What are the alternative treatment options for a patient with multifocal, non-invasive high-grade papillary urothelial carcinoma involving the right ureter and bladder, with prior unsuccessful surgical resection attempts and denied insurance coverage for Keytruda (pembrolizumab)?

Treatment Options for Multifocal, Non-invasive High-Grade Papillary Urothelial Carcinoma with Failed Surgical Resection

For a patient with multifocal, non-invasive high-grade papillary urothelial carcinoma involving the right ureter and bladder who has had unsuccessful surgical resection attempts and denied insurance coverage for pembrolizumab, intravesical BCG therapy is the recommended first-line treatment option. 1

Primary Treatment Options

Intravesical Therapy

• BCG (Bacillus Calmette-Guérin) is the preferred intravesical agent for high-grade, non-invasive urothelial carcinoma and should be administered as a 6-week induction course followed by maintenance therapy 1
• BCG has demonstrated superior efficacy compared to chemotherapy in preventing recurrences of high-grade Ta tumors, as confirmed by multiple meta-analyses 1
• For patients with anatomically challenging locations like the upper urinary tract, consider alternative delivery methods such as retrograde instillation via ureteral catheter 1

Alternative Intravesical Chemotherapy Options

• Mitomycin C can be used if BCG is unavailable or not tolerated, though it is less effective than BCG for high-grade lesions 1
• Other intravesical chemotherapy options include:
  • Gemcitabine (better tolerability profile than mitomycin) 1
  • Sequential gemcitabine/docetaxel combination 1
  • Gemcitabine/mitomycin combination 1
  • Valrubicin (particularly for BCG-refractory disease) 1
  • Docetaxel 1

Dose Considerations During BCG Shortage

• If BCG supply is limited, consider using one-half or one-third dose for induction therapy 1
• Maintenance BCG should be prioritized for high-risk non-invasive bladder cancer patients 1

Management of BCG-Unresponsive Disease

Definition of BCG Failure

• BCG-refractory: Persistent high-grade disease at 6 months despite adequate BCG treatment 1
• BCG-relapsing: Recurrence of high-grade disease after achieving disease-free state at 6 months 1
• BCG-unresponsive: Combination of BCG-refractory and BCG-relapsing within 6 months of last BCG 1

Treatment Options for BCG-Unresponsive Disease

• Radical cystectomy remains the standard recommendation for BCG-unresponsive disease due to high risk of progression 1
• For patients unwilling or unable to undergo radical cystectomy:
  • Thermochemotherapy has shown 2-year disease-free survival in 47% of patients 1
  • BCG re-induction can be considered as it achieved similar disease control to thermochemotherapy in a randomized trial 1
  • Consider clinical trials of novel agents when available 1

Emerging Therapies for BCG-Unresponsive Disease

• Pembrolizumab (intravenous): While denied by insurance in this case, it has shown complete response rates of 41% in BCG-unresponsive disease with CIS, with median duration of response of 16.2 months 1
• Nadofaragene firadenovec (intravesical gene therapy) has shown 53% complete response at 3 months and 24% at 12 months in BCG-refractory disease 1
• Combination therapies: Emerging evidence suggests potential benefit of combining immunotherapy with targeted agents like erdafitinib in cases with specific mutations 2

Follow-up and Surveillance

• Urinary cytology and cystoscopy every 3 months for the first 1-2 years 1
• Gradually increasing intervals for follow-up examinations after the initial 2 years if no recurrence 1
• Imaging of the upper urinary tract every 1-2 years for high-grade tumors 1
• Consider urine molecular tests for urothelial tumor markers (category 2B recommendation) 1

Special Considerations for Upper Tract Disease

• Upper tract urothelial carcinoma (UTUC) presents unique challenges due to anatomical location 3
• For patients with involvement of both bladder and upper tract:
  • Consider more aggressive follow-up schedule due to higher risk of recurrence 1
  • Evaluate for potential molecular alterations (e.g., FGFR3 mutations) that might guide therapy if disease becomes refractory 2, 3

Pitfalls and Caveats

• Failure to adequately treat both the bladder and upper tract components can lead to recurrence 1
• Incomplete resection of upper tract lesions is common due to anatomical challenges 3
• Delayed recognition of progression to muscle-invasive disease can worsen prognosis 1
• BCG shortage may necessitate prioritization of patients with highest risk disease 1
• Regular reassessment of disease status is critical, as non-invasive disease can progress to invasive disease requiring more aggressive intervention 1