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The New England Journal of Medicine Jul 2013Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.
METHODS
In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.
RESULTS
At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.
CONCLUSIONS
In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).
Topics: Aged; Aged, 80 and over; Bone Neoplasms; Double-Blind Method; Humans; Isotopes; Kaplan-Meier Estimate; Male; Middle Aged; Prostatic Neoplasms; Radium
PubMed: 23863050
DOI: 10.1056/NEJMoa1213755 -
European Journal of Nuclear Medicine... May 2018Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic...
Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.
Topics: Bone Neoplasms; Europe; Humans; Male; Practice Guidelines as Topic; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium
PubMed: 29234845
DOI: 10.1007/s00259-017-3900-4 -
JNCI Cancer Spectrum Oct 2023
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Bone Neoplasms; Radium; Magnetic Resonance Imaging
PubMed: 37952210
DOI: 10.1093/jncics/pkad083 -
Journal of Nuclear Medicine : Official... Apr 2023The radium lutetium (RALU) study evaluated the feasibility of sequential α- and β-emitter use in patients with bone-predominant metastatic castration-resistant...
Safety and Survival Outcomes of Lu-Prostate-Specific Membrane Antigen Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer with Prior Ra treatment: The RALU Study.
The radium lutetium (RALU) study evaluated the feasibility of sequential α- and β-emitter use in patients with bone-predominant metastatic castration-resistant prostate cancer. This preplanned interim retrospective analysis investigated safety and survival outcomes with Lu-PSMA in patients treated with prior Ra. Forty-nine patients were evaluated. Patients received a median of 6 Ra injections; 59% of patients received at least 4 Lu-PSMA cycles. Most (69%) patients received at least 4 life-prolonging therapies before Lu-PSMA. Common Terminology Criteria for Adverse Events grade 3-4 treatment-emergent adverse events during Lu-PSMA therapy and a 30-d follow-up period included anemia (18%) and thrombocytopenia (2%). Median overall survival was 12.6 mo (95% CI, 8.8-16.1 mo) and 31.4 mo (95% CI, 25.7-37.6 mo) from starting Lu-PSMA or Ra, respectively. Lu-PSMA treatment was well tolerated in patients who had received prior Ra. Ra use before Lu-PSMA is feasible and can be considered for future assessment of the optimal treatment sequence.
Topics: Male; Humans; Lutetium; Radium; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome; Retrospective Studies; Prostate; Prostate-Specific Antigen; Dipeptides; Heterocyclic Compounds, 1-Ring
PubMed: 36302656
DOI: 10.2967/jnumed.122.264456 -
Annals of Oncology : Official Journal... Feb 2020
Topics: Bone and Bones; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radium
PubMed: 31959332
DOI: 10.1016/j.annonc.2019.12.005 -
International Journal of Radiation... 2022This paper reviews the history of the radium dial workers in the United States, summarizes the scientific progress made since the last evaluation in the early 1990s, and... (Review)
Review
PURPOSE
This paper reviews the history of the radium dial workers in the United States, summarizes the scientific progress made since the last evaluation in the early 1990s, and discusses current progress in updating the epidemiologic cohort and applying new dosimetric models for radiation risk assessment.
BACKGROUND
The discoveries of radiation and radioactivity led quickly to medical and commercial applications at the turn of the 20th century, including the development of radioluminescent paint, made by combining radium with phosphorescent material and adhesive. Workers involved with the painting of dials and instruments included painters, handlers, ancillary workers, and chemists who fabricated the paint. Dial painters were primarily women and, prior to the mid to late 1920s, would use their lips to give the brush a fine point, resulting in high intakes of radium. The tragic experience of the dial painters had a significant impact on industrial safety standards, including protection measures taken during the Manhattan Project. The dial workers study has formed the basis for radiation protection standards for intakes of radionuclides by workers and the public.
EPIDEMIOLOGIC APPROACH
The mortality experience of 3,276 radium dial painters and handlers employed between 1913 and 1949 is being determined through 2019. The last epidemiologic follow-up was 30 years ago when most of these workers were still alive. Nearly 65% were born before 1920, 37.5% were teenagers when first hired, and nearly 50% were hired before 1930 when the habit of placing brushes in mouths essentially stopped. Comprehensive dose reconstruction techniques are being applied to estimate organ doses for each worker related to the intake of Ra, Ra, and associated photon exposures. Time dependent dose-response analyses will estimate lifetime risks for specific causes of death.
DISCUSSION
The study of radium dial workers is part of the Million Person Study of low-dose health effects that is designed to evaluate radiation risks among healthy American workers and veterans. Despite being one of the most important and influential radiation effects studies ever conducted, shifting programmatic responsibilities and declining funding led to the termination of the radium program of studies in the early 1990s. Renewed interest and opportunity have arisen. With scientific progress made in dosimetric methodology and models, the ability to perform a study over the entire life span, and the potential applicability to other scenarios such as medicine, environmental contamination and space exploration, the radium dial workers have once again come to the forefront.
Topics: Adolescent; Female; Humans; Radiation Injuries; Radiation Protection; Radioisotopes; Radiometry; Radium; United States
PubMed: 33900890
DOI: 10.1080/09553002.2021.1917785 -
Annual Review of Biomedical Engineering Jun 2018α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of... (Review)
Review
α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of α-particle emitters, as well as the distinguishing features that make them unique for radiopharmaceutical therapy. We also review the emerging clinical role of α-particle therapy in managing cancer and recent studies on in vitro and preclinical α-particle therapy delivered by antibodies, other small molecules, and nanometer-sized particles. In addition to their unique radiopharmaceutical characteristics, the increased availability and improved radiochemistry of α-particle radionuclides have contributed to the growing recent interest in α-particle radiotherapy. Targeted therapy strategies have presented novel possibilities for the use of α-particles in the treatment of cancer. Clinical experience has already demonstrated the safe and effective use of α-particle emitters as potent tumor-selective drugs for the treatment of leukemia and metastatic disease.
Topics: Actinium; Alpha Particles; Animals; Cell Survival; Clinical Trials as Topic; Drug Carriers; Humans; Kinetics; Leukemia; Nanomedicine; Nanoparticles; Neoplasm Metastasis; Neoplasms; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Radium
PubMed: 29345977
DOI: 10.1146/annurev-bioeng-062117-120931 -
The British Journal of Radiology Aug 2017Radium-223 (Ra) offers a new option for the treatment of bone metastases from prostate cancer. As cancer treatment progresses towards personalization, the potential for... (Review)
Review
Radium-223 (Ra) offers a new option for the treatment of bone metastases from prostate cancer. As cancer treatment progresses towards personalization, the potential for an individualized approach is exemplified in treatments with radiotherapeutics due to the unique ability to image in vivo the uptake and retention of the therapeutic agent. This is unmatched in any other field of medicine. Currently, Ra is administered according to standard fixed administrations, modified according to patient weight. Although gamma emissions comprise only 1% of the total emitted energy, there are increasing reports that quantitative imaging is feasible and can facilitate patient-specific dosimetry. The aim of this article is to review the application of imaging and dosimetry for Ra and to consider the potential for treatment optimization accordingly, in order to ensure clinical and cost effectiveness of this promising agent.
Topics: Bone Neoplasms; Humans; Male; Precision Medicine; Prostatic Neoplasms; Radioisotopes; Radiometry; Radium
PubMed: 28654303
DOI: 10.1259/bjr.20160748 -
Drug Design, Development and Therapy 2017Prostate cancer is the most common malignant disease in men. Several therapeutic agents have been approved during the last 10 years. Among them, radium-223 dichloride... (Review)
Review
Prostate cancer is the most common malignant disease in men. Several therapeutic agents have been approved during the last 10 years. Among them, radium-223 dichloride (Xofigo) is a radioactive isotope that induces irreversible DNA double-strand breaks and consequently tumor cell death. Radium-223 dichloride is a calcium-mimetic agent that specifically targets bone lesions. Radium-223 dichloride has been approved for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases, without known visceral metastases. In this review, first we summarize the interplay between prostate tumor cells and bone microenvironment; then, we discuss radium-223 dichloride mechanism of action and present the results of the available clinical trials and future developments for this new drug.
Topics: Animals; Antineoplastic Agents; Bone Neoplasms; DNA Breaks, Double-Stranded; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Tumor Microenvironment
PubMed: 28919714
DOI: 10.2147/DDDT.S122417 -
Asian Journal of Andrology 2014In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug... (Review)
Review
In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.
Topics: Animals; Bone Neoplasms; Clinical Trials as Topic; Humans; Male; Mice; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radiopharmaceuticals; Radium; Xenograft Model Antitumor Assays
PubMed: 24713838
DOI: 10.4103/1008-682X.127812