Introduction:

Bacillus Calmette-Guerin (BCG) is currently recommended as adjuvant therapy following complete transurethral resection of bladder tumor (TURBT) for high-risk non-muscle invasive bladder cancer (NMIBC). Unfortunately, continued BCG production shortages have precluded the use of BCG in many urologic practices. Efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) for BCG-failure was established in 2015, and has subsequently been reproduced across multiple institutions. In response to the continuing BCG shortage, Gem/Doce has also been utilized in the BCG-naïve setting, although robust data supporting this practice is lacking. Our institution has transitioned to utilization of first-line Gem/Doce. We report outcomes of a large cohort of patients with high-risk BCG-naïve NMIBC treated with Gem/Doce. 

Methods:

We retrospectively identified all patients with BCG-naïve high-risk NMIBC who were treated with Gem/Doce between May 2013 and April 2021. We included patients with intent to receive 6 weekly intravesical instillations of sequential 1 gram gemcitabine and 37.5mg docetaxel after complete TURBT. Monthly maintenance for 2 years was initiated if disease free at first follow-up. The primary outcome was recurrence-free survival (RFS) and efficacy was evaluated in an intention-to-treat manner. Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as T-stage increase from Ta or CIS to T1, or development of muscle invasive or metastatic disease. Survival was assessed using the Kaplan-Meier method and log rank test, calculated from start of Gem/Doce induction.

Results:

The final cohort included 107 patients and median follow-up for survival was 15 months. The cohort had high-risk characteristics including 44% of patients harboring CIS, 51% with T1 disease, and 7% with micropapillary variant histology (Table 1). There were 19 (18%) patients with recurrence during follow-up. RFS was 89%, 85%, and 82% and high grade-RFS was 91%, 87%, and 84% at 6, 12, and 24 months, respectively (Figure 1). RFS was similar for patients with or without CIS (p=0.42). No patients had disease progression throughout the study period. One patient underwent cystectomy due to end-stage lower urinary tract symptoms, with final pathology pTisN0. No patients died of bladder cancer. Overall survival was 84% at 24 months. The most commonly reported side effects were urinary frequency/urgency (36%), hematuria (11%), and dysuria (8%). Induction was stopped in 3 patients due to hematuria and 1 patient due to frequency/nocturia.  

Conclusion:

We found that use of Gem/Doce in a large cohort of patients with high-risk, BCG-naïve NMIBC resulted in 84% 2-year high-grade RFS, which is comparable to efficacy demonstrated in modern BCG cohorts. No patients had progression of disease and the regimen was well tolerated. In the setting of BCG shortage, these results support an alternative first-line treatment for newly diagnosed high-risk NMIBC, for which prospective evaluation is underway.

Funding: This work was supported by the John & Carol Walter Family Foundation and the Carver College of Medicine.