Reports

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.

101st Annual Meeting of the American Urological Association (AUA)

Atlanta, Georgia / May 20-25, 2006

Research into the origin of enlarged prostate recently has led to the examination of the role of chronic inflammatory infiltrates. In the Medical Therapy of Prostatic Symptoms (MTOPS) trial, 40% of biopsy specimens had evidence of chronic inflammatory infiltrates, which were associated with older age, larger prostates and higher levels of prostate-specific antigen. During 4.5 years of follow-up, 21.4% of patients with inflammatory infiltrates had disease progression compared to 13.2% of patients without infiltrates. Presence of the infiltrates was associated with similar increases in symptom progression and need for invasive therapy (Kramer G, Marberger M. Curr Opin Urol 2006;16(1):25-9). Other data have linked elevated levels of C-reactive protein to patient complaints of three or more urinary symptoms (Novara et al. Eur Urol Suppl 2006;5:401-9).

“From a conceptual, prognostic and predictive basis, and maybe ultimately a therapeutic basis, inflammation might be an interesting avenue to explore in the future,” commented Dr. Steven Kaplan, Weill Medical College, Cornell University, New York.

New Prognostic Variables

The urology community had largely dismissed post-void residual (PVR) urine volume as a contributor to BPH, indicated Dr. Kaplan. However, a new analysis of MTOPS data revealed that patients in the highest PVR quartile had the highest rate and relative risk of overall BPH progression. A similar association was seen for symptomatic progression and acute urinary retention (Roehrborn et al. J Urol 2005; 174(suppl):Abst. 1638).

Another emerging area of investigation relates to associations between lower urinary tract symptoms (LUTS) and sexual dysfunction. Epidemiologic studies involving 12,815 men have demonstrated that LUTS is an independent risk factor for sexual dysfunction. The exact nature of the relationship has yet to be determined, Dr. Kaplan told the audience, but available data suggest that treatment with an alpha-blocker, a phosphodiesterase type 5 inhibitor or a combination of agents might improve both LUTS and sexual function (Rosen RC. Curr Opin Urol 2006;16:11-9).

Prostate transition zone volume (TZV) offers another potential prognostic factor and target for therapy in men with BPH/LUTS, Dr. Kaplan continued. A large clinical study of the 5-alpha reductase inhibitor (5ARI) dutasteride showed that it reduced androgenic stimulation to the TZV and peripheral zone volume. Within each tertile of transition zone index (TZI), it improved symptom score and peak urine flow rate compared to placebo. Men in the highest TZI tertile derived the greatest benefit from therapy (Marks et al. J Urol 2005;174(suppl):Abst. 1703, 1704).

Serum testosterone represents another potential consideration in the management of BPH/LUTS and sexual dysfunction. Low serum testosterone levels have been linked to reduced sexual activity, erectile dysfunction, loss of libido, increased prostate volume and greater BMI. Clinical evaluation of dutasteride has shown that the dual 5ARI effectively reduces prostate symptoms across the spectrum of testosterone levels (Marberger et al. J Clin Endocrinol Metab 2006;91:1323-8).

Resolving a Conundrum

Results of the Prostate Cancer Prevention Trial (PCPT) have confirmed that the era of prostate cancer chemoprevention has arrived. Findings showed that among men who were prostate cancer-free at baseline, treatment for up to seven years with the 5ARI finasteride reduced the incidence of prostate cancer by 24.4% compared to placebo (Thompson et al. N Engl J Med 2003;349:215-24).

The actively treated group did have a significantly higher incidence of high-grade prostate cancers (P<0.001), which raised concern that it might have contributed to the induction of high-grade cancer, reported Dr. Claus Roehrborn, Professor and Chair, Department of Urology, University of Texas Southwestern Medical Center, Dallas. However, data that have emerged since publication of the PCPT results have indicated that the disparity in high-grade cancers resulted from a grading artifact, not from a cancer-inducing effect of the 5ARI. Earlier this year, findings from investigators at the University of Toronto-Princess Margaret Hospital also revealed that a larger prostate reduced a man’s chances of having high-grade cancer diagnosed at biopsy (Kulkarni et al. J Urol 2006;175(2):505-9).

Two studies reported here at the AUA meeting provided additional evidence that a large prostate reduces the chances of detecting high-grade cancer on biopsy. In the PCPT, finasteride treatment reduced the incidence of prostate cancer by 25%. A mathematical model that accounted for the 25% reduction demonstrated that the difference in prostate volume between the treatment groups explained the seemingly higher incidence of high-grade cancer in the finasteride group (Serfling et al. J Urol 2006;175(suppl 482):Abst. 1493).

The second study involved data on 3400 men who underwent radical prostatectomy at two large European centres. Pathologic evaluation of prostatectomy specimens showed that incidence of high-grade cancer decreased significantly as prostate volume increased. Prostate volume remained a significant predictor of high-grade cancer in univariate (P<0.005) and multivariate (P<0.001) analysis (Briganti et al. J Urol 2006;175(suppl 482):Abst. 1494).

Therapy Spectrum

To the extent that reduction in prostate volume influences prognosis in BPH/LUTS, dutasteride would appear to offer an advantage over the selective type 2 5ARI finasteride. The dual 5ARI reduces prostate volume by 26% over four years compared to about 18% with finasteride (Roehrborn et al. Urology 2004;63:709-15, McConnell et al. N Engl J Med 2003;349:2387-98).

“People ask me why they should use one 5ARI versus the other,” said Dr. Kaplan. “From my own personal observation, which is not supported by any data, dutasteride inhibits both forms of 5AR, and that seems to be associated with a more homogenous response. When a patient responds to either 5ARI, the response rate is similar with the two agents, but it just seems to me that there are more responders to dutasteride.”

Data from dutasteride BPH trials suggest that the dual 5ARI has a favourable effect on prostate cancer risk. A pooled analysis of data on 4325 men with BPH and no evidence of prostate cancer showed that actively treated men had a greater than 50% reduction in prostate cancer incidence compared to individuals given placebo at 27 months (Andriole et al. Urology 2004;64:537-41).

Summary

The ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial is evaluating dutasteride as a chemopreventive agent (Gomella LG. Curr Opin Urol 2005;15:29-32). The trial design assumes a 25% reduction in prostate volume in the active treatment group, and the men will undergo 10-core biopsies, in contrast to the 6-core biopsies performed in the PCPT. Unlike PCPT, REDUCE involves “at-risk” men who require a prostate biopsy on the basis of clinical evaluation. “The REDUCE population is a group likely to be targeted by any population-based screening approach as optimum candidates for preventive therapy in the future,” stated Dr. Roehrborn. “The 5ARIs provide a promising new option in chemoprevention of prostate cancer. Results from the REDUCE trial will help clarify the role of dual inhibition of 5AR in the chemoprevention of prostate cancer.”