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SCS AUA 2024: BCG Will Always Be the First Line: Yes

(UroToday.com) The 2024 South Central AUA annual meeting included a session on bladder cancer, featuring a presentation by Dr. Colin Dinney discussing that BCG will always be first line therapy for high risk non muscle invasive bladder cancer (NMIBC). Based on his opinion and experience, Dr. Dinney notes that it is important to understand risk of NMIBC:

  • Low risk (40%): solitary, primary Ta, low grade
    • Recurrence in about 40-50% and progression in <5%
  • High risk (30%): any T1, all Ta high grade, and CIS
    • Recurrence in up to 80%
    • Progression in up to 50% is the main concern
    • Potentially life threatening
  • Intermediate risk (30%): everything else (ie. recurrent/multiple Ta low grade)
    • Recurrence is the main problem, with approximately 15% of patients progressing

The National Bladder Cancer Collaborative Group was established in 1973 to determine the natural history of untreated NMIBC and provide the benchmark for future studies evaluating the impact of therapy for NMIBC. This established that high risk features included high grade histology, lamina propria invasion, CIS, multiplicity, and size.

In 2021, Ourfali and colleagues1 compared disease recurrence and cystectomy rates between November 2011 - September 2013 (control) and October 2013 - December 2016 (first period of restricted BCG supply; the alternative therapy at the time was intravesical chemotherapy). The recurrence rate (54%) increased 2.3-fold for high-risk patients during the period of restricted BCG supply, and the cystectomy rate (16%) also increased 3.1-fold for high-risk patients during the same time-period. As such, the BCG shortage has potentially had an adverse impact on recurrence and cystectomy rates.

Guideline based recommendations for high risk NMIBC before the BCG shortage were as follows:

  • AUA:
    • Recommendation: BCG induction and 3 years of maintenance
    • Option: Radical cystectomy
  • EAU:
    • Grade A: Minimum of 1 year of BCG
    • Grade C: Immediate cystectomy for patients with highest risk of progression

Compared to TURBT alone, several meta-analyses have shown that intravesical chemotherapy reduces the risk of recurrence but does not reduce the risk of progression. With regards to BCG, several meta-analyses have shown that BCG reduces the risk of recurrence and reduces the risk of progression, but only if 1-3 years of maintenance BCG are given.

Dr. Dinney emphasized that randomized trials show clear superiority with a 3 week maintenance schedule. In SWOG 8507,2 there was significant reduction in recurrence (p < 0.0001) and progression (p < 0.04) versus induction alone in 550 randomized patients. In EORTC 30911,3 there was a significant reduction in recurrence (p < 0.0001), metastasis (p = 0.046), and mortality (p = 0.026) versus epirubicin in 957 randomized patients. Additionally, EORTC 309624 showed that for high risk NMIBC, 3 years of full dose BCG was associated with lower recurrence than 1/3 dose, with no difference in toxicity between full dose and 1/3 dose:

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Gemcitabine + docetaxel may also have a potential role as standard of care in the BCG-naïve population. McElree and colleagues5 evaluated 312 patients with high-risk treatment-naive NMIBC, including 174 patients treated with BCG therapy and 138 treated with gemcitabine and docetaxel therapy. High-grade RFS estimates were 76% (95% CI, 69%-82%) at 6 months, 71% (95% CI, 64%-78%) at 12 months, and 69% (95% CI, 62%-76%) at 24 months in the BCG group, and 92% (95% CI, 86%-95%) at 6 months, 85% (95% CI, 78%-91%) at 12 months, and 81% (95% CI, 72%-87%) at 24 months in the gemcitabine and docetaxel group:

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As such, gemcitabine + docetaxel therapy was associated with less high grade disease recurrence and treatment discontinuation than BCG therapy, but we await the results of the BRIDGE trial.

In a more contemporary cohort of patients, Matulay et al.6 retrospectively reviewed patients receiving adequate BCG therapy at MD Anderson Cancer Center between January 2004 and August 2018. Among 542 patients who received adequate BCG, 518 (90%) had EAU high risk disease, with CIS present in 175 (32%) specimens. Over a median follow up of 47.8 months, freedom from high grade recurrence at 1, 3, and 5 years was 81%, 76%, and 74%, respectively, and progression-free survival was 97%, 93% and 92%, respectively.

Dr. Dinney emphasized that BCG is the most established and successful immunotherapy for cancer treatment, but after more than 40 years we still cannot predict responders prior to treatment. Currently, there are no validated predictive biomarkers that have been identified. UroAmp is a Convergent Genomics genetic platform that quantifies mutations and DNA alterations from urine cell free DNA. It utilizes deep NGS of a 60 gene bladder cancer specific panel, and low pass whole genome sequencing to identify aneuploidy. UroAmp also quantifies minimal residual disease by the genomic disease burden, which is a percentile ranking of the variant allele frequency from a sample relative to its percentile ranking within the established training set. Each of the samples in this study was ranked against that distribution to obtain the genomic disease burden percentile rank to characterize the tumor as high risk or low risk for recurrence.

Rac and colleagues7 prospectively examined the utility of urinary comprehensive genomic profiling for predicting recurrence risk following TURBT and evaluating longitudinal intravesical therapy response. Urine was collected before and after intravesical therapy instillation and urinary comprehensive genomic profiling testing was done using the UroAmp platform. Baseline urinary comprehensive genomic profiling following TURBT identified patients with high (61%) and low (39%) recurrence risk. At 24 months, recurrence-free survival was 100% for low-risk and 45% for high-risk patients with a hazard ratio of 9.3:

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Longitudinal urinary comprehensive genomic profiling classified patients as minimal residual disease negative, intravesical therapy responder, or intravesical therapy refractory with 24-month recurrence free survival rates of 100%, 50%, and 32%, respectively. Compared with minimal residual disease negative patients, intravesical therapy refractory patients had a hazard ratio of 10.5:

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Dr. Dinney concluded his presentation by discussing that BCG will always be first line therapy for high risk NMIBC with the following take-home points:

  • Maintenance BCG prevents recurrence, progression, metastasis, and death from bladder cancer for patients with high risk NMIBC
  • Identification of predictive biomarkers will further improve the efficacy of BCG therapy
  • Evidence supporting alternative approaches are retrospective and without evidence that they delay progression/metastasis or prevent death from bladder cancer
  • Trial of gemcitabine + docetaxel versus BCG employed sub-optimal BCG therapy
  • Significant efficacy attrition is expected when moving beyond a retrospective study to a prospective phase 3 trial
  • Gemcitabine + docetaxel treatment requires a significant dedication of time and resources to treat a single patient

Presented by: Colin P. Dinney, MD, The University of Texas MD Anderson Cancer Center, Houston, TX

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 South Central American Urological Association (AUA) Annual Meeting, Colorado Springs, CO, Wed, Oct 30 – Sat, Nov 2, 2024.

References:

  1. Ourfali S, Ohannessian R, Fassi-Fehri H, et al. Recurrence rate and cost consequence of the shortage of Bacillus Calmette-Guerin Connaught Strain for Bladder Cancer Patients. Eur Urol Focus. 2021 Jan;7(1):111-116.
  2. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell of the bladder: A randomized Southwest Oncology Group Study. J Urol. 2000;163:1124-1129.
  3. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  4. 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 year of maintenance. Eur Urol 2013;63:462-472.
  5. McElree IM, Steinberg RL, Mott SL, et al. Comparison of sequential intravesical gemcitabine and docetaxel vs Bacillus Calmette-Guerin for the treatment of patients with high-risk non-muscle-invasive bladder cancer. JAMA Netw Open. 2023 Feb 1;6(2):e230849.
  6. Matulay JT, Li R, Hensley PJ, et al. Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design. J Urol. 2021;205(6):1612-1621.
  7. Rac G, Patel HD, James C, et al. Urinary comprehensive genomic profiling predicts urothelial carcinoma recurrence and identifies responders to intravesical therapy. Mol Oncol. 2024 Feb;18(2):291-304.