BACKGROUND: To assess the association between of type and number of D'Amico high-risk criteria (DHRCs) with rates of cancer-specific mortality (CSM) in prostate cancer (PCa) patients treated with external beam radiotherapy (RT). METHODS: In the Surveillance, Epidemiology, and End Results database (2004-2016), we identified 34,908 RT patients with at least one DHRCs, namely prostate-specific antigen (PSA) >20 ng/dL (hrPSA), biopsy Grade Group (hrGG) 4-5, clinical T stage (hrcT) ≥T2c. Multivariable Cox regression models (CRM), as well as competing risks regression (CRR) model, which further adjust for other cause mortality, tested the association between DHRCs and 5-year CSM. RESULTS: Of 34,908 patients, 14,777 (42%) exclusively harbored hrGG, 5641 (16%) hrPSA, 4390 (13%) had hrcT. Only 8238 (23.7%) harbored any combination of two DHRCs and 1862 (5.3%) had all three DHRCs. Five-year CSM rates ranged from 2.4% to 5.0% when any individual DHRC was present (hrcT, hrPSA, hrGG, in that order), versus 5.2% to 10.5% when two DHRCs were present (hrPSA+hrcT, hrcT+hrGG, hrPSA+hrGG, in that order) versus 14.4% when all three DHRCs were identified. In multivariable CRM hazard ratios relative to hrcT ranged from 1.07 to 1.76 for one DHRC, 2.20 to 3.83 for combinations of two DHRCs, and 5.11 for all three DHRCs. Multivariable CRR yielded to virtually the same results. CONCLUSIONS: Our study indicates a stimulus-response effect according to the type and number of DHRCs. This indicates potential for risk-stratification within HR PCa patients that could be applied in clinical decision making to increase or reduce treatment intensity.

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

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

Department of Surgical and Diagnostic Integrated Sciences University of Genova Genova Italy

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

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

Department of Urology University Hospital Frankfurt Frankfurt am Main Germany

Department of Urology University of Texas Southwestern Dallas Texas USA

Departments of Urology Weill Cornell Medical College New York City New York USA

Division of Experimental Oncology Unit of Urology URI Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

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

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

IRCCS Ospedale Policlinico San Martino Genova Italy

Martini Klinik Prostate Cancer Center University Hospital Hamburg Eppendorf Hamburg Germany

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