EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer

Abstract

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Shore ND. Radium-223 dichloride for metastatic castration-resistant prostate cancer: the urologist's perspective. Urology. 2015;85:717–24.

    Article  PubMed  Google Scholar 

  2. 2.

    Bayer AG. Xofigo Summary of Product Characteristics (SmPC). 2016.

  3. 3.

    Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467–79.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80:1588–94.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Pandit-Taskar N, Larson SM, Carrasquillo JA. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, part 1: alpha therapy with 223Ra-dichloride. J Nucl Med. 2014;55:268–74.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, 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.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, 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.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Nilsson S, Strang P, Aksnes AK, Franzen L, Olivier P, Pecking A, 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.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Parker CC, Pascoe S, Chodacki A, O'Sullivan JM, Germa JR, O'Bryan-Tear CG, 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.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, 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.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Saad F, Carles J, Gillessen S, Heidenreich A, Heinrich D, Gratt J, 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.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Crawford ED, Petrylak DP, Shore N, Saad F, Slovin SF, Vogelzang NJ, et al. The role of therapeutic layering in optimizing treatment for patients with castration-resistant prostate cancer (prostate cancer radiographic assessments for detection of advanced recurrence II). Urology. 2017;104:150–9.

    Article  PubMed  Google Scholar 

  15. 15.

    Du Y, Carrio I, De Vincentis G, Fanti S, Ilhan H, Mommsen C, et al. Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2017;44:1671–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Pezaro CJ, Omlin A, Lorente D, Nava Rodrigues D, Ferraldeschi R, Bianchini D, et al. Visceral disease in castration-resistant prostate cancer. Eur Urol. 2014;65:270–3.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Cook G Jr, Parker C, Chua S, Johnson B, Aksnes AK, Lewington VJ. 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;1:4.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Oyen WJ, Sundram F, Haug AR, Kalevi K, Lewington V, Mäenpää H, et al. Radium-223 dichloride (Ra-223) for the treatment of metastatic castration-resistant prostate cancer: Optimizing clinical practice in nuclear medicine centers. J Oncol Pathol. 2015:1–25. https://doi.org/10.13032/tjop.2052-5931.100121.

  19. 19.

    Dauer LT, Williamson MJ, Humm J, O'Donoghue J, Ghani R, Awadallah R, et al. Radiation safety considerations for the use of (2)(2)(3)RaCl(2) DE in men with castration-resistant prostate cancer. Health Phys. 2014;106:494–504.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer. 2001;91:2214–21.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Nieder C, Haukland E, Pawinski A, Dalhaug A. Anaemia and thrombocytopenia in patients with prostate cancer and bone metastases. BMC Cancer. 2010;10:284.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Wegener R, Schmickler M-R. Wichtige Informationen zu Xofigo®: temporärer Arzneimittelengpass 2014.

  23. 23.

    Chittenden SJ, Hindorf C, Parker CC, Lewington VJ, Pratt BE, Johnson B, et al. A phase 1, open-label study of the biodistribution, pharmacokinetics, and dosimetry of 223Ra-dichloride in patients with hormone-refractory prostate cancer and skeletal metastases. J Nucl Med. 2015;56:1304–9.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Carrasquillo JA, O'Donoghue JA, Pandit-Taskar N, Humm JL, Rathkopf DE, Slovin SF, et al. Phase I pharmacokinetic and biodistribution study with escalating doses of (2)(2)(3)Ra-dichloride in men with castration-resistant metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40:1384–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lassmann M, Nosske D. Dosimetry of 223Ra-chloride: dose to normal organs and tissues. Eur J Nucl Med Mol Imaging. 2013;40:207–12.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Pacilio M, Ventroni G, Cassano B, Ialongo P, Lorenzon L, Di Castro E, et al. A case report of image-based dosimetry of bone metastases with Alpharadin ((223)Ra-dichloride) therapy: inter-fraction variability of absorbed dose and follow-up. Ann Nucl Med. 2016;30:163–8.

    Article  PubMed  Google Scholar 

  27. 27.

    Pacilio M, Ventroni G, De Vincentis G, Cassano B, Pellegrini R, Di Castro E, et al. Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting (223)Ra-dichloride. Eur J Nucl Med Mol Imaging. 2016;43:21–33.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Yoshida K, Kaneta T, Takano S, Sugiura M, Kawano T, Hino A, et al. Pharmacokinetics of single dose radium-223 dichloride (BAY 88-8223) in Japanese patients with castration-resistant prostate cancer and bone metastases. Ann Nucl Med. 2016;30:453–60.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Hindorf C, Chittenden S, Aksnes AK, Parker C, Flux GD. Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun. 2012;33:726–32.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Sartor O, Coleman RE, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34:1402–18.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Thorsten D. Poeppel or Michael Gabriel.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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

Additional information

Preamble

The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association that facilitates communication worldwide between individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. EANM members are physicians, technologists, and scientists specialising in the research and practice of nuclear medicine.

The EANM will periodically define new guidelines for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients throughout Europe. Existing practice guidelines will be reviewed for revision or renewal as appropriate, on their fifth anniversary or sooner, if indicated.

Each practice guideline, representing a policy statement by the EANM, has undergone a thorough consensus process in which it has been subjected to extensive review. The EANM recognises that the safe and effective use of diagnostic nuclear medicine imaging requires specific training, skills, and techniques, as described in each document.

The EANM has written and approved these guidelines to promote the use of nuclear medicine procedures with high quality. These guidelines are intended to assist practitioners in providing appropriate nuclear medicine care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care.

The ultimate judgement regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the guidelines when, in the reasonable judgement of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the guidelines.

The practice of medicine involves not only the science but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognised that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Poeppel, T.D., Handkiewicz-Junak, D., Andreeff, M. et al. EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 45, 824–845 (2018). https://doi.org/10.1007/s00259-017-3900-4

Download citation

Keywords

  • Prostate cancer
  • Radium-223
  • Alpha emitters
  • Radionuclide therapy
  • Bone metastases
  • Survival benefit