Systemic treatment for prostate cancer

Abstract

Patients with symptomatic metastatic prostate cancer should be treated by androgen deprivation. Historically this was accomplished by surgical castration. However, the standard treatment in modern medicine is the use of a luteinizing hormone-releasing hormone (LHRH) agonist such as goserelin acetate (Zoladex ) or leuprorelin acetate (Prostap ), which have an effect equivalent to castration on testosterone level and on prostate cancer response [1]. They act by downregulation of pituitary receptors and the consequent inhibition of release of follicle stimulation hormone (FSH) and leutinizing hormone (LH) with a decrease in testosterone production from the testis. These agents initially mimic the natural hormone and cause a transient rise in testosterone and their inception should be covered by an anti-androgen at full dose to prevent worsening of symptoms such as bone pain or urinary obstruction. A standard approach is to use anti-androgens for 7 days prior to the first LHRH agonist injection and for 14 days following it. Depot preparations of LHRH agonists lasting at least 3 months are as effective as the 1-month preparations. Direct LHRH antagonists such as abarelix have been developed that avoid the tumor flare phenomenon. Preliminary assessments suggest equivalent response rates to the agonists [2]. In hormone-naive patients with symptomatic metastatic disease, approximately 85% have a symptomatic response for a median of 12–18 months. Duration of response appears to relate to the burden of disease and patients treated with hormone therapy for localized or soft tissue disease tend to have longer responses than those with multiple bone metastases. The non-steroidal anti-androgen, bicalutamide appears to be less effective than castration in patients with metastatic disease [3]. A range of trials investigated the concept of complete androgen blockade in which an anti-androgen was added longterm either to surgical castration or to an LHRH agonist. A report based on more than 8000 patients randomized to either androgen ablation or to androgen ablation plus an antiandrogen showed on meta-analysis that combined androgen blockade is not more effective than simple medical or surgical castration with 5-year survival rates of 25.4% and 23.6%, and 10-year survivals of 6.2% and 5.5%, respectively [4]. Another issue, addressed in a more limited way, is whether asymptomatic patients with metastases should be treated immediately or whether hormone therapy should be deferred until they develop symptoms. A Medical Research Council (MRC) trial [5] suggested an advantage to early treatment. However, the advantage was seen in patients with locally advanced rather than disseminated disease. There seemed a clear benefit to early treatment in preventing some of the more distressing complications of metastatic prostate cancer. The advantage of early hormone therapy in locally advanced prostate cancer was also seen in a European Organization for Research and Treatment of Cancer (EORTC) trial [6].