Safety of enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: expanded access in North America.

BACKGROUND: The open-label, single-arm enzalutamide expanded access program (EAP) in the United States and Canada evaluated the safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel. METHODS: Patients (n = 507) received enzalutamide 160 mg/day until disease progression, intolerable adverse events (AEs), or commercial availability occurred. AEs and other safety variables were assessed on day 1, weeks 4 and 12, and every 12 weeks thereafter. Data following transition to commercial drug were not collected. RESULTS: Median age was 71 years (range 43-97); 426 patients (83.9%) had a baseline ECOG score of ≤1. In addition to docetaxel, the majority of patients had received prior prostate cancer treatments such as abiraterone (76.1%) or cabazitaxel (28.6%). Median study treatment duration was 2.6 months (range 0.03-9.07). The most frequently reported reasons for discontinuation were commercial availability of enzalutamide (46.7%) and progressive disease (33.7%). A total of 88.2% of patients experienced AEs; 45.4% experienced AEs with a maximum grade of 1 or 2. Fatigue (39.1%), nausea (22.7%), and anorexia (14.8%) were the most commonly reported AEs. Seizure was reported in four patients (0.8%). The most commonly reported event leading to death was progression of metastatic prostate cancer (7.7%). CONCLUSION: In this heavily pretreated EAP population with progressive mCRPC, enzalutamide was well tolerated and the safety profile was consistent with that of the AFFIRM trial.

Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.

BACKGROUND: In the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC. METHODS: Patients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69). RESULTS: Baseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14-0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10-0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%). CONCLUSIONS: This STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01664923.

Utilization trends in prostate cancer therapy.

PURPOSE: We determined therapeutic trends in the management of adenocarcinoma of the prostate, and in the case of intensity modulated radiation therapy we investigated whether site of service influenced those trends. MATERIALS AND METHODS: A variety of CPT codes to treat adenocarcinoma of the prostate were extracted from the Medicare Part B 5% sample for the years 2006 to 2008 inclusive. Data were stratified by year, type of service and, in the case of radiation therapy, site of service. Treatment trends were calculated by indexing the total number of Medicare beneficiaries receiving a service against needle biopsies of the prostate. RESULTS: The percentage of Medicare beneficiaries receiving therapy indexed to needle biopsies of the prostate increased from 43.8% in 2006 to 49.0% in 2008. Trends in radiation and surgery were similar with 11.5% and 13% increases in each modality, respectively. Total Medicare beneficiaries receiving intensity modulated radiation therapy and laparoscopic radical prostatectomy increased by 25.4% and 22.1%, respectively, while Medicare beneficiaries treated with open radical prostatectomy and 3-dimensional conformal radiation therapy decreased by 27.9% and 37.6%, respectively. The pattern of use for intensity modulated radiation therapy was similar in physician office and hospital facility settings, increasing from 7.3% to 11.1% and 8.3% to 11.3% of Medicare beneficiaries indexed to needle biopsies of the prostate receiving intensity modulated radiation therapy at these sites in 2008, respectively. CONCLUSIONS: Treatment trends in surgery and radiation strongly favor newer technologies, and in the case of intensity modulated radiation therapy, utilization trends for treatment of adenocarcinoma of the prostate are similar across all sites of service.

Weighted Gleason Grade Group (WGGG): A new prostate cancer biopsy reporting system with prognostic potential.

INTRODUCTION: Presently, prostate biopsy (PBx) results report the highest Gleason Grade Group (GGG) as a single metric that gauges the overall clinical aggressiveness of cancer and dictates treatment. We hypothesized a PBx showing multiple cores of cancer with more volume cancer per core would represent more aggressive disease. We propose the Weighted Gleason Grade Group (WGGG), a novel scoring system that synthesizes all histopathologic data and cancer volume into a single numeric value representing the entire PBx, allowing for improved prediction of adverse pathology and risk of biochemical recurrence (BCR) following radical prostatectomy (RP). METHODS: We studied 171 men who underwent RP after standard PBx. The WGGG was calculated by summing each positive core using the formula: GGG + (GGG x %Ca/core). RP pathology was evaluated for extraprostatic extension (EPE), positive surgical margins (PSM), seminal vesicle invasion (SVI), and lymph node involvement (LNI), and patients were followed for BCR. We compared GGG vs. WGGG receiver operating characteristic curves for each outcome, and determined the predictive capability of GGG and WGGG to identify patients with BCR. Categorized WGGG groups were created based on risk of BCR using classification and regression tree analysis. We then sought to externally validate WGGG in a cohort of 389 patients in a separate institutional dataset. RESULTS: In the development cohort, area under the curves (AUCs) for the WGGG vs. GGG were significantly higher for predicting EPE (0.784 vs. 0.690, P = 0.002), SVI (AUC 0.823 vs. 0.721, P = .014), LNI (AUC 0.862 vs. 0.823, P = 0.039), and PSM (AUC 0.638 vs. 0.575, P = 0.031. Analysis of the validation cohort showed similar findings for EPE (AUC 0.764 vs. 0.729, P = 0.13), SVI (AUC 0.819 vs. 0.749, P = 0.01), LNI (AUC 0.939 vs. 0.867, P = 0.02), and PSM (AUC 0.624 vs. 0.547, P = 0.04). Patients with WGGG >30 (high-risk group) demonstrated ∼50% failure at 2 years in both cohorts. CONCLUSIONS: The WGGG, by providing a metric reflecting the entirety of the PBx, is more informative than conventional single GGG alone in identifying adverse pathologic outcomes and risk of BCR following RP. This superior discriminatory capability has been achieved without any consideration of other commonly available clinical disease characteristics.

The sad and bleak future for urology funding at the National Institutes of Health.

The bulk of federal funding for medical research is delivered through the National Institutes of Health (NIH). Because federal funding is coordinated through the annual discretionary budget review process, the budget for NIH varies from year to year. Small changes in the rate of funding growth lead to significant problems for individual researchers and their supporting institutions. There is no single metric that serves as a surrogate to predict the appropriations process. This article begins with a history and physical examination of NIH. Next, the authors review the internal NIH priorities that continue to drive the funding process. Finally, the authors give a brief review of the impact congressionally mandated medical research programs have had on disease-specific funding.

Racial or Ethnic and Socioeconomic Disparities in Prostate Cancer Survivors' Prostate-specific Quality of Life.

OBJECTIVE: To conduct a prospective study to examine whether there are pretreatment and post-treatment disparities in urinary, sexual, and bowel quality of life (QOL) by race or ethnicity, education, or income in men with clinically localized prostate cancer (PCa.) METHODS: Participants (N = 1508; 81% white; 12% black; 7% Hispanic; 50% surgery; 27% radiotherapy; 23% active surveillance) completed the Expanded Prostate Cancer Index Composite measure of PCa-specific QOL prior to treatment, 6 weeks, 6, 12, 18, and 24 months after treatment. We analyzed pretreatment differences in QOL with multivariable linear regression and post-treatment differences with generalized estimating equation models. RESULTS: Blacks and Hispanics (compared with whites) and men with lower income had worse pretreatment urinary function; poorer and less educated men had worse pretreatment sexual function (P < .05). In adjusted models, among men treated surgically, blacks and Hispanics had worse bowel function compared with whites, and men with lower income experienced more sexual bother and slower recovery in urinary function. Not all racial or ethnic differences favored whites; blacks had higher sexual function than whites prior to surgery and improved faster after surgery. Blacks receiving radiotherapy had lower post-treatment bowel bother than whites (P < .05). CONCLUSION: Controlling for baseline QOL, there were some post-treatment disparities in urinary and sexual QOL that suggest the need to investigate whether treatment quality and access to follow-up care is equitable. However, survivorship disparities may, to a greater extent, reflect disadvantages in baseline health that exacerbate QOL issues after treatment.

Histologic Changes in Prostate Cancer Detected Subsequent to the 2012 United States Preventive Services Task Force (USPSTF) Prostate Cancer Screening Recommendation.

We report changes in the histopathology of prostate cancer diagnosed in a large urology group practice after the final United States Preventive Services Task Force (USPSTF) Grade D recommendation against prostate-specific antigen screening. All prostate biopsies performed from 2011 through 2015 in a large urology group practice were retrospectively reviewed; 2012 was excluded as a transition year. The changes in biopsy data in years following the USPSTF decision (2013-2015) were then compared with baseline (2011). A total of 10,944 biopsies were evaluated during the study period. Positive biopsy rates rose from 39.1% at baseline to 45.2% in 2015 (P < 0.01) with a marked shift toward more aggressive cancer throughout the study period. The absolute number of patients presenting with Gleason Grade Group 4 or 5 increased from 155/year at baseline to 231, 297, and 285 in 2013, 2014, and 2015, respectively (P < 0.05), unrelated to age or racial changes over time. Black men represented 16% of the cohort. Since the USPSTF recommendation against prostate cancer screening, trends toward a substantial upward grade migration and increased volume of cancers were noted in a cohort of nearly 11,000 patients in a real-world clinical practice. Additionally, continuing reductions in cancer detection in the United States may exacerbate these trends.

Up and Away: Five Decades of Urologic Investigation in Microgravity.

A renewed global interest in manned space exploration has emerged, propelled by the challenge of reaching a new frontier: travel to the Red Planet, Mars. As the physiological changes induced by microgravity bear direct relevance to the safety and viability of these goals, we provide a historical narrative of the urologic investigations in space. We review the significant contributions to the understanding of the urologic consequences associated with exposure to microgravity, considerations for prolonged missions, and forward-looking efforts to manage emergent conditions remotely. Historical insights gleaned are poised to inform interplanetary travel, where urologic pathology will remain an important practical consideration.

Urinary quality of life outcomes in men who were treated with image-guided intensity-modulated radiation therapy for prostate cancer.

PURPOSE: Quality of life (QoL) outcomes play a major role in the treatment selection for prostate cancer (CaP). We evaluated the urinary QoL outcomes in men who were treated with image-guided intensity-modulated radiation therapy (IG-IMRT) for CaP. METHODS AND MATERIALS: We enrolled men who were diagnosed with CaP and underwent IG-IMRT in a large urological group practice into a prospectively maintained database. The typical radiation treatment dosage to prostates and seminal vesicles was 8100 cGy in 45 fractions. Urinary QoL was self-assessed using the standardized incontinence grade and International Prostate Symptom Score (IPSS) at baseline and at each follow-up visit. We evaluated the cumulative incidence of urinary incontinence and changes in both continence and IPSS over time. RESULTS: Of the 3602 men who were eligible for analysis, 3086 (85.7%) had no urinary incontinence; 479 (13.3 %) had minimal incontinence (no requirement for pads), and 37 (1.0 %) had significant urinary incontinence that required the use of pads or interfered with activities of daily living, at baseline. After a median follow-up of 24 months (range: 12.0-41.0 months), these numbers were 80.6%, 17.4%, and 2.0%, respectively. Radiation therapy appeared to have a beneficial effect on some men: 54.1% of men with minimal incontinence became completely continent of urine during follow-up. Of those with significant urinary incontinence, 29.7% reported resolution and 27.0% reported improved symptoms with no requirement for pads. Of the 1276 men with moderate IPSS, the mean IPSS decreased from 12 to 9.8 at the time of the last follow-up (P < .001). Similarly, of the 233 men with severe IPSS, the mean IPSS decreased from 24 to 13 at the time of the last follow-up (P < .001). CONCLUSION: IG-IMRT for clinically localized CaP is associated with a relatively low incidence of urinary incontinence. Although unexplained, IG-IMRT seems to improve symptoms in some men with baseline urinary incontinence and moderate-to-severe IPSS.

Comparison of Multiparametric MRI Scoring Systems and the Impact on Cancer Detection in Patients Undergoing MR US Fusion Guided Prostate Biopsies.

INTRODUCTION: Multiple scoring systems have been proposed for prostate MRI reporting. We sought to review the clinical impact of the new Prostate Imaging Reporting and Data System v2 (PI-RADS) and compare those results to our proposed Simplified Qualitative System (SQS) score with respect to detection of prostate cancers and clinically significant prostate cancers. METHODS: All patients who underwent multiparametric prostate MRI (mpMRI) had their images interpreted using PI-RADS v1 and SQS score. PI-RADS v2 was calculated from prospectively collected data points. Patients with positive mpMRIs were then referred by their urologists for enrollment in an IRB-approved prospective phase III trial of mpMRI-Ultrasound (MR/TRUS) fusion biopsy of suspicious lesions. Standard 12-core biopsy was performed at the same setting. Clinical data were collected prospectively. RESULTS: 1060 patients were imaged using mpMRI at our institution during the study period. 341 participants were then referred to the trial. 312 participants underwent MR/TRUS fusion biopsy of 452 lesions and were included in the analysis. 202 participants had biopsy-proven cancer (64.7%) and 206 (45.6%) lesions were positive for cancer. Distribution of cancer detected at each score produced a Gaussian distribution for SQS while PI-RADS demonstrates a negatively skewed curve with 82.1% of cases being scored as a 4 or 5. Patient-level data demonstrated AUC of 0.702 (95% CI 0.65 to 0.73) for PI-RADS and 0.762 (95% CI 0.72 to 0.81) for SQS (p< 0.0001) with respect to the detection of prostate cancer. The analysis for clinically significant prostate cancer at a per lesion level resulted in an AUC of 0.725 (95% CI 0.69 to 0.76) and 0.829 (95% CI 0.79 to 0.87) for the PI-RADS and SQS score, respectively (p< 0.0001). CONCLUSIONS: mpMRI is a useful tool in the workup of patients at risk for prostate cancer, and serves as a platform to guide further evaluation with MR/TRUS fusion biopsy. SQS score provided a more normal distribution of scores and yielded a higher AUC than PI-RADS v2. However until our findings are validated, we recommend reporting of detailed sequence-specific findings. This will allow for prospectively collected data to be utilized in determining the impact of ongoing changes to these scoring systems as our understanding of mpMRI interpretation evolves.

Prognostic indicators for long term outcome following radical retropubic prostatectomy for prostate cancer involving the seminal vesicles.

Seminal vesicle involvement at the time of radical prostatectomy (RP) for prostate cancer has been equated with metastatic disease. We review our biochemical freedom from disease results following RP in patients with seminal vesicle involvement with particular attention to identifying variables that may be predictive of disease recurrence. We retrospectively reviewed our surgical database and identified patients with pT3b (2002 AJCC) prostate cancer at RP [corrected]. There were 70 cases without lymph node involvement and with available clinical follow-up identified. Any patient receiving androgen deprivation therapy, radiation therapy, or with a sustained PSA elevation greater than 0.2 ng/mL was considered a biochemical failure. Results were calculated using the Kaplan-Meier method. Mean age was 63.4 (range 45.7-79.5) years, mean preoperative PSA was 11.3 ng/mL (range 2-60), mean biopsy Gleason score was 7.2 (range 4-9), mean RP Gleason score was 7.5 (range 5-9), and median follow-up time was 61.5 months (range 2.3-160.6). Overall, 33/70 (47%) patients were without evidence of disease without further therapy. For patients with pT3bN0Mx prostate cancer, margin status, capsular invasion, and PSA were not statistically significant risk factors for disease progression. Gleason score and major Gleason grade were the only statistically significant variables that predicted disease progression. A specimen Gleason score of greater than 7 and major Gleason grades greater than 3 were associated with an increased rate of disease progression in this patient group.

A contemporary evaluation of cytoreductive nephrectomy with tumor thrombus: Morbidity and long-term survival.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is an aggressive entity that frequently invades the venous system. We evaluated the morbidity and survival of patients with tumor thrombus who undergo cytoreductive nephrectomy. MATERIALS AND METHODS: We identified 56 patients from our institution's database who had a primary renal tumor in place and documented metastases at the time of surgery. We reviewed demographic and pathologic characteristics from these patients as well as complications and overall survival. RESULTS: Median age was 58 (37-77). There were 33 patients (59%) who had tumor thrombus with 21 (64%) involving the renal vein, 10 (30%) involving the infradiaphragmatic inferior vena cava (IVC), and 2 (6%) involving the supradiaphragmatic IVC. Median tumor size for thrombus patients was 12 cm (5-29). There were 8 (14.2%) who had complications, including 1 death. Thrombus patients were significantly more likely to have a complication (P = 0.008). Median survival for all patients was 10.7 months (0.3-61). There was no significant difference in overall survival between patients with and without thrombus (P = 0.76). CONCLUSIONS: Patients who undergo cytoreductive nephrectomy with a tumor thrombus have a higher rate of complications as compared to patients undergoing cytoreductive nephrectomy without tumor thrombus. The long-term survival, however, was not statistically different and thus aggressive surgery for select metastatic RCC patients is warranted.

The relationship of long term global temperature change and human fertility.

UNLABELLED: According to the United Nations, global fertility has declined in the last century as reflected by a decline in birth rates. The earth's surface air temperature has increased considerably and is referred to as global warming. Since changes in temperature are well known to influence fertility we sought to determine if a statistical relationship exists between long-term changes in global air temperatures and birth rates. The most complete and reliable birth rate data in the 20th century was available in 19 industrialized countries. Using bivariate and multiple regression analysis, we compared yearly birth rates from these countries to global air temperatures from 1900 to 1994.A common pattern of change in birth rates was noted for the 19 industrialized countries studied. In general, birth rates declined markedly throughout the century except during the baby boom period of approximately 1940 to 1964. An inverse relationship was found between changes in global temperatures and birth rates in all 19 countries. Controlling for the linear yearly decline in birth rates over time, this relationship remained statistically significant for all the 19 countries in aggregate and in seven countries individually (p<0.05). CONCLUSIONS: The results of our analyses are consistent with the underlying premise that temperature change affects fertility and suggests that human fertility may have been influenced by change in environmental temperatures.