MIDOS: a novel stochastic model towards a treatment planning system for microsphere dosimetry in liver tumors.

PURPOSE: Transarterial radioembolization (TARE) procedures treat liver tumors by injecting radioactive microspheres into the hepatic artery. Currently, there is a critical need to optimize TARE towards a personalized dosimetry approach. To this aim, we present a novel microsphere dosimetry (MIDOS) stochastic model to estimate the activity delivered to the tumor(s), normal liver, and lung. METHODS: MIDOS incorporates adult male/female liver computational phantoms with the hepatic arterial, hepatic portal venous, and hepatic venous vascular trees. Tumors can be placed in both models at user discretion. The perfusion of microspheres follows cluster patterns, and a Markov chain approach was applied to microsphere navigation, with the terminal location of microspheres determined to be in either normal hepatic parenchyma, hepatic tumor, or lung. A tumor uptake model was implemented to determine if microspheres get lodged in the tumor, and a probability was included in determining the shunt of microspheres to the lung. A sensitivity analysis of the model parameters was performed, and radiation segmentectomy/lobectomy procedures were simulated over a wide range of activity perfused. Then, the impact of using different microspheres, i.e., SIR-Sphere®, TheraSphere®, and QuiremSphere®, on the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), and mean absorbed dose was analyzed. RESULTS: Highly vascularized tumors translated into increased TNR. Treatment results (TNR and LSF) were significantly more variable for microspheres with high particle load. In our scenarios with 1.5 GBq perfusion, TNR was maximum for TheraSphere® at calibration time in segmentectomy/lobar technique, for SIR-Sphere® at 1-3 days post-calibration, and regarding QuiremSphere® at 3 days post-calibration. CONCLUSION: This novel approach is a decisive step towards developing a personalized dosimetry framework for TARE. MIDOS assists in making clinical decisions in TARE treatment planning by assessing various delivery parameters and simulating different tumor uptakes. MIDOS offers evaluation of treatment outcomes, such as TNR and LSF, and quantitative scenario-specific decisions.

A stochastic model of blood flow to calculate blood dose during radiotherapy.

Purpose. Lymphopenia is a common side effect in patients treated with radiotherapy, potentially caused by direct cell killing of circulating lymphocytes in the blood. To investigate this hypothesis, a method to assess dose to circulating lymphocytes is needed.Methods. A stochastic model to simulate systemic blood flow in the human body was developed based on a previously designed compartment model. Blood dose was obtained by superimposing the spatiotemporal distribution of blood particles with a time-varying dose rate field, and used as a surrogate for dose to circulating lymphocytes. We discuss relevant theory on compartmental modeling and how to combine it with models of explicit organ vasculature.Results. A general workflow was established which can be used for any anatomical site. Stochastic compartments can be replaced by explicit models of organ vasculatures for improved spatial resolution, and tumor compartments can be dynamically assigned. Generating a patient-specific blood flow distribution takes about one minute, fast enough to investigate the effect of varying treatment parameters such as the dose rate. Furthermore, the anatomical structures contributing most to the overall blood dose can be identified, which could potentially be used for lymphocyte-sparing treatment planning.Conclusion. The ability to report the blood dose distribution during radiotherapy is imperative to test and act upon the current paradigm that radiation-induced lymphopenia is caused by direct cell killing of lymphocytes in the blood. We have built a general model that can do so for various treatment sites. The presented framework is publicly available athttp://github.com/mghro/hedos.

Intra-brain vascular models within the ICRP mesh-type adult reference phantoms for applications to internal dosimetry.

Objective. Phantoms of the International Commission on Radiological Protection provide a framework for standardized dosimetry. The modeling of internal blood vessels-essential to tracking circulating blood cells exposed during external beam radiotherapy and to account for radiopharmaceutical decays while still in blood circulation-is, however, limited to the major inter-organ arteries and veins. Intra-organ blood is accounted for only through the assignment of a homogeneous mixture of parenchyma and blood [single-region (SR) organs]. Our goal was to develop explicit dual-region (DR) models of intra-organ blood vasculature of the adult male brain (AMB) and adult female brain (AFB).Approach. A total of 4000 vessels were created amongst 26 vascular trees. The AMB and AFB models were then tetrahedralized for coupling to the PHITS radiation transport code. Absorbed fractions were computed for monoenergetic alpha particles, electrons, positrons, and photons for both decay sites within the blood vessels and for tissues outside these vessels. RadionuclideS-values were computed for 22 and 10 radionuclides commonly employed in radiopharmaceutical therapy and nuclear medicine diagnostic imaging, respectively.Main results. For radionuclide decays, values ofS(brain tissue ← brain blood) assessed in the traditional manner (SR) were higher than those computed using our DR models by factors of 1.92, 1.49, and 1.57 for therapeutic alpha-emitters, beta-emitters, and Auger electron-emitters, respectively in the AFB and by factors of 1.65, 1.37, and 1.42 for these same radionuclide categories in the AMB. Corresponding ratios of SR and DR values ofS(brain tissue ← brain blood) were 1.34 (AFB) and 1.26 (AMB) for four SPECT radionuclides, and were 1.32 (AFB) and 1.24 (AMB) for six common PET radionuclides.Significance. The methodology employed in this study can be explored in other organs of the body for proper accounting of blood self-dose for that fraction of the radiopharmaceutical still in general circulation.

Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations.

PURPOSE: Radiation-induced lymphopenia has gained attention recently as the result of its correlation with survival in a range of indications, particularly when combining radiation therapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters. METHODS AND MATERIALS: We assembled a cohort of 17 patients with hepatocellular carcinoma treated with proton RT alone in 15 fractions (fx) using conventional dose rates (beam-on time [BOT], 120 seconds) for whom weekly absolute lymphocyte counts (ALCs) during RT and follow-up were available. We used HEDOS, a time-dependent, whole-body, blood flow computational framework, in combination with explicit liver blood flow modeling, to calculate the dose volume histograms for circulating lymphocytes for changing BOTs (1 second-300 seconds) and fractionations (5 fx, 15 fx). From this, we used the linear cell survival model and an exponential model to determine patient-specific lymphocyte radiation sensitivity, α, and recovery, σ, respectively. RESULTS: The in vivo-derived patient-specific α had a median of 0.65 Gy-1 (range, 0.30-1.38). Decreasing BOT to 1 second led to an increased average end-of-treatment ALC of 27.5%, increasing to 60.3% when combined with the 5-fx regimen. Decreasing to 5 fx at the conventional dose rate led to an increase of 17.0% on average. The benefit of both increasing dose rate and reducing the number of fractions was patient specificࣧpatients with highly sensitive lymphocytes benefited most from decreasing BOT, whereas patients with slow lymphocyte recovery benefited most from the shorter fractionation regimen. CONCLUSIONS: We observed that increasing dose rate at the same fractionation reduced ALC depletion more significantly than reducing the number of fractions. High-dose-rates led to an increased sparing of lymphocytes when shortening the fractionation regimen, particularly for patients with radiosensitive lymphocytes at elevated risk.

Improving predictive CTV segmentation on CT and CBCT for cervical cancer by diffeomorphic registration of a prior.

PURPOSE: Automatic cervix-uterus segmentation of the clinical target volume (CTV) on CT and cone-beam CT (CBCT) scans is challenged by the limited visibility and the non-anatomical definition of certain border regions. We study the potential performance gain of convolutional neural networks by regulating the segmentation predictions as diffeomorphic deformations of a segmentation prior. MATERIALS AND METHODS: We introduce a 3D convolutional neural network that segments the target scan by joint voxel-wise classification and the registration of a given prior. We compare this network to two other 3D baseline models: One treating segmentation as a classification problem (segmentation-only), the other as a registration problem (deformation-only). For reference and to highlight the benefits of a 3D model, these models are also benchmarked against a 2D segmentation model. Network performances are reported for CT and CBCT segmentation of the cervix-uterus CTV. We train the networks on the data of 84 patients. The prior is provided by the CTV segmentation of a planning CT. Repeat CT or CBCT scans constitute the target scans to be segmented. RESULTS: All 3D models outperformed the 2D segmentation model. For CT segmentation, combining classification and registration in the proposed joint model proved beneficial, achieving a Dice score of 0.87 and a mean squared error (MSE) of the surface distance below 1.7 mm. No such synergy was observed for CBCT segmentation, for which the joint and the deformation-only model performed similarly, achieving a Dice score of about 0.80 and an MSE surface distance of 2.5 mm. However, the segmentation-only model performed notably worse in this low contrast regime. Visual inspection revealed that this performance drop translated into geometric inconsistencies between the prior and target segmentation. Such inconsistencies were not observed for the deformation-based models. CONCLUSION: Constraining the solution space of admissible segmentation predictions to those reachable by a diffeomorphic deformation of the prior proved beneficial as it improved geometric consistency. Especially for CBCT, with its poor soft-tissue contrast, this type of regularization becomes important as shown by quantitative and qualitative evaluation.

Deformation trajectory prediction using a neural network trained on finite element data-application to library of CTVs creation for cervical cancer.

Purpose. We propose a neural network for fast prediction of realistic, time-parametrized deformations between pairs of input segmentations. The proposed method was used to generate a library of planning CTVs for cervical cancer radiotherapy.Methods.A 3D convolutional neural network (CNN) was introduced to predict a stationary velocity field given the distance maps of the cervix CTV in empty and full bladder anatomy. Diffeomorphic deformation trajectories between the two states were obtained by time integration. Intermediate deformation states were used to populate a library of cervix CTVs. The network was trained on cervix CTV deformations of 20 patients generated by finite element modeling (FEM). Validation was performed on FEM data of 9 healthy volunteers. Additionally, for these subjects, CTV deformations were observed in a series of repeat MR scans as the bladder filled from empty to full. Predicted and FEM libraries were compared, and benchmarked against the observed deformations. Finally, for an independent test set of 20 patients the predicted libraries were evaluated clinically, and compared to the current method.Results.The median Dice score over the validation subjects between the predicted and FEM libraries was >0.95 throughout the deformation, with a median 90 percentile surface distance of <3 mm. The ability to cover observed CTVs was similar for both the FEM-based and the proposed method, with residual offsets being about twice as large as the difference between the two methods. Clinical evaluation showed improved library properties over the method currently used in clinic.Conclusions.We proposed a CNN trained on FEM deformations, which predicts the deformation trajectory between two input states of the cervix CTV in one forward pass. We applied this to CTV library prediction for cervical cancer. The network is able to mimic FEM deformations well, while being much faster and simpler in use.

A biomechanical finite element model to generate a library of cervix CTVs.

PURPOSE: To generate a series of physiologically plausible cervix CTVs by biomechanically modeling organ deformation as a consequence of bladder filling. This series can serve as planning CTVs for radiotherapy treatment of cervical cancer patients using a library of plans (LoP) strategy. METHODS: The model was constructed based on the full and empty bladder scans of 20 cervical cancer patients, for which the bladder, rectum and the clinical target volume (CTV) of the cervix were delineated. Finite element modeling (FEM) was used to deform empty to full bladder anatomy. This deformation comprised two steps. In the first step, the surfaces of the bladder and rectum of the empty bladder anatomy were explicitly deformed to the full bladder anatomy and imported as enforced displacements into the biomechanical model. These surface displacements cause volumetric deformations of the bladder, rectum and cervix CTV meshes, dictated by their respective elastic properties and the type of contact among them. In the second step, the residual offset between the simulated and target CTV was corrected by an additional thin plate spline warp. Intermediate structural outputs of a linear superposition of the biomechanical and residual warp then constituted the library of CTVs for each patient. The residual warp was minimized by optimizing the FEM parameters over the 20 patients. Finally, the model was tested for nine healthy volunteers for which repeat MR scans were available as the bladder filled from empty to full. Small and large movers were identified depending on the extent of CTV motion, and analyzed separately. The proposed method was compared against the method currently used in our institute, in which intermediate structures are linearly interpolated between full and empty bladder anatomy, using a thin plate spline warp. The comparison metrics used were the ability to preserve CTV volume throughout the deformation, and residual offsets between repeat and library CTV. RESULTS: Optimal model parameters were found to be compatible with published values. While for the current method, the median CTV volume shrunk by 4% for large movers halfway the deformation (and by up to 10% for individual cases), the proposed FEM-based method preserved CTV volumes throughout the deformation. Regional residual errors between repeat and library CTV reduced by up to 3 mm when averaged over the group of large movers. For individual cases this regional error reduction could be as large as 8 mm. CONCLUSIONS: We developed a robust and automatic method to create a patient-specific FEM-based LoP. The FEM-based method resulted in more accurate library of planning CTVs as compared to the current method, with the greatest improvements observed for patients with large CTV motion. The biomechanical model simulates volumetric deformations from empty to full bladder anatomy, paving the way for dose accumulation in an LoP setting.

Margin and PTV volume reduction using a population based library of plans strategy for rectal cancer radiotherapy.

PURPOSE: Day-to-day shape variation in the rectum CTV results in considerable geometric uncertainties during rectal cancer radiotherapy. To ensure coverage a large CTV-to-PTV margin is required. The purpose of this study was to increase the accuracy of treatment delivery by building a population based library of planning CTVs for rectal cancer patients and to evaluate its potential for rectum PTV margin and PTV volume reduction. METHODS: Analysis was done retrospectively on 33 early-stage rectal cancer patients with daily repeat CTs who received short-course pre-operative radiotherapy in 5 fractions of 5 Gy. We created signed distance maps from the planning rectum CTV to each of the repeat CTVs, from which we calculated the group mean, systematic and random error. The correlation between different regions of the rectum CTV was analyzed and used in combination with the distance maps to create the library of nine planning CTVs. For each of the repeat CTVs the best fitting CTV structure in the library was automatically selected defined by the plan that minimized the mean absolute distance between the repeat and library CTV. Residual distance maps were calculated from which a new PTV margin was constructed. Bootstrapping was performed on the margin difference to assess its significance. RESULTS: Residual errors were found to decrease with the number of plans in the library, but adding more than five plans yields negligible further error reduction. Margin reduction of up to 50% was achieved at the upper-anterior site of the mesorectum. The average PTV volume decreased by 15.5% when a library is introduced. CONCLUSIONS: A library of plans strategy for rectal cancer based on population statistics is feasible and results in a considerably reduced average rectum PTV volume compared to conventional radiotherapy.