TY - JOUR
T1 - Treatment of High-grade Non–muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations
T2 - Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial “NIMBUS”
AU - Grimm, Marc Oliver
AU - van der Heijden, Antoine G.
AU - for the EAU Research Foundation NIMBUS Study Group
AU - Colombel, Marc
AU - Muilwijk, Tim
AU - Martínez-Piñeiro, Luis
AU - Babjuk, Marko M.
AU - Türkeri, Levent N.
AU - Palou, Joan
AU - Patel, Anup
AU - Bjartell, Anders S.
AU - Caris, Christien
AU - Schipper, Raymond G.
AU - Witjes, Wim P.J.
AU - Horstmann, Jörg
AU - Machtens, Stefan
AU - Mumperow, Eberhard
AU - Ghazal, Andreas Al
AU - Pulte, Thomas
AU - Stephan-Odenthal, Michael
AU - Gakis, Georgios
AU - Kramer, Mario
AU - Zaak, Dirk
AU - Schmitz-Dräger, Bernd
AU - Schreier, Holger
AU - Lehmann, Jan
AU - Werner, Torsten
AU - Klier, Jörg
AU - Marin, Jan
AU - Rulf, Wolfgang
AU - Hellmis, Eva
AU - Schneider, Andreas
AU - Spiegelhalder,
AU - Wirth, Manfred
AU - Klotz, Theodor
AU - Suttmann, Henrik
AU - Siebels, Michael
AU - Rodemer, Gerd
AU - Rudolph, Robert
AU - Zillmann, Roger
AU - de Bruin, M.
AU - Bos, S.
AU - van Moorselaar, R.
AU - de Reijke, T.
AU - Boormans, J.
AU - Wijsman, B.
AU - van Melick, H. H.E.
AU - van Boven, E.
AU - Meijer, R. P.
AU - van der Heijden, A. G.
AU - Vergunst, H.
N1 - Publisher Copyright:
© 2020 European Association of Urology
PY - 2020/11
Y1 - 2020/11
N2 - Background:Intravesical instillation of bacillus Calmette-Guérin (BCG) is an accepted strategy to prevent recurrence of non–muscle-invasive bladder cancer (NMIBC) but associated with significant toxicity. Objective: NIMBUS assessed whether a reduced number of standard-dose BCG instillations are noninferior to the standard number and dose in patients with high-grade NMIBC. Design, setting, and participants: A total of 345 patients from 51 sites were randomised between December 2013 and July 2019. We report results after a data review and safety analysis by the Independent Data Monitoring Committee based on the cut-off date of July 1, 2019. Intervention: The standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine instillations). Outcome measurements and statistical analysis: The primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. Results and limitations: In total, 170 patients were randomised to reduced frequency and 175 to standard BCG. Prognostic factors at initial resection were as follows: Ta/T1: 46/54%; primary/recurrent: 92/8%; single/multiple: 57/43%; and concomitant carcinoma in situ: 27%. After 12 mo of median follow-up, the intention-to-treat analysis showed a safety-relevant difference in recurrences between treatment arms: 46/170 (reduced frequency) versus 21/175 patients (standard). Additional safety analyses showed a hazard ratio of 0.40 with the upper part of the one-sided 97.5% confidence interval of 0.68, meeting a predefined stopping criterion for inferiority. Conclusions: The reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. Patient summary: After surgical removal of the tumour, patients with high-grade non–muscle-invasive bladder cancer are treated with bacillus Calmette-Guérin to prevent recurrence and progression. This is associated with significant side effects. We report the results of a clinical trial showing a reduction in the number of instillations (from 15 to nine in total) being inferior to the standard protocol. From today's perspective, complete tumour resection and a standard number of instillations remain the standard of care.
AB - Background:Intravesical instillation of bacillus Calmette-Guérin (BCG) is an accepted strategy to prevent recurrence of non–muscle-invasive bladder cancer (NMIBC) but associated with significant toxicity. Objective: NIMBUS assessed whether a reduced number of standard-dose BCG instillations are noninferior to the standard number and dose in patients with high-grade NMIBC. Design, setting, and participants: A total of 345 patients from 51 sites were randomised between December 2013 and July 2019. We report results after a data review and safety analysis by the Independent Data Monitoring Committee based on the cut-off date of July 1, 2019. Intervention: The standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine instillations). Outcome measurements and statistical analysis: The primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. Results and limitations: In total, 170 patients were randomised to reduced frequency and 175 to standard BCG. Prognostic factors at initial resection were as follows: Ta/T1: 46/54%; primary/recurrent: 92/8%; single/multiple: 57/43%; and concomitant carcinoma in situ: 27%. After 12 mo of median follow-up, the intention-to-treat analysis showed a safety-relevant difference in recurrences between treatment arms: 46/170 (reduced frequency) versus 21/175 patients (standard). Additional safety analyses showed a hazard ratio of 0.40 with the upper part of the one-sided 97.5% confidence interval of 0.68, meeting a predefined stopping criterion for inferiority. Conclusions: The reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. Patient summary: After surgical removal of the tumour, patients with high-grade non–muscle-invasive bladder cancer are treated with bacillus Calmette-Guérin to prevent recurrence and progression. This is associated with significant side effects. We report the results of a clinical trial showing a reduction in the number of instillations (from 15 to nine in total) being inferior to the standard protocol. From today's perspective, complete tumour resection and a standard number of instillations remain the standard of care.
UR - http://www.scopus.com/inward/record.url?scp=85085219256&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2020.04.066
DO - 10.1016/j.eururo.2020.04.066
M3 - Article
C2 - 32446864
AN - SCOPUS:85085219256
SN - 0302-2838
VL - 78
SP - 690
EP - 698
JO - European Urology
JF - European Urology
IS - 5
ER -