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Radical cystectomy against intravesical BCG for high-risk high-grade non-muscle invasive bladder cancer: Results from the randomized controlled BRAVO-feasibility study

  • James W. F. Catto,
  • Kathryn Gordon,
  • Michelle Collinson,
  • Heather Poad,
  • Maureen Twiddy,
  • Mark Johnson,
  • Sunjay Jain,
  • Rohit Chahal,
  • Matt Simms,
  • Mohantha Dooldeniya,
  • Richard Bell,
  • Phillip Koenig,
  • Samantha Conroy,
  • Louise Goodwin,
  • Aidan P. Noon,
  • Julie Croft,
  • Julia M. Brown,
  • on behalf of the BRAVO study group

Publication: Journal of Clinical Oncology, January 2021

High-grade nonmuscle invasive bladder cancer (HRNMIBC) is a heterogeneous disease. Treatments include intravesical maintenance Bacillus Calmette-Guerin (mBCG) and radical cystectomy (RC). We wanted to understand whether a randomized trial comparing these options was possible.

Materials and methods
We conducted a two-arm, prospective multicenter randomized study to determine the feasibility in Bacillus Calmette-Guerin-naive patients. Participants had new high-risk HRNMIBC suitable for both treatments. Random assignment was stratified by age, sex, center, stage, presence of carcinoma in situ, and prior low-risk bladder cancer. Qualitative work investigated how to maintain equipoise. The primary outcome was the number of patients screened, eligible, recruited, and randomly assigned.

We screened 407 patients, approached 185, and obtained consent from 51 (27.6%) patients. Of these, one did not proceed and therefore 50 were randomly assigned (1:1). In the mBCG arm, 23/25 (92.0%) patients received mBCG, four had nonmuscle invasive bladder cancer (NMIBC) after induction, three had NMIBC at 4 months, and four received RC. At closure, two patients had metastatic BC. In the RC arm, 20 (80.0%) participants received cystectomy, including five (25.0%) with no tumor, 13 (65.0%) with HRNMIBC, and two (10.0%) with muscle invasion in their specimen. At follow-up, all patients in the RC arm were free of disease. Adverse events were mostly mild and equally distributed (15/23 [65.2%] patients with mBCG and 13/20 [65.0%] patients with RC). The quality of life (QOL) of both arms was broadly similar at 12 months.

A randomized controlled trial comparing mBCG and RC will be challenging to recruit into. Around 10% of patients with high-risk HRNMIBC have a lethal disease and may be better treated by primary radical treatment. Conversely, many are suitable for bladder preservation and may maintain their prediagnosis QOL.

Commentary by Dr. Marco Moschini

The standard treatment for high-risk non-muscle-invasive bladder cancer is a transurethral resection of the bladder plus adjuvant intravesical Bacillus Calmette-Guerin (BCG). However, in some cases radical cystectomy (RC) with pelvic lymph node dissection is also considered a possible strategy, considering the high risk of disease progression. RC removes the risk of local progression, but in some cases may represent overtreatment with an important risk of perioperative complications, death within 90 days or a reduction of quality of life. Before the BRAVO study, no direct comparison existed between these two treatment strategies because of the difficulties that come with randomising two treatments so different. The aim of the BRAVO study was to determine the optimal treatment for high-risk non-muscle-invasive bladder cancer patients. 407 patients were screened between October 2016 and March 2018. In total, 215 (52%) of those were considered suitable for participation, and after asking for consent only 50 (12.3% of the patients screened) were randomised (25 assigned to RC and 25 to BCG).

In the BCG arm, four patients had non-muscle-invasive BCa recurrence after induction, three at four months, and four ended up receiving RC. At closure of the study, two patients had metastatic BCa. In the RC arm, 20 (80.0%) participants received cystectomy, including five (25.0%) with no tumour, 13 (65.0%) with HRNMIBC, and two (10.0%) with muscle invasion in their specimen. At follow up, all patients with RC were free of disease. Adverse events and quality of life were similar between the two groups.

The authors have to be complimented for designing the first existing trial comparing BCG and RC in high-risk non-muscle-invasive bladder cancer. Only a small proportion of patients screened could be enrolled, highlighting the difficulties in comparing two treatments that are extremely different, also in the perception of patients. The authors found that some patients in the conservative group incur metastatic disease, suggesting that RC is definitively an option for at least a proportion of high-risk non-muscle-invasive bladder cancer patients. On the other hand, in the RC group all patients were free of tumour, supporting the idea that overtreatment for a portion of them is possible. Quality of life and complications were similar, which does not completely reflect the experience that every urologist has regarding these two different approaches.