Prostate Cancer as a Metabolic Disease - Is Prostate Cancer Diagnosis Associated with Worse Cardiovascular Outcomes?

Metabolic syndrome (MetS) and prostate cancer (PC) share several risk factors. In addition to increased cardiovascular risk, there is evidence that men with MetS have an increased PC risk. Given that both diseases develop over decades, PC diagnosis may precede the onset of MetS, and may be an early indicator of cardiovascular risk. We sought to determine if PC diagnosis is associated with increased risk of subsequent cardiovascular event. In our population-based study using administrative databases, men with PC identified using the Ontario Cancer Registry were hard-matched and propensity score-matched to men without PC diagnosis identified using the Registered Persons Database. Competing risks analyses were performed to compare risk of cardiovascular events. Contrary to our hypothesis, men with PC were less likely to experience a cardiovascular event compared to men without PC (sub-distributional HR=0.92, 95%CI=0.88-0.96). The difference was not clinically significant. Selection bias and confounding may explain this unexpected result.M.Sc

External evaluation of a novel prostate cancer risk calculator (ProstateCheck) based on data of the Swiss arm of the ERSPC

PURPOSE: To externally validate a novel prostate cancer (PCa) risk-calculator (RC), based on data of the Swiss arm of the European Randomize Study of Screening for Prostate Cancer (ERSPC), and to assess whether the RC (ProstateCheck) is superior to the PCPT RC and SWOP RC in an independent Swiss cohort. MATERIALS AND METHODS: Data of all men who underwent prostate biopsy in an academic tertiary care center between 2004 and 2012 were retrospectively analyzed. The probability of having any PCa or high-grade PCa (Gleason score ≥7) upon prostate biopsy was calculated using the ProstateCheck-RC. The RC's performance was assessed using calibration and discrimination and additionally compared with the PCPT- and SWOP-RC by decision curve analyses. RESULTS: Of 1615 men, 401 (25%) were diagnosed with any PCa and 196 (12%) with high-grade PCa. Our analyses of the ProstateCheck-RC revealed good calibration in the low risk range (0 to 0.4) and moderate overestimation in the higher risk range (0.4 to 1) for any and high-grade PCa. The AUC for the discrimination of any PCa and high-grade PCa was 0.69 and 0.72, respectively, which was slightly but significantly higher compared to the PCPT-RC (0.66 and 0.69, respectively) and SWOP-RC (0.64 and 0.70, respectively). Decision analysis taking into account the harms of transrectal ultrasound measurements of prostate volume, found little benefit for ProstateCheck-RC, with inferior properties to the PCPT- and SWOP-RC. CONCLUSION: Our independent external evaluation revealed moderate performance of the ProstateCheck-RC. Its clinical benefit is limited and inferior to the PCPT- and SWOP-RC

Serum Adipokines as Predictors for the Outcome of Prostate Biopsies at Early Stage Prostate Cancer Diagnosis

Purpose: Elevated adipokines in patients with obesity and metabolic syndrome have been linked to increased risk of prostate cancer (PCa). The association between select serum adipokines and the outcome of prostate biopsies alone and in combination with clinical parameters at different early stages of PCa was investigated. Patients and methods: Clinical data and serum adipokines were retrieved from three retrospective cohorts representing men at different points in PCa detection: 1. Subjects with no prior biopsies (n=1061), 2. subjects with a prior negative biopsy (REDUCE trial, control arm) (n=1209), 3. subjects with low-risk PCa on active surveillance (AS) (n=154). Adipokines were chosen based on an unpublished pilot study and included: Resistin, Tumor Necrosis Factor-α, Interleukin-6, Monocyte Chemoattractant Protein-1, Hepatocyte Growth Factor, and Nerve Growth Factor. The primary outcome was the absence of PCa on biopsy and the secondary outcome was diagnosis of low-risk PCa fitting the criteria for continuing AS. Logistic regression analysis was used to assess the association of adipokines and negative and/or low-risk PCa at prostate biopsy. Results: In men with no prior prostate biopsy or with prior negative biopsy, adipokines were not predictors of prostate biopsy outcomes on multivariable regression analysis controlling for known clinical variables. In the AS cohort, MCP-1 and Resistin were significant predictors of biopsy outcome on multivariable analysis (OR 0.20, 95% CI: 0.05–0.85, p= 0.03 & OR 0.30, 95% CI: 0.10 −0.86, p= 0.03). Conclusion: Our findings do not support a strong role for adipokines for predicting the outcome of prostate biopsies at any early stage in PCa diagnosis

The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder

PURPOSE Metformin, a first-line oral therapy for diabetes, has anticancer properties. Our objective was to evaluate the association between metformin use and oncologic outcomes in diabetic patients undergoing radical cystectomy (RC) for bladder cancer (BC). METHODS A single-institution retrospective cohort (January 1997-June 2013) of diabetic patients undergoing RC was assembled. Medication use was assessed at time of surgery. Outcome measures were recurrence-free survival (RFS), BC-specific survival (BCSS), and overall survival (OS). Multivariable Cox proportional hazards models were used. To create parsimonious models, the change of estimate approach (10% threshold) was used as a variable selection strategy for final model inclusion separately for each outcome measure. RESULTS Of 421 patients, 85 (20%) had diabetes. There were 39 (46%) patients on metformin therapy. Among diabetic patients, there were 21 patients with BC recurrence, 16 who died of BC, and 30 who died overall. In univariate analyses, metformin use among diabetic patients was associated with improved RFS (hazard ratio = 0.54, 95% CI: 0.33-0.88, P = 0.013) and trended toward improved BCSS (hazard ratio = 0.65, 95% CI: 0.40-1.07, P = 0.087), but not with OS (P = 0.87). In multivariable models, metformin use among diabetic patients was associated with significantly improved RFS (adjusted hazard ratio = 0.38, 95% CI: 0.20-0.72, P = 0.003) and BCSS (adjusted hazard ratio = 0.57, 95% CI: 0.35-0.91, P = 0.019), but not with OS (P = 0.89). Use of other oral hypoglycemic agents or insulin was not associated with oncologic outcomes. CONCLUSIONS Our study is among the first to report an association between metformin use and improved RFS and BCSS in diabetic patients undergoing RC. Given its low cost and demonstrated safety among nondiabetic patients, further studies are warranted to evaluate potential therapeutic and preventive roles of metformin in BC

Creation and internal validation of a biopsy avoidance prediction tool to aid in the choice of diagnostic approach in patients with prostate cancer suspicion

INTRODUCTION: To reduce unnecessary prostate biopsies while using novel tests judiciously, we created a tool to predict the probability of clinically significant prostate cancer (CSPC) vs. low-risk prostate cancer or negative biopsy (i.e., when intervention is likely not needed) among men undergoing initial or repeat biopsy. METHODS: Separate models were created for men undergoing initial and repeat biopsy, identified from our institutional biopsy database and the placebo arm of the REDUCE trial, respectively, to predict the presence of CSPC (Gleason≥7 or>33% of cores involved). Predictors considered included age, race, body mass index, family history of prostate cancer, digital rectal examination, prostate volume, prostate-specific antigen (PSA), free-to-total PSA, presence of high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation on prior biopsy, number of prior biopsies, and number of cores previously taken. Multivariable logistic regression models that minimized the Akaike Information Criterion and maximized out-of-sample area under the receiver operating characteristics curve (AUC) were selected. RESULTS: Of 7,963 biopsies (initial = 2,042; repeat = 5,921), 1,138 had CSPC (initial = 870 [42.6%]; repeat = 268 [4.5%]). Age, race, body mass index, family history, digital rectal examination, and PSA were included in the initial biopsy model (out-of-sample AUC = 0.74). Age, prostate volume, PSA, free-to-total PSA, prior high-grade prostatic intraepithelial neoplasia, and number of prior biopsies were included in the repeat biopsy model (out-of-sample AUC = 0.81). CONCLUSION: These prediction models may help guide clinicians in avoiding unnecessary initial and repeat biopsies in men unlikely to harbor CSPC. This tool may also allow for the more judicious use of novel tests only in patients in need of further risk stratification before deciding whether to biopsy

The initiation of a multidisciplinary bladder cancer clinic and the uptake of neoadjuvant chemotherapy: A time-series analysis

INTRODUCTION: While level 1 evidence supports the use of neoadjuvant chemotherapy (NAC) for patients with muscle-invasive bladder cancer (MIBC), its uptake has been underwhelming, even in academic centres. Our aim was to determine if the initiation of a multidisciplinary bladder cancer clinic (MDBCC) in 2008 at our institution, where patients are assessed simultaneously by bladder cancer-focused urologists and radiation oncologists with easy access to a medical oncologist, was associated with an increased use of NAC. METHODS: Patients with MIBC initiating treatment between July 2000 and June 2013 were identified and classified by academic year (July 1 to June 30). Time-series analyses using interventional autoregressive integrated moving average (ARIMA) models with ramp intervention functions were then conducted. A sensitivity analysis was performed on clinical N0 patients. RESULTS: The cohort included 278 patients: 168 from 2000-2007 and 110 from 2008-2012 (academic years). Forty-two (15.1%) patients received NAC and 74 (26.6%) received adjuvant chemotherapy (AC). Overall the proportion of patients receiving NAC increased from 7.7% before the MDBCC to 47.6% in 2012 (Interventional ARIMA p=0.036). The results were similar when restricting to cN0 patients (p<0.001). NAC use gradually increased over time regardless of MDBCC attendance, although the proportion of patients receiving NAC appears to have risen more sharply among MDBCC attendees. CONCLUSIONS: At our institution, the initiation of the MDBCC was temporally associated with increased use of NAC. In addition to multidisciplinary collaboration, having a critical mass of NAC physician advocates and support from institutional leaders are essential to the uptake of NAC

A noninvasive urine-based methylation biomarker panel to detect bladder cancer and discriminate cancer grade.

BACKGROUND: Highly sensitive and specific urinary biomarkers for the early detection of bladder cancer (BC) to improve the performance of urinary cytology are needed. OBJECTIVE: To investigate the usefulness of methylation markers in voided urine to identify BC presence and grade. DESIGN, SETTINGS, AND PARTICIPANTS: Using genome-wide methylation strategies in Toronto, Canada and Liège, Belgium, we have identified differentially methylated genes (TWIST1, RUNX3, GATA4, NID2, and FOXE1) in low-grade vs. high-grade BC tissue and urine. We accrued urine samples from 313 patients using a 2:1 ratio in a case-control setting from Toronto, Canada, Halifax, Canada, and Zurich, Switzerland. We studied the usefulness of these 5 methylated genes to identify BC and discriminate cancer grade in voided urine specimens. Urinary cell sediment DNA was evaluated using qPCR-based MethyLight assay. Multivariable logistic regression prediction models were created. RESULTS AND LIMITATIONS: We included 211 BC patients (180 nonmuscle invasive) and 102 controls. In univariate analyses, all methylated genes significantly predicted BC vs. no BC, and high grade vs. low grade (all P < 0.05). In multivariable analysis, NID2, TWIST1, and age were independent predictors of BC (all P < 0.05). Sensitivity of NID2 and TWIST1 to predict BC and BC grade was 76.2% and 77.6%, respectively, whereas specificity was 83.3% and 61.1%, respectively. Multivariable models predicting BC overall and discriminating between high-grade and low-grade BC reached area under the receiver operating characteristics curves of 0.89 and 0.78, respectively. CONCLUSIONS: This multi-centric study in a real life scenario (different countries, techniques, and pathologists) supports the promise of epigenetic urinary markers in noninvasively detecting BC. With sensitivities and specificities in the range of 80%, the overall performance characteristics of this panel of methylated genes probably does not allow such signature to significantly alter clinical care at this stage but is worth further studying for instance in BC surveillance or screening in high-risk populations

Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic

Purpose Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. Although radical cystectomy (RC) currently is viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) that combines transurethral resection of bladder tumor, chemotherapy for radiation sensitization, and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, this study compared the oncologic outcomes between patients treated with RC or TMT by using a propensity score matched-cohort analysis. Methods Data from patients treated in a multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were reviewed retrospectively. Those who received TMT for MIBC were identified and matched (for sex, cT and cN stage, Eastern Cooperative Oncology Group status, Charlson comorbidity score, treatment date, age, carcinoma in situ status, and hydronephrosis) with propensity scores to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox proportional hazards modeling and a competing risk analysis, respectively. Results A total of 112 patients with MIBC were included after matching (56 who had been treated with TMT, and 56 who underwent RC). The median age was 68.0 years, and 29.5% had stage cT3/cT4 disease. At a median follow-up of 4.51 years, there were 20 deaths (35.7%) in the RC group (13 as a result of BC) and 22 deaths (39.3%) in the TMT group (13 as a result of BC). The 5-year DSS rate was 73.2% and 76.6% in the RC and TMT groups, respectively ( P = .49). Salvage cystectomy was performed in 6 (10.7%) of 56 patients who received TMT. Conclusion In the setting of a MDBCC, TMT yielded survival outcomes similar to those of matched patients who underwent RC. Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options, including organ-sparing TMT