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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

22nd Annual European Association of Urology Congress

Berlin, Germany / March 21-24, 2007

Clinical benign prostatic hyperplasia (BPH) is thought to be present in about 80% of men over 80 years old. An enlarged prostate is associated with urinary and sexual problems, pain, and diminished emotional well-being. In his introductory address, Dr. Peter F. A. Mulders, Chairman, Department of Urology and Medical Oncology, University Medical Center St Radboud, Nijmegen, The Netherlands, stated, “Urologists will be increasingly confronted with prostate patients as the population ages.” Another important issue within the field of prostate health, and one often linked to BPH, is prostate cancer. Like BPH, the prevalence of this cancer increases with age, and it affects approximately 40% of men over 80 years old. As confirmed by Dr. Mulders, preventative strategies should be considered. As Charles Turner Thackrah, the father of occupational medicine, put it in a prescient remark 200 years ago, “A study of medicine which disregards the prevention of diseases limits its utility and its honours.”

5a-Reductase Inhibitors: Their Relevance in Prostate Disease

The proliferation and apoptosis of prostate epithelial cells are mediated by circulating androgens such as testosterone. When testosterone enters a prostate epithelial cell, it is converted to dihydrotestosterone (DHT) by the action of 5a-reductase (5AR), which is present as two isoenzymes. According to Dr. Helmut Klocker, Research Laboratory, Department of Urology, University of Innsbruck, Austria, “DHT then binds to an androgen receptor which promotes a survival signal for these cells.” Inhibition of 5AR has been shown to interfere with this survival signal. Two 5a-reductase inhibitors (5ARIs) are currently licensed, finasteride and dutasteride. However, he explained that these two agents have slightly different actions because finasteride only inhibits the type 1 isoenzyme, whereas dutasteride inhibits both. This dual inhibition of 5AR1 and 5AR2 with dutasteride results in greater and more consistent suppression of DHT than inhibition of 5AR2 only. The clinical implication is that all men taking dutasteride have >90% suppression of DHT compared to 70% with finasteride (Clark et al. J Clin Endocrinol Metab 2004;89:2179-84).

Preventing BPH Progression

The progression of BPH is a source of concern for patients for a number of reasons. As described by Dr. François Desgrandchamps, Hôpital Saint-Louis, Paris, France, when a patient visits a urologist, “he is worried about the symptoms and the bother that these cause; he is worried about urinary retention and quality of life; but most of all, he is worried about the risk of other diseases such as cancer, and the risk of surgery.” Clearly, as BPH progresses, symptoms will become worse. He stressed that patients are concerned about the future and preventing further progression should be a major goal of disease management (Kaplan S, Naslund M. Int J Clin Pract 2006;60:1157-65). Fortunately, recent developments have made it possible to predict much more accurately the patients at risk of progression.

In an analysis of the placebo arm of the Medical Therapy of Prostatic Symptoms (MTOPS) study, we now know that total prostate volume ³31 mL or prostate-specific antigen (PSA) levels ³1.6 ng/dL are risk factors for progression (Crawford et al. J Urol 2006;175:1422-6).

The MTOPS study also provided detailed information on the effectiveness of a 5ARI (in this case, finasteride) compared to an a-blocker (McConnell et al. N Engl J Med 2003;349(25):2387-98). After four years, the risk of acute urinary retention was reduced by 68% and the risk of surgery by 64% (P<0.05) compared to placebo, whereas the corresponding reductions for the a-blockers of 35% and 3%, respectively, were not significant. In addition to monotherapy, this study also investigated a combination of the 5ARI with the a-blocker. While the efficacy was additive, so were the effects on safety, yet Dr. Desgrandchamps stressed that they were still manageable.

Although the methodology used to investigate combination therapy can be questioned, these results “opened the door to further study of combination therapy,” he told delegates, and prompted the initiation of the Combination of Avodart and Tamsulosin (COMBAT) study, which is comparing combined dutasteride and tamsulosin therapy with monotherapy. In addition to being an active control study (on ethical grounds), this trial differs from MTOPS in that the inclusion criteria will ensure a more clinically relevant population with more risk factors for progression.

New Trends in Prostate Cancer

Prevalence rates of prostate cancer vary by country but the rates of mortality due to prostate cancer are similar in most Western countries. The various prevalence rates may reflect differences in how well national screening programs work; however, the similar mortality rates suggest that more effective detection does not yet translate into improved survival. In fact, given the aggressive nature of most cancer treatments, this type of treatment is often detrimental. According to Dr. Alexandre Zlotta, Director, Uro-Oncology, Mount Sinai Hospital, Toronto, Ontario, “One of the most exciting and also controversial topics concerning 5ARI is the question of primary prevention, and prostate cancer is a good target for primary prevention because of the long latency period.” Secondary prevention aims to help patients live longer with prostate cancer. At present, many patients suffer from relatively nonaggressive or indolent prostate cancer but die of other causes, and a pertinent question is what will happen to this indolent cancer as life expectancy increases.

Dr. Zlotta reviewed the studies on 5ARI therapy and prostate cancer. The Prostate Cancer Prevention Trial (PCPT), conducted in 18,882 men, found a 25% relative risk reduction for finasteride after seven years of treatment compared to placebo (Thompson et al. N Engl J Med 2003;349:215-24). The increased prevalence of high-grade tumours may have been an artifact due to reduced prostate volume making cancers in general, and high-grade tumours in particular, easier to detect at biopsy. This methodological shortcoming is overcome in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, which has only enrolled biopsy-negative men. Moreover, given that only men with PSA levels of 2.5 to 10.0 ng/dL are participating, the results of this study may offer a clearer picture of risk reduction in a relatively high-risk population.

These studies have addressed the role of 5ARIs in primary prevention of prostate cancer, but Dr. Zlotta mused, “Could 5ARIs reduce progression of prostate cancer once confirmed by biopsy?” The early indications are that 5ARIs can help reduce the progression rate of established prostate cancer: the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) study should provide a more definitive answer. Three hundred men with biopsy-proven, low-grade, low-risk, localized prostate cancer are to receive dutasteride or placebo for 36 months. The primary end point is time to disease progression.

Summary

Our understanding of BPH has greatly improved in recent years. The emergence of the 5ARI finasteride has shifted the therapeutic focus towards delaying disease progression rather than solely treating the symptoms. A second 5ARI, dutasteride, which inhibits both type 1 and type 2 isoenzymes, suppresses DHT more extensively. It is also currently being studied as a primary prevention therapy in men at risk of developing prostate cancer and also as secondary prevention in men with low-grade cancer.

Note: At the time of printing, in Canada, dutasteride is currently not approved for prevention or treatment of prostate cancer, or in combination therapy in the treatment of benign prostatic hyperplasia.