Mechanistic Modeling of Radium-223 Treatment of Bone Metastases

Purpose: Despite the effectiveness of (RaCl2)-Ra-223 for treating patients with symptomatic bone metastatic disease, its mechanisms of action are still unclear. Even established dosimetric approaches differ considerably in their conclusions. In silico tumor models bring a new perspective to this situation because they can quantitatively simulate the interaction of alpha-particles with the target(s). Here, we investigated 3 different mathematical models of tumor growth that consider the radiation effect of radium-223 (Ra-223) treatments and compared the results with clinical data. Methods and Materials: The well-established Gompertz growth model was applied to simulate metastatic tumor burden. On the basis of published measurements of Ra-223 uptake, we have incorporated the radiation effect of alpha-particles into the model and investigated 3 radium distribution scenarios-uniform exposure, exposure of only an outer layer, and exposure of a constant volume of the tumor. For each scenario, the times for various tumor stages to progress to the first symptomatic skeletal event were calculated. Results: Uniform and outer-layer exposure scenarios showed very poor agreement with the Kaplan-Meier patient curves from clinical data. However, the constant-volume effect predicted outcomes very similar to the observed clinical results, suggesting, depending on the dose rate, that relatively small fractions of the cell population see damage from Ra-223. Conclusions: The commonly used assumption of uniform Ra-223 distribution does not accurately reflect clinical responses. The suggestion that only a subpopulation of the tumor might be affected by Ra-223 shows a pressing need to further study the tumor and drug kinetics to schedule more effective treatments in the future. (C) 2018 Elsevier Inc. All rights reserved.