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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”

  • 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,
  • EAU Research Foundation NIMBUS Study Group

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.

Commentary by Dr. Francesco Soria

Adjuvant intravesical Bacillus Calmette-Guerin (BCG) is the standard treatment for patients with high-grade non-muscle invasive bladder cancer (NMIBC) after transurethral resection of the tumour (TURB). BCG has shown to be superior to intravesical chemotherapy in reducing disease recurrence and even progression to muscle-invasive disease, if given with a maintenance schedule for up to three years in high-risk patients. However, due to a non-negligible toxicity rate, only a minority of patients are able to complete the entire schedule (usually consisting of a standard induction followed by a maintenance phase of BCG once weekly for 3 weeks at 3, 6, 12, 18, 24, 30, and 36 months).

This long and intensive approach is responsible for the high number of adverse events leading to treatment discontinuation, with subsequent detrimental effects on long-term oncological outcomes, and negatively impacts on patients’ quality of life and healthcare costs. Moreover, we have to underline that, since almost 9 years, the urological community is facing the BCG-shortage phenomenon. Since early 2019 the global drug demand has almost surpassed its production capacity, thus limiting the access to the BCG. Previously, several attempts have been made to reduce symptom burden associated with BCG by reducing the length or the intensity of the maintenance schedule (e.g., EORTC 30662, CUETO 98013), with unsatisfactory results.

The aim of the NIMBUS trial was to assess whether a reduced number of standard-dose BCG instillations are non-inferior to the standard number and dose in patients with high-grade NMIBC.

The standard BCG schedule (6 weeks of induction followed by 3 weeks of maintenance at 3, 6, and 12 months for a total of 15 instillations) was compared to a reduced frequency BCG schedule (induction at weeks 1, 2, and 6 followed by 2 weeks of maintenance at 3, 6, and 12 months for a total of nine instillations). In total, 170 patients were randomised to reduced frequency and 175 to standard BCG schedule. 

The median follow-up time was 12 months for all patients and 14 months for patients without recurrence. Fewer adverse events were observed in the reduced frequency arm, but no difference regarding treatment discontinuation were reported. Disease recurrence was observed in 67/345 patients: 46/170 (27%) in the reduced frequency arm and 21/175 (12%) in the standard frequency arm. The univariate Cox regression analysis favored the standard frequency arm (HR for recurrence 0.40). These findings were confirmed by subgroup analysis in which only patients followed for at least six months after randomisation were evaluated (HR in this group 0.39).

In conclusion, the reduced frequency schedule showed to be inferior to the standard schedule with regards to time to first recurrence. In patients with high-grade NMIBC, standard BCG schedule remains the standard of care. After reviewing the current data analysis, the Independent Data Monitoring Committee advised stopping the study and the scientific committee immediately stopped patient recruitment. Patients were informed, and those still treated in the reduced frequency arm were given the opportunity to switch to the standard schedule.