Advertisement

Radium-223 dichloride in clinical practice: a review

  • Luigia Florimonte
  • Luca Dellavedova
  • Lorenzo Stefano Maffioli
Review Article

Abstract

The onset of skeletal metastases is typical of advanced-stage prostate cancer and requires a multidisciplinary approach to alleviate bone pain and try to delay disease progression. The current therapeutic armamentarium includes conventional analgesics, chemotherapeutic agents, immunotherapy, androgen-deprivation therapy, osteoclast inhibitors (bisphosphonates, denosumab), surgical interventions, external-beam radiotherapy and radionuclide metabolic therapy. Many studies in recent decades have demonstrated the efficacy of various radiopharmaceuticals, including strontium-89 and samarium-153, for palliation of pain from diffuse skeletal metastases, but no significant benefit in terms of disease progression and overall survival has been shown. The therapeutic landscape of metastatic skeletal cancer significantly changed after the introduction of radium-223, the first bone-homing radiopharmaceutical with disease-modifying properties. In this paper we extensively review the literature on the use of radium-223 dichloride in metastatic castration-resistant prostate cancer.

Keywords

Radium-223 dichloride Bone metastasis α-Emitters Overall survival 

Notes

Acknowledgments

The authors gratefully acknowledge the assistance of Mrs. Sara Vaghi in editing the manuscript and for secretarial support.

Compliance with ethical standards

Funding

None.

Conflicts of interest

L.M. has received financial support to attend EANM symposia from Bayer. The other authors declare no conflicts of interest.

Ethical approval

This article does not describe any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRefPubMedGoogle Scholar
  2. 2.
    Miller DC, Hafez KS, Stewart A, et al. Prostate carcinoma presentation, diagnosis, and staging: an update form the National Cancer Data Base. Cancer. 2003;98:1169–78.CrossRefPubMedGoogle Scholar
  3. 3.
    Mottet N, Bellmunt J, Briers E, et al. Guidelines on prostate cancer. European Association of Urology; 2015. Available at: http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf. Accessed 19 April 2016.
  4. 4.
    Gartrell BA, Coleman R, Efstathiou E, et al. Metastatic prostate cancer and the bone: significance and therapeutic options. Eur Urol. 2015;68:850–8. doi: 10.1016/j.eururo.2015.06.039.CrossRefPubMedGoogle Scholar
  5. 5.
    Lipton A, Uzzo R, Amato RJ, et al. The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors. J Natl Compr Canc Netw. 2009;7 Suppl 7:S1–30.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 2002;62:3120–5.PubMedGoogle Scholar
  7. 7.
    Roodman GD. Mechanism of bone metastases. N Engl J Med. 2004;350:1655–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Ibrahim T, Flamini E, Mercatali L, et al. Pathogenesis of osteoblastic bone metastases from prostate cancer. Cancer. 2010;116:1406–18.CrossRefPubMedGoogle Scholar
  9. 9.
    Blacksburg SR, Witten MR, Haas JA. Integrating bone targeting radiopharmaceuticals into the management of patients with castrate-resistant prostate cancer with symptomatic bone metastases. Curr Treat Options Oncol. 2015;16:325.CrossRefPubMedGoogle Scholar
  10. 10.
    Bienz M, Saad F. Management of bone metastases in prostate cancer: a review. Curr Opin Support Palliat Care. 2015;9:261–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458–68.CrossRefPubMedGoogle Scholar
  12. 12.
    El-Amm J, Freeman A, Patel N, Aragon-Ching JB. Bone-targeted therapies in metastatic castration-resistant prostate cancer: evolving paradigms. Prostate Cancer. 2013;2013:210686. doi: 10.1155/2013/210686.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27(10):1564–71.CrossRefPubMedGoogle Scholar
  14. 14.
    Smith MR, Egerdie B, Hernandez TN, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745–55.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379(9810):39–46.CrossRefPubMedGoogle Scholar
  17. 17.
    Rubini G, Nicoletti A, Rubini D, Asabella AN. Radiometabolic treatment of bone-metastasizing cancer: from 186rhenium to 223radium. Cancer Biother Radiopharm. 2014;29(1):1–11.CrossRefPubMedGoogle Scholar
  18. 18.
    Ariel IM, Hassouna H. Carcinoma of the prostate: the treatment of bone metastases by radioactive phosphorus. Int Surg. 1985;70:63–6.PubMedGoogle Scholar
  19. 19.
    Lewington VJ. Bone-seeking radionuclides for therapy. J Nucl Med. 2005;46:38S–47.Google Scholar
  20. 20.
    Den RB, Doyle LA, Knudsen E. Practical guide to the use of radium-223 dichloride. Can J Urol. 2014;21 Suppl 1:70–6.PubMedGoogle Scholar
  21. 21.
    Porter AT, McEwan AJ, Powe JE, et al. Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 1993;25(5):805–13.CrossRefPubMedGoogle Scholar
  22. 22.
    Mertens WC, Stitt L, Porter AT. Strontium-89 therapy and relief of pain in patients with prostatic carcinoma metastatic to bone: a dose response relationship? Am J Clin Oncol. 1993;16(3):238–42.Google Scholar
  23. 23.
    Finlay IG, Mason MD, Shelley M. Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol. 2005;6(6):392–400.CrossRefPubMedGoogle Scholar
  24. 24.
    Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomized phase II trial. Lancet. 2001;357(9253):336–41.CrossRefPubMedGoogle Scholar
  25. 25.
    Palmedo H, Manka-Waluch A, Albers P, et al. Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: randomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol. 2003;21(15):2869–75.CrossRefPubMedGoogle Scholar
  26. 26.
    Turner JH, Claringbold PG, Hetherington EL, et al. A phase I study of Samarium-153 ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases. J Clin Oncol. 1989;7(12):1926–31.PubMedGoogle Scholar
  27. 27.
    Serafini AN, Houston SJ, Resche I, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16(4):1574–81.PubMedGoogle Scholar
  28. 28.
    Tian JH, Zhang JM, Hou QT, et al. Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med. 1999;26(1):2–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004;63(5):940–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Fizazi K, Beuzeboc P, Lumbroso J, et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2009;27(15):2429–35.CrossRefPubMedGoogle Scholar
  31. 31.
    Ando A, Ando I, Tonami N, et al. 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun. 1998;19(6):587–91.CrossRefPubMedGoogle Scholar
  32. 32.
    Chakraborty S, Das T, Banerjee S, et al. 177Lu-EDTMP: a viable bone pain palliative in skeletal metastasis. Cancer Biother Radiopharm. 2008;23(2):202–13.CrossRefPubMedGoogle Scholar
  33. 33.
    Agarwal KK, Singla S, Arora G, et al. (177)Lu-EDTMP for palliation of pain from bone metastases in patients with prostate and breast cancer: a phase II study. Eur J Nucl Med Mol Imaging. 2015;42(1):79–88.CrossRefPubMedGoogle Scholar
  34. 34.
    Thapa P, Nikam D, Das T, et al. Clinical efficacy and safety comparison of 177Lu-EDTMP with 153Sm-EDTMP on an equidose basis in patients with painful skeletal metastases. J Nucl Med. 2015;56(10):1513–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Guerra Liberal FD, Tavares AA, Tavares JM. Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods. Med Phys. 2014;41(11):114101.CrossRefPubMedGoogle Scholar
  36. 36.
    Hirao M, Hashimoto J, Yamasaki N, et al. Oxygen tension is an important mediator of the transformation of osteoblasts to osteocytes. J Bone Miner Metab. 2007;25:266–76.CrossRefPubMedGoogle Scholar
  37. 37.
    Barensden GW. Responses of cultured cells, tumours and normal tissues to radiations of different linear energy transfer. In: Ebert M, Howard A, editors. Current topics in radiation research, vol. IV. Amsterdam, Netherlands: North-Holland; 1968. p. 293–356.Google Scholar
  38. 38.
    Tinganelli W, Ma NY, Von Neubeck C, et al. Influence of acute hypoxia and radiation quality on cell survival. J Radiat Res. 2013;54 Suppl 1:i23–30.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Seidl C. Radioimmunotherapy with α-particle-emitting radionuclides. Immunotherapy. 2014;6(4):431–58.CrossRefPubMedGoogle Scholar
  40. 40.
    Miller BW, Frost SH, Frayo SL, et al. Quantitative single-particle digital autoradiography with α-particle emitters for targeted radionuclide therapy using the iQID camera. Med Phys. 2015;42(7):4094–105.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gudkov SV, Shilyagina NYU, Vodeneev V, et al. Targeted radionuclide therapy of human tumors. Int J Mol Sci. 2015;28:17(1). doi: 10.3390/ijms17010033
  42. 42.
    IAEA. Technical meeting on “Alpha emitting radionuclides and radiopharmaceuticals for therapy”. Available at: http://www-naweb.iaea.org/napc/iachem/working_materials/TM-44815-report-Alpha-Therapy.pdf - Accessed 20 April 2016.
  43. 43.
    Larsen RH, Henriksen G, Øyvind S. Preparation and use of radium-223 to target calcified tissues for pain palliation, bone cancer therapy, and bone surface conditioning. US6635234. Available at: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6635234.PN.&OS=PN/6635234&RS=PN/6635234. Accessed 20 April 2016.
  44. 44.
    Bruland OS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006;12:6250s–57s.CrossRefPubMedGoogle Scholar
  45. 45.
    Wieder HA, Lassmann M, Allen-Auerbach MS, et al. Clinical use of bone-targeting radiopharmaceuticals with focus on alpha-emitters. World J Radiol. 2014;6(7):480–5.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Gholami Y, Zhu X, Fulton R, et al. Stochastic simulation of radium-223 dichloride therapy at the sub-cellular level. Phys Med Biol. 2015;60:6087–96.CrossRefPubMedGoogle Scholar
  47. 47.
    Carrasquillo JA, O'Donoghue JA, Pandit-Taskar N, et al. Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra-dichloride in men with castration-resistant metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40(9):1384–93.CrossRefPubMedGoogle Scholar
  48. 48.
    Lassmann M, Nosske D. Dosimetry of 223Ra-chloride: dose to normal organs and tissues. Eur J Nucl Med Mol Imaging. 2013;40:207–12.CrossRefPubMedGoogle Scholar
  49. 49.
    Nilsson S, Larsen RH, Foss SD, et al. First clinical experience with α-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11(12):4451–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Nilsson S, Franzen L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587–94.CrossRefPubMedGoogle Scholar
  51. 51.
    Bayer HealthCare. Xofigo (radium Ra 223 dichloride) Injection, for intravenous use: highlights of prescribing information. 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203971lbl.pdf. Accessed 20 April 2016.
  52. 52.
    Bayer HealthCare. Xofigo: radium Ra 223 dichloride Injection. 2015. Available at: http://www.xofigo-us.com/patient/index.php. Accessed 20 April 2016.
  53. 53.
    Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.CrossRefPubMedGoogle Scholar
  54. 54.
    Dauer LT, Williamson MJ, Humm J, et al. Radiation safety considerations for the use of 223RaCl2 DE in men with castration-resistant prostate cancer. Health Phys. 2014;106(4):494–504.CrossRefPubMedGoogle Scholar
  55. 55.
    Nilsson S, Strang P, Aksnes AK, et al. 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. 2012;48:678–86.CrossRefPubMedGoogle Scholar
  56. 56.
    Parker CC, Pascoe S, Chodacki A, et al. 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. 2013;63:189–97.CrossRefPubMedGoogle Scholar
  57. 57.
    Nilsson S, Franzén L, Parker C, et al. 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. 2013;11(1):20–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15:738–46.CrossRefPubMedGoogle Scholar
  59. 59.
    Nilsson S, Sartor O, Bruland OS, et al. Pain analysis from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases [abstract]. J Clin Oncol. 2013;19 Suppl 6:5038.Google Scholar
  60. 60.
    Nilsson S, Tomblyn M, Cislo P, et al. Patient-reported quality of life (QOL) analysis of radium-223 dichloride (Ra-223) evaluating pain relief from the phase 3 ALSYMPCA study [abstract]. J Clin Oncol. 2014;32(5s):5069.Google Scholar
  61. 61.
    Hoskin P, Sartor O, O'Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014;15(12):1397–406.CrossRefPubMedGoogle Scholar
  62. 62.
    Shirley M, McCormack PL. Radium-223 dichloride: a review of its use in patients with castration-resistant prostate cancer with symptomatic bone metastases. Drugs. 2014;74:579–86.CrossRefPubMedGoogle Scholar
  63. 63.
    Ryan CJ, Saylor PJ, Everly JJ, et al. Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer: exploring the implications of new data. The Oncologist. 2014;19:1012–8.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Herranz UA, Fernandez Calvo O, Afonso FJ, et al. Radium-223 dichloride: a new paradigm in the treatment of prostate cancer. Expert Rev Anticancer Ther. 2015;15(3):339–48.CrossRefGoogle Scholar
  65. 65.
    McGann S, Horton ER. Radium-223 dichloride: a novel treatment option for castration-resistant prostate cancer patients with symptomatic bone metastases. Ann Pharmacother. 2015;49(4):469–76.CrossRefPubMedGoogle Scholar
  66. 66.
    Turner PG, O’Sullivan JM. 223Ra and other bone-targeting radiopharmaceuticals—the translation of radiation biology into clinical practice. Br J Radiol. 2015;88:20140752.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Chalhoub E, Chalouhy C, Sartor O. Treatment of skeletal metastases with 223Ra-chloride. Clin Transl Imaging. 2015;3:159–65.CrossRefGoogle Scholar
  68. 68.
    Pandit-Taskar N, Larson SM, Carrasquillo JA. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, part 1: a therapy with 223Ra-dichloride. J Nucl Med. 2014;55:268–74.CrossRefPubMedGoogle Scholar
  69. 69.
    Gartrell BA, Saad F. Pathologic fractures in patients with metastatic prostate cancer. Curr Opin Urol. 2014;24:595–600.CrossRefPubMedGoogle Scholar
  70. 70.
    Graff JN, Beer TM. Pharmacotherapeutic management of metastatic, castration-resistant prostate cancer in the elderly: focus on non-chemotherapy agents. Drugs Aging. 2014;31:873–82.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    George D, Moul JW. Emerging treatment options for patients with castration-resistant prostate cancer. Prostate. 2012;72:338–49.CrossRefPubMedGoogle Scholar
  72. 72.
    Parker C, Gillessen S, Heidenreich A, et al. Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v69–77.Google Scholar
  73. 73.
    NCCN. NCCN Guidelines for Patients: Prostate Cancer. 2015. Available at: http://www.nccn.org/patients/guidelines/prostate/. Accessed 20 April 2016.
  74. 74.
    Vuong W, Sartor O, Pal SK. Radium-223 in metastatic castration resistant prostate cancer. Asian J Androl. 2014;16:348–53.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Mukherji D, El Dika I, Temraz S, et al. Evolving treatment approaches for the management of metastatic castration-resistant prostate cancer: role of radium-223. Ther Clin Risk Manag. 2014;10:373–80.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Gernone A, Bordonaro S, Tralongo P. Optimal sequence of bone target drugs in metastatic prostatic cancer. Expert Rev Anticancer Ther. 2015;15(8):923–9.CrossRefPubMedGoogle Scholar
  77. 77.
    Borsò E, Boni G, Galli L, et al. Radium-223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer. Future Oncol. 2015;11(2):323–31.CrossRefPubMedGoogle Scholar
  78. 78.
    Todenhöfer T, Stenzl A, Hofbauer LC, et al. Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies. Int J Endocrinol. 2015;2015:838202CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Body JJ, Casimiro S, Costa L. Targeting bone metastases in prostate cancer: improving clinical outcome. Nat Rev Urol. 2015;12(6):340–56. doi: 10.1038/nrurol.2015.90.CrossRefPubMedGoogle Scholar
  80. 80.
    Dreicer R. How to approach sequencing therapy in patients with metastatic castration resistant prostate cancer. Can J Urol. 2014;21 Suppl 1:93–7.PubMedGoogle Scholar
  81. 81.
    Sciuto R, Maini CL, Tofani A, et al. Radiosensitization with low dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89. Nucl Med Commun. 1996;17(9):799–804.CrossRefPubMedGoogle Scholar
  82. 82.
    Sciuto R, Festa A, Rea S, et al. Effects of low-dose cisplatin on 89Sr therapy for painful bone metastases from prostate cancer: a randomized clinical trial. J Nucl Med. 2002;43(1):79–86.PubMedGoogle Scholar
  83. 83.
    Ricci S, Boni G, Pastina I, et al. Clinical benefit of bone-targeted radiometabolic therapy with 153Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer. Eur J Nucl Med Mol Imaging. 2007;34(7):1023–30.CrossRefPubMedGoogle Scholar
  84. 84.
    Borsò E, Boni G, Pastina I, et al. Safety and antitumor efficacy of 153Sm-EDTMP and docetaxel administered sequentially to patients with metastatic castration-resistant prostate cancer. Nucl Med Commun. 2014;35(1):88–94.CrossRefPubMedGoogle Scholar
  85. 85.
    Rose JN, Crook JM. The role of radiation therapy in the treatment of metastatic castrate-resistant prostate cancer. Ther Adv Urol. 2015;7(3):135–45.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Basch E, Loblaw EA, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 2014;32:3436–48.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/results?term=radium&show_down=Y. Accessed 20 April 2016.
  88. 88.
    European Union Clinical Trials Register. Available at: https://www.clinicaltrialsregister.eu. Accessed 20 April 2016.
  89. 89.
    Morris MJ, Higano C, Scher HI, et al. Safety of radium-223 dichloride with docetaxel in patients with bone metastases from castration-resistant prostate cancer: a phase 1/2a clinical trial. Ann Oncol. 2014;25 Suppl 4:iv255–79.Google Scholar
  90. 90.
    Finkelstein SE, Michalski JM, O’Sullivan JM, et al. EBRT use and safety with radium-223 dichloride in patients with CRPC and symptomatic bone metastases from the ALSYMPCA trial [abstract]. J Clin Oncol. 2015;33(7):182.Google Scholar
  91. 91.
    Roach 3rd M. Radium-223 vs. EBRT for multiple painful bone metastases: is less more? Oncology (Williston Park). 2014;28(4):297–8.Google Scholar
  92. 92.
    Jayasekera J, Onukwugha E, Bikov K, et al. The economic burden of skeletal-related events among elderly men with metastatic prostate cancer. Pharmacoeconomics. 2014;32:173–91.CrossRefPubMedGoogle Scholar
  93. 93.
    Yong C, Onukwugha E, Mullins CD. Clinical and economic burden of bone metastasis and skeletal-related events in prostate cancer. Curr Opin Oncol. 2014;26:274–83.CrossRefPubMedGoogle Scholar
  94. 94.
    Pani L. Riclassificazione del medicinale per uso umano «Xofigo», ai sensi dell’articolo 8, comma 10, della legge 24 dicembre 1993, n. 537. (Determina n. 576/2015). Gazzetta Ufficiale della Repubblica Italiana. General Series 2015, no. 121.Google Scholar
  95. 95.
    Readler LA. Xofigo (radium Ra 223 dichloride):. the first alpha particle-emitting radioactive agent for the treatment of castration-resistant prostate cancer with symptomatic bone metastases. American Health and Drugs Benefits. Available at: http://www.ahdbonline.com/issues/2014/march-2014-volume-7-special-feature-fifth-annual-payers-guide-to-new-fda-approvals/1733-xofigo-radium-ra-223-dichloride-the-first-alpha-particle-emitting-radioactive-agent-for-the-treatment-of-castration-resistant-prostate-cancer-with-symptomatic-bone-metastases - Last accessed: October 19, 2015.
  96. 96.
    Guirgis HM. Novel methodology for cost evaluation of anticancer drugs in castrate-resistant prostate cancer [abstract]. J Clin Oncol. 2013;31 Suppl 6:200.Google Scholar
  97. 97.
    Renzulli JF 2nd, Collins J, Mega A. Radium-223 dichloride: illustrating the benefits of a multidisciplinary approach for patients with metastatic castration-resistant prostate cancer. J Multidiscip Healthc. 2015;8:279–86.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Shore ND. Radium-223 dichloride for metastatic castration-resistant prostate cancer: the urologist’s perspective. Urology. 2015;85(4):717–24.CrossRefPubMedGoogle Scholar
  99. 99.
    Takalkar A, Adams S, Subbiah V. Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone. Exp Hematol Oncol. 2014;3:23.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Coleman R, Ak A, Naume B, et al. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer Res Treat. 2014;145:411–8.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Silva SC, Wilson C, Woll PJ. Bone-targeted agents in the treatment of lung cancer. Ther Adv Med Oncol. 2015;7(4):219–28.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Chittenden SJ, Hindorf C, Parker CC, et al. A phase 1, open-label study of the biodistribution, pharmacokinetics and dosimetry of radium-223 dichloride (223Ra dichloride) in patients with hormone refractory prostate cancer and skeletal metastases. J Nucl Med. 2015;56(9):1304–9.CrossRefPubMedGoogle Scholar
  103. 103.
    Jadvar H, Challa S, Quinn D, et al. One-year postapproval clinical experience with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer. Cancer Biother Radiopharm. 2015;30(5):195–9.Google Scholar
  104. 104.
    Hindorf C, Chittenden S, Aksnes AK, et al. Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun. 2012;33(7):726–32.CrossRefPubMedGoogle Scholar
  105. 105.
    Pacilio M, Ventroni G, De Vincentis G, et al. Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting 223Ra-dichloride. Eur J Nucl Med Mol Imaging. 2016;43:21–33.CrossRefPubMedGoogle Scholar
  106. 106.
    Follacchio GA, Frantellizzi V, Pellegrini R, et al. Feasibility of 223Ra quantitative imaging for lesion dosimetry [abstract]. Eur J Nucl Med Mol Imaging. 2015;42(1 Suppl):OP236.Google Scholar
  107. 107.
    Murray I, Chittenden SJ, Parker CC, et al. The potential of F-18 fluoride PET as a surrogate for radium-223 chloride lesion dosimetry in hormone refractory prostate cancer patients [abstract]. Eur J Nucl Med Mol Imaging. 2015;42(1 Suppl):OP235.Google Scholar
  108. 108.
    Etchebehere EC, Araujo JC, Fox PS, et al. Prognostic factors in patients treated with 223Ra: the role of skeletal tumor burden on baseline 18F-fluoride PET/CT in predicting overall survival. J Nucl Med. 2015;56(8):1177–84.CrossRefPubMedGoogle Scholar
  109. 109.
    Cook Jr G, Parker C, Chua S, et al. 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. 2011;1(1):4.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Miyazaki KS, Kuang Y, Kwee SA. Changes in skeletal tumor activity on (18)F-choline PET/CT in patients receiving (223)radium radionuclide therapy for metastatic prostate cancer. Nucl Med Mol Imaging. 2015;49(2):160–4.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Sakretz M, Kurth J, Schwarzenböck SM, et al. Automatic bone scan index for therapy response assessment of radium-223-dichloride (Ra-223) therapy in advanced prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42(1 Suppl):P748.Google Scholar
  112. 112.
    Yu EY, Duan F, Muzi M, et al. Castration-resistant prostate cancer bone metastasis response measured by 18F-fluoride PET after treatment with dasatinib and correlation with progression-free survival: results from American College of Radiology Imaging Network 6687. J Nucl Med. 2015;56(3):354–60.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Luigia Florimonte
    • 1
  • Luca Dellavedova
    • 2
  • Lorenzo Stefano Maffioli
    • 3
  1. 1.Nuclear Medicine DepartmentFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
  2. 2.Nuclear Medicine DepartmentA.S.S.T Ovest Milanese, Ospedale di LegnanoLegnanoItaly
  3. 3.Nuclear Medicine and Multi-Hospital Oncology DepartmentA.S.S.T Ovest Milanese Ospedale di LegnanoLegnanoItaly

Personalised recommendations