What are the next steps for a patient with recurrent high-grade bladder cancer despite BCG (Bacillus Calmette-Guérin) therapy?

Radical Cystectomy Should Be Strongly Recommended for This Patient

This patient has BCG-unresponsive high-grade non-muscle invasive bladder cancer (NMIBC) and should undergo radical cystectomy with pelvic lymph node dissection as the primary treatment. 1

Defining BCG-Unresponsive Disease

This patient meets the criteria for BCG-unresponsive disease, which is defined as the combination of BCG-refractory and BCG-relapsing disease within 6 months of the last BCG treatment. 1 Specifically:

• BCG-refractory component: The patient had persistent high-grade disease during maintenance BCG therapy (MD9 dose) 1
• Progression during therapy: The tumor evolved from low-grade at first recurrence (May 2024) to high-grade at second recurrence (during MD9), representing stage progression while on adequate BCG treatment 1
• Multiple recurrences on BCG: Two documented recurrences while receiving BCG maintenance therapy indicates treatment failure 1

Why Radical Cystectomy is the Primary Recommendation

Radical cystectomy should be carried out in high-grade tumors (T1/HG, Ta/HG, CIS) that are unresponsive to BCG due to the high risk of progression to muscle-invasive disease. 1 The evidence supporting this is compelling:

• Survival benefit with early cystectomy: Patients who underwent cystectomy within 2 years after initial BCG treatment demonstrated improved 15-year disease-specific survival compared to those who delayed surgery 1
• Better outcomes treating recurrence vs progression: Improved survival outcomes were noted in patients who underwent cystectomy for recurrent disease compared to those treated after progression to muscle-invasive disease 1
• Risk of understaging: Deferring cystectomy until progression to muscle-invasive disease may negatively impact survival 1

Critical Pitfall: Do Not Give Additional BCG

A clinician should not prescribe additional BCG to a patient with documented recurrence of high-grade NMIBC within six months of induction BCG plus maintenance. 1 This patient has already received:

• Initial induction BCG (elsewhere, one year ago) 1
• Maintenance BCG therapy (at your institution) 1
• Two recurrences during maintenance (May 2024 and during MD9) 1

Continuing BCG in this setting exposes the patient to unnecessary toxicity without meaningful benefit and delays definitive treatment. 1

Alternative Options Only If Cystectomy Refused or Patient Unfit

If the patient is unwilling or medically unfit for radical cystectomy, the following alternatives can be considered, though they are inferior to surgery:

Option 1: Clinical Trial Enrollment (Preferred Alternative)

• Pembrolizumab can be considered for BCG-unresponsive disease in patients who refuse or are unfit for cystectomy, with a complete response rate of 41% at 3 months and median duration of response of 16.2 months 1
• This represents the highest quality alternative to cystectomy for BCG-unresponsive disease 1

Option 2: BCG Re-induction (Less Preferred)

• BCG re-induction achieved similar disease control to thermo-chemotherapy in a randomized trial and can be considered as an alternative only in highly selected cases 1
• However, this contradicts the stronger recommendation against additional BCG in this specific scenario 1

Option 3: Alternative Intravesical Chemotherapy

• Intravesical chemotherapy with mitomycin C, gemcitabine, or other agents may be offered when clinical trials are unavailable 1
• Thermo-chemotherapy can obtain 2-year disease-free survival in 47% of patients unwilling or unable to have cystectomy 1

Surgical Approach and Timing

Radical cystectomy with pelvic lymph node dissection is the standard surgical treatment. 1 Key considerations:

• Timing is critical: Earlier cystectomy (within 2 years of BCG initiation) improves long-term survival 1
• Urinary diversion options: Continent orthotopic neobladder, continent cutaneous catheterizable pouch, or incontinent cutaneous conduit should be discussed based on patient factors 1
• Multidisciplinary evaluation: Tumor board discussion with medical oncology, radiation oncology, and urology is recommended 1

Surveillance Protocol If Surgery Delayed or Refused

If the patient refuses cystectomy or pursues alternative therapy, intensive surveillance is mandatory:

• Cystoscopy and urinary cytology every 3 months for the first 2 years 1
• Upper tract imaging every 1-2 years for high-grade tumors 1
• Escalate to cystectomy immediately if muscle-invasive disease develops 1

Common Pitfalls to Avoid

1. Do not give more than 2 consecutive induction courses of any intravesical agent - this patient has already exceeded this threshold 1
2. Do not delay cystectomy waiting for muscle invasion - survival worsens significantly when surgery is deferred until progression 1
3. Do not underestimate low-grade recurrences - while this patient's first recurrence was low-grade, it progressed to high-grade, demonstrating the aggressive nature of BCG-unresponsive disease 2
4. Do not perform repeat TURBT alone without definitive therapy - complete resection without addressing the underlying BCG failure is inadequate 1