Urothelial Histology Research Articles

Unexpected Early Oncologic Mortality after Open Radical Cystectomy for Bladder Cancer: Who Is to Be Blamed?

Purpose: To investigate prevalence and variables associated with early oncologic mortality (EOM; within ≥30 to ≤90 days) of open radical cystectomy (RC) for bladder cancer. The unexpected rapidity of tumour recurrence and the huge metastatic burden of these patients drew us to analyse this cohort. Methods: We reviewed our RC database. All 1,487 patients were treated with curative intent between January 1986 and December 2008. Imaging for staging was done by CT (chest) and CT or MRI (abdomen). Clinical and histopathological variables were recorded until death to determine whether disease- or treatment-related factors were associated with mortality. Results: There were 93 deaths within 90 days of surgery. Twenty-four patients died from early progression to high volume disseminated metastatic disease. Group 1: unresectable tumours, which were never free of disease. Group 2: resectable tumours, considered tumour-free after RC. Group 1 is characterized by local tumour spread and a low distant failure rate. Group 2 has a low local and a high distant failure rate. Conclusions: Disease related (advanced tumour stage, positive soft tissue surgical margins (+STSM), non urothelial histology, unresectable tumours, atypical occult metastasis), rather than technical factors, had the leading role in EOM. Understaging was universal.

Stereotactic Body Radiotherapy for Large Primary Renal Cell Carcinoma: A Report from the International Radiosurgery Oncology Consortium for Kidney (IROCK)

Thermal ablation is an established option for small renal cell carcinomas (RCC). However, patients with larger (T1b, >4cm) RCC not suitable for surgery have few treatment options as thermal ablation is less effective in this setting. We hypothesize that SBRT has similar local efficacy (>90%) in larger RCC to that of small RCC. Individual patient data from nine IROCK institutions in Germany, Australia, USA, Canada, and Japan were pooled. Outcomes from larger RCC were compared to small RCC. Patients with metastatic disease or urothelial histology were excluded from the database (n=31). Demographics, treatment, oncologic and renal function outcomes were compared between cohorts using the Chi-square test, Fisher’s exact test, two-sample T-test, or Wilcoxon rank sum test as appropriate. Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards regression were generated for oncologic outcomes. There were 95 patients with larger RCC identified from 192 eligible patients. Median follow up was 2.5 years. Median tumor size in the larger RCC group was 4.9 cm compared to 2.9 cm in the small RCC group. In the overall cohort, normal renal function (eGFR>90mL/min) at baseline was recorded in 9.0% of patients, with 26% having moderate to severe dysfunction (eGFR <45mL/min). Patients with large RCC were of poorer performance status (ECOG 0-1 in 81.1% vs. 93.8%, p = 0.008) and were older (mean age: 75 years vs. 69 years, p < 0.001). Toxicities ≥ grade 2 occurred in 12 patients (6.3%) with no differences in toxicity rates between cohorts (p = 0.526). Median baseline eGFR was lower in the larger RCC cohort (59.0mL/min vs. 68.5 mL/min, p = 0.013), and demonstrated a median reduction post-SBRT of -5.8 v mL/min versus -2.9 mL/min, p = 0.073). There were 8 recurrences (8.4%) in larger RCCs, compared to 1 recurrence (1.0%) in the small RCC cohort. Local control at 1-year was 100% in both cohorts, and at 3-years was similar at 96.6% vs. 98.5%, respectively (log-rank p = 0.512). Distant control was worse in larger RCC at 1- and 3-years, at 97.8% vs. 100% and 87.0% vs. 100% respectively (log-rank p = 0.006). Cancer-specific survival (CSS) at 3-years was 91.4% versus 96.2% (log-rank p = 0.224). Overall survival (OS) at 3-years was 72.3% vs. 84.6% (log-rank p = 0.294). On multivariable analysis, higher pre-SABR creatinine (hazard ratio [HR] per 10 μmol/L: 1.08, p = 0.002) and poor performance status (HR: 3.85, p = 0.004) were associated with inferior OS. Increasing tumor size (HR per 1 cm: 1.18, p = 0.028) was associated with inferior CSS. SBRT for larger RCC appears tolerable and similarly locally effective as in small RCC, although associated with a higher likelihood of metastatic progression and death. Efforts to reduce risk of distant recurrence, such as adjuvant systemic therapy, should be further investigated.

Utilization and outcomes of adjuvant radiation therapy after cystectomy for urothelial carcinoma.

487 Background: Positive surgical margins with radical cystectomy for invasive urothelial cancer are associated with adverse prognosis. In non-metastatic patients, adjuvant radiation therapy (ART) is sometimes employed for patients with positive margins or locally advanced stage. However, evidence for benefit of ART in these patients to improve survival is limited. In this study, using a national database we investigate the factors associated with use of ART and its impact of the overall survival. Methods: National Cancer Database was queried for patients who underwent radical cystectomy from 2004-2013 for invasive urothelial cancer. Inclusion criteria were urothelial histology, pT2 stage with positive surgical margins or ³pT3 , and no evidence metastasis. Patients with regional or distant metastasis or patient who underwent adjuvant chemotherapy were excluded. Univariate and multivariate analysis performed to assess the factors associated with the use of ART. Overall survival was compared using log rank test. Results: In total, 18,828 patients met the inclusion criteria, of which 359 (1.91%) underwent ART. Mean duration between radical cystectomy and ART was 4.4 months. On univariable analysis, Black or Hispanic race, Medicare/Medicaid insurance status, treatment at community health center, ileal conduit diversion, advanced pathological stage (pT3/T4) were associated with higher use of ART (all p&lt;0.005). On multivariate analysis community health facility and adequate lymph node dissection (&gt;10 lymph nodes excision) were associated with use of ART (all p&lt;0.05) (see table). The use of ART was not associated with improved overall survival. Conclusions: The utilization of ART after radical cystectomy for urothelial carcinoma is low. The benefit of ART on the overall survival is not clear and would need further investigation. [Table: see text]

Randomized phase III trial of adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer after radical cystectomy: Urothelial carcinoma subgroup analysis.

351 Background: The role of post-operative chemotherapy after radical cystectomy (RC) is not well-defined. While some retrospective studies have shown a benefit, trials have been under-powered. In a phase III Egyptian trial, we evaluated the benefit of adjuvant chemo in locally advanced bladder cancer (LABC) patients treated with post-operative radiotherapy (PORT). In this study, we report a post-hoc subgroup analysis of patients with urothelial histology. We hypothesized that the addition of adjuvant chemo would improve disease-free survival (DFS) compared to PORT alone for LABC. Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC &amp; accrued from 2002–2008 at the NCI in Cairo. Bladder cancer pts ≤70 with at least one of the following factors (≥pT3b, grade 3, positive nodes) with negative margins after RC plus pelvic node dissection were eligible. RT was delivered using 3-D conformal RT to the pelvis to 45Gy in 1.5Gy BID. Chemo+PORT included 2 cycles of gemcitabine/cisplatin before &amp; after RT. The primary endpoint was DFS. Secondary endpoints included overall survival (OS) &amp; late GI toxicity. Results: 153 pts were enrolled. 53% had urothelial carcinoma (41 chemo+PORT &amp; 40 PORT). In the urothelial cohort, the arms were well-balanced. Median age was 55. Median follow-up was 21 months for chemo+PORT (range 4-127) &amp; 15 months for PORT (range 5-70). There were 2 local failures for PORT &amp; none for chemo+PORT. Two-year DFS for chemo+PORT vs. PORT was 62% (95% CI 53-71%) &amp; 48% (95% CI 39-58%), log-rank p=0.031. Two-year OS was 71% (95% CI 63-80%) &amp; 51% (95% CI 40-61%), log-rank p=0.048. On multivariable analysis, chemo+PORT was a significant predictor of improved DFS (HR 0.42 95% CI 0.21-0.85, p=0.016) and OS (HR 0.45, 95% CI 0.21-0.96, p=0.039). In the entire cohort, late grade ≥3 GI toxicity was observed in 5 chemo+PORT patients (7%) &amp; 6 PORT patients (8%). Conclusions: The addition of adjuvant chemo to PORT improved DFS &amp; OS for LABC after RC with acceptable late GI toxicity. The results suggest a role for adjuvant therapies to address both local &amp; distant disease. Clinical trial information: 01734798.

Comparative analyses of trends and survival in patients with urothelial versus nonurothelial bladder carcinoma: National Cancer Database (NCDB) analysis.

402 Background: Bladder cancer is estimated to occur in 81,190 patients in 2018 with estimated death in 17,240. Urothelial cancers make up the majority of cancers but non-urothelial cancers are known to have more aggressive phenotype with worse survival. We have demonstrated previously that non-urothelial histologic subtypes have worse survival outcomes compared to urothelial cancers in a population-based analysis (Aragon-Ching J et al.; J Clin Oncol 36, 2018 (suppl 6S: abstr 425). Methods: The primary objective of this review is to gather data on trends and differences between urothelial versus non-urothelial histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) and compare the demographics, disease characteristics (incidence of metastases, stage presentation, etc), and survival according to the NCDB. Results: Data from diagnosis in year 2004 – 2013 were extracted from the NCDB. A total of 76,858 and 5560 patients were included for urothelial and non-urothelial, respectively. More men were diagnosed with urothelial carcinoma (75%) and non-urothelial carcinoma (61%) than women. The median age was 71 years and 69 years of age, respectively for urothelial and non-urothelial. Majority were Caucasian at 91% and 86%, respectively though there seemed to be more African-Americans in the non-urothelial (11%) compared to 6% in the urothelial cohorts. More patients were diagnosed with higher stages of III and IV in the non-urothelial group (62%) compared to 36% in the urothelial group, although the sites of metastases in the brain, bone or liver were fairly equivalent for both urothelial and non-urothelial cohorts. Median survival time from diagnosis was better in the urothelial compared to non-urothelial arms [69.91 (69.39 – 70.54) vs 64.53 (61.5 – 67.45 months), p-value &lt; 0.001]. Conclusions: Non-urothelial cancers have distinct demographics different from non-urothelial cancers. Patients often present at a higher stage and survival appears to fare worse than urothelial cancers. Further studies to refine treatment options to optimize treatment outcomes are an area of increased unmet need.

Impact of pure versus mixed metastatic urothelial carcinoma (mUC) histology on response with immune checkpoint inhibitors (ICIs).

479 Background: PD1/PD-L1 inhibitors have been evaluated in trials enrolling patients (pts) with pure urothelial or mixed urothelial histology containing non-urothelial components. However, any differential impact of pure vs. mixed urothelial histology on ICI benefit is unclear. We conducted a retrospective study to evaluate the impact of pure vs. mixed urothelial carcinoma histology on outcomes with ICIs in pts with metastatic urothelial carcinoma (mUC). Methods: We obtained data from 120 pts with mUC from a single institution (DFCI) who received ICI therapy. Demographic, clinical variables and outcomes (overall response rate [ORR], overall survival [OS]) were collected. Histology was reviewed at DFCI for all pts and recorded as pure urothelial if only urothelial carcinoma was seen or mixed urothelial if components of any other histology were observed in addition to urothelial. A Cox regression analysis was done to study the association of prognostic variables and histology with objective response. Results: Data was obtained from 120 pts, of whom 110 (91.7%) received a single agent PD1/PD-L1 inhibitor (pembrolizumab=58, atezolizumab=52, nivolumab=4, nivolumab + ipilimumab=3, nivolumab + vaccine=2, durvalumab+tremelimumab=1). The median age was 66, 70.8% were male and 72.5% had received prior chemotherapy. 79 (65.8%) tumors originated from the bladder, 39 (32.5%) from the upper tract, 2 (1.67%) had unknown site of origin. 91 (76.6%) had pure urothelial and 28 (23.3%) had mixed urothelial histology. On univariable analysis, pure vs. mixed urothelial histology was not associated with response (HR 1.52 [95% CI 0.59-3.98, p=0.39]). On multivariable analysis, upper tract vs. bladder primary (HR 3.06 [95% CI 1.10-8.49], p=0.032) and higher blood neutrophil to lymphocyte ratio (HR 0.35 [95% CI 0.17-0.72], p=0.004) were associated with lower response rate. Conclusions: In this hypothesis-generating study, pure vs. mixed urothelial carcinoma histology did not appear to significantly impact response to ICI therapy for mUC. The impact of proportion of non-urothelial histology, pure non-urothelial histology and site of primary on response warrants further study.

Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook.

Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC.

Perioperative and mid-term oncologic outcomes of robotic assisted radical cystectomy with totally intracorporeal neobladder: Results of a propensity score matched comparison with open cohort from a single-centre series

In this study, we compared perioperative and oncologic outcomes of patients treated with either open or robot-assisted radical cystectomy and intracorporeal neobladder at a tertiary care center. The institutional prospective bladder cancer database was queried for "cystectomy with curative intent" and "neobladder". All patients underwent robot-assisted radical cystectomy and intracorporeal neobladder or open radical cystectomy and orthotopic neobladder for high-grade non-muscle invasive bladder cancer or muscle invasive bladder cancer with a follow-up length ≥2 years were included. A 1:1 propensity score matching analysis was used. Kaplan-Meier method was performed to compare oncologic outcomes of selected cohorts. Survival rates were computed at 1,2,3 and 4 years after surgery and the log rank test was applied to assess statistical significance between the matched groups. Overall, 363 patients (299 open and 64 robotic) were included. Open radical cystectomy patients were more frequently male (p=0.08), with higher pT stages (p=0.003), lower incidence of urothelial histologies (p=0.05) and lesser adoption of neoadjuvant chemotherapy (<0.001). After applying the propensity score matching, 64 robot-assisted radical cystectomy patients were matched with 46 open radical cystectomy cases (all p≥0.22). Open cohort showed a higher rate of perioperative overall complications (91.3% vs 42.2%, p0.001). At Kaplan-Meier analysis robotic and open cohorts displayed comparable disease-free survival (log-rank p=0.746), cancer-specific survival (p=0.753) and overall-survival rates (p=0.909). Robot-assisted radical cystectomy and intracorporeal neobladder provides comparable oncologic outcomes of open radical cystectomy and orthotopic neobladder at intermediate term survival analysis.

Cabozantinib (CABO) plus durvalumab (DURVA) in patients with advanced and chemotherapy-treated bladder carcinoma of urothelial and non-urothelial histology: An open-label, single-arm, phase 2 trial.

TPS536 Background: DURVA and CABO have shown single-agent activity in patients (pts) with urothelial carcinoma (UC). Their combination may result in prolonging overall survival (OS) in pts who have failed prior platinum-based chemotherapy (CT). Additionally, DURVA+CABO may be an effective combination for treating subgroup of pts like those with bone metastases only (not having RECIST-measurable disease) or with non-UC histology. Methods: In an open-label, single-arm, multicenter, phase 2 trial, pts will assume CABO 40 mg daily, orally, and will be administered DURVA 1500 mg, intravenously, q28 days, until disease progression (PD, RECIST 1.1) or onset of unacceptable toxicity. Treatment beyond PD is not allowed. Key inclusion criteria: ECOG-PS 0-1, bladder or upper tract primary tumor, UC and non-UC histology, failure of 1 or 2 platinum-based CT for metastatic disease (2nd-to-3rd line only). Neoadjuvant/adjuvant CT is counted if relapse occurred ≤6 months (m) of the last CT cycle. Response is evaluated by RECIST criteria v.1.1 q2 cycles. The primary endpoint of the study is OS. The target is to detect an improvement in median OS from ≤6m (H0) to ≥9m(H1). To achieve 90% power with a one-sided non-parametric test at 5% significance, 122 pts must will be accrued over 36m and follow-up may be closed 12m after the end of accrual. PD-L1 expression will be assessed using with the Ventana SP142 assay, and categorized as high (≥25% of tumor cells [TC] or immune cells [IC]) or low/negative ( &lt; 25% TC or IC). The decision on whether or not to undertake PD-L1+ cohort expansion will be based on predictive power (PP) calculation: a PP ≥30% will be regarded as promising and necessary to continue. An interim analysis is planned after 24m (50% expected events). This analysis will be based on PP. The criterion for stopping the trial because of futility will be a PP &lt; 20%. Analyses on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). FDG-PET response in bone metastases will represent another translational endpoint (EudraCT number 2017-000580-32). Clinical trial information: 2017-000580-32.

Atezolizumab (atezo) and subsequent therapies in patients (Pts) with metastatic urothelial carcinoma (mUC) outside clinical trials.

432 Background: The use of immune checkpoint inhibitors (ICI) has revolutionized treatment of mUC. Little is known about the outcomes and safety profile of pts treated with ICI outside of clinical trials, as well as about responses to subsequent therapies. Methods: A retrospective analysis of consecutive mUC pts who received ≥1 dose of atezo 1200 mg every 3 weeks from May 2016 through April 2017 was conducted. Exploratory assessments included overall response rate according to RECIST v1.1, progression-free survival (PFS) and overall survival (OS) since time of treatment initiation, and treatment-related adverse events (TRAE) according to CTCAE v4.03. Results: A total of 79 pts were identified; median age 72 (29-93), 71% men, 27% never smokers, 66% pure urothelial histology, 49% visceral disease, 76% ECOG PS 0-1 and 61% with 1-2 Bellmunt risk factors. Most pts (79%) had primary tumor in bladder, 62% prior surgery and 75% ≥ 1 prior treatment. Most pts (71%) had 1-2 prior lines of treatment, 4% of pts had 3 lines, and 25% of pts had no prior systemic treatment. Pts received a median of 4 atezo doses (1-18) and median treatment duration was 3.2 months (95%CI 1.9-4.5). In 55 pts evaluable for response, 25% had partial response, 36% stable disease and 38% progressive disease, with a median time to best response of 2.7 months (1.3-7.4) and median PFS 4.5 months (95%CI 3.4-5.6). Estimated OS for the entire cohort was 8.3 months (median not reached) and was not significantly different based on prior therapy. TRAE of any grade were noted in 89% of pts and mostly included fatigue (63%) and anorexia (28%). Two pts had grade 4 hyperbilirubinemia, and no toxic deaths were noted. At time of data analysis, 34% of pts remained on atezo, 16% received 1-2 subsequent treatments with median duration of 1.3 months ( 95%CI 0.5-2.2) and 8% PR as best response, 41% were referred to hospice or died, and 9% were lost to follow-up. Conclusions: Pts with mUC treated with atezo had comparable outcomes and toxicity to those reported in clinical trials. Pts who progressed on atezo were unlikely to receive subsequent treatment and the benefit of such treatment was limited. Results may impact clinical trial designs and timing in regard to ICI.

Propensity matched comparative analysis of survival following chemoradiation or radical cystectomy for muscle‐invasive bladder cancer

To compare survival outcome between chemoradiation therapy (CRT) and radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). We conducted a retrospective analysis of patients with MIBC (≥cT2, N0, M0) in the National Cancer Database (2004-2013). CRT was defined as a radiation dose of ≥40Gy and chemotherapy within 90days of radiation. Descriptive statistics were used to compare groups. RC and CRT patients were propensity matched. Kaplan-Meier analysis was used to compare overall survival (OS). Multivariable Cox regression was used to determine predictors of survival. In all, 8379 (6606 RC and 1773 CRT) patients met the inclusion criteria and 1683 patients in each group were propensity matched. On multivariable extended Cox analysis, significant predictors of decreased OS were age, Charlson-Deyo Comorbidity score of 1, Charlson-Deyo Comorbidity score of 2, stage cT3-4, and urothelial histology. CRT was associated with decreased mortality at year 1 (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.74-0.96; P = 0.01), but at 2years (HR 1.4, 95% CI 1.2-1.6; P < 0.001) and 3years onward (HR 1.5, 95% CI 1.2-1.8; P < 0.001) CRT was associated with increased mortality. The 5-year OS was greater for RC than for CRT (38% vs 30%, P = 0.004). Initially after treatment for MIBC the risk of mortality is lower with CRT compared to RC. However, at ≥2years after treatment the mortality risk favours RC. Patients who are suitable surgical candidates, with a low risk of morbidity, may be better served by RC.

The association between variant urothelial histologies, pathological stage and disease specific survival in patients with bladder cancer.

We aimed to compare the oncological outcomes of patients with variant urothelial histologies (VH) with pure urothelial histology (PUH) in bladder cancer (BC) patients. This study includes 223 patients who underwent radical cystectomies (RCs) between September 2006 and July 2016 with complete follow-up data A retrospective screening was performed to identify the patients with PUH and VH. The primary outcomes of interest were pathological stage of disease at RC and disease-specific survival (DSS). For comparison of categorical variables, Fisher's exact test and Pearson chi- square and for continuous variables Wilcoxon rank-sum and Mann-Whitney U tests were used. Kaplan-Meier (KM) method was used for survival analysis and log-rank test was used for comparison of survival rates. Predictors of survival were detected with mulitivariable Cox-proportional hazards model including the variables such as gender, age, existence of VH, lymph node dissection (LND) type and pathological stage of the disease. A moderate-degree correlation was detected between VH and pathological stages of RC (r=0.45, p<0.001). In PUH group, 39 (25.8%) of 151 patients died after a median follow-up of 20 (0-107) months; whereas 37 (51.4%) of 72 patients with VH died after a median follow-up of 16.5 (0-104) months (p<0.001). In terms of pathological stage, the number of patients with PUH and VH were at stages pT0-2 (n=100; 66.2% vs. n=19; 26.4%), pT3-4 (n=35; 23.2% vs. 38; 52.8%, and in 16 (10.6%) and 15 (20.8%) patients with LN positivity, respectively (p<0.001). KM survival analysis revealed a significantly decreased DSS in patients with VH compared to PUH (p<0.001). Meanwhile, pathological disease stage and existence of VH were found to be associated with decreased DSS in the multivariate model. The present study revealed that VH is associated with advanced pathological tumor stage at RC and decreased DSS compared to patients with PUH in patients with BC.

Predicting local failure after radical cystectomy in patients with bladder cancer: Implications for the selection of candidates at adjuvant radiation therapy

To evaluate incidence and predictors of local failure (LF) after radical cystectomy (RC) due to bladder cancer. We focused on 1,112 patients treated with RC, between 1990 and 2012, at a single center. LF was defined as imaging evidence of recurrence in the pelvic soft tissues or nodes below the aortic bifurcation at least 3 months before the detection of distant metastases. Competing risk analyses tested the relationship between clinical and pathological factors and the risk to develop LF. Regression tree analysis stratified patients into risk-groups based on their characteristics and the corresponding LF rate. Overall, 50 (4.5%) patients developed LF during a median follow-up period of 62 (35-92) months. On univariable competing risk regression analyses, pathological T stage (pT4 vs. pT3; hazard ratio [HR] = 2.55, P = 0.003), soft tissue surgical margin (STSM; HR = 2.95, P = 0.005), and variant histology (HR = 1.79, P = 0.03) were associated with an increased risk of developing LF. The cohort was stratified into 4 risk groups: very low (≤pT3a disease and pure urothelial histology), low (≤pT3a disease and variant histology), intermediate (pT4 disease), and high (positive STSM). LF is an important event in RC patients. We developed a new risk model based on bladder cancer characteristics. Our findings could help with the identification of the best candidate for consideration of adjuvant radiotherapy.

High dose-rate Intra-Operative Radiation Therapy During High Risk Genitourinary Surgery: Initial Observations and a Proposal for its Study in Bladder Cancer.

Background:High dose-rate Intra-Operative Radiation Therapy (HD-IORT) is used to provide effective local control for patients with high-risk locally advanced or recurrent tumors. However, the utility of HD-IORT for patients with bladder cancer has not been studied.Objective:To characterize our institutional experience with HD-IORT in patients with cancer requiring genitourinary surgery, in an effort to identify patients with bladder cancer that may benefit from HD-IORT.Methods:We performed a retrospective review of all patients who have undergone HD-IORT during genitourinary surgery at our institution. Patients were stratified by surgical margin status, and primary outcomes assessed were overall survival, recurrence free survival and 90-day complications. Patients undergoing cystectomy and HD-IORT with sarcomatoid urothelial cancer were compared to a similar cohort undergoing cystectomy alone. A sample case of one such patient is discussed in detail.Results:84 patients at our institution have undergone HD-IORT with genitourinary surgery. Positive surgical margin status was the greatest predictor of both OS (HR = 3.42) and RFS (HR = 2.61). The overall 90-day complication rate was 61%, with wound infections (43%) and GI complications (21%) being most common. 4 of these patients had sarcomatoid urothelial histology, and all are still alive with >2 yrs follow up. This compares to a 52% 1 yr survival in our sarcomatoid urothelial cohort (25 pts) that did not undergo HD-IORT.Conclusions:Our institutional experience with HD-IORT has been promising, particularly among patients with locally advanced disease and sarcomatoid histology. We are currently enrolling patients in a multi-institutional registry to assess the utility of HD-IORT in high risk bladder cancer.

Real-world experience with atezolizumab (atezo) in advanced urothelial cancer (UC).

e16031 Background: Atezo was recently FDA-approved for patients (pts) with UC (IMvigor210 trial). We assessed the safety and efficacy of Atezo in the real world setting and explored the role of putative biomarkers. Methods: Data from 44 consecutive non-trial pts with UC treated with ≥1 dose of Atezo 1200mg IV q3w at Cleveland Clinic (May - Dec 2016) were available. Demographic, clinicopathologic, biomarker data, including blood neutrophil to lymphocyte ratio (NLR) and myeloid derived suppressor cell (MDSC) populations [LinloCD33+/HLADR-(Total), and Granulocytic(CD15+CD14-), Monocytic(CD15-CD14+), Immature(CD15-CD14-), CD11b+ subsets], were collected. Response, progression-free survival (PFS) and overall survival (OS) were measured (RECIST v1.1). Adverse events (AE) were reported (CTCAE v4.03). Outcome data were analyzed with Fisher’s exact test, chi-square tests, log rank test and proportional hazards models. Results: Median age was 68y (34-88), 68% men, 68% pure urothelial histology, 27% never smokers; 61% PS &gt; 0, 61% visceral metastases, 57% CrCl &lt; 60 mL/min, 84% bladder primary, 61% prior cystectomy. In metastatic setting, 25% had ≥2 prior systemic therapies, 84% prior platinum-based regimen, and 9% no prior therapy. With median follow-up of 3.3 months ( &lt; 1 - 6.6) and median number of 3 doses, in 38 pts evaluable for response, 21% had PR; 24% SD; 61% progressed, 27% died; estimated median (m)PFS was 3 months (95%CI 2.2 - 4.3) and mOS was 5.2 months (95%CI 4.6 - NR). Only 3/27 eligible pts got subsequent treatment. Number of metastatic sites, 2 Bellmunt prognostic factors, and NLR ≥ 5.0 negatively impacted response, PFS and OS. MDSC populations (data available in 14 pts) demonstrated non-significant correlation with worse outcome and elevated NLR. Most frequent all-cause AE ( &gt; 20%) were fatigue (60%, G3:9%), anorexia (33%, G3:7%), elevated creatinine (26%, G3:5%); 1 pt had G4 hyperbilirubinemia. There were no treatment-related deaths. Conclusions: To our knowledge, this is the largest real-world experience with Atezo in UC. Response and toxicity were comparable to IMvigor210 trial; estimated mOS was shorter but with limited follow up. Higher NLR had negative prognostic value, while the role of MDSCs merits further exploration.

Cáncer de vejiga

Resumen Introduccion El cancer de vejiga es un tumor de histologia predominantemente urotelial. El consumo de tabaco es el factor etiologico que mas impacto tiene en el desarrollo del mismo. Diagnostico Aproximadamente el 70% de los tumores se diagnostican en estadios iniciales sin afectar al musculo detrusor, por lo que se asocian a altas tasas de supervivencia, aunque pueden recidivar con relativa frecuencia. Tratamiento En los tumores no musculo infiltrante y en funcion de los factores pronosticos se establecen grupos de riesgo (bajo, medio y alto) que determinan el mejor tratamiento posible. En los casos de bajo riesgo es suficiente la administracion de una dosis posoperatoria de quimioterapia intravesical. En los casos de riesgo intermedio el paciente debe recibir quimioterapia o inmunoterapia intravesical adyuvante. En los casos de alto riesgo se recomienda la inmunoterapia intravesical durante un periodo de uno a tres anos. La afectacion del musculo detrusor tiene implicaciones pronosticas y de tratamiento. En el caso de los tumores musculoinfiltrantes, la cirugia con quimioterapia neoadyuvante es el tratamiento estandar. En los tumores metastasicos la quimioterapia basada en cisplatino es el tratamiento de eleccion.

Voided urine versus bladder washing cytology for detection of urothelial carcinoma: which is better?

Objective: Cytology is recommended as part of the follow-up of high-grade non-muscle-invasive bladder cancer (NMIBC). However, currently there are no solid guideline recommendations regarding the use of voided urine versus bladder washing for cytology as part of the diagnosis or follow-up of NMIBC. The aim of this study was to investigate whether the cytological outcome was equal regarding the two techniques.Materials and methods: The authors reviewed all outpatient flexible cystoscopies carried out in their department in 2013. Patient records in the registry of pathology were examined and those with simultaneous urine and bladder washing cytology were included. Previous urothelial disease and positive histology within 3 months after the cystoscopy were registered.Results: A total of 1458 patients had both voided urine and bladder washing cytology and were included in the study, of whom 643 (44%) had a history of urothelial disease. An equal outcome of urine and bladder washing cytology was found in 1447 patients (99.2%). For the remaining 11 patients, only four patients underwent further examinations based on cytology findings in addition to what had already been planned after cystoscopy. Of the included patients, 100 (6.9%) had a positive histological outcome within 3 months.Conclusions: In most patients, no relevant difference between voided urine and bladder washing cytology was observed. Therefore, if cytology is indicated, it is recommended to use the test that is most readily available locally. The additional gain in using both urine and bladder wash is minimal, and can therefore be discarded.

MP58-12 CLINICAL DESTINY OF INDETERMINATE PULMONARY NODULES IN PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR UROTHELIAL CARCINOMA OF THE BLADDER

You have accessJournal of UrologyBladder Cancer: Invasive V1 Apr 2017MP58-12 CLINICAL DESTINY OF INDETERMINATE PULMONARY NODULES IN PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR UROTHELIAL CARCINOMA OF THE BLADDER David Cahn, Brian McGreen, Albert Lee, Karen Ruth, Elizabeth Plimack, Daniel Geynisman, Matthew Zibelman, Benjamin Ristau, Marc Smaldone, Richard Greenberg, Rosalia Viterbo, David Chen, Robert Uzzo, and Alexander Kutikov David CahnDavid Cahn More articles by this author , Brian McGreenBrian McGreen More articles by this author , Albert LeeAlbert Lee More articles by this author , Karen RuthKaren Ruth More articles by this author , Elizabeth PlimackElizabeth Plimack More articles by this author , Daniel GeynismanDaniel Geynisman More articles by this author , Matthew ZibelmanMatthew Zibelman More articles by this author , Benjamin RistauBenjamin Ristau More articles by this author , Marc SmaldoneMarc Smaldone More articles by this author , Richard GreenbergRichard Greenberg More articles by this author , Rosalia ViterboRosalia Viterbo More articles by this author , David ChenDavid Chen More articles by this author , Robert UzzoRobert Uzzo More articles by this author , and Alexander KutikovAlexander Kutikov More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1807AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Perioperative risks and significant quality of life concerns following radical cystectomy (RC) render accurate pre-operative staging paramount. Incidental indeterminate pulmonary nodules (IPNs) are a common pre-operative finding in clinical practice, thus representing a significant management challenge since metastatic patients are unlikely to benefit from extirpation. Thus, we sought to evaluate the natural history of IPNs in a large institutional cohort that underwent RC. METHODS We reviewed our institutional database for patients who underwent RC from 2000-2014 for urothelial carcinoma (UCC) of the bladder & had ≥1 identifiable pulmonary lesion on preoperative staging imaging measuring <2cm in any axis. Patients who were M1 at surgery or had non urothelial histology were excluded. Cumulative incidence of any lung metastasis was estimated, adjusting for competing risk of death; overall survival (OS) was estimating using Kaplan Meier methods. We sought to determine the natural history of these pulmonary lesions and evaluated predictors of metastatic etiology. RESULTS During the study period, 681 RC were performed at our institution. Of which, 73 patients with an identifiable preoperative IPN met inclusion criteria & underwent RC. In this subset, 23% were female, 22% were active smokers & 55% former smokers. The median age at surgery was 70 yrs (range 43-88). 51% received neoadjuvant chemotherapy & 62% of RC were performed using the traditional open approach (vs 38% robotically). Final pathologic staging included 16% pT0N0Mx, 19% pTa/Tis/T1N0Mx, 43% pT2-4N0Mx, & 22% pTanyN+Mx. Median IPN size was 0.7±0.3cm. At median follow up of 23.5 months, the IPNs in 92% (67/73) of patients were clinically benign, with metastatic urothelial cancer confirmed in only 5 patients, & a primary lung malignancy diagnosed in 1 patient. In the IPN cohort, lung metastasis at non-IPN sites were detected in 2 additional patients. Cumulative incidence of any lung metastasis at 12, 24 & 36 months was 5.9% (95%CI 1.9-13.3%), 7.6% (95%CI 2.8-15.7%), & 10.3% (95%CI 3.9-20.2%), respectively. OS at 12, 24 & 36 months was 75.3% (95%CI 62.3-83.9%), 65.8% (95%CI 53-1-75.9%), & 54.0% (95%CI 39.7-66.2%), respectively. CONCLUSIONS The majority of IPNs in patients who proceeded to RC for UCC of the bladder were stable upon follow-up & rarely represented malignancy. Patients with IPNs have OS consistent with previously published literature. As such, in appropriately screened UCC patients, IPNs should not be a barrier to proceeding with extirpative surgical therapy. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e776-e777 Advertisement Copyright & Permissions© 2017MetricsAuthor Information David Cahn More articles by this author Brian McGreen More articles by this author Albert Lee More articles by this author Karen Ruth More articles by this author Elizabeth Plimack More articles by this author Daniel Geynisman More articles by this author Matthew Zibelman More articles by this author Benjamin Ristau More articles by this author Marc Smaldone More articles by this author Richard Greenberg More articles by this author Rosalia Viterbo More articles by this author David Chen More articles by this author Robert Uzzo More articles by this author Alexander Kutikov More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD57-12 A COMPARISON OF POST-CYSTECTOMY RECURRENCE AND SURVIVAL IN NAC-RESPONSIVE MIBC VS. HIGH-RISK NMIBC PATIENTS: SIMILAR PATHOLOGIC STAGE YET DIFFERENT OUTCOMES

You have accessJournal of UrologyBladder Cancer: Epidemiology & Evaluation III1 Apr 2017PD57-12 A COMPARISON OF POST-CYSTECTOMY RECURRENCE AND SURVIVAL IN NAC-RESPONSIVE MIBC VS. HIGH-RISK NMIBC PATIENTS: SIMILAR PATHOLOGIC STAGE YET DIFFERENT OUTCOMES Aaron Brant, Max Kates, Meera Chappidi, Nikolai Sopko, and Trinity Bivalacqua Aaron BrantAaron Brant More articles by this author , Max KatesMax Kates More articles by this author , Meera ChappidiMeera Chappidi More articles by this author , Nikolai SopkoNikolai Sopko More articles by this author , and Trinity BivalacquaTrinity Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2614AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Patients with muscle-invasive bladder cancer (MIBC) who are down-staged after neoadjuvant chemotherapy (NAC) have improved survival over those who remain ≥pT2. It is uncertain whether subgroups of patients with high-risk non-MIBC (NMIBC) would also benefit from NAC. We compared post-surgical outcomes in high-risk NMIBC patients who did not receive NAC with MIBC patients who were down-staged with NAC and without NAC. METHODS We identified 334 patients with urothelial bladder cancer who were pT0, pTis, pTa, or pT1 and N0 at cystectomy from 2005-2015: 111 with cT2 who received NAC (NAC-responsive), 37 with cT2 who did not receive NAC (non-NAC-responsive), and 186 with high-grade cTis, cTa, or cT1 (high-risk NMIBC). Comparisons were made using Kruskal-Wallis for continuous and chi-squared for categorical variables. Log-rank and Cox regression analyses were used to evaluate survival. RESULTS Compared to NAC-responsive and non-NAC-responsive patients, high-risk NMIBC patients had higher prevalence of intravesical therapy (70.4% vs. 14.1% and 13.5%, p<0.01), pure urothelial histology (92.5% vs. 80.2% and 64.9%, p<0.01), tumor ≥2 cm (19.9% vs. 6.6% and 10.8%, p<0.01), and lower prevalence of pT0 pathology (11.8% vs. 41.3% and 46%, p<0.01). Location of recurrence did not differ significantly between the groups (p=0.53), and 23.5% of recurrences in high-risk NMIBC patients occurred outside of the pelvis. Log-rank comparisons showed improved recurrence-free and overall survival in NAC-responsive vs. high-risk NMIBC patients (p<0.02 and p<0.02) but not in non-NAC-responsive vs. high-risk NMIBC patients (p=0.34 and p=0.43). In Cox regression, tumor ≥2 cm was independently associated with increased risk of cancer recurrence (HR=2.31, p=0.02) and overall mortality (HR=2.10, p=0.02) CONCLUSIONS Patients with NAC-responsive MIBC had better post-surgical outcomes than patients with high-risk NMIBC. High-risk NMIBC patients had a higher prevalence of tumor ≥2 cm, which was an independant predictor of cancer recurrence. Despite being node negative, almost a quarter of recurrences in patients with high-risk NMIBC occurred distantly. Further work is needed to identify whether patients with unresectable or high volume NMIBC could benefit from NAC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1125-e1126 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Aaron Brant More articles by this author Max Kates More articles by this author Meera Chappidi More articles by this author Nikolai Sopko More articles by this author Trinity Bivalacqua More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Next generation sequencing of non-muscle invasive bladder cancer to reveal potential biomarkers and rational therapeutic targets.

302 Background: We examined a cohort of index pre-treatment NMIBC tumors using Next Generation Sequencing to identify genetic alterations with potential clinical implications. Methods: 105 patients on a prospective IRB-approved protocol had their pre-treatment index NMIBC tumor and matched germline DNA sequenced with a 341 cancer-associated gene panel in a CLIA-certified clinical laboratory. A genitourinary pathologist reviewed representative H&amp;E slides to confirm grade, stage, and urothelial histology. Restaging TUR was performed in all HGT1 tumors. Results: To characterize the genomic landscape of NMIBC, we analyzed 105 tumors across the disease spectrum including LGTa (n = 23), HGTis (n = 12), HGTa (n = 32) and HGT1 (n = 38). The most frequently altered genes in NMIBC were the TERT promoter (74%), FGFR3 (50%), KDM6A (47%), ARID1A (28%), PIK3CA (27%), KMT2D (24%), STAG2 (21%), and CDKN2A (17%). 81% of tumors had inactivating alterations in a chromatin-modifying gene. Alterations in the RTK/RAS/PIK3 pathway occurred in 83% of tumors, including 58% of high-grade NMIBC having alterations in either ERBB2 or FGFR3. Of the 105 patients, 62 were treated uniformly with a 6-week induction course of BCG without maintenance. We investigated all genes altered on the 341-gene panel in at least 5 patients for their association with recurrence after BCG therapy in this 62 patient cohort. On cox-regression analysis, only truncating mutations in the chromatin-modifying gene ARID1A were associated with recurrence after BCG (HR = 3.14 [95%CI = 1.51, 6.51] p = 0.002). This remained significant when adjusting for multiple comparisons (p = 0.04) and when including ARID1A missense mutations of unknown significance (p = 0.002). Conclusions: Next Generation Sequencing of index pre-treatment NMIBC tumors identified an association between ARID1A mutations and recurrence after BCG therapy. Further investigation is needed to determine whether ARID1A mutations are a potential predictive/prognostic biomarker or therapeutic target. Moreover, most NMIBC tumors had at least one potentially “actionable” alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy.