A PBPK model for PRRT with [Lu]Lu-DOTA-TATE: Comparison of model implementations in SAAM II and MATLAB/SimBiology.

Unlabelled: Physiologically based pharmacokinetic (PBPK) models offer the ability to simulate and predict the biodistribution of radiopharmaceuticals and have the potential to enable individualised treatment planning in molecular radiotherapy. The objective of this study was to develop and implement a whole-body compartmental PBPK model for peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-DOTA-TATE in SimBiology to allow for more complex analyses. The correctness of the model implementation was ensured by comparing its outputs, such as the time-integrated activity (TIA), with those of a PBPK model implemented in SAAM II software.

Implementation of dosimetry for molecular radiotherapy; results from a European survey.

Purpose: The use of molecular radiotherapy (MRT) has been rapidly evolving over the last years. The aim of this study was to assess the current implementation of dosimetry for MRTs in Europe.

Methods: A web-based questionnaire was open for treating centres between April and June 2022, and focused on 2020-2022.

Traceable calibration with Lu and comparison of activity meters at hospitals in Norway and Sweden.

Introduction: The activity meter is used to determine the activity of delivered radiopharmaceuticals, administered activity to patients and reference activity when gamma-cameras are calibrated prior to imaged-based dosimetry. The aim is to describe a procedure for cross-calibration of activity meters at different clinical sites, and report on Lu activity results when using factory-set calibration factors compared to when calibration is performed with traceability to a primary standard.

Methods: Thirty activity meters placed at seven hospitals in Norway and Sweden from four manufacturers: Capintec, Commecer, NuviaTech and Veenstra were included.

Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based Lu-DOTATATE treatment of NET patients.

Purpose: Radionuclide therapy with Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk.

A multicentre and multi-national evaluation of the accuracy of quantitative Lu-177 SPECT/CT imaging performed within the MRTDosimetry project.

Purpose: Patient-specific dosimetry is required to ensure the safety of molecular radiotherapy and to predict response. Dosimetry involves several steps, the first of which is the determination of the activity of the radiopharmaceutical taken up by an organ/lesion over time. As uncertainties propagate along each of the subsequent steps (integration of the time-activity curve, absorbed dose calculation), establishing a reliable activity quantification is essential.

Dosimetric Quantities in Neuroendocrine Tumors over Treatment Cycles with Lu-DOTATATE.

Tumor dosimetry was performed for Lu-DOTATATE with the aims of better understanding the range and variation of the tumor-absorbed doses (ADs), how different dosimetric quantities evolve over the treatment cycles, and whether this evolution differs depending on the tumor grade. Such information is important for radiobiologic interpretation and may inform the design of alternative administration schemes. The data came from 41 patients with neuroendocrine tumors (NETs) of grade 1 ( = 23) or 2 ( = 18) who had received between 2 and 9 treatment cycles.

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases.

This study aimed to compare different image-based methods for bone marrow dosimetry and study the dose-response relationship during treatment with Lu-DOTATATE in patients with and without skeletal metastases. This study included 46 patients with advanced neuroendocrine tumors treated with at least 2 fractions of Lu-DOTATATE at Sahlgrenska University Hospital. High- and low-uptake compartments were automatically outlined in planar images collected at 2, 24, 48, and 168 h after injection.

EANM practical guidance on uncertainty analysis for molecular radiotherapy absorbed dose calculations.

A framework is proposed for modelling the uncertainty in the measurement processes constituting the dosimetry chain that are involved in internal absorbed dose calculations. The starting point is the basic model for absorbed dose in a site of interest as the product of the cumulated activity and a dose factor. In turn, the cumulated activity is given by the area under a time-activity curve derived from a time sequence of activity values.

Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force.

Background: The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented.

Biologically effective dose in fractionated molecular radiotherapy--application to treatment of neuroblastoma with (131)I-mIBG.

In this work, the biologically effective dose (BED) is investigated for fractionated molecular radiotherapy (MRT). A formula for the Lea-Catcheside G-factor is derived which takes the possibility of combinations of sub-lethal damage due to radiation from different administrations of activity into account. In contrast to the previous formula, the new G-factor has an explicit dependence on the time interval between administrations.

Hybrid Imaging for Patient-Specific Dosimetry in Radionuclide Therapy.

Radionuclide therapy aims to treat malignant diseases by systemic administration of radiopharmaceuticals, often using carrier molecules such as peptides and antibodies. The radionuclides used emit electrons or alpha particles as a consequence of radioactive decay, thus leading to local energy deposition. Administration to individual patients can be tailored with regards to the risk of toxicity in normal organs by using absorbed dose planning.

Uncertainty propagation for SPECT/CT-based renal dosimetry in (177)Lu peptide receptor radionuclide therapy.

A computer model of a patient-specific clinical (177)Lu-DOTATATE therapy dosimetry system is constructed and used for investigating the variability of renal absorbed dose and biologically effective dose (BED) estimates. As patient models, three anthropomorphic computer phantoms coupled to a pharmacokinetic model of (177)Lu-DOTATATE are used. Aspects included in the dosimetry-process model are the gamma-camera calibration via measurement of the system sensitivity, selection of imaging time points, generation of mass-density maps from CT, SPECT imaging, volume-of-interest delineation, calculation of absorbed-dose rate via a combination of local energy deposition for electrons and Monte Carlo simulations of photons, curve fitting and integration to absorbed dose and BED.

Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in (177)Lu-DOTATATE peptide receptor radionuclide therapy.

Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with (177)Lu-DOTATATE.

Long-Term Retention of 177Lu/177mLu-DOTATATE in Patients Investigated by γ-Spectrometry and γ-Camera Imaging.

Unlabelled: Dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE is based on patient imaging during the first week after administration and determination of the activity retention as a function of time for different tissues. For calculation of the absorbed dose, it is generally assumed that the long-term activity retention follows the pattern determined from the first week. This work aimed to investigate the validity of this assumption by performing additional patient measurements between 5 and 10 wk after administration.

The evidence base for the use of internal dosimetry in the clinical practice of molecular radiotherapy.

Molecular radiotherapy (MRT) has demonstrated unique therapeutic advantages in the treatment of an increasing number of cancers. As with other treatment modalities, there is related toxicity to a number of organs at risk. Despite the large number of clinical trials over the past several decades, considerable uncertainties still remain regarding the optimization of this therapeutic approach and one of the vital issues to be answered is whether an absorbed radiation dose-response exists that could be used to guide personalized treatment.

Dynamic (99m)Tc-MAG3 renography: images for quality control obtained by combining pharmacokinetic modelling, an anthropomorphic computer phantom and Monte Carlo simulated scintillation camera imaging.

In dynamic renal scintigraphy, the main interest is the radiopharmaceutical redistribution as a function of time. Quality control (QC) of renal procedures often relies on phantom experiments to compare image-based results with the measurement setup. A phantom with a realistic anatomy and time-varying activity distribution is therefore desirable.

On the biologically effective dose (BED)-using convolution for calculating the effects of repair: II. Numerical considerations.

We have previously shown analytically that the biologically effective dose (BED), including effects of repair during irradiation and of incomplete repair between fractions, can be formulated using a convolution between the absorbed dose rate function and the function describing repair. In this work, a discrete formalism is derived along with its implementation via the fast Fourier transform. The implementation takes the intrinsic periodicity of the discrete Fourier transform into consideration, as well as possible inconsistencies that may arise due to discretization and truncation of the functions describing the absorbed dose rate and repair.

On the biologically effective dose (BED)-using convolution for calculating the effects of repair: I. Analytical considerations.

This work presents a new mathematical formulation of biologically effective dose (BED) for radiation therapy where effects of repair need to be considered. The formulation is based on the observation that the effects of repair, both during protracted irradiation and of incomplete repair between fractions, can be written using a convolution, i.e.

Patient-specific whole-body attenuation correction maps from a CT system for conjugate-view-based activity quantification: method development and evaluation.

For activity quantification based on planar scintillation camera measurements, photon attenuation is an important factor that needs to be corrected for in a patient- and organ-specific manner. One possibility for obtaining attenuation correction maps is to use X-ray CT scout images. Since the intensity of scout images is in relative numbers, their image values need to be multiplied by a factor to become quantitative and thus useful for attenuation correction.

Evaluation of quantitative planar 90Y bremsstrahlung whole-body imaging.

With high-dose administration of (90)Y labeled antibodies, it is possible to image (90)Y without an admixture of (111)In. We have earlier shown that it is possible to perform quantitative (90)Y bremsstrahlung SPECT for dosimetry purposes with reasonable accuracy. However, whole-body (WB) activity quantification with the conjugate view method is not as time consuming as SPECT and has been the method of choice for dosimetry.

High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma.

We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1.