In non-muscle-invasive bladder cancer (NMIBC), the occurrence of a high-grade (HG) recurrence following Bacillus Calmette-Guérin (BCG) treatment identifies a disease category that is associated with a particularly poor prognosis and for which radical cystectomy (RC) is the gold standard. The latest definition of European Association of Urology (EAU) BCG-unresponsive disease has been endorsed by the United States Food and Drug Administration for clinical trials and adopted by EAU guidelines, despite limited clinical data supporting it.
To provide a clinical validation of the current EAU definitions of BCG failure.
This is an international retrospective multicenter study. Patients with NMIBC treated with at least five out of six BCG induction instillations after January 2000 and presenting with disease recurrence were included. The minimum allowed follow-up was 6 mo. Patients presenting with disease progression at 3 mo and those receiving RC prior to the first follow-up cystoscopy were excluded.
The main objective of the study was to validate the prognostic value of the different categories of BCG failure, focusing on the EAU definitions of BCG-refractory, BCG-relapsing and BCG-unresponsive disease. The primary endpoint was the time to progression to muscle-invasive disease, the development of nodal disease or distant metastases. Patients were classified according to the EAU definitions of BCG failure, which were applied a priori and subsequently evaluated for their association with disease progression.
Overall, 776 patients with recurrence after BCG were included. Of these, 448 (58%) experienced a HG recurrence. The BCG-refractory subgroups displayed the highest progression rates, the worst being represented by HG recurrence at 6 mo during BCG maintenance (46% progression at 5 yr), followed by T1HG recurrence at 3 mo (30% at 5 yr). BCG-relapsing disease showed a marginally more favorable outcome. Notably, early BCG recurrences included in the definition of BCG-unresponsive disease conveyed progression-free survival similar to BCG-refractory (35% at 5 yr), thus supporting their inclusion in this disease category.
We have provided the first clinical validation of the EAU definitions of BCG failure/unresponsive disease. They are prognostically informative and can be used to support clinical decision-making.
European urology oncology. 2026 May 20 [Epub ahead of print]
P Gontero, F Soria, M Babjuk, M Burger, J Palou Redorta, D D'Andrea, B Pradere, M Moschini, A Birtle, E M Compérat, J L Dominguez-Escrig, F Liedberg, P Mariappan, B W G van Rhijn, T Seisen, S F Shariat, J Teoh, E Xylinas, O Capoun, B P Rai, V Soukup, O R Faba, D Cohen, L Foster, N Beaud, F Girtner, J Breyer, J Hornak, S M H Einerhand, J Anract, J Bobjer, E Linares, A Rodriguez-Serranos, R Cathomas, K Saba, V Hernandez, C Lorente, M Rouanne, T Lebret, A Masson-Lecomte, M Rouprêt, R J Sylvester
Division of Urology, Department of Surgical Sciences, AOU Città della salute e della Scienza di Torino, Torino School of Medicine, Corso Bramante, Torino, Italy. Electronic address: ., Division of Urology, Department of Surgical Sciences, AOU Città della salute e della Scienza di Torino, Torino School of Medicine, Corso Bramante, Torino, Italy., Department of Urology, Teaching Hospital Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic., Department of Urology, St. Josef Medical Center University of Regensburg, Regensburg, Germany., Department of Urology, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Department of Urology, La Croix Du Sud Hospital, Quint-Fonsegrives, France., Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy., Rosemere Cancer Centre, Lancashire Teaching Hospitals NHS Foundation Trust, Preston; University of Manchester, Manchester; University of Central Lancashire, Preston, UK., Department of Pathology, Medical University of Vienna, Vienna, Austria., Department of Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain., Institution of Translational Medicine, Lund University; Department of Urology, Skåne University Hospital, Malmö, Sweden., Edinburgh Bladder Cancer Surgery, University of Edinburgh, Western General Hospital, Edinburgh, UK., Department of Surgical Oncology (Urology), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; European Association of Urology, Non-Muscle Invasive Bladder Cancer Guidelines Panel, Arnhem, The Netherlands., Urology, GRC 5 Predictive Onco-Uro, AP-HP, Pitie-Salpetriere Hospital, Sorbonne University, Paris, France., S.H. Ho Urology Centre, Department of Surgery, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China., Department of Urology, Bichat-Claude Bernard Hospital, AP-HP, Université de Paris, Paris, France., Department of Urology, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Department of Urology, Royal Free Hospital, London, UK., Department of Surgical Oncology (Urology), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., Department of Urology, St. Louis Hospital, AP-HP, Université de Paris, Paris, France., Department of Urology, Hospital La Paz, Madrid, Spain., Department of Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland., Urology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain., Department of Urology, Foch Hospital, University of Versailles-Saint-Quentin-en-Yvelines, Suresnes, France., European Association of Urology, Non-Muscle Invasive Bladder Cancer Guidelines Panel, Arnhem, The Netherlands.