Toward a gold standard for dose enhanced radiotherapy [electronic resource] : physics simulations and biological experiments to better understand the mechanisms of a new cancer treatment
Keywords: Physics.

Dose enhanced radiotherapy uses high atomic number materials, e.g., iodine and gold, to increase local dose from radiation, such as x-rays. The efficacy of this technique has been demonstrated in many systems but results have not been consistent, especially for recent studies with gold nanoparticles. The fundamental enhancement mechanism could be due to photoelectrons, Auger electrons, chemical, or biological effects. This study aims to further scientific understanding of the dose enhancement mechanisms by performing detailed Monte Carlo simulations that match a specific biological system. I performed clonogenic assays with CHO-AA8 cells to measure dose enhancement from iodine with 100 kVp and 225 kVp beams. Enhancement is linear with concentration and higher for the 100 kVp beam than the 225 kVp beam. The measured enhancement varied depending on the analysis technique used: least squares fitting to the linear-quadratic (LQ) model, general linear model fitting to the LQ-model, or a simultaneous fit to all concentrations to a modified LQ-model. This variation was largest using a least square fit to individual concentration curves with the dose enhancement measured through the Sensitization Enhancement Ratio (SER). The SER requires a choice of specific surviving fraction, which is arbitrary. For reasonable choices of surviving fraction, the measured enhancement varied from 2.0 to 2.3 for the 225 kVp beam with 30 mg/mL of iodine. Using a generalized linear model fit to individual concentrations resulted in smaller variations. The simultaneous fit provided a direct measure of enhancement that required fewer fit parameters. Geant4 was used to simulate dose enhancement in a cell monolayer geometry due to iodine, gold, and tungsten. Individual cellular and nuclear volumes were specified, with a production cut below 1 keV. No significant difference was seen between measuring dose enhancement in the cellular and nuclear volumes. Enhancement was linear with concentration. Photoelectrons were primarily responsible for enhancement, with no significant contribution seen from Auger electrons. A double strand break (DSB) yield model was used in addition to the Geant4 simulation as a second measure of enhancement. Enhancement was calculated from the energy spectrum of electrons entering the nucleus, with the DSB-yield model predicting that lower energy electrons would contribute greater DNA damage. The DSB-yield enhancement agreed with the Geant4 enhancement for the 225 kVp beam, but predicted greater dose enhancement for the 100 kVp beam. The gamma-H2AX assay was used to directly probe double strand breaks in cells following irradiation. While evidence for dose enhancement was seen over a small range of doses, it was not possible to quantitatively measure dose enhancement. The Geant4-modeled dose enhancement under-predicts the enhancement measured in the biological system with the clonogenic assay. For the 100 kVp beam, the increased enhancement from the DSB-yield model remedies this difference. Further improvements must be made to the simulation model to better predict the biological response.