Prostate Cancer and Prostatic Diseases (2005) 8, 140–151 & 2005 Nature Publishing Group All rights reserved 1365-7852/05 $30.00 www.nature.com/pcan Review Evaluating the use of early hormonal therapy in patients with localised or locally advanced prostate cancer AV Kaisary1* 1Department of Urology, Royal Free Hospital, London, UK This article evaluates the use of early hormonal therapy in patients with localised or locally advanced prostate cancer. In patients receiving radiotherapy, an overall survival benefit is proven for adjuvant goserelin (‘Zoladex’) in locally advanced disease. Adjuvant to radical prostatectomy, castration (goserelin or orchiectomy) has demonstrated an overall survival benefit in patients with lymph node metastases. Survival advantages have not yet been proven with nonsteroidal antiandrogens, but immediate or adjuvant bicalutamide (‘Casodex’) improves objective progression-free survival in patients with locally advanced disease, with certain quality-of-life advantages over castration. Prostate Cancer and Prostatic Diseases (2005) 8, 140–151. doi:10.1038/sj.pcan.4500800 Published online 26 April 2005 Keywords: prostate cancer; hormonal therapy; castration; luteinising hormone- releasing hormone agonist; nonsteroidal antiandrogen Introduction of those who undergo watchful waiting progress and require treatment initiation within 5 y,7 although among Since the onset and widespread use of prostate-specific those with low-risk, localised disease (pcT2a, low antigen (PSA) testing, an increasing proportion of Gleason score and low PSA level), this proportion may prostate cancer cases are being diagnosed at an earlier be reduced to around 20%.8 stage and in younger men.1 In the USA in 2004, an Prostate cancer progression can have a serious impact estimated 86% of prostate cancer diagnoses were for on patients’ quality of life.9,10 Advancing disease may be localised or locally advanced disease.2 associated with debilitating disease-related complications, Men with localised or locally advanced prostate cancer such as painful bone metastases and urinary tract obstru- and a life expectancy of X10 y are typically offered ction,11,12 and can cause considerable emotional distress.13 primary therapy of curative intent, that is, radical Moreover, disease progression poses a significant eco- prostatectomy, external beam radiotherapy or brachy- nomic burden.14,15 A recent large retrospective cohort therapy. However, a significant proportion of patients evaluation of US patients with prostate cancer showed undergoing these therapies experience disease progres- that healthcare resource charges were more than 50% sion (clinical and/or biochemical) and may ultimately higher among those with metastatic progression compared die from their prostate cancer.3–6 Watchful waiting with those with no evidence of progression (Po0.0001).14 (where patients receive palliative therapy only) is an In patients with locally advanced disease (pT3, N0), option for men who are not suitable for, or opt not to external beam radiotherapy as adjuvant to radical receive, primary therapy of curative intent. Around half prostatectomy has been shown to significantly improve clinical progression-free survival compared with radical prostatectomy alone (83 vs 75% at 5 y median follow-up; *Correspondence: AV Kaisary, Royal Free Hospital, Pond Street, P ¼ 0.004).16 However, both radical prostatectomy and London NW3 2QG, UK. radiotherapy target the prostatic area and neither single E-mail: [email protected] nor combined local therapies are able to eradicate distant ‘Casodex’ and ‘Zoladex’ are trademarks of the AstraZeneca group of companies. disease. Many treatment failures after local therapies are Received 10 March 2005; accepted 23 March 2005; published online 26 likely to be due to the presence of distant micrometas- April 2005 tases that were undetectable at the time of diagnosis. Early hormonal therapy in men with prostate cancer AV Kaisary The use of early hormonal therapy (ie given immedi- (HR) for overall survival (HR 1.23) indicated a non- 141 ately rather than being deferred until clinical progre- significant 23% trend in favour of early castration ssion) has been evaluated with a view to improving the therapy (Table 1). outcomes of primary therapy of curative intent and as an Turning to the nonsteroidal antiandrogens, the on- alternative to watchful waiting. As there are several going bicalutamide Early Prostate Cancer (EPC) pro- different hormonal approaches that can be considered, gramme recently demonstrated that bicalutamide physicians need to help patients weigh the potential (‘Casodex’) monotherapy significantly reduces the risk benefits of treatment (in terms of reduced risk of disease of disease progression in patients with locally advanced progression and death from prostate cancer and in- disease.20 The EPC programme is the world’s largest creased overall survival) and the potential side effects. prostate cancer treatment programme, consisting of three Only through this process can physicians be confident randomised, placebo-controlled trials conducted in dif- that their patients are able to select the approach most ferent geographical areas and involving 8113 patients. appropriate in their specific circumstances. The programme is evaluating bicalutamide given in In this article, I review findings from randomised trials addition to standard care (watchful waiting, radical examining the use of early hormonal therapy (castration prostatectomy or radiotherapy) in patients with localised therapy and/or antiandrogens) as an alternative to or locally advanced disease. A subgroup of 2285 patients watchful waiting, and as adjuvant or neoadjuvant in the programme are undergoing watchful waiting as therapy in patients receiving radical prostatectomy or standard care; among these patients, analysis at 5.4 y radiotherapy. median follow-up revealed that the relative effect of bicalutamide was dependent on disease stage (Table 1).20 In the watchful waiting patients with locally advanced disease, bicalutamide significantly reduced the risk of Effects on clinical progression and objective progression by 47% compared with watchful overall survival waiting alone (HR 0.53; Po0.0001; Figure 1).20 This does appear to be translating into a survival benefit as there Hormonal therapy alone was a trend toward improved overall survival with bicalutamide (HR 0.81; P ¼ 0.097; Figure 2). On examining the evidence, I found that there are clear In the watchful waiting patients with localised disease, benefits associated with using early hormonal therapy as the effect of bicalutamide on progression was smaller an alternative to watchful waiting in patients with locally (HR 0.81; P ¼ 0.018; Figure 1) and there was a trend advanced disease (Table 1). For this patient group, who towards reduced overall survival with bicalutamide (HR have a high chance of progression, the results from trials 1.23; P ¼ 0.05; Figure 2).20 These data suggest that, for of castration therapy17–19 or a nonsteroidal antiandro- patients with localised disease not suitable for primary gen20 indicate to me that a watchful waiting approach is therapy of curative intent because of age or comorbid- not appropriate and that hormonal therapy is best ities, watchful waiting with hormonal therapy deferred started at, or soon after, diagnosis. until signs of progression may be the best option. A significant clinical benefit in favour of early This strategy would be consistent with a recent report castration therapy was first demonstrated in a trial on the use of active surveillance for patients with low- conducted by the Medical Research Council (MRC). This risk localised disease, with selective delayed intervention trial evaluated early orchiectomy or a luteinising being initiated depending on specific disease progression hormone-releasing hormone agonist (LHRHa) vs the criteria (eg rapid PSA progression).8 The active surveil- same treatment deferred until clinical progression in lance approach offers a practical compromise between patients with either nonmetastatic (M0) disease consid- therapy of curative intent for all, which results in ered too advanced for primary therapy of curative intent overtreatment in those with indolent disease, and or asymptomatic metastatic (M1) disease. Among the watchful waiting with palliative therapy only, which subgroup of 500 patients with M0 disease, a first analysis results in undertreatment in those with aggressive (performed after 74% of the overall trial population had disease. Klotz8 conducted the first feasibility study of died; median follow-up time not reported) demonstrated the active surveillance approach in 299 patients with significant advantages for early vs deferred castration low-risk, localised disease (mostly pcT2a disease, PSA therapy in reducing progression to M1 disease (38 vs level o10 ng/ml and Gleason score p6), and concluded 59%; Po0.001) and improving overall survival (mortality that a PSA doubling time of o3 y is the optimal 59 vs 70%; P ¼ 0.02) (Table 1).17 A later analysis threshold for radical intervention, and that this included (performed after 86% of the overall trial population around 20% of patients in his series. Klotz did not had died) found that the treatment difference in overall consider the use of hormonal therapy in their study survival was no longer statistically significant (Table 1).18 design, but in light of the recent data from the EPC The reduction in this treatment difference was explained programme, one