were differences with respect to the scheduling and duration of treatment. A total of 977 men with T3 disease, with or without nodal metastases, or T1 2 disease with nodal metastases (either de novo, or as determined following radical prostatectomy) were enrolled in the RTOG trial [7,10,11]. Goserelin (3.6 mg every 4 weeks) was commenced during the last week of radiotherapy (60 70 Gy depending on whether the patient had undergone prior prostatectomy) and continued indefinitely. With a median follow-up of 7.3 years, the estimated 5-year local progression rates in the adjuvant goserelin and control arms were 15% and 30%, respectively, while 10-year estimates were 23% and 39%, respectively (both p < 0:0001) [10]. The corresponding rates of metastatic progression were 15% versus 29% and 25% versus 39% (both p < 0:0001). Furthermore, a benefit for adjuvant goserelin over radiotherapy alone was seen in terms of overall survival at 10 years (53% versus 38%; p < 0:0043). Patients in the EORTC trial ( n ¼ 415) had either T1 2 disease of World Health Organization (WHO) grade 3 or T3 4 disease of any histological grade, with or without nodal involvement [8,9]. Adjuvant goserelin (3.6 mg every 4 weeks) was commenced on the first day of radiotherapy and continued for 3 years only. With a median follow-up of 5.5 years, adjuvant goserelin given for 3 years increased the estimated 5-year clinical disease-free survival from 40% to 74% ( p ¼ 0:0001); improvements were seen for rates of both locoregional progression (1.7% versus 16.4%) and metastatic progression (9.8% versus 29.2%) [9]. Adjuvant goserelin reduced the risk of mortality from any cause during follow-up by 49% (hazard ratio [HR] 0.51, 95% confidence interval [CI]: Overall survival (%) Radiotherapy alone 10 Radiotherapy and hormone therapy (goserelin) Time since randomization (years) Log-rank test p = HR 0.51, 95% CI: 0.36, 0.73 Fig. 1. Kaplan Meier plot of overall survival in EORTC study. Reprinted from [9] with kind permission of Elsevier. 0.36, 0.73; p ¼ 0:0002; Fig. 1); 5-year estimates of overall survival were 78% in the adjuvant group and 62% in the control group. Adjuvant hormone therapy with goserelin achieved an even greater improvement in disease-specific survival (HR 0.26, 95% CI: 0.15, 0.44; p ¼ 0:0001); 5-year estimates were 94% and 79%, respectively. A further, much smaller ( n ¼ 91), study of hormone therapy (orchiectomy) as adjuvant to radiotherapy supports the above findings, although on the basis of clinical staging, many patients in this study had localized, rather than locally advanced, disease [12]. At follow-up (median 9.3 years), 31% of men in the adjuvant arm had evidence of local or distant progression compared with 61% in the control arm ( p ¼ 0:005), while 61% and 38%, respectively, were still alive ( p ¼ 0:020). Median survival was increased by more than 3 years in the adjuvant orchiectomy group. When the results were analyzed according to pelvic lymph node status determined by lymphadenectomy prior to treatment (52 negative, 39 positive), the benefits of adjuvant therapy with respect to overall and disease-specific survival were apparent in nodepositive patients only ( p ¼ 0:007 and p ¼ 0:010, respectively) Duration of hormone therapy The studies discussed above did not establish the optimum duration and scheduling of hormone therapy, although the results of EORTC and RTOG suggest that indefinite therapy (such as orchiectomy) might be unnecessary. A comparison of data from the T3 patients entered in the RTOG and trials shows a significant advantage for long-term over short-term hormone therapy

4 M. Mason / European Urology Supplements 2 (2003) with respect to biochemical disease-free survival, metastatic progression and disease-specific survival [13], but not for overall survival. However, as this analysis was conducted using data from two different trials with slightly different eligibility criteria (with respect to disease volume), it may be subject to bias and should be interpreted with caution. Two ongoing trials are examining the issue of the optimal duration of hormone therapy in combination with radiotherapy in a prospective manner. The RTOG trial has randomized patients ( n ¼ 1554) with T2c 4 disease to receive hormone therapy (goserelin plus flutamide) for 2 months before and during radiotherapy only or to receive an additional 2 years therapy with goserelin only [14]. Preliminary data (median follow-up 4.8 years) show significant gains for longversus short-term hormone therapy with respect to local progression, metastatic progression and disease-free survival. The full publication of the results of this study is awaited. Recruitment to the second trial, the EORTC protocol, began in April 1997 and has recently been completed (target was 966). The patients recruited to this trial all received therapy with an LHRH agonist and an antiandrogen (commenced with the radiotherapy) for 6 months and were then randomized to receive the LHRH agonist for a further 2.5 years (i.e. a total of 3 years hormone therapy) or no further therapy. 4. Outcomes with hormone therapy Evidence supporting immediate hormone therapy, as opposed to deferring therapy until symptoms arise, comes mainly from the MRC PR03 study of immediate versus deferred hormone therapy conducted in men with locally advanced or asymptomatic metastatic prostate cancer [15,16]. Of the 938 patients recruited to this trial between 1985 and 1993, 500 had nonmetastatic disease confirmed by bone scan. The hormone therapy used initially was orchiectomy, but once the LHRH agonists became available, the protocol was modified to allow use of these agents depending on the patient s preference. In the first analysis of this study (August 1996), after 74% of the patients had died, 30% of the immediate hormone therapy group were still alive compared with 22% in the deferred group ( p ¼ 0:02) [15]. In patients with non-metastatic disease at study entry, survival was 41% in the immediate therapy group versus 30% in the deferred therapy group ( p ¼ 0:02) (Fig. 2). Patients receiving immediate therapy also benefited in terms of reduced risks of metastatic progression and bone pain. Furthermore, a difference in the risk of disease-related complications (pathological fracture, spinal cord compression, ureteric obstruction, extra-skeletal metastases) favoring immediate therapy was found, although this was more apparent in those patients with metastatic than nonmetastatic disease. A further analysis undertaken after 86% of the patients had died [16] continued to show significant survival benefits (both overall and diseasespecific survival) in the study population as a whole, although the difference was no longer significant in the non-metastatic subgroup. A trial of immediate versus deferred hormone therapy (LHRH agonist [goserelin] therapy or orchiectomy) in men found to have positive lymph nodes at radical prostatectomy provides further support for the early initiation of hormone therapy [17,18]. This study reported a 23% increase in overall survival with immediate hormone therapy (72% versus 49%; 100 Overall survival (%) p = Immediate hormone therapy Deferred hormone therapy Time since randomization (years) Fig. 2. Kaplan Meier plot of overall survival in the non-metastatic subgroup of the MRC PR03 trial. Reproduced from [15] with kind permission of Blackwell Publishing.

5 18 M. Mason / European Urology Supplements 2 (2003) p ¼ 0:025) and a 30% increase in cause-specificsurvival (87% versus 57%; p ¼ 0:001) after a median follow-up of 10.0 years [18]. An ongoing EORTC protocol (30891) is comparing immediate versus delayed hormone therapy in patients with asymptomatic non-metastatic disease (T0-4, N0-2, M0). This trial had a target sample size of 900 and closed recruitment in The Prostate Cancer Trialists Collaborative Group also intend to conduct a meta-analysis of studies of hormone therapy in order to clarify the optimal timing of therapy. 5. Choice of hormone therapy Traditionally, studies of hormone therapy (either as adjuvant to radiotherapy or monotherapy) for locally advanced disease have used medical or surgical castration. Castration, however, invariably leads to loss of libido, erectile dysfunction and fatigue [19] and this may have a detrimental impact on the quality of life of men with locally advanced prostate cancer, the majority of whom are still sexually and physically active prior to treatment. Furthermore, patients with locally advanced disease can expect to require treatment for several years and hypogonadal testosterone levels can cause serious long-term complications such as anemia [20], osteoporosis [21], and declining cognitive function [22]. As testosterone levels are maintained during non-steroidal antiandrogen monotherapy, it is entirely plausible that these agents have the potential to avoid such castrationrelated side effects. There is evidence that this is indeed the case as regards quality of life and bone mineral density (as discussed below), but studies to compare other toxicities further are warranted. Two phase III randomized trials of similar design have compared bicalutamide ( Casodex ) 150mg monotherapy and castration (goserelin 3.6 mg every 4 weeks or orchiectomy) in men with either locally advanced or metastatic disease [23,24]. Endpoints included both survival and quality of life. In patients with locally advanced disease ( n ¼ 480), a mature analysis (56% deaths) at a median follow-up of 6.3 years, showed that overall survival did not differ significantly between the bicalutamide 150 mg monotherapy and castration groups (HR 1.05, 95% CI: 0.81, 1.36; p ¼ 0:70; Fig. 3) [24]. Ten domains of quality of life were assessed at 12 months after randomization: physical capacity; emotional wellbeing; sexual interest; sexual function; vitality; social function; pain; activity limitation; bed disability; and overall health. However, only a small proportion of patients responded to the question on sexual function and therefore statistical analysis for this domain was not undertaken. Significant advantages for bicalutamide 150 mg over castration in the domains of physical capacity ( p ¼ 0:046) and sexual interest ( p ¼ 0:029) were seen (Fig. 4); trends favoring bicalutamide 150 mg in six of the remaining seven domains were also apparent (Fig. 4). Furthermore, a recent prospective, open-label, parallel-group study in 103 men with prostate cancer (T1 4, Nx, M0) randomized to receive bicalutamide 150 mg or medical castration for 2 years, showed that baseline bone mineral density was maintained in patients receiving bicalutamide 150 mg monotherapy, and progressively decreased in castrated patients, over the 2 years [25]. Bicalutamide 150 mg is also currently being evaluated in the Early Prostate Cancer (EPC) program as an addition to standard care (either adjuvant to radiotherapy or radical prostatectomy, or as monotherapy Proportion surviving Bicalutamide 150 mg Castration Time to death (days) Fig. 3. Kaplan Meier plot of overall survival in patients with non-metastatic disease receiving either bicalutamide 150 mg monotherapy or castration. Reprinted from [24] with kind permission.

6 M. Mason / European Urology Supplements 2 (2003) Favors castration Favors bicalutamide 150 mg Physical capacity p = Emotional wellbeing Sexual interest p = Vitality Social functioning Pain Activity limitation Bed disability Overall health Treatment effect and 95% 2-sided CI Fig. 4. Analysis of quality of life at 12 months post-randomization (last value carried forward) in the locally advanced disease patients enrolled in the two pivotal trials of bicalutamide 150 mg monotherapy versus castration. Reprinted from [24] with kind permission. in patients who would otherwise be candidates for watchful waiting) in a total of 8113 patients with localized or locally advanced prostate cancer [26]. In the program as a whole, there was a significant increase in progression-free survival in the bicalutamide 150 mg group at median follow-up of 3 years (HR 0.58, 95% CI: 0.51, 0.66; p 0:0001). This benefit was seen consistently in each of the three primary therapy subgroups, including patients undergoing radiotherapy (HR 0.63, 95% CI: 0.46, 0.85; p ¼ 0:0024; n ¼ 1370, including 305 patients with locally advanced disease). The greatest benefits were seen in patients at greatest risk of disease progression (such as those with higher disease stage or high serum PSA). As yet there are too few events for the assessment of overall survival, but when the data have greater maturity, this study will be of pivotal importance in defining future management. 6. Role of radiotherapy in locally advanced disease Although the data from the EORTC and RTOG trials are persuasive, suggesting that radiotherapy supplemented by hormone therapy should be the standard approach to locally advanced disease, a hormone therapy alone arm was not included in any of these trials, and therefore the extent of the contribution of radiotherapy to the outcomes reported cannot be established. Indeed, it may be that hormone therapy alone can achieve a similar survival outcome to hormone therapy added to radiotherapy. Furthermore, whatever the magnitude of the benefit of radiotherapy, this has to be balanced against the possibility of longterm complications, such as proctitis [27,28]. One previous study, conducted by the Medical Research Council (MRC PR02), has attempted to address the role of radiotherapy in patients receiving hormone therapy [29], randomizing 277 previously untreated patients with T2 4 disease to hormone therapy (orchiectomy) alone, radiotherapy alone and radiotherapy combined with hormone therapy. However, although a significantly ( p < 0:005) higher incidence of distant metastases was observed in the radiotherapy arm than in the other two treatment arms, the trial had insufficient statistical power to detect clinically relevant differences in survival. Two ongoing trials are now addressing the contribution of radiotherapy to the outcome of locally advanced disease treated with hormone therapy NCIC/MRC/SWOG PR.3/PR07 International Intergroup trial This study involves the National Cancer Institute of Canada (NCIC), the MRC, and the National Cancer Institute (NCI) in the United States. It was designed to follow on from the EORTC trial and has similar inclusion criteria: T3 4, N0 or Nx, M0 disease or T2 disease with poor prognostic factors (e.g. high Gleason grade, high pre-treatment PSA level) (Fig. 5). Patients enrolled in this trial are essentially previously untreated,

7 20 M. Mason / European Urology Supplements 2 (2003) Eligible patient ct3-4, N0/Nx, M0 ct2, N0/Nx, M0 with PSA >40 ng/ml ct2, N0/Nx, M0 with PSA >20 ng/ml, Gleason >8 RANDOMIZE Arm A Hormone therapy alone Patient's choice of LHRHa or orchiectomy ± oral antiandrogen Arm B Hormone therapy as in Arm A + Radical radiotherapy Gy, F LHRHa, luteinizing hormone-releasing hormone agonist; PSA, prostate-specific antigen Fig. 5. Design of the NCIC, MRC and NCI International Intergroup trial comparing hormone therapy alone with hormone therapy combined with radiotherapy. although up to 12 weeks hormone therapy prior to randomization is permitted, provided the patient had a negative bone scan and a baseline PSA level taken in the 4 weeks before starting hormone therapy. The International Intergroup trial has two treatment arms: hormone therapy alone and hormone therapy combined with radiotherapy (Fig. 5). Hormone therapy may be an LHRH agonist or orchiectomy alone, or combined with an antiandrogen (maximum androgen blockade). The protocoled dose of radiotherapy is Gy, with individual fractions of cgy. Patients with pathologically confirmed negative lymph nodes receive the entire radiation dose confined to the prostate and peri-prostatic tissues. Other patients receive 45 Gy to the whole pelvis (unless the clinician deems this inappropriate, e.g. the patient is unfit) and a Gy boost to the prostate. Patient follow-up is scheduled every 6 months for the first 24 months after randomization and annually thereafter. The primary endpoint of the trial is overall survival and secondary endpoints are time to progression, symptomatic local control and quality of life. Quality of life is being assessed using the Eastern Co-Operative Oncology Group Functional Assessment of Cancer Therapy-Prostate (ECOG FACT-P) questionnaire. This patient-completed instrument includes assessments of physical wellbeing, social/family wellbeing, the patient s relationship with their doctor, emotional wellbeing, and functional wellbeing. The aim of the quality-of-life assessment is to establish whether the known detrimental short-term effect of radiotherapy on quality of life is maintained over the longer term. This study has been recruiting since 1995; having reached the initial target of 650 patients, it has been expanded to a new target of 1200 patients. Survival data from this trial are expected from 2008 onwards SPCG-7/SFUO-3 trial This Scandinavian trial is designed to address the same issue as the International Intergroup trial, although there are differences between the two protocols. Patients are eligible for the trial if they have previously untreated T1b 2, N0, M0 disease of WHO grade 2 3 or T3, N0, M0 disease of any grade; the absence of involved pelvic lymph nodes must be confirmed by lymphadenectomy. All patients must also have a PSA level <70 ng/ml. The hormone therapy also differs from that in the International Intergroup trial, with all patients in the Scandinavian trial receiving both an LHRH agonist and antiandrogen for 3 months prior to randomization, followed by the antiandrogen alone from randomization until progression. Patients randomized to radiotherapy receive a total radiation dose of 70 Gy. The recruitment target for this trial is 660. The results of this trial may be available before those of the International Intergroup trial. 7. Conclusions In conclusion, the optimum approach to the treatment of locally advanced prostate cancer is still being investigated. The addition of hormone therapy (goserelin) to conventional radiotherapy has been shown to improve outcome compared with conventional

8 M. Mason / European Urology Supplements 2 (2003) radiotherapy alone, and is generally regarded as standard in this setting, although the optimal duration of hormone therapy is unclear. Hormone therapy per se is a component of the improved survival seen with combined therapy. The extent of the contribution of radiotherapy to outcome in hormone-treated patients, and whether this is of sufficient magnitude to justify routine use, cannot be established from current data. Data from ongoing trials addressing this issue should be available towards the end of the decade. Although castration has been traditionally used for the treatment of locally advanced disease, either as monotherapy or adjuvant therapy, bicalutamide 150 mg may provide an alternative hormone treatment option, offering quality-oflife benefits while achieving a similar survival outcome. 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9 22 M. Mason / European Urology Supplements 2 (2003) [25] Sieber PR, Keiller DL, Kahnoski RJ, Garcia-Vargas JE, Gallo J, McFadden S. Bone mineral density is maintained during bicalutamide ( Casodex ) treatment. Proc Am Soc Clin Oncol 2002;21:196a. [26] See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, et al. on behalf of the Casodex Early Prostate Cancer Trialist Group. Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the Early Prostate Cancer program. J Urol 2002;168: [27] Pollack A, Zagars GK, Starkschall G, Antolak JA, Lee JJ, Huang E, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53: [28] Lilleby W, Fossa SD, Waehre HR, Olsen DR. Long-term morbidity and quality of life in patients with localized prostate cancer undergoing definitive radiotherapy or radical prostatectomy. Int J Radiat Oncol Biol Phys 1999;43: [29] Fellows GJ, Clark PB, Beynon LL, Boreham J, Keen C, Parkinson MC, et al. Treatment of advanced localised prostatic cancer by orchiectomy, radiotherapy, or combined treatment. A Medical Research Council Study. Urological Cancer Working Party Subgroup on Prostatic Cancer. Br J Urol 1992;70:304 9.