Introduction:

Due to patient or surgeon preference many patients diagnosed with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) are not treated according to AUA, EAU or NCCN guidelines. Data suggests that delaying or forgoing radical cystectomy may put patients at risk for disease progression and inferior oncologic outcomes. However, the natural history of bladder-sparing therapy (BST) in patients with BCG-unresponsive disease is not well defined. Alternate intravesical, and recently systemic, treatment options are given to patients without full knowledge of the oncologic risks over time with the first and subsequent lines of BST. The primary aim of this retrospective study is to determine the oncologic risks of BST over time in patients with BCG-unresponsive NMIBC who do not undergo radical cystectomy.

Methods:

Data for this study came from a larger multi-center, international cohort of patients with BCG-unresponsive disease that included 594 patients who underwent either upfront radical cystectomy or upfront BST. Patients were included if they had BCG-unresponsive disease after adequate BCG therapy according to FDA criteria, defined as 1) >  T1 high-grade (HG) disease on the first assessment following adequate BCG, 2) high grade recurrence with papillary NMIBC within 6 months of adequate induction and maintenance BCG therapy, or 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 with upper tract disease or who were pathologic T2, node-positive, or metastatic at time of BCG-unresponsiveness were excluded. BSTs at time of BCG-unresponsiveness were collected, in addition to subsequent lines of BST. Survival analysis was performed to create life tables and time-to-event calculations.

Results:

422 patients with BCG unresponsive disease underwent at least 1 BST. The most common initial BST was BCG or alternate BCG in 204 (48.3%) patients (Table 1). Alternative intravesical agents, including sequential intravesical gemcitabine and docetaxel, intravesical Mitomycin C , or various experimental clinical trial therapies were given in 151 (35.8%) patients. For all patients undergoing at least 1 BST, intravesical HG recurrence occurred in 22% and 37% of patients at 6 and 12 months after BCG-unresponsiveness, respectively (Table 2). Rates of cystectomy, metastasis, bladder cancer death, and all-cause mortality were low at 6 months at 2%, 1%, 0%, and 1%, respectively. However, at 12 months, these rates rose to 12%, 3%, 2%, and 4%, respectively. 90 patients received 2^nd and third lines of BST. In this group, rates of cystectomy, metastasis, bladder cancer death, and all-cause mortality were also low at 6 months with 1% in each outcome and started to rise 9 months after BCG-unresponsiveness.

Conclusion:

This study reviewed oncologic outcomes from a large retrospective multi-center cohort of patients with BCG-unresponsive NMIBC. Patients who underwent initial BST appeared to have acceptable oncologic outcomes 6-9 months after BCG-unresponsive diagnosis. In clinical practice, this may translate to initial trial of BST in well-selected patients in which BCG is ineffective. Worse oncologic outcomes arise 12 months after being deemed BCG-unresponsive, particularly in patients treated with second and third lines of BST. The results from this study provide important reference data which may aid in patient counseling. Larger prospective patient cohorts are required to validate these data and confirm the safety of delaying cystectomy in select patients with BCG-unresponsive NMIBC.

Funding: N/A