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.

29th Congress of the Société Internationale d’Urologie

Paris, France / September 2-6, 2007

The PCPT (Prostate Cancer Prevention Trial) randomized 18,882 cancer-free men with a prostate-specific antigen (PSA) level of ³3.0 ng/mL and a normal digital rectal examination (DRE) to either the 5-alpha reductase inhibitor (5ARI) finasteride 5 mg/day or placebo to determine if active treatment could reduce the development of cancer. They were followed-up with yearly DRE and PSA examinations for seven years.

As reported by Dr. Ian M. Thompson, Chair and Professor, Department of Urology, University of Texas Health Science Center, San Antonio, biopsy was recommended among placebo-treated men in this study during yearly examinations if the DRE was abnormal or PSA was >4.0 ng/mL. PSA levels in actively-treated participants were adjusted periodically to insure a similar number of biopsy recommendations. The study’s Data and Safety Monitoring Committee terminated it 15 months early because of overwhelming evidence that the primary end point had been achieved. Finasteride significantly reduced the risk of prostate cancer by 24.8% (P<0.001), with an overall reduction of about 350 tumours. At the same time, however, 37 more high-grade tumours were observed than was expected, and that has given pause to many front line physicians.

Enhanced Sensitivity of Tumour Detection

“But basically this was a detection bias, which is a benefit in disguise,” Dr. Thompson told the audience. “The majority of these high-grade tumours were found in biopsies driven by PSA and DRE, but at the end of the trial after seven years’ exposure to the drug, there was no increased risk; no more high-grade tumours were detected beyond the original 37. Now, if you are going to find prostate cancer, you must suspect it by PSA or DRE and you must diagnose it. In other words, the biopsy needle must strike the tumour, and that is made easier with finasteride, so high-grade tumours are more easily detected.”

According to Dr. Thompson, the 5ARI dramatically improves the sensitivity of PSA for prostate cancer detection. It improves sensitivity of DRE (from 16.7% to 21.3%) and biopsy for cancer and high-grade disease. For example, using a PSA cut-off point of 4 ng/mL, sensitivity for detection of high-grade prostate cancer is only 24% with placebo, but increases dramatically to 37.8% in patient groups taking finasteride. That is also true for high-grade disease; with a Gleason score of 7 or above, cancer detection sensitivity increases from 40% to 53%; a Gleason score of 8 improves sensitivity from 50% to almost 65%. The sensitivity of DRE is similarly enhanced.

“As will be published in the next issue of the Journal of the National Cancer Institute, finasteride improves biopsy detection of prostate cancer,” Dr. Thompson reiterated. “If you have a large gland, the likelihood that you will strike the high-grade component is reduced. The simple way to look at this is that if you have high-grade cancer in your prostate and are not taking the 5ARI, the needle will miss it 50% of the time. With finasteride, presumably because of the gland size reduction, you will hit it 70% of the time. The PCPT confirmed that because finasteride decreases prostate gland volume by 25%, high-grade cancer, if present, is more likely to be detected in a man receiving finasteride and more often missed with placebo.”

This is a major advantage for men undergoing screening who are relying on a biopsy grade to determine if aggressive treatment is needed, Dr. Thompson observed. Another finding he characterized as “fascinating” is that risk reduction is essentially the same across all risk strata. He explained that most men who get prostate cancer are not at high risk at their initial visit, so a man has a choice: if he chooses not to take the 5ARI, he has a one in six or seven chance of developing cancer and about a 9% risk of BPH side effects at seven years. If high-grade cancer is present, it will be missed half the time and the patient will run a greater risk of unnecessary biopsies in the future due to elevated PSA, an even greater risk that the cancer will be missed by DRE and a still higher risk of prostatic intraepithelial neoplasia (PIN). On the other hand, choosing finasteride will render PSA and DRE more sensitive to cancer detection and improve the chances of finding existing high-grade disease by 40% while reducing the risk of prostate cancer by 25% and at the same time lowering the risk of urologic complications for BPH and the high risk of PIN.

Regarding the side effects of finasteride, not only was there a lower rate of transurethral resection of the prostate, urinary retention, BPH and prostatitis, but also an evaluation within the PCPT study protocol found no clinically significant effect on sexual function. The agent’s impact on mortality, however, remains problematic, Dr. Thompson commented. For a chemoprevention trial to show a reduction in mortality, a sample size of 200,000 men would have to be recruited. The primary goal of chemoprevention is to reduce the burden of disease and treatment complications.

“There is now an effective way to prevent the most common cancer in men. It is far better to prevent the disease than to cure it, since prevention eliminates the nuisance, suffering and consequences of its treatment,” Dr. Thompson concluded.

Prostate Volume Reduction: Findings from MTOPS and PLESS

Delivering a report prepared by Dr. Steven Kaplan, Weill Cornell Medical College, New York, Dr. Claus Roehrborn, Chairman, Department of Urology, University of Texas Southwestern Medical Center, Dallas, told listeners that combination therapy with doxazosin and finasteride compared to monotherapy with either of the two agents provides the greatest benefit for lower urinary tract symptoms (LUTS) patients with small- to moderate-size prostates of 25 to 40 cc. Combination treatment significantly reduces the risk of clinical BPH progression compared to either treatment alone.

“It is now being hypothesized that a reduction in volume even in these small prostates is due to finasteride and was additive to the combination therapy benefit,” Dr. Roehrborn noted. Consequently, more than 6000 men with LUTS or BPH were enrolled in the MTOPS (Medical Therapy of Prostatic Symptoms) and PLESS (Proscar Long-term Efficacy and Safety Study) studies, respectively, to determine the effect of finasteride 5 mg, either alone or in combination with doxazosin 4 to 8 mg, on total prostate volume across the full range of baseline total prostate volume values in MTOPS; PLESS compared finasteride to placebo only. Treatment duration averaged four to 4.5 years. The primary end points were urinary symptoms in PLESS and clinical progression in MTOPS.

Dr. Roehrborn reported that patients on long-term treatment with doxazosin in MTOPS experienced increased total prostate volume between 2% and 10%, depending on their baseline volume. Patients treated with the 5ARI achieved a clinically significant reduction >20% and combination therapy patients had a similar 20% reduction in prostate size. A 20% reduction was seen over the entire spectrum in men with relatively small prostates (25 to 30 mL), as well as those with moderate-size (30 to <40 mL) and enlarged prostates (³40 mL) at baseline. The very smallest prostates achieved only a mean reduction of about 15%.

“The MTOPS study showed a superior risk reduction in overall progression for finasteride compared to doxazosin in men with large- and moderate-size prostates [25 to 40 cc] and there is speculation that this is due to finasteride-induced prostate volume reductions,” Dr. Roehrborn stated. “The question remains whether the treatment leads to a consistent reduction.”