What is the role of adjuvant chemotherapy after nephroureterectomy for Upper Tract Urothelial Carcinoma (UTUC)?

Role of Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Carcinoma (UTUC)

Adjuvant cisplatin-based chemotherapy should be administered to patients with locally advanced UTUC (pT2-T4 pN0-N3 M0 or pT any N1-3 M0) following radical nephroureterectomy, based on significant improvement in disease-free survival demonstrated in the POUT trial. 1, 2

Patient Selection for Adjuvant Chemotherapy

Adjuvant chemotherapy is indicated for patients with:

• High-risk pathology: pT2-T4 disease and/or positive lymph nodes (N+) 1, 2
• No prior neoadjuvant chemotherapy 1
• Adequate renal function to tolerate cisplatin-based regimens 1, 2

Risk Stratification

UTUC is stratified into two risk categories that guide treatment:

• Low-risk UTUC: Unifocal tumors <1 cm, low-grade disease, no invasive features on CT urography
• High-risk UTUC: Tumors >2 cm, hydronephrosis, high-grade disease, multifocal disease, variant histology, or previous radical cystectomy for bladder cancer 1, 2

Evidence Supporting Adjuvant Chemotherapy

The strongest evidence comes from the POUT trial, a phase 3 randomized controlled trial that demonstrated:

• Significant improvement in disease-free survival (HR 0.45,95% CI 0.30-0.68, p=0.0001) 3
• 3-year event-free estimates of 71% for chemotherapy vs. 46% for surveillance 3
• Benefit was consistent across all subgroups examined 3

Additional supporting evidence includes:

• National Cancer Database analysis showing overall survival benefit in pT3/T4 and/or pN+ patients (HR 0.77,95% CI 0.68-0.88) 4
• Prospective randomized trial showing improved progression-free survival, overall survival, and cancer-specific survival in high-risk UTUC patients with cardiovascular comorbidity 5

Chemotherapy Regimen and Timing

• Preferred regimen: Cisplatin-based combinations such as gemcitabine plus cisplatin 1, 2
• Timing: Should be initiated within 90 days after radical nephroureterectomy 2, 3
• Duration: Minimum of 3-4 cycles of cisplatin-based combination 1, 3

Important Caveats

• Carboplatin substitution: Carboplatin-based adjuvant chemotherapy is not recommended due to insufficient evidence of efficacy (Level II, D) 1, 2
• Renal function assessment: Critical before initiating cisplatin-based therapy, as nephroureterectomy reduces renal function 2, 6
• Immune checkpoint inhibitors: Currently not recommended as adjuvant therapy for UTUC based on CheckMate 274 study results showing less benefit compared to bladder cancer counterparts 1

Treatment Algorithm

1. Primary treatment: Radical nephroureterectomy with bladder cuff excision for high-risk UTUC 1, 2

2. Post-surgical assessment:

   • Evaluate pathologic stage and nodal status
   • Assess renal function (GFR)
   • Review comorbidities and performance status

3. Treatment decision:

   • If pT2-T4 and/or N+ disease AND adequate renal function: Adjuvant cisplatin-based chemotherapy
   • If inadequate renal function for cisplatin: Observation (not carboplatin) 1, 2

4. Follow-up surveillance:

   • Cystoscopy at 3-month intervals initially
   • Regular imaging of the upper tract collecting system
   • Urinary cytology at regular intervals 2

Potential Adverse Events

• Grade 3 or worse treatment-emergent adverse events occurred in 44% of patients receiving adjuvant chemotherapy in the POUT trial 3
• Common toxicities include myelosuppression, nausea, and fatigue
• No treatment-related deaths were reported in the POUT trial 3

While neoadjuvant chemotherapy has theoretical advantages by being administered when patients have two functioning kidneys, the evidence for adjuvant therapy in UTUC is stronger and more definitive based on the POUT trial results 7, 6.