The clinical applications of five-alpha reductase inhibitors.

INTRODUCTION Five-alpha reductase (5-AR) deficiency was first identified by Imperato-McGinley and Walsh as the cause of pseudohermaphroditism in two separate studies. The discoveries led to the development of finasteride (inhibitor of type 2 isoenzyme of 5-AR) and dutasteride (inhibitor of type 1 and type 2 isoenzymes of 5-AR. Both drugs have been proven effective for the treatment of benign prostatic hyperplasia and improve voiding symptoms, reduce the risk of urinary retention and the need for prostate surgery. Five-alpha reductase inhibitors 5-ARIs have been demonstrated to be chemopreventive agents and reduce the risk of prostate cancer, although the risk of selecting out or mediating higher grade prostate cancer remains uncertain. A lower dose of finasteride has been shown to be effective in the treatment of male pattern baldness. MATERIALS AND METHODS: A Medline search was performed using mesh terms, benign prostatic hypertrophy, prostate cancer, male pattern baldness, female and 5-AR. RESULTS: The Prostate Long Term Efficacy and Safety Study (PLESS) was a randomized double-blind study that established that finasteride resulted in a 22% increase in maximum flow rate and a 19% decrease in prostate volume. Further studies demonstrated that finasteride caused a significant reduction in the risk of the need for surgery and urinary retention in a 4 year period. Additional studies showed similar beneficial results with dutasteride. The potential benefits of 5-ARIs as chemopreventive agents were examined in the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) studies. In the 7 year PCPT trial, 18.4% of the finasteride group developed prostate cancer compared to 24.4% in the placebo group. In the 4 year REDUCE trial, there was a 22.8% reduction of prostate cancer at the conclusion of the study. Despite the reduction of prostate cancer in both the PCPT and REDUCE trials, each study showed an increased risk of prostate cancer in the treatment arms. The explanation for these observations remains an area of investigation. Low dose finasteride has also been used successfully for the treatment of male pattern baldness. CONCLUSIONS: The use of 5-ARIs has been a major advance in urologic clinical practice. Urologists should be familiar with the underlying pharmacology of 5-ARIs as well as the clinical indications for their use.

Overactive bladder in an integrated delivery system: a longitudinal cohort study.

BACKGROUND: Overactive bladder (OAB) is common and morbid. Medication and diagnosis claims may be specific, but lack sensitivity to identify patients with overactive bladder. We used an "electronic health record (EHR) phenotype" to identify cases and describe treatment choices and anticholinergic burden for OAB. METHODS: We conducted a retrospective cohort study in a large, integrated health delivery system between July 2011 and June 2012 (2-year follow-up). We examined care from primary care and specialty clinics, medication and procedure use, and anticholinergic burden for each patient. RESULTS: There were 7362 patients with an EHR OAB phenotype; 50% of patients were > 65 years old, 74% were female, and 83% were white. The distribution of care included primary care physician (PCP)/specialty co-management (25% of patients); PCP care only (18%); urology only (13%); or some other combination of specialty care (33%). Only 40% of patients were prescribed at least 1 OAB medication during the study. The mean duration of prescribed medication was 1.5 months (95% confidence interval [CI], 1.4 to 1.6 months; range, < 1 month to 24 months). Independent predictors of receipt of an OAB medication included increasing age (odds ratio [OR], 1.4 for every 10 years; 95% CI, 1.4 to 1.5), women (OR, 1.6 compared with men; 95% CI, 1.4 to 1.8), diabetes (OR, 1.3; 95% CI, 1.1 to 1.5), and certain sources of care compared with PCP-only care: PCP/specialty co-management (OR, 1.8; 95% CI, 1.5 to 2.0), urology (OR, 2.2; 95% CI, 1.8 to 2.6), and multiple specialists (OR, 1.4; 95% CI, 1.2 to 1.8). Very few patients received other treatments: biofeedback (< 1%), onabotulinumtoxinA (2%), or sacral nerve stimulation (1%). Patients who received OAB medications had significantly higher anticholinergic burden than patients who did not (anticholinergic total standardized daily dose, 125 versus 46; P < .001). CONCLUSIONS: Although OAB is common and morbid, in a longitudinal study using an EHR OAB phenotype 40% of patients were treated with OAB medication and only briefly.

A decision analysis comparing 3 active surveillance protocols for the treatment of patients with low-risk prostate cancer.

BACKGROUND: Active surveillance (AS) is a viable management option for approximately 50% of men who are newly diagnosed with prostate cancer. To the authors' knowledge, no direct comparisons between the different variants of AS protocols have been conducted to date. The authors developed a microsimulation decision model to evaluate which of 3 alternative AS protocols is optimal for men with low-risk prostate cancer, and compared each of these with immediate treatment. METHODS: Men who were diagnosed with low-risk prostate cancer at age 65 years were modeled as having been treated with either immediate therapy or via each of 3 AS protocols. Modeled AS protocols represent those in the literature; a modified AS protocol was included in a sensitivity analysis. Immediate therapy included radical prostatectomy, external-beam radiotherapy, or brachytherapy. Outcome measures were quality-adjusted life-years (QALYs) and costs. Cost-effectiveness analysis and deterministic and probabilistic sensitivity analyses were performed. RESULTS: Immediate therapy produced fewer QALYs than all variants of AS. Of the AS protocols evaluated, biennial biopsy was found to be the only efficient option, with an incremental cost-effectiveness ratio of $3490 per QALY compared with immediate therapy. It delayed the need for curative therapy by a mean of 56 months, and was found to be preferred in >86.9% of cases in probabilistic sensitivity analysis. A modified version of low-intensity AS dominated all other options. CONCLUSIONS: For a 65-year-old man with low-risk prostate cancer, AS with biennial biopsy appears to be highly cost-effective compared with common alternatives. An AS protocol using triennial biopsy was found to dominate all other strategies and should be considered for men who are comfortable with a longer period between biopsies. The optimal strategy depends on a patient's tolerance for periodic biopsies and comfort with delaying radical treatment. Physicians should incorporate these patient preferences into decision making.

Global warming: the implications for urologic disease.

Global warming is receiving more attention in both the lay and scientific press. However, many individuals still view global warming as an abstract, distant concern that has little, if any, impact on their daily lives. As urologists, it is important to realize that global warming may influence some of the diseases that we treat. Much of the scientific basis for the link between climate and urologic disease is still in its nascent stages. However, a review of the emerging literature suggests that climatic changes may well alter the frequency of some urologic conditions.

NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection provide recommendations for prostate cancer screening in healthy men who have elected to participate in an early detection program. The NCCN Guidelines focus on minimizing unnecessary procedures and limiting the detection of indolent disease. These NCCN Guidelines Insights summarize the NCCN Prostate Cancer Early Detection Panel's most significant discussions for the 2016 guideline update, which included issues surrounding screening in high-risk populations (ie, African Americans, BRCA1/2 mutation carriers), approaches to refine patient selection for initial and repeat biopsies, and approaches to improve biopsy specificity.

The relationship between total testosterone levels and prostate cancer: a review of the continuing controversy.

PURPOSE: For many years it was believed that higher total testosterone contributed to prostate cancer and caused rapid cancer growth. International guidelines consider that adequate data are not available to determine whether there is additional risk of prostate cancer from testosterone replacement. Numerous studies with multiple designs and contradictory conclusions have investigated the relationship between total testosterone and prostate cancer development. To establish current knowledge in this field we reviewed the literature on total testosterone and the subsequent risk of prostate cancer as well as the safety of exogenous testosterone administration in patients with a history of prostate cancer. MATERIALS AND METHODS: We searched the literature to identify articles from 1994 to 2014 related to the relationship between total testosterone and prostate cancer. Emphasis was given to prospective studies, series with observational data and randomized, controlled trials. Case reports were excluded. Articles on testosterone replacement safety were selected by patient population (under active surveillance or with a prostate cancer history). We organized our results according to the relationship between total testosterone and prostate cancer, including 1) the possible link between low total testosterone and prostate cancer, 2) the effect of high levels and 3) the absence of any link. Finally, we summarized studies of the risk of exogenous testosterone administration in patients already diagnosed with prostate cancer, treated or on active surveillance. RESULTS: We selected 45 articles of the relationship between total testosterone and prostate cancer, of which 18 and 17 showed a relationship to low and high total testosterone, respectively, and 10 showed no relation. Total testosterone was defined according to the definition in each article. Contradictory findings have been reported, largely due to the disparate methodologies used in many studies. Most studies did not adhere to professional society guidelines on total testosterone measurements. One of 18 series of low total testosterone and prostate cancer adhered to published guidelines while none of 17 showing a relationship of high total testosterone to prostate cancer and only 1 of 10 that identified no relationship between total testosterone and prostate cancer adhered to measurements recommended in the guidelines. In 11 studies the risk of exogenous testosterone was examined in patients with a prostate cancer history. Many studies were limited by small cohort size and brief followup. However, overall this literature suggests that the risk of exogenous testosterone replacement in patients with prostate cancer appears to be small. CONCLUSIONS: The relationship between total testosterone and prostate cancer has been an area of interest among physicians for decades. Conflicting results have been reported on the relationship between total testosterone and subsequent prostate cancer. Much of this controversy appears to be based on conflicting study designs, definitions and methodologies. To date no prospective study with sufficient power has been published to unequivocally resolve the issue. The preponderance of studies of the safety of exogenous testosterone in men with a prostate cancer history suggests that there is little if any risk. However, because the risk has not proved to be zero, the most prudent course is to follow such men with regular prostate specific antigen measurements and digital rectal examinations.

Intravenous siRNA Silencing of Survivin Enhances Activity of Mitomycin C in Human Bladder RT4 Xenografts.

PURPOSE: Survivin inhibits apoptosis and enables tumor cells to escape from therapy induced senescence. High survivin expression is associated with bladder cancer aggressiveness and recurrence. We evaluated whether survivin expression is reduced by siRNA and whether survivin silencing would enhance mitomycin C activity in human RT4 bladder transitional cell tumors in vitro and in vivo. MATERIALS AND METHODS: We assessed the effectiveness of siRNA therapy using 2 newly developed pegylated cationic liposome carriers, PCat and PPCat. Each has a fusogenic lipid to destabilize the endosomal membrane. PPCat further contains paclitaxel to enhance in vivo delivery and transfection of survivin siRNA. In vitro antitumor activity was evaluated by short-term MTT and long-term clonogenicity cytotoxicity assays. In vivo intravenous therapy was assessed in mice bearing subcutaneous tumors. RESULTS: Nontarget siRNA showed no antitumor activity in vitro or in vivo. Treatment of cultured cells with mitomycin C at a 50% cytotoxic concentration enhanced survivin mRNA and protein levels. Adding PPCat or PCat containing survivin siRNA reversed survivin induction and enhanced mitomycin C activity (p <0.05). In tumor bearing mice single agent mitomycin C delayed tumor growth and almost tripled the survivin protein level in residual tumors. Adding PPCat-survivin siRNA, which alone resulted in a minor survivin decrease of less than 10%, completely reversed mitomycin C induced survivin and enhanced mitomycin C activity (p <0.05). CONCLUSIONS: Results indicate that there is effective in vivo survivin silencing and synergism between mitomycin C and PPCat-survivin siRNA. This combination represents a potentially useful chemo-gene therapy for bladder cancer.

Novel non-invasive biomarkers that distinguish between benign prostate hyperplasia and prostate cancer.

BACKGROUND: The objective of this study was to discover and to validate novel noninvasive biomarkers that distinguish between benign prostate hyperplasia (BPH) and localized prostate cancer (PCa), thereby helping to solve the diagnostic dilemma confronting clinicians who treat these patients. METHODS: Quantitative iTRAQ LC/LC/MS/MS analysis was used to identify proteins that are differentially expressed in the urine of men with BPH compared with those who have localized PCa. These proteins were validated in 173 urine samples from patients diagnosed with BPH (N = 83) and PCa (N = 90). Multivariate logistic regression analysis was used to identify the predictive biomarkers. RESULTS: Three proteins, ß2M, PGA3, and MUC3 were identified by iTRAQ and validated by immunoblot analyses. Univariate analysis demonstrated significant elevations in urinary ß2M (P < 0.001), PGA3 (P = 0.006), and MUC3 (P = 0.018) levels found in the urine of PCa patients. Multivariate logistic regression analysis revealed AUC values ranging from 0.618 for MUC3 (P = 0.009), 0.625 for PGA3 (P < 0.008), and 0.668 for ß2M (P < 0.001). The combination of all three demonstrated an AUC of 0.710 (95% CI: 0.631 - 0.788, P < 0.001); diagnostic accuracy improved even more when these data were combined with PSA categories (AUC = 0.812, (95% CI: 0.740 - 0.885, P < 0.001). CONCLUSIONS: Urinary ß2M, PGA3, and MUC3, when analyzed alone or when multiplexed with clinically defined categories of PSA, may be clinically useful in noninvasively resolving the dilemma of effectively discriminating between BPH and localized PCa.

NCCN Clinical Practice Guidelines Prostate Cancer Early Detection, Version 2.2015.

Prostate cancer represents a spectrum of disease that ranges from nonaggressive, slow-growing disease that may not require treatment to aggressive, fast-growing disease that does. The NCCN Guidelines for Prostate Cancer Early Detection provide a set of sequential recommendations detailing a screening and evaluation strategy for maximizing the detection of prostate cancer that is potentially curable and that, if left undetected, represents a risk to the patient. The guidelines were developed for healthy men who have elected to participate in the early detection of prostate cancer, and they focus on minimizing unnecessary procedures and limiting the detection of indolent disease.