A bone marrow toxicity model for²²³Ra alpha-emitter radiopharmaceutical therapy

Abstract

Purpose Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metasteses 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. Methods 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. Results The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histograms 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 Gy to 20 Gy. Conclusion 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.

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

“…Absorbed doses are primarily delivered to the red marrow from circulating blood and from uptake on the bone surfaces. However, a emissions will irradiate only a small fraction of the red marrow because of their short range (28). The absorbed dose delivered from the circulating activity may therefore be a more relevant guide to the potential for marrow toxicity than that due to activity on the bone surfaces.…”

Radium-223: Insight and Perspectives in Bone-metastatic Castration-resistant Prostate Cancer

“…The physically larger alpha particle manifests a shallow penetration until the cortical bone region where the metastases should be located (64). In their model, for the estimation of osseous radiation absorption, Hobbs et al attested that the majority of radiation dose is deposited near the trabecular elements (65). Moreover, dosimetric considerations indicated that assuming a 0.67 Bq/mm 2 dose of 223 Ra on the surface of a sphere with 250 μm radius, the estimated absorbed dose quickly decreased from 65 Gy to 0 Gy at from 5 μm to 70 μm deep, respectively.…”

Bone-Seeking Radiopharmaceuticals for Treatment of Osseous Metastases, Part 1: α Therapy with 223Ra-Dichloride

“…The high linear energy transfer of a radiation results in a greater biologic effectiveness than b radiation, as well as generation of double-strand DNA breaks, and gives rise to cytotoxicity that is independent of dose rate, cell cycle growth phase, and oxygen concentration (19). The range of the a particles (,100 mm) is much smaller than the 0.7-cm path length of 89 Sr and the 0.33-cm path length of 153 Sm; as a result, less hematologic toxicity for a given bone surface dose would be expected from a emitters than from b emitters (20). It is estimated that as few as 1-20 a tracks crossing the nucleus will result in cell death (19).…”

“…Hobbs et al estimated the percentage of cells that receive a potentially toxic absorbed dose (2 or 4 Gy). On the basis of the model, it is estimated that the majority of the radiation dose is deposited near the trabecular elements, substantially decreasing the risk of marrow toxicity at higher doses (20). Using an International Commission on Radiological Protection biokinetic model for alkaline earth elements, Lassman et al estimated the absorbed dose to organs from 223 Ra.…”

“…Compared with b emitters, 223 Ra has the theoretic advantage of sparing much of the marrow irradiation given the short-range emissions (15,20,28). Although the activity of administered 223 Ra has ranged from single injections of 5 kBq/kg to 250 kBq/kg and maximum fractionated activity of up to 300 kBq/kg (12,24), a maximum tolerated dose has not been reached.…”