What are the management options for a patient with high‑risk non‑muscle‑invasive bladder cancer according to the EAU guidelines?

Management Options for EAU High-Risk NMIBC

For high-risk non-muscle invasive bladder cancer, BCG induction (6 weekly instillations) followed by maintenance therapy for at least 1-3 years is the standard of care after complete TURBT with mandatory repeat resection. 1

Initial Surgical Management

Complete TURBT is essential for all high-risk NMIBC patients, with resection extending deep into the detrusor muscle. 1, 2

• For tumors <1 cm, perform en bloc resection including underlying bladder wall 1
• For larger tumors, resect in separate fractions: exophytic component first, then underlying bladder wall with detrusor muscle, then resection edges—each fraction sent in separate containers 1
• The pathology specimen must contain detrusor muscle tissue for accurate staging 1, 2

Repeat TURBT within 2-6 weeks is mandatory for all high-risk tumors (T1, high-grade Ta, or CIS), incomplete initial resection, or absence of muscle in the specimen. 1

• Residual tumor is found in 20-71% of T1 patients at repeat TURBT 1
• Repeat TURBT reduces recurrence rates from 58% to 16% in Ta disease and improves staging accuracy 1
• Patients with T0 (no residual tumor) on repeat TURBT have significantly better outcomes: 39% recurrence vs 83% with residual disease 3

Primary Treatment Options After Complete Resection

Option 1: BCG Therapy (Preferred Standard)

Full-dose BCG induction (6 weekly instillations) plus maintenance for 1-3 years is the gold standard treatment. 1, 4

• The optimal maintenance schedule follows the SWOG regimen: 3 weekly instillations at 3 and 6 months after induction, then every 6 months for up to 3 years 4, 2
• BCG with maintenance demonstrates 32% reduction in recurrence risk compared to mitomycin C 1
• Full-dose BCG for 3 years is superior to 1/3 dose or 1-year treatment (64.2% vs 54.5% five-year recurrence-free survival) 5
• Maintenance BCG significantly improves both recurrence-free survival (p=0.001, HR 0.16) and progression-free survival (p=0.008, HR 0.097) 3

Option 2: Immediate Radical Cystectomy (Selected High-Risk Patients)

Immediate radical cystectomy should be offered to the highest-risk patients, as early cystectomy improves long-term survival compared to delayed cystectomy. 1, 4, 2

Specific indications for immediate cystectomy include: 1, 5

• Multiple, recurrent high-grade T1 tumors
• T1 tumors with concomitant CIS
• Variant histology (due to high upstaging rates)
• Lymphovascular invasion
• Tumors at sites difficult to resect completely
• Young patients with T1 high-grade plus additional poor prognostic factors
• Residual T1 disease after repeat TURBT

Option 3: Pembrolizumab (BCG-Unresponsive Disease Only)

For BCG-unresponsive high-risk NMIBC with CIS in patients ineligible for or refusing cystectomy, pembrolizumab 200 mg IV every 3 weeks achieves 41% complete response rate. 6

• BCG-unresponsive is defined as persistent disease despite adequate BCG therapy (at least 5 of 6 induction doses plus either 2 of 3 maintenance doses or 2 of 6 second induction doses) 6
• Median duration of response is 16.2 months, with 46% maintaining response ≥12 months 6
• Treatment continues for up to 24 months unless unacceptable toxicity or disease progression occurs 6

Management of BCG Failure

BCG failure is categorized as BCG-refractory (no response), BCG-relapsing (recurrence after initial response), or BCG-intolerant (unable to complete treatment). 4, 2

For persistent or recurrent high-grade disease within 6 months of two BCG induction courses or within 1 year after BCG maintenance, radical cystectomy is strongly recommended. 4, 2

• Additional BCG should not be given for persistent/recurrent disease within 6 months of two induction courses 4
• Patients who recur as T1 high-grade at 3 months after BCG induction require immediate cystectomy 2, 5
• Delaying cystectomy until progression to muscle-invasive disease negatively impacts survival 5

Critical Pitfalls to Avoid

• Never skip repeat TURBT for high-risk disease—incomplete initial resection occurs in 70% of cases, with 30% having macroscopic residual tumor 1
• Do not use reduced-dose BCG (1/3 dose) or shortened duration (1 year) for high-risk patients—these are suboptimal treatments 5
• Avoid immediate postoperative chemotherapy instillation in high-risk disease—there is no significant benefit compared to low-risk disease 1
• Do not delay cystectomy in BCG failure patients who are surgical candidates—early cystectomy improves survival 4, 5

Surveillance Protocol

High-risk patients require intensive surveillance: cystoscopy and cytology at 3 months, then every 3 months for 2 years, every 6 months until 5 years, then annually. 2, 5

• Upper tract imaging (CT urography) is recommended, especially with CIS or high-risk features 2
• Incomplete resection accounts for up to 45% of tumors noted at first follow-up cystoscopy 4