Purpose:
To determine whether omitting antimicrobial prophylaxis (AMP) in TURB is safe in patients undergoing TURB without an indwelling pre-operative catheter/nephrostomy/DJ and a negative pre-operative urinary culture.
Material and methods:
A multi-centered randomized controlled trial (RCT) from 17-09-2017 until 31-12-2019 in 5 hospitals.
Patients with a pre-operative indwelling catheter/DJ-stent or nephrostomy and a positive pre-operative urinary culture (> 104 uropathogens/mL) were excluded.
Post-operative fever was defined as body temperature ≥ 38.3°C. A non-inferiority design with a 6% noninferiority margin and null hypothesis (H0) that the infection risk is at least 6% higher in the experimental (E) than in the control (C) group; H0: C (AMP-group) − E (no AMP-group) ≥ Δ (6% noninferiority margin).
A multivariable, logistic regression was performed for AMP and post-TURB fever with covariates: tumor size and (clot-) retention. The R Project® for statistical computing was used for statistical analysis and a p value of 0.05 was considered as statistically significant.
Results:
459 Patients were included and 202/459 (44.1%) received AMP vs 257/459 (55.9%) without AMP.
Fever occurred in 6/202 (2.9%; 95% CI [1.2%-6.6%]) patients with AMP vs 8/257 (3.1%; 95% CI [1.5%-6.1%]) without AMP (p=0.44). Multivariable, logistic regression showed no significant harm in omitting AMP when controlled for (clot-)retention and tumor size (p=0.85) and an adjusted risk difference in developing post-TURB fever of 0.0016; 95% CI [-0.029; 0.032].
Conclusion:
Our data suggest the safety of omitting AMP in patients undergoing TURB without an indwelling, pre-operative catheter/nephrostomy/DJ and a negative pre-operative urinary culture.

A randomized trial regarding antimicrobial prophylaxis (AMP) in transurethral resection of bladder tumor (TURB).

Introduction & Objectives
The majority of patients with non-metastatic (M0) muscle-invasive bladder cancer (MIBC) are treated with neo-adjuvant chemotherapy followed by radical cystectomy (RC) and extended lymph node dissection. Despite this aggressive treatment the outcome is poor and ultimately 30% of the patients with ≥ pathological (p)T3 tumors develop a pelvic recurrence, which is rarely salvageable and is often associated with debilitating sequels. In the past, adjuvant external beam radiotherapy (EBRT) has shown to increase disease free survival, but excessive toxicity hampered enthusiasm for further implementation. In this phase 2 trial the place of adjuvant EBRT after RC for high-risk MIBC is re-investigated.

Materials & methods
In this Belgian multicentric prospective phase 2 trial, seventy-two patients were included and received treatment. Eligible patients were patients with MIBC, treated with RC and presenting with ≥1 of the following characteristics: pT3 stage + presence of lymphovascular invasion on pathological examination, pT4 stage, <10 lymph nodes removed, positive lymph nodes, positive surgical margins. Prior to EBRT, a post-operative 18F-FDG-PET-CT was performed to rule out distant metastases. A median dose of 50 Gy in 25 fractions was administered, using Volumetric-Modulated Arc Therapy (VMAT), to the pelvic lymph node regions with inclusion of the cystectomy bed in case of a positive surgical margin. A simultaneous integrated boost up to 70 Gy was delivered to PET-CT positive lymph nodes. The primary endpoint was acute grade ≥3 gastro-intestinal (GI) toxicity and in case of a neobladder reconstruction grade 4 urinary toxicity, within 12 weeks after EBRT. Secondary endpoints were late toxicity, local control, disease free survival and overall survival (OS). Toxicity was scored using the Radiation Therapy Oncology Group (RTOG) criteria and the Common Terminology Criteria for Adverse Events (CTCEA) v4.0.

Results
The median follow up was 15 months (1-72 months). Five (7%) patients had acute grade ≥3 GI toxicity. The 2-year probability of developing grade ≥3 and grade ≥2 GI toxicity was 18% and 79%, respectively. Of the seventeen neobladder patients 18% and 11% reported acute and late grade 2 urinary toxicity, respectively. Grade ≥3 urinary toxicity was not reported. The 2-year local recurrence-free survival and clinical relapse-free survival (CRFS) rates were 88% ±4% and 44% ±7, respectively. The mean CRFS time was 31 months (95% CI: 22-39 months). The 2-year OS rate was 52% ±7%, with a mean OS time of 39 months (95% CI: 31-48 months).

Conclusions
Using newer techniques such as VMAT, toxicity after adjuvant EBRT is acceptable. Preliminary survival data are encouraging and underline the importance of further evaluating the place of adjuvant EBRT in patients with high-risk and poor prognostic MIBC characteristics.

Adjuvant radiotherapy after radical cystectomy for patients with muscle invasive bladder cancer: results of a phase II trial

Introduction: Muscle-invasive bladder cancer (MIBC) is highly heterogeneous with distinct molecular subtypes. We aimed to investigate the heterogeneity of different molecular subtypes from a tumor microenvironment perspective and develop a model to predict the molecular subtype, prognosis and immunotherapy response.
Methods: MIBC patients in The Cancer Genome Atlas (TCGA) and IMvigor210 were classified into luminal and basal subtypes according to the UNC classification. The proportions of tumor-infiltrating immune cells (TIICs) were evaluated through The Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm. Immune-related genes that were differently expressed between luminal and basal subtypes and associated with prognosis were selected to develop the immune prognostic signature (IPS). Nomogram based on the IPS was developed. Functional enrichment analysis (GSEA) was performed on the IPS. In addition, the RNA-sequence data of ten MIBC samples in our center were utilized to validate hub genes expression between molecular subtypes.
Results: Half of TIICs were differently distributed between luminal and basal subtypes. The IPS was highly associated with molecular subtypes, critical immune checkpoint genes expression, prognoses and immunotherapy response. Several validation data sets (GSE32894, GSE31684, GSE13507 and GSE48277) and meta-analysis further validated the prognostic value of IPS. GSEA revealed that some oncogenic pathways were coenriched in the high risk group. An IPS-based nomogram was constructed for prognostic predictions with good calibration and clinical usefulness. The expression of hub genes was significantly different between luminal and basal subtypes in MIBC samples from our center.
Conclusion: Dysregulation of TIICs contributed to the heterogeneity between luminal and basal subtypes. The IPS can facilitate molecular subtyping, prognostic evaluation and personalized immunotherapy.

Development and validation of a molecular subtype-associated immune prognostic signature for muscle invasive bladder cancer

Introduction & Objectives
A fundamental factor in the classification of bladder cancer is the involvement of the muscle layer in the pathological process. Despite the progress achieved in the morphological diagnosis of bladder cancer, the issues of scientific support for the creation of new high-precision and effective methods for early diagnosis are an urgent problem of modern oncourology.
Purposes of the study: determination of optical markers of bladder cancer using Raman spectroscopy.
Materials & Methods
We studied the material obtained from 85 patients diagnosed with bladder cancer (male –65, female – 20), who were examined and treated at the oncology department of the BSMU Clinic. Tumor tissues of the urinary bladder removed during TUR of the bladder and radical cystoprostatvesiculectomy were examined. Tumor tissue sample: without sample preparation. The study of the samples was carried out on a Horiba Scientific apparatus. Configuration: wavelength 785 nm, grating 1200 gr / mm, filter 100%, confocal aperture 300 μm. Integration time 50 s. Spectral data analysis was carried out using Spectragryph software.
Results
Recurrence after 3 months was detected in 2 patients (primary histology peaks corresponded to T1G3. Secondary histology - T2G3). Peaks: high peaks 564 cm-1, 1450 cm-1, 1650 cm-1, 850 cm-1, 2930 cm-1. Recurrence after 6 months - in 5 patients (2 patients T1G3: 1 patient - T1G3, 2 patients - transfer to T2G3, after 12 months in both of them no recurrence was not verified, 3 patients - T2G3: 2 patients completed radical cystectomy and 1 evisceration). Peaks: Patient 2 - transfer to T2G3: initially high peaks at 564 cm-1, 865 cm-1, 1450 cm-1, 1650 cm-1, 850 cm-1, 2935 cm-1 (primary histology matched T2G3 peaks). 3 patients - T2G3 - 2 radical cystectomy and 1 evisceration: 565 cm-1, 655 cm-1, 850 cm-1, 1420 cm-1, 1450 cm-1, 1650 cm-1, 2290 cm-1, 2870 cm -1, 2930 cm-1, 3120 cm-1, 3254 cm-1, 3150 cm-1 (initially histologically T2G3, MRI revealed no germination, primary histology had peaks T3-T4G3). Recurrence after 12 months - 3 patients (2 patients initially T2G3, 1 patient with primary histology T1G3 – recurrence corresponded to multifocal lesion - the patient completed radical cystectomy). Patient T1G3: 560 cm-1, 1450 cm-1, 1650 cm-1, 2930 cm-1, 3055 cm-1, 3120 cm-1 (peaks from T3-4G3).
Conclusions
Raman spectroscopy can be used in the early diagnosis of bladder cancer, to confirm the fact of tumor invasion, in the algorithm for treating patients.

Specific optical spectral tumor markers of bladder cancer

Background:
Rapid autopsies are unique in their ability to provide adequate tissue specimens sampled across multiple anatomic locations, allowing biological studies in the metastatic disease. We have established a bladder cancer rapid autopsy program to acquire bladder cancer metastases, and build patient-derived xenograft (PDX) and organoid models for biological and preclinical studies.
Methods:
Patients with metastatic bladder cancer were consented and rapid autopsies were performed 2-6 hours after death to allow acquisition of normal and metastatic specimens. Frozen and formalin-fixed, paraffin embedded specimens were deposited into University of Washington GU biorepository. Pathological evaluation of each specimen was performed. Additionally, fresh tumors were implanted subcutaneously into SCID mice to establish PDXs. Once PDXs were established, PDXs were dissociated for companion organoid culture. Clinical history and treatment information was documented for each participant.
Results:
We have performed 20 bladder cancer rapid autopsies to date, and have acquired 243 metastatic and 97 normal specimens. The tumor histologies of the tumors include urothelial cell carcinoma (7/20), squamous cell carcinoma (5/20), plasmacytoid variant of urothelial carcinoma (6/10) and neuroendocrine carcinoma (2/10). The cohort represented one treatment naïve patient (1/20), and patients treated with BCG only (2/20), chemotherapy (4/20), immune checkpoint inhibitors (5/20), and chemotherapy with immune checkpoint inhibitors (8/20). The most common sites of metastases were liver (14/20), lymph node (13/20), followed by lung (11/20), intestine (6/20), adrenal gland (3/20), and omentum (2/20). More than half of the patients with liver metastasis 10/14) had extensive disease that allowed acquisition of multiple tumor foci. We have successfully developed PDX and organoid models from two independent metastases (omentum – CoCaB 14.1 and liver –CoCaB 14.2) from the same patient, representing the first PDX developed from bladder cancer metastasis.
Conclusions:
Rapid autopsies allow multiple and simultaneous collection of metastatic disease tissue specimens. The availability of metastatic bladder cancer specimens, PDXs and organoids represent a valuable resource for molecular and preclinical study to advance the much needed therapeutic discovery for metastatic bladder cancer. The accrual is ongoing and molecular analyses of these specimens are in progress.

Bladder Cancer Rapid Autopsy Program provides a critical resource for the biological study of advanced bladder cancer

Most patients with bladder cancer have non muscle-invasive disease (NMIBC), requiring multiple invasive procedures during follow-up. Surveillance guidelines do not adjust for increasing age or frailty. We aim to evaluate the influence of frailty on the natural history of NMIBC.
Patients who died between 1/1/2017-1/1/2020 with bladder cancer and underwent a flexible cystoscopy within two years were identified via clinical coding. Notes were reviewed to establish relevant clinical parameters and follow-up procedures. Frailty was assessed using the 9-point Rockwood Clinical Frailty Scale (CFS): 1-3 no frailty, 4 vulnerable, 5-9 mild/severe frailty. The Charlson co-morbidity index and American Society of Anesthesiologists (ASA) score were similarly categorised.
69 patients were identified (mean age 78) with a median overall survival (OS) of 32.5 months. 36, 20 and 13 patients had frailty scores of 1-3, 4, and 5-9, respectively. There was no difference in the proportion of higher risk NMIBC between groups (table 1). Increasing frailty was associated with reduced OS (58.5, 28.5, 13 months; p <0.05) but not recurrence-free survival (24, 16, 27 months; p =0.98) or progress-free survival (144, n/a, n/a months; p =0.58) (figure 1). There was no clear difference in the number procedures per year of follow-up between groups (table 2). Progression or disease-specific mortality was the same across all groups (table 2). Similar results were obtained for the Charlson index and ASA scores. There were no frail patients with low or intermediate NMIBC who had a clinically significant progression prior to death from other causes (table 3).
There are frail patients with NMIBC who have limited life expectancy. For such patients with lower risk NMIBC, protocol-driven cystoscopic surveillance may not improve survival and watchful waiting may be more appropriate. Further investigation is required to determine the feasibility of this approach.

Analysing cause of death during follow-up for non-muscle invasive bladder cancer: Is there a role for watchful waiting?

Introduction and Objectives: Intravesical therapy is currently used to prevent disease recurrence following transurethral resection of bladder tumours for superficial non-muscle invasive bladder cancer (NMIBC). We review the history and development of these agents.
Methods: A systematic literature search using MedLine, Embase, and secondary historical sources was performed to identify the key historical medical advances in intravesical therapy.
Results: Mitomycin-C was first conceived as an antibiotic derived from streptomyces species but was later found to have antineoplastic properties. This discovery by T. Hata with S. Wakagi in Japan in the late 1950’s led to the first intravesical injections. Thiotepa, an alkylating agent and organophosphate, was first synthesised in 1952 after the mutagenic effects of mustard gas were discovered in World War I. J. Bateman of the USA trialled its injections into cavities for breast and ovarian cancer, leading to intravesical use in 1961 by H.C. Jones and J. Swinney. However, the use of thiotepa was superseded by mitomycin-C after K. Shida and his team published their positive findings in 1967.
J.D. Coe and J.E. Feldman (1965), and Bloomberg (1975) in the USA demonstrated the effect of Bacillus Calmette-Guerin (BCG) toxin on guinea pig and dog bladders, respectively. Following their success, A. Morales of Canada trialled intravesical BCG in humans in 1976. This revolutionised the treatment of high risk NMIBC with one of the earliest forms of immunotherapy, which remains the most efficacious therapy to date.
Conclusions: The rapid global development of intravesical therapy since the 1950’s has created agents that remain standard of care today. While new therapeutic agents are being trialled, the importance of these discoveries and their stories should be reflected upon as we have the privilege to deliver these treatments today.

The evolution of intravesical therapy for bladder cancer

INTRODUCTION
Cutaneous metastasis associated with urothelial carcinomas are extremely rare with an incidence of 1% to 2%, mostly secondary to iatrogenic tumor cell implantation or hematogenous spread. They are usually diagnosed in advanced stages of the disease and are associated with poor survival (median 2-year survival of 14.2%).
PATIENT INFORMATION, DIAGNOSIS AND TREATMENT
We present the case of a 65-year-old male ex-smoker diagnosed with high-grade T1 bladder carcinoma in 2008 who was treated with bladder TUR plus induction treatment with endovesical instillations of BCG. During the clinical follow-up, in view of the pathological result of a cytological study (C4 suspicious of malignancy), endoscopic bladder exploration under anesthesia, standardized multiple mapping biopsy and prostate biopsy were indicated with a diagnosis of prostatic infiltration by high histological grade papillary urothelial carcinoma in the prostate samples, in addition to a focus of prostate adenocarcinoma Gleason 3 + 3.
The case was presented in uroconcologic committee proposing radical cystectomy and ileal conduit (Bricker) plus ileo-obturator lymphadenectomy performed in September 2014. The anatomopathological study showed high-grade infiltrating urothelial carcinoma of the prostate and prostatic urethra (pT4a N0 M0). Subsequently, intensity-modulated radiation therapy (IMRT) was started on the prostate bed (60 Gy to 2Gy/day) as adjuvant treatment.
After 4 years of follow-up the patient reported the appearance of a lesion compatible with Zoon's balanitis in the penis. Circumcision and biopsy of the glans was decided with an anatomopathological diagnosis of intraepithelial carcinoma with presence of carcinomatous lymphangitis (metastatic cutaneous form). MRI showed multiple external iliac and femoral lymphadenopathies and a lesion in the midline of the corpus spongiosum, of uncertain nature (Image 1). Before the radiological findings a cold endoscopic biopsy of the urethral lesion was performed, which was found to be compatible with urothelial carcinoma in situ.
An extension study was performed by CT finding mediastinal and iliac lymph node metastases and multiple liver metastases not present in the previous study performed two months earlier (PT4 N3M1).
First line systemic treatment was started according to CDDP-Gemcitabine scheme, after 3 cycles rapid progression of liver and bone disease was observed and second line treatment with Atezolizumab was tried for 3 months until significant deterioration of the patient and death.
CONCLUSION
High risk urothelial carcinoma is a serious entity with a high recurrence rate that can exceed 80%. It is important strict follow-up by periodic endoscopic study (urethrocystoscopies) and not only with urine cytology studies as was carried out in this case. Early diagnosis of progression is imperative for right management and prognosis of the disease.

CARCINOMATOUS LYMPHANGITIS ASSOCIATED WITH UROTHELIAL CARCINOMA

INTRODUCTION & OBJECTIVES:
Radical cystectomy (RC) is the standard treatment for patients with muscle-invasive bladder cancer (MIBC) and no evidence of metastasis. Despite surgical treatment and improvements in neoadjuvant chemotherapy, a significant proportion of patients develop disease recurrence. Recent studies report neutrophil-to-lymphocyte ratio (NLR) as an useful biomarker of systemic inflammatory response in several cancer types. NLR has been proposed as a prognostic factor for patients with MIBC following RC.
The aim of our study was to evaluate the clinical usefulness of preoperative NLR as a prognostic marker in patients treated with RC for MIBC.
MATERIALS & METHODS:
A retrospective analysis was performed at our institution between January 2013 and January 2021. Baseline clinical, demographic and histopathological features and related outcomes are reported. We established a NLR cut-off value of 3 based on previous publications.
Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan-Meier method, and the log-rank test was used to determine significance. Multivariate analysis was performed based on these survival endpoints using a Cox regression. Statistics were evaluated with IBM™ SPSS software, version 23.
RESULTS:
120 patients were included, of which 103 men (86%) and 17 women (14%). Median age at diagnosis was 70 years (range: 40-86). 55 (46%) patients were active smokers, 37 (31%) former smokers and 28 (23%) never smoked.
Median NLR was 2.6. No association was found between NLR and age (p=0.12), gender (p=0.38), smoking status (p=0.45) or comorbidities assessed by Charlson Index (p=0.42). Statistically significant associations were found between NLR > 3 and advanced pathological tumour stages (p=0.02) and lymphovascular invasion (p=0.01).
Survival analysis showed that NLR > 3 was associated with worse DFS (29.6 vs 61.2 months, p=0.001) and OS (36.3 vs 66.0 months, p=0.002). In multivariate analysis, a NLR > 3 was independently associated with both DFS (HR 2.18; 95% CI 1.25-3.82, p=0.006) and OS (HR 2.22; 95% CI 1.24–3.97, p=0.007).
CONCLUSIONS:
MIBC is associated with high morbidity and mortality. Consequently, there is a need to identify predictors of survival. Our results suggest that patients with preoperative NLR > 3 undergoing RC for MIBC have worse outcomes, both DFS and OS. As an easy achievable and not expensive biomarker, NLR can be useful and needs to be validated in risk stratification models.

PREOPERATIVE NEUTROPHIL-TO-LYMPHOCYTE RATIO PREDICTING OUTCOME IN MUSCLE INVASIVE BLADDER CANCER UNDERGOING RADICAL CYSTECTOMY

Introduction
Urothelial carcinomas represent the sixt most common tumors in developed countries and 5-10% of cases are located at upper urinary tract. At diagnosis, more than half of patients with upper urinary tract urothelial carcinoma (UTUC) present an invasive tumor. Patients with low risk tumors (solitary tumor, size <2cm, low grade biopsy and negative high grade citology) and select patients with chronic kidney disease or solitary kidney, kidney sparing management is a primary treatment option.
We present 3 UTUC cases with endoscopic treatment: biopsy with NGage® basket 1.7 + Holmium laser (HoL) + base biopsy with Piranha® forceps and retrograde instillation of mitomycin C (MMC).
Patient information and treatment
Case 1: 80 year old woman patient, with solitary kidney (right nephroureterectomy 5 years ago due to high grade UTUC pT2N0M0) and chronic kidney disease. URO-TC performed yearly, showed a lesion in upper pyelocaliceal cavity, suggestive of neoformative process. Endoscopic exam revealed normal bladder and 25mm exofitic tumor in upper pyelocaliceal cavity. Anatomopathology reported urothelial carcinoma pTaG3. In order to decrease risk recurrence, retrograde instillation with MMC during 6 sessions was performed. 6 months later, endoscopic control showed 5mm papillary lesion on the previous tumor area and resection with HoL was made. After 6 additional instillations with MMC, endoscopic control shows no recurrence with negative citology. Other cycle of 3 instillations with MMC was made, and nowadays endoscopic revision is expected to perform.
Case 2: 54 year old male patient, with solitary kidney (right nephroureterectomy 1 year before because high grade UTUC pT2N0M0). Successive control with URO-TC evidence 9mm lesion in left renal pelvis. Endoscopic procedure revealed 20mm papillary lesion. Patological report showed urothelial carcinoma pTaG3, and local treatment with cycle of 6 MMC instillations was carried out. Endoscopic control at 6 months showed no lesions. During 2 years subsequent instillations with MMC each 6 months and endoscopic control has carried out and has no shown relapse.
Case 3: 72 year old woman patient, with chronic kidney disease due to mellitus diabetes, presented with left renal colic and haematuria. URO-TC showed a 12mm solid lesion in left pelvis kindey. Cystoscopy ruled out bladder tumor. Endoscopic examination showed papillary tumor in pelvis kindey. Anatomopathological result: urothelial carcinoma pTaG3. To complete treatment, retrograde instillation with MMC during 6 sessions was made. 6 months after first surgery, endoscopic control shows no relapse. At present, she is being treated with MMC maintenance schedule and subsequent endoscopic control will be performed.
Conclusions
Kidney sparing treatment for UTUC by endoscopic management is not standardized. In patients with low risk UTUC, solitary kidney and chronic kidney disease can be a safe option as long as close follow-up is carried out.

Endoscopic management on upper urinary tract tumor

Introduction: According to the KEYNOTE-045 Phase III trial, pembrolizumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) that progressed after the first-line with platinum-based chemotherapy with benefit in OS, PFS and ORR, regardless of PD-L1 expression. However, in clinical practice, pembrolizumab is effective in a limited number of patients with mUC and the role of PD-L1 expression in second-line therapy is uncertain. Therefore, the development of clinical biomarkers with prognostic value is essential to personalize the choice of treatments and improve outcomes.
Objective: The aim of this retrospective study is to evaluate the prognostic and predictive value of neutrophil/lymphocyte ratio (NLR) and PD-L1 expression as clinical biomarkers in the patients with metastatic urothelial carcinoma treated with pembrolizumab in second-line.
Methods: We analyzed retrospectively 16 patients with metastatic urothelial carcinoma refractory to platinum-based chemotherapy who received second-line pembrolizumab between December 2017 and March 2021. Pretreatment NLR was calculated by dividing the number of neutrophils by the number of lymphocytes in peripheral blood, before the first administration of pembrolizumab and the PD-L1 expression was evaluated in the tumor specimen (CPS). Progression-free survival (PFS) and overall survival (OS) were compared by the Kaplan-Meier method and the Cox proportional hazard model.
Results: Overall 80% are male, with a median age of 70 (range: 55-82) years. Patients with NLR ≤ 5 before starting treatment with pembrolizumab had a median PFS of 13 months (7.71-14.57) and those with NLR > 5 was 8 months (4.07-10.35 ) (p < 0.001). In the multivariate analysis, the presence of bone metastases (HR: 3.01, 95% CI: 1.73-5.61, p = 0.021) and NLR> 5 (HR: 2.97, 95% CI: 2, 69-9.02, p<0.001) were independent predictors for shorter PFS and lower ORR. When the same analysis was performed for OS, it was not statistically significant, however, NLR ≤ 5 pretreatment with pembrolizumab and PD-L1 CPS > 10 were associated with better OS (p < 0.027) and ORR (p < 0.001).
Conclusion: These data suggest that pretreatment NLR can estimate the ORR, PFS and OS of patients with mUC treated with second-line pembrolizumab and that NLR ≤ 5 is a potential biomarker predicting response to second-line pembrolizumab as well as PD -L1 CPS > 10 and it may represent accessible tools in clinical practice to identify appropriate patients for second-line treatment with pembrolizumab. Prospective studies and clinical trials are needed to validate NLR as predictive biomarker of response to checkpoint inhibitors in mUC.

Prognostic value of Pretreatment Neutrophil-to-lymphocyte ratio and status PD-L1 for pembrolizumab in second-line in metastatic Urothelial Carcinoma in a portuguese Center – Real World Data

Introduction and objective: Cisplatin is preferred to carboplatin when treating metastatic urothelial carcinoma of the bladder (mUCB), despite its greater toxicity. Randomised studies underpinning this have been performed in non-contemporary populations with limitations in sample sizes and analyses, affecting their validity in current clinical practice. The objective of this study is to estimate overall survival (OS) and assess the benefit of cisplatin-based regimens over carboplatin-based regimens in a contemporary cohort of patients with mUCB.
Methods: A nationwide retrospective cohort study of patients diagnosed with de novo mUCB in the Netherlands between 2016 and 2019 who underwent first-line treatment with cisplatin- or carboplatin-based chemotherapy, based on data from the Netherlands Cancer Registry. A propensity model for receiving cisplatin-based chemotherapy based on age, sex, age-adjusted Charlson Comorbidity Index, renal function, performance status, serum haemoglobin, and the presence of visceral and bone metastases was used to produce inverse probability weights (IPW) per patient. Unadjusted and IPW-adjusted Kaplan–Meier OS curves of both chemotherapy groups were compared by restricted mean survival times (RMST).
Results: Of the 1041 patients with mUCB, 359 received either cisplatin (n = 170; 47%) or carboplatin (n = 189; 53%) first line. The cisplatin group was younger, had fewer comorbidities, and had better performance status and renal function. The median OS in the cisplatin and carboplatin groups was 13.1 and 11.5 months, respectively. After IPW-adjustment, prognostic factors were balanced between the two chemotherapy groups (standardised differences <0.1) and differences in RMST were <2.0 months and not statistically significant up to 24 months.
Conclusion: After accounting for all known prognostic factors, we found no significant survival benefit for cisplatin over carboplatin as a first-line chemotherapy in mUCB.

Overall survival of patients receiving cisplatin and carboplatin for primary metastatic urothelial carcinoma of the bladder: a contemporary Dutch nationwide cohort study

Introduction
Bladder cancer is the 4th most common tumor, however, secondary bladder tumors are rare, involving less than 1% of all tumors in this organ. We present three cases of bladder involvement due to extraurothelial lineage tumors.
Patient information and clinical findings
Case 1: 34 years old male patient, who presented episodes of acute urine retention (AUR), macroscopic hematuria and pain in the right iliac fossa in October 2020. Magnetic resonance (MRI) revealed a mass in right seminal vesicle.
Case 2: 46 years old male patient, underwent subtotal gastrectomy for carcinoid tumor in december 2018, that in control PET-CT shows recurrence in form of a tumor mass in seminal vesicles. Asymptomatic, from urologic point of view.
Case 3: 54 years old male patient, diagnosed of intestinal origin GIST located in left iliac fossa, with left kidney involvement, therefore was performed nephroureterectomy in march 2020. Patient has presented macroscopic hematuria.
Diagnosis and Treatment:
Case 1: Biopsy was diagnostic of squamous carcinoma. TAP CT revealed involvement mesorectal fascia, iliac chains, bladder wall and left distal ureter. Multidisciplinary committee decides start treatment with neoadjuvant chemotherapy and radiotherapy, achieving a partial response to treatment. Therefore, radical cystoprostatectomy and rectal resection were performed in July 2021.
Case 2: An extension study through CT TAP and pelvic MRI was performed, which confirmed the mass in seminal vesicles, with bladder and anterior rectal wall infiltration. Biopsy was diagnostic of neuroendocrine tumor. Radical cystoprostatectomy and rectal resection were performed in december 2019. Nonetheless, he presents disease progression and he is in treatment with Irinotecan.
Case 3: Despite Imatinib treatment, control MRI revealed disease progression as well as bladder wall involvement, that was confirmed by cystoscopy. Currently, we're waiting to pathologic diagnosis, to assess the attitude towards bladder lesion. Conclusions:
Metastasis bladder are rare and usually, it occur as a manifestation of advanced disease and for dissemination from adjoining organs (prostate, female genital tract, colon). Most patients with secondary bladder involvement present symptoms, like hematuria and AUR. In the same way, it's common that there is involvement of other organs at the time of diagnosis.
Definitive diagnosis and management of secondary bladder tumors is often complicated. It's important rule out the primary origin of the bladder lesions and and confirm the diagnosis of metastasis by radiological and pathological study. In the presence of histology other than urothelial, we must rule out the metastatic origin of the lesion.

BLADDER INVOLVEMENT DUE TO EXTRA- UROTHELIAL LINEAGE TUMORS: REPORT OF THREE CASES

Introduction: 
The urachus is an embryologic remnant which is formed from the obliteration of the allantois. Urachal abnormalities are caused when defective obliteration of the urachus happens. They are an infrequent condition. 
Clinical case: 
We present the case of a 38-year-old male patient, with no previous medical history, evaluated in the urology consultation due to dysuria and the presence of whitish exudate after urination for years of evolution, without any other symptom. 
The physical examination is normal, with negative urethral exudate and negative urine culture. A cystoscopy is requested: a dome image suspicious of urachal pathology is observed. A CT scan was performed that showed a 19x24x45 cm tubular structure with a cystic appearance, compliant with a urachal diverticulum. After these findings, the case was discussed in a clinical session and a systematic search of the literature was carried out to determine the attitude to follow. 
There is no clear indication in the literature about the management of urchal pathology, being able to opt for surgery o conservative management. Given the persistent symptoms and despite the low risk of urachal cancer (incidence of 0.18 per 100,000), we performed a laparoscopic resection The histological analysis report a mucinous cystic tumor with low potential for malignancy. Urooncological committee decided very close monitoring, with imaging test. 
Conclusion: 
Despite the low risk of urachal cancer in adults, we must consider the possibility of resection or close control of it, given the possibility of malignancy.

URACHAL REMNANT, risk of malignancy. A CASE REPORT.

Introduction: 
The early intravesical Instillation of mitomycin C (MMC) is accepted as safe adjuvant therapy after TURBT by non-muscle- invasive bladder cancer if there is no perforation and it has been shown to reduce recurrence. 
Case report: 
We report a 69-year-old male patient, former-smoker with a history of alcoholic cirrhosis with adequate functional reserve. On follow-up in urology consultations for recurrent bladder neoplasia (low-grade Ta) since 2012 with predominance at the anterior bladder wall.  The last transurethral resection was in July 2020 with low-grade Ta urotelial neoplasia and received immediate postoperative MMC. After control cystoscopy, it was included in the surgical waiting list due to suspicion of tumor recurrence and symptoms of dysuria with a fatty “supernatant” in the urine. During the surgical procedure, a 3-4 cm cottony, overgrowing lesion is seen on the anterior side. After compressing it, lipid drops come out, showing fat necrosis. The pathological anatomy confirms the presence of connective tissue with extensive areas of necrosis. Conservative treatment was performed with bladder catheterization and antibiotic therapy, and a cystographic control was carried out which confirmed the persistence of the defect in the anterior bladder wall. The bladder catheter was kept for a further 3 months and, given the persistence of a leak in the imaging tests, it was proposed to repair the fistula vs partial cystectomy. 
Conclusions: 
The most common side effects reported about de MMC are irritative symptoms (10%) and allergic skin reactions (3%). Rare complications such as necrosis of the bladder wall or perforation are rarely mentioned in the literature, but we must take them into account in patients with suggestive symptoms and signs in order to opt for an adequate definitive treatment.

BLADDER NECROSIS AFTER INMEDIATE POSTOPERATIVE MITOMYCIN-C

Introduction: 
Immunotherapy has become a therapeutic strategy that has changed the natural history of several tumors. Data on the expression of PDL-1 among other immunological biomarkers, have allowed the development of modern immunotherapeutics in the treatment of urothelial cancer for those patients whose disease progresses after chemotherapy treatment or are not Fit for it. 
Material and methods: 
We present our series of 15 patients treated with immunotherapy for urothelial cancer. Review of the characteristics of the sample, toxicity and overall survival. 
Results: 
15 patients with a mean age of 69 years, in a range between 55 and 85 years, have been treated. 14 males and 1 female. 14 of the cases have their origin in the bladder and one in the renal pelvis. Most are ECOG 0-1. Out of the 14 patients with bladder cancer, 12 with stage IV: 7 underwent cystectomy. 4 were treated with immunotherapy for being unfit for chemotherapy regimens and 10 after disease progression. The patient with urothelial cancer of the upper urinary tract was treated with chemotherapy and immunotherapy was indicated after progression. 6 of the patients have died. The average overall survival of these patients was 2.5 months. 10 months for nivolumab, 5 months for pembrolizumab, and 1.5 months for atezolizumab. The immunotherapy associated toxicity profile is related to the immune system. Most had fatigue, a diabetic debut?? and skin reactions were also observed. Three serious adverse reactions have been detected that required discontinuing the treatment. Pulmonary embolism with Pembrolizumab, a colitis that required admission and severe cholangitis. Immunotherapy toxicity requires multidisciplinary management, supported by endocrinology, dermatology, pulmonology, digestive, etc. 
Conclusions: 
The majority of toxicities observed are Grade I (fatigue). Treatment has been discontinued in 3 of the cases due to severe toxicity (colitis, cholangitis and PE). The immunotherapy toxicity profile requires multidisciplinary management (dermatology, endocrinology, etc.). 
In our experience, the overall survival is 2.5 months on median. Underway Clinical trials working hand in hand with translational research allow us to continue defining the role of immunotherapy in this type of tumors.

Immunotherapy in advanced urothelial cancer: first steps, multidisciplinary approach

Introduction
Inhibition of programmed death receptor-1 (PD-1)/PD-L1 checkpoint has demonstrated significant benefit in patients with unresectable and metastatic Bladder Cancer for first-line treatment in cisplatin-unfit patients in case of positive PD-L1 status. Data have been presented with encouraging results, showing that using the PD-1 inhibitor pembrolizumab reported a complete pathological remission (pT0) in 42% and pathological response (< pT2) in 54% of patients.
Case report
A 72-year-old male presented with acute bilateral obstructive uropathy, haematuria and abdominal pain. A CT-Urogram was performed, manifesting left ureteral rupture and bladder wall enlargement. Bilateral nephrostomy and a bladder-prostate transurethral resection (TURBT + TURP) were performed, showing bladder tumour with prostate and left ureteral invasion. Tissue analysis exhibited high grade urothelial carcinoma PD-L1 positive. Following the surgery, disease was updated with Thorax-Abdomen-Pelvis CT-scan, observing retroperitoneal lymph node invasion. After urinary diversion with bilateral nephrostomy, patient persisted with GFR< 30 ml/min, so after discussing the case in a multidisciplinary team, it was decided to start a treatment with Pembrolizumab. Following 8 Pembrolizumab-cycles Thorax-Abdomen-Pelvis CT-scan was repeated, showing response, so our multidisciplinary team proposed radical cystectomy + lymphadenectomy and Bricker urinary diversion. Surgical piece was analyzed, exhibiting absence of tumour (pT0 N0). During the next 17-months follow-up, Thorax-Abdomen-Pelvis CT-scan have not shown tumour relapse or metastasis.
Conclusions
Immunotherapy is a promising therapy in the treatment of urothelial cancer for patients unfit for chemotherapy, showing pathological remission in 30-40% of patients, therefore it is a key-point for those who are not able to benefit from first line therapies.

Pembrolizumab: complete pathological remission in metastatic bladder cancer. A case report

Introduction & Objectives
Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for patients with metastatic colorectal cancer, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib and trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020).
Despite development of several new therapies for metastatic urothelial cancer, response durations generally remain short and the majority of patients succumb to the disease, highlighting the need for additional therapeutic approaches. Given 20-30% of metastatic urothelial cancers have molecular alterations of the ErbB family, tucatinib + trastuzumab warrants further evaluation.
SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international Phase 2 study evaluating tucatinib + trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic urothelial cancer (UC).
Materials & Methods
Eligible patients must have HER2+ or HER2-mutated locally advanced or metastatic solid tumors, with progression on or after the last systemic therapy for advanced disease. Additionally, an ECOG PS ≤1, adequate hepatic, hematological, renal, and cardiac function, and no prior exposure to HER2-directed therapy in the UC cohort.
For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in prior or pre‑screening NGS assay of ctDNA or prior tissue NGS assay.
The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. Patients with HER2-mutated UC will be enrolled into a cohort of 30 patients with HER2-mutated solid tumors (except breast and non-squamous non‑small cell lung cancers).
The primary objective is antitumor activity, with confirmed ORR as the primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints.
Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenous on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1.
Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2-6, with a peak concentration sampled in Cycle 3. Quality of life will be evaluated q2 cycle using EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia.

SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: urothelial cancer cohort (Trial in Progress)

Introduction & objectives: Radical surgery is the mainstay of treatment for urothelial bladder cancer (UBC) and invasive upper tract urothelial cancer (UTUC) but, even when surgery is combined with cisplatin‐based (neo)adjuvant chemotherapy, recurrence rates are high. Many patients are ineligible for, do not respond to cisplatin-based chemotherapy, or refuse this treatment because of toxicity concerns. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in 60% of UTUC and 21–38% of muscle-invasive UBC and are candidates for targeted therapy. Infigratinib (BGJ398) is an ATP-competitive FGFR1–3 selective oral tyrosine kinase inhibitor that has shown clinical activity and tolerability in patients with advanced urothelial carcinoma (UC) harboring susceptible FGFR3 alterations. PROOF 302 was designed to investigate the efficacy and safety of adjuvant infigratinib versus placebo in patients with high-risk, muscle-invasive UC and susceptible FGFR3 alterations.
Materials & methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase 3 trial (NCT04197986). Eligible patients have high-risk, muscle-invasive UTUC or UBC (85% and 15%, respectively) with susceptible FGFR3 alterations (activating mutations, gene fusions, or rearrangements by FoundationOne® CDx test), and are ≤120 days following nephroureterectomy, distal ureterectomy, or cystectomy. The protocol was amended to include patients with carcinoma in situ, and those ineligible for or refusing cisplatin-based chemotherapy. Pathologic disease stage is ≥ypT2 and/or yN+ M0 after cisplatin-based neoadjuvant chemotherapy. For patients who are ineligible for, or have refused, cisplatin-based therapy, pathologic disease stage is: UTUC (≥pT2 pN0–2 M0 [post-lymphadenectomy or no lymphadenectomy]); UBC (≥pT3 or pN+). Patients are randomized 1:1 to receive oral infigratinib 125 mg or placebo, QD on days 1–21 every 28 days for up to 52 weeks (13 cycles) or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS), analyzed via stratified log-rank test, and Cox model (hazard ratio [HR]). Secondary endpoints: investigator-reviewed DFS; metastasis-free survival; overall survival; safety/tolerability. Exploratory endpoints: quality of life; pharmacokinetics, determination of the prevalence of genomic alterations and correlation with features of UC; genomic and proteomic assessment of tumor tissue and cell-free DNA samples from baseline and at recurrence to identify the predictive/prognostic value of biomarkers. Based on the HR of 0.5 for infigratinib vs. placebo, an interim analysis for adaptation and futility will be conducted after ~35 centrally confirmed DFS events. The initial sample size of 218 patients may be increased up to 328 patients based on an adaptive design. The power to detect a difference in DFS is 80%. PROOF 302 was initiated in March 2020 and is open internationally and expected to end in 2024.

A randomized, double-blind, placebo-controlled, phase 3 trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 genetic alterations: PROOF 302

Introduction
Plasmacytoid urothelial carcinoma (PUC) is rare, and is known to mimic invasive lobular carcinoma of the breast and signet cell gastric adenocarcinoma. PUC has a very poor prognosis, with high cancer mortality, despite being chemo-sensitive, largely due to its high recurrence rate. Metastatic lesions presenting as bladder tumours, are also rare and has poor prognosis when presenting as a widespread metastatic disease process.

Patient Background
A 69-year-old woman with a history of metastatic lobular carcinoma of the breast was noted to have new unilateral hydronephrosis with associated luminal thickening of the proximal right ureter. She originally had a previously wide local excision thirteen years prior, subsequently re-excision then requiring salvage mastectomy due to positive margins. She underwent appropriate neoadjuvant chemotherapy and anastrozole. She then developed evidence of gastric involvement of lobular carcinoma. She was then placed on exemestane which showed radiological and biochemical regression. The finding of hydronephrosis was identified on surveillance imaging with no haematuria.

Clinical findings
Given the clinical findings the patient came forwards for ureteroscopy. Upon entering the bladder, a small raised erythematous lesion was identified just below the right ureteric orifice and was biopsy. Ureteroscopy of the affected ureter was abandoned due to excessive tightness of the ureter. Ureteric washings of the renal pelvis were taken, and a retrograde pyelogram was performed. A 6 Fr stent was placed.

Diagnosis
Despite the initial histology suggestion of PUC, clinical correlation and evaluation of the ureteric washing sample was in keeping with metastatic lobular. Evaluation of the ureteric washings revealed mammaglobin positive, and oestrogen receptor and progesterone receptor positive.

Treatment
Given the asymptomatic nature of metastatic disease, the patient was kept under observation. Unfortunately, the patient presented acutely with contralateral hydronephrosis, due to extrinsic compression from a metastatic peritoneal deposit. Retrograde decompression with a JJ stent was performed and subsequent palliative paclitaxel and then Palbociclib were trailed.

Conclusion
PUC is a rare variant malignancy, and clinicians should be aware of its mimicry of metastatic malignancy. The need for clear communication between surgical and pathology teams is also highlighted for accurate reporting. Positive staining of mammaglobin and hormone receptors in a bladder tumour with initial appearance of plasmacytoid urothelial carcinoma should raise suspicion for metastatic lobular carcinoma of the breast.

Metastatic Invasive Lobular Carcinoma Mimicking Plasmacytoid Urothelial Carcinoma of the Bladder

INTRODUCTION
Despite the low progression and mortality rates of non-muscle-invasive bladder cancer these cancers can demonstrate high recurrence rates and have the potential to progress to panurothelial disease.
PATIENT INFORMATION OR CLINICAL FINDINGS
A 61-year old male presented with a history of recurrent non-muscle-invasive bladder cancer. Since the initial diagnosis of low-grade Ta transitional-cell carcinoma in 2014 he had four recurrences after treatment with transurethral resection and adjuvant bacillus Calmette-Guérin and mitomycine C till 2015. Last pathology report showed high-grade pT1. In 2015 an early radical cystoprostatectomy was performed with ileal orthotopic neobladder urinary diversion, resection revealed a Ta/Tis partially low-grade but predominantly high-grade disease with negative lymph nodes. Eight months later a single lesion of 3cm in the right renal pelvis was diagnosed without evidence of lymphadenopathy or metastatic disease. He underwent a nephro-ureterectomy on the right side, final pathology showed a low-grade Ta urothelialcell carcinoma with negative section margins. In 2019 detection of local recurrence in the cranial aspect of the neobladder with involvement of both distal ureters and a metachrone lesion in the proximal left lumbal ureter. A resection of the neobladder, residual right ureter and complete left ureter and reconstruction with pyelo-ileoconduit was performed. Pathology report revealed high grade urothelialcell carcinoma from the right ureter expanding into the neobladder, with a positive section margin of the proximal left ureter. The patient developed tumor recurrences in his solitary kidney. He declines left side nefrectomy since it necessitates dialysis. Decision was made to treat him endoscopically. Since then he had 6 recurrences all treated endoscopic with biopsy and lasering. Pathology samples has always shown Ta or T1. Since december 2020 he underwent adjuvant intracavitary chemotherapy with Epirubicine but continues to develop recurrences.
DIAGNOSIS AND TREATMENT
Multiple recurrence of urothelialcell carcinoma of the upper urinary tract after extended excision of the urothelial surface. Currently nephron sparing endoscopic restrain on 3-monthly intervals with adjuvant intracavitary Epirubicine. Intracavitary chemotherapy is impeded by rapid washout.
CONCLUSION
A radical approach with extended excision in order to further decrease the urothelial surface and reduce the risk of recurrence might be necessary in some patients with non-muscle-invasive bladder cancer and upper tract urothelial carcinoma but can not prevent all recurrence.

MANAGEMENT OF RECURRENT UROTHELIAL DISEASE IN NON MUSCLE INVASIVE UROTHELIAL CANCER OF A SOLITARY KIDNEY AFTER PYELO-ILEOCONDUIT

Background: In this study we investigated the recurrence rate of NMIBC (Non Muscle Invasive Bladder Cancer) following Hyperthermic Mitomycin C (MMC) therapy (COMBAT). Currently there are no guidelines about standard regimes.
Methods: We retrospectively reviewed data on 56 patients who were offered Hyperthermic MMC therapy for NMIBC between 2018 and 2021. Patients with high grade NMIBC were treated for 1 year following a BCG style SWOG regime, intermediate NMIBC patients were treated with 6 weeks induction. We investigated recurrence rates following treatment.
Results: Of the 56 patients, 10 were removed from the trial due to side effects. 3 patients developed new urinary symptoms, 5 had previous urinary symptoms that worsened and 2 developed a rash.
46 patients were therefore reviewed in total. 34 (74%) had high risk NMIBC and 12 (26%) had intermediate NMIBC, as defined by EAU. Only 3 patients had the full maintenance course of MMC, see below for the flowchart indicating the dropout rates.
The overall recurrence rate was 47.8%. In intermediate disease this dropped to 25% and in high risk disease it was 55.9%. In patients who were BCG naïve, the recurrence rate was 31% and in patients who had been previously given BCG treatment, the recurrence rate was 56.7%. In patients with no CIS in the sample, the recurrence rate was 33.3%, but in patients with CIS, the recurrence rate rose to 68.4%
The follow up range was 2-29 months (average recurrence was at 7 months).
Conclusion:Hyperthermic MMC has shown to have benefit in decreasing recurrence rates in bladder cancer patients. BCG naïvity improved recurrence rates, as did the lack of CIS in the initial sample. In general, the more courses of maintenance doses the patient had, the lower the recurrence rates. Our data is in line with previous data for recurrence rates, however we had a higher drop-out rate in the induction period than previously has been recorded, this may be due to our BCG style regime, and therefore consideration will be given to alternative regimes in our centre.

Recurrence rate following Hyperthermic Mitomycin C treatment (COMBAT system), with BCG style regime.

Introduction: Although neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND) is standard of care for patients with MIBC, patients experience disease recurrence or progression. The PD-1 inhibitor pembrolizumab has been effective for cisplatin-ineligible and platinum-resistant/refractory metastatic urothelial carcinoma (mUC) and Bacillus Calmette-Guerin–unresponsive high-risk non–muscle-invasive bladder cancer. Enfortumab vedotin (EV) is a Nectin-4–directed antibody-drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E, which has been effective in patients with mUC who previously received a PD-1/PD-L1 inhibitor. Results of KEYNOTE-869/EV-103, a phase 1/2 study (NCT03288545), showed that EV + pembrolizumab had encouraging antitumor activity and acceptable safety as first-line treatment for cisplatin-ineligible patients with metastatic urothelial cancer, suggesting that combination therapy might be promising (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044).
Methods: KEYNOTE-B15/EV-304 (NCT04700124) is a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Approximately 784 patients will be randomly assigned 1:1 to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m2+ cisplatin 70 mg/m2 Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS ≥10 or CPS <10), and geographic region (United States or Europe or most of world). Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Imaging (CT or MRI) will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. After postcystectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathologic complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathologic downstaging, and safety and tolerability.
Results: The KEYNOTE-B15/EV-304 stu

Perioperative Enfortumab Vedotin Plus Pembrolizumab Versus Chemotherapy in Cisplatin-Eligible Patients With Muscle-Invasive Bladder Cancer (MIBC): Randomized Phase 3 KEYNOTE-B15/EV-304 Study

Introduction & Objectives
Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) and pelvic lymph node dissection is standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC).
Gemcitabine-cisplatin (GC) has similar efficacy to the MVAC regimen with lower toxicity in advanced BC and both regimens are considered adequate options for NAC.
We report the experience of our centre with NAC for MIBC.
Material & Methods
We conducted an observational, retrospective, single-centre cohort study. All patients (pts) with non-metastatic MIBC (≥cT2) after initial transurethral resection of the bladder tumour (TURBT), treated with GC between 2012 and 2020 were included.
The primary objective was to evaluate pathological complete response (pCR) rates after NAC, defined as ypT0N0 or ypTisN0. We also assessed disease free survival (DFS) and overall survival (OS) as secondary objectives.
Results
Thirty-nine pts with MIBC were treated with NAC followed by RC between 2012 and 2020. The median age was 66yo (range, 46-79), 31 (80%) were males. At the pre-NAC staging, 36 tumours were T2 (92%), 2 T3 (5%) and 1 T4 (3%). Thirty-four pts received the full 4 cycles of NAC; 11 pts (28%) had to delay at least 1 cycle of NAC due to toxicity and 4 pts (10%) required dose reductions. Eleven pts (28%) had grade 3 or 4 toxicities, mainly hematological (73%). The pCR rate was 28% (11 pts).
With a median follow-up of 57 months, 17 pts (44%) had tumour recurrence, 1 pt after pCR, and 14 pts (36%) died, none of those with pCR.
The association between pCR and DFS (median 22 months if residual disease versus not reached if pCR, log rank p=0.017) and between pCR and OS (median not reached for both groups, log rank p=0.01) were confirmed.
Conclusions
In our single institution cohort, the observed pCR rate (28%) was lower than that reported in the phase III GETUG/AFU V05 VESPER trial comparing dose-dense MVAC with GC (42% vs 36%). However, we alsodocumented a positive association between pCR and both DFS and OS.
While less toxic than MVAC, the full 12-week NAC with GC was only tolerated without treatment delays or dose reductions in 23 of the 39 pts.

Platin-based neoadjuvant chemotherapy for muscle invasive bladder cancer

For 2021, our focus remains: turning new data into your daily practice. The programme will consist of state-of-the-art lectures, case discussions and panel debates. Our faculty is a group of international & multidisciplinary experts.

We will take you on our journey to Ghent and beyond. Prior the congress, we send out case challenges, where you can compare your opinion with peers & experts. These cases will be part of the Global Congresses on Prostate & Bladder Cancer programme during the congress days (12 & 13 October for PROSCA and 14 & 15 October for BLADDR). After these days, you will be updated on prostate & bladder cancer management.