Evaluation of the 223Ra-dichloride biodistribution models for the assessment of the doses from internal exposure


Prostate cancer is the most common men urogenital tumor. For most patients with the disseminated neoplastic process in the prostate after the hormonal therapy, the disease gradually progresses in the form of castration-resistant prostate cancer (mCRPC). The use of 223Ra agents is aimed at the treatment of the bone lesions as part of palliative therapy. The physical properties of 223Ra significantly complicate the require direct radiometry for patients with alpha emitters. Hence, the distribution of 223Ra in the body should be evaluated based on the dedicated biodistribution models. The aim of this study was to review and analyze the existing approaches to the evaluation of the biodistribution of 223Ra and its pharmaceutical forms (223Ra-dichloride) for the further assessment of absorbed doses in radiosensitive organs and tissues. The study includes the mathematical models for the estimation of the absorbed doses in various organs and tissues of the body. A review of three different 223Ra biodistribution models is presented: two ICRP models for occupational exposure and a model based on the results of an experimental assessment of 223Ra distribution in patients with mCRPC. It was indicated that the latter model is in good agreement with the results of direct radiometry of patients. A significant drawback of all models is the simulation of the red bone marrow and bone surface as single chambers. During the radionuclide therapy, 223Ra will specifically accumulate in bone metastases, instead of being evenly distributed in the skeleton. Hence, the use of any of the reviewed models will lead both to a significant overestimation of the absorbed dose in a healthy part of the bone surface and red bone marrow, and to an underestimation of the absorbed dose in bone metastases. Currently, this problem has not been solved. That requires the development of new improved models that consider the accumulation of 223Ra in the healthy part of the skeleton and in skeletal metastases.

About the authors

Aleksandr V. Vodovatov

Saint-Petersburg Research Institute of Radiation Hygiene named after Professor P.V.Ramzaev. St.-Petersburg

Author for correspondence.
Email: vodovatoff@gmail.com

Russian Federation, 197101, Saint-Petersburg, Mira st.,8

PhD, head of the laboratory of the radiation hygiene of medical facilities

Larisa A. Chipiga

Saint-Petersburg Research Institute of Radiation Hygiene after Professor P.V. Ramzaev; A. M Granov Russian Scientific Center of Radiology and Surgical Technologies

Email: larisa.chipiga@gmail.com

Russian Federation, 197101, Saint-Petersburg, Mira st.,8 Russia; 197758, Saint Petersburg, Pesochniy village, Leningradskaya st., 70, Russia

PhD, research fellow, laboratory of the radiation hygiene of medical facilities, 

Anna E. Petrova

UO “International Sakharov Environmental Institute of Belarussian State University”

Email: anyapetrova2797@gmail.com

Belarus, 220070, Minsk, Dolgobrodskaya st., 23/1, Republic of Belarus

Andrey A. Stanzhevsky

A. M Granov Russian Scientific Center of Radiology and Surgical Technologies

Email: stanzhevsky@gmail.com

Russian Federation, 197758, Saint Petersburg, Pesochniy village, Leningradskaya st., 70, Russia

deputy director for science


  1. Каприна, А.Д. Злокачественные новообразования в России в 2018 году (заболеваемость и смертность) / А.Д. Каприна, В. В. Старинский, Г. В. Петрова. – Москва: МНИОИ им. П. А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2019.
  2. Практические рекомендации по лекарственному лечению рака предстательной железы / под редакцией Д.А. Носова, Н.А. Воробьева, О.А. Гладкова [и др.] – doi: 10.18027/2224-5057-2016-4s2-343-352 // Злокачественные опухоли. – 2016. – № 4, спецвыпуск 2. – С. 343–352.
  3. Рак предстательной железы / Клинические рекомендации Министерства здравоохранения Российской Федерации. – URL: http://www.consultant.ru/document/cons_doc_LAW_325156 (дата обращения: 10.02.2020). – Текст : электронный.
  4. Nilsson S, Franzén L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: A randomised, multicentre, placebo-controlled phase II study. The Lancet Oncology. 2007; 8 (7): 587–94. doi: 10.1016/s1470-2045(07)70147-x.
  5. Kerr C. (223)Ra targets skeletal metastases and spares normal tissue. The Lancet Oncoljgy. 2002; 3 (8): 453. doi: 10.1016/s1470-2045(02)00835-5.
  6. 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. European Journal of Cancer. 2012; 48 (5): 678–86. doi: 10.1016/j.ejca.2011.12.023.
  7. 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. European Urology. 2013; 63: 189–97. doi: 10.1016/j.eururo.2012.09.008.
  8. 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. The Lancet Oncology. 2014; 15 (7): 738–46. doi: 10.1016/s1470-2045(14)70183-4.
  9. Nilsson S, Cislo P, Sartor O, et al. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Annals of Oncology. 2016; 27 (5): 868–74. doi: 10.1093/annonc/mdw065.
  10. Sgouros G, Roeske JC, McDevitt MR, et al. MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alphaparticle emitters for targeted radionuclide therapy. Journal of Nuclear Medicine. 2010; 51 (2): 311-28. Available from: http://jnm.snmjournals.org/content/51/2/311.
  11. Ritter MA, Cleaver JE, Tobias CA. High-LET radiations induce a large proportion of non-rejoining DNA breaks. Nature. 1977; 266 (5603): 653-5. doi: 10.1038/266653a0.
  12. Hall E, Giaccia A. Radiobiology for the radiologist. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2012.
  13. Hobbs RF, Song H, Watchman CJ, et al. A bone marrow toxicity model for Ra-223 αemitter radiopharmaceutical therapy. Physics in Medicine and Biology. 2012; 57 (10): 3207-22. doi: 10.1088/0031-9155/57/10/3207.
  14. Dauer LT, Mayer D. Applications of systematic error bounds to detection limits for practical counting. Health Physics. 1993; 65 (1): 89-91. doi: 10.1097/00004032-199307000-00011.
  15. ICRP Publication 107. Nuclear Decay Data for Dosimetric Calculations. Annals of the ICRP. 2008; 38 (3): 96. doi: 10.1016/j.icrp.2008.10.004.
  16. 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 Physics. 2014; 106 (4): 494–504. doi: 10.1097/hp.0b013e3182a82b37.
  17. Loevinger R, Loevinger R, Budinger TF, et al. MIRD Primer for absorbed dose calculations. Revised Edition. New York. The Society of Nuclear Medicine. 1991.
  18. Barrett PH, Bell BM, Cobelli C, et al. SAAM II: simulation, analysis, and modeling software for tracer and pharmacokinetic studies. Metabolism. 1998; 47 (4): 484–92. doi: 10.1016/s0026-0495(98)90064-6.
  19. ICRP Publication 128. Radiation Dose to Patients from Radiopharmaceuticals: A Compendium of Current Information Related to Frequently Used Substances. Annals of the ICRP. 2015; 44 (2). doi: 10.1177/2f0146645314558019.
  20. Nuclear Medicine Physics: A Handbook for Teachers and Students. In: Bailey DL, Humm JL, Todd-Pokropek A, VanAswegen A, editors. Vienna: IAEA; 2014.
  21. Bolch WE, Eckerman EF, Sgouros G, et al. MIRD Pamphlet No. 21. A generalized schema for radiopharmaceutical dosimetry – standartization of nomenclature. Journal of Nuclear Medicine. 2009; 50 (3): 477–84. doi: 10.2967/jnumed.108.056036.
  22. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: The second-generation personal computer software for internal dose assessment in nuclear medicine. Journal of Nuclear Medicine. 2005; 46 (6): 1023–27.
  23. Andersson M, Johansson L, Minarik. D. An internal radiation dosimetry computer program, IDAC 2.0, for estimation of patient dose for radiopharmaceuticals Radiation Protection Dosimetry. 2014; 162 (3): 299–305. DOI: 0.1093/rpd/nct337.
  24. Lassmann M, Nosske D. Dosimetry of 223Ra-chloride: dose to normal organs and tissues European Journal of Nuclera Medicine and Molecular Imaging. 2012; 40 (2): 207–12. doi: 10.1007/s00259-012-2265-y.
  25. ICRP, 1973. Alkaline Earth Metabolism in Adult Man. ICRP Publication 20. Pergamon Press, Oxford.
  26. ICRP Publication 67. Age-dependent doses to members of the public from intake of radionuclides. Part 2. Ingestion dose coefficients. Annals of the ICRP. 1993; 233 (3-4).
  27. Leggett RW. A generic age-specific biokinetic model for calciumlike elements. Radiation Protection Dosimetry. 1992; 41 (2-4): 183–98. doi: 10.1093/oxfordjournals.rpd.a081254.
  28. Harrison GE. Whole body retention of the alkaline earths in adult man. Health Physics. 1981; 40 (1): 95-9.
  29. Schlenker RA, Keane T, Holtzman RB. The retention of Ra-226 in human soft tissue
  30. and bone; implications for the ICRP 20 alkaline earth model. Health Physics. 1982; 42 (5): 671–93. doi: 10.1097/00004032-198205000-00010.
  31. Parks NJ, Keane AT. Consideration of age-dependent radium retention in people on the basis of the beagle model. Health Physics. 1983; 44 (1): 103–12. doi: 10.1097/00004032-198306001-00008.
  32. Keane AT. 1987. Long-term loss of radium in 63 subjects exposed at ages 6 to 46. In: Age-related factors in radionuclide metabolism and dosimetry. Gerber GB, Metivier H, Smith H, editors. Proceedings of a workshop in Angers. Dordrecht: Martinus Nijhoff Publishers; 1986.
  33. Lloyd RD, Mays CW, Taylor GN, et al. Radium-224 retention, distribution, and dosimetry in beagles. Radiation Research. 1982; 92 (2): 280–95. doi: 10.2307/3576005.
  34. Lloyd RD, Bruenger FW, Jones CW, et al. Retention in mature beagles injected at 5 years of age. Radiation Research. 1982; 94 (1): 210–216. doi: 10.2307/3575876.
  35. Lloyd RD, Bruenger FW, Mays CW, et al. Skeletal radon-to-radium ratios in neonatal, juvenile and mature beagles and in adult St. Bernards. Health Physics. 1983; 44 (1): 61–63.
  36. Lloyd RD, Jones CW, Bruenger FW, et al. Radium retention and dosimetry in juvenile beagles. Radiation Research. Radiation Research. 1983; 94 (2): 295-304. doi: 10.2307/3575964.
  37. Lloyd RD, Taylor GN, Jones CW, et al. Radium retention and dosimetry in the St. Bernard. Radiation Research. 1983; 95 (1): 150–7. doi: 10.2307/3576080.
  38. Parks NJ, Pool RR, Williams JR, et al. Age and dosage-level dependence of radium retention in beagles. Radiation Research. 1978; 75 (3): 617–32. doi: 10.2307/3574848.
  39. Newton D, Harrison GE, Kang C, et al. Metabolism of injected barium in six healthy men. Health Physics. 1991; 61 (2): 191-201. doi: 10.1097/00004032-199108000-00002.
  40. ICRP, 2018. Occupational Intakes of Radionuclides: Part 3. ICRP Publication 137. Annals of the ICRP. 46 (3-4). doi: 10.1177/0146645317734963.
  41. Radium-226: Concentration and distribution in human bone. Chinese Journal of Radiological Medicine and Protection. 1988; 8 (3): 224–5.
  42. Atherton DR, Stover BJ, Mays C. Soft tissue retention of Ra-226 in the beagle. Health Physics. 1965; 11 (2): 101–8. doi: 10.1097/00004032-196502000-00004.
  43. Stark G. Studies on synthetic hydroxyapatite crystals with regard to metabolism of calcium, strontium, barium and radium in bone. The discrimination against calcium. Biophysik. 1968; 5 (1): 42–54. doi: 10.1007/bf01388131.
  44. Neuman WF. Blood-bone exchange. In: Bone biodynamics, Frost HM, editor. Boston, Little, Brown and Co.; 1964.
  45. Maletskos CJ, Keane AT, Telles NC, et al. Retention and absorption of Ra-224 and Th-234 and some dosimetric considerations of Ra-224 in human beings. In: Delayed effects of bone-seeking radionuclides. Mays CW, Jee WSS, Lloyd RD, Stover BJ, Dougherty JH, Taylor GN, editors. Salt Lake City, UT, University of Utah Press; 1969.
  46. Taprogge J, Murray I, Gear J, et al. Compartmental model for 223Ra-Dichloride in patients with metastatic bone disease from castration-resistant prostate cancer. International Journal of Radiation Oncology, Biology, Physics. 2019; 105 (4): 1–9. doi: 10.1016/j.ijrobp.2019.07.022.
  47. Chittenden SJ, Hindorf C, Parker CC, 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. Journal of Nuclear Medicine. 2015; 56 (9): 1304–9. doi: 10.2967/jnumed.115.157123.
  48. Arsela P, Sara ER, Federica B, et al. Radium-223 in patients with metastatic castration-resistant prostate cancer: Efficacy and safety in clinical practice. Oncology Letters. 2019; 17 (2):1467–76. doi: 10.3892/ol.2018.9785.
  49. International Atomic Energy Agency. Radiation Protection and Safety of Radiation Sources: International Basic Safety Standards. GSR Part 3. Vienna: IAEA; 2015.
  50. International Atomic Energy Agency. Radiation Protection and Safety in Medical Uses of Ionizing Radiation. Specific Safety Guide № SSG-46. Vienna: IAEA; 2018.
  51. О радиационной безопасности населения Федеральный закон № 3-ФЗ : Принят Государственной Думой 5 декабря 1995 года.
  52. Публикация 103 МКРЗ. Рекомендации Международной Комиссии по Радиационной Защите от 2007 г. Пер. с англ. / под общей редакцией М.Ф. Киселева, Н.К. Шандалы. – Москва: Изд. ООО ПКФ «Алана», 2009. – 312 с.
  53. Контроль эффективных доз облучения пациентов при медицинских рентгенологических исследованиях. Методические указания МУ – Москва: Роспотребнадзор, 2011. – 40 с.
  54. International Commission on Radiological Protection. Radiological Protection in Ion Beam Radiotherapy. ICRP Publication 127. Annals of the ICRP. 2014; 43 (4):5-113. doi: 10.1177/0146645314559144.
  55. International Commission on Radiological Protection. Preventing Accidental Exposures from New External Beam Radiation Therapy Technologies. ICRP Publication 112. Annals of the ICRP. 2009; 39 (4): 1–2. doi: 10.1016/j.icrp.2009.12.001.
  56. Loreti G, Delis H, Healy B, et al. IAEA education and training activities in medical physics. Medical physics international Journal. 2015; 3 (2): 81–86. doi: 10.1016/j.ejmp.2014.07.164.



Abstract - 166

PDF (Russian) - 65


Article Metrics

Metrics Loading ...




  • There are currently no refbacks.

Copyright (c) 2020 Pharmacy Formulas

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies