Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer

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Abstract
Hormone therapy for early prostate cancer has demonstrated an improvement in clinical and pathological variables, but not always an improvement in overall survival. We performed a systematic review of both adjuvant and neo-adjuvant hormone therapy combined with surgery or radiotherapy in localised or locally advanced prostate cancer. The objective of this review was to undertake a systematic review and, if possible, a meta-analysis of neo-adjuvant and adjuvant hormone therapy in localised or locally advanced prostate cancer. We searched MEDLINE (1966-2006), EMBASE, The Cochrane Library, Science Citation Index, LILACS, and SIGLE for relevant randomised trials. Handsearching of appropriate publications was also undertaken. Randomised or quasi-randomised controlled trials of patients with localised or locally advanced prostate cancer, that is, stages T1-T4, any N, M0, comparing neo-adjuvant or adjuvant hormonal deprivation in combination with primary therapy (radical radiotherapy or radical prostatectomy) versus primary therapy alone were included in this review. Data were extracted from eligible studies and assessed for quality, and included information on study design, participants, interventions, and outcomes. Comparable data were pooled together for meta-analysis with intention-to treat principle. Men with prostate cancer have different clinical outcomes based on their risk (T1-T2, T3-T4, PSA levels and Gleason score). However, the majority of studies included in this review did not report results by risk groups; therefore, it was not possible to perform sub-group analysis. Neo-adjuvant hormonal therapy prior to prostatectomy did not improve overall survival (OR 1.11, 95% CI 0.67 to 1.85, P = 0.69). However, there was a significant reduction in the positive surgical margin rate (OR 0.34, 95% CI 0.27 to 0.42, P < 0.00001) and a significant improvement in other pathological variables such as lymph node involvement, pathological staging and organ confined rates. There was a borderline significant reduction of disease recurrence rates (OR 0.74, 95% CI 0.55 to 1.0, P = 0.05), in favour of treatment. The use of longer duration of neo-adjuvant hormones, that is either 6 or 8 months prior to prostatectomy, was associated with a significant reduction in positive surgical margins (OR 0.56, 95% CI 0.39 to 0.80, P = 0.002). In one study, neo-adjuvant hormones prior to radiotherapy significantly improved overall survival for Gleason 2 to 6 patients; although, in two studies, there was no improvement in disease-specific survival (OR 0.99, 95% CI 0.75 to 1.32, P = 0.97). However, there was a significant improvement in both clinical disease-free survival (OR 1.86, 95% CI 1.93 to 2.40, P < 0.00001) and biochemical disease-free survival (OR 1.93, 95% CI 1.45 to 2.56, P < 0.00001). Adjuvant androgen deprivation following prostatectomy did not significantly improve overall survival at 5 years (OR 1.50, 95% CI 0.79 to 2.85, P = 0.2); although one study reported a significant disease-specific survival advantage with adjuvant therapy (P = 0.001). In addition, there was a significant improvement in disease-free survival at both 5 years (OR 3.73, 95%CI 2.30 to 6.03, P < 0.00001) and 10 years (OR 2.06, 95% CI 1.34 to 3.15, P = 0.0009). Adjuvant therapy following radiotherapy resulted in a significant overall survival gain apparent at 5 (OR 1.46, 95% CI 1.17 to 1.83, P = 0.0009) and 10 years (OR 1.44, 95% CI 1.13 to 1.84, P = 0.003); although there was significant heterogeneity (P = 0.09 and P = 0.07, respectively). There was also a significant improvement in disease-specific survival (OR 2.10, 95% CI 1.53 to 2.88, P = 0.00001) and disease-free survival (OR 2.53, 95% CI 2.05 to 3.12, P < 0.00001) at 5 years. Hormone therapy combined with either prostatectomy or radiotherapy is associated with significant clinical benefits in patients with local or locally advanced prostate cancer. Significant local control may be achieved when given prior to prostatectomy or radiotherapy, which may improve patient's quality of life. When given adjuvant to these primary therapies, hormone therapy, not only provides a method for local control, but there is also evidence for a significant survival advantage. However, hormone therapy is associated with significant side effects, such as hot flushes and gynaecomastia, as well as cost implications. The decision to use hormone therapy should, therefore, be taken at a local level, between the patient, clinician and policy maker, taking into account the clinical benefits, toxicity and cost. More research is needed to guide the choice, the duration, and the schedule of hormonal deprivation therapy, and the impact of long-term hormone therapy with regard to toxicity and the patient's quality of life.

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