title: Very High-Risk Localized Prostate Cancer: Outcomes Following Definitive Radiation.
abstract: OBJECTIVE
  Existing definitions of high-risk prostate cancer consist of men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of National Comprehensive Cancer Network (NCCN) high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multiple NCCN high-risk factors, primary Gleason pattern 5 disease and/or ≥5 biopsy cores with Gleason sums of 8 to 10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients.
  
  
  METHODS
  All men consecutively treated with definitive radiation by a single provider from 1993 to 2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 patients (34%) with VHR disease. Multivariate-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariate-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men.
  
  
  RESULTS
  Men with VHR disease compared to other NCCN high-risk men experienced a higher 10-year incidence of BF (54.0% vs 35.4%, respectively, P<.001), DM (34.9% vs 13.4%, respectively, P<.001), PCSM (18.5% vs 5.9%, respectively, P<.001), and OM (36.4% vs 27.0%, respectively, P=.04). VHR men with a detectable prostate-specific antigen (PSA) concentration at the end of radiation (EOR) remained at high risk of 10-year PCSM compared to VHR men with an undetectable EOR PSA (31.0% vs 13.7%, respectively, P=.05).
  
  
  CONCLUSIONS
  NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be explored further, as should novel agents.
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Amol K
authors: AK
authors: Narang
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Carol
authors: C
authors: Gergis
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Scott P
authors: SP
authors: Robertson
authors: Department of Statistics, Stanford University, Palo Alto, California.
authors: Pei
authors: P
authors: He
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Ashwin N
authors: AN
authors: Ram
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Todd R
authors: TR
authors: McNutt
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Emily
authors: E
authors: Griffith
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Theodore A
authors: TA
authors: DeWeese
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Stephanie
authors: S
authors: Honig
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Harleen
authors: H
authors: Singh
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Danny Y
authors: DY
authors: Song
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Phuoc T
authors: PT
authors: Tran
authors: Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: deweese@jhmi.edu.
authors: Theodore L
authors: TL
authors: DeWeese
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D007987:Gonadotropin-Releasing Hormone / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011467:Prostate / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy / Q000401:mortality; D011471:Prostatic Neoplasms / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy; D020266:Radiotherapy, Conformal / Q000379:methods / Q000401:mortality; D012044:Regression Analysis; D012306:Risk; D017211:Treatment Failure
chemical_list: D000726:Androgen Antagonists; D007987:Gonadotropin-Releasing Hormone; D017430:Prostate-Specific Antigen