Gurdarshan S. Sandhu

Overdiagnosis of Prostate Cancer

This chapter addresses issues relevant to prostate cancer overdiagnosis. Factors promoting the overdiagnosis of prostate cancer are reviewed. First is the existence of a relatively large, silent reservoir of this disease, as can be seen by evaluating autopsy studies and histologic step-sectioning results of prostates removed for other causes. The second main factor responsible for prostate cancer overdiagnosis is fairly widespread prostate-specific antigen and digital rectal examination-based screening, which has been fairly widely practiced in the United States for the past 20 years among heterogeneous groups of men. This has resulted in the identification of many men from this reservoir who otherwise may never have been diagnosed with symptomatic prostate cancer and is substantially responsible for the current annual incidence to mortality ratio for prostate cancer of approximately 6 to 1. Finally, the relatively indolent natural history and limited cancer-specific mortality as reported in a variety of contemporary randomized screening and treatment trials is reviewed. We attempt to quantitate the proportion of newly diagnosed prostate cancers that are overdiagnosed using various trial results and models. We explore the impact of prostate cancer overdiagnosis in terms of patient anxiety and the potential for overtreatment, with its attendant morbidity. We explore strategies to minimize overdiagnosis by targeting screening and biopsy only to men at high risk for aggressive prostate cancer and by considering the use of agents such as 5-alpha reductase inhibitors. Future prospects to prevent overtreatment, including better biopsy and molecular characterization of newly diagnosed cancer and the role of active surveillance, are discussed.

Off-Clamp Robot-Assisted Partial Nephrectomy: Initial Washington University Experience

BACKGROUND AND PURPOSE Because of the impact warm ischemia time may have on renal function, various surgical techniques have been proposed to minimize or eliminate warm ischemia. The purpose of this study is to evaluate our initial renal functional outcomes of off-clamp robot-assisted partial nephrectomy (RAPN), while assessing the safety profile of this unconventional surgical approach. PATIENTS AND METHODS We performed a retrospective review of our off-clamp RAPN experience between August 2007 and January 2012. All patients with baseline and postoperative serum creatinine determinations were included. Patient demographics, operative information, perioperative outcomes, and renal functional outcomes were evaluated for this cohort. RESULTS Forty-two patients with a mean age of 59.9 years (standard deviation [SD]=12) had a median follow-up of 100 days (range 1-1007 days). In all cases, warm ischemia time was 0 minutes. Mean operative time was 143 minutes (SD=59), and median estimated blood loss was 138 mL (range 50-1500 mL). No intraoperative complications were encountered, and all surgical margins were negative. Our postoperative complication rate was 14.3%. At the most recent follow-up, the mean estimated glomerular filtration rate (eGFR) was 76.2 mL/min/1.73 m(2) (SD=27.6), compared with 78.5 mL/min/1.73 m(2) (SD=28.9) preoperatively (P=0.11). Therefore, the mean eGFR decline of 2.3 mL/min/1.73 m(2) (SD=9.1) was not significant. CONCLUSIONS Off-clamp RAPN is associated with minimal morbidity and minimal decline in renal function on short-term follow-up. Further studies and continued monitoring of renal function are needed to determine if off-clamp RAPN provides any advantage in renal function preservation relative to the traditional RAPN with vascular clamping.

The Effect of Increasing Doses of Saw Palmetto Fruit Extract on Serum Prostate Specific Antigen: Analysis of the CAMUS Randomized Trial

PURPOSE Saw palmetto extracts are used to treat lower urinary tract symptoms in men despite level I evidence that saw palmetto is ineffective in reducing these lower urinary tract symptoms. We determined whether higher doses of saw palmetto as studied in the CAMUS (Complementary and Alternative Medicine for Urologic Symptoms) trial affect serum prostate specific antigen levels. MATERIALS AND METHODS The CAMUS trial was a randomized, placebo controlled, double-blind, multicenter, North American trial conducted between June 5, 2008 and October 10, 2012, in which 369 men older than 45 years with an AUA symptom score of 8 to 24 were randomly assigned to placebo or dose escalation of saw palmetto, which consisted of 320 mg for the first 24 weeks, 640 mg for the next 24 weeks and 960 mg for the last 24 weeks of this 72-week trial. Serum prostate specific antigen levels were obtained at baseline and at weeks 24, 48 and 72, and were compared between treatment groups using the pooled t test and Fishers exact test. RESULTS Serum prostate specific antigen was similar at baseline for the placebo (mean ± SD 1.93 ± 1.59 ng/ml) and saw palmetto groups (2.20 ± 1.95, p = 0.16). Changes in prostate specific antigen during the study were similar, with a mean change in the placebo group of 0.16 ± 1.08 ng/ml and 0.23 ± 0.83 ng/ml in the saw palmetto group (p = 0.50). In addition, no differential effect on serum prostate specific antigen was observed between treatment arms when the groups were stratified by baseline prostate specific antigen. CONCLUSIONS Saw palmetto extract does not affect serum prostate specific antigen more than placebo, even at relatively high doses.

Prostate Cancer Chemoprevention

Prostate cancer is a leading cause of morbidity and mortality in men and has significant treatment-associated complications. Prostate cancer chemoprevention has the potential to decrease the morbidity and mortality associated with this disease. Chemoprevention research to date has primarily focused on nutrients and 5 alpha-reductase inhibitors (5ARIs). A large randomized trial (SELECT) found no favorable effect of selenium or vitamin E on prostate cancer prevention. Two large randomized placebo controlled trials (the PCPT and REDUCE trials) have been published and have supported the role of 5ARIs in prostate cancer chemoprevention; however, these trials also have prompted concerns regarding the increase in high-grade disease seen with treatment and have not been approved by the US Food and Drug Administration (FDA) for chemoprevention. Conclusive evidence for the chemopreventive benefit of nutrients or vitamins is lacking, whereas the future role of 5ARIs remains to be clarified.

Randomized Controlled Trial of Oxybutynin Extended Release Versus Placebo for Urinary Symptoms During Intravesical Bacillus Calmette-Guérin Treatment

PURPOSE Intravesical bacillus Calmette-Guérin is used to decrease recurrence rates of nonmuscle invasive urothelial carcinoma. Irritative urinary symptoms are a common side effect of treatment and frequently limit treatment tolerance. While anticholinergic medications may be used for symptom prophylaxis, to our knowledge they have not been evaluated in a randomized controlled trial. MATERIALS AND METHODS A total of 50 bacillus Calmette-Guérin naïve patients were randomized to 10 mg extended release oxybutynin daily or placebo starting the day before 6 weekly bacillus Calmette-Guérin treatments. A questionnaire assessing urinary symptoms (frequency, burning on urination, urgency, bladder pain, hematuria), systemic symptoms (flu-like symptoms, fever, arthralgia) and medication side effects (constipation, blurred vision, dry mouth) was recorded daily throughout the therapeutic course. A linear mixed repeated measures model tested the differences between each point and baseline score. RESULTS The treatment group had a greater increase in urinary frequency and burning on urination compared to placebo (p = 0.004 and p = 0.04, respectively). There were no significant differences between groups for other urinary symptoms, which increased in severity after bacillus Calmette-Guérin but concomitantly returned to baseline in both groups. The treatment group experienced increases in fever, flu-like symptoms, dry mouth and constipation compared to placebo (p <0.0001, p = 0.0008, p = 0.045 and p = 0.001, respectively). There were otherwise no significant differences in nonurinary symptoms or medication adverse reactions. CONCLUSIONS Oxybutynin increased urinary frequency and burning on urination compared to placebo in patients receiving intravesical bacillus Calmette-Guérin treatment. Our results do not support the routine use of oxybutynin as prophylaxis against urinary symptoms during bacillus Calmette-Guérin therapy.

Survival Impact of Followup Care after Radical Cystectomy for Bladder Cancer

PURPOSE Due to substantial variation in patient followup after radical cystectomy for bladder cancer, we sought to understand the effect of urine and laboratory tests, physician visits and imaging on overall survival. MATERIALS AND METHODS We analyzed a cohort of patients treated in the fee for service Medicare population from 1992 through 2007 using Surveillance Epidemiology and End Results (SEER)-Medicare data. Using propensity score analysis, we assessed the relationship between time and geography standardized expenditures on followup care and overall survival during 3 postoperative periods, including perioperative (0 to 3 months), early followup (4 to 6 months) and later followup (7 to 24 months). Using instrumental variable analysis, we assessed the overall survival impact of the quantity of followup care by category, including physician visits, imaging, and laboratory and urine tests. RESULTS We found no improvement in survival due to followup care in the perioperative and early followup periods. Receiving followup care during later followup was associated with improved survival in the low, middle and high expenditure tertiles (HR 0.23, 95% CI 0.15-0.35, HR 0.27, 95% CI 0.18-0.40 and HR 0.47, 95% CI 0.31-0.71, respectively). Instrumental variable analysis suggested that only physician visits and urine testing improved survival (HR 0.96, 0.93-0.99 and 0.95, 0.91-0.99, respectively). CONCLUSIONS Followup care after radical cystectomy in the later followup period was associated with improved survival. Physician visits and urine tests were associated with this improved survival. Our results suggest that aspects of followup care significantly improve patient outcomes but imaging could be done more judiciously after cystectomy.

Robot-assisted partial nephrectomy: off-clamp technique.

Robot-assisted partial nephrectomy (RAPN) has been established as a viable alternative to open and laparoscopic partial nephrectomy for small renal tumors. Multiple variations in surgical technique have been described to reduce warm ischemia time (WIT). We present our off-clamp technique for RAPN. From August 2007 to January 2012, off-clamp RAPN was performed on 47 tumors in 39 patients. WIT was 0 minutes in all cases. The mean operative time was 147 minutes (SD=58); the mean and median estimated blood loss were 219 mL (SD=253) and 150 mL (range 50-1500), respectively; the mean length of stay was 1.9 days (SD=1.1). There were no intraoperative complications, and results for all surgical margins were negative. In experienced hands, our off-clamp technique for RAPN is a safe and feasible technique that eliminates WIT.

Active Surveillance for Prostate Cancer: Barriers to Widespread Adoption

Prostate cancer (PCa) representsa significant societal burden, accounting for substantial morbidity and mortality in men with an annualworldwide incidence of about 1million cases and about 250 000 deaths [1]. The introduction of screening prostate-specific antigen (PSA) level has resulted in a stage migration whereby the majority of screen-detected tumors are small, low-grade, organ-confined lesions, which generally have a protracted natural history and limited cancerspecificmortality.Mostmendiagnosedwith screen-detected PCa are likely todiewith, rather than from, PCa. This hasbeen shown in both the European and American screening trials and validates concerns related to PSA-induced overdiagnosis and overtreatment of potentially indolent cancers. While high-level evidence exists to support radical prostatectomy over watchful waiting in selected young men with clinically detected PCa [2], radical prostatectomy in that setting is associated with moderate overtreatment (the number needed to treat to prevent one PCa death ranges from 7 to 15) and potentially prolonged side effects [3]. A more recent trial, performed in US Department of Veterans Affairs hospitals, of radical prostatectomy for predominately screen-detected cancers has shown no mortality benefit for surgery over observation [4]. Despite these findings, a considerablemajority ofmen in theUnited States andEurope who are diagnosed with screen-detected localized tumors receive aggressive treatment [5,6]. In the face of these considerations, active surveillance (AS) ofPSA-detected tumorswithdelayedcurative interventionat the time of disease progression or at the discretion of the patient should be considered as an acceptable management option [7]. The excellent systematic review by Dall’Era et al. [8] in this issue of European Urology comprehensively

Description of a multicenter safety checklist for intraoperative hemorrhage control while clamped during robotic partial nephrectomy

BackgroundThe adoption of robotic assistance has contributed to the increased utilization of partial nephrectomy for the management of renal tumors. However, partial nephrectomy can be technically challenging because of intraoperative hemorrhage, which limits the ability to identify the tumor margin and may necessitate the conversion to open surgery or radical nephrectomy. To our knowledge, a comprehensive safety checklist does not exist to guide surgeons on the management of hemorrhage during robotic partial nephrectomy. We developed such an safety checklist based on the cumulative experiences of high volume robotic surgeons.MethodsA treatment safety checklist for the management of hemorrhage during robotic partial nephrectomy was collaboratively developed based on prior experiences with intraoperative hemorrhage during robotic partial nephrectomy.ResultsReducing the risk of hemorrhage during robotic partial nephrectomy begins with reviewing the preoperative imaging for renal vasculature and tumor anatomy, with a focus on accessory vessels and renal tumor proximity to the renal hilum. During hilar exposure, an attempt is made to identify additional accessory renal arteries. The decision is then made on whether to clamp the hilum (artery +/- vein). If bleeding is encountered during resection, management is based on whether the bleeding is suspected to be arterial or from venous backbleeding. Operative maneuvers that may increase the chance of success are highlighted in safety checklists for arterial and venous bleeding.ConclusionsSafely performing robotic partial nephrectomy is dependent on attention to prevention of hemorrhage and rapid response to the challenge of intraoperative bleeding. Preparation is essential for maximizing the chance of success during robotic partial nephrectomy.

Off-Clamp Robot-Assisted Partial Nephrectomy for Complex Renal Tumors

BACKGROUND AND PURPOSE Considering the potential impact of warm ischemia time (WIT) on renal functional outcomes after robot-assisted partial nephrectomy (RAPN), many techniques that reduce or eliminate WIT have been studied. We present our institutional experience and progression using one such technique-off-clamp RAPN-as well as the results of this technique in the management of complex cases. PATIENTS AND METHODS A retrospective chart review of 65 patients undergoing off-clamp RAPN was performed, 15 of whom underwent off-clamp RAPN for 26 complex tumors. Complex features included hilar location, completely endophytic growth, and ipsilateral multifocality. In all cases, hilar vessels were dissected but not clamped. RESULTS Mean tumor size was 2.5 cm (standard deviation; [SD]=1.4), while mean nephrometry score was 8.7 (SD=1.5). One (7%) intraoperative complication occurred. Mean estimated blood loss was 403 mL (SD=381), mean operative time was 190 minutes (SD=68), and WIT was 0 minutes in all cases. Mean length of stay was 1.8 days (SD=0.9), with one patient needing a postoperative blood transfusion (Clavien II complication). Final pathology results demonstrated clear-cell carcinoma (n=16), papillary carcinoma (n=4), angiomyolipoma (n=1), oncocytoma (n=2), and cystic nephroma (n=3). Margins were negative for tumor for 96% (25/26) of resected masses. Estimated glomerular filtration rate (eGFR) decreased by an average of 3.1 mL/min/1.73 m(2) (SD=9.8, P=0.24), at a mean follow-up of 177 days (SD=296). Five patients with radiographic follow-up of at least 6 months have no evidence of disease recurrence. CONCLUSIONS Off-clamp RAPN can be safely and effectively performed even in the case of complex tumors, but occurs with higher estimated blood loss. Minimal changes in eGFR were experienced by patients undergoing off-clamp RAPN at an average follow-up of roughly 6 months. Longer follow-up and direct comparison with conventional clamped RAPN technique are needed to establish the efficacy of off-clamp RAPN in complex cases.