title: High-dose calcitriol, zoledronate, and dexamethasone for the treatment of progressive prostate carcinoma.
abstract: BACKGROUND
  Preclinical and clinical data have suggested that high-dose calcitriol (1,25-dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse-dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse-dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression.
  
  
  METHODS
  Patients with progressive prostate carcinoma were eligible for the current study. In cohorts of 3-6 patients, calcitriol was administered for 3 consecutive days per week, starting at a dose of 4 microg per day. Doses were escalated to 30 microg per day. Intravenous zoledronate (4 mg) was administered monthly. Dexamethasone could be added to the regimen at disease progression. Toxicities, markers of bone turnover, plasma calcitriol levels, and clinical outcomes were recorded.
  
  
  RESULTS
  Thirty-one patients were treated in cohorts that were defined by the calcitriol dose administered (4, 6, 8, 10, 14, 20, 24, or 30 microg). Seven patients received dexamethasone. Three patients had their doses reduced due to calcium-related laboratory findings. Patients tolerated therapy well, even in the 30 microg cohort; therefore, a maximum tolerated dose was not defined. Peak plasma levels observed in the 24 microg and 30 microg cohorts ranged from 391 to 968 pg/mL. Minimal antitumor effects were observed.
  
  
  CONCLUSIONS
  Calcitriol was well tolerated at doses up to and including 30 microg 3 times per week in combination with intravenous zoledronate 4 mg monthly, with or without dexamethasone, in patients with progressive prostate carcinoma. Peak plasma levels in the 24 microg and 30 microg cohorts were greater than the levels associated with antitumor effects preclinically. Due to the cumbersome dosing schedule and the lack of significant activity observed, Phase II trials of this regimen are not planned.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. morrism@mskcc.org
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Oren
authors.initials: O
authors.lastname: Smaletz
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.forename: W Kevin
authors.initials: WK
authors.lastname: Kelly
authors.forename: Susan
authors.initials: S
authors.lastname: Slovin
authors.forename: Carlos
authors.initials: C
authors.lastname: Flombaum
authors.forename: Tracy
authors.initials: T
authors.lastname: Curley
authors.forename: Anthony
authors.initials: A
authors.lastname: Delacruz
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schwartz
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.forename: Andrew
authors.initials: A
authors.lastname: Zhu
authors.forename: Meghan
authors.initials: M
authors.lastname: Diani
authors.forename: Mary
authors.initials: M
authors.lastname: Fallon
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002117:Calcitriol / Q000008:administration & dosage*; D002277:Carcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D003907:Dexamethasone / Q000008:administration & dosage*; D004164:Diphosphonates / Q000008:administration & dosage*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020551:Pulse Therapy, Drug; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D003907:Dexamethasone; D002117:Calcitriol