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Clinical Applications of Nuclear Medicine Targeted Therapy pp 379–391Cite as

Novel Approaches of Treatment with Radium-223 Targeted Therapy

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Abstract

The role of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) with bone metastases and no visceral disease is well established in clinical practice. Treatment with Ra-223 is well tolerated and significantly improves overall survival and time to first symptomatic skeletal event. Several questions, however, remain open. Patient selection is critical, and treatment assessment is challenging. There is no standard imaging, and PSA has limited usefulness in this setting.

Furthermore, the optimal schedule and dosing of Ra-223 remain to be defined by current trials. Combined treatments with AR-targeting agents such as abiraterone and enzalutamide will probably extend the use of Ra-223 to cases with concomitant bone and visceral disease. Due to ist peculiar mechanism of action and good toxicity profile, Ra-223 is being explored beyond mCRPC in several other neoplasms with predominant bone disease.

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References

  1. Saad F, Clarke N, Colombel M. Natural history and treatment of bone complications in prostate cancer. Eur Urol. 2006;49:429–40.

    Article  CAS  PubMed  Google Scholar 

  2. Attard G, Parker C, Eeles RA, et al. Prostate cancer. Lancet. 2016;387:70–82.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Nilsson S, Cislo P, Sartor O, et al. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016;27:868–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Parker C, Zhan L, Cislo P, et al. Effect of radium-223 dichloride (Ra-223) on hospitalisation: an analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Eur J Cancer. 2017;71:1–6.

    Article  CAS  PubMed  Google Scholar 

  7. Parker C, Finkelstein SE, Michalski JM, et al. Efficacy and safety of radium-223 dichloride in symptomatic castration-resistant prostate cancer patients with or without baseline opioid use from the phase 3 ALSYMPCA trial. Eur Urol. 2016;70:875–83.

    Article  CAS  PubMed  Google Scholar 

  8. Vogelzang NJ, Coleman RE, Michalski JM, et al. Hematologic safety of radium-223 dichloride: baseline prognostic factors associated with myelosuppression in the ALSYMPCA trial. Clin Genitourin Cancer. 2017;15:42–52.

    Article  PubMed  Google Scholar 

  9. 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;15:1397–406.

    Article  CAS  PubMed  Google Scholar 

  10. Sartor O, Hoskin P, Coleman RE, et al. Chemotherapy following radium-223 dichloride treatment in ALSYMPCA. Prostate. 2016;76:905–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bombardieri E, Ceresoli GL, Setti L, et al. Role of radium-223 in the treatment of metastatic castration resistant prostate cancer (mCRPC): clinical practice and future perspectives. Clin Oncol. 2016;1:1173.

    Google Scholar 

  12. Saad F, Carles J, Gillessen S, et al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol. 2016;17:1306–16.

    Article  CAS  PubMed  Google Scholar 

  13. Etchebehere E, Brito AE, Rezaee A, et al. Therapy assessment of bone metastatic disease in the era of radium 223. Eur J Nucl Med Mol Imaging. 2017;44(Suppl 1):84–96. [Epub ahead of print]

    Article  CAS  PubMed  Google Scholar 

  14. Evangelista L, Bertoldo F, Boccardo F, et al. Diagnostic imaging to detect and evaluate response to therapy in bone metastases from prostate cancer: current modalities and new horizons. Eur J Nucl Med Mol Imaging. 2016;43:1546–62.

    Article  CAS  PubMed  Google Scholar 

  15. Messiou C, Cook G, Reid AH, et al. The CT flare response of metastatic bone disease in prostate cancer. Acta Radiol. 2011;52:557–61.

    Article  PubMed  Google Scholar 

  16. Gorin MA, Rowe SP, Denmeade SR. Clinical applications of molecular imaging in the management of prostate cancer. PET Clin. 2017;12:185–92.

    Article  PubMed  Google Scholar 

  17. Uprimny C, Kroiss A, Nilica B, et al. 68-Ga-PSMA ligand PET versus 18F-NaF PET: evaluation of response to Ra-223 therapy in a prostate cancer patient. Eur J Nucl Med Mol Imaging. 2015;42:362–3.

    Article  PubMed  Google Scholar 

  18. Sartor O, Coleman RE, Nilsson S, et al. An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223. Ann Oncol. 2017;28:1090–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. McNamara MA, George DJ. Pain, PSA flare, and bone scan response in a patient with metastatic castration-resistant prostate cancer treated with radium-223, a case report. BMC Cancer. 2015;15:371.

    Article  PubMed  PubMed Central  Google Scholar 

  20. De Vincentis G, Follacchio GA, Frantellizzi V, et al. Prostate-specific antigen flare phenomenon during 223-Ra-dichloride treatment for bone metastatic castration-resistant prostate cancer: a case report. Clin Genitourin Cancer. 2016;14:e529–33.

    Article  PubMed  Google Scholar 

  21. Miyahira AK, Morris M, Soule HR, PCF Radium-223 Scientific Working Group. Meeting report from the Prostate Cancer Foundation scientific working group on radium-223. Prostate. 2017;77:245–54.

    Article  PubMed  Google Scholar 

  22. Bertoldo F. Biology and pathophysiology of bone metastasis in prostate cancer. In: Bertoldo, et al., editors. Bone metastases from prostate cancer. Switzerland: Springer; 2017.

    Chapter  Google Scholar 

  23. Hensel J, Thalmann GN. Biology of bone metastases in prostate cancer. Urology. 2016;92:6–13.

    Article  PubMed  Google Scholar 

  24. Gartrell BA, Coleman R, Efstathiou E, et al. Metastatic prostate cancer and the bone: significance and therapeutic options. Eur Urol. 2015;68:850–8.

    Article  PubMed  Google Scholar 

  25. Wang N, Docherty FE, Brown HK, et al. Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models. J Bone Miner Res. 2014;29:2688–96.

    Article  CAS  PubMed  Google Scholar 

  26. Suominen MI, Fagerlund KM, Rissanen JP, et al. Radium-223 inhibits osseous prostate cancer growth by dual targeting of cancer cells and bone microenvironment in mouse models. Clin Cancer Res. 2017;23(15):4335–46. [Epub ahead of print]

    Article  CAS  PubMed  Google Scholar 

  27. Suominen MI, Rissanen JP, Käkönen R, et al. Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J Natl Cancer Inst. 2013;105:908–16.

    Article  PubMed  Google Scholar 

  28. Malamas AS, Gameiro SR, Knudson KM, Hodge JW. Sublethal exposure to alpha radiation (223Ra dichloride) enhances various carcinomas’ sensitivity to lysis by antigen-specific cytotoxic T lymphocytes through calreticulin-mediated immunogenic modulation. Oncotarget. 2016;7:86937–47.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

    Article  CAS  PubMed  Google Scholar 

  30. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14:365–79.

    Article  CAS  PubMed  Google Scholar 

  31. Loi M, Desideri I, Greto D, et al. Radiotherapy in the age of cancer immunology: current concepts and future developments. Crit Rev Oncol Hematol. 2017;112:1–10.

    Article  PubMed  Google Scholar 

  32. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Parker C, Vogelzang NJ, Sartor O, et al. 3-year safety follow-up of radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases from ALSYMPCA. J Clin Oncol. 2015;33(suppl 7):195.

    Article  Google Scholar 

  34. Observational study for the evaluation of long-term safety of radium-223 used for the treatment of metastatic castration resistant prostate cancer (REASSURE). NCT02141438. www.clinicaltrials.gov.

  35. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med. 1994;330:592–6.

    Article  CAS  PubMed  Google Scholar 

  36. Nekolla EA, Kellerer AM, Kuse-Isingschulte M, et al. Malignancies in patients treated with high dose of radium-224. Radiat Res. 1999;152(suppl 6):S3–7.

    Article  CAS  PubMed  Google Scholar 

  37. A three arm randomized, open-label phase II study of radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) versus 80 kBq/kg (88 kBq/kg after implementation of NIST update), and versus 50 kBq/kg (55 kBq/kg after implementation of NIST update) in an extended dosing schedule in subjects with castration-resistant prostate cancer metastatic to the bone. NCT02023697. www.clinicaltrials.gov.

  38. Sartor O, Heinrich D, Mariados N, et al. Radium-223 (Ra-223) re-treatment: first experience from an international, multicenter, prospective study in patients with castration-resistant prostate cancer and bone metastases (mCRPC). J Clin Oncol. 2016;34(suppl 2S):197.

    Article  Google Scholar 

  39. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983–92.

    Article  CAS  PubMed  Google Scholar 

  41. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.

    Article  CAS  PubMed  Google Scholar 

  42. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.

    Article  CAS  PubMed  Google Scholar 

  43. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Logothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012;13:1210–7.

    Article  CAS  PubMed  Google Scholar 

  45. Loriot Y, Miller K, Sternberg CN, et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol. 2015;16:509–21.

    Article  CAS  PubMed  Google Scholar 

  46. Gartrell BA, Saad F. Managing bone metastases and reducing skeletal related events in prostate cancer. Nat Rev Clin Oncol. 2014;11:335–45.

    Article  CAS  PubMed  Google Scholar 

  47. Gartrell BA, Coleman R, Efstathiou E, et al. Metastatic prostate cancer and the bone: significance and therapeutic options. Eur Urol. 2015;68:850–8.

    Article  PubMed  Google Scholar 

  48. Vignani F, Bertaglia V, Buttigliero C, et al. Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer. Cancer Treat Rev. 2016;44:61–73.

    Article  CAS  PubMed  Google Scholar 

  49. A phase III randomized, double-blind, placebo-controlled trial of radium-223 dichloride in combination with abiraterone acetate and prednisone/prednisolone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve subjects with bone predominant metastatic castration-resistant prostate cancer (ERA III). NCT02043678. www.clinicaltrials.gov.

  50. A randomized multicenter Phase III trial comparing enzalutamide vs. a combination of Ra-223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone (PEACE III). NCT02194842. www.clinicaltrials.gov.

  51. Morris MJ, Loriot Y, Sweeney C, et al. Updated results: a phase I/IIa randomized trial of radium-223 + docetaxel versus docetaxel in patients with castration-resistant prostate cancer and bone metastases. J Clin Oncol. 2016;34(suppl):5075.

    Google Scholar 

  52. A phase I/IIa study of safety and efficacy of Alpharadin® with docetaxel in patients with bone metastasis from castration-resistant prostate cancer. NCT01106352. www.clinicaltrials.gov.

  53. Grasso CS, YM WU, Robinson DR, et al. The mutational landscape of lethal castrate resistant prostate cancer. Nature. 2012;487:239–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Beltran H, Yelensky R, Frampton GM, et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 2013;63:920–6.

    Article  CAS  PubMed  Google Scholar 

  55. Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Evans JR, Zhao SG, Chang SL, et al. Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for high-risk prostate cancer. JAMA Oncol. 2016;2:471–80.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hager S, Ackermann CJ, Joerger M, et al. Anti-tumour activity of platinum compounds in advanced prostate cancer—a systematic literature review. Ann Oncol. 2016;27:975–84.

    Article  CAS  PubMed  Google Scholar 

  58. Sternberg CN, Petrylak DP, Sartor O, et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009;27:5431–8.

    Article  CAS  PubMed  Google Scholar 

  59. Phase IB trial of radium-223 and niraparib in patients with castrate resistant prostate cancer (RAPARP). NCT03076203. www.clinicaltrials.gov.

  60. Menis J, Litière S, Tryfonidis K, Golfinopoulos V. The European Organization for Research and Treatment of Cancer perspective on designing clinical trials with immune therapeutics. Ann Transl Med. 2016;4:267.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Nesslinger NJ, Ng A, Tsang KY, et al. A viral vaccine encoding prostate-specific antigen induces antigen spreading to a common set of self-proteins in prostate cancer patients. Clin Cancer Res. 2010;16:4046–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. A phase 2 study of sipuleucel-T with or without radium-223 in men with asymptomatic or minimally symptomatic bone-metastatic castrate-resistant prostate cancer. NCT02463799. www.clinicaltrials.gov.

  63. A randomized, Phase II study evaluating the addition of pembrolizumab (MK-3475) to Radium-223 in metastatic castration-resistant prostate cancer (mCRPC). NCT03093428. www.clinicaltrials.gov.

  64. A phase Ib, open-label study of the safety and tolerability of atezolizumab in combination with Radium-223 dichloride in patients with castrate-resistant prostate cancer who have progressed following treatment with an androgen pathway inhibitor. NCT02814669. www.clinicaltrials.gov.

  65. Humm JL, Sartor O, Parker C, et al. Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. Int J Radiat Oncol Biol Phys. 2015;91:898–906.

    Article  PubMed  Google Scholar 

  66. Coleman R. Treatment of metastatic bone disease and the emerging role of radium-223. Semin Nucl Med. 2016;46:99–104.

    Article  PubMed  Google Scholar 

  67. Androgen deprivation therapy with or without radium-223 dichloride in patients with newly diagnosed metastatic prostate cancer with bone metastases: Hoosier Cancer Research Network GU13-170. NCT02582749. www.clinicaltrials.gov.

  68. Coleman R, Aksnes AK, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride versus placebo when administered to metastatic HER2 negative hormone receptor positive breast cancer subjects with bone metastases treated with hormonal treatment background therapy. NCT02258464. www.clinicaltrials.gov.

  70. A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride in combination with exemestane and everolimus versus placebo in combination with exemestane and everolimus when administered to metastatic HER2 negative hormone receptor positive breast cancer subjects with bone metastases. NCT02258451. www.clinicaltrials.gov.

  71. Anderson PM, Subbiah V, Rohren E. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: Samarium-153-EDTMP and radium-223. Adv Exp Med Biol. 2014;804:291–304.

    Article  CAS  PubMed  Google Scholar 

  72. 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–7s.

    Article  CAS  PubMed  Google Scholar 

  73. Phase I dose escalation of monthly intravenous Ra-223 dichloride in osteosarcoma. NCT 01833520. www.clinicaltrials.gov.

  74. Subbiah V, Anderson PM, Kairemo K, et al. Alpha particle radium-223 dichloride (223RaCl2) in high risk osteosarcoma. J Clin Oncol. 2016;34(suppl):11029.

    Google Scholar 

  75. Subbiah V, Anderson P, Rohren E. Alpha Emitter radium 223 in high-risk osteosarcoma: first clinical evidence of response and blood-brain barrier penetration. JAMA Oncol. 2015;1:253–5.

    Article  PubMed  Google Scholar 

  76. A phase 1b/2 trial to evaluate the safety and efficacy of radium-223 dichloride (BAY88-8223) in combination with bortezomib and dexamethasone in early relapsed multiple myeloma. NCT02928029. www.clinicaltrials.gov.

  77. Pilot trial of radium-223 and atezolizumab in patients with urothelial carcinoma with bone metastases who have had disease progression after platinum-based chemotherapy. NCT03208712. www.clinicaltrials.gov.

  78. Single arm phase II trial evaluating the efficacy of radium-223 in radioactive iodine refractory bone metastases from differentiated thyroid cancer. NCT02390934. www.clinicaltrials.gov.

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Authors and Affiliations

  1. Department of Medical Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy

    Giovanni Luca Ceresoli, Letizia Gianoncelli, Maria Bonomi & Eleonora Cerchiaro

  2. Thoracic and GU Oncology Unit, Cliniche Humanitas Gavazzeni, Bergamo, Italy

    Giovanni Luca Ceresoli

  3. Department of Nuclear Medicine, Cliniche Humanitas Gavazzeni, Bergamo, Italy

    Emilio Bombardieri

Authors
  1. Giovanni Luca Ceresoli
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  2. Letizia Gianoncelli
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  3. Maria Bonomi
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  4. Eleonora Cerchiaro
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  5. Emilio Bombardieri
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Correspondence to Giovanni Luca Ceresoli .

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Editors and Affiliations

  1. Department of Nuclear Medicine, Humanitas Gavazzeni Hospital, Bergamo, Italy

    Emilio Bombardieri

  2. Nuclear Medicine Therapy and Endocrinology, Istituto Nazionale dei Tumori, Milano, Italy

    Ettore Seregni

  3. Nuclear Medicine and Molecular Imaging Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy

    Laura Evangelista

  4. Nuclear Medicine Division, Istituto Nazionale dei Tumori, Milano, Italy

    Carlo Chiesa

  5. Nuclear Medicine, Humanitas Research Hospital, Rozzano, Milano, Italy

    Arturo Chiti

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Ceresoli, G.L., Gianoncelli, L., Bonomi, M., Cerchiaro, E., Bombardieri, E. (2018). Novel Approaches of Treatment with Radium-223 Targeted Therapy. In: Bombardieri, E., Seregni, E., Evangelista, L., Chiesa, C., Chiti, A. (eds) Clinical Applications of Nuclear Medicine Targeted Therapy . Springer, Cham. https://doi.org/10.1007/978-3-319-63067-0_28

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