Bladder-Sparing Therapy vs. Radical Cystectomy in BCG-Unresponsive NMIBC

A large, multicenter retrospective study has found that bladder-sparing therapy provides comparable survival outcomes to upfront radical cystectomy in select patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Published in BJU International, the study highlights that while bladder-sparing therapy delays the need for cystectomy, recurrence and progression rates increase over time, emphasizing the need for careful patient selection and close surveillance (2025; https://doi.org/10.1111/bju.16509). Bladder cancer is a major cause of cancer-related morbidity and mortality worldwide, with NMIBC accounting for approximately 75 percent of new bladder cancer cases. Despite the effectiveness of intravesical BCG therapy, up to 40 percent of patients experience disease recurrence and many develop BCG-unresponsive NMIBC. Current guidelines recommend radical cystectomy as the standard treatment due to its high cancer-specific survival rates. However, concerns regarding perioperative complications and quality of life have led many patients to opt for bladder-sparing approaches, including intravesical chemotherapy, immunotherapy, and participation in clinical trials. This study aimed to compare the long-term oncological outcomes of bladder-sparing therapy with immediate radical cystectomy in patients with BCG-unresponsive NMIBC. Study Methods The study analyzed data from 578 patients with BCG-unresponsive NMIBC treated at 10 academic institutions across the U.S., Canada, and France. Patients met the U.S. FDA criteria for BCG-unresponsive disease, which included high-grade NMIBC recurrence despite adequate BCG therapy. Patients were categorized into two treatment groups: upfront radical cystectomy (28%); and bladder-sparing therapy (72%), which included re-resection, additional BCG, intravesical chemotherapy, systemic immunotherapy, or clinical trial participation. The primary endpoint was overall survival, with secondary endpoints including cancer-specific survival, metastasis-free survival, and recurrence rates. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate differences between treatment groups. Research Results Among the 578 patients, 416 (72%) pursued bladder-sparing therapy, while 162 (28%) underwent immediate radical cystectomy. The median follow-up period was 50 months. Survival outcomes showed no statistically significant differences between the bladder-sparing therapy and radical cystectomy groups. Metastasis-free survival: HR: 0.88; 95% CI: 0.53-1.46; P=0.62 Cancer-specific survival: HR: 0.91; 95% CI: 0.54-1.53; P=0.73 Overall survival: HR: 1.31; 95% CI: 0.91-1.90; P=0.15 However, recurrence and progression rates were significantly higher in the bladder-sparing therapy group. At 12 and 24 months, high-grade recurrence rates were 37 percent and 52 percent, respectively. Disease progression to muscle-invasive bladder cancer occurred in seven percent of patients at 12 months and 13 percent at 24 months. Pathological Outcomes Among patients who initially chose bladder-sparing therapy, 32 percent ultimately required cystectomy. These patients had a higher rate of nodal disease (13%) compared to those who underwent immediate radical cystectomy (4%) (P=0.030). Additionally, patients who delayed cystectomy had more advanced extravesical disease (≥pT3 or N+) (24%) compared to those who underwent upfront surgery (16%). At 5 years, metastatic progression occurred in 14 percent of patients in both the bladder-sparing and radical cystectomy groups, while bladder cancer-specific mortality was 14 percent in both groups. All-cause mortality at 5 years was 28 percent in the bladder-sparing therapy group and 22 percent in the radical cystectomy group. To gain deeper insights into the study's findings, Oncology Times connected with Yair Lotan, MD, Professor of Urology, Chief of Urologic Oncology, and holder of the Jane and John Justin Distinguished Chair in Urology at UT Southwestern Medical Center. He is also Vice Chair for Clinical Affairs in the Urology Department and Medical Director of the Urology Clinic at Parkland Health and Hospital System. Oncology Times: What are key factors that influence a clinician's decision to recommend bladder-sparing therapy over radical cystectomy in patients with BCG-unresponsive NMIBC? How do patient-specific considerations affect this choice? Lotan: “The main factors that impact decisions relate to a patient's medical condition, stage of disease, and patient preferences. The first question is whether a patient can tolerate a radical cystectomy. If a patient is too frail to undergo major surgery, then that is not a good therapeutic option and other treatments need to be considered. The second question is whether bladder-sparing is a reasonable consideration. We recognize that patients with invasive disease (Stage T1) may do worse, especially if the disease is high volume or multifocal. They should consider cystectomy more heavily than a patient with Ta or CIS alone. Finally, patient priorities play an important decision. Cystectomy has the best chance for cure and any approach to spare the bladder comes at some risk of progression and metastasis, even if it is relatively low in the short term.” Oncology Times: How do the survival outcomes and quality-of-life considerations compare between patients undergoing initial bladder-sparing therapy versus immediate radical cystectomy? What role does patient preference play in clinical decision-making? Lotan: “This is an important question. Our study has some inherent limitations. We did not evaluate QOL and this is a significant reason why patients want to keep their bladder. Prospective studies like the CISTO trial and an upcoming registry that we are organizing through BCAN will help answer these questions. The other limitation with our study is that there were few treatments available for patients other than more BCG, intravesical gemcitabine and docetaxol, and clinical trials. There are quite a few new treatments available or soon to be available for treating this disease state. One benefit of our study was that, despite the absence of many options, we found that in the first 6-12 months, there were few patients who developed metastatic or progressive disease, suggesting that an attempt at bladder-sparing initially will be of relatively low risk to patients.” Oncology Times: What are potential implications of delayed cystectomy after initial bladder-sparing therapy on nodal disease involvement and overall treatment success? How should clinicians counsel patients regarding this risk? Lotan: “As noted above, any patient who has persistent disease and does not respond to bladder-sparing therapy may have progression of disease. This is an important discussion that providers should have with patients. There is a trade-off that patients need to understand. On the other hand, cystectomy is a procedure with high morbidity and even a small risk of mortality. Since few patients develop metastatic disease even if progression locally, we did not find an overall difference in metastasis or cancer-specific survival.” Dibash Kumar Das is a contributing writer.

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