Gain of Chromosome 5q Predicts a Favorable Prognosis in Localized Renal Cell Carcinoma.

Approximately 65% of renal cell carcinomas (RCC) are diagnosed at a localized stage. We investigated the chromosome 5q gain impact on disease-free survival (DFS) in RCC patients. Overall, 676 patients with stages 1-2 RCC and having cytogenetic analysis were included. Gain of 5q was observed in 108 patients, more frequently in clear cell (ccRCC) than non-clear cell tumors. Gain of 5q is likely an independent prognostic factor since the concerned patients had a decreased recurrence risk in stages 1-2 RCC, confirmed in multivariable analysis. Detecting 5q gain could enhance recurrence risk assessment, allowing tailored post-surgery surveillance, and reducing unnecessary treatments.

N-803 Plus BCG Treatment for BCG-Naïve or -Unresponsive Non-Muscle Invasive Bladder Cancer: A Plain Language Review.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC).One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive). WHAT HAPPENED IN THE STUDIES?: In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 µg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 µg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 µg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row. WHAT WERE THE KEY TAKEAWAYS?: N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease.Clinical Trial Registration: NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).

Addition of the IL-15 superagonist N-803 to BCG therapy produces a high rate of success in eliminating non-muscle invasive bladder cancer in both BCG-naive and BCG-unresponsive patients, with long-lasting effects that allow patients to avoid surgical removal of the bladder.

Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial.

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is a recurrent disease, thus requiring repeated transurethral resection of bladder tumor under general anesthesia. We evaluated the efficacy and safety of UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC. MATERIALS AND METHODS: This prospective, phase 2b, open-label, single-arm trial recruited patients with biopsy-proven LG IR NMIBC to receive 6 once-weekly instillations of UGN-102. The primary end point was complete response (CR) rate, defined as the proportion of patients with negative endoscopic examination, negative cytology and negative for-cause biopsy 3 months after treatment initiation. Patients with CR were followed quarterly up to 12 months to assess durability of treatment effect. Safety and adverse events were monitored throughout the trial. RESULTS: A total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received ≥1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. A total of 13 patients had documented recurrences. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis. Common adverse events (incidence ≥10%) included dysuria, urinary frequency, hematuria, micturition urgency, urinary tract infection and fatigue. CONCLUSIONS: Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC.

Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report.

PURPOSE: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.

Cost-Effectiveness Analysis of Pembrolizumab for Bacillus Calmette-Guérin-Unresponsive Carcinoma In Situ of the Bladder.

PURPOSE: Patients with bacillus Calmette-Guérin-unresponsive carcinoma in situ are treated with radical cystectomy or salvage intravesical chemotherapy. Recently, pembrolizumab was approved for bacillus Calmette-Guérin-unresponsive carcinoma in situ. MATERIALS AND METHODS: We used a decision-analytic Markov model to compare pembrolizumab, salvage intravesical chemotherapy (with gemcitabine-docetaxel induction+monthly maintenance) and radical cystectomy for patients with bacillus Calmette-Guérin-unresponsive carcinoma in situ who are radical cystectomy candidates (index patient 1) or are unwilling/unable to undergo radical cystectomy (index patient 2). The model used a U.S. Medicare perspective with a 5-year time horizon. One-way and probabilistic sensitivity analyses were performed. Incremental cost-effectiveness ratios were compared using a willingness to pay threshold of $100,000/quality-adjusted life year. RESULTS: For index patient 1, pembrolizumab was not cost-effective relative to radical cystectomy (incremental cost-effectiveness ratios $1,403,008/quality-adjusted life year) or salvage intravesical chemotherapy (incremental cost-effectiveness ratios $2,011,923/quality-adjusted life year). One-way sensitivity analysis revealed that pembrolizumab only became cost-effective relative to radical cystectomy with a >93% price reduction. Relative to radical cystectomy, salvage intravesical chemotherapy was cost-effective for time horizons <5 years and nearly cost-effective at 5 years (incremental cost-effectiveness ratios $118,324/quality-adjusted life year). One-way sensitivity analysis revealed that salvage intravesical chemotherapy became cost-effective relative to radical cystectomy if risk of recurrence or metastasis at 2 years was less than 55% or 5.9%, respectively. For index patient 2, pembrolizumab required >90% price reduction to be cost-effective (incremental cost-effectiveness ratios $1,073,240/quality-adjusted life year). Pembrolizumab was cost-effective in 0% of 100,000 microsimulations in probabilistic sensitivity analyses for both index patients. CONCLUSIONS: At its current price, pembrolizumab is not cost-effective for bacillus Calmette-Guérin-unresponsive carcinoma in situ relative to radical cystectomy or salvage intravesical chemotherapy. Although gemcitabine-docetaxel is not cost-effective relative to radical cystectomy at 5 years, further studies may validate its cost-effectiveness if recurrence and metastasis thresholds are met.

The Impact of Upper Tract Urothelial Carcinoma Diagnostic Modality on Intravesical Recurrence after Radical Nephroureterectomy: A Single Institution Series and Updated Meta-Analysis.

PURPOSE: Diagnostic ureteroscopic biopsy for upper tract urothelial carcinoma (UTUC) has been hypothesized to increase intravesical recurrence of urothelial carcinoma after radical nephroureterectomy (RNU). Moreover, the impact of ureteroscopy without biopsy or percutaneous biopsy on intravesical recurrence remains unknown. Herein, we compared post-RNU intravesical recurrences across UTUC diagnostic modalities. MATERIALS AND METHODS: Patients undergoing RNU at our institution between 1995 and 2019 were categorized by UTUC diagnostic modality: 1) no ureteroscopy or percutaneous biopsy; 2) percutaneous biopsy; 3) ureteroscopy without biopsy; 4) ureteroscopic biopsy. Intravesical recurrences were compared using Kaplan-Meier analyses and Cox-proportional hazard models. Results of group 4 vs 1 were pooled with the literature using a fixed effects meta-analysis. RESULTS: In a cohort of 834 RNU patients, 210 (25.2%) had undergone no ureteroscopy, 57 (6.6%) percutaneous biopsy, 125 (15.0%) ureteroscopy without biopsy, and 442 (53.0%) ureteroscopic biopsy. Two-year intravesical recurrence rates were 15.0%, 12.7%, 18.4%, and 21.9% for groups 1 through 4, respectively (p=0.09). Multivariable analysis found that group 4 had increased intravesical recurrences (HR 1.40, p=0.04) relative to group 1 while group 2 (HR 1.07, p=0.87) and group 3 (HR 1.15, p=0.54) did not. Group 4 remained associated with intravesical recurrence on subset analyses accounting for post-RNU surveillance cystoscopy frequency. On meta-analysis including 11 other series, ureteroscopic biopsy was associated with intravesical recurrence (HR 1.47, p <0.01). CONCLUSIONS: Ureteroscopic biopsy before RNU, but not percutaneous biopsy or ureteroscopy without biopsy, was associated with increased intravesical recurrence. Clinical trials of intravesical chemotherapy after ureteroscopic biopsy are warranted to reduce intravesical recurrences.

Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.

BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma.

The Role of Opioids and Their Receptors in Urological Malignancy: A Review.

PURPOSE: We reviewed the literature surrounding the role of opioids and their receptors in urological malignancy. Recent studies have suggested clinically significant effects of agonism or antagonism of opioid receptors on cancer related outcomes and tumorigenesis. The focus of these efforts has centered on nonurological malignancies. However, a compelling body of evidence is growing in the fields of prostate, bladder and kidney cancer. MATERIALS AND METHODS: A systematic review of English language articles published through 2020 was conducted with key phrases related to kidney, bladder or prostate cancer, and opioids or narcotics. A total of 837 unique records were identified, of which 49 were selected for full text review and 33 were included in the qualitative analysis. Eight records were identified via citation review and 1 study was recently presented at a national meeting. RESULTS: Retrospective reviews suggest poorer disease specific and recurrence-free survival with increased perioperative opioid administration in patients undergoing prostate or bladder cancer surgery. However, the data are controversial. Kappa opioid receptors are implicated in both proliferation and inhibition of prostate cancer cell growth across in vitro studies, with a proposed interaction with the androgen cascade. Similarly opioid growth factor receptor is highly expressed in prostate cancer cells and repressed by androgens. Prostate cancer tissue stains more intensely for the mu opioid receptor, and patients with higher expression have poorer oncologic outcomes. Opioid agonism in vitro induces urothelial cell carcinoma proliferation, migration and invasion, with possible additional influence from interactions with the bradykinin b2 receptor. Agonism of the mu, kappa and delta opioid receptors induces renal cell carcinoma tumorigenesis, possibly via upregulation of survivin. Meanwhile, opioid growth factor receptor agonism has the opposite effect in renal cell carcinoma. CONCLUSIONS: Evidence surrounding the role of opioids and their receptors in urological malignancy is provocative and should serve as an impetus for further investigation.

The association between N-methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, and clinical outcomes in patients undergoing robotic-assisted radical cystectomy.

PURPOSE: To assess the impact of N-methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, on the post-operative recovery of patients undergoing robotic-assisted radical cystectomy for bladder cancer. METHODS: We retrospectively reviewed patients undergoing robotic-assisted radical cystectomy by a single surgeon (KC) prior to (control group) and after (treatment group) the routine use of N-methylnaltrexone. Kaplan-Meier curves and the log-rank test were used to quantify time to flatus, bowel movement, and discharge. Daily mean opioid use, daily pain assessment rating, and episodes of severe pain (7-10/10) were compared. Gastrointestinal-related complications, including ileus, emesis, and/or need for post-op nasogastric tube placement, and 30-day readmissions were also compared between groups. Charge capture data were compared between groups to analyze cost impact. RESULTS: 29 patients each in the control and treatment group met inclusion criteria. Patients receiving N-methylnaltrexone had reduced length of stay compared with no N-methylnaltrexone (median 4 vs. 7 days, p < 0.01). Time to flatus and bowel movement, however, were similar. In a multivariable analysis controlling for possible confounders, however, the improvement in length of stay associated with N-methylnaltrexone use did not reach statistical significance (p = 0.11). Episodes of severe pain and composite gastrointestinal-related complications were reduced in the N-methylnaltrexone group (44.8% vs. 10.3%, p < 0.01). The reduction in length of stay was associated with approximately $10,500 in cost savings per patient. CONCLUSIONS: In this study, N-methylnaltrexone was associated with reduced length of stay, fewer episodes of severe pain, and reduced costs. These results provide the impetus for further study.

Analysis of guideline recommended use of renal mass biopsy and association with treatment.

INTRODUCTION: Renal mass biopsy (RMB) may not be indicated when the results are unlikely to impact management, such as in young and/or healthy patients and in elderly and/or frail patients. We analyzed the utility of RMB in three patient cohorts stratified by age-adjusted Charlson comorbidity index score (ACCI). MATERIALS AND METHODS: We identified patients with cT1a renal tumors in the National Cancer Database from 2004-2014. We combined age and Charlson-Deyo scores to identify young and/or healthy patients ('healthy-ACCI'), elderly and/or frail patients ('frail-ACCI'), and a reference cohort. We performed multivariable logistic regression to identify predictors of RMB and treatment. We evaluated the impact of RMB on management by analyzing the proportion of high-grade disease on final pathology as a surrogate for risk stratification. RESULTS: We identified 36,720 healthy-ACCI, 2,516 frail-ACCI, and 18,989 reference-ACCI patients. Healthy-ACCI patients were less likely to undergo RMB (7.5% versus 10.8%; p < 0.001) while frail-ACCI patients underwent RMB at similar rates (11.8% versus 10.8%; p = 0.14) compared with reference-ACCI patients. On multivariable logistic regression, in both healthy-ACCI and frail-ACCI patients, RMB was associated with decreased odds of surgical treatment, and increased odds of ablation and surveillance (all p < 0.01). In the frail-ACCI patients, higher grade disease at surgery was identified in the RMB cohort (32.9% versus 23.5%, p = 0.05). CONCLUSIONS: RMB is performed less frequently in healthy-ACCI patients compared with the reference cohort. RMB is associated with decreased odds of surgical treatment and increased odds of surveillance and ablation in all cohorts. In frail-ACCI patients who underwent surgery, RMB may provide additional risk stratification as these patients had lower rates of low-grade disease.

Bladder Cancer: A Review.

IMPORTANCE: Bladder cancer is a common malignancy in women and is the fourth most common malignancy in men. Bladder cancer ranges from unaggressive and usually noninvasive tumors that recur and commit patients to long-term invasive surveillance, to aggressive and invasive tumors with high disease-specific mortality. OBSERVATIONS: Advanced age, male sex, and cigarette smoking contribute to the development of bladder cancer. Bladder tumors can present with gross or microscopic hematuria, which is evaluated with cystoscopy and upper tract imaging depending on the degree of hematuria and risk of malignancy. Non-muscle-invasive tumors are treated with endoscopic resection and adjuvant intravesical therapy, depending on the risk classification. Enhanced cystoscopy includes technology used to improve the detection of tumors and can reduce the risk of recurrence. Patients with high-risk non-muscle invasive tumors that do not respond to adjuvant therapy with the standard-of-care immunotherapy, bacille Calmette-Guérin (BCG), constitute a challenging patient population to manage and many alternative therapies are being studied. For patients with muscle-invasive disease, more aggressive therapy with radical cystectomy and urinary diversion or trimodal therapy with maximal endoscopic resection, radiosensitizing chemotherapy, and radiation is warranted to curb the risk of metastasis and disease-specific mortality. Treatment of patients with advanced disease is undergoing rapid changes as immunotherapy with checkpoint inhibitors, targeted therapies, and antibody-drug conjugates have become options for certain patients with various stages of disease. CONCLUSIONS AND RELEVANCE: Improved understanding of the molecular biology and genetics of bladder cancer has evolved the way localized and advanced disease is diagnosed and treated. While intravesical BCG has remained the mainstay of therapy for intermediate and high-risk non-muscle-invasive bladder cancer, the therapeutic options for muscle-invasive and advanced disease has expanded to include immunotherapy with checkpoint inhibition, targeted therapies, and antibody-drug conjugates.

Melanoma-associated antigen-A and programmed death-ligand 1 expression are associated with advanced urothelial carcinoma.

BACKGROUND: Melanoma-associated antigen-A (MAGE-A) and programmed-death ligand 1 (PD-L1) are present in urothelial carcinoma (UC). We assessed survival outcomes in patients with MAGE-A and PD-L1 expression. METHODS: MAGE-A and PD-L1 expression on neoplastic cells was analyzed using tissue microarrays from patients with UC. We compared differential expression between disease stage and grade. MAGE-A and PD-L1 co-expression was subcategorized. Fisher's exact test was done for categorical variables followed by univariable and multivariable analysis of recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: Co-expression of MAGE+/PD-L1+ was higher in advanced disease; however, only MAGE+/PD-L1- was associated with shorter RFS [hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.19-2.99; p = .006]. MAGE+/PD-L1+ was associated with the worst PFS (HR 17.1; 95% CI 5.96-49.4; p ≤ .001). MAGE-A expression was more prevalent with high-grade (p = .015), and higher-stage ≥ pT2 (p = .001) disease. The 5-year RFS was 44% for MAGE+ versus 58% for MAGE- patients. On multivariable analysis, MAGE+ was also associated with shorter RFS (HR 1.55; 95% CI 1.05-2.30; p = .03). Similarly, MAGE+ was associated with shorter PFS (HR 3.12; 95% CI 1.12-8.68; p = .03). CONCLUSION: MAGE-A and PD-L1 expression is increased in advanced disease and associated with shorter PFS. Furthermore, MAGE-A expression was significantly associated with higher-grade and -stage disease and associated with shorter RFS and PFS. The worse prognosis associated with MAGE-A+/PD-L1+ provides evidence that a combinatorial treatment strategy co-targeting MAGE/PD-L1 might be feasible. Further studies are needed to validate these findings.

Second primary lung cancer in United States Cancer Survivors, 1992-2008.

PURPOSE: Lung cancer is common and lethal, and can occur in survivors of previous cancers. We sought to describe the incidence and mortality attributable to second primary lung cancers (SPLC) among survivors of other cancers, and to identify survivors at highest risk. METHODS: We identified adults diagnosed with a localized malignancy from non-pulmonary cancer sites from surveillance, epidemiology, and end results (SEER) data from 1992 to 2008. We explored factors associated with the incidence and death from SPLC using bivariable and multivariable models. Finally, we compared standardized incidence rates for SPLC in our cohort with the control arm of the National Lung Screening Trial (NLST), a randomized lung cancer screening trial. RESULTS: We identified 1,450,837 survivors of non-pulmonary cancers, of whom 25,472 developed SPLC at a mean (SD) follow-up of 5.7 (3.6) years. Over half (57%) of patients with SPLC died of the disease. Survivors of cancer of the hypopharynx, oropharynx, tonsil, and larynx, experienced SPLC at standardized incidence rates which greatly exceeded that observed in the control arm of the NLST (572/100,000 person-years). Additionally, survivors of bladder and esophageal cancer had rates that approached the NLST control arm rate. Increasing age and being divorced/widowed/separated were independent risk factors for SPLC in most primary cancer types. CONCLUSION: The incidence of SPLC in survivors of certain primary cancers greatly exceeds the rate observed in the control arm of the NLST. Further study could help determine if screening for lung cancer in these cancer survivors could prevent death from lung cancer.

Diagnostic biomarkers in non-muscle invasive bladder cancer.

Successful treatment of non-muscle invasive bladder cancer (NMIBC) relies heavily on our ability to accurately detect disease typically in the presence of hematuria as well as to detect the early recurrent tumors in patients with a history of NMIBC. Unfortunately, the current biomarker landscape for NMIBC is a work in progress. Cystoscopy continues to be the gold standard, but can still miss 10% of tumors. Therefore, physicians frequently use additional tools to aid in the diagnosis of bladder cancer, such as urinary cytology. The urinary cytology is a good option for high-grade disease; however, it is limited by low sensitivity in detecting low-grade disease, as well as variable interpretation among cytopathologists. Thus, the limitations of cystoscopy and urinary cytology have brought to light the need for more robust diagnostic assays. In this non-systematic review, we discuss the performance, potential advantages or disadvantages of these tests, and the future direction of biomarkers in NMIBC.

Treatment utilization and overall survival in patients receiving radical nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma: evaluation of updated treatment guidelines.

PURPOSE: While radical nephroureterectomy (RNU) is the gold standard treatment for upper tract urothelial carcinoma (UTUC), select patients may benefit from endoscopic treatment (ET). European Association of Urology guidelines recommend ET for patients with low-risk (LR) disease: unifocal, < 2 cm, low-grade lesions without local invasion. To inform the utility of ET, we compare the overall survival (OS) of patients receiving ET and RNU using current and previous guidelines of LR disease. MATERIALS AND METHODS: Patients with non-metastatic, cT1 or less UTUC diagnosed in 2004-2012 were collected from the National Cancer Database. OS was analyzed with inverse probability of treatment weighted Cox proportional hazard regression. Analyses were conducted for LR disease under updated (size < 2 cm) and previous guidelines (size < 1 cm). RESULTS: Patients who were older, healthier, and treated at an academic facility had higher odds of receiving ET. In 851 identified patients with LR disease, RNU was associated with increased OS compared with ET (p = 0.006); however, there was no difference between ET and RNU (p = 0.79, n = 202) under the previous guidelines (size < 1 cm). In, otherwise, LR patients, the largest tumor size with no difference between ET and RNU was ≤ 1.5 cm (p = 0.07). CONCLUSIONS: RNU is associated with improved survival when compared with ET in the management of LR UTUC using current guidelines with a size threshold of < 2 cm. In appropriately selected LR patients, we find no difference between RNU and ET up to a tumor size of ≤ 1.5 cm. However, in the absence of prospective studies, the usage of ET is best left up to clinician discretion.

SIU-ICUD consultation on bladder cancer: treatment of muscle-invasive bladder cancer.

PURPOSE: To provide a comprehensive overview and update of the Joint Société Internationale d'Urologie-International Consultation on Urological Diseases (SIU-ICUD) Consultation on Bladder Cancer for muscle-invasive presumably node-negative bladder cancer (MIBC). METHODS: Contemporary literature was analyzed for the latest evidence in treatment options, outcomes, including radical surgery, neoadjuvant and adjuvant treatment modalities, and bladder-sparing approaches. An international multi-disciplinary expert panel evaluated and graded the data according to guidelines from the Oxford Centre for Evidence-Based Medicine. RESULTS: Radical cystectomy (RC) is the standard of care for MIBC patients considered to be surgical candidates. While associated with substantial morbidity and mortality, this has been mitigated with improved technique, minimally invasive technology, and better perioperative care pathways (e.g., enhanced recovery after surgery). Neoadjuvant (NA) cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥ cT2N0 patients. Adjuvant (Adj) cisplatin-based combination chemotherapy may be considered, particularly for pT3-4 and/or pN+ disease without prior NA chemotherapy. Trimodal bladder-preserving treatment via maximum transurethral resection of bladder tumor followed by concurrent chemoradiation is safe and, when combined with early salvage RC for recurrence, offers long-term survival rates in selected patients comparable to RC. Immunotherapy is still experimental and is given either alone or in combination with chemotherapy and/or radiation. CONCLUSION: A multi-disciplinary approach is paramount to achieving optimal outcomes for MIBC patients, irrespective of their age, performance and nutritional status, fitness/frailty, renal and other organ function, or disease severity.

Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials.

PURPOSE: We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care. MATERIALS AND METHODS: We searched PubMed® for English language articles published through January 2017 using the keywords "renal cell carcinoma," "kidney cancer," "immunotherapy," "targeted therapy" and "adjuvant therapy." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included. RESULTS: Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon-α and high dose interleukin-2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence-free survival benefit of sorafenib or sunitinib over placebo, while S-TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence-free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit. CONCLUSIONS: Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S-TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated.

Trends in urinary diversion after radical cystectomy for urothelial carcinoma.

PURPOSE: To assess how trends in urinary diversion (UD) type following radical cystectomy (RC) have changed in recent years and investigate pre-operative predictors of UD type. METHODS: Data were abstracted from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2011 to 2015. We quantified the percentages of continent diversions (CD) versus incontinent diversions (ID) completed over this time frame. Using univariate and multivariable logistic regression analyses, we compared UD type across year of operation as well as predictors of type of diversion. RESULTS: We identified 4790 patients in the cohort, of which 81% underwent an incontinent diversion. Patients undergoing incontinent diversions were older (p < 0.001), more likely to be female (p < 0.001), had higher American Society of Anesthesiologists (ASA) classification (p < 0.001) and had more comorbidities with worse preoperative lab values. On multivariable analysis, the odds of incontinent diversion increased per year (OR 1.16, 95% CI 1.06-1.26; p = 0.001). Neoadjuvant chemotherapy (NAC) was associated with lower odds of receiving an ID (OR 0.33, 95% CI 0.17-0.64; p = 0.001). Being male, healthy and young were associated with higher odds of CD. CONCLUSION: We demonstrate that there has been a decrease in continent diversion use in recent years. Neoadjuvant chemotherapy, proxies of life expectancy and gender are significant predictors of continent diversion. Further investigation to determine the underlying cause of decreased utilization of CD is warranted.

Overall survival in patients with residual disease after radical cystectomy and neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been shown to improve survival in patients with urothelial carcinoma (UC). However, there are a subset of patients who do not respond or progress despite systemic treatment. METHODS: Data from the National Cancer Database on patients who underwent a radical cystectomy (RC) with or without NAC from 2006 to 2013 were abstracted. Covariates were balanced using inverse probability weighting methods. The primary outcome of overall survival in patients with residual disease by stage was evaluated using 90-day conditional landmark analysis and Cox proportional hazards modeling. Secondary outcome of predictors of residual disease was evaluated using multivariable logistic regression analysis. RESULTS: A total of 20,128 patients met our inclusion criteria; 16,058 patients underwent RC only (80%) and 4070 underwent RC with NAC (20%). Patients who received NAC were younger and healthier, treated at an academic center, and presented with higher stage. NAC was associated with improved overall survival amongst patients with cT3-4aN0 (HR 0.84 95% CI 0.73-0.97; p = 0.02) and cN+ (HR 0.70, 95% CI 0.58-0.86; p = 0.001). Predictors of no residual disease were NAC (OR 0.17, 95% CI 0.14-0.21; p < 0.001) and treatment at an academic facility (OR 0.47, 95% CI 0.37-0.60; p < 0.001). Patients with cT3-4a or cN+ had increased odds of having residual UC (OR 2.01, 95% CI 1.53-2.64; p < 0.001, and OR 2.14, 95% CI 1.43-3.21; p < 0.001, respectively) compared with cT2. CONCLUSION: In patients with residual UC, NAC is associated with a significant survival benefit in higher stage disease only. Furthermore, those treated with NAC or at an academic center were less likely to have residual disease. Given the toxicity of NAC, more prudent patient selection for NAC is warranted and requires further study.

Continuous saline bladder irrigation for two hours following transurethral resection of bladder tumors in patients with non-muscle invasive bladder cancer does not prevent recurrence or progression compared with intravesical Mitomycin-C.

BACKGROUND: Intravesical Mitomycin-C (MMC) following transurethral resection of bladder tumor (TURBT), while efficacious, is associated with side effects and poor utilization. Continuous saline bladder irrigation (CSBI) has been examined as an alternative. In this study we sought to compare the rates of recurrence and/or progression in patients with NMIBC who were treated with either MMC or CSBI after TURBT. METHODS: We retrospectively reviewed records of patients with NMIBC at our institution in 2012-2015. Perioperative use of MMC (40 mg in 20 mL), CSBI (two hours), or neither were recorded. Primary outcome was time to recurrence or progression. Descriptive statistics, chi-squared analysis, Kaplan-Meier survival analysis, and Cox multivariable regression analyses were performed. RESULTS: 205 patients met inclusion criteria. Forty-five (22.0%) patients received CSBI, 71 (34.6%) received MMC, and 89 (43.4%) received no perioperative therapy. On survival analysis, MMC was associated with improved DFS compared with CSBI (p = 0.001) and no treatment (p = 0.0009). On multivariable analysis, high risk disease was associated with increased risk of recurrence or progression (HR 2.77, 95% CI: 1.28-6.01), whereas adjuvant therapy (HR 0.35, 95% CI: 0.20-0.59) and MMC (HR 0.43, 95% CI: 0.25-0.75) were associated with decreased risk. CONCLUSIONS: Postoperative MMC was associated with improved DFS compared with CSBI and no treatment. The DFS benefit seen with CSBI in other studies may be limited to patients receiving prolonged irrigation. New intravesical agents being evaluated may consider saline as a control given our data demonstrating that short-term CSBI is not superior to TURBT alone.