Editorial Note: Transurethral resection of bladder tumor (TURBt) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), but the postoperative tumor recurrence rate remains high, posing a significant clinical challenge. To prevent tumor recurrence, different intravesical therapies are administered post-TURBt based on the patient’s recurrence risk level. At the 2024 39th Annual European Association of Urology (EAU24) Congress, several studies focused on postoperative intravesical therapy strategies for NMIBC. Professor Fufu Zheng from The First Affiliated Hospital of Sun Yat-sen University provided a detailed analysis of these studies, exploring precise and individualized treatment strategies for NMIBC.
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Oncology Frontier: Can you introduce the treatment and management strategies for non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBt)?
Professor Fufu Zheng: Non-muscle-invasive bladder cancer (NMIBC) refers to superficial urothelial carcinoma of the bladder that has not invaded the muscle layer. Its prognosis is relatively better than muscle-invasive bladder cancer (MIBC), but NMIBC is characterized by multicentricity and high recurrence rates. Therefore, standardized treatment and follow-up management post-TURBt are essential.
The recurrence risk of NMIBC is categorized into low, intermediate, and high risk. Low risk includes primary, single, Ta, G1 (low-grade), tumor diameter less than 3 cm, and no carcinoma in situ (CIS). Intermediate risk does not meet the criteria for low or high risk. High risk includes T1, G3, CIS, and Ta low-grade tumors with multiple recurrences and a diameter greater than 3 cm.
In terms of treatment and management, low-risk patients need immediate postoperative instillation; intermediate-risk patients require immediate instillation followed by induction and maintenance instillation for about one year. High-risk patients also undergo immediate instillation, followed by induction and maintenance instillation (with BCG as the first choice) for 1 to 3 years. For NMIBC patients with multiple recurrences and those with CIS and T1G3 who are unresponsive to TURBt and instillation (extremely high risk), radical cystectomy is recommended. If patients cannot tolerate radical surgery, maintenance instillation therapy is performed.
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Oncology Frontier: For low-risk patients, active surveillance (AS) can be performed post-TURBt with only a single immediate instillation. Can recurrent low-risk patients continue with active surveillance without induction/maintenance instillation? Please share your views based on the progress at this EAU conference.
Professor Fufu Zheng: For primary, single, Ta, G1, <3 cm, and CIS-free low-risk patients, recurrence shifts them to the intermediate-risk group, and postoperative management should adjust to maintenance instillation. However, whether patients with recurrent single, low-grade, small tumors can continue active surveillance remains debatable.
A European multicenter study (abstract A0732) presented at this EAU conference explored the feasibility of active surveillance in recurrent NMIBC patients. This study focused on recurrent low-grade (G1), pTa NMIBC patients, predominantly low-risk. Out of 240 patients, after a median follow-up of 40 months, 111 (46%) experienced active surveillance failure, necessitating cystectomy. Multivariate Cox regression analysis identified the number and size (≥5 mm) of lesions as significant factors for surveillance failure.
This study suggests that recurrent NMIBC patients suitable for continued active surveillance can be further screened, particularly those with single, small (＜5 mm), low-grade tumors.
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Oncology Frontier: For high-risk NMIBC patients, BCG is the standard instillation therapy, but it has poor tolerability and supply issues. Can you discuss the progress in instillation therapy for high-risk NMIBC presented at this EAU conference?
Professor Fufu Zheng: This issue is highly relevant in clinical practice. BCG (Bacillus Calmette-Guérin) is the standard of care (SOC) for high-risk NMIBC instillation therapy, while intermediate-risk patients typically receive chemotherapeutic agents like epirubicin or mitomycin for intravesical instillation. BCG, as an attenuated live vaccine, has notable side effects, including urinary frequency, urgency, dysuria, reduced bladder capacity, hematuria, and systemic symptoms like fever, fatigue, and arthralgia. Therefore, there is ongoing exploration of BCG alternatives or sequential chemotherapeutic agents to reduce adverse effects.
A multicenter randomized controlled study (abstract A0736) reported at this EAU conference included 72 high-risk NMIBC patients randomized into BCG-only (81 mg, weekly for 6 weeks induction, maintenance at 3, 6, 12 months) and sequential BCG with mitomycin C (4 mg) groups. Unfortunately, the study did not meet its primary endpoint, showing no significant difference in recurrence rates (19% vs. 24%, P=0.611) and disease-free intervals (HR 1.23, P=0.640) between groups. The sequential group also experienced higher adverse event rates.
Though this study did not yield positive results, it provides insights and directions for future clinical exploration. Continued research is needed to improve instillation strategies for high-risk NMIBC patients.
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Oncology Frontier: For BCG-unresponsive high-risk NMIBC patients, radical cystectomy is typically recommended. How have immunotherapy and targeted therapy opened new treatment avenues for these patients?
Professor Fufu Zheng: For BCG-unresponsive high-risk NMIBC patients, guidelines recommend radical cystectomy. However, some patients cannot accept the quality-of-life impact of urinary diversion, and some elderly or comorbid patients cannot tolerate cystectomy.
Advances in medical technology and the advent of new drugs, especially PD-1/PD-L1 immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs), have provided new treatment options for BCG-unresponsive high-risk NMIBC patients. Previous reports from the KEYNOTE-057 study indicated that pembrolizumab achieved a 12-month complete response (CR) rate of 46% and a disease-free survival (DFS) rate of 43.5%.
At this EAU conference, a phase 1b/2 BladderGATE study (abstract A0731) was presented, enrolling 36 BCG-failure high-risk NMIBC patients. They received atezolizumab q3w up to 1 year along with continued BCG therapy (6 weeks induction, maintenance at 3, 6, 12 months). The study reported a 2-year DFS rate of 72.8%, with only 3 patients (8%) progressing to MIBC. The safety profile was acceptable, with 7 patients discontinuing treatment due to immune-related adverse events (irAEs), all of which were manageable.
A domestic study (abstract A0738) reported on HER2 ADC (RC48) ± PD-1 immunotherapy (tislelizumab) for high-risk NMIBC patients unable to undergo surgery, enrolling 24 patients. The study showed promising preliminary efficacy, with 16 patients (66.7%) achieving CR and 8 patients (33.3%) achieving stable disease (SD). Grade 3-4 treatment-related adverse events (TRAEs) were observed in only 16.7% of patients, indicating good safety.
