Extended pelvic lymph node dissection in muscle invasive bladder cancer.

PURPOSE OF REVIEW: Bilateral pelvic lymph node dissection (PLND) at the time of radical cystectomy (RC) provides important staging information and oncologic benefit in patients with bladder cancer. The optimal extent of the PLND remains controversial. Our aim is to highlight nodal mapping studies and the data that guides optimization of both staging and oncologic outcomes. We then review contemporary randomized trials studying the extent of PLND. RECENT FINDINGS: A recent randomized trial (RCT) powered for a 15% improvement in recurrence-free survival (RFS) of extended (e) over limited (l)PLND was completed but failed to identify this large difference in outcome. Concerns over study design limit the ability to interpret the oncologic results. Importantly, ePLND minimally changed surgical morbidity. An ongoing, similar RCT (SWOG S1011) powered to detect a 10% difference in RFS has completed accrual, but no published outcomes are available. SUMMARY: RC and ePLND can provide cure in 33% of LN positive bladder cancer patients. Current data support a 5% improvement in RFS if ePLND is routinely used in MIBC patients. Two randomized trials powered to identify much larger (15 and 10%) improvements in RFS are unlikely to identify such an ambitious benefit by extending the PLND.

Tips and tricks in achieving zero peri-operative opioid used in onco-urologic surgery.

PURPOSE: To review non-opioid based protocols in urologic oncologic surgery and describe our institutional methods of eliminating peri-operative opioids. METHODS: A thorough literature review was performed using PUBMED to identify articles pertaining to reducing or eliminating narcotic use in genitourinary cancer surgery. Studies were analyzed pertaining to protocols utilized in genitourinary cancer surgery, major abdominal and/or pelvic non-urologic surgery. RESULTS: Reducing or eliminating peri-operative narcotics should begin with an institutionalized protocol made in conjunction with the anesthesia department. Pre-operative regimens should consist of appropriate counseling, gabapentin, and acetaminophen with or without a non-steroidal anti-inflammatory medications. Prior to incision, a regional block or local anesthetic should be delivered. Anesthesiologists may develop opioid-free protocols for achieving and maintaining general anesthesia. Post-operatively, patients should be on a scheduled regimen of ketorolac, gabapentin, and acetaminophen. CONCLUSION: Eliminating peri-operative narcotic use is feasible for major genitourinary oncologic surgery. Patients not only have improved peri-operative outcomes but also are at significantly reduced risk of developing long-term opioid use. Through the implementation of a non-opioid protocol, urologists are able to best serve their patients while positively contributing to reducing the opioid epidemic.

Risk Factors for Intravesical Recurrence after Minimally Invasive Nephroureterectomy for Upper Tract Urothelial Cancer (ROBUUST Collaboration).

PURPOSE: Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence. RESULTS: A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031). CONCLUSIONS: IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

Immunotherapy in non-muscle-invasive bladder cancer: current status and future directions.

PURPOSE: Patients harboring high-grade non-muscle-invasive bladder cancer (NMIBC) experience high rates of both recurrence and progression. Currently, few treatment options besides cystectomy exist for this at-risk population, especially those with BCG-unresponsive disease. The purpose of this review is to present the current status and describe future directions of immunotherapy in NMIBC. METHODS: The PubMed and Google Scholar databases were searched for articles pertaining to immunotherapy in NMIBC. Relevant planned and ongoing clinical trials were identified using www.ClinicalTrials.gov . Published randomized control trials, reviews, other retrospective and prospective studies deemed relevant were used in this review paper. RESULTS: Novel immunotherapies used in the treatment of high-grade NMIBC and BCG-unresponsive disease allow patients more options and have the potential to reduce the need for radical cystectomy. Currently, several options target the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis as this mechanism of immunotherapy has been shown to be effective in several cancers, including bladder, melanoma, and lung cancers. In addition, other immunotherapy options for the treatment of NMIBC include viral gene therapies, interleukin-15 superagonists, small molecule inhibitors of indoleamine (2,3)-dioxygenase 1, and vaccines. CONCLUSIONS: The current landscape of immunotherapy in bladder cancer is rapidly evolving, with much literature pertaining to muscle-invasive and metastatic disease. However, the implementation of these treatment options in high-grade NMIBC may allow patients to avoid life-altering surgery. Reliable biomarkers for response are needed to further select patients who may benefit from such therapies.

Response to 2 Induction Courses of Bacillus Calmette-Guèrin Therapy Among Patients With High-Risk Non-Muscle-Invasive Bladder Cancer: 5-year Follow-Up of a Phase 2 Clinical Trial.

Importance: With the ongoing bacillus Calmette-Guèrin (BCG) shortage, alternate therapeutic options for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are needed. Objective: To report the 5-year outcomes of a cohort from a prospective phase 2 trial of patients with high-risk NMIBC who underwent 12 instillations of induction BCG without maintenance. Design, Setting, and Participants: Between November 2015 and June 2018, patients at Memorial Sloan Kettering Cancer Center with primary or recurrent NMIBC (high-grade Ta, T1 tumors, with or without carcinoma in situ) were prospectively enrolled to receive 2 induction courses (12 intravesical instillations) of BCG without maintenance therapy. The analysis itself took place on July 28, 2023. Main Outcomes and Measures: Recurrence-free survival (RFS) and cancer-specific survival (CSS) was assessed by landmark analysis at 7.5 months. Recurrence was defined as pathologic high-grade disease. Results: Among 81 patients (65 men [84%] and 12 women [16%] with a median [IQR] age of 72 [64-77] years) who consented to participate in the study, 75 remained evaluable for long-term follow-up analysis. Twenty-one patients experienced high-grade recurrence, yielding a 5-year RFS rate of 69% (95% CI, 58%-81%), with a median (IQR) follow-up of 4.4 (3.8-5.3) years for patients without recurrence. Three patients died of bladder cancer, corresponding to a CSS rate of 97% (95% CI, 93%-100%) with a median (IQR) follow-up of 4.9 (4.2-5.7) years for survivors. Using 2 induction courses reduced the amount of BCG per patient from 27 vials to 12 vials. Conclusion and Relevance: Twelve induction instillations of BCG without maintenance for patients with high-risk NMIBC reduced the number of vials needed per patient while providing acceptable oncologic outcomes. Given the ongoing BCG shortage, this modified regimen may provide a suitable alternative in this setting.

Feasibility and tissue concordance of genomic sequencing of urinary cytology in upper tract urothelial carcinoma.

BACKGROUND: There is limited ability to accurately diagnose and clinically stage patients with upper tract urothelial carcinoma (UTUC). The most easily available and widely used urinary biomarker is urine cytology, which evaluates cellular material yet lacks sensitivity. We sought to assess the feasibility of performing next-generation sequencing (NGS) on urine cytology specimens from patients with UTUC and evaluate the genomic concordance with tissue from primary tumor. METHODS: In this retrospective study, we identified 48 patients with a diagnosis of UTUC treated at Memorial Sloan Kettering Cancer Center (MSK) between 2019 and 2022 who had banked or fresh urine samples. A convenience cohort of matching, previously sequenced tumor tissue was used when available. Urine specimens were processed and the residual material, including precipitated cell-free DNA, was sequenced using our tumor-naïve, targeted exome sequencing platform that evaluates 505 cancer-related genes (MSK-IMPACT). The primary outcome was at least 1 detectable mutation in urinary cytology specimens. The secondary outcome was concordance to matched tissue (using ANOVA or Chi-Square, as indicated). RESULTS: Genomic sequencing was successful for 45 (94%) of the 48 urinary cytology patient samples. The most common mutations identified were TERT (62.2%), KMT2D (46.7%), and FGFR3 (35.6%). All patients with negative urine cytology and low-grade tissue had successful cytology sequencing. Thirty-six of the 45 patients had matching tumor tissue available; concordance to matched tissue was 55% overall (131 of the total 238 oncogenic or likely oncogenic somatic mutations identified). However, in 94.4% (n = 34/36) of patients, the cytology had at least 1 shared mutation with tissue. Eleven (30.6%) patients had 100% concordance between cytology and tissue. CONCLUSIONS: Sequencing urinary specimens from selective UTUC cytology is feasible in nearly all patients with UTUC. Prospective studies are underway to investigate a clinical role for this promising technology.

Targeted Therapies in Advanced and Metastatic Urothelial Carcinoma.

This review describes the current landscape of targeted therapies in urothelial carcinoma. The standard of care for advanced urothelial carcinoma patients remains platinum-based combination chemotherapy followed by immunotherapy. However, median overall survival for these patients is still <1 year and there is an urgent need for alternative therapies. The advent of next-generation sequencing has allowed widespread comprehensive molecular characterization of urothelial tumors and, subsequently, the development of therapies targeting specific molecular pathways implicated in carcinogenesis such as FGFR inhibition, Nectin-4, Trop-2, and HER2 targeting. As these therapies are demonstrated to be effective in the second-line setting, they will be advanced in the treatment paradigm to localized and even non-muscle invasive disease.

The impact of discharge location on outcomes following radical cystectomy.

PURPOSE: Hospital readmission is associated with adverse outcomes and increased cost, and as such, has been identified as a metric for surgical quality and a target for shifts in health policy. However, the disposition of patients who undergo radical cystectomy for bladder cancer and the association between discharge locations and readmission rates is poorly understood. Understanding the patterns and characteristics of readmission after radical cystectomy will help inform discharge planning and expectations and may have long-term impacts on quality and cost of care delivery. We hypothesize that patients will have varying readmission rates based on their discharge location. MATERIALS AND METHODS: An observational analysis of the Nationwide Readmissions Database was performed for all patients who underwent elective radical cystectomy in 2016 to 2017. The patients were grouped by the following criteria: whether they were discharged home, home with care, or to a facility. Univariate analysis was performed using the Chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables. A multivariable logistic regression was conducted to evaluate if discharge locations impact patient readmissions at 30- and 90-days. RESULTS: The final dataset included 4,947 patients discharged home with care, 2,127 patients discharged to home or self-care, and 1,232 patients discharged to a facility. Discharge to a facility was strongly associated with higher 30-day (OR 1.49, CI 1.26-1.76) and 90-day readmission rates (OR 1.46, CI 1.23-1.74). Additionally, home health care was strongly associated with increased 30-day readmission rates (OR 1.22, CI 1.08-1.37) relative to routine discharge home. CONCLUSIONS: Our analysis suggests that discharge location independently predicts readmission following RC. Further study with more granular patient- and system-level data may aid in identifying structural characteristics and processes that can reduce readmissions and their associated economic impact, while maintaining quality of care delivered.

Robotic assisted radical cystectomy versus open radical cystectomy: a review of what we do and don't know.

Radical cystectomy (RC) is the gold standard treatment for muscle-invasive and high-risk, noninvasive bladder cancer. Since 2003, robot-assisted radical cystectomy (RARC) has been gaining popularity. Metanalyses show that the primary advantage of RARC is less blood loss and the primary advantage of open radical cystectomy (ORC) is shorter operative times. There do not appear to be significant differences in complications, cancer-related outcomes or survival between the two approaches. Cost analyses comparing RARC and ORC are complicated by the often-ill-defined distinction between the cost to the hospital versus the cost to payors. However, it is likely that for both hospitals and payors, RARC is cost effective at high-volume centers. It is feasible that in the future, increased experience with RARC will lead to improved outcomes and justify the use of RARC over ORC.

Novel treatment of upper tract urothelial carcinoma in situ with docetaxel in BCG refractory patients.

INTRODUCTION: Patients with upper-tract carcinoma in situ (UT-CIS) that have failed treatment with BCG are recommended for radical nephroureterectomy (RNU). We describe a cohort of patients with BCG-refractory UT-CIS that were treated with docetaxel, a novel agent in the approach to topical therapy. METHODS: Patients with pathologically proven UT-CIS from 2012 to 2020 with an imperative indication for organ preservation and history of BCG-refractory disease were included. Each patient underwent ureteroscopy with biopsy and selective cytology pre- and postinduction, and after each maintenance course. Complete response (CR) was defined as the absence of visualized lesions on ureteroscopy, negative selective cytology, and absence of clinical progression. No response (NR) was defined as persistence of lesions after induction or absence of visualized lesions with persistently positive cytology. RESULTS: Seven patients and 10 renal units were treated. Six of the 10 renal units had initial CR (60%). Three patients with NR went on to have RNU, one of which subsequently died due to cancer-specific mortality. One patient with bilateral disease had NR in 10 renal unit and cure in the other. This patient subsequently developed recurrence in his remaining renal unit. A second patient had CR in both kidneys for 6 years, but 1 year after finishing maintenance regimen developed HG disease in 1 ureter. Average follow-up was 33 months. CONCLUSION: This study demonstrates efficacy of docetaxel as a treatment option for patients with UT-CIS with a contraindication to RNU after failing BCG. Response rates of 60% appear to be similar to those of BCG-refractory bladder CIS.

Long-Term Outcomes of Laser Incision and Triamcinolone Injection for the Management of Ureteroenteric Anastomotic Strictures.

Purpose: Benign ureteroenteric anastomotic stricture (UEAS) is a common postoperative complication after urinary diversion with an incidence of 3%-10%. Our objective is to report long-term follow-up of our technique for endoscopically managing UEAS after cystectomy. Materials and Methods: Patients with endoscopically managed benign UEAS after cystectomy were included. Intervention entailed anetegrade flexible ureteroscopy with biopsy followed by laser incision of the stricture and of periureteral and peri-ileal tissues 1 cm below and 1 cm above the stricture into fat. Triamcinolone injection was then performed, followed by balloon dilation of the incised area to 24F. Parallel Double-J ureteral stents or upside down nephrostomy tubes were placed for 6 weeks. CT scans were obtained at 3 months and 1 year after surgery, and renal ultrasound at 6 and 9 months, and then annually. Results: Twenty-one patients, and a total of 24 UEAS were treated. Urinary diversion included ileal conduit (n = 12), neobladder (n = 7), and Indiana pouch (n = 2). Twenty out of 24 strictures had no recurrence, including three patients who had bilateral disease, yielding an overall success rate of 83.3%. The remaining three patients with recurrence had evidence of stricture within 3 months. Follow-up ranged from 8 to 102 months, with a median of 30 months. Conclusions: Patients treated endoscopically for UEAS have been shown to have acceptable immediate success with less morbidity when compared with ureteral reimplantation. Our technique of laser incision, triamcinolone injection, balloon dilation, and temporary stent placement has a success rate of over 80% and is unique in that long-term data confirms the durability of this endoscopic procedure.

Can anesthetics affect bladder cancer recurrence? Total intravenous versus volatile anesthesia in patients undergoing robot-assisted radical cystectomy: A single institution retrospective analysis.

BACKGROUND: Radical cystectomy is standard of care and part of a multidisciplinary approach for long-term survival in patients with muscle-invasive bladder cancer (MIBC) or high-grade non-MIBC. Recent data have suggested that anesthetic technique can affect long-term survival and recurrence in patients undergoing cancer related surgery. METHODS: The records of all patients who underwent robot-assisted radical cystectomy for high-risk non-MIBC or MIBC at a single academic institution from 2014 to 2020 were retrospectively reviewed. Patients were grouped according to whether they received total intravenous (TIVA) or volatile inhalation anesthesia (VIA). Univariable and multivariable cox proportional hazards models were used to compare hazard ratios for distant recurrence. Kaplan-Meier recurrence-free survival curves were constructed from the date of surgery to recurrence. RESULTS: A total of 231 patients were included, of which 126 (55%) received TIVA and 105 (45%) received VIA. Distant recurrence occurred in 8.7% and 26.7% of patients who received TIVA and VIA, respectively (P < 0.001). Kaplan-Meier analysis demonstrated significant improvement in distant recurrence-free survival with TIVA (log-rank P < 0.001). Multivariable analysis revealed a significant increase in recurrence risk with VIA (HR: 3.4, 95%CI: 1.5-7.7, P < 0.01) and increasing tumor pathological stage (pT2, pT3, pT4, all P < 0.05). CONCLUSIONS: The use of volatile inhalation anesthetics during robot-assisted radical cystectomy may be associated with an increased risk of distant recurrence. Further studies will be necessary to validate these findings.

Implementation of a nonopioid protocol following robot-assisted radical cystectomy with intracorporeal urinary diversion.

PURPOSE: The implementation of robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) for management of patients with muscle-invasive or high-risk noninvasive bladder cancer has increased in utilization over the last decade. Here, we seek to describe institutional opioid prescription and utilization patterns following implementation of a nonopioid (NOP) perioperative pain management protocol in patients who received RARC with ICUD. MATERIALS AND METHODS: The records of all patients who underwent RARC that utilized a NOP perioperative pain management protocol at a single academic institution from 2016 to 2020 were retrospectively reviewed. Descriptive statistical analyses were performed. For comparison, we included 74 consecutive patients who received the same NOP protocol with extracorporeal urinary diversion (ECUD). RESULTS: A total of 116 patients who received ICUD were included in our analysis. The median operation time for the ICUD group was 305 minutes (interquartile range [IQR]: 262-352). 12.1% (n = 14) of patients who underwent ICUD required narcotics during inpatient hospitalization. For these patients, the median morphine milligram equivalent requirement was 52.0 (IQR: 7.62-157). Additionally, only 12.1% (n = 14) of patients were prescribed opioids postoperatively at discharge. We identified that within 6 months of surgery only 5 (4.3%) patients required a second narcotic prescription. Furthermore, of patients who did not use mu-opioid blockers, a minority experienced postoperative ileus (15.7%, n = 16). 30- and 90-day all Clavien complication rates for patients were 44.8% (n = 52) and 49.1% (n = 57), respectively. Nineteen (16.4%) patients were readmitted within 30 days of discharge, of which none were pain related. When compared to ECUD, patients who received ICUD experienced similar complication and readmission rates. CONCLUSIONS: The implementation of a NOP protocol for patients undergoing RARC with ICUD allows for both decreased postoperative narcotic use and reduced need for narcotic prescriptions at discharge with acceptable complication and readmission rates.

The effect of tumor location on overall survival for pT2-4 bladder and upper tract urothelial carcinoma following radical surgery.

INTRODUCTION: Historically, staging and treatment for upper tract urothelial carcinoma were extrapolated from bladder urothelial carcinoma literature. However, embryological, genetic, and anatomical differences exist between them. We sought to explore the relationship between location of urothelial cancer and overall survival (OS). METHODS: Data was culled from the National Cancer Database from 2004-2015. Patients with pT2-pT4 treated with definitive surgery were included; those with metastatic disease or who received neoadjuvant or adjuvant treatment were excluded. Patients were stratified by tumor location and pathological stage. The primary outcome was OS. Secondary outcomes were predictors of mortality in each pT stage stratum. RESULTS: A total of 11 330 patients with bladder, 954 patients with ureteral, and 1943 patients with renal pelvis urothelial carcinoma were analyzed. Mean followup was 43.3, 39.4, and 41.4 months for bladder, ureteral, and renal pelvis, respectively. On univariable analysis, ureteral pT2 was associated with worse OS compared to both bladder (61.3 vs. 80.4 months, p=0.007) and renal pelvis (61.3 vs. 80.5 months, p=0.014). Renal pelvis pT3 was associated with improved OS compared to both bladder (42.5 vs. 28.6 months, p=0.003) and ureteral (42.5 vs. 25.7 months, p<0.001). Renal pelvis pT4 had decreased survival compared to bladder (11.4 vs. 17.7 months, p<0.001). On multivariable Cox regression, only renal pelvis pT3 was associated with a 20% decreased risk of mortality compared to bladder pT3 (hazard ratio 0.80, 95% confidence interval 0.72-0.88, p<0.001). CONCLUSIONS: Renal pelvis pT3 is associated with lower mortality. Mutational and embryological differences may play a role in this disparity.

Urologic oncology practice during COVID-19 pandemic: A systematic review on what can be deferrable vs. nondeferrable.

PURPOSE: To provide a review of high-risk urologic cancers and the feasibility of delaying surgery without impacting oncologic or mortality outcomes. MATERIALS AND METHODS: A thorough literature review was performed using PubMed and Google Scholar to identify articles pertaining to surgical delay and genitourinary oncology. We reviewed all relevant articles pertaining to kidney, upper tract urothelial cell, bladder, prostate, penile, and testicular cancer in regard to diagnostic, surgical, or treatment delay. RESULTS: The majority of urologic cancers rely on surgery as primary treatment. Treatment of unfavorable intermediate or high-risk prostate cancer, can likely be delayed for 3 to 6 months without affecting oncologic outcomes. Muscle-invasive bladder cancer and testicular cancer can be treated initially with chemotherapy. Surgical management of T3 renal masses, high-grade upper tract urothelial carcinoma, and penile cancer should not be delayed. CONCLUSION: The majority of urologic oncologic surgeries can be safely deferred without impacting long-term cancer specific or overall survival. Notable exceptions are muscle-invasive bladder cancer, high-grade upper tract urothelial cell, large renal masses, testicular and penile cancer. Joint decision making among providers and patients should be encouraged. Clinicians must manage emotional anxiety and stress when decisions around treatment delays are necessary as a result of a pandemic.