Single-centre Experience of Use of Radium 223 with Clinical Outcomes Based on Number of Cycles and Bone Marrow Toxicity

Abstract

Background: Bone is the most common site of metastatic disease in advanced prostate cancer. Radium-223 (223 Ra) is a calcium-mimetic alpha-particle emitter, which has been shown to have activity in prostate cancer with clinical benefit in patients with symptomatic bone metastasis. The recommended schedule is six cycles of 223 Ra, 5 kBq/kg, at 4-weekly intervals. Although previous studies have assessed clinical outcomes in patients who received six cycles of Ra 223 , there is very little information about outcomes of patients receiving fewer courses of treatment. Patients and Methods: Patients with hormone-refractory metastatic prostate cancer treated from May 2014 to August 2016 were included in this retrospective study. A total of 113 patients were identified with a median age of 76 (range=52-92) years. The median number of cycles administered was 5 (range=1-6) with 54 (48%) completing six cycles of treatment. Eighty-five patients (75%) received 223 Ra prior to docetaxel chemotherapy and 28 (25%) received it after receiving docetaxel. Results: Eleven patients developed grade 2/3 thrombocytopenia, and none of these received further 223 Ra. Only 25% of patients who had a haemoglobin level of 10 g/dl or below at the start of the treatment were able to complete six courses of 223 Ra. Of the patients who completed fewer than six cycles of 223 Ra (1-5 cycles), the survival was 121 days, compared to 398 days in men who received six cycles (odds ratio(OR)=4.767, 95% confidence internal(CI)=1.07-21.25; p=0.0005). Conclusion: Careful selection of patients is essential to obtain good clinical outcomes from 223 Ra therapy. When fewer than six cycles were delivered then a beneficial survival effect was not seen. Prostate cancer is the second most common cancer in men, with a worldwide incidence of 1.1 million new cases/year (1, 2). The treatment of metastatic prostate cancer has evolved with the use of docetaxel chemotherapy and third-generation endocrine agents such as abiraterone and enzalutamide (3-7). Since the first trials with mitoxantrone plus prednisolone, numerous agents have been found to improve outcomes for patients with this disease. Bone is the most common site of metastasis in prostate cancer and leads to an increased risk of skeletal-related events which include pathological fractures, spinal cord/nerve root compression, limited mobility, increased morbidity, hypercalcaemia, increased pain and dependence on opioids. These can have a serious impact on quality of life and in turn affect survival in patients with advanced disease (8, 9). Newer bone-targeted therapies with different mechanisms of action, such as zolendronate and denosumab, are significant additions to the management of prostate cancer (10). Radium-223 (223 Ra) is a first in its class calcium-mimetic alpha-particle emitter which has been shown to have activity in prostate cancer, with clinical benefit in patients with symptomatic bone metastasis. It has a half-life of 11.43 days and is taken up preferentially in areas of high bone turnover, partic...

α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [223Ra]RaCl2-treated prostate cancer patients

“…223 Ra treatment of castration-resistant prostate cancer patients has been observed to prolong lives of patients [ 4 , 5 ]. It can lead to prolonged internal irradiation of bone, blood, and other organs [ 10 , 11 ], which may induce hematotoxicity [ 11 , 25 ]. The bone-seeking properties of 223 Ra lead to exposure of the bone marrow and the exposure to α-emitters can lead to DNA damage [ 8 , 9 ] and complex chromosome aberrations [ 6 , 7 ].…”

Quantifying the survival benefit of completing all the six cycles of radium-223 therapy in patients with castrate-resistant prostate cancer with predominant bone metastases

“…Two UK and a single Canadian studies looked at the effect of completing at least five cycles of treatment and similar to our results, there was a survival benefit but at 5-9 months was less than the 25 months we found in our patient group. [ 16 17 18 ] The reason for this difference is unclear but maybe related to difference in patient selection at different treatment centers. For example, it was a policy in our region to refer patients for radium-223, if suitable, as soon as they failed chemical castration or chemotherapy.…”

Safety and activity of radium-223 in metastatic castration-resistant prostate cancer: the experience of Istituto Nazionale dei Tumori

“…Concerning the safety profile, the incidence and type of drug-related toxicities were consistent with what was reported in the registration trial of radium-223 and in other real-world studies in the same disease setting. 14,16–20 Specifically, the main any grade observed AEs were anemia, decreased platelet count, fatigue, diarrhea, nausea, vomiting, and hyporexia; grade 3/4 toxicities included fatigue and hematologic AEs and represented the cause of treatment discontinuation in about 12% of patients. No febrile neutropenia or treatment-related deaths were observed, and no unexpected clinically relevant AEs were reported.…”

“…Recently, a number of real-life studies provided data regarding the safety and activity of radium-223 in clinical practice, outside of trials. 16–20 We retrospectively collected data from patients with mCRPC, treated at our institution, to assess the safety and activity of radium-223 in a real-world population. These data represent a source of information useful to define a better treatment strategy and improve clinical outcomes in everyday clinical practice.…”