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

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.

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.

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.

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.