Incontinence
Incontinence Incontinence New Drug Under Development for Stress and Urge Urinary Incontinence Reviewed by Hitoshi Masuda, MD, PhD, Michael Chancellor, MD Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA [Rev Urol. 2004;6(4):217-218] © 2004 MedReviews, LLC Duloxetine vs Placebo in the Treatment of Stress Urinary Incontinence: A FourContinent Randomized Clinical Trial Millard RJ, Moore K, Rencken R, et al. BJU Int. 2004;93:311-318. uloxetine is the first new drug under evaluation for the treatment of stress urinary incontinence. This is a report on a US Food and Drug Administration phase III study of duloxetine treatment for women with stress urinary incontinence (SUI) from around the world. The study included a double-blind, placebo-controlled trial of 458 women age 27 to 79 years. Women with predomi- D Duloxetine is the first oral agent for the indication of SUI. nantly SUI were identified using a validated clinical algorithm and received placebo randomly (231) or duloxetine 40 mg 2 times per day (227) for a 12-week period. The questionnaires for incontinence episode frequency (IEF) and the incontinence quality of life (I-QOL) were among the primary outcomes variables with mean baseline IEF at 18.4 per week. IEF with duloxetine showed a significantly greater median decrease than did placebo (54% vs 40%, P = .05) and showed significant improvements in quality of life than placebo (I-QOL score increases of 10.3 vs 6.4, P = .007). The improved duloxetine results were also associated with greater voiding intervals when compared with placebo (20.4 minutes vs 8.5 minutes, P < .001). Interestingly, the placebo responses were greater (10.7% and 12.5%) than in 2 other European and North American phase III trials, which may point to a greater num- ber of patients who were naïve to incontinence management. Rates for discontinuation due to side effects ranged from 1.7% for placebo to 17.2% for duloxetine (P < .001), with nausea being the most common reason for discontinuation (3.1%). Nausea was the most common side effect for duloxetine. However, nausea was reported to be mild to moderate for most patients (81%). Nausea did not worsen in any of the patients and in 60% of patients resolved within a 7-day period and in 86% of patients resolved within a month (for ongoing patients). Of the women who experienced some nausea with duloxetine, 88% of them completed the trial. The safety and efficacy data from this study support duloxetine as the first oral agent for the indication of SUI. Duloxetine could fill an unmet medical need by providing a primary treatment for women who seek a pharmacotherapy treatment for their SUI, for those who are unable or unwilling to perform pelvic floor muscle training, or for those who wish to postpone or avoid continence surgery. Randomized, Double-Blind Placebo- and Tolterodine-Controlled Trial of the Once-Daily Antimuscarinic Agent Solifenacin in Patients with Symptomatic Overactive Bladder Chapple CR, Rechberger T, Al-Shukri S, et al. BJU Int. 2004;93:303-310. An international, multicenter, randomized, double-blind trial, conducted at 98 centers, was presented comparing tolterodine and placebo with 2 doses of a new antimuscarinic drug, solifenacin, in patients with symptoms of overactive bladder (OAB), which include urgency, incontinence, and frequency. Adult patients with symptomatic OAB for 3 months were eligible. After a single-blind 2-week Both solifenacin at 5 mg and 10 mg once daily were effective and well tolerated for the treatment of OAB. placebo run-in period, patients were randomized equally to a 12-week double-blind treatment with tolterodine 2 mg twice daily, placebo, or solifenacin 5 mg or 10 mg once daily. Efficacy variables included change from baseline in the mean number of urgency, incontinence, and urge incontinence episodes, and change from baseline in voids/24 h and mean volume voided/void. A total of 1281 patients were enrolled; 1081 were randomized and 1077 treated and 1033 evaluated for efficacy. The change from baseline (1.41, 32.7%) in the mean VOL. 6 NO. 4 2004 REVIEWS IN UROLOGY 217 Prostate Cancer continued number of urgency episodes in a 24-hour period, when compared with placebo, was significantly lower with solifenacin 5 mg (2.85, 51.9%) and 10 mg (3.07, 54.7%; both P < .001), but not with tolterodine (2.05, 37.9%; P = .0511). There was a statistically insignificant decrease in episodes of incontinence with tolterodine (1.14; P = .1122) but a significant decrease in patients treated with solifenacin 5 mg (1.42; P = .008) and 10 mg (1.45; P = .0038). The mean number of voids per 24 hours was significantly lower in patients receiving tolterodine (1.88, 15%; P = .0145), solifenacin 5 mg (2.19, 17%) and 10 mg (2.61, 20%; both P < .001) than with placebo (1.20, 8.1%). With all 3 active treatments the mean volume voided/void was significantly higher (P < .001). The use of solifenacin was well tolerated, with dry mouth, mostly mild, the most commonly reported side effect. This was reported in 18.6% of patients receiving tolterodine and in 4.9% receiving placebo, while also reported in 14.0% receiving 5 mg and 21.3% receiving 10 mg solifenacin. At 5 mg and 10 mg once per day, solifenacin was effective and well tolerated for the treatment of OAB patients with acceptable anticholinergic side effects reported. As is true for all antimuscarinic agents, side-effect profiles with solifenacin should be balanced against efficacy. The low discontinuation rates should provide evidence for clinically meaningful efficacy and tolerability profile. Prostate Cancer Management of Localized Prostate Cancer Reviewed by Michael K. Brawer, MD Northwest Prostate Institute, Northwest Hospital, Seattle, WA [Rev Urol. 2004;6(4):218-219] © 2004 MedReviews, LLC he optimum management of clinically localized adenocarcinoma of the prostate remains controversial. The more aggressive approaches involving radical prostatectomy or radiation therapy have generally been applied in the United States. In Western Europe and particularly Scandinavia, watchful waiting has been primarily advocated. A landmark publication by Johansson and colleagues reported in the Journal of the American Medical T 218 VOL. 6 NO. 4 2004 REVIEWS IN UROLOGY Association in 1997 demonstrated that without initial treatment, only a small proportion of patients actually died from prostate cancer within 15 years of diagnosis.1 Natural History of Early, Localized Prostate Cancer Johansson JE, Andrén O, Andersson SO, et al. JAMA. 2004;291:2713-2719. This year, Johansson and colleagues have provided an update of their initial study.2 The mean follow-up on the initial cohort is now 21 years, and 91% of the patients have died. A total of 223 patients were initially enrolled in this population-based study. Outcome parameters included progression-free, cause-specific, and overall survival. Of the total, 39 men (17%) developed metastatic disease. The authors noted that most patients had a relatively uneventful course during the initial 15 years of monitoring. However, patients suffered a significant decrease in progression-free survival (from 45% to 36%) with longer follow-up. Metastasis-free survival decreased from 76.9% to 51.2%. Prostate cancer–specific survival also decreased from 78.7% to 54.4%. Perhaps most dramatically, the prostate cancer mortality rate increased from 15 per 1000 person-years during the first 15 years of follow-up to 44 per 1000 person-years in the cohort followed beyond 15 years. The authors concluded, “Although most prostate cancers diagnosed at an early stage have indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.” Clearly, this is an important addition to the prostate cancer literature. The authors are to be commended for continuing to follow their initial cohort. Several caveats should be noted. At the time of diagnosis, the average age was 72 years, which is older than that at current diagnosis. Thus, the issue of competing mortality is more problematic in the Johansson series. No comparison groups (ie, men treated with surgery or radiation from the initial cohort) are provided. This renders meaningful comparison with those seeking active treatment difficult, at best. The power of a randomized clinical trial cannot be minimized. Johansson and associates, as well as others, have clearly stated that the only way to compare treatment with expectant management is by randomized clinical trials. A trial in which men were randomized to radical prostatectomy versus watchful waiting conducted in Scandinavia was reported by Holmberg and associates in 2002.3