Radiopharmaceutical Therapy Research Articles

Accuracy of two dosimetry software programs for 177Lu radiopharmaceutical therapy using voxel-based patient-specific phantoms

PurposeVirtual dosimetry using voxel-based patient-specific phantoms and Monte Carlo (MC) simulations offer the advantage of having a gold standard against which absorbed doses may be benchmarked to establish the dosimetry accuracy. Furthermore, these reference values assist in investigating the accuracy of the absorbed dose methodologies from different software programs. Therefore, this study aimed to compare the accuracy of the absorbed doses computed using LundADose and OLINDA/EXM 1.0. MethodsThe accuracy was based on 177Lu-DOTATATE distributions of three voxel-based phantoms. SPECT projection images were simulated for 1, 24, 96, and 168 h post-administration and reconstructed with LundADose using 3D OS-EM reconstruction. Mono-exponential curves were fitted to the bio-kinetic data for the kidneys, liver, spleen, and tumours resulting in SPECT time-integrated activity (SPECT-TIA). The SPECT-TIA were used to compute mean absorbed doses using LundADose (LND-DSPECT) and OLINDA (OLINDA-DSPECT) for the organs. Pre-defined true activity images, were used to obtain TRUE-TIA and, together with full MC simulations, computed the true doses (MC-DTrue). The dosimetry accuracy was assessed by comparing LND-DSPECT and OLINDA-DSPECT to MC-DTrue. ResultsOverall, the results presented an overestimation of the mean absorbed dose by LND-DSPECT compared to the MC-DTrue with a dosimetry accuracy ≤6.6%. This was attributed to spill-out activity from the reconstructed LND-DSPECT, resulting in a higher dose contribution than the MC-DTrue. There was a general underestimation (<8.1%) of OLINDA-DSPECT compared to MC-DTrue attributed to the geometrical difference in shape between the voxel-based phantoms and the OLINDA models. Furthermore, OLINDA-DSPECT considers self-doses while MC-DTrue reflects self-doses plus cross-doses. ConclusionThe better than 10% accuracy suggests that the mean dose values obtained with LND-DSPECT and OLINDA-DSPECT approximate the true values. The mean absorbed doses of the two software programs, and the gold standard were comparable. This work shall be of use for optimising 177Lu dosimetry for clinical applications.

Repair of α-particle-induced DNA damage in peripheral blood mononuclear cells after internal ex vivo irradiation with 223Ra

PurposeAs α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [223Ra]RaCl2.MethodsBlood samples of ten volunteers were irradiated by adding [223Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q.ResultsFor 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h−1 for 25 mGy, (0.16 ± 0.04) h−1 for 50 mGy and (0.13 ± 0.02) h−1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar.ConclusionThe results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.

Introduction to Radiopharmaceutical Therapy

Radiopharmaceutical therapy (RPT) is a precision medicine modality in which administered radionuclides are preferentially taken up by target cells or nearby tissues and emit radiation from within the patient, leading to targeted cell death. Many radiopharmaceuticals are currently FDA-approved with multiple others under investigation. This manuscript will give a broad introduction to RPT including how to become an authorized user, patient evaluation pre- and post-treatment, dosing strategies, and the physical spaces needed to run an RPT clinic. RPT may seem daunting at first but is feasible. As approved radiopharmaceuticals and RPT uses increase, patients will benefit from greater access to these new and evolving treatment options.

Basics of Physics and Radiobiology for Radiopharmaceutical Therapies

Radiopharmaceuticals are diagnostic or therapeutic radioactive compounds typically consisting of a radionuclide, a linker/chelator, and a specific ligand for target localization. These structural components affect pharmacokinetics, biodistribution, and dosimetry, which in turn affect therapeutic efficacy and potential toxicities of any radiopharmaceutical therapy (RPT). The type of radiation emitted from the radioisotope (β+, γ, α, β-, Auger) influences whether the radiopharmaceutical can be used for imaging or therapy.

Abstract 213: Assessing the role of X-ray radiation in combination with a DNA-PK inhibitor on cellular activity and adhesion using an in vitro HER2-positive breast cancer model

Abstract Introduction: Breast cancer (BC) is the most common cancer for women regardless of ethnicity, and the leading cause of cancer-related deaths in women. Radiation therapy (XRT) plays a vital role in multidisciplinary treatment approaches. Although XRT has been found to reduce breast cancer recurrence and mortality rate, like all other therapeutics, XRT contains some risks. Radiation can increase the mortality rate due to the risk of ischemic heart diseases. As part of an overall effort to understand the interaction between different types of radiations (e.g., radiopharmaceutical therapy (RPT) with β or α-particle emitters) and DNA double-strand break repair (DSB) repair pathways, we observed that impairment of DNA DSB by DNA-PKcs inhibitor (NU7441) fragmented HER2-positive BC spheroids in the presence of XRT. This could be possibly due to the modulation of cellular adhesion protein mediated by DNA-PK inhibition. In this study, we aim to assess the spheroids fragmentations and also measure the cell viability and levels of a cell adhesion protein, β1-integrin in irradiated HER2-positive monolayer cells, to get a mechanistic view for XRT and NU7441 combinatorial action so as to compare with β- or α-emitter RPT. Methods: In brief, NT2.5 BC spheroids were formed in agarose-coated 96-well plates. For both spheroids and monolayer cells, half of the media was replaced with fresh media containing 1 nM-5μM of NU7441 every other day. A colorimetric cell viability kit was used to measure cell viability and western blot analysis was performed to measure the β1-integrin level, which was normalized against β-actin. Results: Microscopic analysis suggested that XRT increased spheroid fragmentations in the presence of NU7441 compared to the XRT alone. Interaction between XRT and NU7441 (6.68% of the total variation, P&amp;lt;0.0001) was found for the cell viability data, where XRT (74.07% of the total variation, P&amp;lt;0.0001) and NU7441 (5.07% of the total variation, P&amp;lt;0.0001) both regulated cell viability on their own. Western blot data suggest that β1-integrin level was reduced for 8 Gy XRT and 5 μM NU7441 combination compared to the no XRT and vehicle combination. Moreover, 2-way ANOVA analysis revealed that XRT plays a role to regulate the β1-integrin level in NT2.5 monolayer cells (57.61% of the total variation, P&amp;lt;0.0001). Conclusion: XRT increased BC spheroids fragmentations when DNA damage was inhibited by a small molecule inhibitor. XRT and NU7441 both regulated NT2.5 cell viability with an interaction between them. Furthermore, XRT reduced β1-integrin level in monolayer NT2.5 cells. The XRT and NU7441 combination may induce fragmentations by decreasing cell viability and adhesion proteins. Future studies assessing the mechanisms of XRT and DNA PK inhibitor in BC spheroids and in vivo are warranted to confirm these results. Citation Format: Mahmud Hasan, Ioanna Liatsou, George Sgouros. Assessing the role of X-ray radiation in combination with a DNA-PK inhibitor on cellular activity and adhesion using an in vitro HER2-positive breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 213.

Abstract 3313: Single-cell level absorbed dose assessment and radiosensitivity modeling for alpha-emitter radiopharmaceutical therapy

Abstract The radiobiological response to alpha-emitter radiopharmaceutical therapy (αRPT) is often studied in cell monolayers. In these experiments, the goal is to establish the relationship between absorbed dose and cell survival probability. However, absorbed dose is not readily known and needs to be estimated. Current models to estimate this commonly idealize cells as biologically inert spheres (geometric model). This results in inaccurate and non-generalizable results, which could hamper the rigorous study of the underlying radiobiology. The purpose of this study was to estimate the variability in absorbed dose on a single-cell level by combining 3D measurements of cell geometries, as well as the dynamics of carrier molecule binding and trafficking in individual cells with full physics simulations of the alpha emissions. This comprehensive integration of the biological and physical aspects allows for a more accurate way to model cell survival in these αRPT experiments. Live cells were imaged on a confocal microscope. Experimental conditions of previous cell survival experiments with 212Pb on NT2.5 HER2+ breast cancer cells were replicated. A relevant antibody was tagged with AF488. 3D time lapses of membrane binding kinetics and internalization were recorded. All cells were segmented into nuclei, membrane and cytosol compartments using a purpose-build algorithm. Pharmacokinetic models were fit to the temporal antibody signals, which enabled validation with experimental binding assays. Monte Carlo simulations using the exact antibody locations in each time frame allowed for the precise estimation of dose rate over time. Single-cell absorbed dose estimates were used to model previously obtained cell survival curves. Over 300 cells were measured between 0 and 26 hours post incubation. A large range in absorbed doses was observed (coefficient of variation 0.74). The median contribution of membrane-bound activity to absorbed dose was in agreement with geometric models (error less than 6%). However the contribution of antibody internalization and perinuclear trafficking to absorbed dose varied widely between cells and over time. Cell clustering contributed 46% of the total dose, and was 6x higher than in the geometric model. Applying this to previous cell survival data yielded an estimated radiosensitivity kappa of 7.1 (geometric model: 2.8). Cell clustering has a larger, and cell geometry has a smaller impact than is assumed in current models. Perinuclear trafficking of internalized Ab positively impacts cell nucleus absorbed dose, which is typically ignored. Dose variability should be included in radiosensitivity modeling. More accurate absorbed dose estimations which result from a better understanding of the different contributing factors, will improve generalizability of the radiobiological models established in these cell monolayer experiments to more complex models. Citation Format: Remco Bastiaannet, Ioanna Liatsou, Robert Hobbs, George Sgouros. Single-cell level absorbed dose assessment and radiosensitivity modeling for alpha-emitter radiopharmaceutical therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3313.

Practical Considerations for Implementation of 177Lu-DOTATATE Neuroendocrine Tumor Treatment Programs.

The 2018 FDA approval of 177Lu-DOTATATE for the treatment of somatostatin receptor-positive (SSTR) neuroendocrine tumors (NETs) represents a paradigm shifting approach to cancer treatments around the globe. Gastroenteropancreatic (GEP) NETs overexpress the somatostatin subtype receptor 2, which is now exploited for receptor-based imaging and therapy, thus generating significant progress in the diagnosis and treatment of this orphan disease. The recent FDA approval of receptor-based PET radiopharmaceuticals and a new peptide receptor radiopharmaceutical therapy (PRRT), 177Lu-DOTATATE, has dramatically impacted NET patient management. The focus of this paper is to review clinical considerations associated with implementing a 177Lu-DOTATATE program. We review receptor-based NET radiopharmaceuticals, 177Lu-DOTATATE patient selection criteria, administration methods, clinical, regulatory, and radiation safety considerations, technical factors, tissue dosimetry, and reimbursement guidelines.

The preparation, biodistribution, and human's absorbed dose evaluation of Radio-Scandium-HYNIC-TOC for somatostatin-receptor-positive neuroendocrine tumors therapy by animal study.

Most of the neuroendocrine tumors (NETs) express Somatostatin receptors (SSTr), which are the main bases for the development of several radiopharmaceuticals for therapy and imaging of these types of tumors. In this study, 46 Scandium nuclide was used to label a peptide compound via hydrazinonicotinyl-Tyr3-Octreotide (HYNIC-TOC) and researched further for somatostatin-receptor NETs treatment. The labeling procedure was conducted at 95°C for 10 min. The compound stability was tested in the environment of human serum at 37°C. The biodistribution of compound was investigated in balb/c normal mice and mice bearing AR4-2J tumor. Absorbed Doses of Human Organs were estimated by extrapolation of the biokinetics data of compound in mice to human's organs and then the absorbed doses were estimated by application of MATLAB and MIRDOSE software. Labeling yield was more than 90% with 555 MBq/mg specific activity. The radio-labeled compound expressed well consistency in human serum. The tumor uptake reached 3.831 ID/g% until 4 h post-injection and increased to 5.564%ID/g until 24 h post-injection. The main achievement of this study was high tumor uptake of 46 Sc-HYNIC-TOC which may be therapeutically valuable for the therapy of NETs. The estimation of the absorbed dose of human from 47 Scandium-HYNIC-TOC showed low absorbed doses in critical organs and the elimination of the radiopharmaceutical was through the gastrointestinal tract.

Validation of Monte Carlo 131 I radiopharmaceutical dosimetry workflow using a 3D-printed anthropomorphic head and neck phantom.

PurposeApproximately 50% of head and neck cancer (HNC) patients will experience loco‐regional disease recurrence following initial courses of therapy. Retreatment with external beam radiotherapy (EBRT) is technically challenging and may be associated with a significant risk of irreversible damage to normal tissues. Radiopharmaceutical therapy (RPT) is a potential method to treat recurrent HNC in conjunction with EBRT. Phantoms are used to calibrate and add quantification to nuclear medicine images, and anthropomorphic phantoms can account for both the geometrical and material composition of the head and neck. In this study, we present the creation of an anthropomorphic, head and neck, nuclear medicine phantom, and its characterization for the validation of a Monte Carlo, SPECT image‐based, 131I RPT dosimetry workflow.Methods3D‐printing techniques were used to create the anthropomorphic phantom from a patient CT dataset. Three 131I SPECT/CT imaging studies were performed using a homogeneous, Jaszczak, and an anthropomorphic phantom to quantify the SPECT images using a GE Optima NM/CT 640 with a high energy general purpose collimator. The impact of collimator detector response (CDR) modeling and volume‐based partial volume corrections (PVCs) upon the absorbed dose was calculated using an image‐based, Geant4 Monte Carlo RPT dosimetry workflow and compared against a ground truth scenario. Finally, uncertainties were quantified in accordance with recent EANM guidelines.ResultsThe 3D‐printed anthropomorphic phantom was an accurate re‐creation of patient anatomy including bone. The extrapolated Jaszczak recovery coefficients were greater than that of the 3D‐printed insert (∼22.8 ml) for both the CDR and non‐CDR cases (with CDR: 0.536 vs. 0.493, non‐CDR: 0.445 vs. 0.426, respectively). Utilizing Jaszczak phantom PVCs, the absorbed dose was underpredicted by 0.7% and 4.9% without and with CDR, respectively. Utilizing anthropomorphic phantom recovery coefficient overpredicted the absorbed dose by 3% both with and without CDR. All dosimetry scenarios that incorporated PVC were within the calculated uncertainty of the activity. The uncertainties in the cumulative activity ranged from 23.6% to 106.4% for Jaszczak spheres ranging in volume from 0.5 to 16 ml.ConclusionThe accuracy of Monte Carlo‐based dosimetry for 131I RPT in HNC was validated with an anthropomorphic phantom. In this study, it was found that Jaszczak‐based PVCs were sufficient. Future applications of the phantom could involve 3D printing and characterizing patient‐specific volumes for more personalized RPT dosimetry estimates.

Extending the relative seriality formalism for interpretable deep learning of normal tissue complication probability models

We formally demonstrate that the relative seriality (RS) model of normal tissue complication probability (NTCP) can be recast as a simple neural network with one convolutional and one pooling layer. This approach enables us to systematically construct deep relative seriality networks (DRSNs), a new class of mechanistic generalizations of the RS model with radiobiologically interpretable parameters amenable to deep learning. To demonstrate the utility of this formulation, we analyze a simplified example of xerostomia due to irradiation of the parotid gland during alpha radiopharmaceutical therapy. Using a combination of analytical calculations and numerical simulations, we show for both the RS and DRSN cases that the ability of the neural network to generalize without overfitting is tied to ‘stiff’ and ‘sloppy’ directions in the parameter space of the mechanistic model. These results serve as proof-of-concept for radiobiologically interpretable deep learning of NTCP, while simultaneously yielding insight into how such techniques can robustly generalize beyond the training set despite uncertainty in individual parameters.

A Pipeline for Automated Voxel Dosimetry: Application in Patients with Multi-SPECT/CT Imaging After 177Lu-Peptide Receptor Radionuclide Therapy.

Patient-specific dosimetry in radiopharmaceutical therapy (RPT) is impeded by the lack of tools that are accurate and practical for the clinic. Our aims were to construct and test an integrated voxel-level pipeline that automates key components (organ segmentation, registration, dose-rate estimation, and curve fitting) of the RPT dosimetry process and then to use it to report patient-specific dosimetry in 177Lu-DOTATATE therapy. Methods: An integrated workflow that automates the entire dosimetry process, except tumor segmentation, was constructed. First, convolutional neural networks (CNNs) are used to automatically segment organs on the CT portion of one post-therapy SPECT/CT scan. Second, local contour intensity-based SPECT--SPECT alignment results in volume-of-interest propagation to other time points. Third, dose rate is estimated by explicit Monte Carlo (MC) radiation transport using the fast, Dose Planning Method code. Fourth, the optimal function for dose-rate fitting is automatically selected for each voxel. When reporting mean dose, we apply partial-volume correction, and uncertainty is estimated by an empiric approach of perturbing segmentations. Results: The workflow was used with 4-time-point 177Lu SPECT/CT imaging data from 20 patients with 77 neuroendocrine tumors, segmented by a radiologist. CNN-defined kidneys resulted in high Dice values (0.91-0.94) and only small differences (2%-5%) in mean dose when compared with manual segmentation. Contour intensity-based registration led to visually enhanced alignment, and the voxel-level fitting had high R 2 values. Across patients, dosimetry results were highly variable; for example, the average of the mean absorbed dose (Gy/GBq) was 3.2 (range, 0.2-10.4) for lesions, 0.49 (range, 0.24-1.02) for left kidney, 0.54 (range, 0.31-1.07) for right kidney, and 0.51 (range, 0.27-1.04) for healthy liver. Patient results further demonstrated the high variability in the number of cycles needed to deliver hypothetical threshold absorbed doses of 23 Gy to kidney and 100 Gy to tumor. The uncertainty in mean dose, attributable to variability in segmentation, averaged 6% (range, 3%-17%) for organs and 10% (range, 3%-37%) for lesions. For a typical patient, the time for the entire process was about 25 min (∼2 min manual time) on a desktop computer, including time for CNN organ segmentation, coregistration, MC dosimetry, and voxel curve fitting. Conclusion: A pipeline integrating novel tools that are fast and automated provides the capacity for clinical translation of dosimetry-guided RPT.

A mesh-based model of liver vasculature: implications for improved radiation dosimetry to liver parenchyma for radiopharmaceuticals

PurposeTo develop a model of the internal vasculature of the adult liver and demonstrate its application to the differentiation of radiopharmaceutical decay sites within liver parenchyma from those within organ blood.MethodComputer-generated models of hepatic arterial (HA), hepatic venous (HV), and hepatic portal venous (HPV) vascular trees were algorithmically created within individual lobes of the ICRP adult female and male livers (AFL/AML). For each iteration of the algorithm, pressure, blood flow, and vessel radii within each tree were updated as each new vessel was created and connected to a viable bifurcation site. The vascular networks created inside the AFL/AML were then tetrahedralized for coupling to the PHITS radiation transport code. Specific absorbed fractions (SAF) were computed for monoenergetic alpha particles, electrons, positrons, and photons. Dual-region liver models of the AFL/AML were proposed, and particle-specific SAF values were computed assuming radionuclide decays in blood within two locations: (1) sites within explicitly modeled hepatic vessels, and (2) sites within the hepatic blood pool residing outside these vessels to include the capillaries and blood sinuses. S values for 22 and 10 radionuclides commonly used in radiopharmaceutical therapy and imaging, respectively, were computed using the dual-region liver models and compared to those obtained in the existing single-region liver model.ResultsLiver models with virtual vasculatures of ~ 6000 non-intersecting straight cylinders representing the HA, HPV, and HV circulations were created for the ICRP reference. For alpha emitters and for beta and auger-electron emitters, S values using the single-region models were approximately 11% (AML) to 14% (AFL) and 11% (AML) to 13% (AFL) higher than the S values obtained using the dual-region models, respectively.ConclusionsThe methodology employed in this study has shown improvements in organ parenchymal dosimetry through explicit consideration of blood self-dose for alpha particles (all energies) and for electrons at energies below ~ 100 keV.

ASTRO's Framework for Radiopharmaceutical Therapy Curriculum Development for Trainees

In 2017, the American Society for Radiation Oncology (ASTRO) board of directors prioritized radiopharmaceutical therapy (RPT) as a leading area for new therapeutic development, and the ASTRO RPT workgroup was created. Herein, the workgroup has developed a framework for RPT curriculum development upon which education leaders can build to integrate this modality into radiation oncology resident education. Through this effort, the workgroup aims to provide a guide to ensure robust training in an emerging therapeutic area within the context of existing radiation oncology training in radiation biology, medical physics, and clinical radiation oncology. The framework first determines the core RPT knowledge required to select patients, prescribe, safely administer, and manage related adverse events. Then, it defines the most important topics for preparing residents for clinical RPT planning and delivery. This framework is designed as a tool to supplement the current training that exists for radiation oncology residents. The final document was approved by the ASTRO board of directors in the fall of 2021.

Reply: Single-Time-Point Tumor Dosimetry Assuming Normal Distribution of Tumor Kinetics.

REPLY: We thank Dr. Kao for carefully reading our article ([ 1 ][1]) and for illustrating the value of single–time-point imaging in the practical implementation of patient-specific dosimetry for radiopharmaceutical therapy. We chose to focus on fundamental knowns and unknowns, particularly tumor

A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma-LuDO-N.

BackgroundHalf the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. “A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N” (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule.MethodsThe LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022.ResultsThe pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3–5 years.DiscussionIn this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.

Evaluation of an 131I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers

Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N-succinimidyl 3-guanidinomethyl 5-[131I]iodobenzoate (iso-[131I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models. In head-to-head comparisons to [131I]SGMIB-2Rs15d, a HER2-targeted radiopharmaceutical currently under clinical investigation, iso-[131I]SGMIB-VHH_1028 exhibited significantly higher tumor uptake and significantly lower kidney accumulation. The results demonstrated 2.9 and 6.3 times more favorable tumor-to-kidney radiation dose ratios in the SKOV-3 and BT474 xenograft models, respectively. Iso-[131I]SGMIB-VHH_1028 was prepared using a solid-phase extraction method for purification of the prosthetic agent intermediate Boc2-iso-[131I]SGMIB that reproducibly scaled to therapeutic-level doses and obviated the need for its HPLC purification. Single-dose (SKOV-3) and multiple-dose (BT474) treatment regimens demonstrated that iso-[131I]SGMIB-VHH_1028 was well tolerated and provided significant tumor growth delay and survival prolongation. This study suggests that iso-[131I]SGMIB-VHH_1028 is a promising candidate for RPT of HER2-expressing cancers and further development is warranted.

MIRD Pamphlet No. 27: MIRDcell V3, a Revised Software Tool for Multicellular Dosimetry and Bioeffect Modeling.

Radiopharmaceutical therapy is growing rapidly. However, yet to be addressed is the implementation of methods to plan treatments for circulating tumor cells, disseminated tumor cells, and micrometastases. Given the capacity of radiopharmaceuticals to specifically target and kill single cells and multicellular clusters, a quality not available in chemotherapy and external-beam radiation therapy, it is important to develop dosimetry and bioeffect modeling tools that can inform radiopharmaceutical design and predict their effect on microscopic disease. This pamphlet describes a new version of MIRDcell, a software tool that was initially released by the MIRD committee several years ago. Methods: Version 3 (V3) of MIRDcell uses a combination of analytic and Monte Carlo methods to conduct dosimetry and bioeffect modeling for radiolabeled cells within planar colonies and multicellular clusters. A worked example is provided to assist users to learn old and new features of MIRDcell and test its capacity to recapitulate published responses of tumor cell spheroids to radiopharmaceutical treatments. Prominent capabilities of the new version include radially dependent activity distributions, user-imported activity distributions, cold regions within the cluster, complex bioeffect modeling that accounts for radiation type and subcellular distribution, and a rich table of output data for subsequent analysis. Results: MIRDcell V3 effectively reproduces experimental responses of multicellular spheroids to uniform and nonuniform distributions of therapeutic radiopharmaceuticals. Conclusion: MIRDcell is a versatile software tool that can be used for educational purposes and design of radiopharmaceutical therapies.

Quantification of uptake in pelvis F-18 FLT PET-CT images using a 3D localization and segmentation CNN.

The purpose of this work was to develop and validate a deep convolutional neural network (CNN) approach for the automated pelvis segmentation in computed tomography (CT) scans to enable the quantification of active pelvic bone marrow by means of Fluorothymidine F-18 (FLT) tracer uptake measurement in positron emission tomography (PET) scans. This quantification is a critical step in calculating bone marrow dose for radiopharmaceutical therapy clinical applications as well as external beam radiationdoses. An approach for the combined localization and segmentation of the pelvis in CT volumes of varying sizes, ranging from full-body to pelvis CT scans, was developed that utilizes a novel CNN architecture in combination with a random sampling strategy. The method was validated on 34 planning CT scans and 106 full-body FLT PET-CT scans using a cross-validation strategy. Specifically, two different training and CNN application options were studied, quantitatively assessed, and statisticallycompared. The proposed method was able to successfully locate and segment the pelvis in all test cases. On all data sets, an average Dice coefficient of 0.9396 0.0182 or better was achieved. The relative tracer uptake measurement error ranged between 0.065% and 0.204%. The proposed approach is time-efficient and shows a reduction in runtime of up to 95% compared to a standard U-Net-based approach without a localizationcomponent. The proposed method enables the efficient calculation of FLT uptake in the pelvis. Thus, it represents a valuable tool to facilitate bone marrow preserving adaptive radiation therapy and radiopharmaceutical dose calculation. Furthermore, the method can be adapted to process other bone structures as well asorgans.

SIR-Spheres Activity Measurements Reveal Systematic Miscalibration.

The purpose of this work was to perform an independent and National Institute of Standards and Technology-traceable activity measurement of 90Y SIR-Spheres (Sirtex). γ-spectroscopic measurements of the 90Y internal pair production decay mode were made using a high-purity germanium detector. Methods: Measured annihilation radiation detection rates were corrected for radioactive decay during acquisition, dead time, source attenuation, and source geometry effects. Detection efficiency was determined by 2 independent and National Institute of Standards and Technology-traceable methods. Results: Measured SIR-Spheres vials (n = 5) contained more activity than specified by the manufacturer calibration; on average, the ratio of measured activity to calibrated was 1.233 ± 0.030. Activity measurements made using 2 distinct efficiency calibration methods agreed within 1%. Conclusion: The primary SIR-Spheres activity calibration appears to be a significant underestimate of true activity.

Implications of physics, chemistry and biology for dosimetry calculations using theranostic pairs.

Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using radiopharmaceuticals that target identical molecular targets for both imaging (using emitted gamma rays) and radiopharmaceutical therapy (using emitted beta, alpha or Auger-electron particles) for the treatment of various diseases, such as cancer. If the therapeutic radiopharmaceutical cannot be imaged quantitatively, a “theranostic pair” imaging surrogate can be used to predict the absorbed radiation doses from the therapeutic radiopharmaceutical. However, theranostic dosimetry assumes that the pharmacokinetics and biodistributions of both radiopharmaceuticals in the pair are identical or very similar, an assumption that still requires further validation for many theranostic pairs. In this review, we consider both same-element and different-element theranostic pairs and attempt to determine if factors exist which may cause inaccurate dose extrapolations in theranostic dosimetry, either intrinsic (e.g. chemical differences) or extrinsic (e.g. injecting different amounts of each radiopharmaceutical) to the radiopharmaceuticals. We discuss the basis behind theranostic dosimetry and present common theranostic pairs and their therapeutic applications in oncology. We investigate general factors that could create alterations in the behavior of the radiopharmaceuticals or the quantitative accuracy of imaging them. Finally, we attempt to determine if there is evidence showing some specific pairs as suitable for theranostic dosimetry. We show that there are a variety of intrinsic and extrinsic factors which can significantly alter the behavior among pairs of radiopharmaceuticals, even if they belong to the same chemical element. More research is needed to determine the impact of these factors on theranostic dosimetry estimates and on patient outcomes, and how to correctly account for them.