Is a reduced bacillus Calmette-Guérin regimen feasible?

“Journal Article of the Month” is a new Urology Times section in which Badar M. Mian, MD (left), offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, Albany, NY.

Maintenance intravesical bacillus Calmette-Guérin (BCG) for high-grade urothelial bladder cancer has been the standard of care for nearly 2 decades. The 36-month maintenance regimen, popularly known as the Lamm protocol, has proven quite effective but many patients are unable to complete the protocol due to adverse effects of BCG. Thus, the dose and duration of intravesical BCG has been a subject of numerous studies over the years to develop a more tolerable and efficacious regimen.

Grimm et al report on the latest of such trials assessing the efficacy of an alternative schedule of maintenance BCG.¹ The NIMBUS trial was designed to assess whether reduced number of instillations using the standard-dose (full-vial) BCG was “noninferior” to the standard number of instillations.

BCG-naïve patients with high-grade, non-muscle-invasive bladder cancer (NMIBC: Ta or T1), with or without carcinoma in situ (CIS), were recruited between December 2013 and October 2019. The study was conducted at 51 sites in 5 countries. The control group (standard frequency, SF) received induction BCG, once per week for 6 consecutive weeks, followed by maintenance instillations, weekly for 3 weeks at 3, 6, and 12 months (total instillations: 15). The experimental group (reduced frequency, RF) received induction BCG once per week at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3, at 3, 6, and 12 months (total instillations: 9). The strain used in the study was BCG Medac in 90% of cases.

The primary end point of interest was time to first recurrence of urothelial cancer, and secondary end points included risk of disease progression, as well as the number and severity of adverse effects. The initial statistical plan called for 500 patients per study arm, but it was revised to 412 patients due to the BCG shortage and prolonged time needed for recruitment and follow-up. The trial was designed to show that the recurrence rate in the RF arm was not inferior to that of the SF arm. A hazard ratio of < 0.75 would have signified inferiority of the RF schedule.

At this pre-planned interim analysis, 175 patients had been randomized to the SF arm and 170 patients to the RF arm. Majority of these patients had primary tumor (92%), without CIS (75%) and stage T1 (54%). At a median follow-up of about 12 months, cancer recurrence was noted in 27% in the RF arm and 12% in the SF arm. Most of the recurrence in the RF arm occurred in the first 6 months. Only 1 patient (0.5%) experienced disease progression to muscle-invasive stage in the SF arm, while 6 patients (3.5%) in the RF arm progressed to muscle-invasive disease.

Further recruitment halted

On Cox regression analysis, HR of 0.40 for time to first recurrence was noted in favor of the SF arm. These data prompted the independent data monitoring committee to halt further recruitment because the primary end point-non-inferiority of RF arm-could not be proved with continuation of the study. Reduced frequency of maintenance instillations (even with the full dose of BCG) was inferior to the standard frequency of BCG maintenance.

The toxicity profile of each arm was determined by analyzing the frequency and severity of adverse effects (Grade ≥ 3). There were no deaths related to the study drugs. In the RF arm, 113 patients (68.5%) experienced 670 adverse effects. In the SF arm, 136 patients (82.4%) reported 1469 adverse effects. Three patients in the RF arm and 14 patients in the SF arm withdrew their consent. The study cohorts will continue to be monitored for adverse effects.

Importantly, the study design required repeat transurethral resection to ensure complete resection and reduce under-staging which is frequently noted after initial transurethral resection. In the RF arm, nearly 60% of the recurrences occurred early; ie, within the first 6 months. The reduced number of instillations given in the RF arm for induction course (3 instillations instead of 6) could explain the poor efficacy of this approach resulting in increased risk of early recurrence and possibly disease progression.

In the era of BCG shortage, it would have been highly desirable to demonstrate the efficacy and safety of fewer BCG instillations for high-risk bladder cancer. However, reduced frequency of maintenance BCG instillations is associated with increased risk of cancer recurrence, albeit with fewer adverse effects. Previous attempts at reducing the toxicity associated with maintenance BCG while maintaining efficacy have demonstrated that 1 instillation every 3 months resulted in increased risk of recurrence than the standard schedule. Similarly, reduced dose (1/3rd dose) was associated with increased risk of recurrence compared with standard dose instillations.

We no longer have the luxury to use organ-preserving BCG regimens as we did a few years ago for high-risk NMIBC. Reserving the use of BCG to those with BCG-naïve, high-risk NMIBC, with a full 6-week induction course, followed by standard maintenance schedule for at least 1 year appears to be most practical and efficacious in the current circumstances. BCG therapy should be avoided in those without high-risk disease. If necessary, intravesical chemotherapy (mitomycin or gemcitabine) may be used in intermediate-risk situations. Depending upon the BCG supply at hand, it may be necessary to use reduced dose of BCG (½ or 1/3rd vial) for each maintenance instillation. Every attempt should be made to optimize the delivery and retention of intravesical agents (dehydration, anticholinergics).

For the foreseeable future, the BCG shortage will necessitate vigilance, modification of recommendations, changes in workflow, and training of clinical staff to maximize the use of available BCG.

Reference

1. Grimm MO, van der Heijden AG, Colombel M et al. 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”. European Urology. 2020 May 20;S0302-2838(20)30334-1. doi: 10.1016/j.eururo.2020.04.066 Online ahead of print