Timothy H. Wilson

Effect of dutasteride on the risk of prostate cancer

BACKGROUND We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease. METHODS In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. RESULTS Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P=0.03). CONCLUSIONS Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.)

Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS)

Study Type – Therapy (RCT)

The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT study.

BACKGROUND Knowledge of baseline factors that influence outcomes for men with benign prostatic hyperplasia (BPH) receiving medical therapy may help to improve outcomes and cost effectiveness. OBJECTIVES To examine the influence of baseline parameters on changes in International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Q(max)) in men with BPH receiving dutasteride, tamsulosin, or a combination of the two using 2-yr Combination of Avodart and Tamsulosin (CombAT) study data. DESIGN, SETTING, AND PARTICIPANTS CombAT is an ongoing, 4-yr, multicentre, randomised, double-blind study in 4844 men aged >or=50 yr with clinical diagnosis of BPH, IPSS >or=12, prostate volume >or=30 cm(3), prostate-specific antigen (PSA) 1.5-10 ng/ml, and Q(max) >5 and <or=15 ml/s with minimum voided volume >or=125 ml. INTERVENTION Daily tamsulosin 0.4 mg, dutasteride 0.5 mg, or the combination. MEASUREMENTS Post hoc analyses of mean IPSS and Q(max) changes from baseline by treatment group and by baseline prostate volume, PSA, age, body mass index (BMI), IPSS, IPSS quality of life (QoL) score, BPH Impact Index score, Q(max), and previous BPH medical therapy. RESULTS AND LIMITATIONS Combination therapy was more effective than either monotherapy after 24 mo in improving IPSS in all baseline subgroups, with benefit onset varying by baseline prostate volume. Combination therapy was also more effective in improving Q(max) versus tamsulosin in all subgroups and versus dutasteride in 10 of 18 subgroups. At 24 mo, dutasteride monotherapy resulted in significantly greater IPSS improvements versus tamsulosin in men with lower age, worse symptoms, worse QoL, less bother, higher BMI, greater Q(max), higher prostate volume, and higher PSA at baseline. Post hoc analyses, the lack of placebo control, and the exclusion of men with unsuccessful medical BPH treatment are study limitations. CONCLUSIONS Combination therapy with tamsulosin and dutasteride affords the greatest and the most rapid symptomatic benefit among men with higher baseline prostate volume and is effective regardless of previous BPH medical therapy. Dutasteride monotherapy is more effective than tamsulosin in men with higher baseline prostate volume or PSA and worse symptoms.

The Effect of Dutasteride on the Usefulness of Prostate Specific Antigen for the Diagnosis of High Grade and Clinically Relevant Prostate Cancer in Men With a Previous Negative Biopsy: Results From the REDUCE Study

PURPOSE We assessed whether dutasteride enhances the usefulness of total prostate specific antigen for diagnosing clinically significant prostate cancer. MATERIALS AND METHODS The 4-year REDUCE study evaluated the efficacy and safety of 0.5 mg dutasteride daily for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative prostate biopsy. Specificity, sensitivity, and positive and negative predictive values of prostate specific antigen for the diagnosis of prostate cancer were assessed. RESULTS Final prostate specific antigen before biopsy and change from month 6 to final prostate specific antigen performed better for the diagnosis of Gleason score 7-10 tumors in men who received dutasteride vs placebo as assessed by the area under the ROC curves (0.700 vs 0.650, p = 0.0491; and 0.699 vs 0.593, p = 0.0001, respectively). Increases in prostate specific antigen were associated with a higher likelihood of biopsy detectable, Gleason score 7-10 and clinically significant (modified Epstein criteria) prostate cancer. Percentage decreases in prostate specific antigen from baseline to month 6 in the dutasteride arm did not predict prostate cancer overall or Gleason score 7-10 cancer. CONCLUSIONS In men with a previously negative prostate biopsy, prostate specific antigen performed better during the 4-year study as a marker of prostate cancer in men who received dutasteride vs placebo. The degree of prostate specific antigen increase after 6 months was a better indicator of clinically significant cancer in the dutasteride arm than in the placebo arm. Conversely, the initial decrease in prostate specific antigen in men taking dutasteride did not predict the likelihood of prostate cancer.

Effect of Dutasteride on Prostate Biopsy Rates and the Diagnosis of Prostate Cancer in Men with Lower Urinary Tract Symptoms and Enlarged Prostates in the Combination of Avodart and Tamsulosin Trial

BACKGROUND A 23% relative risk reduction (RRR) in prostate cancer (PCa) was shown in men receiving dutasteride in the 4-yr Reduction by Dutasteride of Prostate Cancer Events study, in whom biopsies were protocol dependent. OBJECTIVE Our aim was to explore PCa risk reduction in men with benign prostatic hyperplasia (BPH) from the Combination of Avodart and Tamsulosin (CombAT) study, in which biopsies were undertaken for cause. DESIGN, SETTING, AND PARTICIPANTS CombAT was a 4-yr randomized double-blind parallel group study in 4844 men ≥50 yr of age with clinically diagnosed moderate to severe BPH, International Prostate Symptom Score ≥12, prostate volume ≥30 ml, and serum prostate-specific antigen (PSA) 1.5-10 ng/ml. Men underwent annual PSA measurement and digital rectal examination (DRE), and prostate biopsies were performed for cause. INTERVENTION All patients took tamsulosin 0.4 mg/d, dutasteride 0.5 mg/d, or a combination of both. MEASUREMENTS The primary end point was incidence of PCa. Secondary end points included postbaseline prostate biopsy rates and Gleason score of cancers. RESULTS AND LIMITATIONS Dutasteride (alone or in combination with tamsulosin) was associated with a 40% RRR of PCa diagnosis compared with tamsulosin monotherapy (95% confidence interval, 16-57%; p=0.002) and a 40% reduction in the likelihood of biopsy. There were similar reductions in low- and high-grade Gleason score cancers. The biopsy rate in the groups receiving dutasteride trended toward a higher diagnostic yield (combination: 29%, dutasteride: 28%, tamsulosin: 24%). One limitation was the lack of a standardized approach to PCa diagnosis and grading. CONCLUSIONS Dutasteride, alone or in combination with tamsulosin, significantly reduced the relative risk of PCa diagnosis in men with BPH undergoing annual DRE and PSA screening. Consistent with the increased usefulness of PSA for PCa detection, men receiving dutasteride had a numerically lower biopsy rate and higher yield of PCa on biopsy. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103).

The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study.

Study Type – Therapy (RCT) 
Level of Evidence 1b

The effects of dutasteride, tamsulosin, and the combination on storage and voiding in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the Combination of Avodart and Tamsulosin study.

This article reports the results of a post hoc analysis of the multicenter, randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) study, which aimed to investigate the effects of dutasteride (0.5 mg), tamsulosin (0.4 mg), and their combination on storage and voiding symptoms in 4844 men aged ⩾50 years with moderate-to-severe lower urinary tract symptoms (International Prostate Symptom Score ⩾12), prostate volume (PV) ⩾30 cm3 and PSA 1.5–10 ng ml−1. After 24 months, combination treatment achieved significantly greater mean reductions in both voiding and storage symptoms than either monotherapy, in each of the three baseline PV tertiles (30 to <42, 42 to <58, ⩾58 cm3). Dutasteride was as effective as tamsulosin for control of storage symptoms, but provided significantly greater relief of voiding symptoms than tamsulosin.

WebSphere Studio overview

In this paper we provide an overview of IBM WebSphere Studio, a family of tools for developing distributed applications for J2EE™ servers for state-of-the-art information technology systems. In todays business environment such systems are complex, comprise multiple platforms, and make use of a wide range of technologies and standards. Through a representative development scenario we illustrate the way WebSphere Studio satisfies the challenging requirements for a modern integrated development environment. The scenario covers a variety of technologies and standards, including database access, Web services standards, Enterprise JavaBeans™ implementation, integrated application testing, Web page design, and performance optimization. We also describe the Eclipse Modeling Framework, the open source technology base on which WebSphere Studio is built.

Dutasteride Improves Outcomes of Benign Prostatic Hyperplasia When Evaluated for Prostate Cancer Risk Reduction: Secondary Analysis of the REduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial

OBJECTIVE To investigate the effect of dutasteride versus placebo on the symptoms and associated complications of male lower urinary tract symptoms and benign prostatic hyperplasia (BPH) across a range of prostate volumes and BPH symptoms in men evaluated for prostate cancer risk reduction in the 4-year REduction by DUtasteride of prostate Cancer Events (REDUCE) trial. METHODS REDUCE was a multicenter, randomized, double-blind, placebo-controlled study of prostate cancer risk reduction with daily dutasteride 0.5 mg or placebo. Eligible men were aged 50-75 years, with a prostate-specific antigen level of 2.5-10 ng/mL and a prostate volume of ≤80 cm3. The prespecified and post hoc analyses were performed on the incidence of acute urinary retention, BPH-related surgery, and urinary tract infections, as well as on changes in prostate volume, International Prostate Symptom Score, BPH Impact Index, and maximal urinary flow rate (Qmax). RESULTS A total of 8122 men were included in the efficacy population. During the 4-year study, the International Prostate Symptom Score increased in placebo-treated patients, while dutasteride-treated patients had a stabilized or decreased International Prostate Symptom Score and improved BPH Impact Index and quality of life due to urinary symptom scores across all prostate volume quintiles (including prostate glands smaller than those studied in previous dutasteride trials). 48 months, the incidence of acute urinary retention or BPH-related surgery was significantly less in the dutasteride group (2.5%) than in the placebo group (9%) overall (P<.001) and in each baseline prostate volume quintile (P<.01). CONCLUSION During the 4-year study, dutasteride was associated with a decreased risk of BPH progression in men with mild-to-moderate symptoms and normal or enlarged prostates.

Low serum testosterone levels are poor predictors of sexual dysfunction.

Study Type – Prognosis (RCT)