title: Very-high-risk localized prostate cancer: definition and outcomes.
abstract: BACKGROUND
  Outcomes in men with National Comprehensive Cancer Network (NCCN) high-risk prostate cancer (PCa) can vary substantially-some will have excellent cancer-specific survival, whereas others will experience early metastasis even after aggressive local treatments. Current nomograms, which yield continuous risk probabilities, do not separate high-risk PCa into distinct sub-strata. Here, we derive a binary definition of very-high-risk (VHR) localized PCa to aid in risk stratification at diagnosis and selection of therapy.
  
  
  METHODS
  We queried the Johns Hopkins radical prostatectomy database to identify 753 men with NCCN high-risk localized PCa (Gleason sum 8-10, PSA >20 ng ml(-1), or clinical stage ≥T3). Twenty-eight alternate permutations of adverse grade, stage and cancer volume were compared by their hazard ratios for metastasis and cancer-specific mortality. VHR criteria with top-ranking hazard ratios were further evaluated by multivariable analyses and inclusion of a clinically meaningful proportion of the high-risk cohort.
  
  
  RESULTS
  The VHR cohort was best defined by primary pattern 5 present on biopsy, or ≥5 cores with Gleason sum 8-10, or multiple NCCN high-risk features. These criteria encompassed 15.1% of the NCCN high-risk cohort. Compared with other high-risk men, VHR men were at significantly higher risk for metastasis (hazard ratio 2.75) and cancer-specific mortality (hazard ratio 3.44) (P<0.001 for both). Among high-risk men, VHR men also had significantly worse 10-year metastasis-free survival (37% vs 78%) and cancer-specific survival (62% vs 90%).
  
  
  CONCLUSIONS
  Men who meet VHR criteria form a subgroup within the current NCCN high-risk classification who have particularly poor oncological outcomes. Use of these characteristics to distinguish VHR localized PCa may help in counseling and selection optimal candidates for multimodal treatments or clinical trials.
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sundi
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Wang
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Pierorazio
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Han
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Bivalacqua
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Ball
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Partin
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Schaeffer
authors.affiliation: Brady Institute of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Ross
mesh_terms: D001706:Biopsy; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy
chemical_list: D017430:Prostate-Specific Antigen