Oncology Prostate Cancer Hormone Therapy in the Management of Prostate Cancer Bertrand Tombal1 and Annabelle Stainier2 1. Chairman; 2. Assistant Professor, Division of Urology, Saint-Luc Hospital, Catholic University of Leuven
Abstract
Hormone therapy (HT) is the mainstay systemic treatment of prostate cancer. It is most usually delivered by androgen deprivation therapy (ADT) by surgical castration or leutinising-hormone-releasing hormone (LHRH) agonists, or by antiandrogens. When used alone, HT is a palliative treatment since it rapidly alleviates cancer-related symptoms, such as pain or urinary obstruction, but modestly improves survival. Its use should therefore be restricted to patients with advanced cancer at risk of progression. Indeed, recent studies have raised concerns about side-effects that appear with long-term use, including an increased risk of cardiovascular disease and osteoporotic fractures. Physicians should be aware of these chronic toxicities and learn to deliver ADT using a safer approach. Despite being used for more than 60 years, HT is constantly evolving. Recent progress has been made in improving the pharmacology of LHRH analogues while new intracellular pathways are being targeted to delay the onset of resistance to castration and hopefully increase patient survival.
Keywords
Prostate cancer, androgen deprivation therapy, leutinising-hormone-releasing hormone (LHRH) agonists, LHRH antagonists, cancer treatment- induced bone loss, cardiovascular disease, antiandrogen
Disclosure: Bertrand Tombal is an advisor and an investigator for Amgen, Astellas, Medivation, Ferring, Janssen and Novartis. Annabelle Stainier has no conflicts of interest to declare. Received: 18 October 2010 Accepted: 28 November 2010 Citation: European Urological Review, 2010;5(2):22–6 Correspondence: Bertrand Tombal, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium. E:
bertrand.tombal@
uclouvain.be
Despite 60 years of intense use, androgen deprivation therapy (ADT) is still used as it was described by Charles Huggins in the 1940s. The noticeable exception is that luteinising-hormone-releasing hormone (LHRH) agonists have replaced surgical castration as the main ADT modality, not only because patients favour injection over surgery, but primarily because that treatment is reversible.1
With the introduction
of prostate-specific androgen (PSA) testing, men are often diagnosed with prostate cancer (PCa) when still asymptomatic and ADT is more frequently initiated at diagnosis in men who are not candidates for radical treatment or are willing to postpone this treatment. This is based on the conventional wisdom that any patient with PCa will die from it and should be treated.2
However, there is no clear
evidence that ADT prolongs survival in all settings. Inconclusive recommendations and intense commercial support have resulted in wide variations in indications for ADT between urologists and medical oncologists.3
Fewer Indications for Upfront Androgen Deprivation Therapy as a Single Modality Many asymptomatic men receive ADT for a localised PCa (T1-2, N0, M0) to avoid or postpone radical therapy. Kawakami et al. reviewed the files of 7,045 men with localised PCa and found that 14.1% were treated primarily with ADT.5
After five years, 67.3% of these patients
Recent surveys confirm that the indications for ADT are driven more by the characteristics of the urologist (e.g. board certification and academic affiliation) than by tumour or patient characteristics. Non-academic urologists, for example, prescribe ADT more frequently for localised PCa, a setting in which the benefits are uncertain.4
This stresses the need for better post-graduate education so physicians can keep up with the rapidly evolving evidence and oppose the intense marketing of LHRH analogues without validated recommendations. This article will address the more recent evolutions in this area and the challenges that need to be tackled and thus try to predict the future role of ADT.
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This survey did not show a benefit in 10-year overall survival (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.96–1.05) compared with conservative management, even in men with poorly differentiated cancer (HR 0.92, 95% CI 0.84–1.01). Early initiation of ADT was associated with an increased mortality in the Early Prostate Cancer trial that was conducted on 8,113 men with non-metastatic PCa (all M0) to assess the efficacy of early treatment with bicalutamide 150mg.7
At a median follow-up of 7.4 years, there was a clear trend (HR 1.16; p=0.07) towards shortened survival in patients with localised disease treated with immediate HT.
This paradigm does not only apply to localised disease. A pivotal trial from European Organisation for Research and Treatment of Cancer (EORTC) suggested that ADT is as effective when postponed in patients with locally advanced PCa (T1–2, N+, M0 or T3–4, Nx, M0) that are not
© TOUCH BRIEFINGS 2010
were still receiving ADT and only 13.8% had received radical treatment. This type of use, however, is unlikely to bring benefit to the patients. Lu-Yao et al. reviewed the files 19,271 men aged 66 years or older receiving Medicare who did not receive definitive local therapy for clinical stage T1–T2 prostate cancer, including 41% who were treated by ADT.6
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