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: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial “NIMBUS”

Research output: Contribution to journalArticle

Abstract

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. In high-grade non–muscle-invasive bladder cancer, a reduced frequency of bacillus Calmette-Guérin (BCG) instillations during induction and maintenance is inferior to the standard BCG schedule regarding time to first recurrence. Repeated transurethral resection followed by the standard BCG regimen, as recommended by the European Association of Urology guideline, remains the state of the art.

Details

Authors
  • Marc Oliver Grimm
  • Antoine G. van der Heijden
  • Marc Colombel
  • Tim Muilwijk
  • Luis Martínez-Piñeiro
  • Marko M. Babjuk
  • Levent N. Türkeri
  • Joan Palou
  • Anup Patel
  • Anders S. Bjartell
  • Christien Caris
  • Raymond G. Schipper
  • Wim P.J. Witjes
  • European Association of Urology Research Foundation NIMBUS Study Group
Organisations
External organisations
  • Universitätsklinikum Jena
  • Radboud University Medical Center
  • Hôpital Edouard Herriot
  • University Hospitals Leuven
  • University Hospital La Paz
  • University Hospital Motol
  • Acıbadem Mehmet Ali Aydınlar University
  • Fundació Puigvert
  • Skåne University Hospital
  • Charles University in Prague
  • No affiliation available (private)
  • European Association of Urology, Research Foundation
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Urology and Nephrology

Keywords

  • Bacillus Calmette-Guérin, Instillation therapy, Non–muscle-invasive bladder cancer, Reduced frequency
Original languageEnglish
Pages (from-to)690-698
Number of pages9
JournalEuropean Urology
Volume78
Issue number5
Early online date2020 May 20
Publication statusPublished - 2020 Nov
Publication categoryResearch
Peer-reviewedYes