Early Radical Cystectomy Research Articles

Abstract B004: Deep learning unveils molecular footprints in histology: predicting molecular subtypes from bladder cancer histology slides

Abstract Introduction: Transurethral resection followed by intravesical bacillus Calmette-Guerin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (HR-NMIBC) patients. However, ≈20% of HR-NMIBC patients progress to muscle-invasive or metastatic disease, which is associated with a high-risk of death. Early identification of patients who are unlikely to benefit from BCG treatment could benefit from an early radical cystectomy or bladder-sparing alternatives. Previously, we showed that molecular subtyping or HR-NMIBC identified BCG response subtypes (BRS 1/2/3). BRS3 tumors were associated with a poor response to BCG and a high-risk of progression. However, molecular subtyping relies on resource-intensive and costly sequencing methods such as next-generation sequencing, and microarray analysis. We employed deep learning (DL) to predict BRS3 vs BRS1/2 molecular subtypes from digitized histology slides. Methods: Haematoxylin and eosin (H&E)-stained slides were digitized, and quality control was performed. The areas where the RNA was extracted were annotated pixel-wise by a trained pathology assistant, using QuPath. Image tiles of 512 × 512 pixels at 10X, 20X, and 40X magnifications were extracted with a 25% overlap. For classification, BRS1 and BRS2 images were grouped, while BRS3 images were categorized separately. After applying Macenko normalization, tiles were split based on individual patients into a 75/25 training/validation ratio via stratified 4-fold cross-validation. Four DL models (DenseNet, Inception, ShuffleNet, ResNet) were trained to classify tiles into BRS3 and BRS1/2, with tile labels based on the patient’s subtype. Patient-level classification was performed using majority voting from tile predictions. Model efficacy was gauged using the area under the ROC curve (AUC). Results: Out of 245 H&E slides, 45 were discarded after quality control. From 200 patients – with a 70:30 distribution between BRS1&2 and BRS3 The DenseNet model at 10x magnification was the best-performing model, achieving the highest AUC compared to all other models and magnifications. On the image tile level, the best DenseNet achieved an average AUC of 0.65 with a standard deviation of 0.03 across the four folds of the validation set. At the patient-level prediction, the best DenseNet reached an average AUC of 0.80 and a standard deviation of 0.05 on the validation set. Conclusion: Our study demonstrates that deep learning classifies BSR3 from BSR1 and 2 subtypes from H&E slides. This method holds potential to identify BRS3 HR-NMIBC patients who may benefit from alternative treatments than BCG. With further refinement, this deep learning strategy can become a key tool in histology, aiding in swift, affordable, and efficient subtype identification. Hence, this method has the potential to bridge the gap between molecular techniques and clinical practice. Future research should prioritize evaluating the model on an external test cohort and consider predicting additional molecular markers to fine-tune prediction outcomes. Citation Format: Farbod Khoraminia, Flouros C de Jong, Farhan Akram, Geert Litjens, Maarten D.J. Jansen, Alberto Nakuama Gonzalez, Danique Lichtenburg, Andrew Stubbs, Nadieh Khalili, Tahlita C.M. Zuiverloon. Deep learning unveils molecular footprints in histology: predicting molecular subtypes from bladder cancer histology slides [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B004.

Cost-utility of Initial Management of High-grade T1 Bladder Cancer With Intravesical BCG vs Immediate Radical Cystectomy

ObjectivesTo compare the cost-utility of initial management of high-grade T1 non-muscle invasive bladder cancer (HGT1 NMIBC) with intravesical BCG versus immediate radical cystectomy. High risk NMIBC patients may climb a costly ladder of treatments, culminating in radical cystectomy for oncologic or symptomatic benefit in up to one-third. This high healthcare resource utilization presents a challenging dilemma in balancing sufficiently aggressive management with cost, toxicity, and quality-of-life. MethodsCost-utility of initially managing HGT1 with intravesical BCG and early radical cystectomy with ileal conduit urinary diversion was compared using decision-analytic Markov models. Five-year oncologic outcomes, adverse event rates, and published utility values were extracted from literature. Costs were calculated from a US Medicare perspective in 2021 US dollars. Sensitivity analysis identified drivers of cost and break-even points for recurrence and progression. ResultsMean costs were $26,093 for intravesical BCG and $39,720 for immediate radical cystectomy, though cystectomy generated a gain of 2.2 QALYs compared to intravesical BCG. Immediate cystectomy was a more cost-effective management strategy for HGT1 NMIBC with an ICER of $7120/QALY.The costs associated with cystectomy, TURBT, and BCG toxicity had the greatest impact on ICER. One-way sensitivity analysis demonstrated that intravesical BCG became a cost-effective management strategy if the five-year recurrence rate of HG T1 was less than 56% or the five-year progression rate to MIBC was less than 4%. ConclusionsAt current prices, treatment of high-grade T1 NMIBC with early radical cystectomy is more cost-effective management strategy than initial treatment with intravesical BCG.

Primary signet-ring cell carcinoma of the urinary bladder ‒ A rare bladder tumor

AimPrimary Signet Ring Cell Carcinoma (SRCC) of the bladder accounts for only 1%‒4% of all bladder malignancies. To date, few studies have been conducted to investigate the characteristics of SRCC. This study aimed to investigate the clinical features and treatments of SRCC and explore the independent risk factors of survival in SRCC patients. Patients and methodsA retrospective study was conducted on 32 eligible patients. The survival rate was calculated with the Kaplan-Meier method, and the COX proportional hazards model was used to investigate the independent risk factors of prognosis. ResultsIn the present study, the 1-year and 2-year survival rates of SRCC patients were 53.1% and 9.4%, respectively. The TNM stage, tumor differentiation, and metastasis after treatment were risk factors for the prognosis of SRCC patients (p < 0.05), while surgical treatment, chemotherapy, and positive GATA3 expression were protective for prognosis (p < 0.05). Multivariate analysis showed that GATA3 was an independent protective factor for prognosis (p < 0.05), and T-stage was an independent risk factor (p < 0.05). ConclusionsPrimary SRCC of the bladder is highly malignant and has a poor prognosis. Its clinical and imaging findings are usually non-specific. Early radical cystectomy and postoperative adjuvant systemic chemotherapy are helpful to improve the survival rate. T-stage is an independent risk factor for survival, and positive GATA3 expression is protective for primary SRCC of the bladder.

Oncological Outcomes for Patients with European Association of Urology Very High-risk Non–muscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin or Early Radical Cystectomy

BackgroundEuropean Urology Association (EAU) guidelines recommend immediate radical cystectomy (early RC) for patients with very high-risk (VHR) non–muscle invasive bladder cancer (NMIBC), with bacillus Calmette-Guérin (BCG) recommended only for those who refuse or are unfit for RC. ObjectiveTo describe oncological outcomes following BCG or early RC in a contemporary cohort of patients with VHR NMIBC (EAU criteria). Design, setting, and participantsPatients diagnosed with VHR NMIBC between 2000 and 2020 were identified from our institutional NMIBC registry. Outcome measurements and statistical analysisThe primary outcomes were overall survival (OS) and cancer-specific mortality (CSM). Secondary outcomes were the progression rate and high-grade recurrence (HGR) rate for patients receiving BCG. Results and limitationsWe identified 235 patients with VHR NMIBC, of whom 157 (67%) received BCG and 78 (33%) underwent early RC. The median follow-up was 52.8 mo. OS and CSM rates were 80.2% and 5.3% in the BCG group, and 88.1% and 4.9% in the early RC group, respectively with no significant difference in OS (p = 0.6) or CSM (p = 0.8) between the two groups. Among the patients treated with BCG, 5-yr HGR and progression rates were 41.9% and 17.4%, respectively; 39 patients (25%) underwent delayed RC after BCG. No significant difference in CSM emerged when comparing patients treated with delayed RC (after BCG) with those undergoing early RC (p = 0.86). ConclusionsOur findings suggest that intravesical BCG can be offered to patients as a resonable alternative to early RC for selected patients with VHR NMIBC. Patient summaryWe evaluated outcomes for patients with very high-risk non–muscle-invasive bladder cancer (NMIBC) treated with BCG (bacillus Calmette-Guérin) versus early surgical removal of the bladder and found no differences in survival. We conclude that BCG could be offered to selected patients with this type of bladder cancer as a reasonable alternative to early bladder removal.

Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guérin.

The recommended treatment for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. If progression to advanced disease occurs, then patients must undergo a radical cystectomy with risks of substantial morbidity and poor clinical outcome. Identifying tumors unlikely to respond to BCG can translate into alternative treatments, such as early radical cystectomy, targeted therapies, or immunotherapies. Here, we conducted molecular profiling of 132 patients with BCG-naive HR-NMIBC and 44 patients with recurrences after BCG (34 matched), which uncovered three distinct BCG response subtypes (BRS1, 2 and BRS3). Patients with BRS3 tumors had a reduced recurrence-free and progression-free survival compared with BRS1/2. BRS3 tumors expressed high epithelial-to-mesenchymal transition and basal markers and had an immunosuppressive profile, which was confirmed with spatial proteomics. Tumors that recurred after BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive patients with HR-NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological variables. For clinical application, we confirmed that a commercially approved assay was able to predict BRS3 tumors with an area under the curve of 0.87. These BCG response subtypes will allow for improved identification of patients with HR-NMIBC at the highest risk of progression and have the potential to be used to select more appropriate treatments for patients unlikely to respond to BCG.

Bladder-sparing Treatment in Patients with Bacillus Calmette-Guerin–unresponsive Non–muscle-invasive Bladder Cancer: An Analysis of Long-term Survival Outcomes

BackgroundData for bladder-sparing treatment (BST) in bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients report short-term outcomes limited to 1–2 yr. ObjectiveTo assess long-term survival outcomes of BCG-unresponsive NMIBC patients treated with BST. Design, setting, and participantsBCG-unresponsive NMIBC patients diagnosed between January 2000 and September 2021 from an institutional NMIBC registry were evaluated. InterventionLong-term survival outcomes for patients receiving BST, early radical cystectomy (RC), and delayed RC were compared. Outcome measurements and statistical analysisThe primary endpoints were overall survival (OS) and cancer-specific survival (CSS). Results and limitationsIn total, 114 patients with a median follow-up of 71.2 mo (interquartile range: 32.6–132.2) were analyzed. There were no significant differences in OS (hazard ratio [HR]: 1.40, 95% confidence interval [CI]: 0.68–2.89, p = 0.4) or CSS (HR: 0.88, 95% CI: 0.22–3.55, p = 0.9) between patients undergoing early RC (n = 38) and BST (n = 76). At 60 mo, BST patients had a high-grade recurrence-free rate, muscle-invasive disease/metastasis progression-free rate, and avoidance of RC rate of 37%, 83%, and 58%, respectively. Current smoker status (HR: 4.44, 95% CI: 1.41–13.97, p = 0.011) was the only variable predictive of high-grade recurrence following a multivariable analysis. The median time to RC from BCG-unresponsive date was 2.1 and 11.7 mo for those undergoing early RC and delayed RC (after BST), respectively. Patients treated with early RC had a higher incidence of cT1 disease (53% vs 36%, p = 0.049) and lymphovascular invasion (LVI; 11% vs 0%, p = 0.011) compared to patients treated with BST. Survival outcomes were similar between groups: 10-yr OS—58% versus 50% (HR: 1.40, 95% CI: 0.68–2.89, p = 0.4), and 10-yr CSS—81% versus 85% (HR: 0.88, 95% CI: 0.22–3.55, p = 0.9). ConclusionsAn analysis of long-term survival of BCG-unresponsive NMIBC patients receiving BST suggests that it may be safe in patients without LVI and/or variant histology and nonsmokers. Survival outcomes for patients treated with BST may not be inferior to those receiving early RC. Patient summaryBladder-sparing treatment can be offered to appropriately selected patients who have bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer. Long-term outcomes may not be inferior to those for patients who opt for early radical cystectomy.

PD13-12 BLADDER SPARING TREATMENT IN PATIENTS WITH BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: AN ANALYSIS OF LONG-TERM SURVIVAL OUTCOMES

You have accessJournal of UrologyCME1 Apr 2023PD13-12 BLADDER SPARING TREATMENT IN PATIENTS WITH BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: AN ANALYSIS OF LONG-TERM SURVIVAL OUTCOMES Wei Shen Tan, Valentina Grajales, Roberto Contieri, Patrick Hensley, Kelly Bree, Pavlos Msaouel, Charles Guo, Neema Navai, Colin Dinney, and Ashish Kamat Wei Shen TanWei Shen Tan More articles by this author , Valentina GrajalesValentina Grajales More articles by this author , Roberto ContieriRoberto Contieri More articles by this author , Patrick HensleyPatrick Hensley More articles by this author , Kelly BreeKelly Bree More articles by this author , Pavlos MsaouelPavlos Msaouel More articles by this author , Charles GuoCharles Guo More articles by this author , Neema NavaiNeema Navai More articles by this author , Colin DinneyColin Dinney More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003260.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In recent years, more patients are selecting to forgo radical cystectomy (RC) and select bladder sparing treatment (BST) for Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). Herein, we assessed long-term survival outcomes of BCG unresponsive NMIBC patients treated with BST versus early RC. METHODS: We performed an IRB approved retrospective study analyzing patients with BCG unresponsive NMIBC diagnosed between April 2001 and September 2021 at our institution. Survival outcomes between the following patient cohorts were compared: 1) Early RC versus BST and 2) Early RC versus delayed RC. Primary endpoint was overall-(OS) and cancer-specific survival (CSS). Cox-regression was used to estimate OS, CSS, high-grade recurrence-free survival (RFS) and progression-free survival (PFS) endpoints. RESULTS: A total 118 patients who met criteria for BCG unresponsive disease were identified (80 BST versus 38 early RC). Patients undergoing early RC were more likely to have higher T1 stage (52.6% vs 35.0%, p=0.048) and lymphovascular invasion (10.5% vs 0%, p=0.003) compared to those treated with BST. Comparative outcomes for OS (HR: 1.34, 95% CI: 0.65-2.76, log-rank p=0.429) and CSS (HR: 0.84, 95% CI: 0.21-3.38, log-rank p=0.803) between early RC and BST were not significant (inconclusive). With a median follow-up of 72.1 months (IQR: 30.1-134.0), at 60 months, BST treated patients had a high-grade RFS rate of: 37%, PFS to muscle-invasive disease/metastasis rate: 84% and avoidance of RC rate: 81%. The risk of high-grade recurrence was higher in current smokers (HR: 6.00, 95% CI: 1.73-20.6, p=0.005). For patients undergoing RC for BCG unresponsive disease, median time to RC were 2.1 months and 15.8 months for early and delayed RC respectively. Comparative outcomes were similar for the early and delayed RC: OS (58% vs 54%) (HR: 1.17, 95% CI: 0.50-2.71, p=0.717) and CSS (81% vs 81%) (HR: 1.07, 95% CI: 0.23-4.92, log-rank p=0.927). CONCLUSIONS: Long-term survival outcomes following BST (with delayed RC when indicated) in patients with BCG unresponsive NMIBC is not inferior compared to early RC. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research, the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant, NIH/NCI UTMD Anderson SPORE in Genitourinary Cancer (P50CA091846) and the Cancer Center Support Grant (NCI Grant P30 CA016672) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e410 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wei Shen Tan More articles by this author Valentina Grajales More articles by this author Roberto Contieri More articles by this author Patrick Hensley More articles by this author Kelly Bree More articles by this author Pavlos Msaouel More articles by this author Charles Guo More articles by this author Neema Navai More articles by this author Colin Dinney More articles by this author Ashish Kamat More articles by this author Expand All Advertisement PDF downloadLoading ...

MP22-20 CONTEMPORARY TRENDS IN THE MANAGEMENT OF T1 BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP22-20 CONTEMPORARY TRENDS IN THE MANAGEMENT OF T1 BLADDER CANCER Michael Hung, Adithya Balasubramanian, and Douglas Scherr Michael HungMichael Hung More articles by this author , Adithya BalasubramanianAdithya Balasubramanian More articles by this author , and Douglas ScherrDouglas Scherr More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003247.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The current treatment strategy for T1 non muscle invasive bladder cancer is centered around bladder preservation with an emphasis on complete tumor resection and BCG therapy. However, the insidious nature of T1 bladder cancer lead many to offer early radical cystectomy with or without additional systemic therapy. We sought to examine the contemporary treatment patterns in the management of T1 bladder cancer in a nationwide cohort. METHODS: The National Cancer Database (NCDB) was queried to identify all cases of cT1 bladder cancer from 2004 to 2017. Demographic and clinical characteristics were compared and trended over the study period. We identified subsequent surgical therapy after initial diagnosis and stratified patients who underwent radical cystectomy and those who underwent bladder preserving surgery alone. Kaplan Meier curves were used to estimate survival in these cohorts, stratified by the treatment facility. RESULTS: The total of 128,400 patients were identified in the study period. The rate of radical cystectomy in patients with T1 bladder cancer increased from 4.6% in 2004 to 7.5% in 2017 (Figure 1a). In patients who underwent radical cystectomy, the overall rate of neoadjuvant and adjuvant chemotherapy was 11% and 17%, respectively. There was no significant difference in median OS among patients who received neoadjuvant chemotherapy compared to no systemic therapy (8.6 yrs vs 7.5 yrs, p=0.15), and no difference in rates of pathologic upgrade to T2-4 at cystectomy (36.7% vs 34.6%, p=0.42). Patients who underwent cystectomy had significantly longer median OS compared to those who had bladder preserving surgery alone (7.5 yrs vs 7 yrs, p=0.01). A majority (58%) of all radical cystectomies were performed at academic facilities and median OS was significantly higher at academic facilities versus community hospitals (8.1 yrs vs 6.1 yrs, p<0.01) (Figure 1b). CONCLUSIONS: Rates of radical cystectomy for the management of T1 bladder cancer have increased over time, congruent with evidence suggesting improved survival compared to local therapy alone. However, increased rates of neoadjuvant chemotherapy were observed despite the lack of clear guidelines or benefits for use. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e305 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Hung More articles by this author Adithya Balasubramanian More articles by this author Douglas Scherr More articles by this author Expand All Advertisement PDF downloadLoading ...

Radical cystectomy for bladder urothelial carcinoma with aggressive variant histology.

The aim of this study is to report our experience in managing bladder cancer in patients with variant pathology. Retrospective data collection for all patients managed by radical cystectomy over the last 3 years for a variant pathol-ogy was completed. We specifically included micropapillary and nested variants. Ten patients were identified, with eight having micropapillary carcinoma (MPC) and two having nested vari-ants. Nine patients were male. The median age was 75. The two patients with nested variant were 56 and 62 years old, respec-tively, whereas all patients with MPC were over the age of 70. Upon cystectomy of all micropapillary cases, three patients (37.5%) had positive lymph node invasion and the final patholo-gy was T2 (two patients), T3 (two patients), and T4 (four patients). Barring a grade III complication Clavien-Dindo classi-fication due to wound dehiscence that necessitated secondary surgical closure, there were no specific perioperative complica-tions. Given the urethral invasion, cystourethrectomy was per-formed on the female patient. Within a median 13-month fol-low-up, three patients developed local recurrence, including two urethral and one new lateral pelvic mass. Considering the muscle invasive nature of micropapillary and nested bladder cancer, aggressive surgical management should not be postponed. Moreover, due to notable prevalence of concurrent and/or recurrent urethral involvement, initial urethrectomy or early and frequent postoperative ure-throscopy should be provided. Patients with variant histology bladder cancer may benefit from early radical cystectomy when compared to bladder sparing protocols and prostate sparing cystectomy treatment options.

Effectiveness of Early Radical Cystectomy for High-Risk Non-Muscle Invasive Bladder Cancer.

Simple SummaryThere is currently contradictory evidence available regarding the use of early radical cystectomy for high-risk non-muscle-invasive bladder cancer that can be performed either upfront or in a delayed setting after BCG failure. Thus, we aimed to compare the perioperative and oncological outcomes between patients who underwent upfront vs. delayed early radical cystectomy. Our results suggest similar perioperative outcomes between the two treatment groups, with an increased risk of pathological upstaging after upfront early radical cystectomy that did not impact survival, as compared to delayed early radical cystectomy. However, further studies are needed to determine whether a subgroup of patients might still benefit from upfront early radical cystectomy, given the highly heterogeneous prognosis of this population. This supports the initial use of intravesical instillations of BCG for patients with high-risk non-muscle-invasive bladder cancer, but further studies are needed to determine if any specific subgroup could still benefit from upfront early radical cystectomy.Purpose: The purpose of this study is to compare perioperative and oncological outcomes of upfront vs. delayed early radical cystectomy (eRC) for high-risk non-muscle-invasive bladder cancer (HR-NMIBC). Methods: All consecutive HR-NMIBC patients who underwent eRC between 2001 and 2020 were retrospectively included and divided into upfront and delayed groups, according to the receipt or not of BCG. Perioperative outcomes were evaluated and the impact of upfront vs. delayed eRC on pathological upstaging, defined as ≥pT2N0 disease at final pathology, was assessed using multivariable logistic regression. Recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS) were compared between upfront and delayed eRC groups using inverse probability of treatment weighting (IPTW)-adjusted Cox model. Results: Overall, 184 patients received either upfront (n = 87; 47%) or delayed (n = 97; 53%) eRC. No difference was observed in perioperative outcomes between the two treatment groups (all p > 0.05). Pathological upstaging occurred in 55 (30%) patients and upfront eRC was an independent predictor (HR = 2.65; 95% CI = (1.23–5.67); p = 0.012). In the IPTW-adjusted Cox analysis, there was no significant difference between upfront and delayed eRC in terms of RFS (HR = 1.31; 95% CI = (0.72–2.39); p = 0.38), CSS (HR = 1.09; 95% CI = (0.51–2.34); p = 0.82) and OS (HR = 1.19; 95% CI = (0.62–2.78); p = 0.60). Conclusion: our results suggest similar perioperative outcomes between upfront and delayed eRC, with an increased risk of upstaging after upfront eRC that did impact survival, as compared to delayed eRC.

PD14-08 COMPARATIVE OUTCOMES OF PRIMARY AND RECURRENT HIGH GRADE NON-MUSCLE INVASIVE AND PRIMARY AND PROGRESSIVE MUSCLE-INVASIVE BLADDER CANCER AFTER RADICAL CYSTECTOMY: RESULTS FROM A RETROSPECTIVE MULTICENTER STUDY

PD14-08 COMPARATIVE OUTCOMES OF PRIMARY AND RECURRENT HIGH GRADE NON-MUSCLE INVASIVE AND PRIMARY AND PROGRESSIVE MUSCLE-INVASIVE BLADDER CANCER AFTER RADICAL CYSTECTOMY: RESULTS FROM A RETROSPECTIVE MULTICENTER STUDY

IJU this Issue

This issue of International Journal of Urology contains one Review Article, 10 Original Articles, and eight editorial comments. Yuan et al. (Jiangsu, China) updated a meta-analysis for the diagnostic performance of the Vesical Imaging–Reporting And Data System (VI-RADS) for predicting muscle-invasive bladder cancer (MIBC) with 20 studies published between September 2018 and July 2021. VI-RADS was introduced in 2018 to define a standardized approach to imaging and reporting multiparametric magnetic resonance imaging for patients with bladder cancer. The diagnostic performance of the VI-RADS for predicting MIBC was excellent in both cutoff points of the VI-RADS 3 and 4. Multiple image acquisition planes of diffusion-weighted imaging should be given more attention in the VI-RADS. We hope that VI-RADS will become more mature and prevalent, which should lead to better management of bladder cancer via further studies. In the original articles, Nishimura et al. (Nara, Japan) evaluated the clinical outcomes and prognostic factors in Japanese patients with bacillus Calmette-Guerin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC) who underwent early radical cystectomy (RC) using a large-scale multicenter retrospective study and concluded the highest-risk status among the pre-BCG factors was associated with upstaging to extravesical tumors and poor prognosis, despite early RC procedures. The Japanese Urological Association Clinical Practice Guidelines for Bladder Cancer 2019 recommended that patients with BCG-unresponsive disease are considered unlikely to benefit from further BCG therapy and early RC. This study seems to be one of those with the evidence based on a pathological evaluation. Although some new strategies such as intravesical nadofargene firadenovec gene therapy (Lancet Oncol. 2021; 22: 107–17), pembrolizumab monotherapy (Lancet Oncol. 2021; 22: 919–30) have been reported, there is no doubt that BCG-unresponsive disease is a risk factor and RC will continue to be required in a certain proportion of patients with BCG-unresponsive NMIBC. Kato et al. (Osaka, Japan) evaluated the long-term incidence and clinical features of post-transplant lymphoproliferative disorders (PTLD) in kidney transplant recipients from two major transplantation centers in Japan. Graft survival has improved due to a reduction in the acute rejection rate by advances in immunosuppressive agents; however long-term survival after kidney transplantation remains unchanged. Therefore, it is extremely important to focus on malignancy, especially PTLD after kidney transplantation. They emphasized the strategies to identify PTLD and suggested the benefits of positron emission tomography-computed tomography for ascertaining PTLD. They also revealed that mycophenolate mofetil contributed the onset of PTLD, and rituximab was not significantly associated with the incidence of PTLD. We have to be careful for each immunosuppressive agent. Yamashita et al. (Shizuoka, Japan) examined the incidence and location of lower extremity deep vein thrombosis (DVT) in patients undergoing RC. Venous thromboembolism (VTE) including DVT and pulmonary embolism is a serious perioperative complication in urological surgery. RC, whether open or robot-assisted surgery, is the procedure with the highest risk of perioperative VTE in urological surgery according to the European Association of Urology (EAU) guidelines on thromboprophylaxis in urological surgery. They also identified that preoperative D-dimer level was a significant risk factor for preoperative DVT, and preoperative D-dimer level, type of urinary diversion (ileal neobladder), and preoperative DVT were significant risk factors for postoperative DVT. EAU guidelines strongly recommended the use of pharmacological prophylaxis in all patients undergoing open and robot-assisted RC. These results might suggest appropriate patients for pharmacological prophylaxis in RC. Unfortunately, the limited space does not allow me to introduce all the articles. However, all the papers are very interesting and informative. Please enjoy this issue of the International Journal of Urology. None declared.

Editorial Comment from Dr Shindo to Prognostication in Japanese patients with bacillus Calmette‐Guérin‐unresponsive non‐muscle‐invasive bladder cancer undergoing early radical cystectomy

Editorial Comment from Dr Shindo to Prognostication in Japanese patients with bacillus Calmette‐Guérin‐unresponsive non‐muscle‐invasive bladder cancer undergoing early radical cystectomy

Squamous or Glandular Differentiation Predicts Poor Prognosis in pT1 Urothelial Carcinoma.

The aim of this study was to evaluate the prognosis of patients with T1N0M0 urothelial carcinoma with squamous differentiation (UCSD) or glandular differentiation (UCGD) because it has not been determined whether these variant histologies behave more aggressively than pure urothelial carcinoma (PUC). Ninety-nine patients diagnosed with pT1N0M0 bladder cancer and treated conservatively with transurethral resection of bladder tumor at Kanazawa University Hospital between 2007 and 2019 were included in this study. The overall survival, cancer-specific survival (CSS), and recurrence-free survival of the variant histology and PUC groups were evaluated and compared. The variant histology group had significantly lower overall survival (p=0.006) and CSS (p=0.0095) than the PUC group did. Variant histology was found to be an independent prognostic factor in univariate and multivariate analyses for overall survival and CSS. On the other hand, no significant difference in progression-free survival was observed between the two groups (p=0.439). However, the variant histology group had significantly lower overall survival (p=0.004) and CSS (p=0.004) after progression. The prognosis for patients with pT1 bladder cancer with UCSD or UCGD treated conservatively with transurethral resection of bladder tumor was poor. Considering the worse prognosis of these patients after stage progression, early radical cystectomy could be recommended.

Predictors of response to BCG therapy in non-muscle invasive bladder cancer

Intravesical BCG (Bacillus Calmette?Guerin) therapy represents the therapy of choice for intermediaryand high-risk non-muscle invasive bladder cancers after transurethral resection. However, up to 40% of these patients do not show adequate response to the therapy (BCG failure) and 15% of them experience the progression of the disease to muscle-invasive bladder cancer. In such cases, radical cystectomy is indicated. Studies suggest that early radical cystectomy in patients with BCG failure is followed by better survival compared to delayed radical cystectomy. The prediction of response to BCG therapy could enable early identification of patients on which this therapy would have no effect and who should undergo early radical cystectomy.

Non-muscle invasive micropapillary urothelial carcinoma of the bladder: Variable use of initial cystectomy versus intravesical bacillus calmette-guérin

Introduction and Objective Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive histologic variant of bladder cancer. Treatment guidelines recommend forgoing Bacillus Calmette-Guérin (BCG) therapy in favor of early radical cystectomy for non-muscle invasive (NMI)-MPUC due to high rates of disease progression. We aimed to evaluate its management in patients with immediate cystectomy and BCG across various centers. Methods Patients with MPUC were identified from the National Cancer Database (2004-2017). Treatment trends and rates of pathological upstaging were identified. Bivariate and multivariate analyses were performed to assess differences in outcomes by treatment approach. Results 1,685 patients were diagnosed with MPUC during the study period with 531 identified with localized Ta, T1, or Tis disease. BCG was administered as an initial therapy in 24.1% of NMI-MPBC patients and in 16.3% of NMI-non-MPUC patients (p&lt;0.001). Cystectomy was performed as primary therapy for NMI disease in 29.9% of MPUC and in 2.7% of non-MPUC patients (p&lt;0.001). Of the patients who underwent primary cystectomy, upstaging from NMI-MPUC to T2-T4 disease was seen in 46.5% of the MPUC patients compared to 37.3% in patients with non-MPUC (p=0.025). Upstaging to pathologic N1-3 disease was observed in 33.1% of MPUC patients compared to 11.9% non-MPUC patients (p&lt;0.001). Cox regression analysis, adjusting for patient age, sex, race, comorbidities, and disease stage, care at academic cancer centers were associated with increased odds of having cystectomy as primary therapy compared to community cancer centers (OR = 4.29, 95% CI 2.73-6.76). Conclusion The current study lends evidence to current practice guidelines by reporting treatment patterns for patients with micropapillary bladder cancer across a broad spectrum of clinical practice. NMI-MPUC patients treated at academic cancer centers were more likely to receive radical surgery as primary treatment compared to patients at the community cancer centers.

Non-muscle invasive micropapillary urothelial carcinoma of the bladder: Variable use of initial cystectomy versus intravesical bacillus calmette-guérin

Introduction and Objective Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive histologic variant of bladder cancer. Treatment guidelines recommend forgoing Bacillus Calmette-Guérin (BCG) therapy in favor of early radical cystectomy for non-muscle invasive (NMI)-MPUC due to high rates of disease progression. We aimed to evaluate its management in patients with immediate cystectomy and BCG across various centers. Methods Patients with MPUC were identified from the National Cancer Database (2004-2017). Treatment trends and rates of pathological upstaging were identified. Bivariate and multivariate analyses were performed to assess differences in outcomes by treatment approach. Results 1,685 patients were diagnosed with MPUC during the study period with 531 identified with localized Ta, T1, or Tis disease. BCG was administered as an initial therapy in 24.1% of NMI-MPBC patients and in 16.3% of NMI-non-MPUC patients (p&lt;0.001). Cystectomy was performed as primary therapy for NMI disease in 29.9% of MPUC and in 2.7% of non-MPUC patients (p&lt;0.001). Of the patients who underwent primary cystectomy, upstaging from NMI-MPUC to T2-T4 disease was seen in 46.5% of the MPUC patients compared to 37.3% in patients with non-MPUC (p=0.025). Upstaging to pathologic N1-3 disease was observed in 33.1% of MPUC patients compared to 11.9% non-MPUC patients (p&lt;0.001). Cox regression analysis, adjusting for patient age, sex, race, comorbidities, and disease stage, care at academic cancer centers were associated with increased odds of having cystectomy as primary therapy compared to community cancer centers (OR = 4.29, 95% CI 2.73-6.76). Conclusion The current study lends evidence to current practice guidelines by reporting treatment patterns for patients with micropapillary bladder cancer across a broad spectrum of clinical practice. NMI-MPUC patients treated at academic cancer centers were more likely to receive radical surgery as primary treatment compared to patients at the community cancer centers.

Prognostication in Japanese patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer undergoing early radical cystectomy.

The US Food and Drug Administration recently defined the clinical term "bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer" as a disease state resistant to adequate bacillus Calmette-Guérin therapy. There is a significant lack of prognostication for this disease even in patients who have undergone early radical cystectomy. This study aimed to identify the clinical outcomes and prognostic factors in Japanese patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer who underwent early radical cystectomy. Data from a large-scale multicenter retrospective study included 2879 patients with highest-risk or high-risk non-muscle-invasive bladder cancer who received intravesical bacillus Calmette-Guérin induction therapy between January 2000 and December 2019. A total of 141 patients (4.3%) met the criteria for bacillus Calmette-Guérin-unresponsive disease, of whom 47 (33.3%) underwent early radical cystectomy. Prognostic factors for three clinical endpoints, namely, unresectable lesion-free survival, cancer-specific survival, and overall survival, were identified. The highest-risk status at induction bacillus Calmette-Guérin was associated with short unresectable lesion-free survival (hazard ratio 7.85; P<0.05), cancer-specific survival (hazard ratio 12.24; P<0.05), and overall survival (hazard ratio 9.25; P<0.01). Moreover, extravesical tumors (pathological T3 or T4) on the radical cystectomy specimens were associated with poor prognosis and were found at a higher rate in patients with the highest-risk status at induction bacillus Calmette-Guérin than in those with high-risk status (35.7% vs 21.2%). The highest-risk status among the pre-bacillus Calmette-Guérin factors was associated with upstaging to extravesical tumors and poor prognosis despite early radical cystectomy procedures. Appropriate decision-making and the correct timing of radical cystectomy are vital to avoid treatment delays and improve outcomes.

High-Grade Non-Muscle Invasive Bladder Cancer: When to Move to Early Radical Cystectomy?

ObjectivesTo compare the outcomes of bladder preservation therapy with early or deferred radical cystectomy (RC) in high-grade non-muscle invasive bladder cancer.MethodsProspectively collected data were obtained for patients undergoing transurethral resection of bladder tumor (TURBT) at a tertiary care center between 2007 and 2018. Patients with a high-grade tumor (HGT1) were divided into three groups, depending on the treatment plan: conservative (GI), early RC (GII), or deferred RC (GIII). Kaplan-Meier analysis was performed to assess the cancer-specific survival (CSS).ResultsSeventy-one patients were included, and the patients had a median (range) age of 49 (32-72) years. The GI, GII, and GIII groups included 34 (47.9%), 14 (19.7%), and 23 (32.4%) patients, respectively. A significantly lower number of GII patients underwent >2 TURBTs (14.3% vs. 100%, p<0.001). Compared to GIII patients, GII patients had a shorter time to RC from the initial diagnosis (5.7 vs. 36.2 months, p=0.03). Ileal conduit and orthotropic bladder diversions were comparable between both groups, with significantly higher postoperative complications in GIII patients. The median (IQR) follow-up times for the groups were 84 (49-102), 82 (52-112), and 73 (36-89) months, respectively. The five-year and 10-year CSS for GII and GIII patients was 79% vs. 75% and 78% vs. 64%, respectively (log rank=0.19).ConclusionEarly RC should be considered an alternative treatment option in selected patients with HGT1 BC with expected longer life expectancy, which may significantly decrease postoperative complications and improve the CSS. However, selection bias in the current retrospective study may influence these outcomes.

Early cystectomy-patient selection and technique

Early radical cystectomy (RC) is atherapeutic option for non-muscle invasive bladder cancer (NMIBC). The 15-year overall survival after early RC in NMIBC patients is about 70%. Nevertheless, RC is associated with significant morbidity and mortality and therefore requires careful patient selection. The aim of the following review is to assess the selection process for early RC in NMIBC. Especially, the new European Association of Urology (EAU) risk calculator identifying NMIBC patients with very high risk for disease progression is described in detail. Furthermore, the technical aspects of the procedure are evaluated. Areview of the current literature (PubMed) and national and international guideline recommendations was also conducted.