EANM guidance document: dosimetry for first-in-human studies and early phase clinical trials.

The numbers of diagnostic and therapeutic nuclear medicine agents under investigation are rapidly increasing. Both novel emitters and novel carrier molecules require careful selection of measurement procedures. This document provides guidance relevant to dosimetry for first-in human and early phase clinical trials of such novel agents. The guideline includes a short introduction to different emitters and carrier molecules, followed by recommendations on the methods for activity measurement, pharmacokinetic analyses, as well as absorbed dose calculations and uncertainty analyses. The optimal use of preclinical information and studies involving diagnostic analogues is discussed. Good practice reporting is emphasised, and relevant dosimetry parameters and method descriptions to be included are listed. Three examples of first-in-human dosimetry studies, both for diagnostic tracers and radionuclide therapies, are given.

The contest between internal and external-beam dosimetry: The Zeno's paradox of Achilles and the tortoise.

Radionuclide therapy, also called molecular radiotherapy (MRT), has come of age, with several novel radiopharmaceuticals being approved for clinical use or under development in the last decade. External beam radiotherapy (EBRT) is a well-established treatment modality, with about half of all oncologic patients expected to receive at least one external radiation treatment over their disease course. The efficacy and the toxicity of both types of treatment rely on the interaction of radiation with biological tissues. Dosimetry played a fundamental role in the scientific and technological evolution of EBRT, and absorbed doses to the target and to the organs at risk are calculated on a routine basis. In contrast, in MRT the usefulness of internal dosimetry has long been questioned, and a structured path to include absorbed dose calculation is missing. However, following a similar route of development as EBRT, MRT treatments could probably be optimized in a significant proportion of patients, likely based on dosimetry and radiobiology. In the present paper we describe the differences and the similarities between internal and external-beam dosimetry in the context of radiation treatments, and we retrace the main stages of their development over the last decades.

EANM procedural recommendations for managing the paediatric patient in diagnostic nuclear medicine.

PURPOSE: The manuscript aims to characterize the principles of best practice in performing nuclear medicine procedures in paediatric patients. The paper describes all necessary technical skills that should be developed by the healthcare professionals to ensure the best possible care in paediatric patients, as it is particularly challenging due to psychological and physical conditions of children. METHODS: We performed a comprehensive literature review to establish the most relevant elements of nuclear medicine studies in paediatric patients. We focused the attention to the technical aspects of the study, such as patient preparation, imaging protocols, and immobilization techniques, that adhere to best practice principles. Furthermore, we considered the psychological elements of working with children, including comforting and distraction strategies. RESULTS: The extensive literature review combined with practical conclusions and recommendations presented and explained by the authors summarizes the most important principles of the care for paediatric patient in the nuclear medicine field. CONCLUSION: Nuclear medicine applied to the paediatric patient is a very special and challenging area, requiring proper education and experience in order to be performed at the highest level and with the maximum safety for the child.

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.

EANM enabling guide: how to improve the accessibility of clinical dosimetry.

Dosimetry can be a useful tool for personalization of molecular radiotherapy (MRT) procedures, enabling the continuous development of theranostic concepts. However, the additional resource requirements are often seen as a barrier to implementation. This guide discusses the requirements for dosimetry and demonstrates how a dosimetry regimen can be tailored to the available facilities of a centre. The aim is to help centres wishing to initiate a dosimetry service but may not have the experience or resources of some of the more established therapy and dosimetry centres. The multidisciplinary approach and different personnel requirements are discussed and key equipment reviewed example protocols demonstrating these factors are given in the supplementary material for the main therapies carried out in nuclear medicine, including [131I]-NaI for benign thyroid disorders, [177Lu]-DOTATATE and 131I-mIBG for neuroendocrine tumours and [90Y]-microspheres for unresectable hepatic carcinoma.

EANM practice guideline for quantitative SPECT-CT.

PURPOSE: Quantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging together with the concept of theranostics more generally. The aim of this document is to provide guidelines for nuclear medicine departments setting up and developing their quantitative SPECT-CT service with guidance on protocols, harmonisation and clinical use cases. METHODS: These practice guidelines were written by members of the European Association of Nuclear Medicine Physics, Dosimetry, Oncology and Bone committees representing the current major stakeholders in Quantitative SPECT-CT. The guidelines have also been reviewed and approved by all EANM committees and have been endorsed by the European Association of Nuclear Medicine. CONCLUSION: The present practice guidelines will help practitioners, scientists and researchers perform high-quality quantitative SPECT-CT and will provide a framework for the continuing development of quantitative SPECT-CT as an established modality.

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.

Joint EANM, SNMMI, and IAEA Enabling Guide: How to Set up a Theranostics Center.

The theranostics concept using the same target for both imaging and therapy dates back to the middle of the last century, when radioactive iodine was first used to treat thyroid diseases. Since then, radioiodine has become broadly established clinically for diagnostic imaging and therapy of benign and malignant thyroid disease, worldwide. However, only since the approval of SSTR2-targeting theranostics following the NETTER-1 trial in neuroendocrine tumors, and the positive outcome of the VISION trial has theranostics gained substantial attention beyond nuclear medicine. The roll-out of radioligand therapy for treating a high-incidence tumor such as prostate cancer requires the expansion of existing and the establishment of new theranostics centers. Despite wide global variation in the regulatory, financial and medical landscapes, this guide attempts to provide valuable information to enable interested stakeholders to safely initiate and operate theranostic centers. This enabling guide does not intend to answer all possible questions, but rather to serve as an overarching framework for multiple, more detailed future initiatives. It recognizes that there are regional differences in the specifics of regulation of radiation safety, but common elements of best practice valid globally.

Milestones in dosimetry for nuclear medicine therapy.

Nuclear Medicine therapy has reached a critical juncture with an unprecedented number of patients being treated and an extensive list of new radiopharmaceuticals under development. Since the early applications of these treatments dosimetry has played a vital role in their development, in both aiding optimisation and enhancing safety and efficacy. To inform the future direction of this field, it is useful to reflect on the scientific and technological advances that have occurred since those early uses. In this review, we explore how dosimetry has evolved over the years and discuss why such initiatives were conceived and the importance of maintaining standards within our practise. Specific milestones and landmark publications are highlighted and a thematic review and significant outcomes during each decade are presented.

Joint EANM, SNMMI and IAEA enabling guide: how to set up a theranostics centre.

The theranostics concept using the same target for both imaging and therapy dates back to the middle of the last century, when radioactive iodine was first used to treat thyroid diseases. Since then, radioiodine has become broadly established clinically for diagnostic imaging and therapy of benign and malignant thyroid disease, worldwide. However, only since the approval of SSTR2-targeting theranostics following the NETTER-1 trial in neuroendocrine tumours and the positive outcome of the VISION trial has theranostics gained substantial attention beyond nuclear medicine. The roll-out of radioligand therapy for treating a high-incidence tumour such as prostate cancer requires the expansion of existing and the establishment of new theranostics centres. Despite wide global variation in the regulatory, financial and medical landscapes, this guide attempts to provide valuable information to enable interested stakeholders to safely initiate and operate theranostics centres. This enabling guide does not intend to answer all possible questions, but rather to serve as an overarching framework for multiple, more detailed future initiatives. It recognizes that there are regional differences in the specifics of regulation of radiation safety, but common elements of best practice valid globally.

EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands.

The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA.

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.

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.

Dosimetry for Radiopharmaceutical Therapy: The European Perspective.

This review presents efforts in Europe over the last few years with respect to standardization of quantitative imaging and dosimetry and comprises the results of several European research projects on practices regarding radiopharmaceutical therapies (RPTs). Because the European Union has regulatory requirements concerning dosimetry in RPTs, the European Association of Nuclear Medicine released a position paper in 2021 on the use of dosimetry under these requirements. The importance of radiobiology for RPTs is elucidated in another position paper by the European Association of Nuclear Medicine. Furthermore, how dosimetry interacts with clinical requirements is described, with several clinical examples. In the future, more efforts need to be undertaken to increase teaching and standardization efforts and to incorporate radiobiology for further individualizing patient treatment, with the aim of improving the outcome and safety of RPTs.

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.