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ECCO12 Poster No. 543 Tolerability of a novel bone-seeking radionuclide, the alpha emitter radium-223, in patients with skeletal metastases from breast and prostate cancer S. Nilsson1, L.Balteskard2, S. D. Fosså3, J.E. Westlin4, K. W. Borch5, R. H. Larsen5, Ø. S. Bruland3 1Karolinska Hospital, Stockholm, Sweden, 2The University Hospital of Tromsø, Norway, 3The Norwegian Radium Hospital, Oslo, Norway, 4Mälarsjukhuset, Eskilstuna, Sweden, 5Algeta AS, Oslo, Norway. Platelets - All Dosegroups - 550 Blood clearance after intravenous administration of Ra-223 Serum-ALP change after intravenous administration of radium-223 100 110 90 10 ALP (% change) Percent of injected dose 100 1 0.1 80 70 Men, n=15 60 50 Women, n=10 40 0 50 100 150 200 Time after administration (hours) 37 kBq/kg 70 kBq/kg 130 kBq/kg 170 kBq/kg 200 kBq/kg 450 +/- SEM 20 10 20 30 40 50 60 Figure 2. Reduction in serum-ALP levels in patients given a single injection of radium-223 (all dose levels combined) 250 200 150 10 20 30 40 50 60 Results: Dose-limiting haemotoxicity was not observed in the dose escalating part of the study. Reversible myelosuppression occurred, with nadir 2-3 weeks after injection and recovery during the follow-up period. Neutropenia of maximum grade 3 occurred in 2 of the 25 patients. For thrombocytes, even at the two highest dose levels only grade 1 toxicity was observed. See detailed results in Table 1 and Figure 3. Few adverse events were reported, with nausea as the most frequent event (4 of 5 patients) at the highest dose level. Reversible diarrhoea, grades 1 and 2, responding well to medication, were occasionally observed in all dose groups. Several patients reported pain palliation. Radium-223 was rapidly cleared from blood; after 24 hours the blood activity level was below 1 % of the initial level for all dose groups (Figure 1). For all patients a decline in serum-ALP values was observed Figure 2). To date, no trends towards increased myelosuppression upon repeated dosing have been observed. In patients were gamma-camera scintigraphy was performed, accumulation of 223Ra in skeletal lesions in accordance with 99mTc-MDP was seen (Figure 4). Parameters Neutrophile W BC Haemoglobin Single dose Re- Multiple dosing CTC Grade 37 kBq/kg 74 kBq/kg 130 kBq/kg 170 kBq/kg 200 kBq/kg treatment 40 kBq/kg 100 kBq/kg n=5 n=5 n=5 n=5 n=5 n=2 n=3 n=3 0 5 5 4 5 2 2 2 1 1 0 0 1 0 3 0 3 0 0 4 3 3 2 2 2 1 3 1 0 1 0 1 0 0 0 0 2 1 1 1 2 2 0 2 0 3 0 0 1 0 1 0 0 0 0 4 4 3 2 2 2 1 2 1 0 0 0 0 0 0 0 0 2 1 1 1 2 2 0 2 1 3 0 0 1 1 1 0 0 0 0 4 2 4 2 2 1 0 0 1 0 2 0 2 3 1 2 1 2 1 1 1 1 0 0 1 2 Table 1. Myelotoxicity Reference 1: Henriksen, Breistøl, Bruland, Fodstad and Larsen, Cancer Res. 62, 3120-3125, 2002 99mTc-MDP CTC Tox Grade 1 100 Days after injection Days after injection Figure 1. Blood clearance of radium-223 300 0 Platelets 0 350 50 10 0 400 I II III IV V 9 Figure 3. Platelets, Single dose Dosegroup I: 37 kBq/kg Dosegroup II: 70 kBq/kg Dosegroup III: 130 kBq/kg Dosegroup IV: 170 kBq/kg Dosegroup V: 200 kBq/kg Toxicity 30 0.01 Dosegroup Dosegroup Dosegroup Dosegroup Dosegroup 500 Platelet counts (x10 /L) Background: Pre-clinical dosimetry and experimental therapeutic studies of the alpha emitter radium-223 (t1/2 = 11.4 days) indicate a significant therapeutic potential against skeletal metastases (Ref. 1). Patients and methods: 31 patients (10 breast cancer and 21 prostate cancer patients) have been enrolled in an ongoing phase I trial. In the first part of the study 25 patients were given a single intravenous injection of radium-223 as part of a cohort dose escalating design. Cohorts of 5 patients were followed weekly for 8 weeks. Initial dose level was 37 kBq kg-1 b.w. increasing to 74, 130, 170 and 200 kBq kg-1 b.w. In the second part of the study, 2 of the patients were given a second injection, resulting in a total dose of 200 kBq kg-1 b.w. The tolerability of repeated dosing (100 kBq kg-1 b.w. X 2, six weeks interval, or 40 kBq kg-1 b.w. X 5, three weeks interval) were studied in 6 prostate cancer patients. The primary objective was to evaluate the safety and tolerance of the drug. Toxicity was monitored using NCI common toxicity criteria and quality of life was assessed (EORTC QLQ-C 30) for all patients. Blood clearance of radium-223 was studied in the initial 25 patients. 223Ra Anterior Posterior Figure 4. Scintigraphic images demonstrating accumulation of 223Ra in skeletal lesions in accordance with 99mTc-MDP uptake . (Image quality is dependent on dose administered: 750 MBq 99mTc-MDP vs. 12 MBq 223Ra) Conclusions: Radium-223 was well tolerated by patients with skeletal metastases. Surprisingly low haematological toxicity was observed at potentially therapeutic doses. These results justify further studies to explore the efficacy of radium-223 as a novel targeted internal radioisotope treatment.