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.

Department of Medicine London Health Science Centre Western University London Ontario Canada

Department of Pathology Medical University of Vienna Vienna Austria

Department of Surgical Oncology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Urology APHP Saint Louis Hospital Université de Paris Paris France

Department of Urology Bichat Claude Bernard Hospital Assistance Publique Hôpitaux de Paris Université de Paris Cité Paris France

Department of Urology Città della Salute e della Scienza University of Torino School of Medicine Torino Italy

Department of Urology Comprehensive Cancer Center Vienna General Hospital Medical University Vienna Vienna Austria

Department of Urology Freeman Hospital The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

Department of Urology Fundación Instituto Valenciano de Oncología Valencia Spain

Department of Urology General University Hospital and 1st Faculty of Medicine Charles University Praha Prague Czech Republic

Department of Urology San Raffaele Hospital and Scientific Institute Milan Italy

Department of Urology Skåne University Hospital Malmö Sweden

Department of Urology The Stokes Centre for Urology Royal Surrey Hospital Guildford UK

Department of Urology UROSUD La Croix Du Sud Hospital Quint Fonsegrives France

Edinburgh Bladder Cancer Surgery Western General Hospital The University of Edinburgh Edinburgh UK

GRC 5 Predictive Onco Urology Department of Urology Pitié Salpêtrière Hospital AP HP Sorbonne University Paris France

Rosemere Cancer Centre Lancashire Teaching Hospitals NHS Foundation Trust Preston UK

S H Ho Urology Centre Department of Surgery Faculty of Medicine The Chinese University of Hong Kong Hong Kong China

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