Bone-Seeking Radiopharmaceuticals as Targeted Agents of Osteosarcoma: Samarium-153-EDTMP and Radium-223

  • Peter M. Anderson
  • Vivek Subbiah
  • Eric Rohren
Part of the Advances in Experimental Medicine and Biology book series (volume 804)


Osteosarcoma is a cancer characterized by formation of bone by malignant cells. Routine bone scan imaging with Tc-99m-MDP is done at diagnosis to evaluate primary tumor uptake and check for bone metastases. At time of relapse the Tc-99m-MDP bone scan also provides a specific means to assess formation of bone by malignant osteosarcoma cells and the potential for bone-seeking radiopharmaceuticals to deliver radioactivity directly into osteoblastic osteosarcoma lesions. This chapter will review and compare a bone-seeking radiopharmaceutical that emits beta-particles, samarium-153-EDTMP, with an alpha-particle emitter, radium-223. The charged alpha particles from radium-223 have far more mass and energy than beta particles (electrons) from Sm-153-EDTMP. Because radium-223 has less marrow toxicity and more radiobiological effectiveness, especially if inside the bone forming cancer cell than samarium-153-EDTMP, radium-223 may have greater potential to become widely used against osteosarcoma as a targeted therapy. Radium-223 also has more potential to be used with chemotherapy against osteosarcoma and bone metastases. Because osteosarcoma makes bone and radium-223 acts like calcium, this radiopharmaceutical could possibly become a new targeted means to achieve safe and effective reduction of tumor burden as well as facilitate better surgery and/or radiotherapy for difficult to resect large, or metastatic tumors.


Osteosarcoma Internal radiotherapy Radium-223 Samarium-153 Alpha particle Beta particle Bone scan for screening Double strand DNA breaks Resistance is futile Radiobiological effectiveness (RBE) 



Peter M. Anderson acknowledges Greg Wiseman and Oyvind Bruland for their advice and sharing ideas during in the development of bone-seeking radiopharmaceuticals for osteosarcoma and Norman Jaffe for his mentorship when working with metastatic osteosarcoma patients. Research has been supported by the Shannon Wilkes Osteosarcoma fund, and Lauren Edwards Behr sarcoma research fund, Sarah’s Garden of Hope. The University of Texas MD Anderson Cancer Center is supported by Cancer Center Support Grant No. CA 016672. Dr. Anderson was supported by the Curtis Distinguished Professorship and is currently partially supported by Levine Cancer Institute.


  1. 1.
    Raymond AK, Jaffe N (2009) Osteosarcoma multidisciplinary approach to the management from the pathologist’s perspective. Cancer Treat Res 152:63–84PubMedCrossRefGoogle Scholar
  2. 2.
    Parker C et al (2013) Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369(3):213–223PubMedCrossRefGoogle Scholar
  3. 3.
    Beck JC et al (1976) The role of radiation therapy in the treatment of osteosarcoma. Radiology 120(1):163–165PubMedCrossRefGoogle Scholar
  4. 4.
    Trapeznikov, N.N., et al., [Treatment of limb osteosarcoma at the turn of the century (half century of experience in research)]. Vestn Ross Akad Med Nauk, 2001(9): p. 46-9.Google Scholar
  5. 5.
    Ciernik IF et al (2011) Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer 117(19):4522–4530PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    DeLaney TF et al (2009) Phase II study of high-dose photon/proton radiotherapy in the management of spine sarcomas. Int J Radiat Oncol Biol Phys 74(3):732–739PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    DeLaney TF et al (2005) Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 61(2):492–498PubMedCrossRefGoogle Scholar
  8. 8.
    Mahajan A et al (2008) Multimodality treatment of osteosarcoma: radiation in a high-risk cohort. Pediatr Blood Cancer 50(5):976–982PubMedCrossRefGoogle Scholar
  9. 9.
    Matsunobu A et al (2012) Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk. Cancer 118(18):4555–4563PubMedCrossRefGoogle Scholar
  10. 10.
    Imai R et al (2006) Cervical spine osteosarcoma treated with carbon-ion radiotherapy. Lancet Oncol 7(12):1034–1035PubMedCrossRefGoogle Scholar
  11. 11.
    Schwarz R et al (2009) The role of radiotherapy in oseosarcoma. Cancer Treat Res 152:147–164PubMedCrossRefGoogle Scholar
  12. 12.
    Wagner TD et al (2009) Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys 73(1):259–266PubMedCrossRefGoogle Scholar
  13. 13.
    Hernberg MM et al (2011) Chemoradiotherapy in the treatment of inoperable high-grade osteosarcoma. Med Oncol 28(4):1475–1480PubMedCrossRefGoogle Scholar
  14. 14.
    Wang XS et al (2012) Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial. Lancet Oncol 13(4):395–402PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Ricardi U et al (2012) Stereotactic body radiation therapy for lung metastases. Lung Cancer 75(1):77–81PubMedCrossRefGoogle Scholar
  16. 16.
    Dhakal S et al (2012) Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival. Int J Radiat Oncol Biol Phys 82(2):940–945PubMedCrossRefGoogle Scholar
  17. 17.
    Ozaki T et al (2003) Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 21(2):334–341PubMedCrossRefGoogle Scholar
  18. 18.
    Ozaki T et al (2002) Osteosarcoma of the spine: experience of the Cooperative Osteosarcoma Study Group. Cancer 94(4):1069–1077PubMedCrossRefGoogle Scholar
  19. 19.
    Machak GN et al (2003) Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the extremities. Mayo Clin Proc 78(2):147–155PubMedCrossRefGoogle Scholar
  20. 20.
    Anderson P, Salazar-Abshire M (2006) Improving outcomes in difficult bone cancers using multimodality therapy, including radiation: physician and nursing perspectives. Curr Oncol Rep 8(6):415–422PubMedCrossRefGoogle Scholar
  21. 21.
    Anderson PM (2003) Effectiveness of radiotherapy for osteosarcoma that responds to chemotherapy. Mayo Clin Proc 78(2):145–146PubMedCrossRefGoogle Scholar
  22. 22.
    Anderson P et al (2008) Outpatient chemotherapy plus radiotherapy in sarcomas: improving cancer control with radiosensitizing agents. Cancer Control 15(1):38–46PubMedGoogle Scholar
  23. 23.
    Dincbas FO et al (2005) The role of preoperative radiotherapy in nonmetastatic high-grade osteosarcoma of the extremities for limb-sparing surgery. Int J Radiat Oncol Biol Phys 62(3):820–828PubMedCrossRefGoogle Scholar
  24. 24.
    Mialou V et al (2005) Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome – the French pediatric experience. Cancer 104(5):1100–1109PubMedCrossRefGoogle Scholar
  25. 25.
    Goorin AM et al (2002) Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 20(2):426–433PubMedCrossRefGoogle Scholar
  26. 26.
    Anderson P, Nunez R (2007) Samarium lexidronam (153Sm-EDTMP): skeletal radiation for osteoblastic bone metastases and osteosarcoma. Expert Rev Anticancer Ther 7(11):1517–1527PubMedCrossRefGoogle Scholar
  27. 27.
    Anderson P (2006) Samarium for osteoblastic bone metastases and osteosarcoma. Expert Opin Pharmacother 7(11):1475–1486PubMedCrossRefGoogle Scholar
  28. 28.
    Goeckeler WF et al (1987) Skeletal localization of samarium-153 chelates: potential therapeutic bone agents. J Nucl Med 28(4):495–504PubMedGoogle Scholar
  29. 29.
    Lattimer JC et al (1990) Clinical and clinicopathologic response of canine bone tumor patients to treatment with samarium-153-EDTMP. J Nucl Med 31(8):1316–1325PubMedGoogle Scholar
  30. 30.
    Aas, M., et al., Internal radionuclide therapy of primary osteosarcoma in dogs, using 153Sm-ethylene-diamino-tetramethylene-phosphonate (EDTMP). Clin Cancer Res, 1999. 5(10 Suppl): p. 3148 s-3152s.Google Scholar
  31. 31.
    Essman SC et al (2003) Effects of 153Sm-ethylenediaminetetramethylene phosphonate on physeal and articular cartilage in juvenile rabbits. J Nucl Med 44(9):1510–1515PubMedGoogle Scholar
  32. 32.
    Bruland OS et al (1996) Targeted radiotherapy of osteosarcoma using 153 Sm-EDTMP. A new promising approach. Acta Oncol 35(3):381–384PubMedCrossRefGoogle Scholar
  33. 33.
    Sandeman TF, Budd RS, Martin JJ (1992) Samarium-153-labelled EDTMP for bone metastases from cancer of the prostate. Clin Oncol (R Coll Radiol) 4(3):160–164CrossRefGoogle Scholar
  34. 34.
    Sartor O (2004) Overview of samarium sm 153 lexidronam in the treatment of painful metastatic bone disease. Rev Urol 6(Suppl 10):S3–S12PubMedPubMedCentralGoogle Scholar
  35. 35.
    Sartor O et al (2004) Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 63(5):940–945PubMedCrossRefGoogle Scholar
  36. 36.
    Higano CS et al (2008) Safety analysis of repeated high doses of samarium-153 lexidronam in men with hormone-naive prostate cancer metastatic to bone. Clin Genitourin Cancer 6(1):40–45PubMedCrossRefGoogle Scholar
  37. 37.
    Menda Y et al (2000) Efficacy and safety of repeated samarium-153 lexidronam treatment in a patient with prostate cancer and metastatic bone pain. Clin Nucl Med 25(9):698–700PubMedCrossRefGoogle Scholar
  38. 38.
    Morris MJ et al (2009) Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J Clin Oncol 27(15):2436–2442PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Tu SM et al (2009) Phase I study of concurrent weekly docetaxel and repeated samarium-153 lexidronam in patients with castration-resistant metastatic prostate cancer. J Clin Oncol 27(20):3319–3324PubMedCrossRefGoogle Scholar
  40. 40.
    Loeb DM et al (2009) Dose-finding study of 153Sm-EDTMP in patients with poor-prognosis osteosarcoma. Cancer 115(11):2514–2522PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Loeb DM et al (2010) Tandem dosing of samarium-153 ethylenediamine tetramethylene phosphoric acid with stem cell support for patients with high-risk osteosarcoma. Cancer 116(23):5470–5478PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Hobbs RF et al (2011) A treatment planning method for sequentially combining radiopharmaceutical therapy and external radiation therapy. Int J Radiat Oncol Biol Phys 80(4):1256–1262PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Senthamizhchelvan S et al (2012) Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma. J Nucl Med 53(2):215–224PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Anderson PM et al (2002) High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol 20(1):189–196PubMedCrossRefGoogle Scholar
  45. 45.
    Turner JH et al (1992) 153Sm-EDTMP and melphalan chemoradiotherapy regimen for bone marrow ablation prior to marrow transplantation: an experimental model in the rat. Nucl Med Commun 13(5):321–329PubMedCrossRefGoogle Scholar
  46. 46.
    Turner JH et al (1993) Radiopharmaceutical therapy of 5 T33 murine myeloma by sequential treatment with samarium-153 ethylenediaminetetramethylene phosphonate, melphalan, and bone marrow transplantation. J Natl Cancer Inst 85(18):1508–1513PubMedCrossRefGoogle Scholar
  47. 47.
    Anderson PM et al (2005) Gemcitabine radiosensitization after high-dose samarium for osteoblastic osteosarcoma. Clin Cancer Res 11(19 Pt 1):6895–6900PubMedCrossRefGoogle Scholar
  48. 48.
    Franzius C et al (2001) High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin 40(6):215–220PubMedGoogle Scholar
  49. 49.
    Franzius C et al (1999) High-activity samarium-153-EDTMP therapy in unresectable osteosarcoma. Nuklearmedizin 38(8):337–340PubMedGoogle Scholar
  50. 50.
    Franzius C, Schuck A, Bielack SS (2002) High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol 20(7):1953–1954PubMedGoogle Scholar
  51. 51.
    Kassis AI (2008) Therapeutic radionuclides: biophysical and radiobiologic principles. Semin Nucl Med 38(5):358–366PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Zhu X et al (2010) Solid-tumor radionuclide therapy dosimetry: new paradigms in view of tumor microenvironment and angiogenesis. Med Phys 37(6):2974–2984PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Huang CY et al (2012) Microdosimetry for targeted alpha therapy of cancer. Comput Math Methods Med 2012:153212PubMedPubMedCentralGoogle Scholar
  54. 54.
    Baidoo KE, Yong K, Brechbiel MW (2013) Molecular pathways: targeted alpha-particle radiation therapy. Clin Cancer Res 19(3):530–537PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Bruland OS et al (2008) Radium-223: from Radiochemical Development to Clinical Applications in Targeted Cancer Therapy. Curr Radoipharmaceut 1(1):203–208CrossRefGoogle Scholar
  56. 56.
    Bruland, O.S., et al., High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res, 2006. 12(20 Pt 2): p. 6250 s-6257s.Google Scholar
  57. 57.
    Henriksen G et al (2003) Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med 44(2):252–259PubMedGoogle Scholar
  58. 58.
    Nilsson S et al (2007) Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8(7):587–594PubMedCrossRefGoogle Scholar
  59. 59.
    Nilsson S et al (2005) First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 11(12):4451–4459PubMedCrossRefGoogle Scholar
  60. 60.
    Nilsson S et al (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
  61. 61.
    Henriksen G et al (2002) Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res 62(11):3120–3125PubMedGoogle Scholar
  62. 62.
    Larsen RH et al (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
  63. 63.
    Nilsson S et al (2013) 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 Cancer 11(1):20–26PubMedCrossRefGoogle Scholar
  64. 64.
    Parker, C., et al., 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). J Clin Oncol, 2012. 30(suppl; abstr LBA4512).Google Scholar
  65. 65.
    Anderson P (2011) Osteosarcoma: an opportunity for targeted radiotherapy. In: Speer TW (ed) Targeted radionuclide therapy. Lippincott Williams & Wilkins, Wolters Kluwer Health, Philadelphia, PA, pp 473–477Google Scholar
  66. 66.
    Garg AK et al (2012) Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer 118(20):5069–5077PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Sze WM et al (2004) Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev (2): CD004721Google Scholar
  68. 68.
    Sze WM et al (2003) Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy – a systematic review of randomised trials. Clin Oncol (R Coll Radiol) 15(6):345–352CrossRefGoogle Scholar
  69. 69.
    Wu JS et al (2004) Radiotherapy fractionation for the palliation of uncomplicated painful bone metastases - an evidence-based practice guideline. BMC Cancer 4:71PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Wu JS et al (2003) Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 55(3):594–605PubMedCrossRefGoogle Scholar
  71. 71.
    Chow E et al (2007) Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25(11):1423–1436PubMedCrossRefGoogle Scholar
  72. 72.
    Goel A et al (2006) Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma. Blood 107(10):4063–4070PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Peter M. Anderson
    • 1
    • 2
  • Vivek Subbiah
    • 3
  • Eric Rohren
    • 3
  1. 1.Levine Children’s HospitalCharlotteUSA
  2. 2.Carolinas Healthcare SystemLevine Children’s Hospital and Levine Cancer InstituteCharlotteUSA
  3. 3.MD Anderson Cancer CenterHoustonUSA

Personalised recommendations