Introduction:

The recommended treatment per guidelines for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is radical cystectomy (RC). Yet many patients are ineligible for RC based on comorbid/performance status or refuse RC based on preference to avoid radical surgery. Recently, gemcitabine and docetaxel (Gem/Doce) combination intravesical therapy has gained popularity in both BCG-naïve and BCG-unresponsive NMIBC disease states. However, there is limited data on the efficacy of Gem/Doce as bladder-sparing therapy (BST) compared to patients who get upfront RC, as prior single and multi-institutional data focused only on patients who received Gem/Doce without including upfront RC as a comparator. The purpose of this study was to compare oncologic outcomes in patients undergoing salvage BST with Gem/Doce compared to patients who receive upfront RC in a large multinational cohort of patients with BCG-unresponsive NMIBC.

Methods:

Patients from a larger multinational cohort of patients with BCG-unresponsive NMIBC from 10 academic medical centers were retrospectively collected. This analysis included only patients who underwent upfront RC or BST with Gem/Doce specifically. Patients were included if they had BCG-unresponsive disease after adequate BCG therapy according to FDA criteria, defined as 1) >1 T1 HG disease on the first assessment following adequate BCG, 2) > Ta within 6 months of adequate induction and maintenance BCG therapy, 3) any component of CIS within 12 months of adequate induction and maintenance BCG. Adequate BCG was defined as 5/6 doses for induction and 2/3 doses for maintenance. Patients who were pathologic > T2, node-positive, or metastatic at time of BCG-unresponsiveness were excluded. Demographic data, recurrence and progression, and oncologic outcomes are reported. Survival outcomes were calculated using Kaplan-Meier method.

Results:

172 patients underwent upfront RC and 95 received BST with Gem/Doce at diagnosis of BCG-unresponsive disease. Median age was 70 and 73 for upfront RC and Gem/Doce, respectively. 44/95 (46%) patients undergoing Gem/Doce as first line BST recurred intravesically at a median of 21m, and 42% underwent a 2^nd separate line of BST. At 2 years after BCG-unresponsive diagnosis, 9% of patients undergoing upfront RC developed metastases compared to 8% Gem/Doce arm (p=0.38). At median follow-up of 39m, patients treated with Gem/Doce had higher cancer specific survival than patients undergoing upfront RC (HR=0.27, p=0.036) (Figure 1). Overall survival was not statistically different. At a median f/u of 32m, 17 patients (18%) in Gem/Doce arm underwent RC. The node positivity rate was higher in Gem/Doce group (5/17 (29%)) compared to in the upfront RC group (9/172 (5.3%)) (p=0.004). Overall pathologic T-stage was not statistically different.

Conclusion:

In a large multi-center cohort of BCG-unresponsive NMIBC patients, BST treatment with Gem/Doce does not appear to significantly compromise oncologic outcomes. Furthermore, cancer specific survival appeared non-inferior in patients undergoing Gem/Doce BST compared to upfront RC. A large percentage of patients receiving Gem/Doce recurred and underwent additional salvage therapy, suggesting close to half of these patients will require additional measures at 2 years be it further effective BST or eventual radical cystectomy. These data suggest that in the carefully selected patient, oncologic outcomes are likely not compromised in the near term over the first two years, and a trial of intravesical Gem/Doce salvage therapy can be appropriate for patients that decline RC as upfront therapy after diagnosis of BCG-unresponsive disease.

Funding: N/A