BEST IN PHYSICS (THERAPY): Tumor Dose Heterogeneity Informed Biological Optimization of Combination Lu-177 PSMA Radiopharmaceutical Therapy and Ir-192 High Dose Rate Prostate Brachytherapy
Abstract
Purpose
Focal dose escalation to the dominant intraprostatic lesion (GTV) improves biochemical control but is limited by urethral toxicity. 177Lu-PSMA radiopharmaceutical therapy (RPT) offers a targeted boost, yet its spatial heterogeneity in uptake leaves GTV sub-regions underdosed. Current combinatorial approaches plan these modalities independently rather than as synergistic partners. This study introduces the first heterogeneity-aware joint biological optimization framework that treats patient-specific RPT dose as spatial background, enabling HDR brachytherapy to selectively target intraprostatic RPT cold-spots.
Methods
A patient-specific dosimetry workflow using pre-HDR brachytherapy 18F-PSMA PET/CT data was developed. Tumor time-integrated activity was predicted via single-time-point dosimetry by scaling PET uptake with a population tumor pharmacokinetic model based on 177Lu-PSMA multi-timepoint SPECT/CT images (N=17 patients, 162 lesions; R2=0.92). Voxel-level absorbed doses were calculated using GPU-accelerated Monte Carlo simulation and converted to biologically effective dose (BED) from physical dose rate per 7.4GBq injection. The retrospective intraprocedural HDR CT was then rigidly registered to the prostate in the PET/CT. A novel optimization algorithm using FISTA with group minimax concave penalty for catheter selection and sparsity was applied that simultaneously optimized catheter positions and dwell times to generate three comparative plans: (1) standard HDR monotherapy (16 catheters), (2) joint RPT+HDR (16 catheters), and (3) de-escalated joint RPT+HDR (12 catheters). All HDR components were normalized to equivalent PTV V100%=95%.
Results
The simulated 177Lu-PSMA dose distribution confirmed substantial GTV dose heterogeneity (2-85Gy(BED)). Joint optimization leveraged this heterogeneity to enable a 25% catheter reduction (16 to 12) while maintaining OAR doses within existing constraints for EBRT+HDR (urethra D0.1cc:78.6<120Gy(EQD2); rectum D2cc:32.1<75Gy(EQD2)). The optimized HDR contribution formed a spatial complement concentrated in PSMA-cold regions receiving less RPT coverage, with minimal contribution where RPT provided greater dose.
Conclusion
This study demonstrates the framework for heterogeneity-aware joint optimization for combined RPT and HDR brachytherapy, establishing methodology for prospective clinical implementation.