Treatment of Osteoblastic Skeletal Metastases by the Alpha-Emitting Bone-Seeker Radium-223

Part of the Medical Radiology book series (MEDRAD)


Radium-223 dichloride selectively targets osteoblastic bone metastases with high-energy, short-range alpha-particles following intravenous injection. It is the first targeted alpha-emitter to improve overall survival in randomized phase 2 and 3 studies and provides a novel treatment option with favorable safety profile in castrate-resistant prostate cancer patients with bone metastases.


Overall Survival Bone Metastasis Prostate Cancer Patient Skeletal Metastasis Track Length 
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  1. Anderson RM, Stevens DL, Sumption ND et al (2007) Effect of linear energy transfer (LET) on the complexity of alpha-particle induced chromosome aberrations in human CD341 cells. Radiat Res 167:541–550PubMedCrossRefGoogle Scholar
  2. Barnes EA (2011) Radiopharmaceuticals for painful bone metastases: perspective from radiation oncology. J Support Oncol 9(6):208–209PubMedCrossRefGoogle Scholar
  3. British Association of Surgical Oncology (1999) The management of metastatic bone disease in the United Kingdom. Eur J Surg Onc 25:3–23CrossRefGoogle Scholar
  4. Bruland OS, Hird A, Chow E (2008a) Radiotherapy of skeletal metastases. In: ASBMR-primer, Chapter 86, 7th edn. American Society for Bone and Mineral Research, USA, pp 404–407Google Scholar
  5. Bruland OS, Jonasdottir TJ, Fisher DR, Larsen RH (2008b) Radium-223: from radiochemical development to clinical applications in targeted cancer therapy. Curr Radiopharm 1:203–208CrossRefGoogle Scholar
  6. Bruland ØS, Nilsson S, Fisher DR, Larsen RH (2006) High linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res 12:6250s–6257sPubMedCrossRefGoogle Scholar
  7. Casimiro S, Guise TA, Chirgwin J (2009) The critical role of the bone microenvironment in cancer metastases. Mol Cell Endocrinol 310:71–81PubMedCrossRefGoogle Scholar
  8. Chung LW (2003) Prostate carcinoma bone-stroma interaction and its biologic and therapeutic implications. Cancer 97:772–778PubMedCrossRefGoogle Scholar
  9. Cook G Jr, Parker C, Chua S, Johnson B, Aksnes AK, Lewington VJ (2011a) 18F-fluoride PET: changes in uptake as a method to assess response in bone metastases from castrate-resistant prostate cancer patients treated with 223Ra-chloride (Alpharadin). EJNMMI Res 1(1):4PubMedCentralPubMedCrossRefGoogle Scholar
  10. Cook GJ, Venkitaraman R, Sohaib AS, Lewington VJ, Chua SC, Huddart RA, Parker CC, Dearnaley DD, Horwich A (2011b) The diagnostic utility of the flare phenomenon on bone scintigraphy in staging prostate cancer. Eur J Nucl Med Mol Imaging 38(1):7–13PubMedCrossRefGoogle Scholar
  11. Cooper CR, Chay CH, Gendernalik JD et al (2003) Stromal factors involved in prostate carcinoma metastasis to bone. Cancer 97:739–747PubMedCrossRefGoogle Scholar
  12. Guise TA, Mundy GR (1998) Cancer and bone. Endocr Rev 19:18–54PubMedGoogle Scholar
  13. Hage WD (2000) Incidence, location, and diagnostic evaluation of metastatic bone disease. Orthop Clin N Am 31:515–528CrossRefGoogle Scholar
  14. Hall EJ (2000) Radiobiology for the radiologist, Chapter 10, 5th edn. Lippincott Williams & Wilkins, Philadelphia, p 153Google Scholar
  15. Harvie DI (1999) The radium century. Endeavour 23(3):100–105PubMedCrossRefGoogle Scholar
  16. Henriksen G, Alstad J, Hoff P, Larsen RH (2001) 223Ra for endotherapeutic applications prepared from an immobilized 227Ac/227Th source. Radiochim Acta 89:661–666CrossRefGoogle Scholar
  17. Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH (2002) Significant antitumor effect from bone-seeking, alpha-particle-emitting 223Ra demonstrated in an experimental skeletal metastases model. Cancer Res 62:3120–3125PubMedGoogle Scholar
  18. Henriksen G, Fisher DR, Roeske JC, Bruland OS, Larsen RH (2003) Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med 44:252–259PubMedGoogle Scholar
  19. Hindorf C, Chittenden S, Aksnes AK, Parker C, Flux GD (2012) Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun 33(7):726–732PubMedCrossRefGoogle Scholar
  20. Kerr C (2002) 223Ra targets skeletal metastases and spares normal tissue. Lancet Oncol 3:453PubMedCrossRefGoogle Scholar
  21. Lange P, Vessella R (1999) Mechanisms, hypotheses and questions regarding prostate cancer micrometastases to bone. Cancer Metastasis Rev 17:331–336CrossRefGoogle Scholar
  22. Larsen RH, Saxtorph H, Skydsgaard M, Borrebaek J, Jonasdottir TJ, Bruland OS, Klastrup S, Harling R, Ramdahl T (2006) Radiotoxicity of the alpha-emitting bone-seeker 223Ra injected intravenously into mice: histology, clinical chemistry and hematology. In Vivo 20(3):325–331PubMedGoogle Scholar
  23. Lassmann M, Nosske D, Reiners C (2002) Therapy of ankylosing spondylitis with 224Ra-radium chloride: dosimetry and risk considerations. Radiat Environ Biophys 41:173–178PubMedGoogle Scholar
  24. Lee SE, Min CK, Yahng SA et al (2011) Bone scan images reveal increased osteoblastic function after bortezomib treatment in patients with multiple myeloma. Eur J Haematol 86:83–86PubMedCrossRefGoogle Scholar
  25. Lewington VJ (2005) Bone-seeking radionuclides for therapy. J Nucl Med 46(Suppl 1):38S–47SPubMedGoogle Scholar
  26. Li Y, Russell PJ, Allen BJ (2004) Targeted alpha-therapy for control of micrometastatic prostate cancer. Expert Rev Anticancer Ther 4:459–468PubMedCrossRefGoogle Scholar
  27. Liepe K (2009) Alpharadin, a 223Ra-based alpha-particle-emitting pharmaceutical for the treatment of bone metastases in patients with cancer. Curr Opin Investig Drugs 10:1346–1358PubMedGoogle Scholar
  28. Lin SH, Cheng CJ, Lee YC et al (2008) A 45-kDa ErbB3 secreted by prostate cancer cells promotes bone formation. Oncogene 27:5195–5203PubMedCentralPubMedCrossRefGoogle Scholar
  29. Lipton A, Berenson JR, Body JJ et al (2006) Advances in treating metastatic bone cancer: summary statement for the first Cambridge conference. Clin Cancer Res 12:6209s–6212sPubMedCentralPubMedCrossRefGoogle Scholar
  30. Loberg RD, Logothetis CJ, Keller ET, Pienta KJ (2005) Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype. J Clin Oncol 23:8232–8241PubMedCrossRefGoogle Scholar
  31. Macklis RM (2002) Portrait of science. Scientist, technologist, proto-feminist, superstar. Science 295(5560):1647–1648PubMedCrossRefGoogle Scholar
  32. Martland HS, Humphries RE (1929) Osteogenic sarcoma in dial painters using luminous paint. Arch Pathol 7:406–417Google Scholar
  33. Mould RF (1999) Marie and Pierre Curie and radium: history, mystery, and discovery. Med Phys 26(9):1766–1772PubMedCrossRefGoogle Scholar
  34. Mundy GR (2002) Metastasis to bone: causes, consequences, and therapeutic opportunities. Nat Rev Cancer 2:584–593PubMedCrossRefGoogle Scholar
  35. Nekolla EA, Kreisheimer M, Kellerer AM, Kuse IM, Gossner W, Spiess H (2000) Induction of malignant bone tumors in radium-224 patients: risk estimates based on the improved dosimetry. Radiat Res 153:93–103PubMedCrossRefGoogle Scholar
  36. Nielsen OS, Munro AJ, Tannock IF (1991) Bone metastases: pathophysiology and management policy. J Clin Oncol 9:509–524PubMedGoogle Scholar
  37. Nilsson S, Balteskard L, Fosså SD et al (2005) First clinical experiences with alpha emitter radium-223 in the treatment of skeletal metastases from breast and prostate cancer. Clin Cancer Res 11:4451–4459PubMedCrossRefGoogle Scholar
  38. Nilsson S, Franzén L, Parker C et al (2007) Bone-targeted radium-223 in symptomatic, hormone refractory prostate cancer: a randomized, placebo-controlled, phase 2 study. Lancet Oncol 8:587–594PubMedCrossRefGoogle Scholar
  39. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, O’Bryan-Tear CG, Thuresson M, Bolstad B, Bruland OS (in press) Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients With castration-resistant prostate cancer and bone metastases. Clin Genitourin CancerGoogle Scholar
  40. Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, Staffurth J, Vasanthan S, Andersson C, Bruland ØS (2012) A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer 48(5):678–686PubMedCrossRefGoogle Scholar
  41. Norris WP, Speckman TW, Gustafson PF (1955) Studies of the metabolism of radium in man. Am J Roentgenol 73:785–802Google Scholar
  42. Paes FM, Ernani V, Hosein P, Serafini AN (2011) Radiopharmaceuticals: when and how to use them to treat metastatic bone pain. J Support Oncol 9(6):197–205PubMedCrossRefGoogle Scholar
  43. Pandit-Taskar N, Batraki M, Divgi CR (2004) Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. J Nucl Med 45:1358–1365PubMedGoogle Scholar
  44. Parker C, Nilsson S, Heinrich D, et al (2012) Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). Oral presentation at Annual Meeting of the American Society of Clinical Oncology Abstract LBA4512Google Scholar
  45. Parker CC, Pascoe S, Chodacki A, O’Sullivan JM, Germá JR, O’Bryan-Tear CG, Haider T, Hoskin P (2013) A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol 63(2):189–197PubMedCrossRefGoogle Scholar
  46. Ritter MA, Cleaver JE, Tobias CA (1977) High-LET radiations induce a large proportion of non-rejoining DNA breaks. Nature 266:653–655PubMedCrossRefGoogle Scholar
  47. Roudier MP, Morrissey C, True LD et al (2008) Histopathological assessment of prostate cancer bone osteoblastic metastases. J Urol 180:1154–1160PubMedCentralPubMedCrossRefGoogle Scholar
  48. Sartor O, Bruland O (2011) Stromal targeted therapies in prostate and renal cancer: new concepts and knowledge. Clin Genitourin Cancer 9(1):1–2PubMedGoogle Scholar
  49. Sartor O, Goeckeler W, Bruland O (2011) Stromal targeted therapy in bone metastatic prostate cancer: promise delivered. Asian J Androl 13(6):783–784PubMedCentralPubMedCrossRefGoogle Scholar
  50. Sartor O, Hoskin P, Bruland OS (2013) Targeted radio-nuclide therapy of skeletal metastases. Cancer Treat Rev 39(1):18–26PubMedCrossRefGoogle Scholar
  51. Shah SK, Ryan CJ, Kilian C et al (2010) Bone scan “flare” in patients receiving abiraterone acetate (AA) for metastatic castration resistant prostate cancer (mCRPC): analysis of data from a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium. J Clin Oncol 28:15sCrossRefGoogle Scholar
  52. Sikes RA, Nicholson BE, Koeneman KS et al (2004) Cellular interactions in the tropism of prostate cancer to bone. Int J Cancer 110:497–503PubMedCrossRefGoogle Scholar
  53. Silberstein EB (2000) Systemic radiopharmaceutical therapy of painful osteoblastic metastases. Semin Radiat Oncol 10:240–249PubMedCrossRefGoogle Scholar
  54. Spiess H (2010) Life-span study on late effects of 224Ra in children and adults. Health Phys 99(3):286–291PubMedCrossRefGoogle Scholar
  55. Tiepolt C, Grunning T, Franke WG (2001) Reaissance of 224Ra treatment in ankylosing spondylitis. J Nucl Med 42S:128PGoogle Scholar
  56. Tomblyn M (2012) The role of bone-seeking radionuclides in the palliative treatment of patients with painful osteoblastic skeletal metastases. Cancer Control 19(2):137–144PubMedGoogle Scholar
  57. Vogel CL, Schoenfelder J, Shemano I, Hayes DF, Gams RA (1995) Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer. J Clin Oncol 13:1123–1128PubMedGoogle Scholar
  58. Weilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11:411–425PubMedCentralPubMedCrossRefGoogle Scholar
  59. Wheldon TE, O’Donoghue JA (1990) The radiobiology of targeted radiotherapy. Int J Radiat Biol 58:1–21PubMedCrossRefGoogle Scholar
  60. Wick RR, Atkinson MJ, Nekolla EA (2009) Incidence of leukaemia and other malignant diseases following injections of the short-lived alpha-emitter 224Ra into man. Radiat Environ Biophys 48(3):287–294PubMedCrossRefGoogle Scholar
  61. Wick RW, Nekolla EA, Gøssner W, Kellerer AM (1999) Late effects in ankylosing spondylitis patients treated with 224Ra. Radiation Res 152:S8–S11PubMedCrossRefGoogle Scholar
  62. Yates C (2011) Prostate tumor cell plasticity: a consequence of the microenvironment. Adv Exp Med Biol 720:81–90PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of OncologyThe Norwegian Radium Hospital, Institute for Clinical Medicine, University of OsloOsloNorway
  2. 2.Sciencons Ltd.OsloNorway

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