title: Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer.
abstract: OBJECTIVE
  In patients with a rising prostate-specific antigen (PSA) level during treatment with androgen deprivation therapy, identification of men who progress to bone metastasis and death remains problematic. Accurate risk stratification models are needed to better predict risk for bone metastasis and death among patients with castration-resistant prostate cancer (CRPC). This study evaluates whether alkaline phosphatase (AP) kinetics predicts bone metastasis and death in patients with CRPC.
  
  
  METHODS
  A retrospective cohort study of 9,547 patients who underwent treatment for prostate cancer was conducted using the Center for Prostate Disease Research Multi-center National Database. From the entire cohort, 347 were found to have CRPC and, of those, 165 had 2 or more AP measurements during follow-up. To determine the AP velocity (APV), the slope of the linear regression line of all AP values was plotted over time. Rapid APV was defined as the uppermost quartile of APV values, which was found to be ≥6.3 IU/l/y. CRPC was defined as 2 consecutive rising PSA values after achieving a PSA nadir<4 ng/ml and documented testosterone values less than 50 ng/dl. The primary study outcomes included bone metastasis-free survival (BMFS) and overall survival (OS).
  
  
  RESULTS
  Rapid APV and PSA doubling time (PSADT) less than 10 months were strong predictors of both BMFS and OS in a multivariable analysis. Faster PSADT was a stronger predictor for BMFS (odds ratio [OR] = 12.1, P<0.0001 vs. OR = 2.7, P = 0.011), whereas rapid APV was a stronger predictor of poorer OS (OR = 5.11, P = 0.0001 vs. OR = 3.98, P = 0.0034). In those with both a rapid APV and a faster PSADT, the odds of developing bone metastasis and death exceeded 50%.
  
  
  CONCLUSIONS
  APV is an independent predictor of OS and BMFS in patients with CRPC. APV, in conjunction with PSA-based clinical parameters, may be used to better identify patients with CRPC who are at the highest risk of metastasis and death. These findings need validation in prospective studies.
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD. Electronic address: adam.metwalli@nih.gov.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Metwalli
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Inger L
authors.initials: IL
authors.lastname: Rosner
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cullen
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Timothy
authors.initials: T
authors.lastname: Brand
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Brassell
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: James
authors.initials: J
authors.lastname: Lesperance
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Christopher
authors.initials: C
authors.lastname: Porter
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sterbis
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: David G
authors.initials: DG
authors.lastname: McLeod
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism*; D000726:Androgen Antagonists / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000556:secondary; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000032:analysis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000726:Androgen Antagonists; D000469:Alkaline Phosphatase; D017430:Prostate-Specific Antigen
keywords: Alkaline phosphatase; Alkaline phosphatase velocity (APV); Bone metastasis; Bone metastasis–free survival; Overall survival; PSA doubling time (PSADT); Prostate cancer; Prostate-specific antigen (PSA)