A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial).
BACKGROUND
The most frequent site of metastases from prostate cancer is bone. Bisphosphonates reduce excessive bone turnover while preserving bone structure and mineralization in patients with other tumor types. We conducted a double-blind, placebo-controlled, randomized trial to determine whether the first-generation bisphosphonate sodium clodronate could improve bone progression-free survival (BPFS) times among men with bone metastases from prostate cancer.


METHODS
Between June 1994 and July 1998, 311 men who were starting or responding to first-line hormone therapy for bone metastases were randomly assigned to receive oral sodium clodronate (2080 mg/day) or placebo for a maximum of 3 years. The primary endpoint of the trial was symptomatic BPFS. Secondary endpoints included overall survival, treatment toxicity, and change in World Health Organization (WHO) performance status. Time-to-event data were analyzed using the log-rank chi-square test and Kaplan-Meier curves. All statistical tests were two-sided.


RESULTS
Baseline characteristics were balanced across the two groups. After a median follow-up of 59 months, the sodium clodronate group showed statistically nonsignificant better symptomatic BPFS (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.61 to 1.02; P =.066) and overall survival (HR = 0.80, 95% CI = 0.62 to 1.03; P =.082) than the control group. Patients in the clodronate group were less likely to have a worsened WHO performance status (HR = 0.71, 95% CI = 0.56 to 0.92; P =.008). However, the clodronate group reported more gastrointestinal problems and increased lactate dehydrogenase levels and required more frequent modification of the trial drug dose (HR for any adverse event = 1.71, 95% CI = 1.21 to 2.41; P =.002). Results of subgroup analyses suggested that clodronate might be more effective the sooner after diagnosis of metastatic bone disease it is started.


CONCLUSIONS
These results suggest that further studies of the effect of newer generation bisphosphonates on BPFS in men with metastatic prostate cancer are warranted.
Dearnaley
David P
DP
Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK.
Sydes
Matthew R
MR
Mason
Malcolm D
MD
Stott
Mark
M
Powell
Christopher S
CS
Robinson
Anne C R
AC
Thompson
Peter M
PM
Moffat
Leslie E
LE
Naylor
Sharon L
SL
Parmar
Mahesh K B
MK
D000284:Administration, Oral; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000009:adverse effects; D000726:Androgen Antagonists / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D001859:Bone Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000556:secondary; D004002:Clodronic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D004064:Digestive System / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010146:Pain / Q000209:etiology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012107:Research Design; D016019:Survival Analysis; D016896:Treatment Outcome; D006113:United Kingdom; D000077211:Zoledronic Acid
D018712:Analgesics, Non-Narcotic; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid