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      Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer

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          Abstract

          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. 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. 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. 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.).

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          Most cited references14

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          Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates.

          Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy. Eligible patients had histologically confirmed malignancy, > or = 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks. Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P < .001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P = .01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups. Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.
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            Estimating clinically meaningful changes for the Functional Assessment of Cancer Therapy--Prostate: results from a clinical trial of patients with metastatic hormone-refractory prostate cancer.

            To determine clinically meaningful changes (CMCs) for the Functional Assessment of Cancer Therapy-Prostate (FACT-P). We obtained data from a Phase III trial of atrasentan in metastatic hormone-refractory prostate cancer patients (n = 809). We determined anchor-based differences using Karnofsky Performance Status (KPS), bone alkaline phosphatase (BAP), hemoglobin, time to disease progression (TTP), adverse events (AE), and survival. One-third and one-half standard deviation and standard error of measurement (SEM) were used as distribution-based criteria for CMCs. Comparison across baseline FACT-P domains and derived scales [FACT-P total score, Trial Outcome Index (TOI) score, prostate cancer subscale (PCS) score, pain-related score, and FACT Advanced Prostate Symptom Index (FAPSI)] were conducted for KPS, BAP, and hemoglobin using Student's t tests. Twelve-week change scores were compared for TTP, AE, and survival using ANCOVA. CMCs were estimated as 6 to 10 for FACT-P total score, 5 to 9 for FACT-P TOI score, 2 to 3 for FACT-P PCS, 1 to 2 for the 4 PCS pain-related questions, and 2 to 3 for FAPSI. CMCs were also estimated using distribution-based criteria. Kappa statistics were computed to determine the degree of correspondence between the recommended guideline of 1.0 SEM and empirically derived standards. Most of the kappas for health-related quality of life domains and SEM standards had "substantial" to "almost perfect" concordance. The significant relationship between clinical and quality of life data provides support for the use of CMCs to increase interpretability of FACT-P scores.
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              Radioisotopes for the palliation of metastatic bone cancer: a systematic review.

              Strontium-89 and samarium-153 are radioisotopes that are approved in the USA and Europe for the palliation of pain from metastatic bone cancer, whereas rhenium-186 and rhenium-188 are investigational. Radioisotopes are effective in providing pain relief with response rates of between 40% and 95%. Pain relief starts 1-4 weeks after the initiation of treatment, continues for up to 18 months, and is associated with a reduction in analgesic use in many patients. Thrombocytopenia and neutropenia are the most common toxic effects, but they are generally mild and reversible. Repeat doses are effective in providing pain relief in many patients. The effectiveness of radioisotopes can be greater when they are combined with chemotherapeutic agents such as cisplatin. Some studies with 89Sr and 153Sm indicate a reduction of hot spots on bone scans in up to 70% of patients, and suggest a possible tumoricidal action. Further studies are needed to address the questions of which isotope to use, what dose and schedule to use, and which patients will respond.
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                Massachusetts Medical Society
                0028-4793
                1533-4406
                July 18 2013
                July 18 2013
                : 369
                : 3
                : 213-223
                Article
                10.1056/NEJMoa1213755
                23863050
                ae1f7ebe-36e0-432f-9177-77e9d7a118e8
                © 2013
                History
                Product
                Self URI (article page): http://www.nejm.org/doi/10.1056/NEJMoa1213755

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