Technical note: Errors introduced when using Dose Voxel Kernels for estimating absorbed dose from radiopharmaceutical therapies involving alpha emitters.

BACKGROUND: In radiopharmaceutical therapies (RPT) involving beta emitters, absorbed dose (Dabs ) calculations often employ the use of dose voxel kernels (DVK). Such methods are faster and easier to implement than Monte Carlo (MC) simulations. Using DVK methods implies a non-stochastic distribution of particles. This is a valid assumption for betas where thousands to tens of thousands of particles traversing the cell nucleus are required to achieve cell kill. However, alpha particles have linear energy transfers (LET) that are ∼500 times higher than LETs of betas. This results in a significant probability of killing a cell from even a single traversal through its nucleus. Consequently, the activity used for therapy involving alphas is very low, and the use of DVKs for estimating Dabs will generate results that may be erroneous. PURPOSE: This work aims at illustrating how use of DVKs affect the resulting Dabs in small tumors when irradiated with clinically relevant amounts of beta- and alpha-emitters. The results are compared with those from using a Monte Carlo method where the energy deposition from individual tracks is simulated. METHODS: To illustrate the issues associated with DVK for alpha radiopharmaceutical therapies at the microscale, a tumor cluster model was used to compare beta (177 Lu) and alphas (211 At, 225 Ac, and 227 Th) irradiations. We used 103 beta particles and 20 alpha particles per cell, which is within the range of the required number of particle traversals through its nucleus to sterilize a cell. Results from using both methods were presented with Dabs histograms, dose volume histograms, and Dabs error maps. RESULTS: For beta-emitter (177 Lu) irradiating the modeled tumor cluster, resulting Dabs was similar for both DVK and MC methods. For all alpha emitters, the use of DVK led to an overestimation of Dabs when compared to results generated using a MC approach. CONCLUSIONS: Our results demonstrate that the use of DVK methods for alpha emitters can lead to an overestimation in the calculated Dabs . The use of DVKs for therapies involving alpha emitters may therefore not be appropriate when only referring to the mean Dabs metric.

Technical note: Impact of dose voxel kernel (DVK) values on dosimetry estimates in 177 Lu and 90 Y radiopharmaceutical therapy (RPT) applications.

BACKGROUND: Radiopharmaceutical therapy (RPT) is an increasingly adopted modality for treating cancer. There is evidence that the optimization of the treatment based on dosimetry can improve outcomes. However, standardization of the clinical dosimetry workflow still represents a major effort. Among the many sources of variability, the impact of using different Dose Voxel Kernels (DVKs) to generate absorbed dose (AD) maps by convolution with the time-integrated activity (TIA) distribution has not been systematically investigated. PURPOSE: This study aims to compare DVKs and assess the differences in the ADs when convolving the same TIA map with different DVKs. METHODS: DVKs of 3 × 3 × 3 mm3 sampling-nine for 177 Lu, nine for 90 Y-were selected from those most used in commercial/free software or presented in prior publications. For each voxel within a 11 × 11 × 11 matrix, the coefficient of variation (CoV) and the percentage difference between maximum and minimum values (% maximum difference) were calculated. The total absorbed dose per decay (SUM), calculated as the sum of all the voxel values in each kernel, was also compared. Publicly available quantitative SPECT images for two patients treated with 177 Lu-DOTATATE and PET images for two patients treated with 90 Y-microspheres were used, including organs at risk (177 Lu: kidneys; 90 Y: liver and healthy liver) and tumors' segmentations. For each patient, the mean AD to the volumes of interest (VOIs) was calculated using the different DVKs, the same TIA map and the same software tool for dose convolution, thereby focusing on the DVK impact. For each VOI, the % maximum difference of the mean AD between maximum and minimum values was computed. RESULTS: The CoV (% maximum difference) in voxels of normalized coordinates [0,0,0], [0,1,0], and [0,1,1] were 5%(21%), 9%(35%), and 10%(46%) for the 177 Lu DVKs. For the case of 90 Y, these values were 2%(9%), 4%(14%), and 4%(16%). The CoV (% maximum difference) for SUM was 9%(33%) for 177 Lu, and 4%(15%) for 90 Y. The variability of the mean tumor and organ AD was up to 19% and 15% in 177 Lu-DOTATATE and 90 Y-microspheres patients, respectively. CONCLUSIONS: This study showed a considerable AD variability due exclusively to the use of different DVKs. A concerted effort by the scientific community would contribute to decrease these discrepancies, strengthening the consistency of AD calculation in RPT.

Therapeutic efficacy of 166Holmium siloxane in microbrachytherapy of induced glioblastoma in minipig tumor model.

Glioblastoma is considered the most common malignant primary tumor of central nervous system. In spite of the current standard and multimodal treatment, the prognosis of glioblastoma is poor. For this reason, new therapeutic approaches need to be developed to improve the survival time of the glioblastoma patient. In this study, we performed a preclinical experiment to evaluate therapeutic efficacy of 166Ho microparticle suspension administered by microbrachytherapy on a minipig glioblastoma model. Twelve minipigs were divided in 3 groups. Minipigs had injections into the tumor, containing microparticle suspensions of either 166Ho (group 1; n = 6) or 165Ho (group 2; n = 3) and control group (group 3; n = 3). The survival time from treatment to euthanasia was 66 days with a good state of health of all minipigs in group 1. The median survival time from treatment to tumor related death were 8.6 and 7.3 days in groups 2 and control, respectively. Statistically, the prolonged life of group 1 was significantly different from the two other groups (p < 0.01), and no significant difference was observed between group 2 and control (p=0.09). Our trial on the therapeutic effect of the 166Ho microparticle demonstrated an excellent efficacy in tumor control. The histological and immunohistochemical analysis showed that the efficacy was related to a severe 166Ho induced necrosis combined with an immune response due to the presence of the radioactive microparticles inside the tumors. The absence of reflux following the injections confirms the safety of the injection device.

Impact of radiopharmaceutical therapy (177Lu, 225Ac) microdistribution in a cancer-associated fibroblasts model.

BACKGROUND: The aim of this study is to elucidate the difference in absorbed dose (Dabs) patterns in radiopharmaceutical therapies between alpha emitters (225Ac) and beta emitters (177Lu) when targeting cancer-associated fibroblasts (CAF) or tumor cells. Five spherical models with 3 mm diameter were created, representing spherical tumor masses that contain tumor clusters, interspersed with CAFs. The mean distance from a tumor cell to the nearest CAF (Lmean) varied throughout these models from 92 to 1030 µm. Dabs calculations were performed while selecting either CAFs or tumor cells as sources, with Convolution/Superposition with 177Lu and Monte Carlo simulations (GATE) with 225Ac. Analyses were conducted with Dose Volume Histograms and efficacy ratios (ER), which represents the ratio of mean Dabs that is deposited in the target volume. RESULTS: 225Ac is the most optimal radionuclide when CAFs are both targeted and irradiating themselves, as ERs increase from 1.5 to 3.7 when Lmean increases from 92 to 1030 µm. With 177Lu, these numbers vary from 1.2 to 2.7. Conversely, when CAFs are sources and tumors are targets with 225Ac, ERs decreased from 0.8 to 0.1 when Lmean increases from 92 to 1030 µm. With 177Lu, these numbers vary from 0.9 to 0.3 CONCLUSION: When targeting CAFs to irradiate tumors, the efficacy of using 225Ac decreases as the average size of the tumor clusters (or Lmean) increases. In such situations, 177Lu will be more effective than 225Ac when targeting CAFs due to the longer beta particle range.

Effect of microdistribution of alpha and beta-emitters in targeted radionuclide therapies on delivered absorbed dose in a GATE model of bone marrow.

Acute hematologic toxicity is a frequent adverse effect of beta-emitter targeted radionuclide therapies (TRTs). Alpha emitters have the potential of delivering high linear energy transfer (LET) radiation to the tumor attributed to its shorter range. Antibody-based TRTs have increased blood-pool half-lives, and therefore increased marrow toxicity, which is a particular concern with alpha emitters. Accurate 3D absorbed dose calculations focusing on the interface region of blood vessels and bone can elucidate energy deposition patterns. Firstly, a cylindrical geometry model with a central blood vessel embedded in the trabecular tissue was modeled. Monte Carlo simulations in GATE were performed considering beta (177Lu, 90Y) and alpha emitters (211At, 225Ac) as sources restricted to the blood pool. Subsequently, the radioactive sources were added in the trabecular bone compartment in order to model bone marrow metastases infiltration (BMMI). Radial profiles, dose-volume histograms and voxel relative differences were used to evaluate the absorbed dose results. We demonstrated that alpha emitters have a higher localized energy deposition compared to beta emitters. In the cylindrical geometry model, when the sources are confined to the blood pool, the dose to the trabecular bone is greater for beta emitting radionuclides, as alpha emitters deposit the majority of their energy within 70 µm of the vessel wall. In the BMMI model, alpha emitters have a lower dose to untargeted trabecular bone. Our results suggest that when alpha emitters are restricted to the blood pool, as when labeled to antibodies, hematologic toxicities may be lower than expected due to differences in the microdistribution of delivered absorbed dose.

Monte Carlo dosimetry of a realistic multicellular model of follicular lymphoma in a context of radioimmunotherapy.

PURPOSE: Small-scale dosimetry studies generally consider an artificial environment where the tumors are spherical and the radionuclides are homogeneously biodistributed. However, tumor shapes are irregular and radiopharmaceutical biodistributions are heterogeneous, impacting the energy deposition in targeted radionuclide therapy. To bring realism, we developed a dosimetric methodology based on a three-dimensional in vitro model of follicular lymphoma incubated with rituximab, an anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin lymphomas, which might be combined with a radionuclide. The effects of the realistic geometry and biodistribution on the absorbed dose were highlighted by comparison with literature data. Additionally, to illustrate the possibilities of this methodology, the effect of different radionuclides on the absorbed dose distribution delivered to the in vitro tumor were compared. METHODS: The starting point was a model named multicellular aggregates of lymphoma cells (MALC). Three MALCs of different dimensions and their rituximab biodistribution were considered. Geometry, antibody location and concentration were extracted from selective plane illumination microscopy. Assuming antibody radiolabeling with Auger electron (125 I and 111 In) and ß- particle emitters (177 Lu, 131 I and 90 Y), we simulated energy deposition in MALCs using two Monte Carlo codes: Geant4-DNA with "CPA100" physics models for Auger electron emitters and Geant4 with "Livermore" physics models for ß- particle emitters. RESULTS: MALCs had ellipsoid-like shapes with major radii, r, of ~0.25, ~0.5 and ~1.3 mm. Rituximab was concentrated in the periphery of the MALCs. The absorbed doses delivered by 177 Lu, 131 I and 90 Y in MALCs were compared with literature data for spheres with two types of homogeneous biodistributions (on the surface or throughout the volume). Compared to the MALCs, the mean absorbed doses delivered in spheres with surface biodistributions were between 18% and 38% lower, while with volume biodistribution they were between 15% and 29% higher. Regarding the radionuclides comparison, the relationship between MALC dimensions, rituximab biodistribution and energy released per decay impacted the absorbed doses. Despite releasing less energy, 125 I delivered a greater absorbed dose per decay than 111 In in the r ~ 0.25 mm MALC (6.78·10-2 vs 6.26·10-2  µGy·Bq-1 ·s-1 ). Similarly, the absorbed doses per decay in the r ~ 0.5 mm MALC for 177 Lu (2.41·10-2  µGy·Bq-1 ·s-1 ) and 131 I (2.46·10-2  µGy·Bq-1 ·s-1 ) are higher than for 90 Y (1.98·10-2  µGy·Bq-1 ·s-1 ). Furthermore, radionuclides releasing more energy per decay delivered absorbed dose more uniformly through the MALCs. Finally, when considering the radiopharmaceutical effective half-life, due to the biological half-life of rituximab being best matched by the physical half-life of 177 Lu and 131 I compared to 90 Y, the first two radionuclides delivered higher absorbed doses. CONCLUSION: In the simulated configurations, ß- emitters delivered higher and more uniform absorbed dose than Auger electron emitters. When considering radiopharmaceutical half-lives, 177 Lu and 131 I delivered absorbed doses higher than 90 Y. In view of real irradiation of MALCs, such a work may be useful to select suited radionuclides and to help explain the biological effects.