© 2007 ASTRAZENECA JOURNAL COMPILATION © 2 0 0 7 B J U I N T E R N A T I O N A L | 9 9 , 1 3 8 3 – 1 3 8 9 | doi:10.1111/j.1464-410X.2007.06802.x 1383 Urological Oncology EARLY VS DEFERRED HORMONAL TREATMENT OF LAPC BOUSTEAD and EDWARDS Systematic review of early vs deferred hormonal treatment of locally advanced prostate cancer: a meta-analysis of randomized controlled trials Gregory Boustead and Steven J. Edwards* Department of Urology, Lister Hospital, Stevenage, and *Outcomes Research, AstraZeneca UK Ltd, Luton, UK Accepted for publication 15 December 2006 and objective disease progression. The meta- analysis used a fixed-effects model. RESULTS Of the 108 trials identified, seven met the inclusion criteria and were of sufficient quality to be included in the analysis. Early intervention with hormonal treatment significantly reduced all-cause mortality compared with deferred treatment (relative risk, RR, 0.86; 95% confidence interval, CI, 0.82–0.91; P < 0.001). Similarly, early vs deferred use of hormonal treatment significantly reduced: prostate cancer- specific mortality (RR 0.72; 95% CI 0.65–0.79); overall progression (RR 0.74; 0.69–0.78); local progression (RR 0.65; 0.57–0.73); and distant progression (RR 0.67; 0.61–0.74; all P < 0.001). Results were robust to changes in inclusion/exclusion criteria and use of a random-effects model for the meta- analyses. Heterogeneity and publication bias had no significant effect on the analyses. CONCLUSIONS Early intervention with hormonal treatment for patients with LAPC provides significantly lower mortality and objective disease progression than deferring their use until standard care has failed. KEYWORDS systematic review, meta-analysis, locally advanced prostate cancer, hormonal therapy, androgen ablation OBJECTIVE To compare the effectiveness of hormonal treatment (luteinizing hormone-releasing hormone agonists and/or antiandrogens) as an early or as a deferred intervention for patients with locally advanced prostate cancer (LAPC), as radiotherapy is currently the standard treatment for LAPC, with hormonal treatment considered a reserve option. METHODS We systematically reviewed randomized controlled trials (RCTs) in patients with LAPC treated with standard care (radical prostatectomy, radiotherapy, and/or watchful waiting) or standard care plus hormonal treatment. Outcomes assessed were mortality INTRODUCTION The global incidence of prostate cancer has been estimated at > 500 000 new cases each year [1]; this equates to ∼ 10% of all cancers in men. In 2000, it was estimated that there were 180 400 new cases of prostate cancer and 31 900 prostate cancer deaths in the USA [2]. In 2002, > 30 000 men in the UK were diagnosed with prostate cancer, which has now overtaken lung cancer to become the most common cancer in men [3]. Although prostate cancer usually progresses slowly, a patient’s prognosis and subsequent treatment depends heavily on the grade of the tumour at diagnosis [4]. A 10-year prostate cancer-specific survival of > 90% was reported in men with early, low-grade tumours, and of > 75% among those with intermediate-grade tumours [5]. As would be expected, there is a significant decline in 10-year prostate cancer-specific survival among patients with more aggressive high- grade tumours. Locally advanced prostate cancer (LAPC) is a serious condition in the UK, accounting for > 27% of all new presentations of prostate cancer [6]. Of patients thought to have organ-confined (T1c or T2) prostate cancer, 25–40% fail after radical prostatectomy (RP) or radiation therapy [7]. Options for treating LAPC include watchful waiting, RP, and hormonal monotherapy or radiation therapy combined with androgen deprivation. Radiotherapy is the most commonly used treatment in conjunction with neoadjuvant, concomitant and/or adjuvant hormone treatment [8]. The aim of adding hormone treatment is first to reduce the risk of distant metastases, by sterilizing micrometastatic deposits at the time of diagnosis. Second, it reduces the risk of local recurrence, possibly by acting synergistically to enhance radiation-induced apoptosis [9,10]. The Veterans Administration Cooperative Urological Research Group [11–14] first investigated the concept of early vs deferred hormonal treatment in patients with APC and LAPC. The hormonal treatment used in these trials was diethylstilbestrol (DES) as adjuvant therapy to orchidectomy, vs orchidectomy, DES and placebo. In patients with stage III and IV disease there was no difference in prostate cancer-specific mortality. A post hoc analysis of the deaths in the trials showed a reduction in prostate cancer-specific mortality in patients taking adjuvant DES, but an increase in cardiovascular-specific mortality. Since this time, better tolerated hormonal treatments, (primarily LHRH agonists and nonsteroidal antiandrogens (NSAAs)), have become the standard for hormonal therapy. We examined the impact on survival (overall and prostate cancer-specific) of androgen- deprivation therapy in men with LAPC, using a systematic review of the available RCTs comparing early hormonal treatment (LHRH