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Background: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear., Patients and Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up., Results: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status., Conclusions: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Keynote-045 trial illustrates that the long-term benefit (LTB) of treatment does not always translate to improved progression-free survival (PFS). Milestone survival and flexible parametric survival model with cure (FPCM) have been proposed as complementary statistical approaches to more comprehensively evaluate LTBs of treatments., Objective: The current study compares milestone survival and FPCM analyses to evaluate treatment effects of immune checkpoint inhibitor (ICI) phase III trials., Design, Setting, and Participants: Individual patient data, from initial and follow-up analyses of Keynote-045 (urothelial cancer) and Checkmate-214 (advanced renal cell carcinoma), were reconstructed for PFS., Outcome Measurements and Statistical Analysis: Each trial was reanalyzed using the Cox proportional hazard regression and two complementary methods (milestone survival and FPCM) to estimate treatment impact on the LTB., Results and Limitations: For each trial, there was evidence of nonproportional hazards. For the long-term analysis of the Keynote-045 trial, FPCM identified a time-dependent effect on PFS, but the Cox model found no statistical difference in PFS (hazard ratio, 0.90; 95% confidence interval, 0.75-1.08). Milestone survival and FPCM identified improvements in the LTB fractions. This was consistent with the results from the reanalysis of Keynote-045, based on the shorter follow-up, although the LTB fraction was not retained. The increase in PFS in Checkmate-214 was identified by both Cox model and FPCM. Experimental treatment-dependent improvement in the LTB fraction was demonstrated using milestone survival and FPCM. The LTB fraction estimated with FPCM was consistent with the results from the reanalysis of the shorter follow-up period., Conclusions: Although ICIs show substantial shifts toward LTBs in terms of PFS, based on a conventional Kaplan-Meier or Cox model analysis, our approach provides an alternative assessment of benefit-risk ratios for new therapeutics and facilitates communicating risk to patients. Kidney patients treated with ICIs can be counseled that they are potentially cured, but future work will need to definitively validate this conclusion., Patient Summary: Although immune checkpoint inhibitor treatments show substantial shifts toward long-term benefits in terms of progression-free survival, a more rigorous attempt to quantify this shift, rather than simply using a Kaplan-Meier estimate or comparing progression-free survival curves using the classic Cox model, is warranted. Our results suggest that advanced renal cell carcinoma patients who had not received a previous treatment are functionally cured by nivolumab and ipilimumab, which is not the case for second-line urothelial carcinoma., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714)., Patients and Methods: Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each)., Conclusions: Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements., Competing Interests: Disclosures AN received honoraria from Astellas, AstraZeneca, BMS, Foundation Medicine, Janssen, MSD, and Roche; served as a consultant and/or advisor to AstraZeneca, Basilea Pharmaceutica, Bayer, Bicycle Therapeutics, BMS, Catalym, Clovis Oncology, GlaxoSmithKline, Incyte, Janssen, MSD, Rainier Therapeutics, Roche, and Seattle Genetics/Astellas; received research funding paid to the institution from AstraZeneca, Gilead, Ipsen, and MSD; received payments for travel and accommodations from AstraZeneca, Janssen, MSD, Pfizer, Rainer Therapeutics, and Roche; and reports that his spouse is an employee and shareholder of Bayer. DP received research grants paid to his institution from AstraZeneca, BMS, Merck Sharp & Dohme, Roche, and Seattle Genetics; received honoraria from AstraZeneca, Astellas Pharma, BMS, Ipsen, MSD Oncology, and Pfizer/Astellas; served as a consultant for Astellas Pharma, BMS/Medarex, Merck, MSD Oncology, and Pfizer; and received payments for travel and accommodations from AstraZeneca and Pfizer. RL received honoraria from AstraZeneca, Bayer, BMS, Isotopia, Janssen, MSD, Pfizer, and Roche; served as a consultant and/or advisor for Astellas Medivation, AstraZeneca, Bayer, Immunai, Kamada, NeoPharm, Oncohost, Pfizer, and Sanofi; received travel support from Janssen and Pfizer; and served as a principal investigator on studies from BMS, Eisai, Incyte, Janssen, MSD, and Pfizer. SG received research funding from Acrotech, Astellas, AstraZeneca, BMS, Clovis Oncology, Daiichi Sankyo/Lilly, Five Prime Therapeutics, Hoosier Cancer Research Network, Immunocore, Incyte, LSK BioPharma, MedImmune, Merck, Mirati Therapeutics, Novartis, Pfizer, QED Therapeutics, Rexahn Pharmaceuticals, Seattle Genetics, and Viralytics. AF received honoraria from Astellas, Janssen, Merck, MSD, Pfizer, and Seagen. JGD received researching funding from Astellas, BMS, GSK, Ipsen, Janssen, Pfizer, Roche, and Sanofi and honoraria for serving as a speaker for AstraZeneca, BMS, Janssen, and Roche. MAB has acted as a paid consultant for and/or as a member of the advisory boards of AstraZeneca, Bayer, BMS, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Genomic Health, Janssen, Nektar, Pfizer, Sanofi, and SeaGen and has received grants to his institution from AAA, AstraZeneca, Bayer, BMS, Genentech/Roche, Genome & Company, Incyte, Merck, Nektar, Peloton Therapeutics, Pfizer, SeaGen, Tricon Pharmaceuticals, and Xencor for work carried out as outside of the current study. PRD received grants to institution from Pfizer; received consulting fees for participation on advisory boards from BMS, Ipsen, Merck, and Pfizer; received honoraria for lectures from Bayer; received travel support from Janssen; serves as a substitute board member for the Clinical Trials College, Federal Public Service, Kingdom of Belgium; and holds stock or stock options in Alkermes and Biocartis Group NV. MIM received research grants paid to his institution from Alliance for Clinical Trials in Oncology, Alliance Foundation Trials, ALX Oncology, Arvinas, BMS, Clovis Oncology, G1 Therapeutics, Hoosier Cancer Research Network, Incyte, Loxo, Merck, Mirati Therapeutics, Roche/Genentech, and Seagen; served as a consultant for Loxo/Lilly; owns stock in Gilead Sciences, Merck, and Pfizer; and reports a relationship with Elsevier, Research to Practice, and Medscape. TF received honoraria and payments for travel and accommodations from Astellas; had a consulting or advisory role for AADi Therapeutics, Basilea Pharmaceutica, and Seagen/Astellas; and received research funding paid to the institution from BMS, Roche/Genentech, Seagen, and Trishula. MM served as a consultant and/or advisor to Alfasigma, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Incyte, Merck Serono, Merck Sharpe & Dohme, Pierre Fabre, Roche, Sanofi, and Sciclone and owns shares in Epigen Therapeutics and Theravance. AG, XL, and MLV are employees and shareholders of Incyte. YL received honoraria from AstraZeneca, Astellas, BMS, Gilead, Janssen, Merck KGaA, MSD, and Pfizer and received payments for travel and accommodations from Astellas, BMS, Janssen, Merck KGaA, MSD, Pfizer, and Roche., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC)., Materials and Methods: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox' regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as 'organ-confined' (≤pT2N0), 'locally advanced' (pT3-4N0) and 'node-positive' (pTanyN1-3)., Results: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively., Conclusions: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management., (© 2023 BJU International.)

Introduction: Mutations in the TP53 gene are indicative of worse outcome in bladder cancer and are usually assessed by immunohistochemistry. To define p53-overexpression, a threshold of >10% is most commonly used (cut-off1). Recently, a novel cut-off (aberrant = 0% or ≥50%) (cut-off2) showed better correlation to clinical outcome. In this study, we evaluate the association between p53-immunohistochemistry cut-offs, clinico-pathological variables and disease-specific survival (DSS). Methods: Seven-hundred-fifty chemotherapy-naïve patients who underwent radical cystectomy were included (92% muscle-invasive bladder cancer. In addition to cut-off1 and cut-off2, a third cut-off (cut-off3) was determined based on the highest Youden-index value. Cut-off values were associated with clinico-pathological variables and FGFR3 mutation status. The Kaplan-Meier method was used to estimate DSS. Results: Aberrant p53-expression was found in 489 (65%) (cut-off1) and 466 (62%) (cut-off2) tumors. Cut-off3 was determined at 25% and aberrant p53-expression in 410 cases (55%) (cutoff3). p53-expression levels were significantly associated with higher pT-stage (cut-off1/2/3: P = 0.047, P = 0.006 and P = 0.0002, respectively), higher grade (all, P < 0.0001), and FGFR3 wild-type (cut-off1: P = 0.02, cut-offs2&3: P = 0.001). Median follow-up was 5.3 years (interquartile range, 4.0-6.0 years). p53-expression was not associated with DSS for any of the three cut-offs (cut-off1/2/3: P-log-rank = 0.566, 0.77 and 0.50, respectively). If we only considered locally advanced bladder cancer, results on DSS remained non-significant. Conclusion: This multi-center, multi-laboratory study showed that, regardless of the cut-off used, p53-immunohistochemistry did not enable selection of patients with worse outcome. Our results suggest that p53-immunohistochemistry alone is not suitable to guide clinical decision making after radical cystectomy.

Background: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC)., Methods: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities., Results: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (&lt; or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients., Conclusion: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Organ-sparing strategies in the management of local or locally advanced cancers meet a dual objective: tumor control and preservation of the function of the involved organ. Given the morbidity and mortality of cystectomy and its impact on quality of life and bladder function, bladder-sparing strategies have emerged for the management of urothelial muscle invasive bladder cancer, mostly through trimodal treatment, which consists in maximal trans-urethral resection of bladder tumor, followed by chemo-radiotherapy. This review presents the modalities of trimodal treatment, before exposing the advantages and limitations of this strategy compared to cystectomy among operable patients. Despite the absence of comparative data from randomized trials, the two approaches seem to provide similar oncological results among appropriately selected patients. In modern series, the rate of salvage cystectomy is approximately 15% at 5 years; this delayed cystectomy does not seem to be associated with greater morbidity and mortality as compared to upfront cystectomy. Emphasis is placed in the review on quality of life data of these two approaches. In order to optimize the selection of patients eligible to trimodal therapy, the classical predictive factors of response to radio(chemo)therapy are critically analyzed, with the perspective of innovative molecular biomarkers. Finally, a close multidisciplinary collaboration is needed for the choice and the execution of the therapeutic strategy, and the patient should be fully involved in the decision-making process., (Copyright © 2022 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Background: Prior durvalumab (anti-PD-L1 agent) studies in platinum-refractory metastatic urothelial carcinoma evaluated a dose of 10 mg/kg administered every two weeks. The nonrandomised phase 3b STRONG study (NCT03084471) evaluated the safety and efficacy of fixed-dose durvalumab at a more convenient dosing schedule in a previously treated patient population, more similar to a real-world clinical setting., Patients and Methods: 867 patients with urothelial or nonurothelial urinary tract carcinoma (UTC) who progressed on or after platinum or nonplatinum chemotherapy were treated with durvalumab 1500 mg every four weeks; 87% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, and 13% had an ECOG PS of 2. The primary end-point was the incidence of adverse events of special interest (AESIs), including immune-mediated AEs (imAEs). Secondary and exploratory end-points included overall survival (OS), objective response rate (ORR) and disease control rate (at six and 12 months) (DCR)., Results: AESIs of any grade were reported in 51% of patients (8% grade ≥ 3). The incidence of imAEs was 11% (2% grade ≥ 3). The median OS was 7.0 months (95% confidence interval [CI]: 6.4-8.2) and ORR was 18% (95% CI: 14.8-20.6), with complete responses in 5% of patients and a DCR at six months of 19% (95% CI: 16.1-22.1)., Conclusion: Fixed-dose durvalumab monotherapy every four weeks has an acceptable safety profile and yields durable clinical activity in previously chemotherapy-treated patients with UTC. Safety and efficacy are consistent with previous durvalumab studies and other anti-PD-1/PD-L1 agents in this setting. CLINICALTRIALS., Gov Identifier: NCT03084471https://clinicaltrials.gov/ct2/show/NCT03084471., Competing Interests: Conflict of interest statement The following authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: Sang Joon Shin and Guilhem Roubaud. The following authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Guru P. Sonpavde: Has received grants or contracts (institution) from AstraZeneca, Janssen, and Sanofi; Consulting fees from Astellas Pharma, AstraZeneca, Bicycle Therapeutics, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech, Janssen, Merck, Pfizer and Seattle Genetics; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Medscape, Onclive, Physicans' Education Resource and Research to Practice; Support for attending meetings and/or travel from Bristol-Myers Squibb; Other financial or non-financial interests from Astellas Pharma, AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, Debiopharm Group, Elsevier and QED Therapeutics. Cora N. Sternberg: Has received consulting fees from Astellas Pharma, AstraZeneca, Bayer, Genzyme, Immunomedics, Incyte, Medscape, Merck, Merck Sharp & Dohme, Pfizer, Roche and UroToday. Yohann Loriot: Has received grants or contracts (institution) from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, CureVac, Exelixis, Incyte, Janssen Oncology, Medivation, Merck Sharp & Dohme Oncology, Nektar, Oncogenex, Pfizer and Sanofi; Consulting fees from Astellas Pharma, AstraZeneca; Clovis Oncology, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme Oncology, Roche and Seattle Genetics and institution consulting fees from Janssen and Merck Sharp & Dohme Oncology; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer and Sanofi; Support for attending meetings and/or travel Astellas Pharma, AstraZeneca; Janssen Oncology, Merck Sharp & Dohme Oncology, Roche and Seattle Genetics. Jae Lyun Lee: Has received grants or contracts (institution) from AstraZeneca/MedImmune, Bayer Schering Pharma, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer and Roche/Genentech and Seattle Genetics; Consulting fees from Alteogen, Bristol-Myers Squibb, GI Innovation, Merck Sharp & Dohme, Pfizer and Sanofi/Aventis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Pfizer; Stock or stock options from Immunomedics and Myovant Sciences. Aurelien Marabelle: Has received grants or contracts (institution) from Boehringer Ingelheim, Bristol-Myers Squibb, MERUS, MSD and Transgene; Consulting fees from AstraZeneca Bayer, Boehringer Ingelheim, CERENIS THERAPEUTICS, Eisai, Gritstone Oncology, HiFiBiO Therapeutics, ImCheck therapeutics, Innate Pharma, Lytix Biopharma, Merck Serono, Molecular Partners, Merck Sharp & Dohme, OSE Immunotherapeutics, Pierre Fabre, Redx Pharma, Roche, Sanofi, SERVIER, Sotio, Symphogen; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme; Support for attending meetings and/or travel from AstraZeneca and Merck Sharp & Dohme; Patents planned, issued or pending from Stanford University (Monoclonal antibodies against CD81); Stock or stock options from HiFiBiO Therapeutics and PEGASCY and PEGASCY (insitition); Other financial or non-financial interests from PEGASCY; Honoraria received from Elsevier as an editor for the European Journal of Cancer. AudeFléchon: Has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and/or support for attending meetings and/or travel rom Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Merck Sharp & Dohme Oncology, Pfizer, Roche/Genentech and Sanofi/Aventis. Damien Pouessel: Has received has received grants or contracts (institution) from AstraZeneca, Bristol-Myers Squibb, Incyte, Janssen Oncology, Merck Sharp & Dohme, Roche and Seattle Genetics; Consulting fees from Astellas Pharma, AstraZeneca, Janssen Oncology, Pfizer and Sanofi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen Oncology and Merck; Support for attending meetings and/or travel from AstraZeneca, Janssen Oncology and Pfizer. Vittorina Zagonel: Has received has received grants or contracts (institution) from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Lilly and Roche; Consulting fees from Bristol-Myers Squibb and Merck; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Roche and Servier; Support for attending meetings and/or travel from Bayer, Roche and Servier. Fabio Calabro: Has received consulting fees from Merck Sharp & Dohme Oncology and Pfizer. Giuseppe L. Banna: Has received consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen-Cilag and Roche; Support for attending meetings and/or travel from AstraZeneca/MedImmune, Bristol-Myers Squibb, Ipsen and Pierre Fabre; Patents planned, issued or pending with ST Microelectronics “Deep Learning Motion Algorithm for Lung Cancer Early Detection in Embedded Systems” and “Image processing method, corresponding system and computer program product”. Francisco E. Vera-Badillo: Has received grants or contracts (institution) from AstraZeneca/MedImmune. Thomas Powles: Has received has received grants or contracts, consulting fees and/or payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Seattle Genetics; Support for attending meetings and/or travel from AstraZeneca, Ipsen, Merck Sharp & Dohme, Pfizer and Roche. Eva Hellmis: Has received support for attending meetings and/or travel from Janssen-Cilag. Paulo A. P. Miranda is a current employee of AstraZeneca with AstraZeneca stock or stock options. Ugochi Emeribe and Sun Min Oh are current employees of AstraZeneca. Ana Rita Lima is currently employed as a Third Party Service Provider to AstraZeneca. Sebastien J. Hotte: Has received grants or contracts (institution) from Astellas Pharma, AstraZeneca, Ayala Pharmaceuticals, Bristol-Myers Squibb, Clovis Oncology, Janssen Oncology, Merck, Pfizer, Roche/Genentech, Seattle Genetics and SignalChem; Consulting fees from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Pfizer and Roche Canada; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Scientific and Medical Affairs Inc, Bayer, Janssen Oncology and Merck; Support for attending meetings and/or travel from Eisai., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort., Patients and Methods: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS)., Results: pT-stage was

Basal/squamous (Ba/Sq) subtype represents an intrinsic and robust group in the consensus molecular classification of muscle-invasive bladder cancer (MIBC), with poor outcome and controversial chemosensitivity. We aimed to investigate the spectrum of intratumor heterogeneity (ITH) in the Ba/Sq subtype. First, we validated a 29-gene NanoString CodeSet to predict the Ba/Sq subtype for FFPE samples. We identified heterogeneous Ba/Sq tumors in a series of 331 MIBC FFPE samples using dual GATA3/KRT5/6 immunohistochemistry (IHC). Heterogeneous regions with distinct immunostaining patterns were studied separately for gene expression using the 29-gene CodeSet, for mutations by targeted next-generation sequencing, and for copy number alteration (CNA) by microarray hybridization. Among 83 Ba/Sq tumors identified by GATA3/KRT5/6 dual staining, 19 tumors showed heterogeneity at the IHC level. In one third of the 19 cases, regions from the same tumor were classified in different distinct molecular subtypes. The mutational and CNA profiles confirmed the same clonal origin for IHC heterogeneous regions with possible subclonal evolution. Overall, two patterns of intratumoral heterogeneity (ITH) were observed in Ba/Sq tumors: low ITH (regions with distinct immunostaining, but common molecular subtype and shared CNA) or high ITH (regions with distinct immunostaining, molecular subtype, and CNA). These results showed multilayer heterogeneity in Ba/Sq MIBC. In view of personalized medicine, this heterogeneity adds complexity and should be taken into account for sampling procedures used for diagnosis and treatment choice. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Purpose: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC)., Methods: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan-Meier method was used to estimate DSS stratified by margins' status and location. Log-rank statistics and Cox' regression models were used to determine significance., Results: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p  <  0.001) and lymph-node metastases (OR 1.86, p  =  0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p  =  0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p  =  0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p  <  0.001)., Conclusions: PSMs' location represents distinct risk factors' patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer (BC). FGFR3 mutations are common in noninvasive BC and associated with favorable BC prognosis. Overexpression was reported in up to 40% of FGFR3 wild-type muscle-invasive BC. We analyzed FGFR3 mutations, FGFR3, and p53 protein expression and assessed their prognostic value in a cohort of 1000 chemotherapy-naive radical cystectomy specimens. FGFR3 mutations were found in 11%, FGFR3 overexpression was found in 28%, and p53 overexpression was found in 69% of tumors. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression versus 22% among FGFR3 wild-type tumors. FGFR3 mutations were significantly associated with lower pT stage, tumor grade, absence of carcinoma in situ, pN0, low-level p53, and longer disease-specific survival (DSS). FGFR3 overexpression was associated only with lower pT stage and tumor grade. Moreover, FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. In conclusion, FGFR3 mutations identified patients with favorable BC at cystectomy. Our results suggest that FGFR3 mutations have a driver role and are functionally distinct from FGFR3 overexpression. Hence, patients with FGFR3 mutations would be more likely to benefit from anti-FGFR3 therapy. Ideally, further research is needed to test this hypothesis. PATIENT SUMMARY: Oncogenic fibroblast growth factor receptor 3 (FGFR3) mutations are very common in bladder cancer. In this report, we found that these FGFR3 mutations were associated with favorable features and prognosis of bladder cancer compared with patients with FGFR3 overexpressed tumors only. As a consequence, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with FGFR3 protein overexpression only., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available., Materials and Methods: We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors., Results: From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes., Conclusions: In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although human epidermal growth factor receptor 2 (HER2) may represent a therapeutic target, its evaluation in urothelial carcinoma of the bladder does not rely on a standardized scoring system by immunohistochemistry or fluorescent in situ hybridization (FISH), as reflected by various methodology in the literature and clinical trials. Our aim was to improve and standardize HER2 amplification detection in bladder cancer. We assessed immunohistochemical criteria derived from 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAPs) guidelines for breast cancer and investigated intratumoral heterogeneity in a retrospective multicentric cohort of 188 patients with locally advanced urothelial carcinoma of the bladder. Immunohistochemistry was performed on 178 primary tumors and 126 lymph node metastases, eligible cases (moderate/strong, complete/incomplete membrane staining) were assessed by FISH. HER2 overexpression was more frequent with 2013 ASCO/CAP than 2007 ASCO/CAP guidelines (p < 0.0001). The rate of positive HER2 FISH was similar between primary tumor and lymph node metastases (8%). Among positive FISH cases, 48% were associated with moderate/strong incomplete membrane staining that were not scored eligible for FISH by 2007 ASCO/CAP criteria. Among 3+ immunohistochemistry score cases, 67% were associated with HER2-positive FISH. Concordance between primary tumors and matched lymph node metastases was moderate for immunohistochemistry (κ = 0.54 (CI 95%, 0.41-0.67)) and FISH (κ = 0.50 (CI 95%, 0.20-0.79)). HER2-positive FISH was more frequent in micropapillary carcinomas (12%) and carcinoma with squamous differentiation (11%) than in pure conventional carcinoma (6%). Intratumoral heterogeneity for HER2 immunohistochemistry was observed in 7% primary tumor and 6% lymph node metastases; 24% positive HER2 FISH presented intratumoral heterogeneity. Our study suggests that HER2 evaluation should include an immunohistochemistry screening step with eligibility for FISH including incomplete/complete and moderate/strong membrane staining. Spatial or temporal intratumoral heterogeneity prompts to perform evaluation on both tumor and lymph node, and for each histological variant observed.

Background: In the past decade, adjuvant chemotherapy (AC) after radical cystectomy (RC) was preferred worldwide for patients with muscle-invasive urothelial bladder cancer. In this study we aimed to determine the outcome of patients who received AC and evaluated prognostic factors associated with survival., Patients and Methods: We retrospectively analyzed 226 consecutive patients treated in 6 academic hospitals between 2000 and 2009. Multivariate Cox proportional hazards regression adjusted for center to estimate adjusted hazard ratios (HRs) with 95% confidence intervals were used., Results: The median age was 62.4 (range, 35-82) years. Patients had pT3/pT4 and/or pN+ in 180 (79.6%) and 168 patients (74.3%), respectively. Median lymph node (LN) density was 25% (range, 3.1-100). Median time between RC and AC was 61.5 (range, 18-162) days. Gemcitabine with cisplatin, gemcitabine with carboplatin, and MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimens were delivered in 161 (71.2%), 49 (21.7%), and 12 patients (5.3%) of patients, respectively. The median number of cycles was 4 (range, 1-6). Thirteen patients (5.7%) with LN metastases also received adjuvant pelvic radiotherapy (ART). After a median follow-up of 4.2 years, 5-year overall survival (OS) was 40.7%. In multivariate analysis, pT ≥3 stage (HR, 1.73; P = .05), LN density >50% (HR, 1.94; P = .03), and number of AC cycles <4 (HR, 4.26; P = .001) were adverse prognostic factors for OS. ART (HR, 0.30; P = .05) tended to provide survival benefit., Conclusion: Classical prognostic features associated with survival are not modified by the use of AC. Patients who derived benefit from AC had a low LN density and received at least 4 cycles of treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response., Patients and Methods: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201)., Results: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type., Conclusions: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There is continuing controversy regarding the optimal regimen for neoadjuvant chemotherapy (NAC) in bladder cancer., Patients and Methods: We performed a retrospective analysis of 241 consecutive bladder cancer patients who received a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) using a standard (52 patients) or an accelerated schedule (189 patients) as NAC before radical cystectomy in 17 centres of the French GEnito-urinary TUmour Group from March 2004-May 2013., Results: The median age was 62 years. As expected, the median number of cycles, the median total dose of cisplatin and the median cisplatin dose intensity were higher in patients treated with the accelerated regimen. Conversely, the median duration of chemotherapy was shorter. Regarding toxicity, grade III/IV neutropenia, grade III thrombocytopenia and grade III anaemia as well were more frequently observed in patients treated with the standard regimen. Among 211 (88%) patients who proceeded to cystectomy, 75 (35%) patients achieved an ypT0 pN0 status (no pathologic residual tumour cells) with no significant difference according to the MVAC schedule. Three-year overall survival rates were 66.5% (95% confidence interval [CI], 56-79) and 72% (95% CI, 59.5-88) in the standard and accelerated cohorts, respectively. In the multivariate analysis, two independent prognostic parameters were retained: the ypT0 stage and the ypN0 stage. Heterogeneity test did not show any interaction with NAC regimens., Conclusion: Similar pathological response and survival rates were observed whatever the chemotherapy regimen used. Haematological toxicity was greater in patients who received standard MVAC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The management of patients with metastatic bladder cancer is mainly based on cytotoxic chemotherapy. The reference molecule is cisplatin. In 2014, first-line regimens include gemcitabine and cisplatin (GC protocol) or methotrexate, vinblastine, and cisplatin doxorubicin (MVAC protocol). When cisplatin is contra-indicated, another platinum Salt, carboplatin, is used in combination with gemcitabine. Vinflunine is the only molecule to have obtained a marketing approval for patients who failed first-line chemotherapy including a platinum salt. The overall prognosis of patients remains dismal, since the median overall survival is 12 to 14 months for patients being treated with cisplatin, whereas it is less than 1 year for patients receiving carboplatin. The identification of new effective drugs is a major challenge for the coming years.

Purpose: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting., Methods and Materials: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control., Results: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months., Conclusions: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Through a Medline search from January 1, 1998 to February 29, 2012, the literature data supporting the standard use of neoadjuvant or adjuvant chemotherapy in the perioperative setting for muscle-invasive transitional cell carcinoma of the bladder were reviewed. Randomized phase III trials and meta-analyses have shown a significant benefit (level I evidence) in overall survival for neoadjuvant chemotherapy, with a 5% absolute benefit at 5 years, provided cisplatin-based combination regimens are used. Major methodological biases preclude any firm conclusion regarding the routine use of adjuvant therapy. The optimal chemotherapy regimen remains to be determined. Predictive biomarkers are urgently needed in order to determine which patients are more likely to benefit from neoadjuvant chemotherapy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The optimal chemotherapy for patients with advanced transitional cell carcinoma of the urothelium who are not eligible for cisplatin remains to be defined., Objective: To assess the activity of gemcitabine alone (GEM) or in combination with oxaliplatin (GEMOX) in a randomized phase 2 trial., Design, Setting, and Participants: The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors criteria. The sample size was based on a two-stage Fleming design with p0=35% and p1=55%. At the end of the first stage designed to register 20 patients on each treatment arm, the observation of seven or more objective responses would have led to the inclusion of 30 more patients in each arm., Results and Limitations: From July 2004 to March 2009, 44 patients in 10 centers were randomly assigned into the GEM or the GEMOX arm, 22 on each treatment arm. The median age was 76 yr. Seven patients were included for a performance status (PS) of 2 only. The remaining 37 patients had an impaired renal function, 11 of whom also had a PS of 2. The median creatinine clearance was 45 ml/min (range: 30-80 ml/min). The trial was closed after the first part because the GEMOX arm did not reach the targeted objective response rate to proceed further., Conclusions: Oxaliplatin does not add any significant activity (in terms of response rates) compared with gemcitabine alone in patients with advanced transitional cell carcinoma of the urothelium who are ineligible for cisplatin., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Aim: To assess the safety and to obtain preliminary data on the efficacy of the three-drug combination chemotherapy with gemcitabine, oxaliplatin and vinorelbine in patients with metastatic bladder cancer., Patients and Methods: Patients with metastatic or locally unresectable advanced bladder cancer who had received either no or one previous systemic chemotherapy regimen were eligible. All patients received intravenous gemcitabine 700 mg/m(2) and vinorelbine 25 mg/m(2) on day 1, then intravenous oxaliplatin 85 mg/m(2) on day 2, every 14 days., Results: Fifteen patients were enrolled. Twelve patients were unfit for cisplatin. A median of five cycles per patient were delivered. The most common toxicities were neutropenia, nausea and vomiting, mucositis and diarrhoea. Two complete responses and one partial response were observed for an overall response rate of 23%. Median progression-free survival was 5.7 months and overall survival was 8.6 months., Conclusion: Although active and tolerable, the described three-drug combination chemotherapy showed no obvious incremental increase in efficacy compared with two-drug regimens. Further clinical trials are not recommended.

Radical cystectomy with bilateral pelvic lymph node dissection is the standard of care for patients with muscle-invasive bladder cancer, with 5-year survival rates not exceeding 60%. Consequently a multidisciplinary approach including perioperative chemotherapy and/or radiation therapy is required to improve these results. Data from clinical trials and meta-analyses with neoadjuvant chemotherapy have shown a significant benefit in overall survival, with a 5% absolute benefit at five years, provided cisplatin-based combination chemotherapy is used. Reported trials do not support the routine use of adjuvant chemotherapy. The current role of radiation therapy is limited to highly selected cases with a combination of external radiotherapy, partial cystectomy and interstitial brachytherapy.