title: A biopsy-integrated algorithm for determining Gleason 6 upgrading risk stratifies risk of active surveillance failure in prostate cancer.
abstract: BACKGROUND
  A significant proportion of patients that fail active surveillance (AS) for prostate cancer management do so because of cancer upgrading. A previously validated upgrading nomogram generates a score that predicts risk of biopsy Gleason 6 upgrading following radical prostatectomy in lower-risk populations that are candidates for Active Surveillance (Cancer, 2013).
  
  
  OBJECTIVE
  We hypothesize that the upgrading risk (UR) score generated by this nomogram at diagnosis improves the ability to predict patients that will subsequently fail AS.
  
  
  METHODS
  To evaluate the nomogram, retrospective data from several institutional cohorts of patients who met AS criteria, group 1 (n = 75) and group 2 (n = 1230), were independently examined. A UR score was generated using the coefficients from the nomogram consisting of PSA density (PSAD), BMI, maximum % core involvement (MCI), and number of positive cores. AS failure was defined as Gleason score (GS) >6, >50 % maximum core involvement, or >2 positive cores on biopsy. Univariate and multivariate Cox proportional-hazards regression models, upgrading risk score, and other clinicopathologic features were each assessed for their ability to predict AS failure.
  
  
  RESULTS
  Clinicopathologic parameters were similar in both groups with the exception of mean PSAD (0.13 vs. 0.11, p < 0.01) and follow-up (2.1 vs. 3.2 years, p = 0.2). Most common cause of AS failure was GS > 6 (group 1) compared to >2 positive cores (group 2). On univariate analysis in both populations, features at diagnosis including PSAD and the UR score were significant in predicting AS failure by upgrading (Gleason > 6) and any failure. Multivariate analysis revealed the UR score predicts AS failure by GS upgrading (HR 1.8, 95 % CI 1.12-2.93; p = 0.01) and any failure criteria (HR 1.7, 95 % CI 1.06-2.65); p = 0.02) for group 1. Likewise, the UR score in group 2 predicts AS failure with GS upgrading (HR 1.3, 95 % CI 1.15-1.42; p < 0.0001) and any failure criteria (HR 1.18, 95 % CI 1.18-1.38; p < 0.0001). An ROC generated an AUC of 0.66. Decision curve analysis demonstrated a high net benefit for the UR score across a range of threshold probabilities. Based on these outcomes, at 3 years, patients in the lowest risk quartile have a 15 % risk of AS failure versus a 46 % risk in the highest quartile (p < 0.0001).
  
  
  CONCLUSIONS
  The UR score was predictive of pathologic AS failure on multivariate analysis in several AS cohorts. It outperformed single clinicopathologic criteria and may provide a useful adjunct using clinicopathologic data to stratify patients considering AS.
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Madison, WI, 53705, USA.|University of Wisconsin Carbone Comprehensive Cancer Center, 1111 Highland Ave, Madison, WI, 53705, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Blute
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Madison, WI, 53705, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Shiau
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Madison, WI, 53705, USA.|Department of Urology, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY, 14642, USA.
authors.forename: M
authors.initials: M
authors.lastname: Truong
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Madison, WI, 53705, USA.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Madison, WI, 53705, USA.|University of Wisconsin Carbone Comprehensive Cancer Center, 1111 Highland Ave, Madison, WI, 53705, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Abel
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Madison, WI, 53705, USA.|University of Wisconsin Carbone Comprehensive Cancer Center, 1111 Highland Ave, Madison, WI, 53705, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Downs
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Madison, WI, 53705, USA. jarrard@urology.wisc.edu.|University of Wisconsin Carbone Comprehensive Cancer Center, 1111 Highland Ave, Madison, WI, 53705, USA. jarrard@urology.wisc.edu.|Environmental and Molecular Toxicology, University of Wisconsin, 1400 University Ave, Madison, WI, 53706, USA. jarrard@urology.wisc.edu.
authors.forename: D F
authors.initials: DF
authors.lastname: Jarrard
mesh_terms: D000367:Age Factors; D000368:Aged; D000465:Algorithms; D062005:Biopsy, Large-Core Needle; D015992:Body Mass Index; D015331:Cohort Studies; D019468:Disease Management; D006801:Humans; D007610:Kallikreins / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000473:pathology* / Q000628:therapy; D012189:Retrospective Studies; D018570:Risk Assessment; D057832:Watchful Waiting
chemical_list: C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Active surveillance; Nomogram; Prostate cancer; Survival