Comparative Dosimetry of Single and Hybrid 177Lu, 161Tb, and 90Y in PSMA-Targeted Therapy

Background: Patient-specific targeted radionuclide therapy (TRT) requires consideration not only of administered activity but also of the spatial distribution of radiopharmaceutical uptake and radionuclide-specific energy deposition. This study developed a voxel-based computational workplan to compare 177Lu, 161Tb and 90Y, together with hybrid radionuclide models, using patient-specific PSMA PET-derived tumour activity distributions. Methods: PSMA PET/CT data from 20 patients with prostate cancer, comprising 10 18F-PSMA and 10 68Ga-PSMA examinations, were processed to obtain 2285 quality-filtered lesions. Radionuclide-specific dose-point kernels (DPKs) were generated in water using OpenGATE and applied to voxel-wise lesion activity distributions to reconstruct absorbed-dose maps. Kernel characteristics were evaluated using radial energy-containment metrics, and 177Lu, representing 161Tb simulations, was subjected to grid-convergence testing and external comparison with a published DPK. Lesion dosimetry was assessed using Dmean, D90, D95, equivalent uniform dose (EUD) and tumour control probability (TCP), with uncertainty quantified using patient-cluster bootstrap confidence intervals. Kinetic sensitivity and diagnostic tracer subgroup analyses were additionally performed. Results: The study showed that 161Tb produced the highest median lesion-level Dmean, D90, D95 and EUD at 182.79, 136.28, 132.07 and 148.53 Gy, respectively, with a median TCP of 0.981. Corresponding values for 177Lu were 141.33, 105.42, 102.10 and 114.78 Gy (TCP 0.930), while 90Y produced lower local dose metrics but the broadest radial dose distribution, consistent with its longer-range β-particle crossfire. 161Tb remained the highest-ranking radionuclide across the investigated kinetic cases and within both diagnostic tracer subgroups. Hybrid 161Tb/90Y kernels provided a controllable compromise between localised energy deposition and extended crossfire; a 70:30 model increased central dose localisation while retaining an R90 and R95 of 6 and 7 mm, respectively. Grid-convergence and published-DPK comparisons supported the numerical adequacy of the kernel methodology. Radionuclide emission characteristics substantially influence the transformation of heterogeneous tumour uptake into spatial absorbed-dose distributions. Within this model, 161Tb provided the strongest overall lesion-level dosimetric performance, whereas the extended range of 90Y may offer complementary crossfire for selected bulky or heterogeneous lesions. Conclusions: The findings support phenotype-informed radionuclide comparison and provide a computational basis for investigating hybrid strategies. However, the absolute dose estimates and proposed radionuclide combinations remain model-based and require validation using serial therapeutic imaging, heterogeneous patient-specific dosimetry and normal-organ dose constraints before clinical translation.