Influence of dosimetry method on bone lesion absorbed dose estimates in PSMA therapy: application to mCRPC patients receiving Lu-177-PSMA-I&T

Background Patients with metastatic, castration-resistant prostate cancer (mCRPC) present with an increased tumor burden in the skeleton. For these patients, Lutetium-177 (Lu-177) radioligand therapy targeting the prostate-specific membrane antigen (PSMA) has gained increasing interest with promising outcome data. Patient-individualized dosimetry enables improvement of therapy success with the aim of minimizing absorbed dose to organs at risk while maximizing absorbed dose to tumors. Different dosimetric approaches with varying complexity and accuracy exist for this purpose. The Medical Internal Radiation Dose (MIRD) formalism applied to tumors assumes a homogeneous activity distribution in a sphere with unit density for derivation of tumor S values (TSV). Voxel S value (VSV) approaches can account for heterogeneous activities but are simulated for a specific tissue. Full patient-individual Monte Carlo (MC) absorbed dose simulation addresses both, heterogeneous activity and density distributions. Subsequent CT-based density weighting has the potential to overcome the assumption of homogeneous density in the MIRD formalism with TSV and VSV methods, which could be a major limitation for the application in bone metastases with heterogeneous density. The aim of this investigation is a comparison of these methods for bone lesion dosimetry in mCRPC patients receiving Lu-177-PSMA therapy. Results In total, 289 bone lesions in 15 mCRPC patients were analyzed. Percentage difference (PD) of average absorbed dose per lesion compared to MC, averaged over all lesions, was + 14 ± 10% (min: − 21%; max: + 56%) for TSVs. With lesion-individual density weighting using Hounsfield Unit (HU)-to-density conversion on the patient’s CT image, PD was reduced to − 8 ± 1% (min: − 10%; max: − 3%). PD on a voxel level for three-dimensional (3D) voxel-wise dosimetry methods, averaged per lesion, revealed large PDs of + 18 ± 11% (min: − 27%; max: + 58%) for a soft tissue VSV approach compared to MC; after voxel-wise density correction, this was reduced to − 5 ± 1% (min: − 12%; max: − 2%). Conclusion Patient-individual MC absorbed dose simulation is capable to account for heterogeneous densities in bone lesions. Since the computational effort prevents its routine clinical application, TSV or VSV dosimetry approaches are used. This study showed the necessity of lesion-individual density weighting for TSV or VSV in Lu-177-PSMA therapy bone lesion dosimetry.

Influence of dosimetry method on bone lesion absorbed dose estimates in PSMA therapy: application to mCRPC patients receiving Lu-177-PSMA-I&T

Background Patients with metastatic, castration-resistant prostate cancer (mCRPC) present with an increased tumor burden in the skeleton. For these patients, Lutetium-177 (Lu-177) radioligand therapy targeting the prostate-specific membrane antigen (PSMA) has gained increasing interest with promising outcome data. Patient-individualized dosimetry enables quantification of therapy success with the aim of minimizing absorbed dose to organs at risk while maximizing absorbed dose to tumors. Different dosimetric approaches with varying complexity and accuracy exist for this purpose. The relatively simple OLINDA method applied to tumors assumes a homogeneous activity distribution in a sphere with unit density. Voxel S value (VSV) approaches can account for heterogeneous activities but are simulated for a specific tissue. Full patient-individual Monte Carlo (MC) dose simulation addresses both, heterogeneous activity and density distributions. Subsequent CT-based density correction has the potential to overcome the assumption of homogeneous density in OLINDA and VSV methods, which could be a major limitation for the application in bone metastases with heterogeneous density. The aim of this investigation is a comparison of these methods for bone lesion dosimetry in mCRPC patients receiving Lu-177-PSMA therapy. Results In total, 289 bone lesions in 15 mCRPC patients were analyzed. Percentage deviation (PD) of absorbed lesion doses compared to full MC was + 7 ± 13% (min: -60%; max: +47%) for the OLINDA unit density sphere model. With an applied CT-based density weighting to account for density differences in bone lesions, PD was − 15 ± 6% (min: -54%; max: -2%). For a soft tissue VSV approach, large PDs of + 16 ± 13% (min: -56%; max: +57%) were found; after voxel-wise density correction this was reduced to -5 ± 2% (min: -15%; max: -2%). The use of a combination of standard soft tissue and cortical bone VSVs showed deviations of -35 ± 8% (min: -76%; max: +5%). With additional voxel-wise density weighting, the PD was − 3 ± 2% (min: -13%; max: 0%). Conclusion Based on our bone lesion dosimetry results, a VSV approach with subsequent CT-based, voxel-wise density correction enabled dose estimates, that closely replicate computationally-demanding gold-standard full MC dose simulations.

How do velocity structure functions trace gas dynamics in simulated molecular clouds?

Context. Supersonic disordered flows accompany the formation and evolution of molecular clouds (MCs). It has been argued that this is turbulence that can support against gravitational collapse and form hierarchical sub-structures. Aims. We examine the time evolution of simulated MCs to investigate: What physical process dominates the driving of turbulent flows? How can these flows be characterised? Are they consistent with uniform turbulence or gravitational collapse? Do the simulated flows agree with observations? Methods. We analysed three MCs that have formed self-consistently within kiloparsec-scale numerical simulations of the interstellar medium (ISM). The simulated ISM evolves under the influence of physical processes including self-gravity, stratification, magnetic fields, supernova-driven turbulence, and radiative heating and cooling. We characterise the flows using velocity structure functions (VSFs) with and without density weighting or a density cutoff, and computed in one or three dimensions. However, we do not include optical depth effects that can hide motions in the densest gas, limiting comparison of our results with observations. Results. In regions with sufficient resolution, the density-weighted VSFs initially appear to follow the expectations for uniform turbulence, with a first-order power-law exponent consistent with Larson’s size-velocity relationship. Supernova blast wave impacts on MCs produce short-lived coherent motions at large scales, increasing the scaling exponents for a crossing time. Gravitational contraction drives small-scale motions, producing scaling coefficients that drop or even turn negative as small scales become dominant. Removing the density weighting eliminates this effect as it emphasises the diffuse ISM. Conclusions. We conclude that two different effects coincidentally reproduce Larson’s size velocity relationship. Initially, uniform turbulence dominates, so the energy cascade produces VSFs that are consistent with Larson’s relationship. Later, contraction dominates and the density-weighted VSFs become much shallower or even inverted, but the relationship of the global average velocity dispersion of the MCs to their radius follows Larson’s relationship, reflecting virial equilibrium or free-fall collapse. The injection of energy by shocks is visible in the VSFs, but decays within a crossing time.