Is immunotherapy a suitable option for an elderly patient with recurrent high-grade T1 bladder cancer, significant cardiac comorbidities, and a history of failed Bacillus Calmette-Guérin (BCG) and chemoradiotherapy treatments?

Immunotherapy is NOT Recommended for This Patient – Radical Cystectomy is the Standard of Care

For an elderly patient with recurrent high-grade T1 bladder cancer after failed BCG and chemoradiotherapy, radical cystectomy is the guideline-recommended standard of care, not additional immunotherapy. 1, 2 This patient meets the definition of BCG-unresponsive disease (persistent high-grade disease despite adequate BCG treatment), and further BCG immunotherapy is not likely to work. 3

Why BCG Immunotherapy Has Failed and Should Not Be Repeated

Definition of BCG-Unresponsive Disease

• This patient has BCG-unresponsive disease, defined as persistent or recurrent high-grade T1 disease after adequate BCG induction and maintenance therapy. 2, 3
• BCG-unresponsive includes both BCG-refractory (persistent disease at 6 months despite adequate BCG) and BCG-relapsing (recurrence after achieving disease-free state at 6 months). 2
• No more than 2 consecutive induction courses of BCG should ever be given – this patient has already exceeded this threshold. 1

Evidence Against Further BCG

• For patients with persistent high-grade T1 disease after BCG failure, further BCG is not likely to be effective. 3
• The recurrence after both BCG and chemoradiotherapy indicates aggressive disease biology that will not respond to additional intravesical immunotherapy. 1

The Recommended Treatment: Radical Cystectomy

Guideline Recommendations

• Radical cystectomy is the guideline-recommended standard of care for BCG-unresponsive high-risk non-muscle-invasive bladder cancer with high-grade T1 disease. 1, 2
• This is a strong recommendation (Evidence level: 4) from multiple guideline societies. 1
• For patients with high-risk recurrences (T1 stage or high-grade tumor) after BCG failure, radical cystectomy is recommended. 1

Survival Benefit of Early Cystectomy

• Earlier cystectomy (within 2 years of initial BCG treatment) improves 15-year disease-specific survival compared to delayed cystectomy. 2
• Cystectomy for recurrent disease shows better survival outcomes than waiting for progression to muscle-invasive disease. 2
• Delaying cystectomy until progression to muscle-invasive disease negatively impacts survival – this is a critical pitfall to avoid. 2

Addressing the Cardiac Comorbidities

Cardiac Risk Assessment

• The patient's right bundle branch block and cardiac history require preoperative cardiac evaluation, but right bundle branch block alone is not a contraindication to surgery. 4
• Cardiology consultation for perioperative risk stratification is mandatory before proceeding with cystectomy. 4
• The cardiac comorbidities make the patient higher risk for surgery, but do not automatically exclude cystectomy as an option – they require careful perioperative management. 4

Alternative Options ONLY If Cystectomy is Refused or Medically Contraindicated

Systemic Immunotherapy (Pembrolizumab)

• Pembrolizumab may be appropriate for patients with BCG-unresponsive, high-risk, non-muscle-invasive bladder cancer who are ineligible for or have elected not to undergo cystectomy. 1, 2
• However, the data are currently not mature enough to determine if pembrolizumab can be considered curative in this setting. 1
• Pembrolizumab shows a 41% complete response rate at 3 months in BCG-unresponsive patients, but this represents salvage therapy with uncertain long-term outcomes. 2

Other Salvage Options (All Inferior to Cystectomy)

• Intravesical therapy with a different agent (such as valrubicin, the only FDA-approved intravesical drug for BCG failure) can be considered, but valrubicin has limited efficacy and panel disagreement on its value. 1, 2
• Combination intravesical BCG plus chemotherapy may be considered for BCG-unresponsive patients who refuse cystectomy (weak recommendation, Evidence level: 1a-1b). 1
• Clinical trial participation should be strongly encouraged if cystectomy is refused. 1, 3

Critical Pitfalls to Avoid

Do Not Delay Definitive Treatment

• The most dangerous pitfall is delaying cystectomy while attempting multiple salvage intravesical therapies – this allows time for progression to muscle-invasive or metastatic disease. 2
• Approximately 50% of patients who fail BCG after previous radiation therapy eventually require cystectomy, and half of these have pathologically advanced disease (≥pT3) at the time of surgery. 5

Do Not Confuse Intravesical BCG with Systemic Immunotherapy

• The question asks about "immunotherapy" – it is critical to distinguish between:
  • Intravesical BCG immunotherapy (which has already failed in this patient and should not be repeated) 1, 3
  • Systemic checkpoint inhibitor immunotherapy (pembrolizumab, which is an option only if cystectomy is refused/contraindicated) 1, 2

Recognize the Impact of Previous Radiation

• Patients with high-grade NMIBC who previously received prostate radiotherapy have a 50% failure rate with BCG, and those who fail are more likely to have extravesical progression. 5
• This patient's history of chemoradiotherapy makes the disease even more concerning for aggressive biology. 5

Algorithm for Decision-Making

1. Confirm BCG-unresponsive status: Recurrent high-grade T1 after adequate BCG = BCG-unresponsive disease 2, 3
2. Obtain cardiology consultation: Assess perioperative cardiac risk given RBBB and cardiac history 4
3. If surgical candidate: Proceed with radical cystectomy (standard of care) 1, 2
4. If NOT a surgical candidate or patient refuses:
   • First choice: Pembrolizumab (if available and patient meets criteria) 1, 2
   • Second choice: Clinical trial enrollment 1, 3
   • Third choice: Alternative intravesical agent or combination therapy 1
5. Do NOT repeat BCG immunotherapy – it has already failed and will not work 3