Optimizing Radiopharmaceutical Dosage: A DNA Damage-Based Framework to Maximize Tumor Control and Minimize Normal Tissue Damage
Abstract
Purpose
We introduce a framework to optimize administered radioligand activity by calculating DNA lethal lesions (LLs), balancing maximal tumor control with minimal normal tissue damage.
Methods
A 0.8mm micro-tumor model was built in TOPAS with spherical cells (20µm) and nuclei (8µm) at a cellular fraction of 0.24 (29,791 cells), surrounded by six healthy cell layers. Cell Dose Kernels (CDKs) for ²²⁵Ac, ¹⁶¹Tb, and ¹⁷⁷Lu were derived by depositing activity only in the central cell's cytoplasm and measuring the absorbed dose in its nucleus and in neighboring non-radioactive cells. Absorbed dose maps, incorporating crossfire and bystander effects, were generated by convolving the CDKs with tumor time-integrated activity (TIA) maps. These TIA maps were created by randomly sampling patient-derived TIA distributions to simulate stochastic radionuclide decay. Lethal lesion volume histograms (LLVHs) were computed using a modified linear-quadratic model. The survival fraction (SF=e-λ) and Tumor Control Probability (TCP=e-NSF) were calculated from the mean LLs (λ) and initial cells number (N), enabling activity modulation to achieve a desired TCP.
Results
The LLVHs show that one cycle of 225Ac, 161Tb, and 177Lu at clinically utilized doses produced approximately 10, 18, and 4 LLs in 95% of the tumor volume, respectively. When the 225Ac, 161Tb, and 177Lu activities were optimized to induce 5 LLs/cycle, -54% (3.2 MBq/cycle), -71% (2.1GBq/cycle), and +10% (8.2 GBq/cycle) were required, respectively, compared to the clinically utilized dose. ¹⁶¹Tb induced fewer LLs in normal surrounding cells than ²²⁵Ac, because its Auger electrons have a shorter range than the Bragg peaks of alpha particles from ²²⁵Ac.
Conclusion
This framework calculates LLs integrating crossfire, bystander effects, radiation quality, and DNA repair. It enables adaptive, cycle-to-cycle activity modulation based on updated cellular fraction measured from PET and survived clonogenic cells, aiming to achieve optimal TCP at treatment's end while minimizing damage to neighboring healthy tissue.