Adjustment of the iodine ICRP population pharmacokinetic model for the use in thyroid cancer patients after thyroidectomy.

Biokinetic models developed for healthy humans are not appropriate to describe biokinetics in thyroid cancer patients following thyroidectomy. The aim of this study was to adjust the population model for iodine proposed by the International Commission on Radiological Protection (ICRP) for the use in these patients. Rate constants of the ICRP publication 128 model for iodine were adjusted using the population modelling software package Monolix to describe activity retention in whole-body, thyroid, blood and protein-bound iodine observed in 23 patients. The new set of rate constants was compared to the four uptake scenarios proposed in ICRP publication 128. Flow from the inorganic iodide in blood compartment into the first thyroid compartment decreases to 0.15 d-1compared to a value of 7.27 d-1for the ICRP publication 128 model with a medium uptake. The transfer from first to second thyroid compartments and the outflow from the second thyroid compartment increases. An increased turnover rate of extrathyroidal organic iodine is observed. The rate constant from inorganic iodide in blood to kidney was also adjusted. Overall a good agreement was found between the adjusted model and the activity retention in thyroid cancer patients. The adjustment of population pharmacokinetic models to describe the biokinetic properties of specific patient populations for therapeutic radiopharmaceuticals is essential to capture the changes in biokinetics. The proposed set of rate constants for the established ICRP publication 128 model can be used to more accurately assess radiation protection requirements for the treatment of thyroid cancer patients using radioiodine.

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. Each activity value is obtained in terms of a count rate, a calibration factor and a recovery coefficient (a correction for partial volume effects). The method to determine the recovery coefficient and the dose factor, both of which are dependent on the size of the volume of interest (VOI), are described. Consideration is given to propagating estimates of the quantities concerned and their associated uncertainties through the dosimetry chain to obtain an estimate of mean absorbed dose in the VOI and its associated uncertainty. This approach is demonstrated in a clinical example.

The Role of Pretherapy Quantitative Imaging and Dosimetry in Radioiodine Therapy for Advanced Thyroid Cancer.

Radioactive iodine is well established as a successful treatment for differentiated thyroid cancer (DTC), although around 15% of patients have local recurrence or develop distant metastases and may become refractory to radioactive iodine (RAI). A personalized approach to treatment, based on the absorbed radiation doses delivered and using treatments to enhance RAI uptake, has not yet been developed. Methods: We performed a multicenter clinical trial to investigate the role of selumetinib, which modulates the expression of the sodium iodide symporter, and hence iodine uptake, in the treatment of RAI-refractory DTC. The iodine uptake before and after selumetinib was quantified to assess the effect of selumetinib. The range of absorbed doses delivered to metastatic disease was calculated from pre- and posttherapy imaging, and the predictive accuracy of a theranostic approach to enable personalized treatment planning was investigated. Results: Significant inter- and intrapatient variability was observed with respect to the uptake of RAI and the effect of selumetinib. The absorbed doses delivered to metastatic lesions ranged from less than 1 Gy to 1,170 Gy. A strong positive correlation was found between the absorbed doses predicted from pretherapy imaging and those measured after therapy (r = 0.93, P < 0.001). Conclusion: The variation in outcomes from RAI therapy of DTC may be explained, among other factors, by the range of absorbed doses delivered. The ability to assess the effect of treatments that modulate RAI uptake, and to estimate the absorbed doses at therapy, introduces the potential for patient stratification using a theranostic approach. Patient-specific absorbed dose planning might be the key to more successful treatment of advanced DTC.

Effects of Respiratory Motion on Y-90 PET Dosimetry for SIRT.

Respiratory motion degrades the quantification accuracy of PET imaging by blurring the radioactivity distribution. In the case of post-SIRT PET-CT verification imaging, respiratory motion can lead to inaccuracies in dosimetric measures. Using an anthropomorphic phantom filled with 90Y at a range of clinically relevant activities, together with a respiratory motion platform performing realistic motions (10-15 mm amplitude), we assessed the impact of respiratory motion on PET-derived post-SIRT dosimetry. Two PET scanners at two sites were included in the assessment. The phantom experiments showed that device-driven quiescent period respiratory motion correction improved the accuracy of the quantification with statistically significant increases in both the mean contrast recovery (+5%, p = 0.003) and the threshold activities corresponding to the dose to 80% of the volume of interest (+6%, p < 0.001). Although quiescent period gating also reduces the number of counts and hence increases the noise in the PET image, its use is encouraged where accurate quantification of the above metrics is desired.

A Systematic Review and Meta-Analysis of the Relationship Between the Radiation Absorbed Dose to the Thyroid and Response in Patients Treated with Radioiodine for Graves' Disease.

Background: Patients with Graves' disease are commonly treated with radioiodine. There remains controversy over whether the aim of treatment should be to achieve euthyroidism or hypothyroidism, and whether treatments should be administered with standard levels of radioactivity or personalized according to the radiation absorbed doses delivered to the thyroid. The aim of this review was to investigate whether a relationship exists between radiation absorbed dose and treatment outcome. Methods: A systematic review and meta-analysis of all reports published before February 13, 2020, were performed using PubMed, Web of Science, OVID MEDLINE, and Embase. Proportion of patients achieving nonhyperthyroid status was the primary outcome. Secondary outcomes were proportion of patients who were specifically euthyroid or hypothyroid. A random-effects meta-analysis of proportions was performed for primary and secondary outcomes, and the impact of the radiation absorbed dose on treatment outcome was assessed through meta-regression. The study is registered with PROSPERO (CRD42020175010). Results: A total of 1122 studies were identified of which 15, comprising 2303 Graves' disease patients, were eligible for the meta-analysis. A strong association was found between radiation absorbed dose and nonhyperthyroid and hypothyroid outcomes (odds ratio [OR] = 1.11 [95% confidence interval {CI} 1.08-1.14] and OR = 1.09 [CI 1.06-1.12] per 10 Gy increase). Higher rates of euthyroid outcome were found for radiation absorbed doses within the range 120-180 Gy when compared with outside this range (n = 1172, OR = 2.50 [CI 1.17-5.35], p = 0.018). A maximum euthyroid response of 38% was identified at a radiation absorbed dose of 128 Gy. Conclusions: The presented radiation absorbed dose-response relationships can facilitate personalized treatment planning for radioiodine treatment of patients with Graves' disease. Further studies are required to determine how patient-specific covariates can inform personalized treatments.

Comparison of 90Y SIRT predicted and delivered absorbed doses using a PSF conversion method.

PURPOSE: The aims of this study were to develop and apply a method to correct for the differences in partial volume effects of pre-therapy Technetium-99 m (99mTc)-MAA SPECT and post-therapy Yttrium-90 (90Y) bremsstrahlung SPECT imaging in selective internal radiation therapy, and to use this method to improve quantitative comparison of predicted and delivered 90Y absorbed doses. METHODS: The spatial resolution of 99mTc SPECT data was converted to that of 90Y SPECT data using a function calculated from 99mTc and 90Y point spread functions. This resolution conversion method (RCM) was first applied to 99mTc and 90Y SPECT phantom data to validate the method, and then to clinical data to assess the power of 99mTc SPECT imaging to predict the therapeutic absorbed dose. RESULTS: The maximum difference between absorbed doses to phantom spheres was 178%. This was reduced to 27% after the RCM was applied. The clinical data demonstrated differences within 38% for mean absorbed doses delivered to the normal liver, which were reduced to 20% after application of the RCM. Analysis of clinical data showed that therapeutic absorbed doses delivered to tumours greater than 100 cm3 were predicted to within 52%, although there were differences of up to 210% for smaller tumours, even after the RCM was applied. CONCLUSIONS: The RCM was successfully verified using phantom data. Analysis of the clinical data established that the 99mTc pre-therapy imaging was predictive of the 90Y absorbed dose to the normal liver to within 20%, but had poor predictability for tumours smaller than 100 cm3.

Uncertainty analysis of tumour absorbed dose calculations in molecular radiotherapy.

BACKGROUND: Internal dosimetry evaluation consists of a multi-step process ranging from imaging acquisition to absorbed dose calculations. Assessment of uncertainty is complicated and, for that reason, it is commonly ignored in clinical routine. However, it is essential for adequate interpretation of the results. Recently, the EANM published a practical guidance on uncertainty analysis for molecular radiotherapy based on the application of the law of propagation of uncertainty. In this study, we investigated the overall uncertainty on a sample of a patient following the EANM guidelines. The aim of this study was to provide an indication of the typical uncertainties that may be expected from performing dosimetry, to determine parameters that have the greatest effect on the accuracy of calculations and to consider the potential improvements that could be made if these effects were reduced. RESULTS: Absorbed doses and the relative uncertainties were calculated for a sample of 49 patients and a total of 154 tumours. A wide range of relative absorbed dose uncertainty values was observed (14-102%). Uncertainties associated with each quantity along the absorbed dose calculation chain (i.e. volume, recovery coefficient, calibration factor, activity, time-activity curve fitting, time-integrated activity and absorbed dose) were estimated. An equation was derived to describe the relationship between the uncertainty in the absorbed dose and the volume. The largest source of error was the VOI delineation. By postulating different values of FWHM, the impact of the imaging system spatial resolution on the uncertainties was investigated. DISCUSSION: To the best of our knowledge, this is the first analysis of uncertainty in molecular radiotherapy based on a cohort of clinical cases. Wide inter-lesion variability of absorbed dose uncertainty was observed. Hence, a proper assessment of the uncertainties associated with the calculations should be considered as a basic scientific standard. A model for a quick estimate of uncertainty without implementing the entire error propagation schema, which may be useful in clinical practice, was presented. Ameliorating spatial resolution may be in future the key factor for accurate absorbed dose assessment.

Radioactive 3D printing for the production of molecular imaging phantoms.

Quality control tests of molecular imaging systems are hampered by the complexity of phantom preparation. It is proposed that radioisotopes can be directly incorporated into photo-polymer resins. Use of the radio-polymer in a 3D printer allows phantoms with more complex and reliable activity distributions to be produced whilst simplifying source preparation. Initial tests have been performed to determine the practicality of integrating Tc-99m into a photo-polymer and example phantoms produced to test suitability for quality control. Samples of build and support resins were extracted from the print cartridges of an Objet30Pro Polyjet 3D printer. The response of the resin to external factors including ionising radiation, light and dilution with Tc-99m pertechnetate were explored. After success of the initial tests the radio-polymer was used in the production of different phantoms. Radionuclide dose calibrator and gamma camera acquisitions of the phantoms were used to test accuracy of activity concentration, print consistency, uniformity and heterogeneous reproducibility. Tomographic phantoms were also produced including a uniform hot sphere, a complex configuration of spheres and interlacing torus's and a hot rod phantom. The coefficient of variation between repeat prints of a 12 g disk phantom was 0.08%. Measured activity within the disks agreed to within 98 ± 2% of the expected activity based on initial resin concentration. Gamma camera integral uniformity measured across a 3D printed flood field phantom was 5.2% compared to 6.0% measured with a commercial Co-57 flood source. Heterogeneous distributions of activity were successfully reproduced for both 2D and 3D imaging phantoms. Count concentration across regions of heterogeneity agreed with the planned activity assigned to those regions on the phantom design. 3D printing of radioactive phantoms has been successfully demonstrated and is a promising application for quality control of Positron Emission Tomography and Single Photon Emission Computed Tomography systems.

Characterisation of the attenuation properties of 3D-printed tungsten for use in gamma camera collimation.

BACKGROUND: The aim of this work was to characterise the attenuation properties of 3D-printed tungsten and to assess the feasibility for its use in gamma camera collimator manufacture. METHOD: 3D-printed tungsten disks were produced using selective laser melting (SLM). Measurements of attenuation were made through increasing numbers of disks for a Tc-99m (140 keV) and I-131 (364 keV) source. The technique was validated by repeating the measurements with lead samples. Resolution measurements were also made with a SLM tungsten collimator and compared to Monte Carlo simulations of the experimental setup. Different collimator parameters were simulated and compared against the physical measurements to investigate the effect on image quality. RESULTS: The measured disk thicknesses were on average 20% above the specified disk thicknesses. The measured attenuation for the tungsten samples were lower than the theoretical value determined from the National Institute of Standards and Technology (NIST) cross-sectional database (Berger and Hubbell, XCOM: photon cross-sections on a personal computer, 1987). The laser scan strategy had a significant influence on material attenuation (up to 40% difference). Results of these attenuation measurements indicate that the density of the SLM material is lower than the raw tungsten density. However, an improved performance compared to a lead collimator was observed. The SLM tungsten collimator was adequately simulated as 80% density and 110% septal thickness. Scatter and septal penetration were 17% less than a similar lead collimator and 33% greater than tungsten at 100% density. CONCLUSIONS: SLM manufacture of tungsten collimators is feasible. Attenuation properties of SLM tungsten are superior to the lead alternative and the opportunity for bespoke collimator design is appealing.

A quality-control method for SPECT-based dosimetry in targeted radionuclide therapy.

Dosimetry for targeted radionuclide therapy is necessary for treatment planning and radiation protection. Currently, there are no standard methods either for performing dosimetry or to evaluate the uncertainties inherent in the dosimetric calculations. In this paper, we present an experimental method using polymer gel dosimeters, whereby absorbed-dose distributions resulting from nonuniform distributions of activity may be determined directly from T(2) magnetic resonance imaging (MRI) as well as from scintigraphic images. A phantom containing a nonuniform distribution of I-131 was prepared by mixing 58 MBq of activity within the gel as it was solidifying. The resulting absorbed-dose distribution was determined directly from the MRI and from sequential single-photon emission computed tomography (SPECT) images using the Medical Internal Radiation Dose (MIRD) schema. The MRI data were quantified using 12 calibration vials uniformly irradiated by 0-12 MBq of I-131. The agreement between the two absorbed-dose maps was verified by convolving the MRI-based absorbed-dose map with the SPECT system point spread function, which gave a correlation coefficient of 0.96. It was seen that the absorbed-dose distribution, as imaged by the MRI, was misrepresented by the SPECT owing to its relatively poor spatial resolution, which included a shift of the voxel containing the maximum absorbed dose. This technique could provide an independent benchmark for assessing patient-specific dosimetry and, therefore, could be used as a basis for quality control for dosimetry.

InfuShield: a shielded enclosure for administering therapeutic radioisotope treatments using standard syringe pumps.

The administration of radionuclide therapies presents significant radiation protection challenges. The aim of this work was to develop a delivery system for intravenous radioisotope therapies to substantially moderate radiation exposures to staff and operators. A novel device (InfuShield) was designed and tested before being used clinically. The device consists of a shielded enclosure which contains the therapeutic activity and, through the hydraulic action of back-to-back syringes, allows the activity to be administered using a syringe pump external to the enclosure. This enables full access to the pump controls while simultaneously reducing dose to the operator. The system is suitable for use with all commercially available syringe pumps and does not require specific consumables, maximising both the flexibility and economy of the system. Dose rate measurements showed that at key stages in an I mIBG treatment procedure, InfuShield can reduce dose to operators by several orders of magnitude. Tests using typical syringes and infusion speeds show no significant alteration in administered flow rates (maximum of 1.2%). The InfuShield system provides a simple, safe and low cost method of radioisotope administration.

Abdo-Man: a 3D-printed anthropomorphic phantom for validating quantitative SIRT.

BACKGROUND: The use of selective internal radiation therapy (SIRT) is rapidly increasing, and the need for quantification and dosimetry is becoming more widespread to facilitate treatment planning and verification. The aim of this project was to develop an anthropomorphic phantom that can be used as a validation tool for post-SIRT imaging and its application to dosimetry. METHOD: The phantom design was based on anatomical data obtained from a T1-weighted volume-interpolated breath-hold examination (VIBE) on a Siemens Aera 1.5 T MRI scanner. The liver, lungs and abdominal trunk were segmented using the Hermes image processing workstation. Organ volumes were then uploaded to the Delft Visualization and Image processing Development Environment for smoothing and surface rendering. Triangular meshes defining the iso-surfaces were saved as stereo lithography (STL) files and imported into the Autodesk® Meshmixer software. Organ volumes were subtracted from the abdomen and a removable base designed to allow access to the liver cavity. Connection points for placing lesion inserts and filling holes were also included. The phantom was manufactured using a Stratasys Connex3 PolyJet 3D printer. The printer uses stereolithography technology combined with ink jet printing. Print material is a solid acrylic plastic, with similar properties to polymethylmethacrylate (PMMA). RESULTS: Measured Hounsfield units and calculated attenuation coefficients of the material were shown to also be similar to PMMA. Total print time for the phantom was approximately 5 days. Initial scans of the phantom have been performed with Y-90 bremsstrahlung SPECT/CT, Y-90 PET/CT and Tc-99m SPECT/CT. The CT component of these images compared well with the original anatomical reference, and measurements of volume agreed to within 9 %. Quantitative analysis of the phantom was performed using all three imaging techniques. Lesion and normal liver absorbed doses were calculated from the quantitative images in three dimensions using the local deposition method. CONCLUSIONS: 3D printing is a flexible and cost-efficient technology for manufacture of anthropomorphic phantom. Application of such phantoms will enable quantitative imaging and dosimetry methodologies to be evaluated, which with optimisation could help improve outcome for patients.