Radical nephroureterectomy (RNU) with bladder cuff excision is a standard of care in patients with high-risk upper tract urothelial carcinoma (UTUC). Although several recommendations and guidelines on the delayed treatment of urologic cancers exist, the evidence on UTUC is scarce and ambiguous. The present systematic review aimed to summarize the available evidence on the survival outcomes after deferred RNU in patients with UTUC. A systematic literature search of the three electronic databases (PubMed, Embase, and Cochrane Library) was conducted until 30 April 2022. Studies were found eligible if they reported the oncological outcomes of patients treated with deferred RNU compared to the control group, including those patients treated with RNU without delay. Primary endpoints were cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS). In total, we identified seven eligible studies enrolling 5639 patients. Significant heterogeneity in the definition of "deferred RNU" was found across the included studies. Three out of five studies reporting CSS showed that deferring RNU was associated with worse CSS. Furthermore, three out of four studies reporting OS found a negative impact of delay in RNU on OS. One out of three studies reporting RFS found a negative influence of delayed RNU on RFS. While most studies reported a 3 month interval as a significant threshold for RNU delay, some subgroup analyses showed that a safe delay for RNU was less than 1 month in patients with ureteral tumors (UT) or less than 2 months in patients with hydronephrosis. In conclusion, long surgical waiting time for RNU (especially more than 3 months after UTUC diagnosis) could be considered as an important risk factor having a negative impact on oncological outcomes in patients with UTUC; however, the results of the particular studies are still inconsistent. The safe delay for RNU might be shorter in specific subsets of high-risk patients, such as those with UT and/or hydronephrosis at the time of diagnosis. High-quality additional studies are required to establish evidence for valid recommendations.

Department of General Minimally Invasive and Endocrine Surgery Wroclaw Medical University 50 556 Wroclaw Poland

Department of Maternal Infant and Urological Sciences Policlinico Umberto 1 Hospital Sapienza Rome University 00185 Rome Italy

Department of Minimally Invasive and Robotic Urology University Center of Excellence in Urology Wroclaw Medical University 50 556 Wroclaw Poland

Department of Urology 2nd Faculty of Medicine Charles University 15006 Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Urology Medical University of Silesia 41 800 Zabrze Poland

Department of Urology The Jikei University School of Medicine Tokyo 105 8461 Japan

Department of Urology University of Texas Southwestern Dallas TX 75390 USA

Department of Urology Weill Cornell Medical College New York NY 10021 USA

Division of Experimental Oncology Department of Urology Urological Research Institute Vita Salute San Raffaele University 20132 Milan Italy

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman 19328 Jordan

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University 119435 Moscow Russia

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