Targeted Radionuclide Therapy Dosimetry Research Articles

The Questionnaire Survey of Japanese Practice and Environment for Targeted Radionuclide Therapy in 2021

Recently, the targeted radionuclide therapy (TRT) was urgently required to adapt the practice and environment because of the implementation of novel therapeutic radiopharmaceuticals such as alpha- and beta- radionuclides therapy. The present study aimed to clarify the questionnaire survey with the current situation (safety controls for workers and patients) at Japanese TRT facilities. The massive questionnaire survey, 2 months from October to November 2021, was conducted among nationwide 251 facilities that have performed TRT in the past two years. The alpha- and beta- therapeutic radiopharmaceuticals were categorized and answered by one representative of the facility under anonymity. We analyzed the actual situation of each facility related to occupational exposure, radiation protection, contamination inspection, patient release criteria, and dosimetry for TRT. The survey response rate was 69.1% (174 facilities). About 75% of these facilities reported that they either follow the guidelines or take their own measures to reduce occupational exposure. The confirmed means of patient release criteria were 68.0% with the administered radioactivity and 87.2% with the ambient dose rate. The cold run was not performed for the first time at 15.0% and 10.0% of the facilities for β- and α-emitting radionuclides, respectively. The facilities without attachment syringe shields were 39.2% for alpha-radionuclides therapy and 20.3% for beta-radionuclides therapy. We clarified the Japanese problem for TRT practice and environment by the questionnaire survey. Our findings indicated that the Japanese guidelines and manuals for TRT were not partly followed in the nationwide facilities.

Targeted alpha therapy: a critical review of translational dosimetry research with emphasis on actinium-225.

This review provides a general overview of the current achievements and challenges in translational dosimetry for targeted alpha therapy (TAT). The concept of targeted radionuclide therapy (TRNT) is described with an overview of its clinical applicability and the added value of TAT is discussed. For TAT, we focused on actinium-225 (225Ac) as an example for alpha particle emitting radionuclides and their features, such as limited range within tissue and high linear energy transfer, which make alpha particle emissions more effective in targeted killing of tumour cells compared to beta radiation. Starting with the state-of-the-art dosimetry for TRNT and TAT, we then describe the challenges that still need to be met in order to move to a personalized dosimetry approach for TAT. Specifically for 225Ac, we discuss the recoiled daughter effect which may provoke significant damage to healthy tissue or organs and should be considered. Next, a broad overview is given of the pre-clinical research on 225Ac-TAT with an extensive description of tools which are only available in a pre-clinical setting and their added value. In addition, we review the preclinical biodistribution and dosimetry studies that have been performed on TAT-agents and more specifically of 225Ac and its multiple progeny, and describe their potential role to better characterize the pharmacokinetic (PK) profile of TAT-agents and to optimize the use of theranostic approaches for dosimetry. Finally, we discuss the support pre-clinical studies may provide in understanding dose-effect relationships, linking radiation dose quantities to biological endpoints and even moving away from macro- to microdosimetry. As such, the translation of pre-clinical findings may provide valuable information and new approaches for improved clinical dosimetry, thus paving the way to personalized TAT.

Impact of PET and MRI threshold-based tumor volume segmentation on patient-specific targeted radionuclide therapy dosimetry using CLR1404

Variations in tumor volume segmentation methods in targeted radionuclide therapy (TRT) may lead to dosimetric uncertainties. This work investigates the impact of PET and MRI threshold-based tumor segmentation on TRT dosimetry in patients with primary and metastatic brain tumors. In this study, PET/CT images of five brain cancer patients were acquired at 6, 24, and 48 h post-injection of 124I-CLR1404. The tumor volume was segmented using two standardized uptake value (SUV) threshold levels, two tumor-to-background ratio (TBR) threshold levels, and a T1 Gadolinium-enhanced MRI threshold. The dice similarity coefficient (DSC), jaccard similarity coefficient (JSC), and overlap volume (OV) metrics were calculated to compare differences in the MRI and PET contours. The therapeutic 131I-CLR1404 voxel-level dose distribution was calculated from the 124I-CLR1404 activity distribution using RAPID, a Geant4 Monte Carlo internal dosimetry platform. The TBR, SUV, and MRI tumor volumes ranged from 2.3–63.9 cc, 0.1–34.7 cc, and 0.4–11.8 cc, respectively. The average ± standard deviation (range) was 0.19 ± 0.13 (0.01–0.51), 0.30 ± 0.17 (0.03–0.67), and 0.75 ± 0.29 (0.05–1.00) for the JSC, DSC, and OV, respectively. The DSC and JSC values were small and the OV values were large for both the MRI-SUV and MRI-TBR combinations because the regions of PET uptake were generally larger than the MRI enhancement. Notable differences in the tumor dose volume histograms were observed for each patient. The mean (standard deviation) 131I-CLR1404 tumor doses ranged from 0.28–1.75 Gy GBq−1 (0.07–0.37 Gy GBq−1). The ratio of maximum-to-minimum mean doses for each patient ranged from 1.4–2.0. The tumor volume and the interpretation of the tumor dose is highly sensitive to the imaging modality, PET enhancement metric, and threshold level used for tumor volume segmentation. The large variations in tumor doses clearly demonstrate the need for standard protocols for multimodality tumor segmentation in TRT dosimetry.

Quantitative Imaging for Targeted Radionuclide Therapy Dosimetry - Technical Review.

Targeted radionuclide therapy (TRT) is a promising technique for cancer therapy. However, in order to deliver the required dose to the tumor, minimize potential toxicity in normal organs, as well as monitor therapeutic effects, it is important to assess the individualized internal dosimetry based on patient-specific data. Advanced imaging techniques, especially radionuclide imaging, can be used to determine the spatial distribution of administered tracers for calculating the organ-absorbed dose. While planar scintigraphy is still the mainstream imaging method, SPECT, PET and bremsstrahlung imaging have promising properties to improve accuracy in quantification. This article reviews the basic principles of TRT and discusses the latest development in radionuclide imaging techniques for different theranostic agents, with emphasis on their potential to improve personalized TRT dosimetry.

WE‐EF‐BRA‐04: Evaluation of Dosimetric Uncertainties in Individualized Targeted Radionuclide Therapy (TRT) Treatment Planning Using Pre‐Clinical Data

Purpose:Dosimetry for targeted radionuclide therapy (TRT) is moving away from conventional model‐based methods towards patient‐specific approaches. To address this need, a Monte Carlo (MC) dosimetry platform was developed to estimate patient‐specific therapeutic 3D dose distributions based on pre‐treatment imaging. However, because a standard practice for patient‐specific internal dosimetry has not yet been established, there are many sources of dosimetric uncertainties. The goal of this work was to quantify the sensitivity of various parameters on MC dose estimations.Methods:The ‘diapeutic’ agent, CLR1404, was used as a proof‐of‐principle compound in this work. CLR1404 can be radiolabeled with either 12⁴I for PET imaging or 131I for radiotherapy or SPECT imaging. PET/CT images of 5 mice were acquired out to 240 hrs post‐injection of 12⁴I‐CLR1404. The therapeutic 131I‐CLR1404 absorbed dose (AD) distribution was calculated using a Geant4‐based MC dosimetry platform. A series of sensitivity studies were performed. The variables that were investigated included the PET/CT voxel resolution, partial volume corrections (PVC), material segmentation, inter‐observer contouring variability, and the pre‐treatment image acquisition frequency.Results:Resampling the PET/CT voxel size between 0.2–0.8 mm resulted in up to a 13% variation in the mean AD. Application of the PVC increased the mean AD by 0.5–11.2%. Less than 1% differences in ROI mean AD were observed between the tissue segmentation schemes using 4 and 27 different material compositions. Inter‐observer contouring variability led to up to a 20% CoV (stdev/mean) in the mean AD between the users. Varying the number and frequency of pre‐treatment images used resulted in changes in mean AD up to 176% compared to the case using all 12 images.Conclusion:Voxel resolution, contour segmentation, the image acquisition protocol most significantly impacted patient‐specific TRT dosimetry. Further work is needed to develop a standard protocol that optimizes accuracy and efficiency for patient‐specific internal dosimetry.BT and JG are affiliated with Cellectar Biosciences which owns the licensing rights to CLR1404 and related compounds.

SU-F-500-01: Towards Personalized Dosimetry Using Diapeutic Radiopharmaceuticals

Purpose: he efficacy of targeted radionuclide therapy (TRT) depends on the ability to accurately characterize the absorbed dose distribution within tumors as well as other potential dose limiting organs. Clinical data suggests a compelling need for personalized dosimetry given that conventional dose calculation methods fail to accurately predict dose response relationships. This work describes the implementation of a Monte Carlo patient‐specific 3D dosimetry platform for TRT. Methods: CLR1404, a small‐molecule, phospholipid ether analog can serve as a ‘diapeutic’ (diagnostic and therapeutic) agent for the detection and treatment of multiple solid tumors. Because both the I–124 labeled imaging and I–131 labeled therapy agent are administered in similar mass doses, they are expected to display equivalent in vivo pharmacokinetic profiles. Therefore, the 124I‐CLR1404 distribution can be converted to the therapeutic 131I‐CLR1404 distribution by simply accounting for the difference in decay rates. In this study, high grade Glioma patients were scanned at 4.5, 24, and 48 hours post injection of 124I‐CLR1404. PET, CT and MRI images were co‐registered, resampled to the CT resolution and contoured. The 131I‐CLR1404 dose deposition throughout the CT volume was simulated using the Monte Carlo code Geant4.9.4 assuming a source strength in each voxel was proportional to the PET activity. The total cumulated absorbed dose was calculated by numerically integrating the activity over all time on a voxel‐by‐voxel basis. Results: Spatial distributions of the absorbed dose rates, DVHs, and mean, minimum, maximum, and total dose rate values for each contoured region were generated for each time point, clearly illustrating CLR1404's pharmacokinetic properties. The mean cumulated absorbed dose within tumor was 52.3 mGy per injected activity of 131I‐CLR1404. Conclusion: This work demonstrates that a Geant4 based Monte Carlo radiopharmaceutical dose calculation platform is not only feasible, but can serve as invaluable tool for personalized dosimetry in TRT. JJG and JPW are affiliated with Novelos Therapeutics which owns the licensing rights to CLR1404 and related compounds.

A method for energy window optimization for quantitative tasks that includes the effects of model-mismatch on bias: application to Y-90 bremsstrahlung SPECT imaging

Quantitative Yttrium-90 (90Y) bremsstrahlung single photon emission computed tomography (SPECT) imaging has shown great potential to provide reliable estimates of 90Y activity distribution for targeted radionuclide therapy dosimetry applications. One factor that potentially affects the reliability of the activity estimates is the choice of the acquisition energy window. In contrast to imaging conventional gamma photon emitters where the acquisition energy windows are usually placed around photopeaks, there has been great variation in the choice of the acquisition energy window for 90Y imaging due to the continuous and broad energy distribution of the bremsstrahlung photons. In quantitative imaging of conventional gamma photon emitters, previous methods for optimizing the acquisition energy window assumed unbiased estimators and used the variance in the estimates as a figure of merit (FOM). However, for situations, such as 90Y imaging, where there are errors in the modeling of the image formation process used in the reconstruction there will be bias in the activity estimates. In 90Y bremsstrahlung imaging this will be especially important due to the high levels of scatter, multiple scatter, and collimator septal penetration and scatter. Thus variance will not be a complete measure of reliability of the estimates and thus is not a complete FOM. To address this, we first aimed to develop a new method to optimize the energy window that accounts for both the bias due to model-mismatch and the variance of the activity estimates. We applied this method to optimize the acquisition energy window for quantitative 90Y bremsstrahlung SPECT imaging in microsphere brachytherapy. Since absorbed dose is defined as the absorbed energy from the radiation per unit mass of tissues in this new method we proposed a mass-weighted root mean squared error of the volume of interest (VOI) activity estimates as the FOM. To calculate this FOM, two analytical expressions were derived for calculating the bias due to model-mismatch and the variance of the VOI activity estimates, respectively. To obtain the optimal acquisition energy window for general situations of interest in clinical 90Y microsphere imaging, we generated phantoms with multiple tumors of various sizes and various tumor-to-normal activity concentration ratios using a digital phantom that realistically simulates human anatomy, simulated 90Y microsphere imaging with a clinical SPECT system and typical imaging parameters using a previously validated Monte Carlo simulation code, and used a previously proposed method for modeling the image degrading effects in quantitative SPECT reconstruction. The obtained optimal acquisition energy window was 100–160 keV. The values of the proposed FOM were much larger than the FOM taking into account only the variance of the activity estimates, thus demonstrating in our experiment that the bias of the activity estimates due to model-mismatch was a more important factor than the variance in terms of limiting the reliability of activity estimates.

Solid‐tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis

The objective of this study is to evaluate requirements for radionuclide-based solid tumor therapy by assessing the radial dose distribution of beta-particle-emitting and alpha-particle-emitting molecules localized either solely within endothelial cells of tumor vasculature or diffusing from the vasculature throughout the adjacent viable tumor cells. Tumor blood vessels were modeled as a group of microcylindrical layers comprising endothelial cells (one-cell thick, 10 microm diameter), viable tumor cells (25-cell thick, 250 microm radius), and necrotic tumor region (> 250 microm from any blood vessel). Sources of radioactivity were assumed to distribute uniformly in either endothelial cells or in concentric cylindrical 10 microm shells within the viable tumor-cell region. The EGSnrc Monte Carlo simulation code system was used for beta particle dosimetry and a dose-point kernel method for alpha particle dosimetry. The radioactive decays required to deposit cytocidal doses (> or = 100 Gy) in the vascular endothelial cells (endothelial cell mean dose) or, alternatively, at the tumor edge [tumor-edge mean dose (TEMD)] of adjacent viable tumor cells were then determined for six beta (32P, 33P, 67Cu, 90Y 131I, and 1188Re) and two alpha (211At and 213Bi) particle emitters. Contrary to previous modeling in targeted radionuclide therapy dosimetry of solid tumors, the present work restricts the region of tumor viability to 250 microm around tumor blood vessels for consistency with biological observations. For delivering > or = 100 Gy at the viable tumor edge (TEMD) rather than throughout a solid tumor, energetic beta emitters 90Y, 32P, and 188Re can be effective even when the radionuclide is confined to the blood vessel (i.e., no diffusion into the tumor). Furthermore, the increase in tumor-edge dose consequent to beta emitter diffusion is dependent on the energy of the emitted beta particles, being much greater for lower-energy emitters 131I, 67Cu, and 33P relative to higher-energy emitters 90Y, 32P, and 188Re. Compared to alpha particle emitters, a approximately 150-400 times higher number of beta-particle-emitting radioactive atoms is required to deposit the same dose in tumor neovasculature. However, for the alpha particle emitters 211At and 213Bi to be effective in irradiating viable tumor-cell regions in addition to the vasculature the carrier molecules must diffuse substantially from the vasculature into the viable tumor. The presented data enable comparison of radionuclides used for antiangiogenic therapy on the basis of their radioactive decay properties, tumor neovasculature geometry, and tumor-cell viability. For alpha particle emitters or low-energy beta particle emitters, the targeting carrier molecule should be chosen to permit the radiopharmaceutical to diffuse from the endothelial wall of the blood vessel, while for long-range energetic beta particle emitters that target neovasculature, a radiopharmaceutical that binds to newly formed endothelial cells and does not diffuse is preferable. The work is a first approximation to modeling of tumor neovasculature that ignores factors such as pharmacokinetics and targeting capability of carrier molecules. The calculations quantify the interplay between irradiation of neovasculature, the surrounding viable tumor cells, and the physical properties of commonly used radionuclides and can be used to assist estimation of radioactivity to be administered for neovasculature-targeted tumor therapy.

The importance of the accuracy of image registration of SPECT images for 3D targeted radionuclide therapy dosimetry

In this paper, the importance of the accuracy of image registration of time-sequential SPECT images for 3D targeted radionuclide therapy dosimetry is studied. Image registration of a series of SPECT scans is required to allow the computation of the 3D absorbed dose distribution for both tumour sites and normal organs. Three simulated 4D datasets, based on patient therapy studies, were generated to allow the effect of mis-registration on the absorbed dose distribution to be investigated. The tumour sites studied range in size, shape and position, relative to the centre of the 3D SPECT scan. Randomly generated transformations along the x-, y- and z-axes and rotations around the z-axis were employed and the maximum and average absorbed dose distribution statistics, for the tumour sites present, were computed. It was shown that even small mis-registrations, translation of less than 9 mm and rotation of less than 5° might cause differences in the absorbed dose statistics of up to 90%, especially when the size of the tumour is comparable to the induced mis-registration or when the tumour is situated close to the edge of the 3D dataset.

A Generalized 4D Image Registration Scheme for Targeted Radionuclide Therapy Dosimetry

An iterative, generalized four-dimensional (4D) method is presented in this paper that allows simultaneous registration of a series of single-photon emission computed tomography (SPECT) scans acquired in the course of a radionuclide therapy or pretherapy tracer study. The method combines temporal information with voxel-based similarity criteria to carry out simultaneous registration of the SPECT scans. A polynomial function was fitted to the maximum counts of each tumor site over the 4D study. Each tumor site was normalized to its maximum on the reference scan, and a template 4D dataset was generated, employing the polynomial fitting and the normalization map. Then, each 3D scan was registered to the corresponding simulated scan, using a 3D similarity criterion. The correlation coefficient (CC), the mutual information (MI), and the sum-of-absolute differences (SAD) similarity criteria were employed. Simulated data, based on a head-neck (131)I-MIBG study, were used to compare the proposed method for 4D registration with sequential 3D registration. Sequential 3D registration resulted in residual registration errors of 3.5 +/- 2.5, 3.2 +/- 2.0, and 7.0 +/- 3.5 mm for the CC, MI, and SAD criteria respectively, whereas the corresponding 4D method gave errors of 2.4 +/- 1.6, 1.9 +/- 1.1, and 5.3 +/- 2.9 mm for the CC, MI, and SAD criteria, respectively. The 4D method was applied to (186)Re HEDP SPECT patient studies and registration was verified by a dual-cursor display tool.

Overview of dosimetry for systemic targeted radionuclide therapy (STaRT)

The purposes of systemic targeted radionuclide therapy dosimetry include compiling a database of normal organ radiation-absorbed doses that are carrier- and radionuclide-specific, and assuring that the normal organ radiation doses are within a safe range before therapy. Also of importance is quantitation of radiation delivery to tumors vs. normal tissues to correlate absorbed dose with tumor control. For agents with significant and variable excretion, estimates of individual patient distribution/clearance may be needed to optimize the dose-response relationship.

Combination of dosimetry for targeted radionuclide and external beam therapies

In this thesis, issues relevant to the combined use and dosimetry of external beam radiotherapy (EBT) and targeted radionuclide therapy (TRT) are addressed. Methodology was developed to allow a combination of dose information from these two modalities, employing the biologically effective dose (BED) to address the inequivalence of biological effect. It was found that use of this combined modality radiotherapy (CMRT) could result in increased conformality of treatments and reduced doses to normal tissues compared with dose delivery by EBT alone. A model was developed to investigate the radiobiological effects that may arise if the two therapies were delivered concurrently. It was found that under most clinical conditions, the relative temporal delivery of these two therapies is unlikely to significantly influence the overall radiobiological effect to the tumour at the cellular level. Synergistic effects may be more significant in normal tissues and for tumours with low values of . The accuracy with which single photon emission computed tomography (SPECT) can be quantified for TRT dosimetry applied to CMRT was assessed via an phantom imaging study. Good agreement was found between the modeled and experimental data, but recovery of the object by deconvolution was found to be unsuccessful due to the limited spatial resolution of the system and noise content in the image. may therefore be unsuitable for this application. The incorporation of intensity modulated radiotherapy (IMRT) into CMRT was investigated, exploring both physically and biologically based methods of prescribing a nonuniform EBT dose distribution according to the distribution of TRT uptake. This approach was found to be feasible with IMRT providing sufficient dose modulation. The nonuniform EBT prescription can often be reduced to the simpler uniform case if planned as a component of CMRT and the effects of delivery errors are taken into account. In general, it has been found that a combination of EBT and TRT allows normal tissue doses to be reduced compared with dose delivery by EBT alone, and more satisfactory doses in the target to be reached. Methodology developed is applicable both to biologically based radiotherapy planning and to the wider concepts of combined modality therapies.