title: Radium-223 in the treatment of osteoblastic metastases: a critical clinical review.
abstract: The element radium (Ra) was discovered by the Curies in 1898 and within a decade was in broad scientific testing for the management of several forms of cancer. The compound was known to give rise to a series of both high-energy particulate and penetrating γ-emissions. The latter found an important role in early 20th century brachytherapy applications, but the short-range α-particles seemed much less useful. Although highly cytotoxic when released within a few cell diameters of critical cell nuclei, the dense double-strand break damage was poorly repaired, and concerns regarding treatment-related toxicities and secondary malignancies halted clinical development. Moreover, the most common isotope of Ra has an exceptionally long half-life (>1600 years for (226)Ra) that proved daunting when aiming for a systemic cancer therapy. Fortunately, other radium isotopes have more convenient half-lives while still producing cytotoxic α particles. Radium-223 dichloride has a half-life of 11.4 days, and this isotope was identified as an excellent candidate for radionuclide therapy of cancers metastatic to bone. The calcium-mimetic chemical properties of the radium allowed intravenous infusion with rapid uptake to sites of new bone formation. The highly efficient bone localization suggested a potential therapeutic role for osteoblastic bone metastases, and a series of phase 1, 2, and 3 clinical trials was undertaken to explore this possibility. This series of clinical explorations culminated in the ALSYMPCA trial, an international, placebo-controlled, phase 3 study that accrued 921 symptomatic men with bone-metastatic, castrate-resistant prostate cancer. Results of this trial demonstrated a prolongation of overall survival, and regulatory agencies around the world have now approved this product as a treatment for advanced prostate cancer.
authors.affiliation: Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: John L
authors.initials: JL
authors.lastname: Humm
authors.affiliation: Departments of Medicine and Urology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.affiliation: Department of Clinical Oncology, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Parker
authors.affiliation: Department of Oncology, Norwegian Radium Hospital and Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Oyvind S
authors.initials: OS
authors.lastname: Bruland
authors.affiliation: Department of Radiation Oncology, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio. Electronic address: rmmacklis@gmail.com.
authors.forename: Roger
authors.initials: R
authors.lastname: Macklis
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D001610:Beta Particles / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D001943:Breast Neoplasms / Q000532:radiotherapy; D002986:Clinical Trials as Topic; D017326:Clinical Trials, Phase III as Topic; D003106:Colon / Q000000981:diagnostic imaging / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D005260:Female; D041981:Gastrointestinal Tract / Q000000981:diagnostic imaging / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000532:radiotherapy; D016609:Neoplasms, Second Primary / Q000209:etiology; D010012:Osteogenesis / Q000528:radiation effects; D012516:Osteosarcoma / Q000532:radiotherapy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011870:Radiologic Health; D011877:Radionuclide Imaging; D011883:Radium / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D012062:Relative Biological Effectiveness; D014018:Tissue Distribution
chemical_list: D011868:Radioisotopes; C581106:radium Ra 223 dichloride; D011883:Radium