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

The management of early prostate cancer is one of the most controversial areas in the field of cancer medicine with surgery, radiotherapy, primary hormonal therapy (achieved either by medication or by the surgical removal of the testes - orchidectomy) and watchful waiting, all being acceptable forms of initial treatment. Treatment decision making is often based on patient and provider preferences taking into account the risks and benefits of therapies and disease progression. Since prostate cancer is driven, in part by male sex hormones, the use of hormonal treatment to reduce the level of circulating male hormones is a potentially very useful method of treating all stages of this disease. Recently, research on the use of such hormonal therapy in combination with both surgery and radiotherapy has increased. This systematic review combines the results of all the important trials looking at the role of hormones in combination with surgery and radiotherapy for localised and locally advanced prostate cancer.

The results of this review indicate that neo-adjuvant hormone therapy administered three to six months before the primary curative therapy (radical prostatectomy radical radiotherapy) did not, as yet, result in a detectable improvement in overall survival or disease-specific survival. There was, however, a significant improvement in disease-free survival (approximately 90%) when given before radiotherapy. Neo-adjuvant hormone therapy prior to radical prostatectomy also significantly improved pathological variables associated with poor prognosis, such as the positive surgical margin rate and the proportion of patients with positive lymph nodes. Adjuvant hormone therapy following prostatectomy did not change overall or disease-specific survival compared to prostatectomy alone. However, adjuvant therapy following radiotherapy significantly improved overall survival and disease-specific survival up to 10 years post-treatment. Disease-free survival was also significantly improved at 10 years. Hormone therapy is associated with a number of side effects including hot flushes and gynaecomastia. The decision to use these agents has to be made after a full discussion between the patient and the physician regarding the disease risk of the patient, the benefits from the use of additional hormones and the side effects of hormonal therapy.

Authors' conclusions: 

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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Background: 

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.

Objectives: 

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.

Search strategy: 

We searched MEDLINE (1966 to 2006), EMBASE, The Cochrane Library, Science Citation Index, LILACS, and SIGLE for relevant randomised trials. Handsearching of appropriate publications was also undertaken.

Selection criteria: 

Randomised or quasi-randomised controlled trials of patients with localised or locally advanced prostate cancer, that is, stages T1 to 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 collection and analysis: 

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.

Main results: 

Men with prostate cancer have different clinical outcomes based on their risk (T1 to T2, T3 to 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.

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