What are the guidelines for adjuvant therapy in patients with high-risk Upper Tract Urothelial Carcinoma (UTUC)?

Guidelines for Adjuvant Therapy in High-Risk Upper Tract Urothelial Carcinoma (UTUC)

Adjuvant cisplatin-based chemotherapy is recommended for patients with high-risk UTUC (pT2-T4 pN0-N3 M0 or pT any N1-3 M0) following radical nephroureterectomy, based on improved disease-free survival demonstrated in the POUT trial. 1

Risk Stratification for UTUC

High-risk UTUC is defined as having one or more of the following characteristics:

• Tumor size >2 cm
• Presence of hydronephrosis
• High-grade disease on cytology/biopsy
• Multifocal disease
• Variant histology
• Previous radical cystectomy for bladder cancer 1

Primary Surgical Management

For high-risk UTUC patients, the standard primary treatment is:

• Open or laparoscopic radical nephroureterectomy with bladder cuff excision 1
• Regional lymphadenectomy should be performed 1

Adjuvant Therapy Recommendations

Adjuvant Chemotherapy

1. Cisplatin-based chemotherapy:

   • Recommended for patients with locally advanced disease (pT2-T4 pN0-N3 M0 or pT any N1-3 M0) 1
   • Based on the POUT trial showing improved disease-free survival (HR 0.45,95% CI 0.30-0.68) 1
   • Level of evidence: II, C 1

2. Carboplatin-based chemotherapy:

   • Not recommended as adjuvant therapy due to power limitations in analyses 1
   • Level of evidence: II, D 1

3. Timing of adjuvant chemotherapy:

   • Should be initiated within 90 days after radical nephroureterectomy 1
   • A minimum of 3 cycles of a cisplatin-based combination is recommended 1

Immune Checkpoint Inhibitors (ICIs)

• Currently not recommended in the adjuvant setting for UTUC 1
• Patients with UTUC included in the CheckMate 274 study appeared to benefit less from adjuvant nivolumab compared to bladder tumor patients 1
• Overall survival data for ICIs in this setting are unavailable 1

Special Considerations

Patients Ineligible for Cisplatin-Based Therapy

For patients who cannot receive cisplatin-based chemotherapy (due to renal dysfunction, poor performance status, or hearing loss):

• Observation is recommended as adjuvant chemotherapy has not shown clear survival benefit in these patients 1
• For metastatic disease, gemcitabine/carboplatin followed by maintenance avelumab may be considered 1

Monitoring After Treatment

• Cystoscopy at 3-month intervals initially, then at increasing intervals
• Imaging of the upper tract collecting system every 1-2 years for high-grade tumors 1
• Urinary cytology at regular intervals

Emerging Approaches

Recent research suggests potential benefits of neoadjuvant chemotherapy for high-risk UTUC:

• A 2023 multicenter phase II trial of gemcitabine and split-dose cisplatin showed promising results with 63% pathologic response rate and improved survival outcomes 2
• Pathologic complete and partial responses were associated with improved progression-free survival and overall survival 2

Common Pitfalls and Caveats

1. Avoid carboplatin substitution: Carboplatin should not be substituted for cisplatin in the adjuvant setting due to lack of proven efficacy 1

2. Renal function assessment: Careful assessment of renal function is critical before initiating cisplatin-based therapy, as radical nephroureterectomy reduces renal function

3. Bladder recurrence: Adjuvant chemotherapy may help prevent bladder recurrence, which occurs in approximately 26% of patients with UTUC 3

4. Limited evidence base: Due to the rarity of UTUC, most treatment recommendations are extrapolated from evidence in bladder cancer or from small, single-center UTUC studies 1

5. Elderly patients: For elderly patients with significant comorbidities, treatment should be adjusted considering quality of life impacts, with potential consideration of single-agent regimens rather than combination therapy 4

The management of high-risk UTUC continues to evolve, with growing evidence supporting the role of adjuvant cisplatin-based chemotherapy following radical nephroureterectomy to improve disease-free survival and reduce recurrence risk.