A bone marrow toxicity model for 223 Ra alpha-emitter radiopharmaceutical therapy
Open accessAbstract
Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation.
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For bone-targeting alpha RPT such as 223RaCl2, a calculated average marrow absorbed dose will overestimate the potential biologic impact.
“Average marrow absorbed dose from antibody, peptide, or small molecule -based a RPT is likely to predict hematologic toxicity whereas bone targeting agents such as 223 RaCl2 will overestimate the potential biologic impact of a calculated average marrow absorbed dose ( 45 ).”
From Normal-Tissue Tolerance to Radiopharmaceutical Therapies, the Knowns and the Unknowns (2021) · cites this paper as [45]
Average marrow absorbed dose from antibody, peptide, or small molecule-based alpha RPT is likely to predict hematologic toxicity.
“Average marrow absorbed dose from antibody, peptide, or small molecule -based a RPT is likely to predict hematologic toxicity whereas bone targeting agents such as 223 RaCl2 will overestimate the potential biologic impact of a calculated average marrow absorbed dose ( 45 ).”
From Normal-Tissue Tolerance to Radiopharmaceutical Therapies, the Knowns and the Unknowns (2021) · cites this paper as [45]
The Conclusions (page unavailable) say that average marrow dose may not reflect biological outcome for bone-targeted ²²³Ra therapy. The Introduction mentions radioimmunotherapy, but our copy does not say that average marrow dose predicts hematologic toxicity for antibody-, peptide-, or small-molecule-based alpha therapy (searched those agent types and the proposed dose–toxicity relationship). (LLM, conf=0.74)
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- Authors
- Hobbs, R. F., Song, H., Watchman, C. J., Bolch, W. E., Aksnes, A.-K., Ramdahl, T., Flux, G. D., & Sgouros, G.
- Affiliations
- Johns Hopkins University (US)
- University of Arizona (US)
- University of Florida (US)
- Royal Marsden NHS Foundation Trust (GB)
- Corresponding author
- Hobbs, Robert F
- Watchman, Christopher J
- Bolch, Wesley E
- Aksnes, Anne-Kirsti
- Ramdahl, Thomas
- Flux, Glenn D
- Sgouros, George
- Venue
- Physics in Medicine and Biology
- Publisher
- IOP Publishing
- Published
- 2012-05-01
- Volume
- 57
- Issue
- 10
- Pages
- 3207-3222
- ISSN
- 0031-9155 (ISSN-L)
- 1361-6560
- PMC
- PMC3442928
- OpenAlex
- W2109768758
- Cited by
- 122
- References
- 43
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 3 · 2023: 4 · 2022: 13 · 2021: 11 · 2020: 14 · 2019: 8 · 2018: 8 · 2017: 7 · 2016: 13 · 2015: 13 · 2014: 6 · 2013: 7 · 2012: 3
- FWCI
- 7.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Physics in Medicine and Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000064)
- National Cancer Institute (R01CA157542, R01CA116477)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Health Professions › Radiological and Ultrasound Technology › Radioactivity and Radon Measurements
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- radium-223, alpha-emitting radiopharmaceuticals, myelosuppression, fraction absorbed, trabecular bone, bone-seeking radionuclides, prostate cancer bone metastasis, absorbed dose distribution, Geant4 simulation
- MeSH terms
- Alpha Particles, Bone Marrow, Models, Biological, Radiation Dosage, Radium, Radiopharmaceuticals
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