Introduction:

Treatment toxicity and symptom burden can have substantial effects on health-related quality of life (HRQOL). Recurrences after BCG monotherapy are common and patients with non-muscle invasive bladder cancer (NMIBC) need to decide between vastly different management options for which the effect on HRQOL may influence decision-making. Retreatment with BCG remains the standard of care for BCG-exposed high-grade NMIBC. However, response rates to retreatment with BCG is <50% at 6 months, putting patients at substantial risk for disease progression and need for radical cystectomy. Combination intravesical gemcitabine and BCG (GemBCG) is a novel chemoimmunotherapy regimen that may result in additive or synergistic effects through immune enhancement and direct cytotoxicity. Our phase I/II clinical trial demonstrates that combination GemBCG has low rate of adverse events and offers promising oncological control. Herein, we present patient-reported outcomes (PROs) from our phase II single-arm multi-institutional trial with GemBCG in BCG-exposed high grade NMIBC (NCT04179162).

Methods:

Patients with BCG-exposed NMIBC (HGTa/HGT1/Tis) within 24 months of the last treatment with BCG were eligible. Exclusion criteria included contraindication to BCG, BCG-unresponsive NMIBC, concurrent prostatic urethral disease, concurrent UTUC, or history of muscle-invasive or metastatic disease. Patients underwent TURBT followed by intravesical instillation of 2000mg Gemcitabine twice weekly (weeks 1, 4, 7, 10) and once weekly 50mg TICE BCG (weeks 2, 3, 5, 6, 8, 9) followed by 1-year of maintenance BCG in responders. The trial followed an optimal Simon two-stage design; HRQOL questionnaires were administered only to the phase II expansion cohort. PRO-CTCAE was used to evaluate patient-reported toxicity throughout the 10 weeks of GemBCG instillation for granularity within treatment schedule. Longer-term HRQOL outcomes were evaluated using EORTC QLQ-C30 and QLQ-NMIBC24 at baseline, 3, 6, 9, and 12 months. Generalized estimating equation models with autoregressive correlation structure were used to estimate mean scores with 95% confidence intervals.

Results:

A total of 22/28 patients from the phase II trial completed questionnaires. A median of 8.5 and 4 surveys were completed per subject for PRO-CTCAE and EORTC QLQ surveys, respectively. During the 10-week induction course of GemBCG, patients reported worsening dysuria (β=0.05, p=0.003) and other urinary symptoms (β=0.06, p=0.003) on PRO-CTCAE. Similarly, urinary toxicity transiently increased at 3-months on the QLQ-NMIBC24 but returned to baseline at 12-months suggesting no long-term detrimental urinary effects with GemBCG. On PRO-CTCAE, there was no evidence of constitutional, cardiopulmonary, gastrointestinal, or mental toxicity grades changing during induction therapy. However, on the QLQ-C30, Global QOL decreased from baseline 75 (95% CI 64─86) to 63 at 12-months (95% CI 43─84). The QLQ-C30 Summary Score (encompassing all domains aside from financial and Global QOL) mildly decreased from baseline 88 (95% CI 82─94) to 81 at 3-months (95% CI: 73─88) although it plateaued for the remainder of follow-up.

Conclusion:

Patient-reported outcomes from our phase II trial of GemBCG in BCG-exposed high-grade NMIBC support the safety of combination chemoimmunotherapy. The increase in urinary toxicity during induction parallels our prior work evaluating PRO-CTCAE toxicity for BCG monotherapy. After 12-months of treatment, there was a decrease in Global QOL, although this was not driven by increased urinary symptoms. The effects of anxiety and fear of recurrence and/or cancer progression on HRQOL require further characterization, particularly in patients with history of recurrent NMIBC. Moreover, prospective comparisons to induction courses of other intravesical therapies (BCG monotherapy, gemcitabine/docetaxel) are needed to understand the cumulative patient-reported toxicity for NMIBC. Based on the encouraging findings from our phase I/II trial, a randomized phase III clinical trial comparing GemBCG vs. BCG alone (current standard) for patients with BCG-exposed high-grade NMIBC is open for accrual through the National Cancer Institute’s cooperative group National Clinical Trial Network (Alliance A032303/NCT07000084).

Funding: N/A