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Issues in Benign Prostatic Hyperplasia and Prostate Cancer Diagnosis and Prevention

Optimizing Prostate Health Through Disease Risk Reduction

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.

28th Congress of the Société internationale d’urologie

Cape Town, South Africa / November 12-16, 2006

The incidence, prevalence and burden of benign prostatic hyperplasia (BPH) and prostate cancer are expected to increase over the next two decades. Among the reasons is the transition of male baby boomers from middle age to their senior years, when most prostate problems emerge. In 2030, the population of US men aged at least 65 will be double that of the year 2000, and similar demographic changes will occur worldwide. At the same time, enhanced public awareness of the importance of prostate health is bringing more men to their physicians’ offices. This development may also produce more cases of disease, observed Dr. Claus Roehrborn, Chairman, Department of Urology, University of Texas Southwestern Medical Center, Dallas.

Relevance of Two Isoenzymes

Testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase (5AR). DHT is the principal androgen responsible for prostate development and growth, as well as in the emergence of prostate disease such as BPH and cancer. In men with untreated BPH, the prostate continues to grow even at levels of testosterone that are considered hypogonadal, because DHT—which is 10 times more potent than its precursor—continues to be produced. With inhibition of 5-alpha reductase, however, the DHT androgen receptor complex shrinks and the hormonal balance is at least partially restored. Altering the hormonal milieu is also considered crucial to both the treatment and prevention of prostate cancer.

It has recently been discovered that there are two isoenzymes of 5-alpha reductase: type 1 (5AR1) and type 2 (5AR2). The messenger RNA expression and activity of 5AR1 and 5AR2 differ in normal prostate, tissue affected by BPH, and prostate tumours. A study by Iehle et al. (J Steroid Biochem Molec Biol 1999;68:189-95) determined that the expression of both isoenzymes is slightly but significantly higher in BPH than in normal tissue. In cancerous prostate tissue, only 5AR1 was significantly higher than normal, and the level of 5AR2 was lower in cancer than in BPH. “In primary prostate cancer, there is a slight shift that takes place, in which type 1 is overexpressed... and the expression of type 2 decreases compared with BPH and normal tissue,” confirmed Dr. Roehrborn. According to a recent report, 5AR1 protein expression is also increased and 5AR2 expression is decreased in prostatic intra-epithelial hyperplasia, a condition predictive of cancer development. The situation alters as the tumour progresses, however: expression of both isoenzymes increases in advanced and metastatic prostate cancer (Thomas et al. Prostate 2005;63:231-9).

Experiments conducted on animal and human prostate samples have also confirmed that in cancerous as compared with normal tissue, the activity of 5AR2 is significantly decreased and 5AR1 activity increased (Xu et al. Clin Cancer Res 2006;12:4072-9). “The activity of the type 2 enzyme decreases by 90% when we go from BPH tissue to primary prostate cancer to recurrent prostate cancer, while the activity of type 1 remains nearly unchanged,” Dr. Roehrborn explained.

These observations suggest that it may be important to block both types of 5AR to ensure low levels of DHT are achieved in the management of BPH and in the prevention of prostate cancer, he indicated.

5-alpha Reductase Inhibition and Cancer Prevention

Chemoprevention or delayed onset of prostate cancer in men at risk was first shown to be possible in the Prostate Cancer Prevention Trial (PCPT), in which seven years of finasteride treatment was associated with a 24.8% decrease in tumour incidence compared with placebo. At therapeutic doses, finasteride blocks only 5AR2, Dr. Roehrborn noted. A dual 5AR inhibitor, dutasteride, has been shown to offer greater and more consistent DHT suppression. In one comparison, more than 85% of men receiving dutasteride and 2.2% of those receiving finasteride achieved at least 90% suppression of DHT (Roehrborn et al. Eur Urol 2003;1(suppl):161).

Preliminary evidence for a chemopreventive effect of dutasteride emerged in studies of the agent for the treatment of BPH. In one analysis, the period prevalence of prostate cancer was reduced by 50% (Andriole et al. Urology 2004; 64:537-41). Other studies suggest that dutasteride treatment reduces the volume of prostate tumours. These findings, which Dr. Roehrborn described as “intriguing,” encouraged the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study which will assess the cancer preventive impact of dutasteride vs. placebo in 8256 men aged 50 to 75 with prostate-specific antigen (PSA) between 2.5 and 10 ng/mL, prostate volume £ 80 mL, International Prostate Symptom Score (IPSS) <25 and maximum urine flow rate >5 mL/sec. All the patients will undergo biopsies to document absence of prostate cancer at baseline and follow-up biopsies after two and four years. “We would like to see a risk reduction of more than 25% and if we do, then it’s likely we can achieve cost-effective chemoprevention of prostate cancer,” Dr. Roehrborn remarked.

Addressing BPH Symptoms and Progression

BPH may initially be primarily a source of annoyance due to urinary frequency and reduced flow. However, the condition may also eventually progress to serious and costly complications such as acute urinary retention or may require surgical intervention. Men aged 60 or older have a 23% risk of urinary retention over the remainder of their lifetime. The risk reaches nearly 40% in men with large prostate volumes and voiding symptoms, added Dr. Roehrborn. As demonstrated in the Medical Therapy of Prostatic Symptoms (MTOPS) study, PSA levels of >1.6 ng/mL is also significantly associated with acute urinary retention, BPH-related surgery and symptom progression. As such, it is frequently reasonable to institute therapy aimed at preventing long-term adverse outcomes, remarked Dr. Francesco Montorsi, Associate Professor of Urology, Università Vita-Salute San Raffaele, Milan, Italy. Despite the bother engendered by BPH symptoms, “our patients are more worried about long-term effects,” he told the audience.

Effective options for addressing the symptoms of BPH include alpha blockers and 5AR inhibitors. The former offer rapid symptom relief but do not influence prostate volume or long-term outcome of BPH. Finasteride and dutasteride relieve symptoms somewhat more slowly than alpha blockers but suppress DHT, thereby reducing prostate volume and decreasing the risk of disease progression. A regimen combining both classes may be useful, especially in patients at relatively high risk of BPH progression and who are bothered by their symptoms. In the MTOPS trial, subjects who received both finasteride and doxazosin rather than monotherapy with either agent experienced a significant reduction in the risk of clinical progression of BPH. The combination and finasteride monotherapy also significantly decreased the long-term risk of acute urinary retention and surgery for BPH.

The four-year Combination of Avodart and Tamsulosin (CombAT) study, now in progress, will expand the evidence collected by MTOPS by evaluating the effect on symptoms and BPH progression of the dual 5AR inhibitor dutasteride (0.5 mg q.d.), the alpha blocker tamsulosin (0.4 mg q.d.) and a regimen combining both agents. The study population differs from that of MTOPS in that participants were deemed at substantial risk of BPH disease progression according to PSA (³1.5 ng/mL) and prostate volume (³30 cc). The investigators will report changes to patients’ IPSS after a follow-up of two years and disease progression end points (acute urinary retention or BPH-associated surgery) after four years. “This is a major study which will tell us whether or not combination therapy is really the way to go,” Dr. Montorsi predicted.

Summary

Although BPH and prostate cancer are unrelated disease entities, they frequently coexist in aging men. A unified BPH management and chemopreventive approach involving 5AR inhibition now appears reasonable and within reach, Dr. Roehrborn suggested. Studies such as CombAT and REDUCE will assist in the appropriate and cost-effective application of these agents by helping determine the patient groups with the greatest need, he concluded.

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