Faculty Bibliography

PURPOSE/OBJECTIVE:Endoscopic management offers renal-sparing approaches for upper tract urothelial carcinoma (UTUC). We sought to characterize the impact of endoscopically managing UTUC on kidney function and identify predictors of renal function decline. METHODS:We queried a multi-institutional cohort of endoscopically managed UTUC. Estimated glomerular filtration rate values 12 months after endoscopic treatment were assigned according to the National Kidney Function Kidney Disease Outcomes Quality Initiative (KDOQI) chronic kidney disease (CKD) stages. Loss of kidney function was defined as an increase by at least one CKD stage. Severe loss was defined as an increase by at least 2 CKD stages or development of CKD stage 3b-5. RESULTS:A total of 339 patients (521 interventions) were included. 113 patients (33.3%) experienced loss of kidney function and 75 (22.1%) experienced severe loss of kidney function. In multivariable logistic regression, high grade tumor (OR 2.29, 95% CI 1.23-4.33) and renal pelvic location (OR: 2.64, 95% CI 1.32-5.54) were significantly associated with loss of kidney function on a per-patient level. We observed similar results on a per-intervention analysis, with higher odds for kidney function loss for high grade tumor (OR 2.03, 95% CI 1.23-3.35) and renal pelvic location (OR 1.76, 95% CI 1.01-3.08). CONCLUSION/CONCLUSIONS:Despite preservation of the renal unit, one-third of patients undergoing endoscopic management of UTUC experience loss of kidney function. High-grade tumors and renal pelvic location were associated with adverse renal function outcomes.

MAIN PURPOSE/OBJECTIVE:Endoscopic management offers acceptable oncologic control in select patients with upper tract urothelial carcinoma (UTUC) while preserving renal function. Adjuvant intracavitary treatment with chemotherapy or Bacillus Calmette-Guérin (BCG) has been proposed to reduce recurrence risk. We aimed to evaluate the impact of adjuvant intracavitary treatment on ipsilateral UTUC recurrence following endoscopic management. MATERIALS AND METHODS/METHODS:We queried a multi-institutional cohort of patients who underwent endoscopic management for UTUC. Treatment groups were defined as no instillation, single post-operative instillation, or multiple instillations. Ipsilateral UTUC recurrence-free survival (RFS) was estimated using Kaplan-Meier curves and Cox proportional hazards models evaluated factors associated with recurrence. RESULTS:A total of 599 renal units, of which 43 received single instillation and 86 multiple instillations, in 334 patients treated endoscopically for UTUC were analyzed. The median follow-up time for patients without recurrence was 12 months (IQR 4-33). Multiple adjuvant instillations of any intracavitary treatment were associated with a significantly improved RFS (HR 0.52, 95% CI 0.34-0.79), whereas a single instillation was not associated with a significant reduction in recurrence (HR 0.64, 95% CI 0.37-1.13). This association between multiple instillations and improved RFS remained significant after adjustment for clinical risk factors, including tumor grade (adjusted HR 0.36, 95% CI 0.16-0.81), and was confirmed in sensitivity analyses limited to patients with primary UTUC (HR 0.46, 95% CI 0.26-0.85). CONCLUSION/CONCLUSIONS:Multiple intracavitary instillations of BCG or chemotherapy after endoscopic management of UTUC were associated with longer ipsilateral RFS. These findings suggest a potential benefit of repeated instillations and warrant prospective validation.

PURPOSE:With the current movement toward treating oligometastatic hormone sensitive prostate cancer (OMPC), we design a study with the objective of gathering opinions regarding what would be considered a clinically significant benefit from such treatments. METHODS:Data was collected from physicians of the Society of Urologic Oncology using a self-administered questionnaire using SurveyMonkey. The questionnaire was designed to obtain characteristics on clinical practice of the respondents, definitions used for OMPC and also what would be considered a clinically significant benefit according to the respondents. We present a descriptive analysis of the responses obtained. RESULTS:We obtained 119 responses (response rate of 12.6%) after sending the questionnaire twice with one month apart. Most of them being staff/faculty (89%) practicing in the United States of America (84.87%). Most of the responders referred that a significant proportion of their practice comes from PC patients. Most defined OMPC <3 bone/lymph node metastasis seen with conventional imaging, only 26.9% of the responders used positron emission tomography. Regarding the clinical benefit of metastasis-oriented treatment, a curing rate >10% or an increase in 1 year of androgen deprivation therapy-free survival would make the treatment worthwhile. We present examples of sample size calculations for future clinical trials using these parameters as an expected "clinically-significant" benefit. CONCLUSION:This study shows that most clinicians still support the use of conventional imaging to define OMPC. Our findings show that a curing rate of a minimum of 11% and an androgen deprivation therapy-free survival at 1 year are considered clinically significant and this should be used for estimating the sample size in future clinical trials.

BACKGROUND:The therapeutic role of extended (ePLND) versus nonextended pelvic lymph node dissection (nePLND) to remove occult micrometastases in men undergoing radical prostatectomy for localized prostate cancer (PC) is conflicting. Therefore, our aim was to quantify the direct effect of ePLND versus nePLND (removal of occult micrometastases), which is not mediated through the detection of nodal disease and potential adjuvant therapy (indirect effect). METHODS:Retrospective, bi-center cohort study of consecutive patients undergoing radical prostatectomy and PLND for PC (January 2006 and December 2016). Patients were followed until April 2018 for the occurrence of either biochemical recurrence or secondary therapy (composite outcome). ePLND was compared to nePLND by unweighted and weighted survival analysis (total effect) as well as by causal mediation analysis (direct and indirect effect). RESULTS:Positive nodal disease was detected in 71 (7%) out of 1008 patients undergoing radical prostatectomy and PLND for PC (ePLND: 368 [36.5%]; nePLND: 640 [63.5%]). Survival analysis demonstrated results in favor of ePLND (unweighted hazard ratio: 0.77 [95% confidence interval: 0.59-1.01], p = .056; weighted hazard ratio: 0.75 [0.56-0.99], p = .044). The causal mediation analysis confirmed the total effect of 0.77 (0.71-0.82). After disentangling this total effect into an indirect effect (via detection of nodal disease and potential adjuvant therapy) and a direct effect (via removal of occult micrometastases), we identified an even more protective direct effect of 0.69 (0.63-0.75). CONCLUSIONS:Our results not only indicate the utility of ePLND but also that its impact is not restricted to a staging benefit and probably involves a therapeutic benefit mediated through the removal of occult micrometastases.

INTRODUCTION:Utilization of neoadjuvant chemotherapy (NC) in muscle invasive bladder cancer (MIBC) is increasingly recognized as standard of care but trends of use in Ontario remain unknown. Currently, there remains knowledge gaps regarding the effects of perioperative chemotherapy on the rates of interventions requiring hospitalization (IRH) and atheroembolic events (ATEs). METHODS:We conducted a population-based retrospective study within the province of Ontario over 16 years. Patients with non-metastatic MIBC receiving surgery only or planned for perioperative chemotherapy were included. Primary outcomes included 2-year IRH and ATE rates. Univariate/multivariate analysis was used to identify predictors associated with IRHs and ATEs. Cochrane-Armitage was used to assess treatment trends over time. RESULTS:Our study included 3281 patients. RC alone occurred in 2030 (60.9%), NC in 974 (29.6%) and adjuvant chemotherapy in 8.4% (n = 277). A total of 490/974 (50.3%) patients whom initiated NC with RC intent failed to undergo RC. This improved to 20.5% by 2015 (p < 0.001). Use of NC increased by an absolute value of 33% (p < 0.001). Overall, 4.2% of patients experienced IRHs and 11.5% ATEs. On multivariate analysis, advanced age and Charlson index score (CI) were strong predictors of outcomes, not timing of perioperative chemotherapy (p < 0.05.) CONCLUSION: A total of 29.6% of MIBC patients are planned for NC with 20.5% not progressing to their surgery. Use of NC has substantially increased over time. IRHs and ATEs remain stubbornly high at 4.2% and 11.5% respectively. Older age and higher CI scores are the strongest predictors of IRHs and ATEs (p < 0.05), not perioperative chemotherapy.

PURPOSE/OBJECTIVE:The role of percent free prostate specific antigen (%fPSA) in patients who have undergone radical prostatectomy and subsequently experienced disease relapse is unclear. We previously conducted 2 retrospective studies and found %fPSA 15 or greater in the setting of biochemical recurrence confers more aggressive disease. To validate that finding we used biobank specimens collected prospectively when patients were first diagnosed with biochemical recurrence. MATERIALS AND METHODS/METHODS:Biobank specimens of patients with undetectable prostate specific antigen after radical prostatectomy and subsequent biochemical recurrence (prostate specific antigen 0.1 ng/ml or greater) were analyzed for %fPSA. Patients were stratified according to the %fPSA cutoff of 15. Univariable and multivariable logistic regression analysis was performed to predict covariates associated with a higher %fPSA. Cox proportional hazard models were performed to evaluate the prognostic effect of %fPSA on androgen deprivation therapy-free survival, metastasis-free survival, castration resistant-free survival and cancer specific survival. RESULTS:A total of 154 men were included in the study, of whom 126 (82%) had %fPSA less than 15 and 28 (18%) had %fPSA 15 or greater. Median followup for %fPSA less than 15 and %fPSA 15 or greater was 75 and 69 months, respectively. Patients with %fPSA 15 or greater had increased hazard of receiving androgen deprivation therapy (43% vs 25%, adjusted HR 2.40, 95% CI 1.12-5.11), metastatic disease (21% vs 7.9%, adjusted HR 4.10, 95% CI 1.11-15.2) and castration resistant prostate cancer (14% vs 4.0%, unadjusted HR 4.14, 95% CI 1.11-15.5) vs %fPSA less than 15, respectively. CONCLUSIONS:Patients with %fPSA 15 or greater were started on androgen deprivation therapy earlier, and they had progression to castration resistant prostate cancer and metastatic stage earlier. %fPSA 15 or greater in the setting of biochemical recurrence after radical prostatectomy is an indicator of a more aggressive disease. Unlike in the diagnostic setting, a higher %fPSA portends a worse clinical outcome.

INTRODUCTION/BACKGROUND:Digital rectal examination (DRE) is part of the clinical evaluation of men on active surveillance (AS). The purpose of the present study is to analyze the value of DRE as a predictor of upgrading in a population of men with prostate cancer (PCa) treated with AS. METHODS:We used the prostate biopsy (PBx) database from an academic center, including PBx from 2006-2018, and identified 2029 confirmatory biopsies (CxPBx) of men treated with AS, of which 726 men had both diagnostic (initial) and CxPBx information available. We did a descriptive analysis and evaluated sensitivity, specificity, and predictive values of DRE for the detection of clinically significant PCa (csPCa). Multivariable regression analysis was done to identify predictors of csPCa. The primary outcome was to evaluate DRE as a predictor of the presence of csPCa at CxPBx. RESULTS:Among the 2029 patients with a CxPBx, 75% had PCa, and of these, 30.3% had upgrading to International Society of Urologic Pathologists (ISUP) grade ≥2. Thirteen percent of men had a suspicious DRE (done by their treating physician). Sensitivity, specificity, negative and positive predictive values of DRE to detect csPCa were best with a prostate-specific antigen (PSA) <4 ng/ml (27%, 88%, 31%, and 87%, respectively). A suspicious DRE at CxPBx, particularly if the DRE at diagnosis was negative, was a predictor of csPCa (odds ratio [OR] 2.34, p=0.038). The main limitation of our study is the retrospective design and the lack of magnetic resonance imaging. CONCLUSIONS:We believe DRE should still be used as part of AS and can predict the presence of csPCa, even with low PSA values. A suspicious nodule on DRE represents a higher risk of upgrading and should prompt further assessment.

BACKGROUND:Single-arm trials are currently an accepted study design to investigate the efficacy of novel therapies (NT) in non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette-Guérin (BCG) immunotherapy as randomized controlled trials are either unfeasible (comparator: early radical cystectomy; ERC), or unethical (comparator: placebo). To guide the design of such single-arm trials, expert groups published recommendations for clinically meaningful outcomes. The aim of this study was to quantitatively verify the appropriateness of these recommendations. METHODS:We used a discrete event simulation framework in combination with a supercomputer to find the required efficacy at which a NT can compete with ERC when it comes to quality-adjusted life expectancy (QALE). In total, 24 different efficacy thresholds (including the recommendations) were investigated. RESULTS:After ascertaining face validity with content experts, repeated verification, external validation, and calibration we considered our model valid. Both recommendations rarely showed an incremental benefit of the NT over ERC. In the most optimistic scenario, an increase in the IBCG recommendation by 10% and an increase in the FDA/AUA recommendation by 5% would yield results at which a NT could compete with ERC from a QALE perspective. CONCLUSIONS:This simulation study demonstrated that the current recommendations regarding clinically meaningful outcomes for single-arm trials evaluating the efficacy of NT in BCG-unresponsive NMIBC may be too low. Based on our quantitative approach, we propose increasing these thresholds to at least 45%-55% at 6 months and 35% at 18-24 months (complete response rates/recurrence-free survival) to promote the development of clinically truly meaningful NT.

OBJECTIVES/OBJECTIVE:To examine the predictors of prostate-specific antigen discussion with a physician and prostate-specific antigen testing in men aged ≥55 years. METHODS:Utilizing the USA Health Information National Trends Survey, 4th Ed., a cross-sectional study from 2011 to 2014 was carried out to analyze the factors predicting prostate-specific antigen testing and discussion in men ≥55 years. Associations between each covariate and prostate-specific antigen discussion/testing were determined. Multivariable logistic regression models were used to determine clinically relevant predictors of prostate-specific antigen discussion/testing. Due to multiple comparisons, the Bonferroni correction was used. RESULTS:A total of 2731 men included in the Health Information National Trends Survey were analyzed. Several socioeconomic parameters were found to increase the likelihood of men aged ≥55 years to undergo prostate-specific antigen testing: living with a spouse, a higher level of education (college graduate or above), a higher income (>$50 000 annually) and previous history of any cancer. In contrast, current smokers were less likely to undergo prostate-specific antigen testing. Having a prostate-specific antigen discussion with a physician was more likely for men surveyed in 2014, for men who were living with a spouse, who had a higher annual income (>$50 000 annually) and those with a history of any cancer. CONCLUSIONS:Significant inequalities in prostate-specific antigen testing and discussion exist among men in the USA, mainly driven by socioeconomic factors. Ideally, prostate-specific antigen testing and discussion should be based on relevant clinical factors with a shared decision-making approach for every man. Therefore, a better understanding of the socioeconomic factors influencing prostate-specific antigen testing/discussions can inform strategies to reduce existing gaps in care.

OBJECTIVES:To report the oncological and functional outcomes of salvage radical prostatectomy (sRP) after focal therapy (FT). PATIENTS AND METHODS:A retrospective review of all patients who underwent sRP after FT was performed. Clinical and pathological outcomes focussed on surgical complications, oncological, and functional outcomes. RESULTS:In all, 34 patients were identified. The median (interquartile range [IQR]) age was 61 (8.25) years. FT modalities included high-intensity focussed ultrasound (19 patients), laser ablation (13), focal brachytherapy (one) and cryotherapy (one). The median (IQR) time from FT to recurrence was 10.9 (17.6) months. There were no rectal or ureteric injuries. Two (5.9%) patients had iatrogenic cystotomies and four (11.8%) developed bladder neck contractures. The mean (sd) hospital stay was 2.5 (2.1) days. The T-stage was pT2 in 14 (41.2%) patients, pT3a in 16 (47.1%), and pT3b in four (11.8%). In all, 13 (38%) patients had positive surgical margins (PSMs). Six (17.6%) patients received adjuvant radiotherapy (RT). At a mean follow-up of 4.3 years, seven (20.6%) patients developed biochemical recurrence (BCR), and of these, six (17.6%) patients required salvage RT. PSMs were associated with worse BCR-free survival (hazard ratio 6.624, 95% confidence interval 2.243-19.563; P < 0.001). The median (IQR) preoperative International Prostate Symptom Score and International Index of Erectile Function score was 7 (4.5-9.5) and 23.5 (15.75-25) respectively, while in the final follow-up the median (IQR) values were 7 (3.5-11) and 6 (5-12.25), respectively (P = 0.088 and P < 0.001). At last follow-up, 31 (91.2%) patients were continent, two (5.9%) had moderate (>1 pad/day) incontinence, and one (2.9%) required an artificial urinary sphincter. CONCLUSIONS:sRP should be considered as an option for patients who have persistent clinically significant prostate cancer or recurrence after FT. PSMs should be recognised as a risk for recurrent disease after sRP.