Dataset Information

Retrospective Toxicological Profiling of Radium-223 Dichloride for the Treatment of Bone Metastases in Prostate Cancer Using Adverse Event Data.

ABSTRACT: Background and Objective: Radium-223 dichloride (Xofigo®) is a calcium mimetic agent approved for the treatment of castration-resistant prostate cancer patients with symptomatic bone metastases and no known visceral metastatic disease. This targeted, ?-particle-emitting therapy has demonstrated significant survival benefit accompanied by a favorable safety profile. Nevertheless, recent evidence suggests that its combined use with abiraterone and prednisone/prednisolone may be associated with increased risk of death and fractures. While the precise pathophysiologic mechanisms of these events are not yet clear, collecting evidence from more clinical trials and translational studies is necessary. The aim of our present study is to assess whether accessible sources of patient outcome data can help gain additional clinical insights to radium-223 dichloride's safety profile. Materials and Methods: We performed a retrospective analysis of cases extracted from the FDA Adverse Event Reporting System and characterized side effect occurrence by using reporting ratios. Results: A total of ~1500 prostate cancer patients treated with radium-223 dichloride was identified, and side effects reported with the use of radium-223 dichloride alone or in combination with other therapeutic agents were extracted. Our analysis demonstrates that radium-223 dichloride may often come with hematological-related reactions, and that, when administered together with other drugs, its safety profile may differ. Conclusions: While more prospective studies are needed to fully characterize the toxicological profile of radium-223 dichloride, the present work constitutes perhaps the first effort to examine its safety when administered alone and in combination with other agents based on computational evidence from public real-world post marketing data.

SUBMITTER: Soldatos TG

PROVIDER: S-EPMC6572036 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Retrospective Toxicological Profiling of Radium-223 Dichloride for the Treatment of Bone Metastases in Prostate Cancer Using Adverse Event Data.

Soldatos Theodoros G TG Iakovou Ioannis I Sachpekidis Christos C

Medicina (Kaunas, Lithuania) 20190516 5

Background and Objective: Radium-223 dichloride (Xofigo®) is a calcium mimetic agent approved for the treatment of castration-resistant prostate cancer patients with symptomatic bone metastases and no known visceral metastatic disease. This targeted, α-particle-emitting therapy has demonstrated significant survival benefit accompanied by a favorable safety profile. Nevertheless, recent evidence suggests that its combined use with abiraterone and prednisone/prednisolone may b ...[more]

PMID: 31100964

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Project description:BACKGROUND:Radiation therapy with radium-223 dichloride improves overall survival, reduces symptomatic skeletal events in Caucasian patients with castration-resistant prostate cancer (CRPC) and bone metastases, and is well tolerated. We report here the results of the first efficacy and safety study of radium-223 dichloride in a Japanese population. METHODS:In this open-label, uncontrolled, non-randomized, phase I trial, radium-223 dichloride was given to Japanese patients with CRPC and ?2 bone metastases in 4-week cycles. The patients were divided into three cohorts, with cohort 1 and the expansion cohort receiving injections of radium-223 dichloride [55 kBq/kg body weight (BW)] every 4 weeks (Q4W) for up to six injections, and cohort 2 receiving an initial single radium-223 dichloride injection of 110 kBq/kg BW followed by up to five injections of 55 kBq/kg BW Q4W. Safety was determined via adverse event (AE) reporting, and biochemical bone markers were assessed for treatment efficacy. RESULTS:In total 19 patients received at least one dose of radium-223 dichloride and 18 patients experienced at least one treatment-emergent AE (TEAE) of which the most common were anemia, thrombocytopenia, and lymphocytopenia. Serious AEs were reported in three patients but none were drug-related. In the patients of cohort 1 + expansion cohort (55 kBq/kg BW Q4W treatment; n = 16), prostate-specific antigen levels remained stable or slightly increased while the bone alkaline phosphatase (ALP) level significantly decreased. The response rates of bone ALP (?30 and ?50% reductions) were 81.8 and 36.4% at week 12, and 81.3 and 50.0% at the end of treatment. CONCLUSIONS:Radium-223 dichloride was well tolerated in these Japanese patients and, at a dose of 55 kBq/kg BW, efficacy on biomarkers was as expected. The outcomes in Japanese patients were consistent with those reported in other non-Japanese populations. TRIAL REGISTRATION:ClinicalTrials.gov record NCT01565746.

Project description:BACKGROUND:Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium-223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after radium-223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following radium-223. METHODS:In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2:1 to receive six injections of radium-223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed. RESULTS:Overall, 142 radium-223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% radium-223, 72% placebo) and mitoxantrone (16% radium-223, 20% placebo). The majority of patients (61% radium-223, 58% placebo) had received prior docetaxel. Radium-223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In radium-223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3-4 hematologic values (<10%). Platelet count decline, from last measurement before chemotherapy, was numerically greater in radium-223 versus placebo patients. Median overall survivals from start of chemotherapy were 16.0 and 15.8 months following radium-223 and placebo, respectively. CONCLUSIONS:Chemotherapy following radium-223, regardless of prior docetaxel, is feasible and appears to be well tolerated in patients with CRPC and symptomatic bone metastases. Prostate 76:905-916, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

Project description:BackgroundHormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo.MethodsThe US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer.ResultsA 44-year-old white woman with metastatic breast cancer who was estrogen receptor-positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in (18)F-FDG PET/CT and (18)F-NaF bone PET/CT. The patient derived clinical benefit from therapy.ConclusionWe have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA-approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer. A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.

Dataset Information

Retrospective Toxicological Profiling of Radium-223 Dichloride for the Treatment of Bone Metastases in Prostate Cancer Using Adverse Event Data.

Publications

Retrospective Toxicological Profiling of Radium-223 Dichloride for the Treatment of Bone Metastases in Prostate Cancer Using Adverse Event Data.

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