AUA 2018: Results of CALIBER: A Phase II Randomized Feasibility Trial of Chemoablation vs Surgical Management in Low Risk Non-Muscle Invasive Bladder Cancer

San Francisco, CA (UroToday.com) Non-muscle invasive bladder cancer represents approximately 70% of bladder cancer diagnoses. In addition to preventing progression to muscle-invasive disease, a significant focus of management is reducing recurrence rates – unfortunately, due to high rates of recurrence, patients undergo frequent surveillance with cystoscopy and intermittent upper tract evaluations. These repeated interventions are not without risks, and anything to reduce recurrence and thereby reduce the need for interventions has significant patient and the health system implications.

Intravesical therapy has been a mainstay of management for NMIBC. BCG therapy has been utilized primarily for high-risk disease or patients with CIS. Mitomycin-C, an intravesical chemotherapeutic agent, has typically been reserved for less aggressive disease. While most guidelines recommend it for reducing recurrence rates in low-risk disease, primarily as an adjuvant therapy as an immediate post-TURBT instillation,1 the authors of the CALIBER study note that is has been used for intermediate and high-risk NMIBC. Though this premise is a little uncertain, based on this, they wanted to assess whether neoadjuvant intravesical therapy (chemoablation) could be utilized in NMIBC to help reduce recurrence. 

More importantly, they wanted to assess if it was superior to surgery alone (TURBT, formal resection). If so, the hope was that they could replace surgery with chemoablation. However, based on feedback from patients and clinicians (not presented, not validated), they expected a 45% CR rate. 

CALIBER was a UK based clinical trial that had a two stage design and incorporated a surgical control group (to test patient acceptability and feasibility of randomization). They included patients with recurrent low risk NMIBC and randomized these patients 2:1 to chemoablation (4 x 40mg mitomycin C [MMC] weekly intravesical instillations) vs. surgery (standard of care [SOC]). Their primary endpoint was complete response (CR) to chemoablation by visual assessment and histological biopsy at 3 months post-treatment. Secondary endpoints included treatment compliance, time to recurrence in patients disease free at 3 months, transurethral resection and biopsy rates, progression free survival, toxicity (CTCAE v4), quality of life and health service utilization.

Study design is detailed below:
CALIBER

Over a 2 year period, they randomized 82 participants (54 chemoablation, 28 surgery) from 37 UK centers. This seems to be a relatively low amount of newly diagnosed low-risk NMIBC patients over a two year period… but he noted that recruitment was quite difficult. They had acceptance rates of 55% amongst eligible patients. 

  • He specifically notes that even though they accepted patients with EORTC risk score <6, ethically they did not take patients with new diagnosis low-grade bladder cancer (score 0-1). As patients were therefore only from EORTC score 2-6, they represented only patients with recurrent disease.
  • Of note, these patients therefore had an ~25% risk of recurrence
Key demographics are as follows: Median age 70.7 years, 76.8% male, and 63.4% were current/previous smokers. Groups were relatively similar. Patients had had anywhere from 1-12 prior recurrences. 60-70% of both groups had seen prior MMC treatment. 

In the surgical arm, only 2 patients (7.4%) of patients were given post-op MMC – as this was at the discretion of the physician. Apparently, post-op MMC has not been taken up very well.

In August 2017, the trial was closed based on an interim analysis as the pre-defined stage 1 complete respond (CR) threshold of 60% had not been reached. In terms of response, only 17/51 evaluable chemoablation patients were responding (with visual CR confirmed by biopsy in 12/17 cases). Therefore, the estimated CR rate was 37.3% (95% CI: 24.1, 51.9) in the chemoablation group and 80.8% (95% CI: 60.6, 93.4) in the surgery group. Almost all the patients (98.1%) received all 4 MMC instillations and tolerated it well - no grade 3-4 toxicities were observed in either of the treatment groups.

Based on this prospective study, surgery is still superior to chemoablation as a primary therapy for low-risk NMIBC. However, as prior evidence has shown, adjuvant single-instillation MMC does improve the recurrence rates over surgery alone. As such, while this study does not change practice, it does perhaps suggest that neoadjuvant MMC may be of some benefit – but is it better than a single post-operative dose? Additional studies are needed!

Limitations / Discussion Points:
1. Post-op MMC utilization was low – perhaps with its use, the rate in the surgery arm would have been closer to 100%
2. The decision to do 4 MMC treatments was pragmatic (not evidence driven) – at once a week, they felt a 1-month delay would not risk compromising oncologic outcome from surgical resection.


Presented by: Hugh Mostafid, MD, Guildford, United Kingdom

Co-Authors: Joanne Cresswell, Middlesbrough, United Kingdom, Leyshon Griffiths, Leicester, United Kingdom, John Kelly, London, United Kingdom, Allen Knight, Hampshire, United Kingdom, James Catto, Sheffield, United Kingdom, Kim Davenport, Cheltenham, United Kingdom, Andrew Feber, London, United Kingdom, Margaret Knowles, Leeds, United Kingdom, John McGrath, Exeter, United Kingdom, Peter Cooke, Wolverhampton, United Kingdom, Shikohe Masood, Gillingham, United Kingdom, Aicha Goubar, Steven Penegar, Nuria Porta, Laura Wiley, Rebecca Lewis, Emma Hall, London, United Kingdo

References:

1. Sylvester RJ et al. Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation? Eur Urol. 2016 Feb;69(2):231-44. doi: 10.1016/j.eururo.2015.05.050. Epub 2015 Jun 16.

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, @tchandra_uromd at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA
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