What are the recommendations for adjuvant therapy after Radical Nephroureterectomy (RNU) in Upper Tract Urothelial Carcinoma (UTUC) according to European Association of Urology (EAU) guidelines?

Adjuvant Therapy Recommendations After RNU in UTUC According to EAU Guidelines

The EAU guidelines recommend adjuvant platinum-based chemotherapy over neoadjuvant treatment for patients with high-risk UTUC (pT2-T4 and/or pN+ disease) after radical nephroureterectomy, based on level I evidence from the POUT trial showing significant disease-free survival benefit. 1

Primary Recommendation: Adjuvant Platinum-Based Chemotherapy

• Adjuvant platinum-based chemotherapy is the standard of care for patients with pT2-T4 and/or pN+ disease after RNU, demonstrating significant disease-free survival benefit that likely translates to overall survival improvement 1

• The POUT phase 3 randomized controlled trial provides the highest quality evidence supporting this recommendation, showing clear benefit in patients with adverse pathological features 1

• Network meta-analysis confirms that adjuvant platinum-based chemotherapy yields superior oncological benefit over immune checkpoint inhibitors in UTUC patients treated with radical surgery 1, 2

Critical Timing Consideration

• Despite evidence showing neoadjuvant chemotherapy benefits, the EAU guidelines prioritize adjuvant over neoadjuvant treatment 1, 2

• However, a critical caveat exists: renal function declines significantly post-nephroureterectomy, potentially precluding cisplatin-based adjuvant therapy 2

• This creates a clinical dilemma where the guideline recommendation may conflict with practical cisplatin eligibility after surgery 2

Adjuvant Immunotherapy: Limited Role

• Adjuvant nivolumab and pembrolizumab are NOT recommended as first-line options for UTUC specifically, as subgroup analyses from CheckMate-274 and the pembrolizumab trial revealed UTUC patients did not benefit from adjuvant immunotherapy 1, 2

• Nivolumab received EMA approval for adjuvant treatment of muscle-invasive urothelial carcinoma with PD-L1 >1%, but this was primarily based on bladder cancer data (approximately 75% of trial population) 1, 2

• Adjuvant immunotherapy should only be considered for cisplatin-ineligible patients with PD-L1 >1% who decline or cannot receive chemotherapy, acknowledging the limited UTUC-specific benefit 1, 2

Evidence Comparing Neoadjuvant vs Adjuvant Approaches

• Induction (neoadjuvant) chemotherapy plus RNU demonstrated superior overall survival compared to RNU plus adjuvant chemotherapy (HR = 0.58; 95% CI = 0.38–0.89; p = 0.01) in the 2025 EAU meta-analysis 1

• Neoadjuvant chemotherapy achieved pathological downstaging rates of 33-43% and complete response rates of 14-19% in high-grade cT2-T4 disease 1

• Despite this survival advantage for neoadjuvant therapy in node-positive disease, the EAU guidelines maintain their recommendation for adjuvant treatment in the general high-risk population 1, 2

Clinical Algorithm for Decision-Making

Step 1: Assess renal function and cisplatin eligibility pre-operatively

• If adequate renal function and resectable disease, consider neoadjuvant approach despite guideline preference for adjuvant therapy 2

Step 2: For patients proceeding directly to RNU

• Obtain final pathology (pT stage, nodal status, lymphovascular invasion) 2
• High-risk features = pT2-T4 and/or pN+ and/or LVI+ 2

Step 3: Post-RNU assessment

• Reassess renal function and cisplatin eligibility 2
• If cisplatin-eligible: offer adjuvant platinum-based chemotherapy (gemcitabine + cisplatin regimen) 1
• If cisplatin-ineligible with PD-L1 >1%: consider adjuvant immunotherapy (nivolumab or pembrolizumab) with counseling about limited UTUC-specific benefit 1, 2
• If cisplatin-ineligible with PD-L1 <1%: carboplatin-based regimens may be considered as alternative 1

Special Consideration: Node-Positive Disease

• For patients with clinically node-positive (cN+) disease at presentation, induction chemotherapy followed by RNU provides the greatest oncological benefit without increased postoperative complications (HR = 0.52 for overall survival vs RNU alone) 1

• This represents a specific scenario where neoadjuvant approach is clearly superior and should be prioritized in fit patients with resectable disease 1

Common Pitfalls to Avoid

• Do not delay adjuvant chemotherapy assessment: renal function deteriorates rapidly post-RNU, creating a narrow window for cisplatin eligibility 2

• Do not extrapolate bladder cancer immunotherapy data directly to UTUC: the 25% UTUC subgroups in CheckMate-274 and pembrolizumab trials showed no benefit 1, 2

• Do not assume all high-risk features require the same approach: node-positive disease specifically benefits more from neoadjuvant rather than adjuvant strategy 1

• Do not perform lymph node dissection in confirmed Ta/T1 disease: LND is unnecessary given low metastatic risk, though preoperative staging inaccuracy means template-based LND should be offered to all clinically high-risk cases 1, 2