High-dose calcitriol, zoledronate, and dexamethasone for the treatment of progressive prostate carcinoma.
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.
Morris
Michael J
MJ
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. morrism@mskcc.org
Smaletz
Oren
O
Solit
David
D
Kelly
W Kevin
WK
Slovin
Susan
S
Flombaum
Carlos
C
Curley
Tracy
T
Delacruz
Anthony
A
Schwartz
Lawrence
L
Fleisher
Martin
M
Zhu
Andrew
A
Diani
Meghan
M
Fallon
Mary
M
Scher
Howard I
HI
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
D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D003907:Dexamethasone; D002117:Calcitriol