Future trends for patient-specific dosimetry methodology in molecular radiotherapy.

Molecular radiotherapy is rapidly expanding, and new radiotherapeutics are emerging. The majority of treatments is still performed using empirical fixed activities and not tailored for individual patients. Molecular radiotherapy dosimetry is often seen as a promising candidate that would allow personalisation of treatments as outcome should ultimately depend on the absorbed doses delivered and not the activities administered. The field of molecular radiotherapy dosimetry has made considerable progress towards the feasibility of routine clinical dosimetry with reasonably accurate absorbed-dose estimates for a range of molecular radiotherapy dosimetry applications. A range of challenges remain with respect to the accurate quantification, assessment of time-integrated activity and absorbed dose estimation. In this review, we summarise a range of technological and methodological advancements, mainly focussed on beta-emitting molecular radiotherapeutics, that aim to improve molecular radiotherapy dosimetry to achieve accurate, reproducible, and streamlined dosimetry. We describe how these new technologies can potentially improve the often time-consuming considered process of dosimetry and provide suggestions as to what further developments might be required.

Normal organ dosimetry for thyroid cancer patients treated with radioiodine as part of the multi-centre multi-national Horizon 2020 MEDIRAD project.

PURPOSE: Dosimetry is rarely performed for the treatment of differentiated thyroid cancer patients with Na[131I]I (radioiodine), and information regarding absorbed doses delivered is limited. Collection of dosimetry data in a multi-centre setting requires standardised quantitative imaging and dosimetry. A multi-national, multi-centre clinical study was performed to assess absorbed doses delivered to normal organs for differentiated thyroid cancer patients treated with Na[131I]I. METHODS: Patients were enrolled in four centres and administered fixed activities of 1.1 or 3.7 GBq of Na[131I]I using rhTSH stimulation or under thyroid hormone withdrawal according to local protocols. Patients were imaged using SPECT(/CT) at variable imaging time-points following standardised acquisition and reconstruction protocols. Whole-body retention data were collected. Dosimetry for normal organs was performed at two dosimetry centres and results collated. RESULTS: One hundred and five patients were recruited. Median absorbed doses per unit administered activity of 0.44, 0.14, 0.05 and 0.16 mGy/MBq were determined for the salivary glands of patients treated at centre 1, 2, 3 and 4, respectively. Median whole-body absorbed doses for 1.1 and 3.7 GBq were 0.05 Gy and 0.16 Gy, respectively. Median whole-body absorbed doses per unit administered activity of 0.04, 0.05, 0.04 and 0.04 mGy/MBq were calculated for centre 1, 2, 3 and 4, respectively. CONCLUSIONS: A wide range of normal organ doses were observed for differentiated thyroid cancer patients treated with Na[131I]I, highlighting the necessity for individualised dosimetry. The results show that data may be collated from multiple centres if minimum standards for the acquisition and dosimetry protocols can be achieved.

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.

Radiation protection aspects for alpha therapies.

The use of alpha emitting radiotherapeutics is increasing, with further growth expected due to a number of clinical trials currently running involving new alpha emitters. However, literature concerning radiation safety aspects of alpha emitting radionuclides is limited and most of the available literature concerns 223Ra. In general, the occupational exposure from alpha emitting radionuclides is expected to be low, as are doses to the public from external exposure. However, care must be taken to avoid skin contamination, inhalation, and ingestion. Not all alpha emitting radionuclides are identical, they often have very different associated decay chains and emissions. The decay chains and the manufacturing process should be carefully examined to identify any long-lived progeny or impurities. These may have an impact on the radiation safety processes required to limit occupational exposure and for waste management. Doses to the public must also be assessed, either arising directly from exposure to patients treated with radiotherapeutics, or via waste streams. Risk assessments should be in place when starting a new service covering all aspects of the preparation and administration, as well as any foreseeable incidents such as skin contamination or patient death, and the appropriate steps to take in these instances. It is imperative that with the increase in the use of alpha emitting radiotherapeutics more literature is published on radiation safety aspects, especially for new alpha emitting radiotherapeutics which often have very different characteristics than the currently established ones.

Quantification and dosimetry of small volumes including associated uncertainty estimation.

BACKGROUND: Accurate quantification of radioactivity in a source of interest relies on accurate registration between SPECT and anatomical images, and appropriate correction of partial volume effects (PVEs). For small volumes, exact registration between the two imaging modalities and recovery factors used to correct for PVE are unreliable. There is currently no guidance relating to quantification or the associated uncertainty estimation for small volumes. MATERIAL AND METHODS: A method for quantification of small sources of interest is proposed, which uses multiple oversized volumes of interest. The method was applied to three Na[131I]I activity distributions where a Na[131I]I capsule was situated within a cylindrical phantom containing either zero background, uniform background or non-uniform background and to a scenario with small lesions placed in an anthropomorphic phantom. The Na[131I]I capsule and lesions were quantified using the proposed method and compared with measurements made using two alternative quantification methods. The proposed method was also applied to assess the absorbed dose delivered to a bone metastasis following [131I]mIBG therapy for neuroblastoma including the associated uncertainty estimation. RESULTS: The method is accurate across a range of activities and in varied radioactivity distributions. Median percentage errors using the proposed method in no background, uniform backgrounds and non-uniform backgrounds were - 0.4%, - 0.3% and 1.7% with median associated uncertainties of 1.4%, 1.4% and 1.6%, respectively. The technique is more accurate and robust when compared to currently available alternative methods. CONCLUSIONS: The proposed method provides a reliable and accurate method for quantification of sources of interest, which are less than three times the spatial resolution of the imaging system. The method may be of use in absorbed dose calculation in cases of bone metastasis, lung metastasis or thyroid remnants.

Iodine-131 and Iodine-131-Meta-iodobenzylguanidine Dosimetry in Cancer Therapy.

Radioactive iodine was first used for the treatment of benign thyroid disease and thyroid cancer 80 years ago. I-131 mIBG was later developed for the treatment of adult and pediatric neuroendocrine tumors. Physicists were closely involved from the outset to measure retention, to quantify uptake and to calculate radiation dosimetry. As the treatment became widespread, contrasting treatment regimes were followed, either given with empirically derived fixed levels of activity or guided according to the radiation doses delivered. As for external beam radiotherapy, individualized treatments for both thyroid cancer and neuroendocrine tumors were developed based on the aim of maximizing the radiation doses delivered to target volumes while restricting the radiation doses delivered to organs-at-risk, particularly the bone marrow. The challenge of marrow dosimetry has been met by using surrogate measures, often the blood dose for thyroid treatments and the whole-body dose in the case of treatment of neuroblastoma with I-131 mIBG. A number of studies have sought to establish threshold absorbed doses to ensure therapeutic efficacy. Although different values have been postulated, it has nevertheless been conclusively demonstrated that a fixed activity approach leads to a wide range of absorbed doses delivered to target volumes and to normal organs. Personalized treatment planning is now technically feasible with ongoing multicenter clinical trials and investigations into image quantification, biokinetic modelling and radiobiology.

Theoretical aspects on the use of single-time-point dosimetry for radionuclide therapy.

Objective. This study considers the error distributions for time-integrated activity (TIA) of single-time-point (STP) methods for patient-specific dosimetry in radionuclide therapy.Approach. The general case with the same pharmaceutical labelled with different radionuclides for imaging and therapy are considered for a mono-exponential time-activity curve. Two methods for STP dosimetry, both based on the combination of one activity estimate with the population-mean effective decay constant, are investigated. The cumulative distribution functions (CDFs) and the probability density functions for the two methods are analytically derived for arbitrary distributions of the biological decay constant. The CDFs are used for determining 95% coverage intervals of the relative errors for different combinations of imaging time points, physical decay constants, and relative standard deviations of the biological decay constant. Two examples, in the form of kidney dosimetry in [177Lu]Lu-DOTA-TATE therapy and tumour dosimetry for Na[131I]I therapy for thyroid cancer with dosimetry based on imaging of Na[124I]I, are also studied in more detail with analysis of the sensitivity with respect to errors in the mean biological decay constant and to higher moments of the distribution.Main results. The distributions of the relative errors are negatively skewed, potentially leading to the situation that some TIA estimates are highly underestimated even if the majority of estimates are close to the true value.Significance. The main limitation of the studied STP dosimetry methods is the risk of large underestimations of the TIA.

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.

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.

Setting up a quantitative SPECT imaging network for a European multi-centre dosimetry study of radioiodine treatment for thyroid cancer as part of the MEDIRAD project.

BACKGROUND: Differentiated thyroid cancer has been treated with radioiodine for almost 80 years, although controversial questions regarding radiation-related risks and the optimisation of treatment regimens remain unresolved. Multi-centre clinical studies are required to ensure recruitment of sufficient patients to achieve the statistical significance required to address these issues. Optimisation and standardisation of data acquisition and processing are necessary to ensure quantitative imaging and patient-specific dosimetry. MATERIAL AND METHODS: A European network of centres able to perform standardised quantitative imaging of radioiodine therapy of thyroid cancer patients was set-up within the EU consortium MEDIRAD. This network will support a concurrent series of clinical studies to determine accurately absorbed doses for thyroid cancer patients treated with radioiodine. Five SPECT(/CT) systems at four European centres were characterised with respect to their system volume sensitivity, recovery coefficients and dead time. RESULTS: System volume sensitivities of the Siemens Intevo systems (crystal thickness 3/8″) ranged from 62.1 to 73.5 cps/MBq. For a GE Discovery 670 (crystal thickness 5/8″) a system volume sensitivity of 92.2 cps/MBq was measured. Recovery coefficients measured on three Siemens Intevo systems show good agreement. For volumes larger than 10 ml, the maximum observed difference between recovery coefficients was found to be ± 0.02. Furthermore, dead-time coefficients measured on two Siemens Intevo systems agreed well with previously published dead-time values. CONCLUSIONS: Results presented here provide additional support for the proposal to use global calibration parameters for cameras of the same make and model. This could potentially facilitate the extension of the imaging network for further dosimetry-based studies.

Physics aspects of setting up a multicenter clinical trial involving internal dosimetry of radioiodine treatment of differentiated thyroid cancer.

The field of molecular radiotherapy is expanding rapidly, with the advent of many new radiotherapeutics for the treatment of common as well as for rare cancers. Treatment outcome is dependent on the absorbed doses delivered to target volumes and to healthy organs-at-risk, which are shown to vary widely from fixed administrations of activity. There have been significant developments in quantitative imaging and internal dosimetry in recent years, although clinical implementation of these methods has been slow in comparison with external beam radiotherapy, partly due to there being relatively few patients treated at single centers. Multicenter clinical trials are therefore essential to acquire the data required to ensure best practice and to develop the personalized treatment planning that this area is well suited to, due to the unrivalled opportunity to image the therapeutic drug in vivo. Initial preparation for such trials requires a significant effort in terms of resources and trial design. Imaging systems in participating centers must be characterized and set up for quantitative imaging to allow for collation of data. Data transfer for centralized processing is usually necessary but is hindered in some cases by data protection regulations and local logistics. Recent multicenter clinical trials involving radioiodine therapy have begun to establish the procedures necessary for quantitative SPECT imaging in a multicenter setting using standard and anthropomorphic phantoms. The establishment of national and international multicenter imaging and dosimetry networks will provide frameworks to develop and harmonize best practice with existing therapeutic procedures and to ensure rapid and optimized clinical implementation of new radiotherapeutics across all centers of excellence that offer molecular radiotherapy. This will promote networks and collaborations that can provide a sound basis for further developments and will ensure that nuclear medicine maintains a key role in future developments.

Compartmental Model for 223Ra-Dichloride in Patients With Metastatic Bone Disease From Castration-Resistant Prostate Cancer.

PURPOSE: 223Ra-Dichloride is used for treatment of patients with metastatic bone disease from castration-resistant prostate cancer. The uptake and mechanism of action of 223Ra-Dichloride is not well understood. The aim of this work was to develop a compartmental model for 223Ra-Dichloride in patients to improve understanding of the underlying mechanisms. METHODS AND MATERIALS: A compartmental model was developed based on activity retention data from 6 patients (2 treatments of 110 kBq/kg 223Ra-Dichloride) for plasma, bone surfaces, small intestines, large intestines, and excretion data. Rate constants were extracted. Rate constant variability between patients and treatments was assessed. A population model was proposed and compared with the established International Commission on Radiological Protection-67 compartmental model. RESULTS: A single bone compartment cannot accurately describe activity retention in the skeleton. The addition of a second bone compartment improved the fit to skeleton retention data, and the Akaike information criterion decreased. Mean rate constants of 4.0 (range, 1.9-10.9) and 0.15 (0.07-0.39) h-1 were obtained for transport from plasma to first bone compartment and vice versa. Rate constants from first to second bone compartment and back of 0.03 (0.02-0.06) and 0.008 (0.003-0.011) h-1 were calculated. Rate constants for individual patients showed no significant difference between patients and treatments. CONCLUSIONS: The developed compartmental model suggests that 223Ra-Dichloride initially locates at the bone surface and is then incorporated into the bone matrix relatively quickly. This observation could have implications for dosimetry and understanding of the effects of alpha radiation on normal bone tissue. Results suggest that a population model based on patient measurements is feasible.

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.