Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

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.

Health-related Quality of Life After Robotic-assisted vs Open Radical Cystectomy: Analysis of a Randomized Trial.

PURPOSE: We compare health-related quality of life using a broad range of validated measures in patients randomized to robotic-assisted radical cystectomy vs open radical cystectomy. METHODS: We retrospectively analyzed patients that had enrolled in both a randomized controlled trial comparing robotic-assisted laparoscopic radical cystectomy vs open radical cystectomy and a separate prospective study of health-related quality of life. The prospective health-related quality of life study collected 14 patient-reported outcomes measures preoperatively and at 3, 6, 12, 18, and 24 months postoperatively. Linear mixed-effects models with an interaction term (study arm×time) were used to test for differences in mean domain scores and differing effects of approach over time, adjusting for baseline scores. RESULTS: A total of 72 patients were analyzed (n=32 robotic-assisted radical cystectomy, n=40 open radical cystectomy). From 3-24 months post-radical cystectomy, no significant differences in mean scores were detected. Mean differences were small in the following European Organization for Research and Treatment of Cancer QLQ-C30 (Core Quality of Life Questionnaire) domains: Global Quality of Life (-1.1; 95% CI -8.4, 6.2), Physical Functioning (-0.4; 95% CI -5.8, 5.0), Role Functioning (0.7; 95% CI -8.6, 10.0). Mean differences were also small in bladder cancer-specific domains (European Organization for Research and Treatment of Cancer QLQ-BLM30 [Muscle Invasive Bladder Cancer Quality of Life Questionnaire]): Body Image (2.9; 95% CI -7.2, 13.1), Urinary Symptoms (8.0; 95% CI -3.0, 19.0). In Urostomy Symptoms, there was a significant interaction term (P < .001) due to lower open radical cystectomy scores at 3 and 24 months. Other domains evaluating urinary, bowel, sexual, and psychosocial health-related quality of life were similar. CONCLUSIONS: Over a broad range of health-related quality of life domains comparing robotic-assisted radical cystectomy and open radical cystectomy, there are unlikely to be clinically relevant differences in the medium to long term, and therefore health-related quality of life over this time period should not be a consideration in choosing between approaches.

Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma.

PURPOSE: Vascular-targeted photodynamic therapy with the intravascular photosensitizing agent padeliporfin (WST-11/TOOKAD-Soluble) has demonstrated therapeutic efficacy as an ablative treatment for localized cancer with potential adaptation for endoscopic management of upper tract urothelial carcinoma. This Phase I trial (NCT03617003) evaluated the safety of vascular-targeted photodynamic therapy with WST-11 in upper tract urothelial carcinoma. MATERIALS AND METHODS: Nineteen patients underwent up to 2 endoscopic vascular-targeted photodynamic therapy treatments, with follow-up for up to 6 months. Patients who had residual or recurrent upper tract urothelial carcinoma (any grade/size) failing prior endoscopic treatment or unable or unwilling to undergo surgical resection were eligible for inclusion. The primary endpoint was to identify the maximally tolerated dose of laser light fluence. A dose escalation model was employed, with increasing light fluence (100-200 mW/cm) using a modified continual reassessment method. The secondary endpoint was treatment efficacy, defined by absence of visible tumor and negative urine cytology 30 days posttreatment. RESULTS: Fourteen (74%) patients received the maximally tolerated dose of 200 mW/cm, 2 (11%) of whom experienced a dose-limiting toxicity. The initial 30-day treatment response rate was 94% (50% complete, 44% partial). Eight patients underwent a second treatment, with a final observed 68% complete response rate. Leading toxicities were flank pain (79%) and hematuria (84%), which were transient. No ureteral strictures associated with treatment were identified during follow-up. CONCLUSIONS: Vascular-targeted photodynamic therapy with WST-11 has an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option for upper tract urothelial carcinoma. The recently initiated multicenter Phase 3 ENLIGHTED trial (NCT04620239) is expected to provide further evidence on this therapy.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Urethral Melanoma - Clinical, Pathological and Molecular Characteristics.

BACKGROUND: Mucosal melanoma involving the urethra is a rare disease with distinct clinical and molecular characteristics and poor outcomes. Our current knowledge is limited by the small number of reports regarding this disease. OBJECTIVE: To describe the clinical, pathological, and molecular characteristics of urethral melanoma. METHODS: We summarized the clinicopathologic data for 31 patients treated for urethral melanoma from 1986-2017 at our institution. Genomic data from our institutional sequencing platform MSK-IMPACT (n = 5) and gene-specific PCR data on BRAF, KIT, and/or NRAS (n = 8) were compared to genomic data of cutaneous melanomas (n = 143), vulvar/vaginal melanomas (n = 24), and primary non-melanoma urethral tumors (n = 5) from our institutional database. RESULTS: Twenty-three patients were diagnosed with localized disease, 7 had regional/nodal involvement and one had metastases. Initial treatment included surgery in 25 patients; seven had multimodal treatment. Median follow-up was 46 months (IQR 33-123). Estimated 5-year cancer-specific survival was 45%. No significant change in survival was observed based on a year of treatment.Primary urethral melanomas showed a higher frequency of TP53 mutations compared to cutaneous (80.0% vs. 18.2%, p = 0.006) and vulvar/vaginal melanomas (80.0 vs. 25.0%, p = 0.04). BRAF mutations were absent in urethral primaries (0% vs. 46% in cutaneous melanoma, p = 0.02). Tumor mutation burden was higher in cutaneous than urethral melanomas (p = 0.04). Urethral melanomas had a higher number of somatic alterations compared to non-melanoma urethral tumors (median 11 vs. 5, p = 0.03). CONCLUSIONS: Our findings support a unique mutational landscape of urethral melanoma compared to cutaneous melanoma. Survival remains poor and is unchanged over the time studied.

Clinical and Genomic Characterization of Bladder Carcinomas With Glandular Phenotype.

PURPOSE: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy. METHODS: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared. RESULTS: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens. CONCLUSION: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial.

PURPOSE: Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS: Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0. RESULTS: Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 (P = .3 for association between PD-L1 and < pT2N0). CONCLUSION: Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.

Health-related Quality of Life for Patients Undergoing Radical Cystectomy: Results of a Large Prospective Cohort.

BACKGROUND: Radical cystectomy (RC) has the potential for profound changes to health-related quality of life (HRQOL). OBJECTIVE: To evaluate a broad range of HRQOL outcomes in a large RC cohort. DESIGN, SETTING, AND PARTICIPANTS: A single-center prospective study enrolled RC patients from 2008 to 2014. We collected 14 separate patient-reported outcome measures at the presurgical visit and at 3, 6, 12, 18, and 24 mo after RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To visualize the patterns of recovery over time across domains, we used generalized estimating equations (GEEs) with nonlinear terms. Given substantial differences in patient selection for the type of urinary diversion, we separately modeled longitudinal HRQOL within conduit and continent diversion groups. The mean pre-RC scores were compared to illustrate the baseline HRQOL differences between diversion groups. RESULTS AND LIMITATIONS: The analyzed cohort included 411 patients (n = 205 ileal conduit, n = 206 continent diversion). At baseline, patients receiving continent diversion reported better mean physical (p < 0.001), urinary (p = 0.006), and sexual function (p < 0.001), but lower social function (p = 0.015). After RC, GEE modeling showed physical function scores decreasing 5/100 points by 6 mo, and subsequently stabilizing or returning to baseline. By 12 mo, social function improved by 10/100 points among continent diversions, while remaining stable among ileal conduits. Global quality of life exceeded baseline scores by 6 mo. Sexual function scores were low before RC, with limited recovery. Psychosocial domains were stable or improved, except for 10/100-point worsening of body image among ileal conduits. CONCLUSIONS: RC patients reported favorable HRQOL recovery within 24 mo in most areas other than body image (ileal conduits) and sexual function (both). Importantly, large measurable decreases in scores were not reported by 3 mo after RC. These contemporary outcomes and the excellent locoregional control provided by RC further support it as the gold standard therapy for high-risk bladder cancer. PATIENT SUMMARY: We review quality of life in the 24 mo following radical cystectomy. Large decreases in health-related quality of life were not reported, with most areas returning to, or exceeding, baseline, except for sexual function and body image.

Electronic Rapid Fitness Assessment Identifies Factors Associated with Adverse Early Postoperative Outcomes following Radical Cystectomy.

PURPOSE: Frailty is associated with adverse outcomes following radical cystectomy. Prospective tools to identify factors affecting outcomes are needed. We describe a novel electronic rapid fitness assessment to evaluate geriatric patients undergoing radical cystectomy. MATERIALS AND METHODS: Before undergoing radical cystectomy between February 2015 and February 2018, 80 patients older than age 75 years completed the electronic rapid fitness assessment and were perioperatively comanaged by the Geriatrics Service. Physical function and cognitive function over 12 domains were evaluated and an accumulated geriatric deficit score was compiled. Hospital length of stay, discharge disposition, unplanned intensive care unit admissions, urgent care visits, readmissions, complications and deaths were assessed. RESULTS: A total of 65 patients who underwent radical cystectomy for bladder cancer without concomitant procedures completed the assessment. Median age was 80 (77, 84) years and 52 (80%) were male. A higher proportion of patients with intensive care unit admission, urgent care visit and major complications had impairments identified within electronic rapid fitness assessment domains, including Timed Up and Go. Readmission rates were similar between patients with or without deficits identified. Higher accumulated geriatric deficit score was significantly associated with intensive care unit admission (p=0.035), death within 90 days (p=0.037) and discharge to other than home (p=0.0002). CONCLUSIONS: We demonstrated the feasibility of assessing fitness in patients older than 75 years undergoing radical cystectomy using a novel electronic fitness tool. Physical limitations and overall impairment corresponded to higher intensive care unit admission rates and adverse postoperative outcomes. Larger studies in less resourced environments are required to validate these findings.

Goal-directed versus Standard Fluid Therapy to Decrease Ileus after Open Radical Cystectomy: A Prospective Randomized Controlled Trial.

BACKGROUND: Postoperative ileus is a common complication of intraabdominal surgeries, including radical cystectomy with reported rates as high as 32%. Perioperative fluid administration has been associated with improvement in postoperative ileus rates, but it is difficult to generalize because earlier studies lacked standardized definitions of postoperative ileus and other relevant outcomes. The hypothesis was that targeted individualized perioperative fluid management would improve postoperative ileus in patients receiving radical cystectomy. METHODS: This is a parallel-arm, double-blinded, single-center randomized trial of goal-directed fluid therapy versus standard fluid therapy for patients undergoing open radical cystectomy. The primary outcome was postoperative ileus, and the secondary outcome was complications within 30 days post-surgery. Participants were at least 21 yr old, had a maximum body mass index of 45 kg/m and no active atrial fibrillation. The intervention in the goal-directed therapy arm combined preoperative and postoperative stroke volume optimization and intraoperative stroke volume variation minimization to guide fluid administration, using advanced hemodynamic monitoring. RESULTS: Between August 2014 and April 2018, 283 radical cystectomy patients (142 goal-directed fluid therapy and 141 standard fluid therapy) were included in the analysis. Postoperative ileus occurred in 25% (36 of 142) of patients in the goal-directed fluid therapy arm and 21% (30 of 141) of patients in the standard arm (difference in proportions, 4.1%; 95% CI, -5.8 to 13.9; P = 0.418). There was no difference in incidence of high-grade complications between the two arms (20 of 142 [14%] vs. 23 of 141 [16%]; difference in proportions, -2.2%; 95% CI, -10.6 to 6.1; P = 0.602), with the exception of acute kidney injury, which was more frequent in the goal-directed fluid therapy arm (56% [80 of 142] vs. 40% [56 of 141] in the standard arm; difference in proportions, 16.6%; 95% CI, 5.1 to 28.1; P = 0.005; P = 0.170 after adjustment for multiple testing). CONCLUSIONS: Goal-directed fluid therapy may not be an effective strategy for lowering the risk of postoperative ileus in patients undergoing open radical cystectomy.

Primary urethral cancer: treatment patterns and associated outcomes.

OBJECTIVES: To evaluate treatment patterns and associated outcomes of patients with urethral cancer. PATIENTS AND METHODS: After obtaining institutional review board approval we identified 165 patients treated for primary urethral cancer between 1956 and 2017. Treatment included monotherapy (surgery or radiation), dual therapy (surgery+radiation, surgery+chemotherapy, or chemotherapy+radiation) or triple therapy (surgery+radiation+chemotherapy). Rates of different treatments were described by treatment year. The association between treatment type and outcomes was evaluated with multivariable Cox regression models, adjusting for disease characteristics. RESULTS: The study cohort included 74 men and 91 women, with a median age of 61 years. Common histologies were squamous cell (36%), urothelial (27%) and adenocarcinoma (25%). At presentation, 72% of patients had invasive disease, 24% had nodal involvement, and 5% had metastases. Treatment included monotherapy (57%), dual therapy (21%), and triple therapy (10%). The use of monotherapy decreased over time, while rates of dual therapy remained consistent, and rates of triple therapy increased. The median follow-up was 4.7 years. Estimated 5-year local recurrence-free, disease-specific and overall survival were 51%, 48% and 41%, respectively. Monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex and year of treatment (P = 0.017). There was no evidence that treatment type was associated with distant recurrence, cancer-specific or overall survival. CONCLUSIONS: We found preliminary evidence that multimodal therapy, more commonly used in recent years, was of benefit in patients with primary urethral cancer. This finding should be confirmed in further studies involving multiple centres because of the low incidence of the disease.

The Outcome of Post-Chemotherapy Retroperitoneal Lymph Node Dissection in Patients with Metastatic Bladder Cancer in the Retroperitoneum.

PURPOSE: While a definitive cure can be achieved by radical cystectomy and pelvic lymph node dissection in select patients with regional lymphadenopathy, the benefit remains uncertain in patients who present with non-regional metastases. We analyzed the survival outcomes of post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: We reviewed our institutional database and identified 13 patients with radiographically evident or biopsy proven retroperitoneal nodal metastases with a significant response to chemotherapy. These patients underwent consolidative surgery with concomitant or delayed retroperitoneal lymph node dissection. The primary endpoints were progression-free survival and disease-specific survival from the time of retroperitoneal lymph node dissection. RESULTS: All patients had primary urothelial cell carcinoma. Twelve patients underwent concomitant radical cystectomy, pelvic and retroperitoneal lymph node dissection. Seven patients (54%) had residual disease in the retroperitoneum and the median number of retroperitoneal nodes containing metastases was 4 (IQR 2-6). Six (86%) developed disease recurrences within 2 years of surgery and 5 (71%) died of cancer. Of the 6 patients without residual disease in the retroperitoneum, 2 (33%) developed recurrences and died of disease progression. The 2-year disease-specific survival was worse for patients with residual disease in the retroperitoneum than those without residual retroperitoneal disease (34%, 95% CI 5-68 vs 50%, 95% CI 6-85). CONCLUSIONS: The presence of retroperitoneal nodal metastases at post-chemotherapy retroperitoneal lymph node dissection is a poor prognosticator. Consolidative surgery with retroperitoneal lymph node dissection provides important prognostic information and may be therapeutic in a very small subset of these patients.

Propensity-matched analysis of patient-reported outcomes for neoadjuvant chemotherapy prior to radical cystectomy.

PURPOSE: To evaluate patient-reported outcomes (PROs) for bladder cancer patients undergoing neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) using longitudinal data and propensity-matched scoring analyses. METHODS: 155 patients with muscle-invasive bladder cancer scheduled for RC completed the European Organization for Research and Treatment of Cancer questionnaires, EORTC QLQ-C30, EORTC QLQ-BLM30, Fear of Recurrence Scale, Mental Health Inventory and Satisfaction with Life Scale within 4 weeks of surgery. A propensity-matched analysis was performed comparing pre-surgery PROs among 101 patients who completed NAC versus 54 patients who did not receive NAC. We also compared PROs pre- and post-chemotherapy for 16 patients who had data available for both time points. RESULTS: In propensity-matched analysis, NAC-treated patients reported better emotional and sexual function, mental health, urinary function and fewer financial concerns compared to those that did not receive NAC. Longitudinal analysis showed increases in fatigue, nausea and appetite loss following chemotherapy. CONCLUSION: Propensity-matched analysis did not demonstrate a negative effect of NAC on PRO. Several positive associations of NAC were found in the propensity-matched analysis, possibly due to other confounding differences between the two groups or actual clinical benefit. Longitudinal analysis of a small number of patients found small to modest detrimental effects from NAC similar to toxicities previously reported. Our preliminary findings, along with known survival and toxicity data, should be considered in decision-making for NAC.

Comparison of Postradical Cystectomy Ileus Rates Using GIA-80 Versus GIA-60 Intestinal Stapler Device.

OBJECTIVE: To assess the impact on recovery of bowel function using an 80 mm versus 60 mm gastrointestinal anastomosis (GIA) stapler following radical cystectomy and urinary diversion (RC/UD) for bladder cancer. METHODS: We identified 696 patients using a prospectively maintained RC/UD database from January 2006 to November 2010. Two nonrandomized consecutive cohorts were compared. Patients between January 2006- and December 2007 (n = 180) were treated using a 60 mm GIA stapler, and 331 patients between January 2008 and December 2010 were subject to an 80 mm GIA stapler. All patients were treated on the same standardized postoperative recovery pathway. After accounting for baseline patient and perioperative characteristics, using a multivariable logistic regression model, we directly compared rates of postoperative ileus using a standardized definition. RESULTS: Of 511 evaluable patients, ileus was observed in 32% (57/180) for 60 mm GIA versus 33% (110/331) for the 80 mm GIA. Preoperative renal function, age, gender, body mass index, and type of diversion were comparable between cohorts. On multivariate analysis, stapler size was not significantly associated with the development of ileus (GIA-60 vs GIA-80: OR 1.11; 95% CI 0.75, 1.66; P = .6). Positive fluid balance was associated with an increased risk (P = .019) and female sex a decreased risk (P = .008) of developing ileus compared to patients with negative fluid balance. CONCLUSION: The size of the intestinal bowel anastomosis (GIA 80 mm vs 60 mm) does not independently impact the time to bowel recovery following RC/UD.

Multicenter Prospective Phase II Trial of Neoadjuvant Dose-Dense Gemcitabine Plus Cisplatin in Patients With Muscle-Invasive Bladder Cancer.

Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m2 on day 1 and cisplatin 35 mg/m2 on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.

Intratumoral heterogeneity of ERBB2 amplification and HER2 expression in micropapillary urothelial carcinoma.

Micropapillary urothelial carcinoma (MPUC) is a rare but an aggressive variant of urothelial carcinoma. MPUC has been shown to commonly exhibit ERBB2 amplification and HER2 protein overexpression, but the frequency and distribution of these findings within micropapillary (MP) and not otherwise specified (NOS) components of tumors with mixed histology have not been addressed. Therefore, we evaluated ERBB2 amplification and HER2 expression in 43 MPUC cases by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Of the 35 tumors containing both MP and NOS components, ERBB2 amplification was present in both the MP and NOS components of 12 tumors (34.3%), in only the MP component of 11 tumors (31.4%), and exclusively in the NOS component of 4 tumors (11.4%). HER2 protein overexpression was significantly more commonly present in the MP component compared to the NOS component within the same tumor (68.6% versus 34.3%, P = .012). Overall, there was a moderately positive correlation between HER2 protein expression and ERBB2 amplification in both MP (ρ = 0.59, P < .001) and NOS (ρ = 0.70, P < .001) components. All MP/NOS areas with IHC score 3+ and none of MP/NOS areas with IHC score 0 were associated with ERBB2 amplification. We conclude that ERBB2 amplification and HER2 overexpression are preferentially but not exclusively identified in the MP component compared to the NOS component within the same tumor. Our findings identify the presence of intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC and provide grounds for further investigation into the mechanisms underlying the development of MPUC.

Is restaging transurethral resection necessary in patients with non-muscle invasive bladder cancer and limited lamina propria invasion?

OBJECTIVES: To evaluate the influence of lamina propria invasion type at initial transurethral resection (TUR) on restaging pathology. MATERIALS AND METHODS: We reviewed prospectively maintained records of all patients with a high-grade pT1 nonmuscle invasive bladder cancer who underwent both initial and restaging TUR within 6 weeks at our center between 2001 and 2016. The pathology of second TUR specimens was analyzed with regard to the characteristics of lamina propria invasion found at initial resection. RESULTS: We included 198 patients, with a median age of 70 years (interquartile range: 63-79). Muscle was present in the initial TUR specimen in 107 patients (54%). Pathology restaging was pT0 in 73 patients (37%), pTis in 44 (22%), pTa in 27 (14%), pT1 in 50 (25%), and pT2 in 4 (2%). Eighty-seven patients (44%) had tumors with minimal lamina propria invasion at initial TUR: 53 specimens (27%) had focal invasion (few malignant cells in the lamina propria); 15 specimens (7.6%) had superficial invasion (invasion of the lamina propria to the level of the muscularis mucosae [T1a]); and 19 specimens (10%) had multifocal superficial invasion (multiple areas of T1a). Of the patients with minimal lamina propria invasion, residual disease was found in 54 patients (62%). However, none of those patients had T2 disease. CONCLUSIONS: A significant number of patients with T1 tumors have residual disease at restaging TUR as do patients with minimal lamina propria invasion. The extent of T1 invasion does not eliminate the need for repeat TUR.