First and foremost, Dr. Kassouf noted that the most important aspect of patient care is TUR quality. The initial TURBT aims for complete tumor resection with a sampling of the underlying detrusor muscle as the first step of curative-intent treatment of NMIBC (level evidence 2; strong recommendation). When available, blue light cystoscopy (level evidence 1; weak recommendation) can increase tumor detection at first TURBT and reduce recurrence risk. Additionally, a restaging TURBT should be performed in patients with T1 NMIBC (level evidence 2; strong recommendation).
Select NMIBC patients are very high risk and understaging or underestimating the risk of progression may lead patients to be undertreated with BCG, which may ultimately result in death from bladder cancer. The CUA guidelines denote these patients as “very high risk”, which includes HG T1 with any of the following:
- Multiple tumors and >= 3 cm
- Presence of concurrent CIS in the bladder or prostatic urethra
- Presence of lymphovascular invasion
- Variant histology (ie. micropapillary, plasmacytoid, sarcomatoid, neuroendocrine)
Upfront radical cystectomy should be offered to patients with HG T1 disease with additional adverse tumor pathological features (level evidence 3; strong recommendation). Aggressive histological variants, such as micropapillary, plasmacytoid, and sarcomatoid are associated with an increased risk of understaging and progression (level evidence 3).
Dr. Kassouf notes that we often do not make it easy on our pathologists, given that TURBT specimens have poor orientation with tangential sectioning, thermal injury, intense inflammatory response, nested variants mimicking von Brunn’s nests, under-reporting of CIS and LVI, prominent muscularis mucosae looking like detrusor muscle, and lamina propria fat simulating perivesical fat. Ideally, we should send the deep resection separately in order to facilitate assessment for muscle invasion. Pathological review, preferably by a dedicated uro-pathologist, should be considered in settings where variant histology is suspected or atypical tumors are seen during TURBT (level evidence 3; weak recommendation).
Dr. Kassouf emphasized that the standard of care for BCG-naïve high-risk NMIBC (newly diagnosed CIS, HG Ta, or HT T1 tumors) remains a six-week induction course of BCG. In high-risk patients who completely respond to induction BCG, clinicians should continue with 3 years of maintenance BCG. This is based on the SWOG regimen (6+3 protocol) consisting of 6-week BCG induction followed by maintenance course of 3 weekly treatments of BCG at 3, 6, 12, 18, 24, 30, and 36 months, which leads to increased recurrence-free survival.1
Mitomycin C has also been considered for intravesical chemotherapy and has been compared to BCG therapy. Malmstrom et al.,2 in 2009, performed an individual patient data meta-analysis of nine trials (n=2,820), finding that over a median follow-up of 4.4 months, 43% of patients recurred. Overall, there was no difference in the time to first recurrence (p=0.09) between BCG and MMC. In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG compared to MMC was found (p<0.0001), while there was a 28% risk increase (p=0.006) for BCG in the trials without maintenance.
Dr. Kassouf then asked the question “is lower BCG dose and duration as effective?” Oddens et al.3 assessed whether a one-third dose is not inferior to the full dose, if 1 year of maintenance is not inferior to 3 years of maintenance, and if one-third dose and 1 year of maintenance were associated with less toxicity among patients enrolled in EORTC 30962. The analysis included 1,355 patients with a median follow-up of 7.1 years, over which there were no significant differences in toxicity between one-third dose and full-dose. However, one-third dose for 1 year was suboptimal compared with full-dose for three years (HR 0.75, 95% CI, 0.59-0.94). Intermediate-risk patients treated with full-dose BCG do not benefit from an additional 2 years of BCG, and in high-risk patients, 3 years of maintenance is associated with a reduction in recurrence (HR: 1.61; 95% CI, 1.13-2.30; p=0.009) but only when given at full dose:
Dr. Kassouf notes that BCG is well tolerated in that only <10% of patients in clinical trials are unable to tolerate BCG and stop treatment secondary to toxicity.
Is less frequent BCG administration as effective? The NIMBUS trial was recently published in European Urology,4 which assessed whether a reduced number of standard-dose BCG instillations are non-inferior to the standard number and dose in patients with high-grade NMIBC. There were 345 patients randomized to the standard BCG schedule [6 weeks of induction followed by 3 weeks of maintenance at 3, 6, and 12 months (15 instillations)] versus the reduced frequency BCG schedule [induction at weeks 1, 2, and 6 followed by 2 weeks (weeks 1 and 3) of maintenance at 3, 6, and 12 months (nine instillations)]. The schematic for the trial is as follows:
After 12 months 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.
Taken together, the CUA guidelines suggest that treatment adjustments should only be undertaken if there is a BCG shortage. For patients with high-risk NMIBC, full BCG schedule is recommended (level evidence 1; strong recommendation). Only during a BCG shortage, when full dose is not possible due to limited supply, dose reduction to 1/2 or 1/3 may be considered, while maintenance can be reduced to one year (level evidence 3; weak recommendation). For patients with intermediate-risk NMBIC during the BCG shortage, intravesical chemotherapy is recommended as the first-line option. If BCG is planned as second-line therapy for this population, induction might be administered with reduced dosing (1/2 or 1/3 dose) and maintenance can be omitted (level evidence 3; weak recommendation).
Dr. Kassouf summarized his talk by emphasizing that the standard of care treatment for BCG-naïve NMIBC should be a six-week course of induction BCG, and that in high-risk patients who completely respond to induction BCG, clinicians should continue with 3 years of maintenance BCG.
Presented by: Wassim Kassouf, MD, McGill University Health Center, Montreal, Quebec, Canada
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.
References:
- Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: A randomized Southwest Oncology Group Study. J Urol 2000 Apr;163(4):1124-1129.
- Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomized studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol. 2009 Aug;56(2):247-256.
- Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol 2013 Mar;63(3):462-472.
- 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 Randomized Phase III Clinical Trial “NIMBUS”. Eur Urol 2020 May 20:S0302-2838(20)30334-1.