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.

Urology Update 2006

Toronto, Ontario / November 3-4, 2006

As discussed by Dr. John Trachtenberg, Professor of Surgery, Division of Urology, University of Toronto, Ontario, benign prostatic hyperplasia (BPH) frequently gives rise to lower urinary track symptoms (LUTS) such as urgency, frequency, hesitancy, inability to empty the bladder and urinary retention.

As recommended in Canadian guidelines, physicians should objectively assess a patient’s symptoms with a recognized symptom scale such as the International Prostate Symptom Score (Nickel et al. Can J Urol 2005;12(3):2677-83). A prostate-specific antigen (PSA) test should also be offered to any man who is expected to live at least another 10 years and for whom identification of prostate cancer would affect management strategies. Treatment choices should be governed both by symptom severity, bother and patient preference. If symptoms are mild, they can be controlled by fluid restriction, avoidance of caffeine, alcohol and diuretics, organized voiding, pelvic floor exercises, and treatment of constipation.

When medical therapy is indicated, one of the four currently available alpha-blockers is recommended. It may be accompanied by a 5-alpha reductase inhibitor, such as finasteride or dutasteride, for patients with LUTS associated with demonstrable prostatic enlargement.

MTOPS Findings

The best study demonstrating the effectiveness of an alpha-blocker and a 5-alpha reductase inhibitor was the MTOPS (Medical Therapy of Prostate Symptoms). Over 3000 men with moderate to severe LUTS symptoms due to BPH were randomized to either placebo, doxazosin alone, finasteride alone or the combination of doxazosin and finasteride. At a mean follow-up of 4.5 years, the risk of clinical progression (defined as an increase above baseline of at least four points in the American Urological Association symptom score), acute urinary retention, urinary incontinence, renal insufficiency or recurrent urinary tract infections were reduced by 39% in the doxazosin arm and by 34% in the finasteride arm compared with placebo. In the combination arm, clinical progression was decreased by 66%, which was significantly greater than for either treatment alone. Interestingly, the risk of men progressing to either acute urinary retention or the need for surgery was significantly reduced by both combination therapy and finasteride, but not doxazosin monotherapy.

“This was a really important trial because it gave us an idea of who is at risk and also what is likely to mitigate that risk,” Dr. Trachtenberg observed. For example, three risk categories emerged when MTOPS patients were differentiated according to prostate volume or surrogate PSA levels. Those at lowest risk for clinical progression were patients with a small prostate size (<25 cc). Patients with a prostate volume between 25 and 40 cc were at medium risk for progression while those at the highest risk were patients with prostates >40 cc. “If you treat only those at highest risk with a PSA >4 ng/mL or a prostate volume >40 cc, you only need to treat five patients to prevent one from progressing,” Dr. Trachtenberg told the audience.

Conversely, those with the smallest prostates or a PSA <1.5 ng/mL “do just as well on an alpha-blocker and do not need combination therapy,” he noted. According to Dr. Trachtenberg, those in the mid-risk category should receive treatment according to “clinical judgment.” The guidelines also indicate that alpha-blocker therapy may be discontinued after six to 12 months of therapy if patients respond to the combination strategy.

“The biggest effect from a clinical perspective from this trial was that the 5-alpha reductase inhibitors truly prevented progression to retention and surgery,” Dr. Trachtenberg emphasized, “and from a patient’s perspective, they certainly would want to avoid retention or surgery.”

BPH and Prostatitis

As discussed by Dr. Curtis Nickel, Professor of Urology, Queen’s University, Kingston, Ontario, prostatitis is common among healthy men of all ages, but there is considerable overlap with BPH. Unlike BPH, which is characterized by voiding LUTS, prostatitis is primarily characterized by pain, notably pain or discomfort on ejaculation. The most common chronic prostatitis (CP) or chronic pelvic pain syndrome (CPPS) is category III CP/CPPS. A recent National Institutes of Health-sponsored study showed that men with moderate to severe long-standing symptoms related to CP/CPPS who had previously received alpha-blocker therapy did not significantly benefit from either ciprofloxacin or tamsulosin alone, nor from both agents combined, at least at the end of six weeks.

In contrast, the same agents have proven to be effective in newly diagnosed, alpha blocker-naive patients, although they need to be continued for longer than six weeks to be effective. The only randomized, placebo-controlled trial using validated prostatitis outcomes demonstrated that 75% of men treated with finasteride experienced mild improvement in symptoms from chronic non-bacterial prostatitis vs. 54% of placebo controls, while 44% and 27% reported a moderate or marked improvement, respectively. “BPH and CP are common medical conditions that frequently co-occur in older men,” Dr. Nickel concluded, “and alpha blockers and perhaps the 5-alpha reductase inhibitors have a role to play in the management of men who suffer from both conditions.”

PCPT Findings

Most importantly from a chemoprophylactic perspective are findings from the PCPT (Prostate Cancer Prevention Trial). As the largest interventional study reported in urology, this National Cancer Institute-sponsored study showed that finasteride reduced the risk of detectable prostate cancer by 25% compared to placebo controls. Much was subsequently made of the observation that there was an absolute increase of 1.3% of high-grade (Gleason score 8 to 10) tumours in the finasteride arm.

Speaking on behalf of the Canadian Consensus group who reviewed data from the PCPT, Dr. Laurence Klotz, Professor of Surgery, Division of Urology, University of Toronto, stated, “Subsequent analyses strongly suggested that the increased prevalence [of high-grade tumours] was due to a detection bias caused by the reduction in prostate volume in patients on finasteride compared to patients on placebo. The second key part of this,” Dr. Klotz continued, “is that the PSA test is actually more accurate in patients who have been treated with a 5-alpha reductase inhibitor. This means that if we put a patient on a 5-alpha reductase inhibitor and the PSA fails to drop to less than 50% of its baseline value, this is a very important indicator of cancer and the presence of a high-grade tumour.”

After independently reviewing PCPT data, Canadian consensus conference members concluded that the 5-alpha reductase inhibitors are “appropriate and effective treatments” for patients with LUTS seen in association with prostatic enlargement (>30 cc). Assuming a class effect, “all combinations of alpha-antagonists and 5-alpha reductase inhibitors will be equally effective,” researchers added. Nevertheless, the “most robust data” supporting the safety and efficacy of combination therapy are for doxazosin and finasteride, the group noted. For men who have large prostates and LUTS, “5-alpha reductase inhibitors should be considered both for treatment of BPH and prostate cancer risk reduction.” As for prostate cancer prevention, it was agreed that the PCPT did show that finasteride significantly reduced the prevalence of histologically proven prostate cancer, though members noted that “a class effect with respect to dutasteride has not yet been established” in this regard.

Consequently, it was deemed “appropriate” to discuss chemoprevention with finasteride for men who are concerned about prostate cancer, highlighting both the benefits and risks associated with long-term treatment, and subsequently monitoring men for prostate cancer once treatment is initiated.