Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine + Rituximab in Low-grade Lymphomas.

BACKGROUND: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine + rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. PATIENTS AND METHODS: We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N = 51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N = 92). RESULTS: Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P = .18), complete response rate (94% vs. 95%, P = .91), or 5 years progression-free survival (76% vs. 75%, P = .63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. CONCLUSION: The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

An Analytical Microdosimetric Model for Radioimmunotherapeutic Alpha Emitters.

In this work, we present a methodology to analytically determine microdosimetric quantities in radioimmunotherapy and targeted radiotherapy with alpha particles. Monte Carlo simulations using the Geant4-DNA toolkit, which provides interaction models at the microscopic level, are performed for monoenergetic alpha particles traversing spherical sites with diameters of 1, 5 and 10 µm. An analytical function is fitted against the data in each case to model the energy imparted by monoenergetic particles to the site, as well as the variance of the distribution of energy imparted. Those models allow us to obtain the mean and dose-mean values of specific energy (z) and lineal energy (y) for polyenergetic arrangements of alpha particles. The energetic spectrum is estimated by considering the distance that each particle needs to travel to reach the sensitive target. We apply this methodology to a simple case in radioimmunotherapy: a spherical cell that has its membrane uniformly covered by 211At, an alpha emitter, with a spherical target representing the nucleus, placed at the center of the cell. We compare the results of our analytical method with calculations using Geant4-DNA of this specific setup for three nucleus sizes corresponding to our three functions. For nuclei with diameter of 1 µm and 5 µm, all mean and dose-mean quantities for y and z were in an agreement within 4% to Geant4-DNA calculations. This agreement improves to approximately 1% for dose-mean lineal energy and dose-mean specific energy. For the 10-µm-diameter case, discrepancies scale to approximately 9% for mean values and 3% for dose-mean values. Dose-mean values are within Geant4-DNA uncertainties in all cases. Our method provides accurate analytical calculations of dose-mean quantities that may be further employed to characterize radiobiological effectiveness of targeted radiotherapy. The spatial distributions of sources and targets are required to calculate microdosimetric-relevant quantities.

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.

Harnessing radiation to improve immunotherapy: better with particles?

The combination of radiotherapy and immunotherapy is one of the most promising strategies for cancer treatment. Recent clinical results support the pre-clinical experiments pointing to a benefit for the combined treatment in metastatic patients. Charged particle therapy (using protons or heavier ions) is considered one of the most advanced radiotherapy techniques, but its cost remains higher than conventional X-ray therapy. The most important question to be addressed to justify a more widespread use of particle therapy is whether they can be more effective than X-rays in combination with immunotherapy. Protons and heavy ions have physical advantages compared to X-rays that lead to a reduced damage to the immune cells, that are required for an effective immune response. Moreover, densely ionizing radiation may have biological advantages, due to different cell death pathways and release of cytokine mediators of inflammation. We will discuss results in esophageal cancer patients showing that charged particles can reduce the damage to blood lymphocytes compared to X-rays, and preliminary in vitro studies pointing to an increased release of immune-stimulating cytokines after heavy ion exposure. Pre-clinical and clinical studies are ongoing to test these hypotheses.

Assessment of cell death mechanisms triggered by 177Lu-anti-CD20 in lymphoma cells.

The aim of this research was to evaluate the cell cycle redistribution and activation of early and late apoptotic pathways in lymphoma cells after treatment with 177Lu-anti-CD20. Experimental and computer models were used to calculate the radiation absorbed dose to cancer cell nuclei. The computer model (Monte Carlo, PENELOPE) consisted of twenty spheres representing cells with an inner sphere (cell nucleus) embedded in culture media. Radiation emissions of the radiopharmaceutical located in cell membranes and in culture media were considered for nuclei dose calculations. Flow cytometric analyses demonstrated that doses as low as 4.8Gy are enough to induce cell cycle arrest and activate late apoptotic pathways.

Accuracy of Rhenium-188 SPECT/CT activity quantification for applications in radionuclide therapy using clinical reconstruction methods.

The main applications of 188Re in radionuclide therapies include trans-arterial liver radioembolization and palliation of painful bone-metastases. In order to optimize 188Re therapies, the accurate determination of radiation dose delivered to tumors and organs at risk is required. Single photon emission computed tomography (SPECT) can be used to perform such dosimetry calculations. However, the accuracy of dosimetry estimates strongly depends on the accuracy of activity quantification in 188Re images. In this study, we performed a series of phantom experiments aiming to investigate the accuracy of activity quantification for 188Re SPECT using high-energy and medium-energy collimators. Objects of different shapes and sizes were scanned in Air, non-radioactive water (Cold-water) and water with activity (Hot-water). The ordered subset expectation maximization algorithm with clinically available corrections (CT-based attenuation, triple-energy window (TEW) scatter and resolution recovery was used). For high activities, the dead-time corrections were applied. The accuracy of activity quantification was evaluated using the ratio of the reconstructed activity in each object to this object's true activity. Each object's activity was determined with three segmentation methods: a 1% fixed threshold (for cold background), a 40% fixed threshold and a CT-based segmentation. Additionally, the activity recovered in the entire phantom, as well as the average activity concentration of the phantom background were compared to their true values. Finally, Monte-Carlo simulations of a commercial [Formula: see text]-camera were performed to investigate the accuracy of the TEW method. Good quantification accuracy (errors <10%) was achieved for the entire phantom, the hot-background activity concentration and for objects in cold background segmented with a 1% threshold. However, the accuracy of activity quantification for objects segmented with 40% threshold or CT-based methods decreased (errors >15%), mostly due to partial-volume effects. The Monte-Carlo simulations confirmed that TEW-scatter correction applied to 188Re, although practical, yields only approximate estimates of the true scatter.

Dosimetry applications in GATE Monte Carlo toolkit.

PURPOSE: Monte Carlo (MC) simulations are a well-established method for studying physical processes in medical physics. The purpose of this review is to present GATE dosimetry applications on diagnostic and therapeutic simulated protocols. There is a significant need for accurate quantification of the absorbed dose in several specific applications such as preclinical and pediatric studies. METHODS: GATE is an open-source MC toolkit for simulating imaging, radiotherapy (RT) and dosimetry applications in a user-friendly environment, which is well validated and widely accepted by the scientific community. In RT applications, during treatment planning, it is essential to accurately assess the deposited energy and the absorbed dose per tissue/organ of interest, as well as the local statistical uncertainty. Several types of realistic dosimetric applications are described including: molecular imaging, radio-immunotherapy, radiotherapy and brachytherapy. RESULTS: GATE has been efficiently used in several applications, such as Dose Point Kernels, S-values, Brachytherapy parameters, and has been compared against various MC codes which are considered as standard tools for decades. Furthermore, the presented studies show reliable modeling of particle beams when comparing experimental with simulated data. Examples of different dosimetric protocols are reported for individualized dosimetry and simulations combining imaging and therapy dose monitoring, with the use of modern computational phantoms. CONCLUSIONS: Personalization of medical protocols can be achieved by combining GATE MC simulations with anthropomorphic computational models and clinical anatomical data. This is a review study, covering several dosimetric applications of GATE, and the different tools used for modeling realistic clinical acquisitions with accurate dose assessment.

Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients.

HER2/neu is over expressed in 20-25% of breast cancers. HER2 breast cancers are aggressive and are associated with poor prognosis. The aim of this study was to develop the clinical grade Lu-177-trastuzumab and its preliminary evaluation for specific tumor targeting in HER2 positive breast cancer patients. Trastuzumab was conjugated to bifunctional chelator, DOTA, and characterized for integrity and the number of molecules conjugated. Radiolabeling of DOTA-conjugated trastuzumab was optimized using Lu-177. Quality control parameters including radiochemical purity, stability, sterility, pyrogenicity and immunoreactivity were assessed. A preliminary pilot study was conducted on breast cancer patients (n = 6 HER2 positive and n = 4 HER2 negative) to evaluate the ability of Lu-177-trastuzumab for HER2 specific tumor targeting. The conjugates were efficiently labeled with Lu-177 with high radiochemical purity (up to 91%) and specific activity (6-13 µCi/µg). Lu-177-trastuzumab was stable up to 12 hr post labeling. The radioimmunoassay demonstrated good antigen binding ability and specificity for HER2 receptor protein. The patient studies showed the localization of Lu-177-trastuzumab at primary as well as metastatic sites (HER2 positive) in the planar and SPECT/CT images. No tracer uptake was observed in HER2 negative patients that indicated the specificity of Lu-177-trastuzumab. The study demonstrated that in-house developed Lu-177-trastuzumab has specific targeting ability for HER2 expressing lesions and may in future become a palliative treatment option in the form of targeted radionuclide therapy for disseminated HER2 positive breast cancer.

Radioimmunotherapy in non-Hodgkin lymphoma: Prediction and assessment of response.

Non-Hodgkin lymphoma (NHL) is one of the most common malignancies and a major cause of morbidity and mortality. Radioimmunotherapy (RIT) is a novel modality for treating NHL which offers the combined use of monoclonal antibodies for specific targeting of malignant cells and radiation for killing these cells. Despite the promising results favoring RIT in several clinical studies in different target populations and NHL types, Food and Drug Administration (FDA) approval for RIT agents is restricted to a limited number of indications and agents, maybe because of several ambiguities that still exist in the field. One of these ambiguities are the lack of evidence-based prognostic factors that determine what patient population would benefit most from RIT, which is essential to know in order to optimize the efficacy and safety of treatment with RIT. As well as selecting the best patient population for RIT, it is important to assess the response to RIT in order to provide further treatment strategies or avoid unnecessary therapies and diagnostic procedures. In this review we have explored the details of how to predict the efficiency of RIT based on various prognostic factors that have been investigated in the evidence, and also discussed the proposed methods and timing schedules for assessing the response to RIT. We have also pointed out the ambiguities in the aforementioned topics, which call for more investigation.

Monte Carlo Calculation of Radioimmunotherapy with (90)Y-, (177)Lu-, (131)I-, (124)I-, and (188)Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts.

Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like (131)I or (90)Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of (90)Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as (90)Y, (177)Lu, (131)I, (124)I, and (188)Re are used. Tumour control probability (TCP) and normal tissue complication probability (NTCP) curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody) distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC)). (90)Y and (188)Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases.

Comparing the cost-effectiveness of rituximab maintenance and radioimmunotherapy consolidation versus observation following first-line therapy in patients with follicular lymphoma.

BACKGROUND: Phase 3 randomized trials have shown that maintenance rituximab (MR) therapy or radioimmunotherapy (RIT) consolidation following frontline therapy can improve progression-free survival for patients with follicular lymphoma (FL), but the cost-effectiveness of these approaches with respect to observation has not been examined using a common modeling framework. OBJECTIVES: To evaluate and compare the economic impact of MR and RIT consolidation versus observation, respectively, following the first-line induction therapy for patients with advanced-stage FL. METHODS: We developed Markov models to estimate patients' lifetime costs, quality-adjusted life-years (QALYs), and life-years (LYs) after MR, RIT, and observation following frontline FL treatment from the US payer's perspective. Progression risks, adverse event probabilities, costs, and utilities were estimated from clinical data of Primary RItuximab and MAintenance (PRIMA) trial, Eastern Cooperative Oncology Group (ECOG) trial (for MR), and First-line Indolent Trial (for RIT) and the published literature. We evaluated the incremental cost-effectiveness ratio for direct comparisons between MR/RIT and observation. Model robustness was addressed by one-way and probabilistic sensitivity analyses. RESULTS: Compared with observation, MR provided an additional 1.089 QALYs (1.099 LYs) and 1.399 QALYs (1.391 LYs) on the basis of the PRIMA trial and the ECOG trial, respectively, and RIT provided an additional 1.026 QALYs (1.034 LYs). The incremental cost per QALY gained was $40,335 (PRIMA) or $37,412 (ECOG) for MR and $40,851 for RIT. MR and RIT had comparable incremental QALYs before first progression, whereas RIT had higher incremental costs of adverse events due to higher incidences of cytopenias. CONCLUSIONS: MR and RIT following frontline FL therapy demonstrated favorable and similar cost-effectiveness profiles. The model results should be interpreted within the specific clinical settings of each trial. Selection of MR, RIT, or observation should be based on patient characteristics and expected trade-offs for these alternatives.

Tumor-Absorbed Dose Predicts Progression-Free Survival Following (131)I-Tositumomab Radioimmunotherapy.

UNLABELLED: The study aimed at identifying patient-specific dosimetric and nondosimetric factors predicting outcome of non-Hodgkin lymphoma patients after (131)I-tositumomab radioimmunotherapy for potential use in treatment planning. METHODS: Tumor-absorbed dose measures were estimated for 130 tumors in 39 relapsed or refractory non-Hodgkin lymphoma patients by coupling SPECT/CT imaging with the Dose Planning Method (DPM) Monte Carlo code. Equivalent biologic effect was calculated to assess the biologic effects of nonuniform absorbed dose including the effects of the unlabeled antibody. Evaluated nondosimetric covariates included histology, presence of bulky disease, and prior treatment history. Tumor level outcome was based on volume shrinkage assessed on follow-up CT. Patient level outcome measures were overall response (OR), complete response (CR), and progression-free survival (PFS), determined from clinical assessments that included PET/CT. RESULTS: The estimated mean tumor-absorbed dose had a median value of 275 cGy (range, 94-711 cGy). A high correlation was observed between tracer-predicted and therapy-delivered mean tumor-absorbed doses (P < 0.001; r = 0.85). In univariate tumor-level analysis, tumor shrinkage correlated significantly with almost all of the evaluated dosimetric factors, including equivalent biologic effect. Regression analysis showed that OR, CR, and PFS were associated with the dosimetric factors and equivalent biologic effect. Both mean tumor-absorbed dose (P = 0.025) and equivalent biologic effect (P = 0.035) were significant predictors of PFS whereas none of the nondosimetric covariates were found to be statistically significant factors affecting PFS. The most important finding of the study was that in Kaplan-Meier curves stratified by mean dose, longer PFS was observed in patients receiving mean tumor-absorbed doses greater than 200 cGy than in those receiving 200 cGy or less (median PFS, 13.6 vs. 1.9 mo for the 2 dose groups; log-rank P < 0.0001). CONCLUSION: A higher mean tumor-absorbed dose was significantly predictive of improved PFS after (131)I-tositumomab radioimmunotherapy. Hence tumor-absorbed dose, which can be estimated before therapy, can potentially be used to design radioimmunotherapy protocols to improve efficacy.

Monte Carlo simulations of dose distributions with necrotic tumor targeted radioimmunotherapy.

Radio-resistant hypoxic tumor cells are significant contributors to the locoregional recurrences and distant metastases that mark failure of radiotherapy. Due to restricted tissue oxygenation, chronically hypoxic tumor cells frequently become necrotic and thus there is often an association between chronically hypoxic and necrotic tumor regions. This simulation study is the first in a series to determine the feasibility of hypoxic cell killing after first targeting adjacent areas of necrosis with either an α- or ß-emitting radioimmunoconjugate.

Potential of a Cetuximab-based radioimmunotherapy combined with external irradiation manifests in a 3-D cell assay.

Targeting epidermal growth factor receptor (EGFR)-overexpressing tumors with radiolabeled anti-EGFR antibodies is a promising strategy for combination with external radiotherapy. In this study, we evaluated the potential of external plus internal irradiation by [(90) Y]Y-CHX-A″-DTPA-C225 (Y-90-C225) in a 3-D environment using FaDu and SAS head and neck squamous cell carcinoma (HNSCC) spheroid models and clinically relevant endpoints such as spheroid control probability (SCP) and spheroid control dose 50% (SCD50 , external irradiation dose inducing 50% loss of spheroid regrowth). Spheroids were cultured using a standardized platform. Therapy response after treatment with C225, CHX-A"-DTPA-C225 (DTPA-C225), [(90) Y]Y-CHX-A"-DTPA (Y-90-DTPA) and Y-90-C225 alone or in combination with X-ray was evaluated by long-term monitoring (60 days) of spheroid integrity and volume growth. Penetration kinetics into spheroids and EGFR binding capacities on spheroid cells were identical for unconjugated C225 and Y-90-C225. Spheroid-associated radioactivity upon exposure to the antibody-free control conjugate Y-90-DTPA was negligible. Determination of the SCD50 demonstrated higher intrinsic radiosensitivity of FaDu as compared with SAS spheroids. Treatment with unconjugated C225 alone did not affect spheroid growth and cell viability. Also, C225 treatment after external irradiation showed no additive effect. However, the combination of external irradiation with Y-90-C225 (1 µg/ml, 24 hr) resulted in a considerable benefit as reflected by a pronounced reduction of the SCD50 from 16 Gy to 9 Gy for SAS spheroids and a complete loss of regrowth for FaDu spheroids due to the pronounced accumulation of internal dose caused by the continuous exposure to cell-bound radionuclide upon Y-90-C225-EGFR interaction.

End-therapy positron emission tomography for treatment response assessment in follicular lymphoma: a systematic review and meta-analysis.

PURPOSE: Use of 2[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in postchemotherapy response assessment in follicular lymphoma is still a controversial issue. Here, we conducted the first systematic review and meta-analysis to determine the predictive value of FDG-PET in predicting outcome after chemotherapy of follicular lymphoma. EXPERIMENTAL DESIGN: Comprehensive literature search in Ovid-MEDLINE and EMBASE databases was performed to identify studies which evaluate predictive value of end-therapy PET and/or computed tomography (CT) in patients with follicular lymphoma. To quantitatively compare the predictive value of PET and CT, pooled hazard ratios (HRs) comparing progression-free survival (PFS) between patients with positive and negative results were adopted as the primary indicators for meta-analysis. To explore the efficiency in determining complete remission (CR), pooled CR rates of PET- and CT-based response criteria were calculated. Pooling of these parameters was based on the random-effects model. RESULTS: Review of 285 candidate articles identified eight eligible articles with a total of 577 patients for qualitative review and meta-analysis. The pooled HRs of end-therapy PET and CT were 5.1 [95% confidence interval (CI), 3.7-7.2] and 2.6 (95% CI, 1.2-5.8), respectively, which implies that PET is more predictive of PFS after chemotherapy than CT. The pooled CR rates of PET- and CT-based response criteria were 75% (95% CI, 70-79%) and 63% (95% CI, 53-73%), respectively, which implies that PET is more efficient in distinguishing CR (without residual disease) from other states with residual disease. In addition, qualitative systematic review indicates the same findings. CONCLUSIONS: Consistent evidence favoring PET-based treatment assessment should be considered in the management of patients with follicular lymphoma.

Investigation of effect of variations in bone fraction and red marrow cellularity on bone marrow dosimetry in radio-immunotherapy.

A method is described for computing patient-specific absorbed dose rates to active marrow which accounts for spatial variation in bone volume fraction and marrow cellularity. A module has been added to the 3D Monte Carlo dosimetry program DPM to treat energy deposition in the components of bone spongiosa distinctly. Homogeneous voxels in regions containing bone spongiosa (as defined on CT images) are assumed to be comprised only of bone, active (red) marrow and inactive (yellow) marrow. Cellularities are determined from biopsy, and bone volume fractions are computed from cellularities and CT-derived voxel densities. Electrons are assumed to deposit energy locally in the three constituent components in proportions determined by electron energy absorption fractions which depend on energy, cellularity, and bone volume fraction, and which are either taken from the literature or are derived from Monte Carlo simulations using EGS5. Separate algorithms are used to model primary ß particles and secondary electrons generated after photon interactions. Treating energy deposition distinctly in bone spongiosa constituents leads to marrow dosimetry results which differ from homogeneous spongiosa dosimetry by up to 20%. Dose rates in active marrow regions with cellularities of 20, 50, and 80% can vary by up to 20%, and can differ by up to 10% as a function of bone volume fraction. Dose to bone marrow exhibits a strong dependence on marrow cellularity and a potentially significant dependence on bone volume fraction.

A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: comparison with other Monte Carlo codes.

PURPOSE: GATE is a Monte Carlo simulation toolkit based on the Geant4 package, widely used for many medical physics applications, including SPECT and PET image simulation and more recently CT image simulation and patient dosimetry. The purpose of the current study was to calculate dose point kernels (DPKs) using GATE, compare them against reference data, and finally produce a complete dataset of the total DPKs for the most commonly used radionuclides in nuclear medicine. METHODS: Patient-specific absorbed dose calculations can be carried out using Monte Carlo simulations. The latest version of GATE extends its applications to Radiotherapy and Dosimetry. Comparison of the proposed method for the generation of DPKs was performed for (a) monoenergetic electron sources, with energies ranging from 10 keV to 10 MeV, (b) beta emitting isotopes, e.g., (177)Lu, (90)Y, and (32)P, and (c) gamma emitting isotopes, e.g., (111)In, (131)I, (125)I, and (99m)Tc. Point isotropic sources were simulated at the center of a sphere phantom, and the absorbed dose was stored in concentric spherical shells around the source. Evaluation was performed with already published studies for different Monte Carlo codes namely MCNP, EGS, FLUKA, ETRAN, GEPTS, and PENELOPE. A complete dataset of total DPKs was generated for water (equivalent to soft tissue), bone, and lung. This dataset takes into account all the major components of radiation interactions for the selected isotopes, including the absorbed dose from emitted electrons, photons, and all secondary particles generated from the electromagnetic interactions. RESULTS: GATE comparison provided reliable results in all cases (monoenergetic electrons, beta emitting isotopes, and photon emitting isotopes). The observed differences between GATE and other codes are less than 10% and comparable to the discrepancies observed among other packages. The produced DPKs are in very good agreement with the already published data, which allowed us to produce a unique DPKs dataset using GATE. The dataset contains the total DPKs for (67)Ga, (68)Ga, (90)Y, (99m)Tc, (111)In, (123)I, (124)I, (125)I, (131)I, (153)Sm, (177)Lu (186)Re, and (188)Re generated in water, bone, and lung. CONCLUSIONS: In this study, the authors have checked GATE's reliability for absorbed dose calculation when transporting different kind of particles, which indicates its robustness for dosimetry applications. A novel dataset of DPKs is provided, which can be applied in patient-specific dosimetry using analytical point kernel convolution algorithms.

A voxel-dose algorithm of heterogeneous activity distribution for Monte-Carlo simulation of radionuclide therapy dosimetry.

PURPOSE: The organ or tumor activity is not uniform due to inhomogeneous expression/distributions of receptors/antigens and the nonuniform vascularization of the tumor tissue. However, most patient-specific three-dimensional Monte-Carlo methods for radionuclide dosimetry have dealt with quasi-homogeneous activity distributions. A voxel-by-voxel activity sample algorithm (VM) without artifacts is presented to calculate the dose of the heterogeneous activity distribution for radionuclide dosimetry. METHODS: The source particle location is sampled according to the activity spatial distribution. The source particle weight is imparted by the relative activity concentration of its origination voxel. This algorithm is applied to calculate the dose volume histogram for multiple independent activity regions with Gauss diffusion activity distributions and then compared with the level partition method (LM). The minimal response and the mean tolerant initial total activity threshold required by tumor control probability and normal tissue complication probability for radioimmunotherapy ((131)I-RIT) also were evaluated by the voxel-by-voxel sample algorithm and the LM. The effective clearance half-time is assumed to be equal to its physical half-life (i.e., 8.02 days for (131)I). RESULTS: The result shows that the new algorithm is more consistent with the weighted superposition of the quasi-homogeneous activity distribution than the LM, especially for the multiple independent activity regions composed of different amounts of voxels. The new algorithm effectively avoids the leveling/binning artifacts to the heterogeneous activity distribution. The (131)I-RIT simulation also showed that the minimal response initial total activity threshold of tumors will be much more than the mean tolerant initial total activity threshold of normal organs (e.g., kidney) with the activity heterogeneous grade deteriorating. CONCLUSIONS: A VM is presented to simulate the dose of the heterogeneous activity distribution for radionuclide dosimetry. The new algorithm effectively avoids the leveling/binning artifacts to the heterogeneous activity distribution.

Monte Carlo single-cell dosimetry of I-131, I-125 and I-123 for targeted radioimmunotherapy of B-cell lymphoma.

PURPOSE: To study the dosimetric characteristics of a non-internalizing and an internalizing monoclonal antibody (MAb) labeled with (131)I, (125)I or (123)I, which targets a typical lymphoma B-cell. MATERIALS AND METHODS: Using our hybrid Monte Carlo (MC) code which combines detailed- and condensed-history electron track simulation we carry out transport calculations of Auger and beta electrons for different intracellular distributions of radioactivity. RESULTS: Assuming permanent retention of the MAb in cells, (125)I gave the highest absorbed dose and (123)I the highest absorbed dose rate. Under the more realistic scenario of biologic excretion from the cells, (123)I resulted in the highest absorbed dose and absorbed dose rate. CONCLUSION: The present dosimetric analysis shows that biological half-life, subcellular localization, and the proper account of low-energy electrons is critical in assessing the energy deposition inside the targeted cells from the three iodide radioisotopes examined. From a dosimetric point of view and under the present approximations (123)I might be superior to the other two radioiodides in the treatment of microscopic disease in B-cell lymphoma patients.

Three-dimensional patient-specific dosimetry in radioimmunotherapy with 90Y-ibritumomab-tiuxetan.

Aim of the present article was to perform three-dimensional (3D) single photon emission tomography-based dosimetry in radioimmunotherapy (RIT) with (90)Y-ibritumomab-tiuxetan. A custom MATLAB-based code was used to elaborate 3D images and to compare average 3D doses to lesions and to organs at risk (OARs) with those obtained with planar (2D) dosimetry. Our 3D dosimetry procedure was validated through preliminary phantom studies using a body phantom consisting of a lung insert and six spheres with various sizes. In phantom study, the accuracy of dose determination of our imaging protocol decreased when the object volume decreased below 5 mL, approximately. The poorest results were obtained for the 2.58 mL and 1.30 mL spheres where the dose error evaluated on corrected images with regard to the theoretical dose value was -12.97% and -18.69%, respectively. Our 3D dosimetry protocol was subsequently applied on four patients before RIT with (90)Y-ibritumomab-tiuxetan for a total of 5 lesions and 4 OARs (2 livers, 2 spleens). In patient study, without the implementation of volume recovery technique, tumor absorbed doses calculated with the voxel-based approach were systematically lower than those calculated with the planar protocol, with average underestimation of -39% (range from -13.1% to -62.7%). After volume recovery, dose differences reduce significantly, with average deviation of -14.2% (range from -38.7.4% to +3.4%, 1 overestimation, 4 underestimations). Organ dosimetry in one case overestimated, in the other underestimated the dose delivered to liver and spleen. However, both for 2D and 3D approach, absorbed doses to organs per unit administered activity are comparable with most recent literature findings.