Symposium on molecular radiotherapy dosimetry: The first of a series?

The EFOMP Special Interest Group for Radionuclide Internal Dosimetry (SIG_FRID) organised its first scientific meeting, the Symposium on Molecular Radiotherapy Dosimetry, in Athens on November 9th-11th 2023. The Symposium was hosted by the Hellenic Association of Medical Physicists and the National and Kapodistrian University of Athens. This meeting gathered more than 180 scientists from 28 countries. Scientific, clinical and regulatory aspects were addressed by 8 invited experts. Two continuous professional development sessions were organised. A special round table gathering medical physics experts, physicians regulatory authority experts and patient representatives addressed the possibilities to increase clinical dosimetry dissemination. The event was supported by companies and a specific industry session allowed sponsors to present their products, innovations and future perspective in this field.

EFOMP policy statement NO. 19: Dosimetry in nuclear medicine therapy - Molecular radiotherapy.

The European Council Directive 2013/59/Euratom (BSS Directive) includes optimisation of treatment with radiotherapeutic procedures based on patient dosimetry and verification of the absorbed doses delivered. The present policy statement summarises aspects of three directives relating to the therapeutic use of radiopharmaceuticals and medical devices, and outlines the steps needed for implementation of patient dosimetry for radioactive drugs. To support the transition from administrations of fixed activities to personalised treatments based on patient-specific dosimetry, EFOMP presents a number of recommendations including: increased networking between centres and disciplines to support data collection and development of codes-of-practice; resourcing to support an infrastructure that permits routine patient dosimetry; research funding to support investigation into individualised treatments; inter-disciplinary training and education programmes; and support for investigator led clinical trials. Close collaborations between the medical physicist and responsible practitioner are encouraged to develop a similar pathway as is routine for external beam radiotherapy and brachytherapy. EFOMP's policy is to promote the roles and responsibilities of medical physics throughout Europe in the development of molecular radiotherapy to ensure patient benefit. As the BSS directive is adopted throughout Europe, unprecedented opportunities arise to develop informed treatments that will mitigate the risks of under- or over-treatments.

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.

Second primary malignancies induced by radioactive iodine treatment of differentiated thyroid carcinoma - a critical review and evaluation of the existing evidence.

PURPOSE: Concern is growing about long-term side effects of differentiated thyroid cancer treatment, most notably radioactive iodine (RAI) therapy. However, published studies on the subject have had heterogeneous cohorts and conflicting results. This review seeks to provide an updated evaluation of published evidence, and to elucidate the risk of second primary malignancies (SPMs), especially secondary hematologic malignancies (SHMs), attributable to RAI therapy. METHODS: An extensive literature search was performed in Ovid MEDLINE, Ovid MEDLINE and In-Process & Other Non-Indexed Citations, Ovid MEDLINE Epub Ahead of Print, Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed. Studies regarding RAI-induced SPMs or a dose-response relationship between RAI therapy and SPMs were identified, 10 of which were eligible for the analysis. We evaluated risk of bias in each study and judged quality of evidence (QOE) across all studies using the Grading of Recommendations, Assessment, Development and Evaluations approach. RESULTS: For the outcome "SPM", the relative effect (relative risk, hazard ratio, or odds ratio) of RAI vs. no RAI ranged from 1.14 to 1.84 across studies, but most results were not statistically significant. For the outcome "SHM", reported relative effects ranged from 1.30 to 2.50, with 2/3 of the studies presenting statistically significant results. In 7/8 of the studies, increased risk for SPM was shown with increasing cumulative RAI activity. QOE was "very low" regarding SPM after RAI and regarding a dose-response relationship, and "low" for SHM after RAI. CONCLUSION: Based on low quality evidence, an excess risk for the development of SPM cannot be excluded but is expected to be small.

RADAR Guide: Standard Methods for Calculating Radiation Doses for Radiopharmaceuticals, Part 2-Data Analysis and Dosimetry.

This paper presents standardized methods for performing dose calculations for radiopharmaceuticals. Various steps in the process are outlined, with some specific examples given. Special models for calculating time-activity integrals (urinary bladder, intestines) are also reviewed. This article can be used as a template for designing and executing kinetic studies for calculating radiation dose estimates from animal or human data.

RADAR Guide: Standard Methods for Calculating Radiation Doses for Radiopharmaceuticals, Part 1-Collection of Data for Radiopharmaceutical Dosimetry.

This paper presents standardized methods for collecting data to be used in performing dose calculations for radiopharmaceuticals. Various steps in the process are outlined, with some specific examples given. This document can be used as a template for designing and executing kinetic studies for calculating radiation dose estimates, from animal or human data.

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.

EANM dosimetry committee series on standard operational procedures: a unified methodology for 99mTc-MAA pre- and 90Y peri-therapy dosimetry in liver radioembolization with 90Y microspheres.

The aim of this standard operational procedure is to standardize the methodology employed for the evaluation of pre- and post-treatment absorbed dose calculations in 90Y microsphere liver radioembolization. Basic assumptions include the permanent trapping of microspheres, the local energy deposition method for voxel dosimetry, and the patient-relative calibration method for activity quantification.The identity of 99mTc albumin macro-aggregates (MAA) and 90Y microsphere biodistribution is also assumed. The large observed discrepancies in some patients between 99mTc-MAA predictions and actual 90Y microsphere distributions for lesions is discussed. Absorbed dose predictions to whole non-tumoural liver are considered more reliable and the basic predictors of toxicity. Treatment planning based on mean absorbed dose delivered to the whole non-tumoural liver is advised, except in super-selective treatments.Given the potential mismatch between MAA simulation and actual therapy, absorbed doses should be calculated both pre- and post-therapy. Distinct evaluation between target tumours and non-tumoural tissue, including lungs in cases of lung shunt, are vital for proper optimization of therapy. Dosimetry should be performed first according to a mean absorbed dose approach, with an optional, but important, voxel level evaluation. Fully corrected 99mTc-MAA Single Photon Emission Computed Tomography (SPECT)/computed tomography (CT) and 90Y TOF PET/CT are regarded as optimal acquisition methodologies, but, for institutes where SPECT/CT is not available, non-attenuation corrected 99mTc-MAA SPECT may be used. This offers better planning quality than non dosimetric methods such as Body Surface Area (BSA) or mono-compartmental dosimetry. Quantitative 90Y bremsstrahlung SPECT can be used if dedicated correction methods are available.The proposed methodology is feasible with standard camera software and a spreadsheet. Available commercial or free software can help facilitate the process and improve calculation time.

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.

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.