title: Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study.
abstract: BACKGROUND
  The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra.
  
  
  METHODS
  Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat.
  
  
  RESULTS
  Median relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression).
  
  
  CONCLUSIONS
  (223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers.
authors.affiliation: Karolinska Hospital, Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Nilsson
authors.forename: Lars
authors.initials: L
authors.lastname: Franzén
authors.forename: Christopher
authors.initials: C
authors.lastname: Parker
authors.forename: Christopher
authors.initials: C
authors.lastname: Tyrrell
authors.forename: René
authors.initials: R
authors.lastname: Blom
authors.forename: Jan
authors.initials: J
authors.lastname: Tennvall
authors.forename: Bo
authors.initials: B
authors.lastname: Lennernäs
authors.forename: Ulf
authors.initials: U
authors.lastname: Petersson
authors.forename: Dag C
authors.initials: DC
authors.lastname: Johannessen
authors.forename: Michael
authors.initials: M
authors.lastname: Sokal
authors.forename: Katharine
authors.initials: K
authors.lastname: Pigott
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Yachnin
authors.forename: Michael
authors.initials: M
authors.lastname: Garkavij
authors.forename: Peter
authors.initials: P
authors.lastname: Strang
authors.forename: Johan
authors.initials: J
authors.lastname: Harmenberg
authors.forename: Bjørg
authors.initials: B
authors.lastname: Bolstad
authors.forename: Oyvind S
authors.initials: OS
authors.lastname: Bruland
mesh_terms: D000230:Adenocarcinoma / Q000532:radiotherapy / Q000556:secondary; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D001859:Bone Neoplasms / Q000532:radiotherapy* / Q000556:secondary; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011379:Prognosis; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D011883:Radium / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D010919:Placebos; D000469:Alkaline Phosphatase; D017430:Prostate-Specific Antigen; D011883:Radium