Diagnosis Of Muscle-invasive Bladder Cancer Research Articles

Cascade Path Augmentation Unet for bladder cancer segmentation in MRI

Treatment choices for patients with bladder cancer (BCa) are determined by the presence of muscular invasion. The precise segmentation of the inner and outer walls (IW and OW), as well as the bladder tumor (BT), is crucial for improving computer-aided diagnosis of muscle-invasive bladder cancer (MIBC). To propose a novel deep learning-based model to improve the segmentation accuracy of the IW, OW, and BT, which can be useful in clinical practice. We proposed a Cascade Path Augmentation Unet (CPA-Unet) network to conduct multi-regional segmentation of the bladder using 1545 T2-weighted MRI scans. The model employs a cascade strategy to eliminate the redundant information in the background. Unet is used to segment the bladder from the background in the rough segmentation. The path augmentation structure is used in the fine segmentation to mine multi-scale features. Additionally, the partial dense connection is adopted as the skip connection module to concatenate the low- and high-level sematic features. The CPA-Unet is trained using 1391 T2WI slices and tested using 154 T2WI slices. In comparison to previous deep learning-based methods, the CPA-Unet achieves superior segmentation results in terms of Dice similarity coefficient (DSC) and Hausdorff distance (HD) (IW: DSC =98.19%, HD =2.07mm; OW: DSC =82.24%, HD =2.62mm; BT: DSC =87.40%, HD =0.76mm). Our proposed CPA-Unet network is capable of segmenting the bladder into its IW and OW, as well as tumors. The segmentation results provide a reliable and effective foundation for computer-assisted clinical diagnosis of MIBC.

Malignant Central Nervous System Lymphoma after Radical Total Cystectomy : A Diagnostic Challenge

We report a case of primary central nervous system lymphoma (PCNSL) in an 81-year-old man who had undergone radical cystectomy with an ileal conduit urostomy due to a diagnosis of muscle-invasive bladder cancer. The postoperative diagnosis was invasive urothelial carcinoma (pT2bN1M0, stage IV). Gemcitabine-cisplatin therapy was provided as adjuvant chemotherapy, and there was no recurrence during follow-up. Four years after surgery, he visited the emergency department because of weakness of the lower extremities and stuttering. He was found to have a parietal lobe mass on magnetic resonance imaging (MRI) and hospitalized with suspicion of brain metastasis. Despite examination by a neurosurgeon, it was not possible to make a clinical diagnosis, and the patient gradually deteriorated and died 21 days later. The pathology results were diagnostic of PCNSL.

Diet Quality and Survival in a Population-Based Bladder Cancer Study

Nutrition may impact bladder cancer survival. We examined the association between diet quality and overall and bladder cancer-specific survival. Bladder cancer cases from a population-based study reported pre-diagnosis diet. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010). Vital status was ascertained from the National Death Index. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards and competing risks regression models. Overall AHEI-2010 adherence was not associated with overall or bladder cancer-specific survival among non-muscle invasive bladder cancer (NMIBC) cases (HR, 1.00; 95% CI, 0.98-1.01; HR, 1.00; 95% CI, 0.97-1.02) or muscle invasive bladder cancer (MIBC) cases (HR, 0.99; 95% CI, 0.96-1.03; HR, 1.01, 95% CI 0.97-1.06). AHEI-2010 sugar-sweetened beverages adherence was associated with poorer overall survival (HR, 1.04; 95% CI, 1.01-1.08) and AHEI-2010 sodium adherence was associated with better overall and bladder cancer-specific survival after NMIBC diagnosis (HR, 0.92, 95% CI, 0.85-1.00; HR, 0.82; 95% CI, 0.68-0.98). AHEI-2010 fruit adherence was associated with poorer overall and bladder cancer-specific survival after MIBC diagnosis (HR, 1.17; 95% CI, 1.02-1.33; HR, 1.26; 95% CI, 1.03-1.55). Consumption of sugar-sweetened beverages, sodium, and fruit, not overall AHEI-2010 adherence, may be associated with bladder cancer survival.

MP13-20 LONG TERM OUTCOMES IN PATIENTS WITH MUSCLE INVASIVE BLADDER CANCER WHO ARE MISCLASSIFIED AS ACHIEVING A COMPLETE CLINICAL RESPONSE TO NEOADJUVANT CHEMOTHERAPY: HOW COSTLY ARE MISTAKES?

You have accessJournal of UrologyBladder Cancer: Invasive I (MP13)1 Sep 2021MP13-20 LONG TERM OUTCOMES IN PATIENTS WITH MUSCLE INVASIVE BLADDER CANCER WHO ARE MISCLASSIFIED AS ACHIEVING A COMPLETE CLINICAL RESPONSE TO NEOADJUVANT CHEMOTHERAPY: HOW COSTLY ARE MISTAKES? Jane Kurtzman, Rainjade Chung, Helena Vila-Reyes, Guarionex Decastro, Christopher Anderson, Charles Drake, and James McKiernan Jane KurtzmanJane Kurtzman More articles by this author , Rainjade ChungRainjade Chung More articles by this author , Helena Vila-ReyesHelena Vila-Reyes More articles by this author , Guarionex DecastroGuarionex Decastro More articles by this author , Christopher AndersonChristopher Anderson More articles by this author , Charles DrakeCharles Drake More articles by this author , and James McKiernanJames McKiernan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001994.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Correctly classifying patients with muscle invasive bladder cancer (MIBC) as achieving a complete response to neoadjuvant chemotherapy (NAC) is challenging without radical cystectomy (RC) pathology. The accuracy of clinical staging following NAC is debated and the risk of occult residual MIBC is real. In this study, we present the survival outcomes of patients who were misclassified as having achieved a complete clinical response (CCR) to NAC. METHODS: We retrospectively reviewed our prospective database of patients with MIBC who achieved a CCR to NAC and elected active surveillance (AS). CCR criteria includes: negative cytology, benign TUR pathology and negative cross-sectional imaging. We defined misclassified CCR (mCCR) as a patient found to have intravesical MIBC within 6 months of meeting CCR criteria. Kaplan-Meier curves were used to assess overall (OS), cancer-specific (CSS) and metastasis-free (MFS) survival and log-rank tests to evaluate differences between cohorts. RESULTS: We included 54 patients, with a median age of 70 years (IQR 62-75) and median follow-up of 49 months (IQR 26-77) since MIBC diagnosis. 6/54 patients (11%) were mCCR. All 6 underwent RC at a mean of 129 days after CCR classification. Five-year OS, CSS and MFS for mCCR patients was 63%, compared to 80%, 89% and 93%, respectively, for the remaining patients (Figure 1). Log-rank tests revealed a significantly higher OS and MFS in CCR compared to mCCR patients (p=0.03 and p=0.05, respectively), but no difference in CSS (p=0.07). However, this lack of significance was likely due to lack of power. CONCLUSIONS: We observed an 11% rate of occult MIBC in patients who elect AS following a CCR to NAC. Delayed RC in this cohort resulted in a 63% 5-year OS, CSS and MFS. These survival outcomes for mCCR patients are comparable to those previously published for patients who undergo immediate RC following NAC and are found to have residual intravesical MIBC on specimen review. Our findings are useful when describing the risk of occult MIBC to patients contemplating AS. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e251-e251 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jane Kurtzman More articles by this author Rainjade Chung More articles by this author Helena Vila-Reyes More articles by this author Guarionex Decastro More articles by this author Christopher Anderson More articles by this author Charles Drake More articles by this author James McKiernan More articles by this author Expand All Advertisement Loading ...

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study.

BackgroundThe standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis.Methods and findingsWe applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD–positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4–38.9; p = 0.02) compared to utDNA MRD–negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD–positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point.ConclusionsutDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

Abstract 547: Urine tumor DNA MRD detection and correlation with pathologic complete response in muscle-invasive bladder cancer treated with curative-intent radical cystectomy

Abstract Objective: Standard-of-care for muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. The inability to assess molecular residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. We seek to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. Methods: We applied uCAPP-Seq, a targeted next-generation sequencing method for detecting utDNA, to urine cell-free DNA samples acquired on the day of curative-intent radical cystectomy from 42 patients with non-metastatic bladder cancer, 30 of whom had a confirmed diagnosis of MIBC and 19 of whom received neoadjuvant chemotherapy. utDNA mutational calling was performed noninvasively without tumor tissue sequencing knowledge. The overall utDNA level for each patient was represented by the non-silent mutation with the highest duplex-supported variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy donors. The concordance between urine cell-free DNA and tumor tissue was determined for a subset of patients. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of mutations detected in urine cell-free DNA by applying a linear relationship derived from TCGA whole-exome sequencing of 409 MIBC tumors. Results: utDNA analysis revealed a median utDNA level of 0% in healthy donors and 2.4% in non-metastatic bladder cancer patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 87%. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (n = 26), median utDNA levels were 4.3% vs. 0%, respectively (P = 0.002). The lack of utDNA MRD detection was highly correlated with pathologic complete response by Fisher's exact test (P = 0.0001) with Youden's index-determined sensitivity of 81% and specificity of 81%. Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival compared to utDNA MRD-negative patients (HR = 7.2; P = 0.03) with a median follow-up time of 200 days. Leveraging data from TCGA, the median inferred TMB in utDNA MRD-positive patients was 198 mutations per exome. We suggest that 58% of these patients with inferred TMB ≥ this level might have been candidates for early immune checkpoint blockade. Conclusion: The lack of utDNA MRD detection prior to curative-intent radical cystectomy for muscle-invasive bladder cancer correlated significantly with pathologic complete response. utDNA MRD detection status also correlated significantly with progression-free survival. Furthermore, utDNA results can be used to noninvasively infer TMB, which may facilitate the targeted use of adjuvant immunotherapy. Citation Format: Kevin Chen, Pradeep S. Chauhan, Ramandeep K. Babbra, Wenjia Feng, Peter K. Harris, Katherine Dienstbach, Andrew Atkocius, Lenon Maguire, Faridi Qaium, Armaan Nallicheri, Brian C. Baumann, Melissa A. Reimers, Eric H. Kim, Zachary L. Smith, Vivek K. Arora, Aadel A. Chaudhuri. Urine tumor DNA MRD detection and correlation with pathologic complete response in muscle-invasive bladder cancer treated with curative-intent radical cystectomy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 547.

Validation of Vesical Imaging Reporting and Data System score for the diagnosis of muscle-invasive bladder cancer: A prospective cross-sectional study

ObjectiveVesical Imaging Reporting and Data System (VIRADS) score was developed to standardize the reporting and staging of bladder tumors on pre-operative multiparametric magnetic resonance imaging. It helps in avoiding unnecessary repeat transurethral resection of bladder tumor in high-risk non-muscle-invasive bladder cancer patients. This study was done to determine the validity of VIRADS score prospectively for the diagnosis of muscle-invasive bladder cancer. MethodsThis study was conducted from March 2019 to March 2020 at Sawai Man Singh Medical College and Hospital, Jaipur, Rajasthan, India. Patients admitted with the provisional diagnosis of bladder tumor were included as participants. All these patients underwent a 3 Tesla mpMRI to obtain a VIRADS score before they underwent transurethral resection of bladder tumor and these data were analyzed to evaluate the correlation of pre-operative VIRADS score with muscle invasiveness of the tumor in final biopsy report. ResultsA cut-off of VIRADS ≥4 for prediction of detrusor muscle invasion yielded a sensitivity of 79.4%, specificity of 94.2%, positive predictive value of 90.0%, negative predictive value of 87.5%, and diagnostic accuracy of 86.4%. A cut off of VIRADS ≥3 for prediction of detrusor muscle invasion yielded a sensitivity of 91.2%, specificity of 78.8%, positive predictive value of 73.8%, negative predictive value of 93.2%, and accuracy of 83.7%. The receiver operating curve showed the area under the curve to be 0.922 (95% confidence interval: 0.862–0.983). ConclusionVIRADS score appears to be an excellent and effective pre-operative radiological tool for the prediction of detrusor muscle invasion in bladder cancer.

Trimodality Treatment for Muscle-Invasive Bladder Cancer: An Institutional Experience

PurposeAs an alternative to radical cystectomy, tri-modality treatment (TMT) is an effective treatment approach for selected patients with muscle-invasive bladder cancer (MIBC). The purpose of this report is to contribute to the literature by summarizing institutional outcomes of a bladder-preserving TMT approach for patients with MIBC. Methods and MaterialsPatients treated with TMT for MIBC from 1998 to 2019 were identified. Patient, disease, and treatment factors were recorded. Overall survival (OS), disease-free survival (DFS), and bladder-preserved DFS were estimated with the Kaplan-Meier method. Prognostic factors were evaluated with Cox proportional hazards regression. ResultsThirty-two patients treated with TMT to a median dose of 64.8 Gy for T2 (78%), T3 (19%), and T4 (3%) disease were followed for a median of 19 months (mean, 36; range, 6-213); 31% had associated carcinoma in situ; 25% had associated hydronephrosis. Cisplatin was the most commonly used chemotherapeutic agent. OS rates were 84% at 1 year and 61% at 5 years. DFS rates were 84% and 61% and bladder-preserved DFS rates were 84% and 60% at 1 year and 5 years, respectively. Salvage cystectomy rates at 1 year and 5 years were 4% and 9%, respectively. Four patients had locally invasive recurrences at 8, 11, 34, and 37 months after initial MIBC diagnosis, 2 of whom underwent salvage radical cystectomy. Ten (31%) patients developed distant disease at a median of 13 months after diagnosis. Unlike local recurrence, distant recurrences were associated with worse OS and hazard ratios of 3.4 (P = 0.039). ConclusionsOS and DFS were comparable to those of published data. Our outcomes support TMT as an effective option for carefully selected patients with MIBC.

Detecting Muscle Invasion of Bladder Cancer Using a Proposed Magnetic Resonance Imaging Strategy.

Accurate evaluation of the invasion depth of tumors with a Vesical Imaging-Reporting and Data System (VI-RADS) score of 3 is difficult. To evaluate the diagnostic performance of a new magnetic resonance imaging (MRI) strategy based on the integration of the VI-RADS and tumor contact length (TCL) for the diagnosis of muscle-invasive bladder cancer (MIBC). Single center, retrospective. A group of 179 patients with a mean age of 67 years (range, 24.0-96.0) underwent multiparametric MRI (mpMRI) before surgery, including 147 (82.1%) males and 32 (17.9%) females. Twenty-four (13.4%), 90 (50.3%), 43 (24.0%), 15 (8.4%), and 7 (3.9%) cases were Ta, T1, T2, T3, and T4, respectively. A 1.5 T and 3.0 T, T2-weighted turbo spin-echo (TSE), single-shot echo-planar (SS-EPI), diffusion-weighted imaging (DWI), and T1-weighted volumetric interpolated breath-hold examination (T1-VIBE). Three radiologists independently graded the VI-RADS score and measured the TCL on index lesion images. A proposed MRI strategy called VI-RADS_TCL was introduced by modifying the VI-RADS score, which was downgraded to VI-RADS 3F (equal to a VI-RADS score of 2) if VI-RADS=3 and TCL < 3 cm. Intraclass correlation coefficients (ICCs), Mann-Whitney U test, chi-square tests, receiver operating characteristic (ROC) curves, and 2 × 2 contingency tables were applied. Inter-reader agreement values were 0.941 (95% CI, 0.924-0.955) and 0.934 (95% CI, 0.916-0.948) for the TCL and VI-RADS score. The TCL was significantly increased in the MIBC group (6.40-6.85 cm) compared with the NMIBC group (1.98-2.45 cm) (P < 0.05). The specificity and positive predictive values (PPV) of VI-RADS_TCL were 82.46%-87.72% and 90.91%-91.59%, which were significantly greater than VI-RADS score (P < 0.05). Additionally, 52.17%-55.88% NMIBC lesions with VI-RADS 3 were downgraded to 3F by using VI-RADS_TCL. The proposed MRI strategy could reduce the false-positive rate of lesions with a VI-RADS score of 3 while retaining sensitivity. 4 TECHNICAL EFFICACY: 2.

Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study

Transurethral resection of bladder tumour (TURBT) is central to the diagnosis of muscle-invasive bladder cancer (MIBC). With the oncological safety of TURBT unknown, staging inaccuracies commonplace, and correct treatment of MIBC potentially delayed, multiparametric magnetic resonance imaging (mpMRI) may offer rapid, accurate, and noninvasive diagnosis of MIBC. BladderPath is a randomised trial comparing risk-stratified (5-point Likert scale) image-directed care with TURBT for patients with newly diagnosed BC. To date, we have screened 279 patients and randomised 113. Here we report on the first 100 participants to complete staging: 48 in pathway 1 (TURBT) and 52 in pathway 2 (mpMRI for possible MIBC, Likert 3–5). Fifty of 52 participants designated Likert 1–2 (probable NMIBC) from both pathways were confirmed as having NMIBC (96%). Ten of 11 cases diagnosed as NMIBC by mpMRI have been pathologically confirmed as NMIBC, and 10/15 cases diagnosed as MIBC by mpMRI have been treated as MIBC (5 participants underwent TURBT). The specificity of mpMRI for identification of MIBC remains a limitation. These initial experiences indicate that it is feasible to direct possible MIBC patients to mpMRI for staging instead of TURBT. Furthermore, a 5-point Likert scale accurately identifies patients with low risk of MIBC (Likert 1–2), and flexible cystoscopy biopsies appear sufficient for diagnosing BC. Patient summaryWe are conducting a clinical trial to assess whether some bladder tumour surgery can be replaced by magnetic resonance imaging scans to determine the stage of the cancer in patients whose tumours appear to be invasive. Our early data suggest that this approach is feasible. The data also show that using a visual score ('Likert scale') can help to identify bladder tumours that are very unlikely to be invasive, and that taking a biopsy in the outpatient clinic when first inspecting the bladder via a camera (diagnostic flexible cystoscopy) is useful for confirming bladder cancer.

A Modern Day Evaluation of Organ Preservation for Muscle Invasive Bladder Cancer at a High-Volume Cancer Center

The standard of care for muscle invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NACT) followed by cystectomy. Select patients may undergo bladder sparing approaches, characterized by maximum bladder tumor resection followed by concurrent chemoradiation (chemoRT). In this study, we evaluate the experience of bladder preservation for MIBC patients at a high-volume cancer center in the modern era. We retrospectively evaluated the medical records of 48 consecutive MIBC patients treated with bladder preservation from 2010 to 2019. Chi Square tests were used to compare groups. Time to event analyses, including overall survival (OS) and bladder-intact event free survival (BI-EFS) were estimated by Kaplan-Meier methods and compared by the log-rank test, or by Cox regression analysis. Univariable (UVA) and multivariable (MVA) analyses were performed to explore the effect of predictors on defined outcomes. The median age was 69 years (range 39-90). Most patients were male (79%). T category was T2 (85%), T3 (13%) and T4a (2%) with 88% (n = 42) having stage II disease. Seventeen (35%) patients had non-MIBC prior to MIBC diagnosis. The majority (73%) of tumors were urothelial histology only. Mixed histologies included neuroendocrine (10%), squamous (6%), sarcomatoid (6%) and plasmacytoid (4%). Twelve (25%) patients received NACT and of these, 6 had a complete response (CR) at cystoscopy prior to chemoRT. Most patients (83%) were treated with concurrent platinum-based chemoRT. The median radiation dose was 64.5 Gy (range 34.2-64.8). With a median follow-up time of 39.8 months, a quarter of patients progressed after chemoRT with 8 (17%) having local MIBC recurrence and 8 having distant progression. Three patients underwent salvage cystectomy. Only the achievement of a CR after NACT was predictive of less risk for local MIBC recurrence (p = 0.002). The median OS was 66.7 months (range 25.0-108.5), with 2- and 3-yr OS of 77% and 57%, respectively. Predictors of improved OS on UVA included urothelial only histology, lower stage, and no local MIBC recurrence; only urothelial histology was predictive on MVA (HR: 0.20, 95% CI 0.06-0.66, p = 0.008). The median BI-EFS was 52.4 months (range 27.2 - 77.7), with 2- and 3-yr BI-EFS of 65% and 56%, respectively. Urothelial only histology (p = 0.005) and CR after NACT (p = 0.02) were predictive of BI-EFS on UVA, but not MVA. Bladder preservation remains an effective treatment approach for select patients, but mixed histology may portend inferior tumor control. Here we provide modern data from a large cancer center showing a 3-yr BI-EFS similar to the control arm of the accruing SWOG/NRG 1806 trial.

Systematic Review and Meta-Analysis of Vesical Imaging-Reporting and Data System (VI-RADS) Inter-Observer Reliability: An Added Value for Muscle Invasive Bladder Cancer Detection.

Simple SummaryIn our systematic review and meta-analysis of eight observational studies including a total of 1016 patients, we demonstrated excellent pooled inter-observer agreement among Genito-Urinary radiologists when adopting the novel Vesical Imaging-Reporting and Data System (VI-RADS) criteria in the pre-trans-urethral resection of bladder tumor (TURBT) assessment for non-muscle (NMIBC) vs. muscle-invasive bladder cancer (MIBC) detection.The Vesical Imaging-Reporting and Data System (VI-RADS) has been introduced to provide preoperative bladder cancer staging and has proved to be reliable in assessing the presence of muscle invasion in the pre-TURBT (trans-urethral resection of bladder tumor). We aimed to assess through a systematic review and meta-analysis the inter-reader variability of VI-RADS criteria for discriminating non-muscle vs. muscle invasive bladder cancer (NMIBC, MIBC). PubMed, Web of Science, Cochrane, and Embase were searched up until 30 July 2020. The Quality Appraisal of Diagnostic Reliability (QAREL) checklist was utilized to assess the quality of included studies and a pooled measure of inter-rater reliability (Cohen’s Kappa [κ] and/or Intraclass correlation coefficients (ICCs)) was calculated. Further sensitivity analysis, subgroup analysis, and meta-regression were conducted to investigate the contribution of moderators to heterogeneity. In total, eight studies between 2018 and 2020, which evaluated a total of 1016 patients via 21 interpreting genitourinary (GU) radiologists, met inclusion criteria and were critically examined. No study was considered to be significantly flawed with publication bias. The pooled weighted mean κ estimate was 0.83 (95%CI: 0.78–0.88). Heterogeneity was present among the studies (Q = 185.92, d.f. = 7, p < 0.001; I2 = 92.7%). Meta-regression analyses showed that the relative % of MIBC diagnosis and cumulative reader’s experience to influence the estimated outcome (Coeff: 0.019, SE: 0.007; p= 0.003 and 0.036, SE: 0.009; p = 0.001). In the present study, we confirm excellent pooled inter-reader agreement of VI-RADS to discriminate NMIBC from MIBC underlying the importance that standardization and reproducibility of VI-RADS may confer to multiparametric magnetic resonance (mpMRI) for preoperative BCa staging.

Neoadjuvant Chemotherapy or Immunotherapy for Clinical T2N0 Muscle-invasive Bladder Cancer: Time to Change the Paradigm?

A 41-yr-old, otherwise healthy, premenopausal woman presented at our uro-oncology clinic with a diagnosis of muscle-invasive bladder cancer following a transurethral resection of the bladder performed at another center. After a thorough discussion with the patient, she was enrolled in the phase II PURE-01 trial (NCT02736266), testing three cycles of neoadjuvant pembrolizumab (200mg) every 3 wk before radical cystectomy. Before treatment, imaging studies were obtained as per the protocol using computed tomography (CT), [18F]fluorodeoxyglucose positron emission tomography/CT, and multiparametric magnetic resonance imaging of the bladder, defining a clinically localized T2N0M0 stage. As per the protocol, potential biomarkers were assessed, including PD-L1 expression (84% combined positive score), tumor mutational burden (16.67 mut/Mb), and genomic profiling (FoundationONE assay; somatic mutation in TP53, EZH2, APC, TERT, CDKN1A, CDKN1B, and ARID1A genes, and truncation in BRCA2 gene). After immunotherapy, the patient underwent a robot-assisted radical cystectomy with extended pelvic lymph node dissection. The final pathology report revealed absence of residual disease (ie, pathological complete response, ypT0ypN0). During follow-up, the only relevant and permanent immune-mediated adverse event was hypothyroidism secondary to an autoimmune thyroiditis. It appeared 2 mo after radical cystectomy and it was managed successfully with hormonal replacement therapy. Two years after treatment, the patient is asymptomatic and free from disease recurrence. Patient summaryIncreasing evidence suggests that frontline neoadjuvant immunotherapy may be beneficial for patients diagnosed with non–locally advanced, muscle-invasive bladder cancer (cT2N0), with fewer drawbacks than traditional chemotherapy. Although further studies are needed in support, this vision opens the opportunity for future clinical trials testing the potential incremental benefits of immunotherapy and the utility of novel biomarker- and imaging-based strategies to assess response to therapy.

Abstract B15: Bladder cancer susceptibility polymorphisms and mortality from non-muscle and muscle-invasive bladder cancer

Abstract Introduction: Genome-wide association studies (GWAS) have identified several common germline single-nucleotide polymorphisms (SNPs) associated with increased risk of bladder cancer. Little is known about whether these variants are also associated with overall and bladder cancer-specific mortality. We examined the association between 13 GWAS-identified bladder cancer risk SNPs and overall and bladder cancer-specific survival in 316 bladder cancer cases recruited as part of a population-based case-control study. Methods: Residents of New Hampshire with primary bladder cancer diagnosed between 2002-2004 were identified from the New Hampshire State Cancer Registry. Medical history and lifestyle factors were collected via in-person interviews at time of enrollment. DNA was isolated from peripheral blood or buccal specimens and genotyping was performed using the Illumina Human610-Quad BeadChip. Date and cause of death were ascertained from the National Death Index with follow-up through December 31, 2013. Non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) were examined separately. We used Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for overall and bladder cancer-specific survival, assuming a log-additive genetic model. HR estimates for MIBC individuals were adjusted for age at diagnosis, sex, smoking status, American Joint Committee on Cancer stage, initial treatment (including extent of resection, cystectomy, and use of chemotherapy or radiation), and three principal components for genetic ancestry. HR estimates for NMIBC were additionally adjusted for 2004 World Health Organization/International Society of Urologic Pathologists classification. An alpha of 0.05 was used to determine statistical significance. Results: Among 43 participants with MIBC, 30 deaths occurred over a median follow-up of 6.4 years, including 19 from bladder cancer. Among 273 participants with NMIBC, 94 deaths occurred over a median follow-up of 10.3 years, including 23 from bladder cancer. The risk allele [A] of enhancer-associated intergenic SNP rs710521 near TP63 was associated with poorer overall survival after MIBC diagnosis (HR=3.21, 95% CI=1.26-8.16). The risk allele [C] of synonymous SNP rs10936599 of MYNN/TERC was associated with better overall survival after NMIBC diagnosis (HR=0.66, 95% CI=0.46-0.94). No associations with bladder cancer-specific survival were identified. Conclusions: Common bladder cancer susceptibility variants rs710521 and rs10936599 may be associated with overall survival after diagnosis of MIBC and NMIBC, respectively. Citation Format: Reno C. Leeming, Michael S. Zens, John D. Seigne, Brock C. Christensen, Diane Gilbert-Diamond, Margaret R. Karagas, Michael N. Passarelli. Bladder cancer susceptibility polymorphisms and mortality from non-muscle and muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B15.

VI-RADS: Multiinstitutional Multireader Diagnostic Accuracy and Interobserver Agreement Study

BACKGROUND. The Vesical Imaging Reporting and Data System (VI-RADS), based on multiparametric MRI (mpMRI), was developed to provide accurate information for the diagnosis of muscle-invasive bladder cancer (MIBC). OBJECTIVE. The purpose of our study was to evaluate the interobserver agreement and diagnostic performance of VI-RADS among readers with different levels of experience. METHODS. This retrospective study included 91 consecutive patients who underwent mpMRI before transurethral resection of bladder tumor (TURBT) from July 2010 through August 2018. After attending a training session, seven radiologists (five radiologists experienced in bladder MRI and two inexperienced radiologists) reviewed and scored all MRI examinations according to VI-RADS. The interobserver agreement was assessed by kappa statistics. ROC analysis was used to evaluate the diagnostic performance for MIBC. AUCs were estimated. RESULTS. Among 91 patients (72 men and 19 women; mean age ± SD, 73.2 ± 10.2 years), 48 (52.7%) had MIBC and 43 (47.3%) had non-muscle-invasive bladder cancer. Sixty-eight patients were treated with TURBT, and 23 were treated with radical cystectomy. Interobserver agreement was moderate to substantial (κ = 0.60-0.80) among the experienced readers, substantial (κ = 0.67) between the two inexperienced readers, and moderate to substantial (κ = 0.55-0.75) between the experienced and inexperienced readers. The pooled AUC was 0.88 (range, 0.82-0.91) for experienced readers and 0.84 (range, 0.83-0.85) for inexperienced readers, and 0.87 for all readers. Using a VI-RADS score of 4 or greater as the cutoff value for MIBC, the pooled sensitivity and specificity were 74.1% (range, 66.0-80.9%) and 94.1% (range, 88.6-97.7%) for experienced readers and 63.9% (range, 59.6-68.1%) and 86.4% (range, 84.1-88.6%) for inexperienced readers. Using a VI-RADS score of 3 or greater as the cutoff value, the pooled sensitivity and specificity were 83.4% (range, 80.9-85.1%) and 77.3% (range, 61.4-88.6%) for experienced readers and 82.0% (range, 80.9-83.0%) and 73.9% (range, 72.7-75.0%) for inexperienced readers. CONCLUSION. We observed moderate to substantial interobserver agreement and a pooled AUC of 0.87 among radiologists of different levels of expertise using VI-RADS. CLINICAL IMPACT. VI-RADS could help determine the depth and range of excision in TURBT, decreasing the risk of complications and enhancing the accuracy of pathologic diagnosis.

Patterns and predictors of referral among patients with muscle-invasive bladder cancer: A real-world study.

e17051 Background: The multidisciplinary treatment of muscle-invasive bladder cancer (MIBC) has demonstrated considerable challenges in widespread clinical adoption. Despite guidelines recommending multidisciplinary, utilization of neoadjuvant chemotherapy for bladder cancer treatment remains low in the real-world settings. This study aims to examine the real-world referral patterns from urology to medical oncology and/or radiation oncology and the factors that associated with the referral following a diagnosis of MIBC. Methods: Following approval of involved IRBs, investigators followed a common protocol under the auspices of the Rapid Case Ascertainment at the Yale Cancer Center and performed manual chart review of MIBC patients diagnosed in the state of Connecticut from 2004 – 2015 and treated at investigator-affiliated hospitals. Information on medical history, radical or partial cystectomy, chemotherapy, radiation therapy, initial treating physician, and referrals to additional providers were recorded. This data set was linked to the Surveillance, Epidemiology, and End Results (SEER) database for demographic information. Logistic regression analysis adjusted with demographics (i.e. gender, race) and medical histories (i.e. prior cancers) was conducted to identify factors associated with referral. Results: Of the 665 patients whose initial treating physician was urologist, only 291 (43.8%) were referred to a medical oncologist and/or a radiation oncologist. Independent factors associated with lack of referral included: older age (OR = 0.994 for every incremental year, P-value: 0.0055), and greater Charlson comorbidity score (OR = 1.064. P-value: 0.015). Patients with kidney diseases and diabetes were less likely to be referred. Conclusions: Lack of referral to medical oncology and/or radiation oncology is a critical barrier to the use of optimal multidisciplinary therapy. Referral decision made by urologists is impacted by a patient’s age and overall health condition. [Table: see text]

Impact of 18FDG-PET CT in the management of invasive bladder cancer.

444 Background: Guidelines do not recommend FDG-Positron Emission Tomography (PET) Computed Tomography (CT) for the staging of Muscle Invasive Bladder Cancer (MIBC), but rather CT scan for lymph node (LN) and metastatic staging, despite its low accuracy. We performed a retrospective analysis of patients (pts) with MIBC who had a FDG-PET CT for staging, indicated by multidisciplinary team, in two centers, and analyzed its utility in this setting. Methods: All pts who had a FDG-PET CT performed at the time of diagnosis of MIBC from 01/2005 to 12/2017 in Bordeaux (Bergonie Institute and University Hospital) were retrospectively reviewed. Nodal and metastatic staging on CT and FDG-PET CT were done independently according to the 8th TNM classification. The aims of the study were to evaluate the accuracy of the FDG-PET CT for LN staging and to determine the rate of treatment modification (neoadjuvant chemotherapy for curative intent, no surgery for metastatic disease), according to FDG-PET CT results. Results: Among the 130 pts included, with a median age of 65 years, 74% were considered free from nodal metastasis (N0) by CT whereas only 44% were N0 from FDG-PET CT. Based on CT results, 88% of pts were free from distant metastasis (M0) but only 75% were classified M0, on FDG-PET CT. Accuracy of LN staging for CT and FDG-PET CT at initial diagnosis were analyzed for 85 pts (including 70 pts treated with neoadjuvant chemotherapy) and compared to pathological examination of resected LN. Sensitivity of FDG-PET CT was better than CT (respectively 80.8% versus 26.9%) but the specificity was low (respectively 54.2% versus 83.1%). Youden index was better for FDG-PET CT (0.35; 0.1 for CT), being more accurate for determining LN staging of MIBC. FDG-PET CT findings allowed a treatment decision modification in 34/130 pts (26.1%): therapeutic intensification in 12 pts (9.2%), including surgery not previously indicated, modified radiotherapy; or de-escalation in 22 pts (16.9%), mostly avoiding surgery. Conclusions: FDG-PET CT is more sensitive to detect LN involvement at initial diagnosis of MIBC than standard CT scan. Moreover, in the present study, treatment decisions were modified, according to FDG-PET CT results, in a quarter of pts according to LN and distant metastatic staging.

Efficacy of atezolizumab concurrent with radiotherapy in patients with muscle-invasive bladder cancer (MIBC) (SOGUG-2017-A-IEC(VEJ)-4).

TPS601 Background: Radical cystectomy (RC) is the standard of care for patients with T2-T4a MIBC. Organ-preserving treatment is an alternative for patients who wish to attempt bladder preservation therapy or are ineligible for cystectomy. This includes maximal transurethral resection of bladder tumour, external beam radiation therapy (EBRT) and concurrent chemotherapy. The 5 and 10 year OS and disease specific survival (DSS) rates in contemporary RC series are comparable to that reported in bladder-preserving series. Due to EBRT can mediate inmunoestimulatory effects and that radiotherapy has been used in combination with different treatment regimens, a considerable interest has been attracted by combinatorial regimens involving EBRT plus checkpoint inhibitors. The purpose of the present study is to explore feasibility and activity of the combination of atezolizumab associated with EBRT after TURBT in the treatment of localized MIBC with preservation intent. Methods: The primary endpoint of this study is to assess the efficacy of atezolizumab concurrent with EBRT in terms of pathological complete response. The secondary endpoints include OS, DSS, disease free survival, bladder intact disease-free survival, number of patients (pts) with muscle invasive and non-muscle invasive local failure, the rate of distance metastases, the rate of pts with bladder preserved, the rate of immediate or late salvage cystectomy and safety profile and tolerability of the combination. Biomarkers will be evaluated as exploratory endpoints. Elegibility criteria include pts with histologically-confirmed diagnosis of MIBC in clinical stages T2-4a N0 M0, who are not candidates for radical cystectomy by medical reasons, refusal or patient’s choice, unfit for cisplatin and PS (ECOG) 0-2. Pts will receive atezolizumab 1.200 mg by IV infusion on Day1 of each cycle every 3 weeks for a total of 6 treatment courses, concurrent with EBRT 60 Gy in 30 fractions over 6 weeks at 2 Gy/day. With 35 evaluable pts and a pCR of 80%, the 95%CI of the estimation would be 0.62–0.92. The study will be stopped if we do not achieve at least 9 pCR among the first 13 evaluable pts. Otherwise, the study will continue until 39 pts. Clinical trial information: 2018-004348-47.

The impact of underinsurance on bladder cancer diagnosis, survival, and care delivery for individuals under the age of 65years.

Health insurance is a key mediator of health care disparities. Outcomes in bladder cancer, one of the costliest diseases to treat, may be especially sensitive to a patient's insurance status. The Surveillance, Epidemiology, and End Results registry and the National Cancer Data Base were used to identify individuals younger than 65years who were diagnosed with bladder cancer from 2007 to 2014. The associations between the insurance status (privately insured, insured by Medicaid, or uninsured) and the following outcomes were evaluated: diagnosis with advanced disease, cancer-specific survival, delay in treatment longer than 90days, treatment in a high-volume hospital, and receipt of neoadjuvant chemotherapy (NAC). Compared with those with private insurance, uninsured and Medicaid-insured individuals were nearly twice as likely to receive a diagnosis of muscle-invasive bladder cancer (odds ratio [OR] for uninsured individuals, 1.90; 95% confidence interval [CI], 1.70-2.12; OR for Medicaid-insured individuals, 2.03; 95% CI, 1.87-2.20). They were also more likely to die of bladder cancer (adjusted hazard ratio [AHR] for uninsured individuals, 1.49; 95% CI, 1.31-1.71; AHR for Medicaid-insured individuals, 1.61; 95% CI, 1.46-1.79). Delays in treatment longer than 90days were more likely for uninsured (OR, 1.36; 95% CI, 1.12-1.65) and Medicaid-insured individuals (OR, 1.22; 95% CI, 1.03-1.44) in comparison with the privately insured. Uninsured patients had lower odds of treatment at a high-volume facility, and Medicaid-insured patients had lower odds of receiving NAC (P<.001 for both). Compared with privately insured individuals, uninsured and Medicaid-insured individuals experience worse prognoses and poorer care quality. Expanding high-quality insurance coverage to marginalized populations may help to reduce the burden of this disease.

Disparities in Stage at Diagnosis in an Equal-access Integrated Delivery System: A Retrospective Cohort Study of 7244 Patients With Bladder Cancer.

Disparities in bladder cancer survival by race/ethnicity and gender are likely related to differences in diagnosis. We assessed disparities in stage at diagnosis and potential contributing factors within a large, integrated delivery system. We conducted a retrospective cohort study of 7244 patients with bladder cancer age≥ 21 years diagnosed from January 2001 to June 2015 within Kaiser Permanente Southern California. Bivariate analyses compared stage at diagnosis - as well as comorbidities, health plan membership length, and health care utilization prior to diagnosis - by race/ethnicity, gender, and age. Multivariable generalized linear mixed models with urologist as a random effect were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for diagnosis of muscle-invasive bladder cancer (MIBC) versus non-muscle-invasive bladder cancer. In multivariable analyses, stage at diagnosis varied significantly by race/ethnicity (P< .001). Non-Hispanic black patients had significantly higher odds of being diagnosed with MIBC than non-Hispanic white patients (OR, 1.33; 95% CI, 1.05-1.67), whereas Asian patients had significantly lower odds (OR, 0.67; 95% CI, 0.49-0.91). Women were significantly more likely to be diagnosed with MIBC than men (OR, 1.40; 95% CI, 1.22-1.61). Non-Hispanic black women had the highest proportion (39%) of MIBC diagnoses. Among Hispanic and Asian patients, a greater proportion of diagnoses occurred at younger ages. Health care coverage within an equal-access system did not eliminate disparities in stage at diagnosis by race/ethnicity or gender. Studies are needed to identify etiologic factors and aspects of care delivery (eg, patient-physician interactions) that may affect the diagnostic process to inform efforts to improve health equity.