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".
Bacillus Calmette-Guérin
Instillation therapy
Non–muscle-invasive bladder cancer
Reduced frequency
Journal
European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
16
01
2020
accepted:
26
04
2020
pubmed:
25
5
2020
medline:
23
7
2021
entrez:
25
5
2020
Statut:
ppublish
Résumé
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. 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. 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. 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). The primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32446864
pii: S0302-2838(20)30334-1
doi: 10.1016/j.eururo.2020.04.066
pii:
doi:
Substances chimiques
Adjuvants, Immunologic
0
BCG Vaccine
0
Types de publication
Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
690-698Investigateurs
Jörg Horstmann
(J)
Stefan Machtens
(S)
Eberhard Mumperow
(E)
Andreas Al Ghazal
(AA)
Thomas Pulte
(T)
Michael Stephan-Odenthal
(M)
Georgios Gakis
(G)
Mario Kramer
(M)
Marc-Oliver Grimm
(MO)
Dirk Zaak
(D)
Bernd Schmitz-Dräger
(B)
Holger Schreier
(H)
Jan Lehmann
(J)
Torsten Werner
(T)
Jörg Klier
(J)
Jan Marin
(J)
Wolfgang Rulf
(W)
Eva Hellmis
(E)
Andreas Schneider
(A)
None Spiegelhalder
Manfred Wirth
(M)
Theodor Klotz
(T)
Henrik Suttmann
(H)
Michael Siebels
(M)
Gerd Rodemer
(G)
Robert Rudolph
(R)
Roger Zillmann
(R)
M de Bruin
(M)
S Bos
(S)
R van Moorselaar
(R)
T de Reijke
(T)
J Boormans
(J)
B Wijsman
(B)
H H E van Melick
(HHE)
E van Boven
(E)
R P Meijer
(RP)
A G van der Heijden
(AG)
H Vergunst
(H)
E Te Slaa
(E)
A M Leliveld-Kors
(AM)
Marc Colombel
(M)
Alain Ruffion
(A)
Christian Pfister
(C)
Morgan Roupret
(M)
Jacques Irani
(J)
Gabriel Stoica
(G)
Siska Van Bruwaene
(S)
Filip Ameye
(F)
Harm Arentsen
(H)
Steven Joniau
(S)
Pastora Beardo
(P)
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.