Phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.

BACKGROUND: PRX302 is a prostate specific antigen (PSA)-activated pore-forming protein toxin under development as a targeted approach for improving lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) without affecting sexual function. OBJECTIVE: To evaluate the safety and efficacy of PRX302 in men with moderate to severe BPH. DESIGN, SETTING, AND PARTICIPANTS: Eligible subjects were refractory, intolerant, or unwilling to undergo medical therapies for BPH and had International Prostate Symptom Score (IPSS) ≥12, a quality of life (QoL) score ≥3, and prostate volumes between 30 and 80 g. Fifteen patients were enrolled in phase 1 studies, and 18 patients entered phase 2 studies. INTERVENTIONS: Subjects received intraprostatic injection of PRX302 into the right and left transition zone via a transperineal approach in an office-based setting. Phase 1 subjects received increasing concentrations of PRX302 at a fixed volume; phase 2 subjects received increasing volumes per deposit at a fixed concentration. MEASUREMENTS: IPSS, QoL, prostate volume, maximum flow rate (Q(max)), International Index of Erectile Function, serum PSA levels, pharmacokinetics, and adverse events were recorded at 30, 60, 90, 180, 270, and 360 d after treatment with PRX302. RESULTS AND LIMITATIONS: Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had ≥30% improvement compared to baseline in IPSS out to day 360. Patients also experienced improvement in QoL and reduction in prostate volume out to day 360. Patients receiving ≥1 ml of PRX302 per deposit had the best response overall. PRX302 had no deleterious effect on erectile function. Adverse events were mild to moderate and transient in nature. The major study limitation was the small sample size. CONCLUSIONS: The promising safety profile and evidence of efficacy in the majority of treated subjects in these phase 1 and 2 studies supports further development of PRX302 as a minimally invasive, targeted treatment for BPH.

A multicenter, randomized, double-blind, parallel group pilot evaluation of the efficacy and safety of intravesical sodium chondroitin sulfate versus vehicle control in patients with interstitial cystitis/painful bladder syndrome.

OBJECTIVE: The goal of this pilot study was to gather information on differences between intravesical chondroitin sulfate and inactive vehicle control for treatment of interstitial cystitis/painful bladder syndrome (IC/PBS). METHODS: This was a prospective, randomized, double-blind, inactive vehicle-controlled, 12-week study (6-week treatment period, followed by a 6-week follow-up period) in patients with IC/PBS. Patients were randomized to weekly intravesical treatment with 2.0% sodium chondroitin sulfate in phosphate-buffered saline or intravesical vehicle control. Primary efficacy analysis compared responders (moderately or markedly improved) according to the 7-point Global Response Assessment. Secondary endpoints include questionnaires focused on symptoms and quality of life. RESULTS: Sixty-five evaluable patients were randomized. At the primary endpoint analysis (week 7), 22.6% of the vehicle control group were responders compared with 39.4% of the active therapy group (P = .15). There was no statistically significant difference for any of the secondary endpoints. Overall, 76.9% of the patients in the study reported at least 1 adverse event; most were mild or moderate, the majority associated with the vehicle control treatment. Nine nonserious intervention-related adverse events were reported in 3 patients in the vehicle control group compared with 2 in 1 patient in the active treatment group. CONCLUSION: The difference in treatment effect in this small underpowered study was not statistically significant, although twice as many patients reported a clinically significant benefit with intravesical chondroitin sulfate treatment compared with vehicle control treatment. This trial provides data required to design a well-powered randomized vehicle-controlled trial to determine the true efficacy of this potentially promising therapy.

Randomized controlled multisite trial of injected bulking agents for women with intrinsic sphincter deficiency: mid-urethral injection of Zuidex via the Implacer versus proximal urethral injection of Contigen cystoscopically.

OBJECTIVES: To determine whether Zuidex using a non-cystoscopy mid-urethral injection technique produces as good a result (i.e. was not inferior) as Contigen injected endoscopically at the bladder neck in the treatment of urinary stress incontinence secondary to intrinsic sphincter deficiency in adult women. METHODS: A prospective 2:1 randomized trial of mid-urethral injections of Zuidex-Implacer vs proximal urethral cystoscopic injections of Contigen was performed in 344 women with intrinsic sphincter deficiency at 23 North American sites, and followed up for >1 year from last treatment. RESULTS: Outcomes at 12 months from last treatment failed to demonstrate that mid-urethral injected Zuidex was equivalent to cystoscopically injected Contigen in primary and secondary outcome variables. The primary outcome, the proportion of women who achieved a 50% reduction in urinary leakage on provocation testing, was achieved in 84% of Contigen-treated women vs 65% of Zuidex-treated women. CONCLUSIONS: Confounding multiple variables inherent in the study design make a detailed analysis of study outcomes difficult.

Intravesical mycobacterial cell wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed.

PURPOSE: We assessed the clinical efficacy and safety of mycobacterial cell wall-DNA complex after intravesical administration in patients with carcinoma in situ in whom prior therapy with bacillus Calmette-Guerin failed or in those who were treatment naïve. MATERIALS AND METHODS: Patients received 6 weekly instillations of 4 or 8 mg mycobacterial cell wall-DNA complex (formulated as an emulsion) followed by 3 weekly instillations at weeks 12 and 24. Efficacy and safety were evaluated throughout the treatment phase and at months 12 and 18. RESULTS: A total of 55 patients (mean age 74 years, 74.6% male) received 4 mg (25) or 8 mg (30) mycobacterial cell wall-DNA complex emulsion. All patients were previously treated with bacillus Calmette-Guerin except for 8 who were treatment naïve and 2 who received chemotherapy. In the intent to treat population the complete response rate was 27.3% at weeks 12 and 26 in the 4 mg group while 46.4% of patients receiving 8 mg had a complete response at both points. Mycobacterial cell wall-DNA complex was well tolerated by both dose groups. Overall 90% of all adverse events were mild to moderate in severity. CONCLUSIONS: Mycobacterial cell wall-DNA complex has shown antineoplastic activity in patients with bladder cancer with less toxicity than that associated with bacillus Calmette-Guerin administration. The tolerance and efficacy of mycobacterial cell wall-DNA complex might hold promise for the treatment of carcinoma in situ of the bladder.

Canadian guidelines for the management of benign prostatic hyperplasia.

OBJECTIVE: To develop the first Canadian guidelines for the management of lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH). METHODS: These guidelines, developed under a mandate provided by the Canadian Urological Association (CUA), were a collaborative effort between the CUA guidelines committee and the Canadian Prostate Health Council. BPH guidelines developed by the American Urological Association, the European Association of Urology, the World Health Organization International Consultation on BPH, and similar committees from Germany, Sweden and Australia were reviewed. The committee further reviewed a systematic literature search, updated to May 2004, and systematically derived Canadian urological opinion data. RESULTS: The subsequent Canadian BPH guidelines were developed as an evidence based consensus among the committee members. Mandatory evaluation includes history, physical examination and urinalysis, while a symptom inventory and PSA in selected patients are recommended. Serum creatinine, uroflow, voiding diary, post void residual and sexual function questionnaire are optional. Unless there is an indication, other related tests are not recommended. Treatment choices should be governed by the severity of the symptoms, bother and patient preference. Guidelines for medical, surgical and minimally invasive treatment as well as special considerations are described in terms of guideline, option and recommendation. CONCLUSIONS: Diagnostic and treatment guidelines for BPH reflect the Canadian social priorities, economics, socialized medical practice, manpower issues, and medicolegal considerations.

Neoadjuvant hormone therapy and external-beam radiation for localized high-risk prostate cancer: the importance of PSA nadir before radiation.

PURPOSE: To examine the impact of various patient, disease, and treatment characteristics on outcome in patients treated with neoadjuvant hormone therapy (NAHT) and external-beam radiation therapy (EBRT) for clinically localized, high-risk prostate adenocarcinoma (initial prostate-specific antigen [PSA] level >20, Gleason score 8-10 or Stage > or = T3). METHODS AND MATERIALS: A retrospective chart review was conducted on 407 patients treated between 1991 and 2001 with NAHT and EBRT for high-risk prostate cancer. The effect of tumor (PSA level, Gleason score, and T stage) and treatment (NAHT duration, total-hormone duration, preradiation PSA) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival, and overall survival were examined. RESULTS: Median follow-up time was 78 months (range: 5-140 months). Actuarial bDFS at 5 years was 52% (95% confidence interval [CI], 46% to 57%) for the entire group. On multivariate analysis, initial PSA level (p = 0.004), Gleason score (p = 0.005), and preradiation PSA level (p < 0.001) were predictive of bDFS, whereas age, T stage, duration of NAHT, and duration of total hormone therapy were not predictive of outcomes. Gleason score and preradiation PSA level were also predictive of prostate cancer-specific survival rates. CONCLUSION: Improved bDFS in patients with high-risk prostate cancer was associated with lower initial PSA level, lower Gleason score, and lower preradiation PSA level. The duration of NAHT did not have an impact on outcomes, but the preradiation PSA was an important predictor of bDFS in high-risk patients.

Technology review: high-intensity focused ultrasound for prostate cancer.

INTRODUCTION AND OBJECTIVE: High-Intensity Focused Ultrasound (HIFU) is a technology that has moved from being used for benign prostate disease to the treatment of prostate cancer. A technology review was undertaken to guide patients and physicians as to its suitability. METHOD: An evidence-based review of published papers in the English language, with additional material from internet and other sources. RESULTS AND CONCLUSIONS: Only case series have been published; there are no randomized studies. The quality of evidence is poor, with no reports having longer follow-up than a mean of 2 years, with median follow-ups substantially shorter. Efficacy outcomes are thus premature and preclude assessment. Toxicity varies substantially with impotence rates 44%-61%, grade 2-3 incontinence 0%-14%, and rectal fistulae 0.7%-3.2%. There is limited data on the use of HIFU for the salvage therapy after radiation failure. There are no data on the toxicity of subsequent standard curative therapies after HIFU. In view of the lack of efficacy outcomes, and in the presence of significant toxicity, HIFU should only be offered within a research setting.

Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo-controlled multicenter trial.

OBJECTIVES: To perform a Canadian multicenter randomized placebo-controlled trial to evaluate the safety and efficacy of 6 weeks of levofloxacin therapy compared with placebo in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Uncontrolled studies have supported the use of antibiotics in CP/CPPS. METHODS: Men with a National Institutes of Health (NIH) diagnosis of CP/CPPS (specifically, no infection localized to the prostate) were randomized to levofloxacin (500 mg/day) or placebo for 6 weeks in 11 Canadian centers. Patients were assessed at baseline and at 3, 6, and 12 weeks with the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) and global patient assessments (subjective global assessment and patient assessment questionnaire). RESULTS: Eighty men (average age 56.0 years, range 36 to 78; duration of symptoms 6.5 years, range 0.6 to 32) were randomized to receive levofloxacin (n = 45) or placebo (n = 35). All were evaluated in an intent-to-treat analysis. Both groups experienced progressive improvement in symptoms as measured by the NIH-CPSI. However, the difference in response was not statistically or clinically significant at end of treatment (6 weeks) or at the end of the follow-up visits (12 weeks). No patients withdrew because of adverse events. One patient withdrew before the 6-week assessment. Adverse events (all mild) were reported in 20% of the levofloxacin group and 17% of the placebo group. CONCLUSIONS: This pilot placebo-controlled study showed that 6 weeks of levofloxacin therapy in men diagnosed with CP/CPPS resulted in symptom improvement that was not significantly different from that with placebo at end of treatment or follow-up. The clinical ramifications of these findings need to be addressed.

Incorrect biochemistry complicates prostate cancer management.

A man with a prostate specific antigen (PSA) of 6.1 ng/mL, a clinical stage T2b prostate nodule and biopsies that showed Gleason sum 6 adenocarcinoma of the prostate underwent a radical prostatectomy. The final pathology showed organ-confined disease. His postoperative PSA remained elevated at 4.0 ng/mL. The PSA was repeated several times and was in the same range. It was re-evaluated at another lab facility and was unmeasurable (<0.02 ng/mL). He has an antibody that cross-reacts with an assay reagent causing this false reading. The most likely antibody is one against mouse immunoglobulin G (IgG).