Candidates For Radical Cystectomy Research Articles

SOGUG-NEOWIN: A phase 2, open-label, multi-centre, multi-national interventional trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC) whose tumours express FGFR gene alterations.

TPS4623 Background: The standard treatment for nonmetastatic MIBC is neoadjuvant cisplatin-based therapy followed by radical cystectomy (RC). However, many patients are ineligible for cisplatin. Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for metastatic urothelial cancer (mUC), including for cisplatin-ineligible patients. Based on these results, ICIs are being explored as neoadjuvant treatment in resectable UC with preliminary data suggesting antitumour activity. ERDA is a Fibroblast Growth Factor Receptor (FGFR) inhibitor, which has shown efficacy in advanced UC with select FGFR2/3 mutations/fusions. ERDA plus cetrelimab demonstrated clinically meaningful activity in patients with newly diagnosed FGFR-altered mUC in the phase 2 NORSE trial. We hypothesize that ERDA plus cetrelimab will improve the pathological complete response (pCR) rate in patients with FGFR+ MIBC who are candidates for RC and are ineligible for or refuse neoadjuvant cisplatin-based therapy. Methods: SOGUG-NEOWIN is a prospective, non-comparative, open label, multicentre, international trial to assess the efficacy of 9 or 12 weeks of neoadjuvant ERDA (cohort 1) or the combination of cetrelimab and ERDA (cohort 2) in patients with MIBC (cT2-Ta N0/1 M0) and FGFR alterations. Key eligibility criteria include ECOG PS 0-1; pure or predominant UC histology; decline or ineligible for cisplatin-based chemotherapy as defined by one of the following criteria: impaired renal function (GFR < 60 mL/min), ≥ grade 2 hearing loss, or ≥ grade 2 peripheral neuropathy; patients are considered fit for cystectomy; no prior FGFR-targeted or anti-PD-(L)1 therapy; no prior systemic therapy, radiation or surgery (except TURBT or biopsies) for bladder cancer; prior BCG was allowed if completed ≥ 6 weeks before initiation of study treatment; no current retinopathy. A total of 45 patients will be allocated to each cohort by a centralized system. Co-primary endpoints are pCR rate and percentage of pathological downstaging response (<ypT2). Secondary endpoints include event-free survival, overall survival, overall response rate, safety, tolerability, and delay to surgery. Biomarkers of response and resistance will be assessed using baseline archival tissues, blood and urine. Quality of life (QoL) will be assessed using FACT-Bl and EQ-5D-5L. Tumour response assessment via PET-MRI will be performed in a subset of patients. The trial is approved in 4 countries. The first patient was included on 31-Jan-2024. This trial would be the first to systematically address whether ERDA ± cetrelimab improves pCR in patients with FGFR-positive MIBC. (EudraCT 2022-002586-15). Clinical trial information: 2022-002586-15.

Phase 3 KEYNOTE-992 study of pembrolizumab plus chemoradiotherapy versus placebo plus chemoradiotherapy in patients with muscle-invasive bladder cancer (MIBC).

TPS720 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for patients (pts) with MIBC who seek a bladder-preserving alternative to radical cystectomy and/or not candidates for radical cystectomy. The anti–PD-1 antibody pembrolizumab is approved for metastatic bladder cancer and non–muscle-invasive bladder cancer (NMIBC). The randomized, double-blind, phase 3 KEYNOTE-992 study (NCT04241185) is evaluating efficacy and safety of pembrolizumab plus CRT versus placebo plus CRT in pts with MIBC who chose bladder preservation. Methods: Eligibility criteria include adultswho have a histologically confirmed initial diagnosis of MIBC (T2-T4aN0M0) with ≥50% urothelial histology, ECOG PS score of 0 to 2, have received no prior therapy with anti–PD-1/L1 or agents directed to another stimulatory or coinhibitory T-cell receptor, and have planned treatment with one of the specified radiosensitizing chemotherapies. Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted. Approximately 636 pts will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV or placebo IV every 6 weeks for up to 9 cycles, both with CRT. Investigator’s choice of chemotherapy will be specified before random assignment. Pts will be stratified by ECOG PS (0 and 1 vs 2), PD-L1 combined positive score (<10 vs ≥10), T stage (T2 vs T3 and T4), and geographic region (United States vs European Union vs rest of the world). Radiosensitizing chemotherapy will be cisplatin monotherapy (35 mg/m2 IV weekly on day 1), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) plus mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly on days 1 and 4). Radiation therapy will be conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Imaging via CT and CT urography or magnetic resonance urography will be performed 10 weeks after completion of CRT, every 12 weeks until the end of year 2, then every 24 weeks thereafter. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of treatment (90 days for serious AEs). Primary end point is bladder-intact event-free survival (defined as time from random assignment to first documented occurrence of residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause) as assessed by blinded independent central review and/or central pathology review. Secondary end points are overall survival, metastasis-free survival, time to cystectomy, time to occurrence of NMIBC, safety and tolerability, and patient-reported outcomes. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04241185 .

Health Related Quality of Life in Patients with Bladder Cancer Receiving a Radical Cystectomy.

Radical Cystectomy (RC) and Urinary Diversion (UD) is a complex surgery associated with a significant impact on health-related quality of life (HRQoL). However, HRQoL assessment is too often overlooked, with survival and complications being the most commonly investigated outcomes. This study aimed to identify the most impaired HRQoL features in patients receiving RC, compared to a healthy population (HP) control, as well as patients' recovery after surgery, differentiating between patients receiving ORC and RARC. Patients with Bca, who were candidates for RC with curative intent, were enrolled in the "BCa cohort". HRQoL outcomes were collected with an EORTC QLQ-C30 questionnaire. These were collected at baseline, and then at 6-, 12- and 24 mo after surgery in the BCa cohorts, and at baseline in the HP cohort. A 1:1 propensity score matched (PSM)-analysis, adjusted for age, Charlson Comorbidity Index (CCI) and smoking history, was performed. Between January 2018 and February 2023, a total of 418 patients were enrolled in the study, 116 and 302 in the BCa and HP cohorts, respectively. After applying the 1:1 propensity scored match (PSM) analysis, two homogeneous cohorts were selected, including 85 patients in each group. Baseline HRQoL assessment showed a significant impairment in terms of emotional and cognitive functioning, appetite loss and financial difficulties for the BCa cohort. Among secondary outcomes, we investigated patients' recovery after RC and UD, comparing HRQoL outcome questionnaires between the HP and BCa cohorts at 6-, 12- and 24 mo after surgery, and a subgroup analysis was performed differentiating between patients receiving ORC and RARC with totally intracorporeal UD. Interestingly, ORC compared to RARC provided a major impact on HRQoL recovery across the early, mid and long term. In particular, the ORC cohort experienced a major impairment in terms of symptoms scales items such as fatigue, nausea and vomiting, pain and appetite loss. Consequently, comparing ORC and RARC vs. HP reported a major HRQoL impairment in the ORC cohort, possibly defining a benefit of RARC in early, mid- and long-term recovery. To conclude, this study confirmed the undeniable impact of RC on HRQoL. Interestingly, we highlighted the benefit of RARC in early, mid- and long-term recovery, expressed as less impairment of symptoms scales.

A phase II study of toripalimab combined with gemcitabine-cisplatin as neoadjuvant therapy for patients with muscle-invasive bladder cancer (MIBC).

e16602 Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care in MIBC with improved pathologic response (PaR) and overall survival (OS) compared to radical cystectomy (RC) alone. The efficacy of PD-1 inhibitor in combination with chemotherapy as a new neoadjuvant treatment option for MIBC still needs further confirmation. This study evaluated the efficacy and safety of toripalimab (an anti-PD-1 monoclonal antibody) combined with gemcitabine-cisplatin (GC) as neoadjuvant therapy for patients with MIBC. Methods: Eligible pts with MIBC (cT2-T4a, N≤1, M0) who were candidates for RC were enrolled. Toripalimab (240mg, d1) combined with GC (gemcitabine 1000mg/m2 d1,d8 plus cisplatin 35mg/m2 d1,d2) every 21 days, up to 4 cycles. RC was performed within 6 weeks after the last dose treatment. The primary endpoint was PaR (≤ pT1,N0). Secondary endpoints were PFS at 2 years and safety. Results: Between Apr 2021 and Jun 2022, 16 pts (4 pts cT2, 11 pts cT3, 1 pts cT4) were enrolled and received 4 cycles of neoadjuvant therapy, with median age of 63.5 and 75% male. 14 of the 16 pts underwent RC and two declined RC. Among 14 evaluable pts, PaR ≤pT1N0 was achieved in 12 pts (85.71%, 4 were pT0, 8 were pT1/a/is). Survival data are not yet mature. The most common adverse events (AEs) of any grade were anemia (14/16; 87.5%) and nausea/vomiting (11/16; 68.75%). One had Grade≥3 AEs (hemorrhagic shock) while on study that was unrelated to GC or toripalimab. Five pts experienced grade 1-2 immune related AEs, including thyroiditis (3/16, 18.75%) and rash (2/16,12.5%). Conclusions: Neoadjuvant toripalimab combined with GC showed promising safety and efficacy in MIBC with significant pathologic downstaging rates. Clinical trial information: NCT04861584 .

AI-based pathologic biomarker for pathologic downstaging in patients with muscle-invasive bladder cancer undergoing cystectomy after neoadjuvant nivolumab, gemcitabine, and cisplatin: BLAAST-1 Trial.

e16566 Background: The BLASST-1 study is a multi-center phase II trial evaluating the combination of neoadjuvant nivolumab with gemcitabine-cisplatin (N+GC) for muscle-invasive bladder cancer (MIBC) patients undergoing radical cystectomy (RC). The primary endpoint was pathologic down staging (PaR; ≤pT1N0). We previously reported a PaR rate of 65.8% (Gupta S et al. ASCO GU 2020). Given the lack of validated and optimal biomarkers to predict PaR, we studied the association of an AI-based pathologic biomarker measuring pre-treatment morphological features with PaR. Methods: Forty-one patients with MIBC (cT2-T4a, N≤1, M0) and candidates for RC were enrolled between Feb 2018 and June 2019 (cT2N0 90%, cT3N0 7%, cT4N1 3%). Thirty-six patients had transurethral resection of bladder cancer (TURBT) with pre-treatment diagnostic specimens available for analysis. Patients received four cycles of N+GC followed by RC within 8 weeks. A board-certified pathologist selected diagnostic regions from TURBT-derived representative H&E diagnostic slides for each patient. To compute the pathological biomarker, a proprietary deep-learning algorithm (Valar Labs, Palo Alto, CA) first segmented nuclei from digital whole-slide images of the H&E specimens to extract quantitative histological features. The Valar pathologic biomarker was then computed from features associated with immune infiltration and morphological characteristics of neoplastic cells. The Valar biomarker was split based on unsupervised clustering into two groups: Valar-High was associated with PaR and Valar-Low with no PaR. PD-L1 cutoff of 1% was used for dichotomization. To compare the Valar biomarker with PD-L1, a subcohort of 33 patients with available PD-L1 scores were analyzed. T-tests and diagnostic performance metrics were used to distinguish between PaR response rates in each cluster group across tests. Results: Patients designated Valar-High (n=23) had higher PaR compared to no PaR in the Valar-Low (n=13) group (PAR 78.3% vs 38.4%, respectively, p<0.008). Compared to PD-L1, the Valar biomarker had higher sensitivity (85.7 vs 57.1%), specificity (66.6 vs 66%), positive predictive value (81.8 vs 75.0%), negative predictive value (72.7 vs 47.0%), and accuracy (78.8 vs 60.6%) across both cohorts. The Valar biomarker was not correlated to PD-L1 (r^2=0.029) or sex (22 male, 14 female). The combined Valar-High or PD-L1 High test had a high sensitivity for PaR (95.2%). Conclusions: In this hypothesis-generating study, pre-treatment morphological features measured by the AI-based Valar pathologic biomarker identified responders to neoadjuvant N+GC in MIBC. Further prospective studies are needed to study the prognostic vs. predictive utility of this biomarker.

Efficacy and safety of atezolizumab concurrent with radiotherapy in patients with muscle-invasive bladder cancer: An interim analysis of the ATEZOBLADDERPRESERVE phase II trial (SOGUG-2017-A-IEC(VEJ)-4).

4588 Background: Combined-modality treatments are bladder-preserving alternatives for patients (pts) who are not candidates for radical cystectomy by medical reasons, refusal, or patient´s choice. Immune therapies seem to potentiate tumor-specific immune response induced by radiotherapy (RT). Combination of RT with anti-PD-1/PD-L1 therapy appears safe and there are signs of promising activity. The aim of this study is to assess the efficacy and safety of atezolizumab (ATZ) concurrent with external beam radiotherapy (EBRT) for the treatment of muscle-invasive bladder cancer (MIBC) with bladder preservation intent. Here we present an interim analysis. Methods: This is an open, multicenter, and phase II trial, sponsored by SOGUG, in pts with confirmed diagnosis of MIBC in clinical stages cT2-T4a N0 M0 who are not candidates for radical cystectomy. Treatment consists of 6 doses of ATZ 1200 mg IV every 3 weeks, starting on day 1 of EBRT, and 60 Gy of RT in 30 fractions over 6 weeks at 2 Gy/day. The primary endpoint of the study is pathological complete response (pCR) defined as a response of grade 5 according to Miller and Payne criteria, 1 to 2 months after the last dose of ATZ. A planned interim analysis has been performed (data cut-off date: November 2021) on the primary endpoint to avoid exposure to ineffective treatment according to the minimax two-stages Simon’s design (stopping rule: 9 out of the first 13 evaluable pts should achieve pCR). Incidence of adverse events (AE) and serious AE (SAE) has been also secondarily assessed. Results: From September 2019 to November 2021, 39 pts were screened, of whom 13 were excluded due to non-compliance with eligibility criteria. Thus, the evaluable population consisted of 26 pts. The safety analysis was performed in 22 pts who had received at least one dose of ATZ. 14 pts were assessed pathologically and, thus, included in interim efficacy analysis (median age: 78.6 years; clinical stage: 71.4% T2a, 14.3% T2b, 7.1% T3a, 7.1% T3b). All 14 pts had achieved pCR at the cut-off date. 20/22 (91%) pts experienced at least one AE, with asthenia (11 pts), diarrhea (9 pts), and urinary tract infection (4 pts) being the most common. 9 SAEs were reported in 7 (32%) pts (bacteriemia, COVID-19 infection, depressed LVEF, unknown origin fever, hepatic toxicity, kidney failure, rectorrhagia, respiratory infection, and urinary sepsis). 6 (27%) pts suffered AEs leading to treatment discontinuation. No AEs leading to death occurred. 17 pts with available data on survival were alive at the cut-off date. Conclusions: Interim results suggest that ATZ combined with EBRT is a feasible and effective treatment in terms of pCR, with a manageable safety profile. The final results from this trial will provide information about its effects on clinical outcome, including survival and updated safety findings. Clinical trial information: NCT04186013.

Biomarker analysis and updated clinical follow-up from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in patients with muscle-invasive bladder cancer (MIBC) undergoing cystectomy.

528 Background: The BLASST-1 study is multi-center phase II trial evaluating the combination of nivolumab (N) with gemcitabine-cisplatin (GC) as a neoadjuvant therapy for patients (pts) with MIBC undergoing radical cystectomy (RC). The primary endpoint was pathologic down staging (PaR; ≤pT1N0). Safety, Relapse-free survival (RFS), Progression-free survival (PFS) and biomarker analyses were secondary endpoints. We previously reported a PaR rate of 65.8% and pCR rate of 49%. There were no safety concerns or delays to surgery. (ASCO GU 2020) Here, we correlate PaR with biomarkers (Tumor mutational burden (TMB), PD-L1 and molecular subtypes) and provide updated clinical follow-up (FU) data. Methods: Forty-one pts with MIBC (cT2-T4a, N≤1, M0) and candidates for RC were enrolled between Feb 2018 and June 2019; (cT2N0 90%, cT3N0 7%, cT4N1 3%). Pts received C (70mg/m2) IV on D1, G (1000mg/m2) on D1, D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by RC within 8 weeks. For RNA-based analysis, GeneChip Human Exon 1.0 ST Array (Affymetrix) was used; baseline tumors from 37 patients passed quality control and had available transcriptome data. A cohort (n=223) of patients treated with NAC+RC was used as a comparator for molecular subtyping analysis. DNA was extracted from baseline pre-treatment tumor samples and sequenced to an average depth of 150X and the DNA extracted from matched normal tissue (peripheral blood) to a mean depth of 50X. PD-L1 expression was assessed using IHC 28-8 antibody on baseline tumors. Results: At a median FU of 15.8 months,12-month RFS rate was 85.4% and PFS including death from any cause was 83%. There were no long-term safety concerns. Molecular subtyping found patients with a basal-type tumor (Basal or Claudin-low) had a more favorable overall PaR in 13/18 = 73% with PaR in 9/13 in basal (69%) and 4/5 in claudin-low (80%) compared to overall PaR of 58% for the luminal-type tumors (Luminal or Infiltrated luminal) with a breakdown of PaR in 5/8 (63%) in luminal and 6/11 (54%) in infiltrated luminal. In contrast, in the comparator NAC cohort, the PaR rates were similar for basal-type and luminal-type tumors, with 44% and 48% respectively. There was no correlation of PaR with TMB or PD-L1 expression from bassline pre-treatment tumors. Biomarker analyses from residual tumors in RC tissues are ongoing. Conclusions: The combination of N+GC was safe and efficacious in MIBC with encouraging outcomes of pathologic down staging and relapse-free survival at a median FU of 15.8 months. Molecular subtyping results suggest basal-type tumors may respond more favorably to this chemo-immunotherapy treatment regimen. Clinical trial information: NCT03294304.

Use of Neoadjuvant Chemotherapy in Elderly Patients With Muscle-Invasive Bladder Cancer: A Population-Based Study, 2006-2017.

Objectives/Introduction Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) is associated with survival benefit across patients of all ages, yet it is not offered to many elderly patients. We aimed to evaluate age-based disparity in treatment and outcomes of MIBC. Methods Using the National Cancer Database, we identified patients with MIBC from 2006 to 2017. Use of treatment modalities was compared between age groups. A second analysis compared perioperative outcomes and overall survival (OS) in elderly patients (70 years or older) undergoing RC with NAC vs no NAC. Propensity score weighting (PSW) was used for each analysis. Results In 70,911 patients, use of NAC with RC was lower in patients 70 years or older (7.2% vs 20.9%; P < .001). In patients 70 years or older undergoing RC, NAC was associated with shorter inpatient stay (8.5 vs 9.6 days; P < .001), decreased 30-day readmission (8.6% vs 10.6%; P <.001), and lower 30- and 90-day mortality (1.5% vs 3.1%; P = .01; and 4.9% vs 7.7%; P = .003, respectively). On weighted multivariate regressions, NAC predicted shorter length of stay and lower 30-and 90-day mortality. Elderly patients receiving NAC had improved OS compared with RC alone (P = .0011, 2010-2013; P < .001, 2014-2016). Conclusions Despite increased omission of NAC in patients 70 years or older, elderly patients receiving NAC and RC had improved perioperative outcomes and OS compared with those undergoing RC alone. There may be selection bias unaccounted for with our PSW; however, our results provide compelling evidence that NAC does not compromise surgical outcomes in appropriately selected elderly patients. Patients of advanced age who are candidates for RC should be offered NAC.

Value of Prognostic Nutritional Index on Complications After Radical Cystectomy and Ileal Conduit: Retrospective Clinical Research

Objective: Prognostic nutritional index (PNI) is a method that can be easily calculated according to the serum albumin level and lymphocyte count and shows the nutritional and immune status of patients. PNI was originally developed as an indicator of the preoperative nutritional status of patients with gastrointestinal malignancies. The aim of this study is to evaluate the value of PNI in prediction of postoperative complications after radical cystectomy and ileal conduit. Material and Methods: We conducted a retrospective study of patients who underwent radical cystectomy and ileal conduit between 2011 and 2021. A total of 174 patients were included in this study. The patients were divided into 2 groups according to the cutoff value of the PNI: those with a PNI≥46 (normal group) and those with a PNI<46 (low PNI group). The clinicopathological features between the 2 groups were compared using the χ2 test. Results: A total of 174 radical cystectomy with ileal conduit patients were available for analysis. The cohort included 140 males and 34 females. Overall, 36 (20.6%) patients encountered a Grade ≥ III complication after surgery. In the normal group, 9 (17.5%) of patients had Grade ≥ III complication and 27 of patients (34.04%) in low PNI group had Grade ≥ III complication after surgery. When the groups were compared in terms of major complication rates, there were statistically significant more Grade ≥ III complications in the low PNI group (p<0.001). Conclusion: PNI can be used clinically to predict the possibility of serious postoperative complications in patients who are candidates for radical cystectomy.

Management of Localized Muscle-Invasive Bladder Cancer from a Multidisciplinary Perspective: Current Position of the Spanish Oncology Genitourinary (SOGUG) Working Group.

This review presents challenges and recommendations on different aspects related to the management of patients with localized muscle-invasive bladder cancer (MIBC), which were discussed by a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group within the framework of the Genitourinary Alliance project (12GU). It is necessary to clearly define which patients are candidates for radical cystectomy and which are candidates for undergoing bladder-sparing procedures. In older patients, it is necessary to include a geriatric assessment and evaluation of comorbidities. The pathological report should include a classification of the histopathological variant of MIBC, particularly the identification of subtypes with prognostic, molecular and therapeutic implications. Improvement of clinical staging, better definition of prognostic groups based on molecular subtypes, and identification of biomarkers potentially associated with maximum benefit from neoadjuvant chemotherapy are areas for further research. A current challenge in the management of MIBC is improving the selection of patients likely to be candidates for immunotherapy with checkpoint inhibitors in the neoadjuvant setting. Optimization of FDG-PET/CT reliability in staging of MIBC and the selection of patients is necessary, as well as the design of prospective studies aimed to compare the value of different imaging techniques in parallel.

Neoadjuvant Chemotherapy Followed by Cystectomy: a Single-Center Experience.

Nearly 50% of patients with muscle-invasive bladder cancer treated with cystectomy alone will progress to metastatic disease. Surgery alone is not a sufficient therapy in a large number of patients with invasive bladder cancer. Systemic therapy with cisplatin-based chemotherapy has been shown to provide response rates in several bladder cancer studies. There have been multiple randomized controlled studies undertaken to define further the effectiveness of neoadjuvant cisplatin-based chemotherapy in advance of cystectomy. In this study, we have retrospectively reviewed our series of patients who underwent neoadjuvant chemotherapy followed by radical cystectomy for muscle-invasive disease. Between Jan 2005 and Dec 2019, 72 patients underwent radical cystectomy following neoadjuvant chemotherapy over a 15-year period. The data was retrospectively collected and analyzed. The median age was 59.84 ± 8.967years (range, 43 to 74), and the ratio of male to female patients was 5:1. Of the 72 patients, 14 (19.44%) completed all the three cycles, 52 (72.22%) completed at least two cycles, and the remaining 6 (8.33%) completed only one cycle of neoadjuvant chemotherapy. A total of 36 (50%) patients died during the follow-up period. The mean and median survival of the patients was 84.85 ± 4.25months and 91.0 ± 5.83months respectively. Neoadjuvant MVAC should be offered to patients with locally advanced bladder cancer and who are candidates for radical cystectomy. It is safe and effective in patients with adequate renal function. The patients need to be carefully monitored for chemotherapy-induced toxic effects, and appropriate intervention is necessary in the event of severe adverse effects.

Miami Pouch: A Simple Technique for Efficient Continent Cutaneous Urinary Diversion

To report a contemporary series of Miami pouch (MP) enriched with a full technical description and step-by-step video to contribute to wider use. A retrospective charts review of all patients who had a MP at our center between January 2016 and December 2017 was performed. The MP technique uses the terminal 15cm of ileum and the right colon to build an intestinal heterotopic pouch located in the right iliac fossa and connected to the skin by an efferent catheterizable tube. Primary outcome was continence defined as the absence of leakage between clean intermittent self-catheterization (CISC) with a maximal interval of 4 hours between each CISC. Fifteen patients had MP during the study period. Thirty-day postoperative Clavien III complications were observed in 2 (13.3%) patients. At 39 months of median follow-up, continence was obtained for all patients except for 2 patients whom reported intermittent night-time leakages due to long intervals (5 to 7 hours) between 2 CISC. No significant alteration of renal function was reported and no stenosis of the efferent tube neither difficulty to perform CISC was observed. For patients who are candidates for radical cystectomy and not eligible for orthotopic neobladder, intestinal heterotopic pouch with a cutaneous continent urinary diversions as MP may be a reliable alternative. Patients should be informed of the existence of a valid alternative to ileal conduit since it may fit their expectations of a preserved body image without urine collecting appliances.

Cystoscopy and Systematic Bladder Tissue Sampling in Predicting pT0 Bladder Cancer: A Prospective Trial.

Concern for discordance between clinical staging and final pathology drives current management of patients deemed appropriate candidates for radical cystectomy. Therefore, we set out to prospectively investigate reliability and shortcomings of cystoscopic evaluation in radical cystectomy candidates. Patients undergoing radical cystectomy for urothelial carcinoma were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation in predicting pT0 urothelial carcinoma (NCT02968732). Systematic Endoscopic Evaluation consisted of cystoscopy and tissue sampling at the time of radical cystectomy. Systematic Endoscopic Evaluation results were compared to radical cystectomy pathology. The primary end point was the negative predictive value of Systematic Endoscopic Evaluation findings in predicting radical cystectomy pathology. A total of 61 patients underwent Systematic Endoscopic Evaluation and radical cystectomy. Indications included muscle invasive bladder cancer in 42 (68.9%) and high risk nonmuscle invasive bladder cancer in 19 (31.1%). In all, 38 (62.3%, 90.5% of patients with muscle invasive bladder cancer) received neoadjuvant chemotherapy. On Systematic Endoscopic Evaluation, 31 (50.8%) patients demonstrated no visual nor biopsy-based evidence of disease (seeT0), yet 16/31 (51.6%) harbored residual disease (>pT0), including 8 (8/31, 25.8%) with residual ≥pT2 disease upon radical cystectomy. The negative predictive value of Systematic Endoscopic Evaluation predicting a pT0 bladder was 48.4% (CI 30.2-66.9), which was below our prespecified hypothesis. Therefore, the trial was stopped for futility. Approximately 1 of 4 patients with seeT0 at the time of radical cystectomy harbored residual muscle invasive bladder cancer. These prospective data definitively confirm major limitations of endoscopic assessment for pT0 bladder cancer. Future work should focus on novel imaging and biomarker strategies to optimize evaluations before radical cystectomy for improved decision making regarding bladder preservation.

PD50-07 SYSTEMATIC ENDOSCOPIC EVALUATION FALLS SHORT IN PREDICTING PT0 BLADDER CANCER

INTRODUCTION AND OBJECTIVE: Concern for discordance between endoscopic evaluation and final pathology drives current clinical management of patients deemed appropriate candidates for radical cystectomy (RC). Yet, > 30% of patients (pts) who undergo neoadjuvant chemotherapy (NAC) prior to RC do not harbor detectable malignancy within the bladder at the time of extirpative surgery. Our objective was to prospectively assess the reliability of cystoscopic evaluation in RC candidates. METHODS: Pts undergoing RC for urothelial carcinoma (UC) at our institution were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation (SEE) in predicting pT0 UC. SEE consisted of rigid cystoscopy with targeted biopsy (and transurethral resection with loop after protocol amendment) of visible tumor and/or tumor bed/scar, plus two additional random biopsies performed at the time of RC. A standardized bladder map was used to index cystoscopic findings. SEE and biopsy results were compared to RC pathology. Comparisons were considered congruent if both SEE and RC were T0, or if any level of disease seen at both SEE and RC (exception, cT0 with pTis at RC called congruent). This trial design included early stopping rules for futility based on the primary endpoint of a negative predictive value (NPV) less than 70%. RESULTS: In total, 61 pts underwent SEE and RC as part of this trial. The final population included MIBC in 41 pts (67%) and high-risk NMIBC in 20 pts (33%). 38 pts (62%) received platinum-based neoadjuvant chemotherapy. Based on RC final pathology, 16 pts (26%) were pT0 and 28 pts (46%) harbored residual ≥pT2 disease. For detecting any disease, the positive predictive value was 96.7%, but the NPV was 48.4%, necessitating study closure based on pre-specified boundaries for futility. The sensitivity for detecting pT2 at RC disease was 71%. CONCLUSIONS: To our knowledge, this was the first prospective study exploring whether a standardized SEE could sufficiently predict the presence of residual malignancy. The NPV was below the pre-specified threshold, triggering study closure. pT2 or higher disease was missed nearly 30% of the time. This study definitively demonstrates that current cystoscopic techniques are inadequate to guide decisions on bladder preservation.Source of Funding: None

Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy.

439 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) in MIBC improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). The combination of immunotherapy and NAC may improve PaR and outcomes in MIBC. We tested the efficacy and safety of nivolumab (N) with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC in our phase II trial (NCT03294304). Methods: Eligible pts with MIBC (cT2-T4a, N≤1, M0) who were candidates for RC were enrolled. Pts received C (70mg/m2) IV on D1, G (1000mg/m2) on D1,D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by RC within 8 weeks. The primary endpoint was PaR (≤pT1,N0). Secondary objectives were safety of GC+N and PFS at 2 years. The correlative objectives based on pre-treatment biopsies were correlation of PaR with 1) WGS 2) molecular subtypes of BC; 3) PD-L1 expression; 4) baseline TILs, CD3, CD8 and CD56.. Evaluable pts. should have received at least 1 dose of N. PaR will be summarized by the PaR rate as estimated by the sample proportion with exact 95% confidence intervals. We specified a null PaR of 0.35 and an alternative hypothesis of 0.55; we will reject the null hypothesis if at least 20 of 41 pts. have a PaR. Results: Between Feb 2018 and June 2019, 41 pts. were enrolled (cT2N0 90%, cT3N0 7%, cT4N1 3%); 2 patients refused surgery but were included in ITT population. PaR was observed in 27/41 pts. (65.8%), including pts with N1 disease. The combination was safe with manageable toxicities and no deaths from treatment. Majority of AEs were from GC; the overall rates of grade 3-4 AEs was 20%, majority being neutropenia, thrombocytopenia and renal insufficiency. Immune related AEs were seen in 3 patients, 2 had "adenitis" which wasymptomatic,1 pt developed Guillian Barre Syndrome after surgery, which resolved with IVIG; and none of them required steroids. There was no delay in time to RC and no unexpected surgical complications from treatment. Patients are being followed for progression and survival. Correlative work is ongoing. Conclusions: Neoadjuvant N+GC is safe and effective in MIBC with significant pathologic downstaging rates and no added toxicities or delay to surgery. Clinical trial information: NCT03294304.

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

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

Which comorbidity classification is best suited to identify patients at risk for 90-day and long-term non-bladder cancer mortality after radical cystectomy?

There is no consensus on the best comorbidity measure in candidates for radical cystectomy. The aim of this study was to identify tool best suited to identify patients at risk for 90-day or premature long-term non-bladder cancer mortality. We studied 1268 patients who underwent radical cystectomy to identify patients at risk for 90-day and later-than-90-day mortality, respectively. Six classifications were investigated as possible predictors of both types of mortality. Multivariable models including age as continuous variable and each classification separately were calculated. A heuristic ranking was based on the evaluation of the hazard ratios, p values, Akaike's information criteria, and concerning the logit models also the areas under the curve. The median follow-up was 5.7years. Within 90days after surgery, the mortality rate was 4.2%. The greatest independent contribution concerning the prediction of 90-day mortality was seen with the American Society of Anesthesiologists (ASA) physical status classification (classes 3-4 versus 1-2: hazard ratio 7.98, 95% confidence interval 3.54-18.01, p < 0.0001). In the longer term, countable diseases (Canadian Cardiovascular Society classification of angina pectoris, conditions contributing the Charlson score) were of greater importance. The results of heuristic ranking were confirmed by multivariate analyses including age and all classifications together. Besides to chronological age, clinicians should pay particular attention to the ASA classification to identify patients at risk for 90-day mortality after radical cystectomy, whereas long-term mortality is more determined by countable comorbid diseases.

609 - Incidence and impact of histological variants on survival in candidates for radical cystectomy: Results from a multicenter collaboration

609 - Incidence and impact of histological variants on survival in candidates for radical cystectomy: Results from a multicenter collaboration

Contemporary use and survival after perioperative systemic chemotherapy in patients with locally advanced non-metastatic urothelial carcinoma of the bladder treated with radical cystectomy

BackgroundLocally advanced muscle-invasive bladder cancer (MIBC) patients who are candidates for radical cystectomy (RC) should receive perioperative chemotherapy (CHT). However, the adherence to CHT guidelines is low. Thus, we tested contemporary CHT use rates and associated cancer-specific mortality (CSM) and overall mortality (OM) rates. Materials and methodsWithin the SEER database (2004–2015), we identified pT3N0/+ MIBC patients, who underwent RC, with or without perioperative CHT. Estimated annual percentage changes (EAPCs) analyses were used. After inverse probability of treatment weighting (IPTW), Kaplan–Meier (KM) analyses and Cox regression models (CRMs) tested the association of CHT on survival in the overall population (n = 3817), as well as after stratification according to stage, gender and age. Landmark analyses tested for immortal time bias. ResultsOverall, 44.3% of patients received CHT. Between 2004 and 2015, CHT administration rates increased from 32.1% to 55.6% (EAPC: +6.0%; p < 0.001). In CRMs, CHT was associated with lower CSM (HR 0.73, CI 0.65–0.81) and OM (HR 0.69, CI 0.62–0.76). In sensitivity analyses, CHT was also associated with lower CSM and OM in N0 patients (CSM: HR 0.76, 95% CI 0.65–0.88; OM: HR 0.69, 95% CI 0.60–0.79) and in N+ patients (CSM: HR 0.69, 95% CI 0.59–0.80; OM: HR 0.67, 95% CI 0.58–0.77), as well as according to gender and age. Landmark analyses confirmed the above results. ConclusionsPerioperative CHT was associated with better survival and its rate of use increased in locally-advanced MIBC RC patients. The latter confirm one large observational study and several small prospective studies.

Is neoadjuvant chemotherapy for pT2 bladder cancer associated with a survival benefit in a population-based analysis?

BackgroundPatients with organ confined muscle-invasive bladder cancer (MIBC) who are candidates for radical cystectomy (RC) should receive neoadjuvant chemotherapy (CHT). However, the most contemporary CHT use rates indicate low adherence to these guidelines. We tested contemporary neoadjuvant CHT rates and associated cancer-specific mortality (CSM) and overall mortality (OM) in pT2N0 MIBC patients treated with RC. Materials and methodsWithin the SEER database (2004–2015), we identified patients with pT2N0 MIBC patients who underwent RC. CHT administration rates were evaluated using estimated annual percentage changes (EAPCs) analyses. After inverse probability of treatment weighting (IPTW), Kaplan–Meier (KM) analyses and Cox regression models (CRMs) were used to test the effect of CHT vs no CHT on survival. Landmark analyses tested for immortal time bias. ResultsOf 3978 RC patients, 38.2% of patients received CHT. Between 2004 and 2015, CHT rates increased from 15.9% to 66.2% (EAPC: +14.2%; p < 0.001). IPTW-adjusted KM showed 10-year CSM-free survival rates of 78.9% for CHT vs 76.7% for no CHT patients (p = 0.6). Similarly, IPTW-adjusted KM showed 10-year OM-free survival rates of 54.6% for CHT vs 57.9% for no CHT patients (p = 0.8). In IPTW-adjusted MCRMs, CHT was not significantly associated with lower CSM (HR 0.97, CI 0.82–1.14; p = 0.7) or OM (HR 1.02, CI 0.90–1.16; p = 0.7). Virtually the same CSM and OM rates were recorded after landmark analyses. ConclusionsCHT use in pT2N0 MIBC RC patients sharply increased over the study span. However, neoadjuvant CHT was not associated with better survival in this patient group.