A More Precise Way of Calculating the Dose Distribution at a Sub-Cellular Level In Radioligand Therapy
Abstract
Purpose
To accurately calculate the cellular-level absorbed dose for 225Ac, 177Lu, and 161Tb radioligand therapy (RLT), accounting for tumor microstructure, self-irradiation, crossfire, and bystander effects.
Methods
CT perfusion and PSMA-targeted dynamic PET studies were performed on six prostate cancer patients to calculate the tumor cellular fraction (CF) and the time-integrated activity (TIA). A 0.8 mm-sized tumor model was constructed using the TOPAS Monte Carlo toolkit by populating it with 20μm diameter spherical cells and 8μm diameter nuclei with 26μm center-to-center distance matching the same average CF from the patients. The Cell Dose Kernel (CDK), which accounts for crossfire and bystander effects, was introduced and calculated by placing radioactive sources in the central cell’s cytoplasm and calculating the dose at its own nucleus and at neighboring cells' positions. The TIA from the PSMA PET studies were randomly sampled to simulate the actual TIA maps. The convolution of CDK with the randomly sampled TIA maps estimated the dose distribution across the model while accounting for the CF, crossfire, and bystander effects.
Results
The crossfire contribution to dose was estimated to be ~70%, 73%, and 39% for 225Ac,177Lu, and 161Tb, respectively. The dose deposited within successive shells of cells for 177Lu and 161Tb decreases with distance. In contrast, 225Ac exhibits a broad peak in the first shell (~26 µm), reflecting the characteristic long-range alpha-particle Bragg peak. 161Tb has a sharper dose fall-off than 225Ac due to its short-range Auger electrons compared to the long-range alpha particles.
Conclusion
Estimating the absorbed dose considering only the self-irradiation would significantly underestimate the dose for RLT. The CDK framework, as implemented, can calculate the nucleus dose at the cellular level while overcoming the challenges of dose estimation from internalized radioligands. The sharp dose fall-off of 161Tb may help spare surrounding healthy tissue.