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63rd Annual Meeting of the Canadian Urological Association

Edmonton, Alberta / June 22-25, 2008

Prostate volume (PV) and prostatic-specific antigen (PSA) predict not only disease progression in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) but also what type of treatment strategy is likely best suited to individual patients.

Dr. Claus Roehrborn, Professor and Chair, Department of Urology, Southwestern Medical Center, Dallas, Texas, reminded delegates that urologists consistently underestimate the size of the prostate on transrectal ultrasound examination by an average of about 35% overall, and often by more than 50% in the larger glands (40 mL and over). There is a strong linear relationship between PSA levels and PV which can help physicians more accurately assess prostate size.

Based on both a meta-analysis and the MTOPS (Medical Therapy of Prostatic Symptoms Study), the following thresholds of serum PSA yield a specificity of about 70% (i.e. a 30% false positive rate) to identify PV >30 or >40 mL (Table 1).

Table 1. PSA Thresholds and Prostate Volume: Interrelated Predictors of Disease Progression

There is also solid evidence to support PSA as the most powerful predictor of future prostate growth. In PLESS (Proscar Long Term Efficacy and Safety Study), for example, the per cent change at 48 months in prostate growth among placebo-treated men with BPH was 7.4% for the lowest PSA tertile, 16.2% for the middle PSA tertile, and 22% in the highest PSA tertile. In MTOPS, “the higher the PSA, the greater the overall risk of progression, the greater the risk of symptomatic progression and the greater the risk of urinary retention,” Dr. Roehrborn stated, “and the same was true for PV.”

The large community-based Krimpen study also showed that the odds of men developing BPH was 2.86 if the PSA >3 ng/mL at baseline—the highest odds ratio for clinical progression compared with any other risk factor. Indeed, in several comparisons of annualized end points, rising PSA levels as well as increasing PV each predicted the risk of acute urinary retention (AUR) as well as the need for surgery to a very similar degree.

“There is a strong likelihood we can predict degree of progression by baseline parameters and one set of these predictors is PV and PSA,” Dr. Roehrborn confirmed. “They are interrelated and you can use PSA or PV, and incorporate it into your decision algorithm for the benefit of patients.”

Combination Therapy

More accurate assessment of PV is critical, as Dr. Roehrborn went on to demonstrate, for optimal treatment selection. Current practice often favours an alpha blocker (AB) for LUTS and BPH unless a man has a large prostate, at which point, combination therapy with an AB plus a 5-alpha reductase inhibitor (5-ARI) would be introduced. However, in MTOPS, the risk of symptomatic progression, urinary retention and surgery was reduced by the combination of an AB and the 5-ARI by 67% relative to either drug alone. The mean PV in MTOPS was 31 mL.

The 5-ARI was also responsible for the entirety of the risk reduction in both AUR and the need for surgery in MTOPS, as Dr. Roehrborn noted, the AB being no better than placebo when it came to the need for surgery. Importantly as well, the combination benefited men with prostates >40 mL in size as well as men with smaller prostates between 25 to <40 mL, but not in men with the smallest prostates (<25 mL), where there was no benefit with the combination strategy.

In CombAT (Combination of Avodart and Tamsulosin Study), patients were given the 5-ARI dutasteride, the AB tamsulosin or the combination. Findings at the two-year interim analysis again demonstrated superiority of the combination in mean change in International Prostate Symptom Score (IPSS) from baseline, with dutasteride proving to be superior to tamsulosin after 15 months of therapy. Similarly, mean change in Qmax from baseline was greater in the combination arm than either monotherapy arm, with dutasteride proving superior to tamsulosin after six months of treatment.

Regarding mean change in IPSS from baseline by PV, the combination was again more effective than tamsulosin at about one year in men with baseline PV of 30 to <42 mL. In those with higher baseline PV of 42 to <58 mL, the combination was again superior to tamsulosin by month 3, as it was for men with the highest baseline PV of 58 mL and greater. “It all makes very good sense,” Dr. Roehrborn observed. “The larger the gland, the greater the benefit of the contribution of the 5-ARI over the AB and the greater the relative contribution of the 5-ARI to the overall benefit of the combination.”

Yet results from TIMES (Tolterodine and Tamsulosin in Men with LUTS Study) would suggest that the antimuscarinics are particularly effective in the setting of small prostates (<29 mL) and a low PSA (<1.30 ng/mL). The combination of tolterodine plus tamsulosin in the TIMES study had a significantly favourable effect on frequency as well as severity of urgency and IPSS storage symptoms. Taken together, these findings suggest that in men with a small gland and a low PSA, “the antimuscarinics do a surprisingly good job for storage symptoms,” Dr. Roehrborn noted. If a patient has mostly voiding symptoms, “the ABs alone do a fine job,” he added.

The combination of a 5-ARI plus an AB is “here to stay for larger prostates and higher PSA levels, independent of symptoms,” he continued, adding that “CombAT suggested you could envision treatment with a 5-ARI all by itself because eventually the relative contribution of the AB in CombAT was miniscule in really large prostates.”

Lastly, he indicated that physicians might want to consider the combination of an antimuscarinic plus an AB in patients with refractory storage symptoms.

Attenuating Malignant Progression

Symposium chair moderator Dr. Yves Fradet, Head, Department of Surgery, CHUQ-Université Laval, Quebec City, Quebec, also presented promising preliminary evidence that 5-ARI therapy might attenuate malignant progression in men with low-grade prostate cancer. In a study involving 75 patients, median PSA 5.5 ng/mL at study entry, men received either a 5-ARI or placebo and were followed for a median of 8.8 months before a follow-up 12-core biopsy was carried out.

On follow-up biopsy, no cancer was found in 63% of the group, 20% still had Gleason score 6 disease and only 17% (13 patients) were upgraded to a Gleason score of 7 or more. “These men have such a small focus of tumour on biopsy that even without treatment, you won’t find a small tumour if you redo the biopsy in a significant proportion of patients, so how much of [the undetected cancer] is due to study drug is difficult to say,” Dr. Fradet noted in an interview.

Interestingly, however, investigators did find high-grade cancer quite early on. “We know that at least one patient out of six has a high-grade cancer hidden in the prostate and the other 85% of men don’t,” Dr. Fradet added. “So with this approach, not only are we potentially preventing the growth of low-grade cancer, but we are increasing our capability of detecting high-grade cancer with biopsy fairly early on following initiation of 5-ARI therapy.”

On the Horizon

It is hoped that the ongoing REDEEM (Reduction with Dutasteride of Clinical Progression Events in Expectant Management) study will definitively answer whether 5-ARI therapy can extend the time to clinical progression in men with low-grade prostate cancer (Gleason score 6 or less and a PSA <11 ng/mL) treated with dutasteride for three years.

A review of the Prostate Cancer Prevention Trial (PCPT) data by Dr. Laurence Klotz, Professor of Surgery, University of Toronto, Ontario, strongly suggests that like finasteride, dutasteride will reduce the risk of largely significant prostate cancer (Gleason 5 and 6) in high-risk men without increasing high-grade disease, as re-analyses of the PCPT data clearly demonstrated. The ongoing REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial was designed to test the same hypothesis as was tested in the PCPT in a similar cohort treated this time with dutasteride.