Benefit and Harms of Radical Nephroureterectomy as Part of a Multimodal Treatment Strategy for Upper Tract Urothelial Carcinoma Patients Presenting with Clinical Evidence of Regional Lymph Node Metastasis: A Systematic Review and Meta-analysis by the European Association of Urology Guidelines

BACKGROUND AND OBJECTIVE: Given the uncertainty regarding the role of radical nephroureterectomy (RNU) as part of a multimodal treatment strategy for upper tract urothelial carcinoma (UTUC) patients with cN+ disease, we aimed to perform a systematic review and meta-analysis of the corresponding literature. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we identified 17 observational comparative and noncomparative studies, published between January 2000 and September 2024, evaluating UTUC patients with cTanyN+M0 disease (P) who received RNU as part of a multimodal treatment strategy (I), as compared with any treatment strategy if applicable (C), to assess oncological or postoperative outcomes (O). Meta-analyses were further performed, as appropriate. KEY FINDINGS AND LIMITATIONS: Overall, 15 studies evaluated the effectiveness of adding chemotherapy to RNU in the perioperative setting without specifying the exact timing of delivery (n = 1), in the induction setting (n = 14), or in the adjuvant setting (n = 5), while two studies evaluated the effectiveness of adding RNU to chemotherapy. Meta-analyses showed that the use of induction chemotherapy plus RNU versus RNU alone was associated with greater odds of pathological downstaging (risk ratio [RR] = 3.06; 95% confidence interval [CI] = [2.48-3.77]; p < 0.001; I² = 0%; p = 0.44) and pathological complete nodal response (RR = 2.80; 95% CI = [2.03-3.86]; p < 0.001; I² = 0%; p = 0.47) as well as prolonged overall survival (HR = 0.52; 95% CI = [0.42-0.64]; p < 0.001; I² = 14%; p = 0.33) without any significant impact on the risk of overall (RR = 1.14; 95% CI = [0.79-1.64]; p = 0.48; I² = 0%; p = 0.76) and major (RR = 0.48; 95% CI = [0.18-1.24]; p = 0.13; I² = 0%; p = 0.87) postoperative complications. In addition, the use of induction chemotherapy plus RNU versus RNU plus adjuvant chemotherapy (HR = 0.58; 95% CI = [0.38-0.89]; p = 0.01) or chemotherapy alone (HR = 0.49; 95% CI = [0.32-0.76]; p = 0.001; I² = 46%; p = 0.17) was associated with prolonged overall survival. Limitations include the observational design of all included studies. CONCLUSIONS AND CLINICAL IMPLICATIONS: The use of RNU could provide the greatest oncological benefits without any significant harm in selected UTUC patients with fit general condition and resectable cN+ disease responding to induction chemotherapy. PATIENT SUMMARY: In this report, we looked at the outcomes of radical surgery in combination with systemic chemotherapy for upper tract urothelial carcinoma with clinical evidence of dissemination to the surrounding lymph nodes. We observed that the use of radical surgery was associated with the greatest oncological benefits without any increased risk of postoperative complications in patients with fit general condition and resectable disease responding to induction chemotherapy. We conclude that the use of induction chemotherapy plus radical surgery could be the best multimodal treatment strategy for these patients.