BACKGROUND: Preoperative plasma levels of Interleukin 6 (IL6) and its soluble receptor (IL6sR) have previously been associated with oncologic outcomes in urothelial carcinoma of the bladder (UCB); however, external validation in patients treated with radical cystectomy (RC) for UCB is missing. PATIENTS/METHODS: We prospectively collected preoperative plasma from 1,036 consecutive patients at two institutes. These plasma specimens were assessed for levels of IL6 and IL6sR. Logistic and Cox regression analyses were used to assess the correlation of plasma levels with pathologic and survival outcomes. The additional clinical net benefits of preoperative IL6 and IL6sR were evaluated using decision curve analysis (DCA). RESULTS: Median IL6 and IL6sR plasma levels were significantly higher in patients with adverse pathologic features. Elevated biomarker levels were independently associated with an increased risk for lymph node metastasis and ≥ pT3 disease. Both biomarkers were independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The addition to, respectively, fitted pre- and postoperative prognostic models improved the predictive accuracy for lymph node metastasis, ≥ pT3 disease, RFS and CSS on DCA. INTERPRETATION: We confirmed that elevated preoperative plasma levels of IL6 and IL6sR levels are associated with worse oncological disease survival in patients treated with RC for UCB in a large multicenter study. Both biomarkers hold potential in identifying patients with adverse pathological features that may benefit from intensified/multimodal therapy and warrant inclusion into predictive/prognostic models. They demonstrated the ability to improve the discriminatory power of such models and thus guide clinical decision making.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Canada

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

Department of Urology Comprehensive Cancer Center Vienna General Hospital Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Department of Urology Hospital Motol 2nd Faculty of Medicine Charles University Praha Czech Republic

Department of Urology Institut Mutualiste Montsouris Paris France

Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology Luzerner Kantonsspital Lucerne Switzerland

Department of Urology Medical College Jagiellonian University Krakow Poland

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York Presbyterian Hospital New York USA

Division of Urological Surgery and Center for Surgery and Public Health Brigham and Women's Hospital Harvard Medical School Boston MA USA

Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan

European Association of Urology Research Foundation Arnhem Netherlands

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

S H Ho Urology Centre Department of Surgery Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong China

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