Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial.

PURPOSE: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer. PATIENTS AND METHODS: This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile. RESULTS: The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078). CONCLUSIONS: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Expansion of Lymphocytes from Prostatic Adenocarcinoma and Adjacent Nonmalignant Tissue.

Background: The evaluation of tumour-infiltrating lymphocytes (TILs) in solid malignancies has yielded insights into immune regulation within the tumour microenvironment and has also led to the development and optimisation of adoptive T cell therapies. Objectives: This study examined the in vitro expansion of TILs from prostate adenocarcinoma, as a preliminary step to evaluate the potential of TILs for adoptive T cell therapy. Design, Setting, and Participants. Malignant and adjacent nonmalignant tissues were obtained from fifteen men undergoing radical prostatectomy. Interventions. There were no study interventions. Outcome Measurements and Statistical Analysis. Expanded cells were analysed by flow cytometry, and the data was assessed for associations between cell subpopulations and expansion rate. Results: Tumour-infiltrating lymphocytes could be expanded to numbers that would be needed to generate a therapeutic infusion product from nine of 15 malignant specimens (60%). The CD4+ T cells predominated over CD8+ T cells (median 56.8% CD4+, 30.0% CD8+), and furthermore, faster TIL expansion was associated with a higher proportion of CD4+ T cells (median 69.8% in faster-growing cultures; 36.8% in slower-growing cultures). A higher proportion of CD3-CD56+ cells versus CD3+ cells was associated with slower TIL expansion in cultures from malignant specimens (median 13.3% in slower-growing cultures versus 2.05% in faster-growing cultures), but not from nonmalignant specimens. Conclusions: The expansion of TILs for potential therapeutic use is feasible. Our findings also indicate that further examination of TILs from prostate adenocarcinomas may yield insights into mechanisms of regulation of T cells within the tumour microenvironment. Further research is required to evaluate their therapeutic potential.

Time trends for drug specific adverse events in patients on sunitinib; implications for remote monitoring.

INTRODUCTION: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor used to treat metastatic renal cell carcinoma (mRCC). Patients on sunitinib do require regular in-person appointments to monitor for adverse events (AEs). Given the Covid-19 pandemic, regular in-person visits expose patients to an increased risk of infection in addition to potentially preventable travel costs. This study investigated the feasibility of implementing a remote monitoring strategy for patients being treated with sunitinib for mRCC by examining the time trends of AEs. MATERIALS AND METHODS: In this retrospective chart review of patients with a diagnosis of mRCC, 167 patients received sunitinib during their treatment. The time between initiation of treatment and the first AE was recorded. The AEs were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Survival analysis was used to calculate the time-to-AE. RESULTS: Of the 167 patients identified, 145 experienced an AE (86.8%). Hypertension was the most common AE with 80% of AEs were ≤ Grade 2. Incidence of AE dropped by 91% after 3 months follow up and a further 36% after 6 months. The cumulative incidence of AEs were 87.8%, 94.6% and 98.0%, at 3, 6 and 9 months respectively. The severity of AEs observed were 39.3%, 38.6%, 20.7%, 1.4%,0% of Grade 1-5 events respectively. A trend of grade migration to less severe grades was also shown over time, with percentage of Grade ≥ 3 toxicity dropping from 22% between 0-3 months to 14% beyond 6 months follow up. CONCLUSIONS: The role of remote monitoring for mRCC patients on sunitinib remains relevant now with new waves of the Covid-19 pandemic, triggered by novel variants. The majority of AEs observed were of low severity ≤ Grade 2, with a trend of reduced AE frequency and severity most prevalent beyond 3 months of follow up. This data appears to support the implementation of a remote monitoring strategy 3 months after initiation of treatment.

Time trends of drug-specific actionable adverse events among patients on androgen receptor antagonists: Implications for remote monitoring.

INTRODUCTION: In light of COVID-19, reducing patient exposure via remote monitoring is desirable. Patients prescribed abiraterone/ enzalutamide are scheduled for monthly in-person appointments to screen for adverse events (AEs). We determined time trends of drug-specific actionable AEs among users of abiraterone/enzalutamide to assess the safety of remote monitoring. METHODS: A chart review was conducted on 828 prostate cancer patients prescribed abiraterone and/or enzalutamide. Data were collected to determine time to actionable first AEs, including hypertension, elevated liver enzymes (aspartate transaminase [AST], alanine transaminase [ALT]), hyperbilirubinemia, and hypokalemia. Survival analysis was used to determine time to AEs. RESULTS: In this study, 425 and 403 patients received enzalutamide and abiraterone, respectively. In total, 25.6% of those who took enzalutamide experienced an AE, compared to 28.8% of patients on abiraterone. For patients using abiraterone and experiencing an AE, cumulative incidence of AEs at three, six, nine, and 12 months were: 67.2%, 81.9%, 90.5%, and 93.9%, respectively. Among enzalutamide users experiencing an AE, cumulative incidence of AEs at three, six, nine, and 12 months were 51.4%, 70.7%, 82.6%, and 88.1%, respectively. The AEs associated with enzalutamide were hypertension and liver dysfunction (77.1% and 22.9%, respectively). In the abiraterone group, associated AEs were liver dysfunction (47.4%), hypertension (47.4%), and hypokalemia (5.2%). CONCLUSIONS: Attaining AEs secondary to abiraterone/enzalutamide decreases over time and tends to occur within the first six months of therapy. Most actionable AEs can be remotely monitored. Given COVID-19, remote monitoring after six months of initiating abiraterone or enzalutamide appears appropriate.

A Prospective Randomized Controlled Trial of Irrigation "Bag Squeeze" to Manage Pain for Patients Undergoing Flexible Cystoscopy.

PURPOSE: We determined if the "bag squeeze" technique decreases pain during flexible cystoscopy in men. MATERIALS AND METHODS: This single center, prospective, double-blind, randomized controlled trial recruited 200 consenting participants who were ambulatory, outpatient males who had undergone prior cystoscopy and were not expected to require any secondary procedures. Men with prior urethral stricture or bladder neck contracture were excluded from study. Once eligibility was assessed and consent obtained, participants were randomized to undergo cystoscopy with the bag squeeze (group A) or the sham bag squeeze procedure (group B). Following cystoscopy, participants completed a pain questionnaire (visual analogue scale). Differences in mean pain score between groups were evaluated using Students' t-test with a 2-sided alpha of 0.05. RESULTS: A total of 200 patients were randomized and underwent flexible cystoscopy. Ten participants were ineligible because they required secondary procedures. Among the 190 eligible patients 97 were randomized to bag squeeze (group A) and 93 to sham bag squeeze (group B) with mean pain scores of 1.91 and 3.39, respectively (p <0.005). CONCLUSIONS: This study demonstrated a clinically meaningful decrease in pain for men undergoing flexible cystoscopy when the irrigation bag squeeze technique was used vs placebo bag squeeze. Accordingly, this useful, simple and free method to improve patient comfort during flexible cystoscopy should be adopted by clinicians.

A pilot window-of-opportunity study of preoperative fluvastatin in localized prostate cancer.

BACKGROUND: Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Epidemiological and pre-clinical evidence support an association between statin use and delayed prostate cancer (PCa) progression. Here, we evaluated the effects of neoadjuvant fluvastatin treatment on markers of cell proliferation and apoptosis in men with localized PCa. METHODS: Thirty-three men were treated daily with 80 mg fluvastatin for 4-12 weeks in a single-arm window-of-opportunity study between diagnosis of localized PCa and radical prostatectomy (RP) (ClinicalTrials.gov: NCT01992042). Percent Ki67 and cleaved Caspase-3 (CC3)-positive cells in tumor tissues were evaluated in 23 patients by immunohistochemistry before and after treatment. Serum and intraprostatic fluvastatin concentrations were quantified by liquid chromatography-mass spectrometry. RESULTS: Baseline characteristics included a median prostate-specific antigen (PSA) level of 6.48 ng/mL (IQR: 4.21-10.33). The median duration of fluvastatin treatment was 49 days (range: 27-102). Median serum low-density lipoprotein levels decreased by 35% after treatment, indicating patient compliance. Median PSA decreased by 12%, but this was not statistically significant in our small cohort. The mean fluvastatin concentration measured in the serum was 0.2 µM (range: 0.0-1.1 µM), and in prostatic tissue was 8.5 nM (range: 0.0-77.0 nM). At these concentrations, fluvastatin induced PCa cell death in vitro in a dose- and time-dependent manner. In patients, fluvastatin treatment did not significantly alter intratumoral Ki67 positivity; however, a median 2.7-fold increase in CC3 positivity (95% CI: 1.9-5.0, p = 0.007) was observed in post-fluvastatin RP tissues compared with matched pre-treatment biopsy controls. In a subset analysis, this increase in CC3 was more pronounced in men on fluvastatin for >50 days. CONCLUSIONS: Fluvastatin prior to RP achieves measurable drug concentrations in prostatic tissue and is associated with promising effects on tumor cell apoptosis. These data warrant further investigation into the anti-neoplastic effects of statins in prostate tissue.

Replacing surveillance cystoscopy with urinary biomarkers in followup of patients with non-muscle-invasive bladder cancer: Patients' and urologic oncologists' perspectives.

INTRODUCTION: Urinary biomarkers are being developed to detect bladder cancer recurrence/progression in patients with non-muscle-invasive bladder cancer (NMIBC). We conducted a questionnaire-based study to determine what diagnostic accuracy and cost would such test(s) need for both patients and urologic oncologists to comfortably forgo surveillance cystoscopy in favour of these tests. METHODS: Surveys were administered to NMIBC patients at followup cystoscopy visit and to physician members of the Society of Urologic Oncology. Participants were questioned about acceptable false-negative (FN) rates and costs for such alternatives, in addition to demographics that could influence chosen error rates and costs. RESULTS: A total of 137 patient and 51 urologic oncologist responses were obtained. Seventy-seven percent of patients were not comfortable with urinary biomarker(s) alternatives to repeat cystoscopy, with a further 14% willing to accept such alternatives only if the FN rate were 0.5% or lower. Seventy-five percent of urologic oncologists were comfortable with an alternative urinary biomarker test(s), with 37% and 33% willing to accept FN rates of 5% and 1%, respectively. Forty-seven percent of patients were not willing to pay out-of-pocket for such tests, while 61% of urologic oncologists felt that a price range of $100-500 would be reasonable. CONCLUSIONS: This is the first survey evaluating patient and urologic oncologist perspectives on acceptable error rates and costs for urinary biomarker alternatives to surveillance cystoscopy for patients with NMIBC. Despite potential responder bias, this study suggests that urinary biomarker(s) will require sensitivity equivalent to that of cystoscopy in order to completely replace it in surveillance of patients with NMIBC.

Understanding how prostate cancer patients value the current treatment options for metastatic castration resistant prostate cancer.

Several new compounds are now available for castration resistant prostate cancer (CRPC). Individual costs range between $40,000 and $93,000 with mean survival extensions from 2.4 to 4.8 months. Currently, it remains unclear how patients with prostate cancer (PCa) value the effect of these therapies in the setting of CRPC. OBJECTIVE: To assess patient understanding of core cancer concepts, opinions on the cost and overall benefit of CRPC drugs, whether out-of-pocket costs would change opinions and whether patients would ultimately opt out of CRPC drug treatment for an end-of-life (EOL) premium. PATIENTS AND METHODS: We conducted a qualitative survey among patients with various PCa states ranging from active surveillance to CRPC and from various familial, financial and educational demographics. Through a series of hypothetical scenarios, we extrapolated opinions on CRPC drug value, efficacy and monetary worth. We assessed patient willingness to accept an EOL ($50,000) premium in lieu of CRPC drug treatment. Statistically, chi-squared analysis and Fisher's exact test were used when appropriate. RESULTS: In total, 103 patients completed the questionnaire, one-half of whom did not understand "advanced PCa" state and more than one-third of the concept of palliative care despite multiple meetings with Urologists. Patients willingness-to-pay and proposed drug value was higher than that accepted by government when government funded, with costs exceeding $250,000 per person, but lower than that accepted by government when self-funded. A majority (60%) would accept/consider the EOL premium in the setting of CRPC. Patients with higher education were more skeptical about CRPC drug value and more likely to accept the EOL premium (P = 0.003.) CONCLUSION: Patients have an incomplete understanding of their own disease prognosis and its therapeutic options. This ultimately influences patient decision-making. Education, income and out-of-pocket costs diminished opinion of CRPC drugs considerably. As such, an EOL premium should be considered in subsets of patients.

What false-negative rates of non-invasive testing are active surveillance patients and uro-oncologists willing to accept in order to avoid prostate biopsy?

INTRODUCTION: Repeat prostate biopsies in active surveillance patients are associated with significant complications. Novel imaging and blood/urine-based non-invasive tests are being developed to better predict disease grade and volume progression. We conducted a theoretical study to determine what test performance characteristics and costs would a non-invasive test(s) require in order for patients and their physicians to comfortably avoid biopsy. METHODS: Surveys were administered to two populations to determine an acceptable false-negative rate and cost for such test(s). Active surveillance patients were recruited at time of followup in clinic at Princess Margaret Cancer Centre. Physician members of the Society of Urological Oncology were targeted via an online survey. Participants were questioned about their demographics and other characteristics that might influence chosen error rates and cost. RESULTS: 136 patients and 670 physicians were surveyed, with 130 (95.6%) and 104 (15.5%) responses obtained, respectively. A vast majority of patients (90.6%) were comfortable with a non-invasive test(s) in place of biopsy, with 64.8% accepting a false-negative rate of 5-20%. Most physicians (93.3%) were comfortable with a non-invasive test, with 77.9% accepting a rate of 5-20%. Most patients and physicians felt that a cost of less than $1000 per administration would be reasonable. CONCLUSIONS: Most patients/physicians are comfortable with a non-invasive test(s). Although a 5% error rate seems acceptable to many, a substantial subset feels that 99% or higher negative predictive value is required. Thus, a personalized approach with shared decision-making between patients and physicians is essential to optimize patient care in such situations.

A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy.

Purpose: Degarelix, a new gonadotropin-releasing hormone (GnRH) receptor antagonist with demonstrated efficacy as first-line treatment in the management of high-risk prostate cancer, possesses some theoretical advantages over luteinizing hormone-releasing hormone (LHRH) analogues in terms of avoiding "testosterone flare" and lower follicle-stimulating hormone (FSH) levels. We set out to determine whether preoperative degarelix influenced surrogates of disease control in a randomized phase II study.Experimental Design: Thirty-nine patients were randomly assigned to one of three different neoadjuvant arms: degarelix only, degarelix/bicalutamide, or LHRH agonist/bicalutamide. Treatments were given for 3 months before prostatectomy. Patients had localized prostate cancer and had chosen radical prostatectomy as primary treatment. The primary end point was treatment effect on intratumoral dihydrotestosterone levels.Results: Intratumoral DHT levels were higher in the degarelix arm than both the degarelix/bicalutamide and LHRH agonist/bicalutamide arms (0.87 ng/g vs. 0.26 ng/g and 0.23 ng/g, P < 0.01). No significant differences existed for other intratumoral androgens, such as testosterone and dehydroepiandrosterone. Patients in the degarelix-only arm had higher AMACR levels on immunohistochemical analysis (P = 0.01). Serum FSH levels were lower after 12 weeks of therapy in both degarelix arms than the LHRH agonist/bicalutamide arm (0.55 and 0.65 vs. 3.65, P < 0.01), and inhibin B levels were lower in the degarelix/bicalutamide arm than the LHRH agonist/bicalutamide arm (82.14 vs. 126.67, P = 0.02).Conclusions: Neoadjuvant degarelix alone, compared with use of LHRH agonist and bicalutamide, is associated with higher levels of intratumoral dihydrotestosterone, despite similar testosterone levels. Further studies that evaluate the mechanisms behind these results are needed. Clin Cancer Res; 23(8); 1974-80. ©2016 AACR.

Dissecting the association between metabolic syndrome and prostate cancer risk: analysis of a large clinical cohort.

BACKGROUND: A biologic rationale exists for the association between metabolic syndrome (MetS) and prostate cancer (PCa). However, epidemiologic studies have been conflicting. OBJECTIVE: To evaluate the association between MetS and the odds of PCa diagnosis in men referred for biopsy. DESIGN, SETTING, AND PARTICIPANTS: Patients without prior PCa diagnosis undergoing prostate biopsy were identified from a large prostate biopsy cohort (in Toronto, Canada). The definition of MetS was based on the most recent interim joint consensus definition, requiring any three of five components (obesity, elevated blood pressure, diabetes or impaired fasting glucose, low high-density lipoprotein-cholesterol, and hypertriglyceridemia). Both the individual components of MetS and the cumulative number of MetS components were evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes were PCa detection overall, clinically significant PCa (CSPC; defined as any Gleason pattern ≥ 4, >50% involvement of a single biopsy core, or more than one of three total number of cores involved), and intermediate- or high-grade PCa (I-HGPC; Gleason 7-10). Tests for trend and multivariable logistic regression analyses were performed. RESULTS AND LIMITATIONS: Of 2235 patients, 494 (22.1%) had MetS. No individual MetS component was independently associated with PCa. However, increasing number of MetS components was associated with higher PCa grade (p<0.001), as well as progressively higher odds of PCa outcomes (three or more; ie, MetS) compared with no MetS components: Odds ratios were 1.54 for PCa overall (95% confidence interval [CI], 1.17-2.04; p=0.002), 1.56 for CSPC (95% CI, 1.17-2.08; p=0.002), and 1.56 for I-HGPC (95% CI, 1.16-2.10; p=0.003) in multivariable analyses. The main limitation is the retrospective design. CONCLUSIONS: Although the individual MetS components are not independently associated with PCa outcomes, MetS is significantly associated with higher odds of PCa diagnosis, CSPC, and I-HGPC. There is a biologic gradient between the number of MetS components and the risk of PCa, as well as cancer grade. PATIENT SUMMARY: Metabolic syndrome is a collection of metabolic abnormalities that increases one's risk for heart disease. Our study shows that an increasing degree of metabolic abnormality is also associated with an increased risk of diagnosis of overall and aggressive prostate cancer.

Phase II, randomised, double-blind, placebo-controlled trial of methylphenidate for reduction of fatigue levels in patients with prostate cancer receiving LHRH-agonist therapy.

OBJECTIVES: To investigate whether methylphenidate can alleviate fatigue, as measured by the Functional Assessment of Cancer Therapy: Fatigue subscale, in men with prostate cancer (PCa) treated with a luteinizing hormone-releasing hormone (LHRH) for a minimum of 6 months, and to assess changes in global fatigue and quality of life (QoL) as measured by the Bruera Global Fatigue Severity Scale (BFS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), respectively. PARTICIPANTS AND METHODS: We performed a single-centre, randomised, double-blind, placebo-controlled trial with the aim of recruiting 128 participants. Men treated with a LHRH agonist for PCa were screened between February 2008 and June 2012 for fatigue at our outpatient clinics using the BFS. Participants were randomised to receive either 10 mg daily of methylphenidate or placebo. Change in fatigue levels and in SF-36 scores between both groups were compared using linear regression, adjusted for baseline scores. RESULTS: The study was closed prematurely because of poor accrual. Of the 790 subjects screened, 24 men were randomised to methylphenidate or placebo (12 per group). After 10 weeks, the improvement in mean [sd] fatigue score was greater in the methylphenidate than in the placebo arm (+7.7 [7.7] vs +1.4 [7.6]; P = 0.022). The within-group analysis showed a significant improvement in fatigue scores in the methylphenidate arm (P = 0.008) but not in the placebo arm (P = 0.82). The use of methylphenidate also resulted in a significantly greater improvement in QoL as measured by the physical and mental component summary scores than did the use of placebo (P = 0.04 for both component scores). CONCLUSIONS: Our findings support the beneficial effect of methylphenidate on fatigue and QoL among men with LHRH-induced fatigue. Clinicians should be aware of these benefits and should consider discussing these findings with patients who have high levels of fatigue.

The impact of the use of aspirin and other nonsteroidal anti-inflammatory drugs on the risk of prostate cancer detection on biopsy.

OBJECTIVE: To evaluate the association between nonsteroidal anti-inflammatory drug (NSAID) use and the risk of prostate cancer (PC) detection in men undergoing biopsy. METHODS: Men were identified using our academic institution's prospectively maintained prostate biopsy database. Patients were classified as aspirin (ASA) users, users of other NSAIDs, or nonusers. The primary outcome was any PC on biopsy, and the secondary outcome was clinically significant PC (CSPC; Gleason sum ≥7). Multivariate logistic regression analyses were performed to adjust for a priori defined clinical confounders. RESULTS: Of 839 patients, 408 (48.6%) were diagnosed with PC and 201 (24.0%) had CSPC. A higher proportion of ASA users (63.5%) and other NSAID users (61.2%) had PC compared with nonusers (41.9%; P <.001). CSPC was more common among ASA users (34.9%; P <.001) compared with other NSAID users (20.0%) and nonusers (20.9%). In multivariate regression analyses, ASA use (odds ratio [OR] = 2.04; 95% confidence interval [CI] = 1.32-3.13; P = .001) and other NSAID use (OR = 2.42; 95% CI = 1.36-431; P = .003) were associated with higher odds of PC detection, whereas ASA use was associated with higher odds of CSPC (OR = 1.62; 95% CI = 1.00-2.62; P = .048). CONCLUSION: In men undergoing biopsy, ASA and other NSAID use were associated with increased probability of detecting PC, whereas ASA use was associated with the risk of detecting CSPC. Although NSAID use might have a protective biological effect against PC, men who develop elevated prostate-specific antigen levels while on NSAIDs may nonetheless be less likely to have an inflammatory etiology and more likely to harbor PC. It may be warranted for clinicians to consider the influence of NSAIDs when evaluating patients being considered for biopsy.

Obesity is associated with risk of progression for low-risk prostate cancers managed expectantly.

BACKGROUND: Active surveillance (AS) is an expectant management strategy for prostate cancer (PCa). The impact of obesity on progression is not well characterized in this population. OBJECTIVE: To determine if obesity is associated with progression in men on AS for low-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: Men undergoing AS for low-risk PCa (no Gleason pattern ≥4, three or fewer cores involved or one-third or less of the total number of cores involved, and no core with >50% cancer involvement) were identified at our institution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes were pathologic progression (defined as no longer meeting low-risk criteria on follow-up biopsy) and therapeutic progression (defined as intent to initiate active treatment). Kaplan-Meier curves and multivariable logistic regression and Cox proportional hazards models were used, with separate models for reclassification at confirmatory biopsy (first biopsy after diagnostic biopsy) and progression beyond confirmatory biopsy. RESULTS AND LIMITATIONS: In this cohort of 565 men (median follow-up: 48 mo), 124 (22%) were obese (body mass index [BMI] ≥30kg/m(2)). Pathologic and therapeutic progression occurred in 168 men (30%) and 172 men (30%), respectively. No association was noted between obesity and risk of progression at the confirmatory biopsy. However, beyond confirmatory biopsy, obesity was associated with a greater probability of pathologic progression (p=0.007) and therapeutic progression (p=0.007) in Kaplan-Meier analyses. In adjusted Cox models, each 5-unit increase in BMI was associated with an increased risk of pathologic progression (hazard ratio [HR]: 1.5; 95% confidence interval [CI], 1.1-2.1; p=0.02) and therapeutic progression (HR: 1.4; 95% CI, 1.0-1.9; p=0.05). The main limitation is the retrospective design, limiting the ability to assess BMI changes over time. CONCLUSIONS: Obesity was associated with a significantly increased risk of progression beyond the confirmatory biopsy. This suggests an increased risk of long-term biologic progression rather than solely misclassification. PATIENT SUMMARY: As opposed to immediate active treatment (surgery or radiation), active surveillance (AS) involves closely monitoring low-risk prostate cancers and only using active treatment if there are signs of progression. Our study is the first to suggest that obesity is associated with a higher risk of cancer progression while on AS. Further research is needed to determine if diet and exercise can decrease the risk of cancer progression while on AS.

Lean methodology improves efficiency in outpatient academic uro-oncology clinics.

OBJECTIVE: To determine if lean methodology, an industrial engineering tool developed to optimize manufacturing efficiency, can successfully be applied to improve efficiencies and quality of care in a hospital-based high-volume uro-oncology clinic. METHODS: Before the lean initiative, baseline data were collected on patient volumes, wait times, cycle times (patient arrival to discharge), nursing assessment time, patient teaching, and physician ergonomics (via spaghetti diagram). Value stream analysis and a rapid improvement event were carried out, and significant changes were made to patient check-in, work areas, and nursing face time. Follow-up data were obtained at 30, 60, and 90 days. The Student t test was used for analysis to compare performance metrics with baseline. RESULTS: The median cycle time before the lean initiative was 46 minutes. This remained stable at 46 minutes at 30 days but improved to 35 minutes at 60 days and 41 minutes at 90 days. Shorter wait times allowed for increased nursing and physician face time. The average length of the physician assessment increased from 7.5 minutes at baseline to 10.6 minutes at 90 days. The average proportion of value-added time compared with the entire clinic visit increased from 30.6% at baseline to 66.3% at 90 days. CONCLUSION: Using lean methodology, we were able to shorten the patient cycle time and the time to initial assessment as well as integrate both an initial registered nurse assessment and registered nurse teaching to each visit. Lean methodology can effectively be applied to improve efficiency and patient care in an academic outpatient uro-oncology clinic setting.

Obesity is associated with larger prostate volume but not with worse urinary symptoms: analysis of a large multiethnic cohort.

OBJECTIVE: To evaluate the associations between body mass index (BMI) and prostate volume (PV) and lower urinary tract symptoms in a multiethnic cohort. METHODS: A cohort of men without prostate cancer seen at our institution was assembled, excluding those with previous transurethral resection of the prostate. Height and weight were measured to compute BMI, PV was measured by transrectal ultrasound, and the International Prostate Symptom Score (IPSS) questionnaire was administered. After stratified bivariate analyses, multiple linear regression and ordinal logistic regression models were used to assess the independent effect of BMI on PV and IPSS, respectively. RESULTS: The cohort included 1613 patients, and mean BMI was 27.1 kg/m(2). Patients with a BMI of <25.0, 25.0-29.9, and 30.0-34.9 had a median PV of 44.0 mL, 48.0 mL, and 52.0 mL, respectively. The African ethnicity subgroup generally had larger median PVs than European and Asian subgroups and had the largest differences in median PV between normal and obese men. There were no significant differences in IPSS or usage of benign prostatic hyperplasia medications between BMI categories. In multivariable analyses, higher BMI was associated with larger PV (P <.001) but not IPSS (P = .91). On the basis of our model, given a PV of 40 mL, 50 mL, and 60 mL, each 5 kg/m(2) increase in BMI was associated with a 2.19 mL, 2.74 mL, and 3.29 mL increase in PV, respectively. Body weight (P <.001) but not height (P = .13) was associated with PV. CONCLUSION: Higher BMI is associated with larger PV but not worse lower urinary tract symptoms (measured using IPSS). Usage rate of alpha blockers or 5 alpha reductase inhibitors was not significantly different between BMI categories.

Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients.

CONTEXT: Vitamin D3 might benefit prostate cancer (PCa) patients because prostate cells can locally synthesize the active hormone calcitriol. OBJECTIVE: Our objective was to determine the effects of oral vitamin D3 on vitamin D metabolites and PCa proliferative activity in prostate tissue. DESIGN AND SETTING: We conducted a double-blind randomized clinical trial at surgical oncology clinics in Toronto, Canada. PATIENTS: PCa patients (Gleason 6 or 7) participated in the study. Of 66 subjects who were enrolled, 63 completed the dosing protocol. INTERVENTION: Vitamin D3 (400, 10 000, or 40 000 IU/d) was orally administered before radical prostatectomy. MAIN OUTCOME MEASURES: We evaluated vitamin D metabolite levels and Ki67 labeling in surgical prostate tissue. Safety measures, PTH, and prostate-specific antigen (PSA) were also assessed. RESULTS: Prostate tissue and serum levels of vitamin D metabolites, including calcitriol, increased dose dependently (P < .03) and were significantly higher in the 40 000-IU/d group than in every other dose group (P < .03). Prostate vitamin D metabolites correlated positively with serum levels (P < .0001). Ki67 measures did not differ significantly among vitamin D dose groups. However, cross-sectional analysis indicated that the calcitriol level attained in prostate was inversely associated with Ki67 intensity and Ki67 (3+) percent positive nuclei in PCa and benign tissue (P < .05). Safety measures did not change adversely with dosing. Compared with the 400-IU/d group, serum PTH and PSA were lower in the combined higher-dose groups at the end of the study (P < .02). CONCLUSIONS: Oral vitamin D3 raised prostate calcitriol levels (level 1 evidence) and modestly lowered both PSA and PTH. Although Ki67 expression did not differ among dose groups, its levels correlated inversely with prostate calcitriol. These suggestions of clinical benefit justify continued clinical research.

Prevalence and predictors of selenium and vitamin E supplementation in a urology population.

OBJECTIVES: Preclinical and epidemiological studies have suggested the use of supplements such as selenium and vitamin E for prostate cancer (PCa) prevention; however, clinical trials have not demonstrated clear benefit in patients. This study aims to investigate the current prevalence and predictors for use of these supplements in men in a urology population. DESIGN, SUBJECTS, AND OUTCOMES MEASURED: Three hundred and twelve (312) men visiting the Princess Margaret Hospital Ambulatory Urology Clinic were enrolled in this University Health Network Research Ethics Board-approved questionnaire-based study investigating supplement use, reasons for use and demographic characteristics. RESULTS: It was observed that 13.5% and 20.8% of the participants are currently using selenium and vitamin E, respectively, while 10.6% and 15.7% previously used selenium and vitamin E, respectively. Both education (percentage of users comparing less than college education versus college or above education: selenium: 14% versus 28%; p=0.008, vitamin E: 26% versus 41%; p=0.013) and health literacy (mean scores±standard error of the mean of users versus nonusers: selenium question 1: 1.4507±0.09576 versus 1.6083±0.07211; p=0.023, selenium question 2: 2.8750±0.04395 versus 2.7106±0.03774; p=0.000, selenium question 3: 1.4583±0.08377 versus 1.7064±0.06278; p=0.025, vitamin E question 1: 2.8036±0.04545 versus 2.7179±0.04097; p=0.010, vitamin E question 2: 1.5446±0.06698 versus 1.7077±0.07241; p=0.006) are predictors of selenium and vitamin E use on univariable analysis. On multivariable analysis education (selenium odds ratio=2.095, 95% confidence interval=1.019-4.305, p=0.044; vitamin E odds ratio=1.855, 95% confidence interval=1.015-3.338, p=0.045) remains a significant predictor of selenium and vitamin E use. Examining the data on use by education, it was found that more men with a higher education attributed their use of selenium to urologist advice (24%), and those with a lower education attributed their use of selenium to naturopath/homeopath advice (28%). CONCLUSIONS: Many men who visit urology clinics use selenium and vitamin E despite the lack of clinical support for chemoprevention. Education and health literacy are important variables in determining the use of these supplements in these men. This information may aid in addressing the needs of the diverse patient population using these supplements for the prevention of PCa.

Comparison of serum testosterone levels in prostate cancer patients receiving LHRH agonist therapy with or without the removal of the prostate.

INTRODUCTION: : The prostate secretes enzymes and nutrients to promote sperm motility. Recent reports suggest that the prostate may also secrete testosterone, which is believed to be a fuel for prostate tumour growth. The aim of this study was to determine if a difference in serum testosterone levels exists between men on luteinizing hormone releasing-hormone (LHRH) agonists who have undergone radical prostatectomy, radiation or hormone therapy as primary prostate cancer treatment. METHODS: : Serum testosterone levels were evaluated in 165 consecutive prostate cancer patients using LHRH analogues for >3 months. We excluded patients receiving either radiation or chemotherapy at time of time of testosterone measurement. Patients were classified based on primary treatment: (1) radical prostatectomy; (2) radiation; or (3) primary hormone therapy. We used one-way ANOVA to compare testosterone levels. Pearson correlation was used to correlate testosterone with prostate-specific antigen (PSA) and time on LHRH agonists. Multivariable linear regression was used to predict serum testosterone levels. RESULTS: : The median (interquartile range) serum testosterone levels were 1.4 (1-1.9), 1.3 (1-1.625) and 1.25 (0.9-1.525) nmol/L for radical prostatectomy, radiation and primary hormone therapy groups, respectively. There was no statistically significant difference in testosterone levels between the groups (p = 0.3). No correlation was found between testosterone and PSA levels or time on LHRH (r = 0.02 and r = 0.01), respectively. Multivariable linear regression showed that none of the clinical variables were predictors of serum testosterone levels. CONCLUSION: : Our study suggests that primary treatment does not affect serum testosterone levels among men using LHRH analogues.

Measurement of peri-prostatic fat thickness using transrectal ultrasonography (TRUS): a new risk factor for prostate cancer.

UNLABELLED: Study Type - Prognosis (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? ADIPOSE tissue secretes various endocrine and paracrine mediators. Some authors have begun to consider whether peri-prostatic fat (PPF) may interact with the prostate and play a role in carcinogenesis. It has recently been shown that the PPF quantity measured by CT is associated with more aggressive disease in patients undergoing radiation therapy. Our group studied a population not yet diagnosed with prostate cancer. By doing so we were able to identify PPF thickness on transrectal ultrasonography as a risk factor for prostate cancer detection upon biopsy, and as a risk factor for high-grade disease. Our study also raises interesting questions about the underlying mechanisms of the association between PPF quantity and prostate cancer. OBJECTIVE: To determine if the amount of peri-prostatic fat (PPF) on transrectal ultrasonography (TRUS) is a risk factor for incident prostate cancer overall and high-grade prostate cancer (Gleason ≥4). PATIENTS AND METHODS: A prospectively maintained database of patients undergoing prostate biopsy at Princess Margaret Hospital for cancer suspicion was used. • All TRUS examinations were retrospectively reviewed upon 'blinding' to outcome. • PPF thickness, measured as the distance between the prostate and the pubic bone, was used as an index of the quantity of PPF. • PPF measurements, together with other prostate cancer risk factors, were evaluated against prostate cancer and high-grade prostate cancer detection upon biopsy with univariable and multivariable logistic regression and area under the receiver operating characteristic curve (AUC) analysis. RESULTS: Of the 931 patients, 434 (47%) were diagnosed with prostate cancer and 218 (23%) were diagnosed with high-grade prostate cancer. • The mean (range) PPF thickness was 5.3 (0-15) mm. • Increasing PPF thickness was associated with prostate cancer and high-grade prostate cancer diagnosis, with graded effect. When adjusting for other variables, the odds of detecting any prostate cancer and high-grade prostate cancer increased 12% (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.02-1.23) and 20% (OR 1.20, 95% CI 1.07-1.34), respectively, for each millimetre increase in PPF thickness. • The AUCs for the association of PPF with prostate cancer and high-grade prostate cancer were 0.58 (95% CI 0.54-0.62) and 0.59 (95% CI 0.55-0.64), respectively. CONCLUSION: The amount of PPF can be estimated with TRUS and is a predictor of prostate cancer and high-grade prostate cancer at biopsy. To our knowledge, this study is the first to investigate PPF quantity in patients without prior prostate cancer diagnosis.