Original Article
Effect of Dutasteride on the Risk of Prostate Cancer
N Engl J Med 2010; 362:1192-1202April 1, 2010
- Abstract
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.)
Media in This Article
Figure 1
Randomization and Numbers of Study Participants Who Underwent Biopsy.Figure 2
Proportions of Men with a Positive Biopsy for Prostate Cancer, According to Treatment Period and Group.Article Activity
- Article
The 5α-reductase inhibitors that are used to treat benign prostatic hyperplasia block the conversion of testosterone to dihydrotestosterone and may reduce the risk of prostate cancer.1 The results of the Prostate Cancer Prevention Trial showed that finasteride, as compared with placebo, reduced the risk of prostate cancer by 25%, but among the tumors that were detected, there was a 27% increase in the number of those that had Gleason scores of 7 to 10.2 (The Gleason score is the sum of the two most common histologic patterns or grades in a prostate tumor, each of which is graded on a scale of 1 to 5, with 5 being the most cytologically aggressive.) A subsequent analysis showed that the odds ratio for tumors with Gleason scores of 7 to 10 in the finasteride group decreased from 1.27 to 1.03 in a logistic model that included both baseline variables that are known to affect the risk of cancer and the post-baseline prostate volume.3 Guidance on the use of 5α-reductase inhibitors to prevent prostate cancer has been published recently.4
There are two isoforms of 5α-reductase, type 1 and type 2. Expression of type 1 in the prostate is enhanced during the development of prostate cancer, whereas the expression of type 2 is decreased or unchanged.5,6, Unlike finasteride, dutasteride inhibits both isoforms of 5α-reductase. 7 In this trial, we examined the effect of dutasteride on the incidence of prostate cancer detected on biopsy among men at increased risk for the disease.
Methods
Study Conduct
Investigators at GlaxoSmithKline designed the study, in consultation with external consultants. The study protocol and analysis plan can be found in the Supplementary Appendix, available with the full text of this article at NEJM.org. The investigators at GlaxoSmithKline had access to the data when the data were unblinded, and all the authors had access to the data approximately 2 weeks thereafter. Investigators at GlaxoSmithKline and members of the steering committee and the independent data and safety monitoring committee monitored the study and collected and analyzed the data. The steering committee was responsible for overseeing the conduct of the trial; the independent data and safety monitoring committee was responsible for ensuring patient safety and had access to unblinded data.
The first draft was written by one of the academic authors. All the coauthors, along with a consultant who was paid by GlaxoSmithKline for his help, contributed to subsequent versions, and the coauthors made the decision to submit the manuscript for publication. The first author vouches for the accuracy and completeness of the data and analyses. All authors who were not affiliated with GlaxoSmithKline signed confidentiality agreements with GlaxoSmithKline regarding the data in this trial; these agreements have remained in force pending publication of the data.
Participants
The design of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study has been described previously.8 We enrolled men who were considered to be at high risk for prostate cancer, on the basis of their age, an elevated prostate-specific antigen (PSA) level, and a previous suspicion of prostate cancer that led to a prostate biopsy. Men were eligible for the study if they were 50 to 75 years of age; had a serum PSA level of 2.5 to 10.0 ng per milliliter, in the case of men 50 to 60 years of age, or 3.0 to 10.0 ng per milliliter, in the case of men older than 60 years of age; and had undergone a single prostate biopsy (6 to 12 cores) within 6 months before enrollment. Men were excluded if they had undergone more than one biopsy; had prostate cancer of any grade, high-grade intraepithelial neoplasia, atypical small acinar proliferation, a history of prostate cancer, or a prostate volume greater than 80 ml; had undergone previous prostate surgery; or had an International Prostate Symptom Score of 25 or higher, or 20 or higher in the case of men taking alpha-blockers. The International Prostate Symptom Score assesses symptoms related to benign prostatic hyperplasia on a scale of 0 to 35, with 0 to 7 indicating mild symptoms; 8 to 20, moderate symptoms; and 21 to 35, severe symptoms. The protocol was approved by the institutional review board at each research site, and all participants provided written informed consent.
Study Design
We conducted a 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a 4-week placebo-based run-in period, eligible subjects were randomly assigned to receive dutasteride at a dose of 0.5 mg daily or placebo; randomization was stratified according to center. Visits were scheduled every 6 months; the International Prostate Symptom Score and free and total serum PSA levels were measured at each visit. To maintain the blinded nature of the study, the PSA levels in the dutasteride-treated men were doubled, since dutasteride reduces PSA levels by a mean of about 50%, and then were randomly adjusted by 0.1 ng per milliliter so that the final reported values were equally even and odd.8 Prostate volume was measured by ultrasonography at the time of randomization and 2 and 4 years later. Ten-core transrectal, ultrasound-guided biopsies were performed as part of the protocol at 2 and 4 years; biopsies were performed independently of the protocol when they were clinically indicated.
Assessment of Prostate Biopsies
Baseline biopsies had been performed before the start of the study (and independently of the study) and were reread centrally (Bostwick Laboratories) to confirm that the results were negative. Biopsies that were performed as part of the study were also read centrally. The central pathology laboratory had no access to the randomization codes. Biopsies that were performed independently of the study protocol were processed and read locally, and representative slides were read centrally. All positive biopsies were reviewed by the author affiliated with Bostwick Laboratories, who remained unaware of the treatment assignments; the diagnosis and Gleason score that he recorded were the ones that were used in the study. During the first 2 years, a randomly chosen set of 200 biopsies (100 showing cancer and 100 showing no cancer) were reread by an outside expert pathologist; a predefined rate of disagreement on cancer diagnosis of less than 3% was considered to be acceptable. There were two cases (1%) in which the outside pathologist disagreed with the recorded diagnosis of cancer.
End Points
The primary end point was prostate cancer detected on biopsy after 2 or 4 years of treatment. A participant with prostate cancer detected on biopsy at 2 years was withdrawn from the study medication. Biopsies that were performed because of a clinical indication between months 19 and 24 and between months 43 and 48 were classified as per-protocol biopsies and replaced the protocol-mandated biopsies at years 2 and 4, respectively. Those that were performed between months 1 and 18 (360 biopsies) and between months 25 and 42 (450 biopsies) were classified as protocol-independent biopsies. Other end points related to the detection of prostate cancer on biopsy included the Gleason score, the tumor volume, the percent of the biopsy cores that were positive for prostate cancer, the percent of core involvement with cancer, and the presence of high-grade intraepithelial neoplasia or atypical small acinar proliferation (which are lesions that are associated with a higher incidence of cancer on repeat biopsy). End points related to benign prostatic hyperplasia included the International Prostate Symptom Score, the change in total prostate volume from baseline, and the proportions of men who received alpha-blocker therapy, had acute urinary retention, underwent surgery related to benign prostatic hyperplasia, or had a urinary tract infection.
Statistical Analysis
For the primary end point, two-sided P values of 0.01 or less were considered to indicate statistical significance in the assessment of the superiority of dutasteride over placebo. We estimated that with 8000 subjects, the study would have approximately 90% power to show a 20% reduction with dutasteride in the incidence of prostate cancer detected on biopsy (i.e., an estimated rate of 19.0% in the placebo group and 15.2% in the dutasteride group), at a two-sided alpha level of 0.01.
The efficacy population included all randomly assigned subjects who had a baseline prostate biopsy that was considered to be negative on central review and who received at least one dose of the assigned study medication. The safety population included all subjects who underwent randomization. Calculation of three rates of prostate cancer was planned: a restricted crude rate, which included men who had at least one biopsy after baseline; a crude rate, which included all men in the efficacy population; and a modified crude rate, which included men who had a positive result on biopsy and men who underwent the biopsy at the end of the study. All three rates are reported for the primary end point; for other end points, the restricted crude rate is reported. The statistical analysis of the primary end point was performed with the use of the Mantel–Cox test, stratified according to time period and predefined clusters of study sites.9 The Mantel–Haenszel estimate of the relative risk of prostate cancer with dutasteride as compared with placebo for years 1 through 4 was calculated on the basis of the results from years 1 and 2 and from years 3 and 4. For all end points, statistical analyses were performed for years 1 and 2 and for years 1 through 4.
Prespecified subgroup analyses of prostate-cancer rates were performed according to baseline age (<65 or ≥65 years), body-mass index (grouped in thirds), self-reported race or ethnic group, family history of prostate cancer (negative or positive), International Prostate Symptom Score (<8 or ≥8), prostate volume (grouped in thirds), and PSA level (grouped in thirds). For each subgroup, analyses of the incidence of prostate cancer (with the use of the restricted crude rate) were planned, with relative risks and associated confidence intervals calculated for each subgroup with the use of Mantel–Haenszel estimates. P values for the frequencies of any biopsy (assessed in the efficacy population) and of adverse events (assessed in the safety population) were calculated with the use of Fisher's exact test. For the end points related to benign prostatic hyperplasia, log-rank tests of the time to the first episode of acute urinary retention, surgery related to benign prostatic hyperplasia, and urinary tract infection were performed. The survival end point was analyzed with the use of the log-rank test.
To determine the effect of covariates on the primary end point, logistic models were fitted to the data relating the incidence of prostate cancer detected on biopsy (all tumors and tumors with Gleason scores of 7 to 10) to baseline covariates, and to baseline covariates with the addition of post-baseline prostate volume at the time of biopsy (see the Supplementary Appendix).
Results
Participants
Table 1Table 1
Baseline Characteristics of the Study Participants. provides a summary of the baseline characteristics of the participants. Of the 8231 men who underwent randomization (safety population), 109 (1.3%) did not undergo a baseline biopsy, had a positive or suspicious result on the baseline biopsy, or did not receive the study medication (Figure 1Figure 1Randomization and Numbers of Study Participants Who Underwent Biopsy.). Of the remaining 8122 men, 81.6% of the men in the dutasteride group and 84.1% of the men in the placebo group underwent at least one post-baseline study biopsy (P=0.004); 96.9% of the biopsies were needle biopsies.Primary End Point
Overall Population
During the 4 years of the study, 659 of the 3305 men in the dutasteride group (19.9%) and 858 of the 3424 men in the placebo group (25.1%) received a diagnosis of prostate cancer, representing an absolute risk reduction with dutasteride of 5.1 percentage points. For the restricted crude rate of prostate cancer detected on biopsy, dutasteride was associated with a relative risk reduction of 22.8% (95% confidence interval [CI], 15.2 to 29.8; P<0.001). The risk reduction in years 1 and 2 was similar to that in years 3 and 4 (22.4% and 23.7%, respectively) (Figure 2Figure 2
Proportions of Men with a Positive Biopsy for Prostate Cancer, According to Treatment Period and Group.). For the crude rate and the modified crude rate of prostate cancer detected on biopsy over the 4-year study period, the risk reductions were 23.3% (95% CI, 15.6 to 30.3) and 23.1% (95% CI, 15.5 to 30.0), respectively (P<0.001 for both comparisons). Of the protocol-independent biopsies, 16.6% in the dutasteride group and 16.7% in the placebo group showed tumors, of which 7.1% of the tumors in the dutasteride group and 5.6% of those in the placebo group had a Gleason score of 7 to 10.Prespecified Subgroups
The risks of prostate cancer detected on biopsy were significantly lower with dutasteride across all prespecified major subgroups, including subgroups according to age (<65 or ≥65 years), family history of prostate cancer (negative or positive), baseline PSA in thirds (<4.9, 4.9 to <6.8, or ≥6.8 ng per milliliter), baseline prostate volume in thirds (<36.6, 36.6 to <51.8, or ≥51.8 ml), baseline International Prostate Symptom Score (<8 or ≥8), and body-mass index (the weight in kilograms divided by the square of the height in meters) in thirds (<25.5, 25.5 to <28.4, or ≥28.4) (Table 2Table 2
Incidence of Prostate Cancer and Relative Risk Reduction over the Course of the 4-Year Study Period, According to Baseline Subgroups.).Pathological End Points
Gleason Scores
Table 3Table 3
Detection of Prostate Cancer on Biopsy, According to Gleason Score, Treatment Period, and Treatment Group. shows the numbers and proportions of men with prostate cancer according to Gleason score, treatment period, and study group. Over the 4 years of the study, there were 437 tumors with Gleason scores of 5 to 6 in the dutasteride group and 617 in the placebo group (P<0.001), and such tumors accounted for 70% of the total number of cancers. The number of tumors with Gleason scores of 7 to 10 did not differ significantly between the dutasteride group and the placebo group (220 and 233, respectively; P=0.81). There were 29 tumors with Gleason scores of 8 to 10 in the dutasteride group and 19 in the placebo group (P=0.15). Although the numbers of tumors with Gleason scores of 8 to 10 were similar in the two groups during years 1 and 2 (17 and 18 in the dutasteride and placebo groups, respectively), during years 3 and 4, there were 12 tumors with Gleason scores of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003).Biopsy Results
Among the subjects with biopsy specimens that showed cancer, the two study groups were similar with respect to the mean number of positive cores (1.8 in the dutasteride group and 1.9 in the placebo group), percentage of cores with cancer (12.2% and 13.4%, respectively), and tumor volume (0.0022 ml and 0.0024 ml, respectively). These features were also similar between the two groups for tumors with Gleason scores of 7 to 10 (number of positive cores, 2.5 in both groups; percentage of cores with cancer, 20.6% in the dutasteride group and 22.7% in the placebo group), and tumor volume (0.0043 and 0.0049 ml, respectively).
High-Grade Intraepithelial Neoplasia and Atypical Small Acinar Proliferation
The men in the dutasteride group had lower rates of high-grade intraepithelial neoplasia (without atypical small acinar proliferation or prostate cancer) than did the men in the placebo group (3.7% vs. 6.0%; relative risk reduction with dutasteride, 39.2%; 95% CI, 24.2 to 51.1; P<0.001); they also had lower rates of atypical small acinar proliferation (without prostate cancer and with or without high-grade intraepithelial neoplasia) than did the men in the placebo group (3.8% vs. 4.9%; relative risk reduction, 21.2%; 95% CI, 1.3 to 37.1; P=0.04).
End Points Related to Benign Prostatic Hyperplasia
In the placebo group, the mean (±SE) prostate volume increased from 45.8±0.30 ml at baseline to 52.3±0.40 ml at year 2 (a mean increase of 13.0%) and to 56.2±0.44 ml at year 4 (a mean overall increase of 19.7%). In the dutasteride group, the mean prostate volume decreased from 45.7±0.28 ml at baseline to 38.6±0.31 ml at year 2 (a mean decrease of 17.4%) and to 39.0±0.32 ml at year 4 (a mean overall decrease of 17.5%). The difference in the prostate volume between the groups was significant at each time point (P<0.001). Dutasteride significantly reduced the risk of acute urinary retention, the need for surgery related to benign prostatic hyperplasia, and urinary tract infection (Figure 3Figure 3
Proportions of Men Who Had an Episode of Acute Urinary Retention, Who Underwent Surgery Related to Benign Prostatic Hyperplasia (BPH), or Who Had a Urinary Tract Infection over the Course of the 4-Year Study Period.). The men in the dutasteride group who had moderate or severe baseline symptoms of benign prostatic hyperplasia, as indicated by an International Prostate Symptom Score of 12 or higher, had a greater mean reduction in the score than did the men with similar symptoms in the placebo group (reduction of 3.9 points vs. 1.3 points), despite the fact that more men in the placebo group than in the dutasteride group were receiving an alpha-blocker (18.9% vs. 12.7%, P<0.001).Overall Survival
A total of 70 men in the dutasteride group (1.7%) and 77 men in the placebo group (1.9%) died during the course of the study (P=0.65). No deaths were attributed to prostate cancer (see the Supplementary Appendix).
Safety and Side Effects
Table 4Table 4
Incidence of Adverse Events. provides a summary of adverse events, as reported by the investigators. The nature and frequency of common adverse events with dutasteride were similar to those reported in previous studies of dutasteride therapy for men with benign prostatic hyperplasia. A drug-related decrease in libido was reported by 3.3% of the men in the dutasteride group, as compared with 1.6% of the men in the placebo group (P<0.001), and a loss of libido was reported by 1.9% of the men in the dutasteride group, as compared with 1.3% of the men in the placebo group (P=0.03). A drug-related decrease in or loss of erectile function was reported in 9.0% of the men in the dutasteride group and in 5.7% of the men in the placebo group (P<0.001). There was an unexpected imbalance in a composite event termed “cardiac failure,” which included conditions such as congestive heart failure, cardiac failure, acute cardiac failure, ventricular failure, cardiopulmonary failure, and congestive cardiomyopathy. Although there was no significant difference between the two groups in the overall incidence of cardiovascular events or deaths from cardiovascular events, there was a higher incidence of the composite event of cardiac failure in the dutasteride group than in the placebo group (0.7% [30 of 4105 men] vs. 0.4% [16 of 4126 men], P=0.03; relative risk estimate, 1.91; 95% CI, 1.04 to 3.50).Discussion
We found that the dual 5α-reductase inhibitor dutasteride reduced the incidence of prostate cancer detected on biopsy among men who had an increased risk of prostate cancer. This reduction in the incidence of prostate cancer was observed mainly among men who had tumors with Gleason scores of 5 to 6.
It is likely that most tumors that were diagnosed during the trial were present at the time of randomization but had not been detected in the baseline biopsy, performed before the study. Modeling data from the Prostate Cancer Prevention Trial10 and an analysis of prostate-biopsy specimens from men treated with dutasteride for 4 months before surgery11 support the hypothesis that the major effect of dutasteride is the shrinkage of prostate tumors or inhibition of their growth.
During the first 2 years of the trial, there were 141 more tumors with a Gleason score of 5 to 7 in the placebo group than in the dutasteride group (558 among 3346 participants vs. 417 among 3239 participants); the number of tumors with a Gleason score of 8 to 10 was similar in the two groups (18 and 17, respectively). During years 3 and 4, however, only 1 tumor with a Gleason score of 8 to 10 was detected among the 2343 men in the placebo group, whereas 12 such cancers were found among the 2447 men in the dutasteride group (P=0.003). We speculate that if the men in the placebo group who had the 141 excess tumors with a Gleason score of 5 to 7 detected during years 1 and 2 had remained in the study (i.e., if they had not been withdrawn as the trial required), a proportion of the cancers might have been upgraded on biopsy during years 3 and 4 to higher-grade tumors, thus narrowing the difference between the two groups in the number of tumors with a Gleason score of 8 to 10 in years 3 and 4. Supporting this speculation is a study involving 105 men who had prostate tumors with Gleason scores of 7 or lower and who were being followed without treatment (“active surveillance”); a repeat biopsy after a median follow-up period of 22 months showed that in 8 of the men (7.6%) the tumor was upgraded to a Gleason score of 8 to 10.12 An alternative explanation, which is also consistent with our data, is that the difference in the number of cancers with a Gleason score of 8 to 10 was due in part to dutasteride therapy.
The detection of prostate cancer in a biopsy specimen is a function of tumor volume, prostate volume, and the number of cores in the sample.10 Serfling et al. predicted an 11 to 17% increase in biopsy-detected cancer among men treated with dutasteride, as compared with men receiving placebo, assuming that dutasteride did not reduce tumor volume and reduced prostate volume by 25%.10 In our study, the between-group difference in the mean percent change from baseline in prostate volume was 30.4±0.79% at year 2 and 37.1±0.93% at year 4 (P<0.001). The reduction in prostate volume with dutasteride, along with the increase in prostate volume with placebo, could have caused an increase in the number of biopsy-detected prostate cancers among men in the dutasteride group, but the actual result was a 23% relative reduction in prostate cancer, a finding that supports a mechanism of tumor shrinkage with dutasteride. Other biases may enhance the detection of prostate cancer among men who are being treated with 5α-reductase inhibitors, including an improvement in the sensitivity of PSA tests and of digital rectal examination.13,14 By requiring a baseline biopsy and biopsies after 2 and 4 years, the design of the REDUCE trial minimized the proportion of study participants who underwent protocol-independent biopsies (≤7%) and minimized biases that could have caused between-group differences in the rate of protocol-independent biopsies.
Biases could explain the relative risk of 1.27 (95% CI, 1.07 to 1.50) for tumors with Gleason scores of 7 to 10 in the finasteride group of the Prostate Cancer Prevention Trial,2,13,14 and models that account for volume and PSA-driven biases have suggested that there may be reductions of 12 to 27% in the incidence of tumors with Gleason scores of 7 to 10 with finasteride.2,15-18 In our trial, there was no significant increase in the dutasteride group, as compared with the placebo group, in the incidence of tumors with Gleason scores of 7 to 10 over the 4 years of the trial, both before and after adjustment for possible confounding variables (Table 3, and the Supplementary Appendix).
In addition to a reduction in the risk of prostate cancer, the risk of the progression of benign prostatic hyperplasia was reduced with dutasteride. The risks of acute urinary retention and of benign prostatic hyperplasia requiring surgery were reduced with dutasteride therapy by 77.3% and 73.0%, respectively, and the risk of urinary tract infection was reduced by 40.7%. These effects should be balanced against adverse events related to sexual function that were observed in a minority of men receiving dutasteride, typically in the early months of therapy, with such events decreasing in the longer term.19 There was also an increased incidence of cardiac failure in men treated with dutasteride. The rate of discontinuation of the study drug owing to drug-related adverse events was less than 5%.
In conclusion, among men at increased risk for prostate cancer and for benign prostatic hyperplasia, dutasteride reduced the risk of prostate cancers and precursor lesions and improved many outcomes related to benign prostatic hyperplasia. Dutasteride may be considered as a treatment option for men who are at increased risk for prostate cancer.
Supported by GlaxoSmithKline.
Dr. Rittmaster, Ms. Fowler, and Messrs. Somerville and Wilson report being employees of and owning stock and stock options in GlaxoSmithKline; Dr. Andriole, receiving consulting or advisory fees from Aeterna Zentaris, Ferring Pharmaceuticals, EMD Serono, Gen-Probe, Onconome, Veridex, Amgen, GlaxoSmithKline, Steba Biotech, and the France Foundation, lecture fees from GlaxoSmithKline, and grant support from Aeterna Zentaris, owning stock in Cambridge Endo and Envisioneering Medical Technologies, and holding stock options in Viking Medical; Dr. Bostwick, receiving consulting or advisory fees from GlaxoSmithKline, lecture fees from GlaxoSmithKline, and grant support from Accuray, Bioniche, Endo, Capstone, Dendreon, EDAP, Gilead, GlobeImmune, GlaxoSmithKline, GTx, Protox Therapeutics, Sanofi–Aventis, Schering–Plough, Spectrum Pharmaceuticals, and Stiefel Laboratories, and owning stock in GlaxoSmithKline and stock and stock options in Bostwick Laboratories; Dr. Brawley, receiving consulting or advisory fees from GlaxoSmithKline and Sanofi–Aventis; Dr. Gomella, receiving consulting or advisory fees from GlaxoSmithKline, Sanofi–Aventis, Watson Pharmaceuticals, Ferring, and AstraZeneca, lecture fees from the France Foundation, and grant support from Cougar Biotechnology, VIVUS, GE Healthcare, GlaxoSmithKline, Photocure, Dendreon, Antigenics, AstraZeneca, EDAP Technomed and Prostate Conditions Education Council; Dr. Marberger, receiving consulting or advisory fees from Antigenics, Allergan, GlaxoSmithKline, GP Pharm, Merck, Rottapharm–Madaus, and Astellas, and lecture fees from Astellas, Ferring, GE Healthcare, GlaxoSmithKline, and Merck; Dr. Montorsi, receiving consulting or advisory fees from Bayer Schering, GlaxoSmithKline, Pierre Fabre Medicament, and Recordati; Dr. Pettaway, receiving consulting or advisory fees from Ferring Pharmaceuticals and GlaxoSmithKline and lecture fees from Takeda–Abbott Pharmaceuticals; Dr. Tammela, receiving consulting or advisory fees from GlaxoSmithKline, Orion Pharma, and Astellas and lecture fees from GlaxoSmithKline, Orion Pharma, and Astellas; Dr. Teloken, receiving consulting or advisory fees from GlaxoSmithKline and Pfizer; Dr. Tindall, receiving grant support from T.J. Martell Foundation and GlaxoSmithKline; and Dr. Rittmaster, being listed as an inventor on a patent application for the use of dutasteride and testosterone for the treatment of prostate cancer.
No other potential conflict of interest relevant to this article was reported.
We thank the patients, the study investigators, the members of the data and safety monitoring committee and the steering committee, and the staff at GlaxoSmithKline for their dedication in the initiation and conduct of the REDUCE study.
Source Information
From the Division of Urology, Washington University School of Medicine in St. Louis, St. Louis (G.L.A.); Bostwick Laboratories, Glen Allen, VA (D.G.B.); the American Cancer Society and Emory University School of Medicine, Atlanta (O.W.B.); the Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia (L.G.G.); the Medical University of Vienna, Vienna (M.M.); Università Vita-Salute San Raffaele, Milan (F.M.); the University of Texas, M.D. Anderson Cancer Center, Houston (C.A.P.); the Department of Urology, Tampere University Hospital, Tampere, Finland (T.L.T.); Universidade Federal Ciências Saúde de Porto Alegre, Porto Alegre, Brazil (C.T.); the Mayo Clinic, Rochester, MN (D.J.T.); and Glaxo-SmithKline, Research Triangle Park, NC (M.C.S., T.H.W., I.L.F., R.S.R.).
Address reprint requests to Dr. Andriole at the Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, or at andrioleg@wustl.edu.
The principal investigators in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.
- References
References
1
McConnell JD ,Roehrborn CG ,Bautista OM , et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387-2398
Full Text | Web of Science | Medline2
Thompson IM ,Goodman PJ ,Tangen CM , et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-224
Full Text | Web of Science | Medline3
Cohen YC ,Liu KS ,Heyden NL , et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2007;99:1366-1374
CrossRef | Web of Science | Medline4
Kramer BS ,Hagerty KL ,Justman S , et al. Use of 5alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Urol 2009;181:1642-1657
CrossRef | Web of Science | Medline5
Iehle C ,Delos S ,Guirou O ,Tate R ,Raynaud JP ,Martin PM . Human prostatic steroid 5 alpha-reductase isoforms -- a comparative study of selective inhibitors. J Steroid Biochem Mol Biol 1995;54:273-279
CrossRef | Web of Science | Medline6
Thomas LN ,Lazier CB ,Gupta R , et al. Differential alterations in 5alpha-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate 2005;63:231-239
CrossRef | Web of Science | Medline7
Bramson HN ,Hermann D ,Batchelor KW ,Lee FW ,James MK ,Frye SV . Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J Pharmacol Exp Ther 1997;282:1496-1502
Web of Science | Medline8
Andriole G ,Bostwick D ,Brawley O , et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. J Urol 2004;172:1314-1317
CrossRef | Web of Science | Medline9
Stokes ME, Davis CS, Koch GG. Categorical data analysis using the SAS system. 2nd ed. Cary, NC: SAS Institute, 2000.
10
Serfling R ,Shulman M ,Thompson GL , et al. Quantifying the impact of prostate volumes, number of biopsy cores and 5alpha-reductase inhibitor therapy on the probability of prostate cancer detection using mathematical modeling. J Urol 2007;177:2352-2356
CrossRef | Web of Science | Medline11
Gleave M ,Qian J ,Andreou C , et al. The effects of the dual 5 alpha-reductase inhibitor dutasteride on localized prostate cancer -- results from a 4-month pre-radical prostatectomy study. Prostate 2006;66:1674-1685
CrossRef | Web of Science | Medline12
Choo R ,Danjoux C ,Morton G , et al. How much does Gleason grade of follow-up biopsy differ from that of initial biopsy in untreated, Gleason score 4-7, clinically localized prostate cancer? Prostate 2007;67:1614-1620
CrossRef | Web of Science | Medline13
Thompson IM ,Chi C ,Ankerst DP , et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst 2006;98:1128-1133
CrossRef | Web of Science | Medline14
Thompson IM ,Tangen CM ,Goodman PJ , et al. Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection. J Urol 2007;177:1749-1752
CrossRef | Web of Science | Medline15
Goodman PJ ,Thompson IM Jr ,Tangen CM ,Crowley JJ ,Ford LG ,Coltman CA Jr . The Prostate Cancer Prevention Trial: design, biases and interpretation of study results. J Urol 2006;175:2234-2242
CrossRef | Web of Science | Medline16
Pinsky P ,Parnes H ,Ford L . Estimating rates of true high-grade disease in the Prostate Cancer Prevention Trial. Cancer Prev Res 2008;1:182-186
CrossRef | Web of Science17
Redman MW ,Tangen CM ,Goodman PJ ,Lucia MS ,Coltman CA Jr ,Thompson IM . Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res 2008;1:174-181
CrossRef | Web of Science18
Kaplan SA ,Roehrborn CG ,Meehan AG , et al. PCPT: evidence that finasteride reduces risk of most frequently detected intermediate- and high-grade (Gleason score 6 and 7) cancer. Urology 2009;73:935-939
CrossRef | Web of Science | Medline19
Debruyne F ,Barkin J ,van Erps P ,Reis M ,Tammela TL ,Roehrborn C . Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol 2004;46:488-494
CrossRef | Web of Science | Medline
- Citing Articles (124)
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1
Yizhen Lu, Jielin Sun, Andrew K. Kader, Seong-Tae Kim, Jin-Woo Kim, Wennuan Liu, Jishan Sun, Daru Lu, Junjie Feng, Yi Zhu, Tao Jin, Zheng Zhang, Latchezar Dimitrov, James Lowey, Kevin Campbell, Edward Suh, David Duggan, John Carpten, Jeffrey M. Trent, Henrik Gronberg, S. Lilly Zheng, William B. Isaacs, Jianfeng Xu. (2012) Association of prostate cancer risk with snps in regions containing androgen receptor binding sites captured by ChIP-On-chip analyses. The Prostate 72:4, 376-385
CrossRef2
Matthias Oelke. (2012) Re: 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 Trial. European Urology 61:3, 624-625
CrossRef3
Sarah Slater, Cameron Dumas, Glenn Bubley. (2012) Dutasteride for the treatment of prostate-related conditions. Expert Opinion on Drug Safety1-6
CrossRef4
Hashim Uddin Ahmed, Mark Emberton, Gordon Kepner, Jeremy Kepner. (2012) A biomedical engineering approach to mitigate the errors of prostate biopsy. Nature Reviews Urology
CrossRef5
M. R. Goldstein, L. Mascitelli. (2012) Regarding prostate-specific antigen: let's not shoot the messenger. QJM 105:2, 207-210
CrossRef6
Giovanni Corona, Mauro Gacci, Elisabetta Baldi, Rosa Mancina, Gianni Forti, Mario Maggi. (2012) Androgen Deprivation Therapy in Prostate Cancer: Focusing on Sexual Side Effects. The Journal of Sexual Medicineno-no
CrossRef7
Ashley E. Ross, Zhaoyong Feng, Phillip M. Pierorazio, Patricia Landis, Patrick C. Walsh, H. Ballentine Carter, Bruce J. Trock, Edward M. Schaeffer. (2012) Effect of treatment with 5-α reductase inhibitors on progression in monitored men with favourable-risk prostate cancer. BJU Internationalno-no
CrossRef8
James R. Marshall. (2012) Diet and prostate cancer prevention. World Journal of Urology
CrossRef9
Eric A. Klein, Ian M. Thompson. (2012) Chemoprevention of prostate cancer: an updated view. World Journal of Urology
CrossRef10
Naoto Miyanaga, Hideyuki Akaza, Shiro Hinotsu, Tomoaki Fujioka, Seiji Naito, Mikio Namiki, Satoru Takahashi, Yoshihiko Hirao, Shigeo Horie, Taiji Tsukamoto, Mitsuru Mori, Hirokazu Tsuji. (2012) Prostate Cancer Chemoprevention Study: An investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. Cancer Science 103:1, 125-130
CrossRef11
David G Bostwick, Liang Cheng. (2012) Precursors of prostate cancer. Histopathology 60:1, 4-27
CrossRef12
Patrick C. Walsh. (2012) Re: Usefulness of Prostate-Specific Antigen (PSA) Rise as a Marker of Prostate Cancer in Men Treated With Dutasteride: Lessons From the REDUCE Study. The Journal of Urology 187:1, 144-145
CrossRef13
Faris Azzouni, Alejandro Godoy, Yun Li, James Mohler. (2012) The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases. Advances in Urology 2012, 1-18
CrossRef14
J.-A. Thomas, L. Gerber, D. M. Moreira, R. J. Hamilton, L. L. Bañez, R. Castro-Santamaria, G. L. Andriole, W. B. Isaacs, J. Xu, S. J. Freedland. (2012) Prostate cancer risk in men with prostate and breast cancer family history: results from the REDUCE study (R1). Journal of Internal Medicineno-no
CrossRef15
I. Ahmad, D.R. Small, N.S. Krishna, M.N. Akhtar, H.Y. Leung. (2012) Prostate cancer incidence in patients on 5α-reductase inhibitors for lower urinary tract symptoms: A 14-year retrospective study. British Journal of Medical and Surgical Urology
CrossRef16
Chris Parker. (2012) What (if anything) to do about low-risk prostate cancer. The Lancet
CrossRef17
Neil E Fleshner, M Scott Lucia, Blair Egerdie, Lorne Aaron, Gregg Eure, Indrani Nandy, Libby Black, Roger S Rittmaster. (2012) Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. The Lancet
CrossRef18
Dinesh Thapa, Rita Ghosh. (2012) Antioxidants for prostate cancer chemoprevention: Challenges and opportunities. Biochemical Pharmacology
CrossRef19
Tsutomu Nishiyama. (2012) Androgen deprivation therapy in combination with radiotherapy for high-risk clinically localized prostate cancer. The Journal of Steroid Biochemistry and Molecular Biology
CrossRef20
V. M. Adhami, I. A. Siddiqui, D. N. Syed, R. K. Lall, H. Mukhtar. (2011) Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. Carcinogenesis
CrossRef21
Kim, Jeri, Amos, Christopher I., Logothetis, Christopher, . (2011) 5α-Reductase Inhibitors for Prostate-Cancer Prevention. New England Journal of Medicine 365:24, 2340-2340
Full Text22
Rosa Lerose, Pellegrino Musto, Michele Aieta, Carla Papa, Alfredo Tartarone. (2011) Off-label use of anti-cancer drugs between clinical practice and research: the Italian experience. European Journal of Clinical Pharmacology
CrossRef23
Lucy A.M. Simmons, Philippe Autier, Frantiŝek Zát'ura, Johan Braeckman, Alexandre Peltier, Imre Romic, Arnulf Stenzl, Karien Treurnicht, Tara Walker, Dror Nir, Caroline M. Moore, Mark Emberton. (2011) Detection, localisation and characterisation of prostate cancer by Prostate HistoScanning™. BJU Internationalno-no
CrossRef24
C Wu, D M Moreira, L Gerber, R S Rittmaster, G L Andriole, S J Freedland. (2011) Diabetes and prostate cancer risk in the REDUCE trial. Prostate Cancer and Prostatic Diseases 14:4, 326-331
CrossRef25
C. De Nunzio, S.J. Freedland, L. Miano, E. Finazzi Agrò, L. Bañez, A. Tubaro. (2011) The uncertain relationship between obesity and prostate cancer: An Italian biopsy cohort analysis. European Journal of Surgical Oncology (EJSO) 37:12, 1025-1029
CrossRef26
Etienne Audet-Walsh, Judith Bellemare, Geneviève Nadeau, Louis Lacombe, Yves Fradet, Vincent Fradet, Shu-Pin Huang, Bo-Ying Bao, Pierre Douville, Hugo Girard, Chantal Guillemette, Eric Lévesque. (2011) SRD5A Polymorphisms and Biochemical Failure After Radical Prostatectomy. European Urology 60:6, 1226-1234
CrossRef27
Stewart Justman. (2011) What's Wrong With Chemoprevention of Prostate Cancer?. The American Journal of Bioethics 11:12, 21-25
CrossRef28
Étienne Audet-Walsh, Judith Bellemare, Louis Lacombe, Yves Fradet, Vincent Fradet, Pierre Douville, Chantal Guillemette, Éric Lévesque. (2011) The Impact of Germline Genetic Variations in Hydroxysteroid (17-Beta) Dehydrogenases on Prostate Cancer Outcomes After Prostatectomy. European Urology
CrossRef29
Ryan P. Kopp, Misop Han, Alan W. Partin, Elizabeth Humphreys, Stephen J. Freedland, J. Kellogg Parsons. (2011) Obesity and prostate enlargement in men with localized prostate cancer. BJU International 108:11, 1750-1755
CrossRef30
M. Y. Roth, R. E. Dudley, L. Hull, A. Leung, P. Christenson, C. Wang, R. Swerdloff, J. K. Amory. (2011) Steady-state pharmacokinetics of oral testosterone undecanoate with concomitant inhibition of 5α-reductase by finasteride. International Journal of Andrology 34:6pt1, 541-547
CrossRef31
Hidewaki Nakagawa, Shusuke Akamatsu, Ryo Takata, Atsushi Takahashi, Michiaki Kubo, Yusuke Nakamura. (2011) Prostate Cancer Genomics, Biology, and Risk Assessment through Genome-wide Association Studies. Cancer Scienceno-no
CrossRef32
Xiangwei Wu, Scott M. Lippman. (2011) An intermittent approach for cancer chemoprevention. Nature Reviews Cancer
CrossRef33
Judd W. Moul, Adam S. Kibel, Mack Roach, Robert Dreicer. (2011) Indications and Practice With Androgen Deprivation Therapy. Urology 78:5, S478-S481
CrossRef34
Faysal A. Yafi, Armen G. Aprikian, Simon Tanguay, Wassim Kassouf. (2011) Are men on 5α-reductase inhibitors appropriately referred to urology? A survey of primary care physicians. BJU International 108:8, 1269-1273
CrossRef35
Hans T. Chung, Susan M. Noworolski, John Kurhanewicz, Vivian Weinberg, Mack Roach III. (2011) A pilot study of endorectal magnetic resonance imaging and magnetic resonance spectroscopic imaging changes with dutasteride in patients with low risk prostate cancer. BJU International 108:8b, E164-E170
CrossRef36
M. Oelke, S. Madersbacher. (2011) Primär- und Sekundärprävention des benignen Prostatasyndroms. Der Urologe 50:10, 1257-1264
CrossRef37
J. Curtis Nickel, Claus Roehrborn, Francesco Montorsi, Timothy H. Wilson, Roger S. Rittmaster. (2011) Dutasteride Reduces Prostatitis Symptoms Compared With Placebo in Men Enrolled in the REDUCE Study. The Journal of Urology 186:4, 1313-1318
CrossRef38
Henry Botto, Yann Neuzillet, Thierry Lebret, Philippe Camparo, Vincent Molinie, Jean-Pierre Raynaud. (2011) High Incidence of Predominant Gleason Pattern 4 Localized Prostate Cancer is Associated With Low Serum Testosterone. The Journal of Urology 186:4, 1400-1405
CrossRef39
, B.J. Schmitz-Dräger, G. Lümmen, E. Bismarck, C. Fischer. (2011) Primärprävention urologischer Tumore: Prostatakarzinom. Der Urologe 50:10, 1271-1275
CrossRef40
Chun W. Tam, Stephen Y. W. Shiu. (2011) Functional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: potential implications for therapeutic strategies against prostate cancer. Journal of Pineal Research 51:3, 297-312
CrossRef41
A Urbanucci, B Sahu, J Seppälä, A Larjo, L M Latonen, K K Waltering, T L J Tammela, R L Vessella, H Lähdesmäki, O A Jänne, T Visakorpi. (2011) Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer. Oncogene
CrossRef42
J. Noldus. (2011) Prostatakarzinom. Der Urologe 50:S1, 171-172
CrossRef43
Marcelo Langer Wroclawski, Cynthia Kuk, Antonio Finelli, Neil E Fleshner, Alexandre R Zlotta. (2011) Chemoprevention of prostate cancer: is there evidence from clinical trials?. Clinical Investigation 1:9, 1257-1268
CrossRef44
Evangelos Liatsikos, Iason Kyriazis, Panagiotis Kallidonis, Jens-Uwe Stolzenburg. (2011) Bloodless management of benign prostatic hyperplasia: medical and minimally invasive treatment options. The Aging Male 14:3, 141-149
CrossRef45
Cosimo De Nunzio, Simone Albisinni, Stephen J. Freedland, Lucio Miano, Luca Cindolo, Enrico Finazzi Agrò, Riccardo Autorino, Marco De Sio, Luigi Schips, Andrea Tubaro. (2011) Abdominal obesity as risk factor for prostate cancer diagnosis and high grade disease: A prospective multicenter Italian cohort study. Urologic Oncology: Seminars and Original Investigations
CrossRef46
Michael W. Kattan, Stephanie R. Earnshaw, Cheryl L. McDade, Libby K. Black, Gerald L. Andriole. (2011) Cost Effectiveness of Chemoprevention for Prostate Cancer with Dutasteride in a High-Risk Population Based on Results from the REDUCE Clinical Trial. Applied Health Economics and Health Policy 9:5, 305-315
CrossRef47
Claus G. Roehrborn, J. Curtis Nickel, Gerald L. Andriole, R. Paul Gagnier, Libby Black, Timothy H. Wilson, Roger S. Rittmaster. (2011) 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. Urology 78:3, 641-646
CrossRef48
M. Wirth, S. Zastrow. (2011) Prostatakarzinom. Der Urologe 50:S1, 173-175
CrossRef49
C. Cai, S. P. Balk. (2011) Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocrine Related Cancer 18:5, R175-R182
CrossRef50
Sheila M.J. Aubin, Jennifer Reid, Mark J. Sarno, Amy Blase, Jacqueline Aussie, Harry Rittenhouse, Roger S. Rittmaster, Gerald L. Andriole, Jack Groskopf. (2011) Prostate Cancer Gene 3 Score Predicts Prostate Biopsy Outcome in Men Receiving Dutasteride for Prevention of Prostate Cancer: Results From the REDUCE Trial. Urology 78:2, 380-385
CrossRef51
Salvador Arias-Santiago, Miguel Angel Arrabal-Polo, Agustín Buendía-Eisman, Miguel Arrabal-Martín, María Teresa Gutiérrez-Salmerón, María Sierra Girón-Prieto, Antonio Jimenez-Pacheco, Jaime Eduardo Calonje, Ramón Naranjo-Sintes, Zuluaga-Gomez, Salvio Serrano Ortega. (2011) Androgenetic alopecia as an early marker of benign prostatic hyperplasia. Journal of the American Academy of Dermatology
CrossRef52
Xiangwei Wu, Sherri Patterson, Ernest Hawk. (2011) Chemoprevention – History and general principles. Best Practice & Research Clinical Gastroenterology 25:4-5, 445-459
CrossRef53
Xiaoye Zhu, Pim J. van Leeuwen, Meelan Bul, Suzie J. Otto, Harry J. de Koning, Chris H. Bangma, Fritz H. Schröder, Monique J. Roobol. (2011) Disease-Specific Survival of Men With Prostate Cancer Detected During the Screening Interval: Results of the European Randomized Study of Screening for Prostate Cancer–Rotterdam After 11 Years of Follow-Up. European Urology 60:2, 330-336
CrossRef54
Theoret, Marc R., Ning, Yang-Min, Zhang, Jenny J., Justice, Robert, Keegan, Patricia, Pazdur, Richard, . (2011) The Risks and Benefits of 5α-Reductase Inhibitors for Prostate-Cancer Prevention. New England Journal of Medicine 365:2, 97-99
Full Text55
Stephanie T. Page, Lianne Hirano, Janet Gilchriest, Manjiri Dighe, John K. Amory, Brett T. Marck, Alvin M. Matsumoto. (2011) Dutasteride Reduces Prostate Size and Prostate Specific Antigen in Older Hypogonadal Men With Benign Prostatic Hyperplasia Undergoing Testosterone Replacement Therapy. The Journal of Urology 186:1, 191-197
CrossRef56
Surayne Segaran, Mark J. Speakman. (2011) Management of lower urinary tract symptoms and bladder outlet obstruction. Medicine 39:7, 378-383
CrossRef57
Michael Marberger, Timothy H. Wilson, Roger S. Rittmaster. (2011) Low serum testosterone levels are poor predictors of sexual dysfunction. BJU International 108:2, 256-262
CrossRef58
Richard M. Hoffman, Richard G. Roberts, Michael J. Barry. (2011) Battling Prostate Cancer with 5-Alpha-Reductase Inhibitors: a Pyrrhic Victory?. Journal of General Internal Medicine 26:7, 798-801
CrossRef59
Michael Marberger, Stephen J. Freedland, Gerald L. Andriole, Mark Emberton, Curtis Pettaway, Francesco Montorsi, Claudio Teloken, Roger S. Rittmaster, Matthew C. Somerville, Ramiro Castro. (2011) Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study. BJU Internationalno-no
CrossRef60
Alejandro Godoy, Elzbieta Kawinski, Yun Li, Daizo Oka, Borislav Alexiev, Faris Azzouni, Mark A. Titus, James L. Mohler. (2011) 5α-reductase type 3 expression in human benign and malignant tissues: A comparative analysis during prostate cancer progression. The Prostate 71:10, 1033-1046
CrossRef61
Rodolfo Montironi, Peter H. Bartels, Andrea DeCensi, Matteo Puntoni, Rodolfo Hurle, Ottavio Decobelli, Giorgio Carmignani, Roberta Mazzucchelli, Hubert G. Bartels, David S. Alberts, Massimo Maffezzini. (2011) A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry
. Urologic Oncology: Seminars and Original Investigations
CrossRef62
Ewelina Szliszka, Zenon P. Czuba, Anna Mertas, Andrzej Paradysz, Wojciech Krol. (2011) The dietary isoflavone biochanin-A sensitizes prostate cancer cells to TRAIL-induced apoptosis. Urologic Oncology: Seminars and Original Investigations
CrossRef63
Yizhen Lu, Zheng Zhang, Hongjie Yu, S. Lily Zheng, William B. Isaacs, Jianfeng Xu, Jielin Sun. (2011) Functional annotation of risk loci identified through genome-wide association studies for prostate cancer. The Prostate 71:9, 955-963
CrossRef64
Luke T. Lavallée, Dean Fergusson, Rodney H. Breau. (2011) The role of randomized controlled trials in evidence-based urology. World Journal of Urology 29:3, 257-263
CrossRef65
Ola Bratt, Martin C. Schumacher. (2011) Natural history of prostate cancer, chemoprevention and active surveillance. Acta Oncologica 50:S1, 116-119
CrossRef66
David A. Levy, J. Stephen Jones. (2011) Management of Rising Prostate-specific Antigen After a Negative Biopsy. Current Urology Reports 12:3, 197-202
CrossRef67
Roger S. Rittmaster. (2011) Chemoprevention of prostate cancer. Acta Oncologica 50:S1, 127-136
CrossRef68
Niloufar Ilani, Ronald S. Swerdloff, Christina Wang. (2011) Male hormonal contraception: Potential risks and benefits. Reviews in Endocrine and Metabolic Disorders 12:2, 107-117
CrossRef69
R P Kopp, J K Parsons, J Shiau, J Wang-Rodriguez, K Palazzi-Churas, J L Silberstein, I H Derweesh, K Sakamoto. (2011) Prostate atypia: clinical and pathological variables associated with cancer diagnosis on repeat biopsy. Prostate Cancer and Prostatic Diseases 14:2, 149-154
CrossRef70
Lucas P. Nacusi, Donald J. Tindall. (2011) Targeting 5α-reductase for prostate cancer prevention and treatment. Nature Reviews Urology 8:7, 378-384
CrossRef71
S. Memarzadeh, H. Cai, D. M. Janzen, L. Xin, R. Lukacs, M. Riedinger, Y. Zong, K. DeGendt, G. Verhoeven, J. Huang, O. N. Witte. (2011) Role of autonomous androgen receptor signaling in prostate cancer initiation is dichotomous and depends on the oncogenic signal. Proceedings of the National Academy of Sciences 108:19, 7962-7967
CrossRef72
J. Ferrís-i-Tortajada, O. Berbel-Tornero, J. Garcia-i-Castell, J.A. López-Andreu, E. Sobrino-Najul, J.A. Ortega-García. (2011) Non-dietary environmental risk factors in prostate cancer. Actas Urológicas Españolas (English Edition) 35:5, 289-295
CrossRef73
Lucy J. Schmidt, Donald J. Tindall. (2011) Steroid 5 α-reductase inhibitors targeting BPH and prostate cancer. The Journal of Steroid Biochemistry and Molecular Biology 125:1-2, 32-38
CrossRef74
Christoph Klingler. (2011) Re: The Influence of Family History on Prostate Cancer Risk: Implications for Clinical Management. European Urology 59:5, 881-882
CrossRef75
Richard M Hoffman, Anthony Y Smith. (2011) What we have learned from randomized trials of prostate cancer screening. Asian Journal of Andrology 13:3, 369-373
CrossRef76
Kenneth G. Nepple, Gerald L. Andriole. (2011) Prostate cancer chemoprevention with 5α-reductase inhibitors. Urologic Oncology: Seminars and Original Investigations
CrossRef77
P. Stattin. (2011) Commentary: Fatherhood status and prostate cancer risk--the jury is still out. International Journal of Epidemiology 40:2, 488-488
CrossRef78
Patrick C. Walsh. (2011) Urological Oncology: Prostate Cancer. The Journal of Urology 185:4, 1274-1278
CrossRef79
Patrick C. Walsh. (2011) Re: FDA Panel Votes Against Drugs Said to Prevent Prostate Cancer. The Journal of Urology 185:4, 1275-1276
CrossRef80
John M. Fitzpatrick, Joaquim Bellmunt, Robert Dreicer, Neil E. Fleshner, Christopher J. Logothetis, Judd W. Moul, Bertrand Tombal, Alexandre Zlotta. (2011) Maximizing outcomes in genitourinary cancers across the treatment continuum. BJU International 107, 1-12
CrossRef81
Erika Jonietz. (2011) Designing smarter cancer prevention trials. Nature 471:7339, S20-S21
CrossRef82
Michael B. Sporn. (2011) Perspective: The big C — for Chemoprevention. Nature 471:7339, S10-S11
CrossRef83
Abdulmaged M. Traish, John Hassani, Andre T. Guay, Michael Zitzmann, Michael L. Hansen. (2011) Adverse Side Effects of 5α-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients. The Journal of Sexual Medicine 8:3, 872-884
CrossRef84
Samir S. Taneja. (2011) Reply. Urology 77:3, 675-676
CrossRef85
Hans-Jörg Senn, Rudolf Morant, Florian Otto. (2011) The antihormonal preventive therapy of breast cancer and prostate cancer. Hormone Molecular Biology and Clinical Investigation 5:2, 117-123
CrossRef86
Stephan Madersbacher, Antonio Alcaraz, Mark Emberton, Peter Hammerer, Anton Ponholzer, Fritz H. Schröder, Andrea Tubaro. (2011) The influence of family history on prostate cancer risk: implications for clinical management. BJU International 107:5, 716-721
CrossRef87
Guilherme Godoy, George J. Huang, Trushar Patel, Samir S. Taneja. (2011) Long-term Follow-up of Men With Isolated High-grade Prostatic Intra-epithelial Neoplasia Followed by Serial Delayed Interval Biopsy. Urology 77:3, 669-674
CrossRef88
H. Akaza, H. Kanetake, T. Tsukamoto, N. Miyanaga, H. Sakai, N. Masumori, H. Nakatsu, K. Sagiyama, S. Sakamoto, Y. Endo, T. Yamanouchi, . (2011) Efficacy and Safety of Dutasteride on Prostate Cancer Risk Reduction in Asian Men: The Results from the REDUCE Study. Japanese Journal of Clinical Oncology 41:3, 417-423
CrossRef89
Claus G. Roehrborn, Gerald L. Andriole, Timothy H. Wilson, Ramiro Castro, Roger S. Rittmaster. (2011) 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. European Urology 59:2, 244-249
CrossRef90
Pim J. van Leeuwen, Konrad Kölble, Hartwig Huland, Thomas Hambrock, Jelle Barentsz, Fritz H. Schröder. (2011) Prostate Cancer Detection and Dutasteride: Utility and Limitations of Prostate-Specific Antigen in Men with Previous Negative Biopsies. European Urology 59:2, 183-190
CrossRef91
Erik B. Cornel. (2011) Re: Fritz H. Schröder, Monique J. Roobol. The REDUCE Trial. Eur Urol 2010;58:253–255. European Urology 59:1, e1
CrossRef92
J. Paul Monk, Susan Halabi, Joel Picus, Arif Hussain, George Philips, Ellen Kaplan, Tim Ahles, Lin Gu, Nicholas Vogelzang, William K. Kelly, Eric J. Small, . (2011) Efficacy of peripheral androgen blockade in prostate cancer patients with biochemical failure after definitive local therapy. Cancern/a-n/a
CrossRef93
D.M.A. Attia, A.G.H. Ederveen. (2011) Opposing roles of ERα and ERβ in the genesis and progression of adenocarcinoma in the rat ventral prostate. The Prostaten/a-n/a
CrossRef94
Cosimo De Nunzio, Alfonso Carluccini, Antonio Cicione, Stefano Squillacciotti, Alberto Trucchi, Andrea Cantiani, Costantino Leonardo, Andrea Tubaro. (2011) Prostate Cancer Does Not Influence Androgen Levels: A Radical Prostatectomy Cohort Study. Urologia Internationalis 86:2, 161-166
CrossRef95
Cosimo De Nunzio, Stephen J Freedland, Roberto Miano, Alberto Trucchi, Andrea Cantiani, Alfonso Carluccini, Andrea Tubaro. (2011) Metabolic syndrome is associated with high grade gleason score when prostate cancer is diagnosed on biopsy. The Prostaten/a-n/a
CrossRef96
Robert J Hamilton, Stephen J Freedland. (2011) 5-α reductase inhibitors and prostate cancer prevention: where do we turn now?. BMC Medicine 9:1, 105
CrossRef97
Yinong Niu, Rongbin Ge, Libing Hu, Christian Diaz, Zongwei Wang, Chin-Lee Wu, Aria F. Olumi. (2011) Reduced levels of 5-α reductase 2 in adult prostate tissue and implications for BPH therapy. The Prostaten/a-n/a
CrossRef98
Ji-Yeon Han, Myung-Soo Choo. (2011) Drug treatment for lower urinary tract symptoms. Journal of the Korean Medical Association 54:6, 637
CrossRef99
Sung Kyu Hong, Jong Jin Oh, Sangchul Lee, Hak Min Lee, Seok-Soo Byun, Gheeyoung Choe, Sang Eun Lee. (2011) Association of 5α-reductase inhibitor use and pathological features of prostate cancer in men undergoing radical prostatectomy. The Prostaten/a-n/a
CrossRef100
David Kirk. (2010) CURRENT PROSPECTS FOR THE CHEMOPREVENTION OF PROSTATIC CANCER. BJU International 106:11, 1826-1827
CrossRef101
Jacques Irani. (2010) Is Shared Decision Making in Prostate Cancer Restrained by Evidence-Based Medicine?. European Urology Supplements 9:11, 782-787
CrossRef102
J L Silberstein, J K Parsons. (2010) Prostate cancer prevention: concepts and clinical recommendations. Prostate Cancer and Prostatic Diseases 13:4, 300-306
CrossRef103
Sarah L Hulin-Curtis, Dominique Petit, W Douglas Figg, Ann W Hsing, Juergen KV Reichardt. (2010) Finasteride metabolism and pharmacogenetics: new approaches to personalized prevention of prostate cancer. Future Oncology 6:12, 1897-1913
CrossRef104
M. T. Rosenberg, M. Froehner, D. Albala, M. M. Miner. (2010) Biology and natural history of prostate cancer and the role of chemoprevention. International Journal of Clinical Practice 64:13, 1746-1753
CrossRef105
Ruben G. Cremers, Katja K. Aben, Sita H. Vermeulen, Martin den Heijer, Inge M. van Oort, Lambertus A. Kiemeney. (2010) Androgenic alopecia is not useful as an indicator of men at high risk of prostate cancer. European Journal of Cancer 46:18, 3294-3299
CrossRef106
Timothy J. Wilt, Roderick MacDonald, Karen Hagerty, Paul Schellhammer, James Tacklind, Mark R. Somerfield, Barnett S. Kramer. (2010) 5-α-Reductase inhibitors for prostate cancer chemoprevention: an updated Cochrane systematic review. BJU International 106:10, 1444-1451
CrossRef107
Patrick C. Walsh. (2010) Urological Oncology: Prostate Cancer. The Journal of Urology 184:4, 1354-1356
CrossRef108
Jeri Kim. (2010) Chemoprevention of prostate cancer: breakthroughs and controversies. Expert Review of Anticancer Therapy 10:10, 1517-1522
CrossRef109
Yasir Ruhayel, Aleksander Giwercman, David Ulmert, Lars Rylander, Anders Bjartell, Jonas Manjer, Göran Berglund, Yvonne L. Giwercman. (2010) Male infertility and prostate cancer risk: a nested case–control study. Cancer Causes & Control 21:10, 1635-1643
CrossRef110
Steven B Zeliadt, Scott D Ramsey. (2010) Cost–effectiveness of prostate cancer chemoprevention among high-risk men. Expert Review of Pharmacoeconomics & Outcomes Research 10:5, 505-508
CrossRef111
Peter H. Gann. (2010) Prostate cancer: A closer look at the initial results from the REDUCE trial. Nature Reviews Urology 7:10, 535-537
CrossRef112
M. Hohenfellner. (2010) Prostatakarzinom: ein Update. Der Urologe 49:S1, 169-171
CrossRef113
Seth A. Strope, Gerald L. Andriole. (2010) Prostate cancer screening: current status and future perspectives. Nature Reviews Urology 7:9, 487-493
CrossRef114
Roger S. Kirby, Tom A. McNicholas, John M. Fitzpatrick. (2010) CURRENT PROSPECTS FOR THE CHEMOPREVENTION OF PROSTATE CANCER. BJU International 106:6, 751-753
CrossRef115
Wesley M. White, Edward D. Kim. (2010) Prevention: Evolving role of 5-α reductase inhibitors in chemoprevention. Nature Reviews Clinical Oncology 7:9, 487-488
CrossRef116
H. Akaza. (2010) Aim of the Working Group on the Asian Perspectives on Cancer Control: Asian Perspective on Prostate Cancer Prevention. Japanese Journal of Clinical Oncology 40:Supplement 1, i2-i6
CrossRef117
P J van Leeuwen, H A van Vugt, C H Bangma. (2010) The implementation of screening for prostate cancer. Prostate Cancer and Prostatic Diseases 13:3, 218-227
CrossRef118
(2010) Dutasteride and Prostate Cancer. New England Journal of Medicine 363:8, 793-796
Full Text119
Karen A. Johnson, Powel H. Brown. (2010) Drug Development for Cancer Chemoprevention: Focus on Molecular Targets. Seminars in Oncology 37:4, 345-358
CrossRef120
Fritz H. Schröder, Monique J. Roobol. (2010) The REDUCE Trial. European Urology 58:2, 253-255
CrossRef121
Walsh, Patrick C., . (2010) Chemoprevention of Prostate Cancer. New England Journal of Medicine 362:13, 1237-1238
Full Text122
J.A. Arratia-Maqueo, R. Garza-Cortés, L.S. Gómez-Guerra, J.R. Cortés-González. (2010) Effect of one month treatment with dutasteride on transurethral resection of the prostate. Actas Urológicas Españolas (English Edition) 34:10, 866-869
CrossRef123
Yong Hyeuk Choi, Sung Yong Cho, In Rae Cho. (2010) The Different Reduction Rate of Prostate-Specific Antigen in Dutasteride and Finasteride. Korean Journal of Urology 51:10, 704
CrossRef124
Nathan Lawrentschuk, Laurence Klotz. (2010) Active Surveillance for Favorable-Risk Prostate Cancer: A Short Review. Korean Journal of Urology 51:10, 665
CrossRef
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