Modeling and analysis of Gleason score 8-10 prostate cancers in the REDUCE study.

OBJECTIVE: To explore explanations for the numerical imbalance of biopsy-detected Gleason 8-10 prostate cancers (PCa) diagnosed in years 3-4 in the dutasteride and placebo groups of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study. METHODS: REDUCE was a 4-year, randomized, double-blind, placebo-controlled trial of dutasteride (0.5 mg/d) vs placebo for PCa risk reduction. We modeled the incidence of Gleason 8-10 cancer and used logistic regression analysis to evaluate the effects of baseline predictors of PCa, as well as post-baseline prostate volume at the time of biopsy, on PCa diagnosis. We compared needle biopsy Gleason scores with corresponding surgery Gleason scores. All statistical tests conducted were 2-sided. RESULTS: Had there been a scheduled biopsy occurring only at year 4, we estimated a similar incidence of Gleason 8-10 PCa in the dutasteride (n = 45) and placebo (n = 46) groups. Two biopsy Gleason 7 cancers in the placebo group (n = 150) were upgraded to Gleason 8-10 cancer on prostatectomy, and no patients in the dutasteride group (n = 111) were upgraded. Logistic regression analysis demonstrated the effect of prostate volume on Gleason 8-10 cancer diagnosis. CONCLUSION: Although modeling of REDUCE data showed a similar incidence of Gleason 8-10 cancer in the dutasteride and placebo groups at year 4, an association between dutasteride and Gleason 8-10 cancer cannot be definitely excluded. It is likely that several biases, notably study design and prostate size at the time of biopsy, contributed to the numerical imbalance in Gleason 8-10 cancers observed between the treatment groups in years 3-4.

Comparison of Classic and International Society of Urological Pathology 2005 Modified Gleason grading using needle biopsies from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.

CONTEXT: Use of the International Society of Urological Pathology (ISUP) 2005 modified Gleason score may result in higher scores compared with the classic Gleason scoring system. OBJECTIVE: To compare scores derived using the 2 scoring systems. DESIGN: On-study and for-cause biopsies were centrally reviewed and assigned a classic Gleason score in the Reduction by Dutasteride of prostate Cancer Events trial. Positive biopsies were reviewed by an independent pathologist in a secondary review using the ISUP 2005 modified Gleason score. The independent pathologist also recorded a classic Gleason score. RESULTS: In total, 1482/1507 (98%) positive biopsy results were independently reviewed. Scores assigned by the 2 pathologists (classic versus modified) agreed in 83% (1230 of 1481) of cases; 99% (1471 of 1481) of cancers were within ±1 of their previous score. Of discordant cases, similar numbers of biopsies were upgraded and downgraded in the secondary review, with minor differences in the score distributions. Interobserver agreement was good, with κ values ranging from 0.62 (95% confidence interval [CI], 0.56-0.67) to 0.70 (95% CI, 0.65-0.76). The overall number of high-grade tumors (Gleason score 8-10; n = 48) remained constant between reviews, with 3 fewer cases in the placebo group (n = 16) and 3 more in the dutasteride group (n = 32) in the secondary review. When comparing the independent pathologist's modified scores versus the classic, 17 of 1481 cancers (1.1%) were upgraded (including 9 of 17 upgrades [53%] to high-grade tumors). CONCLUSIONS: This analysis showed similar score distributions between the classic and modified Gleason scoring systems. The differences seen between the 2 pathologists' scores likely reflect differences in interpretation rather than the scoring system chosen.

Biopsy misidentification identified by DNA profiling in a large multicenter trial.

PURPOSE: The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) prostate cancer risk reduction study randomly assigned 8,231 men to dutasteride or placebo for 4 years. Protocol-mandated biopsies were obtained after 2 and 4 years. After the discovery of three cases of biopsy sample misidentification in the first 2 years, all protocol-mandated biopsy samples were DNA tested to verify biopsy identity. METHODS: Biopsy and blood DNA profiling was performed retrospectively for the year 2 scheduled biopsies and prospectively for the year 4 scheduled biopsies. Toward the end of year 2, multiple changes were made to improve sample handling and chain of custody. RESULTS: Of the 6,458 year 2 and 4,777 year 4 biopsies, 26 biopsies reflecting 13 sample handling errors at year 2 (0.4%) and one biopsy reflecting one sample handling error at year 4 (0.02%) were confirmed to be mismatched to the patient for whom they were originally submitted. Of 6,733 reference blood samples profiled, 31 (0.5%) were found to be mismatched to the patient's verified identity profile. Sample identification errors occurred at local research sites and central laboratories. CONCLUSION: Biopsy misidentification is a potential problem in clinical laboratories and clinical trials. Until now, biopsy misidentification has not been studied in the setting of a large, multinational clinical trial. In the REDUCE study, process improvement initiatives halfway through the trial dramatically reduced biopsy mismatches. The potential for biopsy mismatches in clinical trials and clinical practice is an under-recognized problem that requires rigorous attention to details of chain of custody and consideration of more widespread DNA identity testing.

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 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.)

Psychometric validation of a patient-reported sensory perception and preference instrument: the Sensory Perceptions Questionnaire.

This study evaluated the psychometric properties of content validity, construct validity, and test-retest reliability of a 23-item Sensory Perceptions Questionnaire (SPQ) used to survey sensory perceptions of intranasal corticosteroid sprays. Two patient cohorts (men and women aged > or =18 years who had at least a 1-year history of allergic rhinitis and had been using a corticosteroid nasal spray) were enrolled. The content validity and construct validity of the SPQ questions were evaluated using a cognitive debriefing method after cohort 1 (n=15) completed the SPQ. Test-retest reliability (assessed with intraclass correlation coefficients [ICCs] of the SPQ questions) was evaluated in cohort 2 (n=50), after they answered a Web-based version of the SPQ on two occasions, each separated by 7 days. In cohort 1, 7 of 15 patients believed all relevant sensory perceptions were addressed in the questionnaire. Although 8 patients mentioned at least 1 sensory perception that was not addressed, only 4 sensory perceptions were mentioned by more than 1 patient, and none was mentioned reliably by more than 2 patients. Those 4 sensory perceptions not addressed in the SPQ were all intentionally excluded, because they were potential symptoms of rhinitis or adverse events associated with intranasal corticosteroid spray use. Patients regarded the questions as straightforward, nonburdensome, and nonthreatening, signs suggesting the questions were not likely to challenge the construct validity of the SPQ. The responses to 2 questions (one in which patients were asked to indicate whether they were pleased or displeased overall with a particular spray; the other to indicate their overall product preference) were somewhat influenced by the effectiveness of the sprays. Results of test-retest reliability (cohort 2) showed both high (>0.8) and low (<0.7) ICCs. A high degree of correspondence between the 2 administrations produced a low between-patient variance, which likely resulted in lower ICCs. The SPQ adequately represents the sensory attributes reported by patients regarding intranasal corticosteroid spray use and, overall, is a valid measure of patient preference based on sensory perception.