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.

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

PURPOSE: The use of molecular radiotherapy (MRT) has been rapidly evolving over the last years. The aim of this study was to assess the current implementation of dosimetry for MRTs in Europe. METHODS: A web-based questionnaire was open for treating centres between April and June 2022, and focused on 2020-2022. Questions addressed the application of 16 different MRTs, the availability and involvement of medical physicists, software used, quality assurance, as well as the target regions for dosimetry, whether treatment planning and/or verification were performed, and the dosimetric methods used. RESULTS: A total of 173 responses suitable for analysis was received from centres performing MRT, geographically distributed over 27 European countries. Of these, 146 centres (84 %) indicated to perform some form of dosimetry, and 97 % of these centres had a medical physicist available and almost always involved in dosimetry. The most common MRTs were 131I-based treatments for thyroid diseases and thyroid cancer, and [223Ra]RaCl2 for bone metastases. The implementation of dosimetry varied widely between therapies, from almost all centres performing dosimetry-based planning for microsphere treatments to none for some of the less common treatments (like 32P sodium-phosphate for myeloproliferative disease and [89Sr]SrCl2 for bone metastases). CONCLUSIONS: Over the last years, implementation of dosimetry, both for pre-therapeutic treatment planning and post-therapy absorbed dose verification, increased for several treatments, especially for microsphere treatments. For other treatments that have moved from research to clinical routine, the use of dosimetry decreased in recent years. However, there are still large differences both across and within countries.

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.

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.

Androgen receptor polyQ alleles and COVID-19 severity in men: a replication study

Ample evidence indicates a sex-related difference in severity of COVID-19, with less favorable outcomes observed in men. Genetic factors have been proposed as candidates to explain this difference. The polyQ polymorphism in the androgen receptor gene has been recently described as a genetic biomarker of COVID-19 severity. In this study, we analyzed this association in a large cohort of 1136 men classified into three groups according to their degree of COVID-19 severity, finding a similar distribution of polyQ alleles among severity groups. Therefore, our results do not support the role of this polymorphism as a biomarker of COVID-19 severity.

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.

Alpha particle microdosimetry calculations using a shallow neural network.

A shallow neural network was trained to accurately calculate the microdosimetric parameters, 〈z1〉 and 〈z12〉 (the first and second moments of the single-event specific energy spectra, respectively) for use in alpha-particle microdosimetry calculations. The regression network of four inputs and two outputs was created in MATLAB and trained on a data set consisting of both previously published microdosimetric data and recent Monte Carlo simulations. The input data consisted of the alpha-particle energies (3.97-8.78 MeV), cell nuclei radii (2-10µm), cell radii (2.5-20µm), and eight different source-target configurations. These configurations included both single cells in suspension and cells in geometric clusters. The mean square error (MSE) was used to measure the performance of the network. The sizes of the hidden layers were chosen to minimize MSE without overfitting. The final neural network consisted of two hidden layers with 13 and 20 nodes, respectively, each with tangential sigmoid transfer functions, and was trained on 1932 data points. The overall training/validation resulted in a MSE = 3.71 × 10-7. A separate testing data set included input values that were not seen by the trained network. The final test on 892 separate data points resulted in a MSE = 2.80 × 10-7. The 95th percentile testing data errors were within ±1.4% for 〈z1〉 outputs and ±2.8% for 〈z12〉 outputs, respectively. Cell survival was also predicted using actual versus neural network generated microdosimetric moments and showed overall agreement within ±3.5%. In summary, this trained neural network can accurately produce microdosimetric parameters used for the study of alpha-particle emitters. The network can be exported and shared for tests on independent data sets and new calculations.

SARS-CoV-2 Point Mutation and Deletion Spectra, and Their Association with Different Disease Outcome

Mutant spectra of RNA viruses are important to understand viral pathogenesis, and response to selective pressures. There is a need to characterize the complexity of mutant spectra in coronaviruses sampled from infected patients. In particular, the possible relationship between SARS-CoV-2 mutant spectrum complexity and disease associations has not been established. In the present study, we report an ultra-deep sequencing (UDS) analysis of the mutant spectrum of amplicons from the nsp12 (polymerase)- and spike (S)-coding regions of thirty nasopharyngeal isolates (diagnostic samples) of SARS-CoV-2 of the first COVID-19 pandemic wave (Madrid, Spain, April 2020) classified according to the severity of ensuing COVID-19. Low frequency mutations and deletions, counted relative to the consensus sequence of the corresponding isolate, were overwhelmingly abundant. We show that the average number of different point mutations, mutations per haplotype and several diversity indices was significantly higher in SARS-CoV-2 isolated from patients who developed mild disease than in those associated with moderate or severe disease (exitus). No such bias was observed with RNA deletions. Location of amino acid substitutions in the three dimensional structures of nsp12 (polymerase) and S suggest significant structural or functional effects. Thus, patients who develop mild symptoms may be a richer source of genetic variants of SARS-CoV-2 than patients with moderate or severe COVID-19. IMPORTANCEThe study shows that mutant spectra of SARS-CoV-2 from diagnostic samples differ in point mutation abundance and complexity, and that significantly larger values were observed in virus from patients who developed mild COVID-19 symptoms. Mutant spectrum complexity is not a uniform trait among isolates. The nature and location of low frequency amino acid substitutions present in mutant spectra anticipate great potential for phenotypic diversification of SARS-CoV-2.

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.

High SARS-CoV-2 viral load is associated with a worse clinical outcome of COVID-19 disease

COVID-19 severity and progression are determined by several host and virological factors that may influence the final outcome of SARS-CoV-2-infected patients. The objective of this work is to determine a possible association between the viral load, obtained from nasopharyngeal swabs, and the severity of the infection in a cohort of 448 SARS-CoV-2-infected patients from a hospital in Madrid during the first outbreak of the pandemic in Spain. To perform this, we have clinically classified patients as mild, moderate and severe COVID-19 according to a number of clinical parameters such as hospitalization requirement, need of oxygen therapy, admission to intensive care units and/or exitus. Here we report a statistically significant correlation between viral load and disease severity, being high viral load associated with worse clinical prognosis, independently of several previously identified risk factors such as age, sex, hypertension, cardiovascular disease, diabetes, obesity, and lung disease (asthma and chronic obstructive pulmonary disease). The data presented here reinforce the viral load as a potential biomarker for predicting disease severity in SARS-CoV-2-infected patients. It is also an important parameter in viral evolution since it relates to the numbers and types of variant genomes present in a viral population, a potential determinant of disease progression.

COVID-19 Outcomes in 4712 consecutively confirmed SARS-CoV2 cases in the city of Madrid.

There is limited information describing features and outcomes of patients requiring hospitalization for COVID19 disease and still no treatments have clearly demonstrated efficacy. Demographics and clinical variables on admission, as well as laboratory markers and therapeutic interventions were extracted from electronic Clinical Records (eCR) in 4712 SARS-CoV2 infected patients attending 4 public Hospitals in Madrid. Patients were stratified according to age and stage of severity. Using multivariate logistic regression analysis, cut-off points that best discriminated mortality were obtained for each of the studied variables. Principal components analysis and a neural network (NN) algorithm were applied. A high mortality incidence associated to age >70, comorbidities (hypertension, neurological disorders and diabetes), altered vitals such as fever, heart rhythm disturbances or elevated systolic blood pressure, and alterations in several laboratory tests. Remarkably, analysis of therapeutic options either taken individually or in combination drew a universal relationship between the use of Cyclosporine A and better outcomes as also a benefit of tocilizumab and/or corticosteroids in critically ill patients. We present a large Spanish population-based study addressing factors influencing survival in current SARS CoV2 pandemic, with particular emphasis on the effectivity of treatments. In addition, we have generated an NN capable of identifying severity predictors of SARS CoV2. A rapid extraction and management of data protocol from eCR and artificial intelligence in-house implementations allowed us to perform almost real time monitoring of the outbreak evolution.

EANM Dosimetry Committee series on standard operational procedures for internal dosimetry for 131I mIBG treatment of neuroendocrine tumours.

The purpose of the EANM Dosimetry Committee Series on "Standard Operational Procedures for Dosimetry" (SOP) is to provide advice to scientists and clinicians on how to perform patient-specific absorbed dose assessments. This SOP describes image and data acquisition parameters and dosimetry calculations to determine the absorbed doses delivered to whole-body, tumour and normal organs following a therapeutic administration of 131I mIBG for the treatment of neuroblastoma or adult neuroendocrine tumours. Recommendations are based on evidence in recent literature where available and on expert opinion within the community. This SOP is intended to promote standardisation of practice within the community and as such is based on the facilities and expertise that should be available to any centre able to perform specialised treatments with radiopharmaceuticals and patient-specific dosimetry. A clinical example is given to demonstrate the application of the absorbed dose calculations.

Variations in the practice of molecular radiotherapy and implementation of dosimetry: results from a European survey.

BACKGROUND: Currently, the implementation of dosimetry in molecular radiotherapy (MRT) is not well investigated, and in view of the Council Directive (2013/59/Euratom), there is a need to understand the current availability of dosimetry-based MRT in clinical practice and research studies. The aim of this study was to assess the current practice of MRT and dosimetry across European countries. METHODS: An electronic questionnaire was distributed to European countries. This addressed 18 explicitly considered therapies, and for each therapy, a similar set of questions were included. Questions covered the number of patients and treatments during 2015, involvement of medical specialties and medical physicists, implementation of absorbed dose planning, post-therapy imaging and dosimetry, and the basis of therapy prescription. RESULTS: Responses were obtained from 26 countries and 208 hospitals, administering in total 42,853 treatments. The most common therapies were 131I-NaI for benign thyroid diseases and thyroid ablation of adults. The involvement of a medical physicist (mean over all 18 therapies) was reported to be either minority or never by 32% of the responders. The percentage of responders that reported that dosimetry was included on an always/majority basis differed between the therapies and showed a median value of 36%. The highest percentages were obtained for 177Lu-PSMA therapy (100%), 90Y microspheres of glass (84%) and resin (82%), 131I-mIBG for neuroblastoma (59%), and 131I-NaI for benign thyroid diseases (54%). The majority of therapies were prescribed based on fixed-activity protocols. The highest number of absorbed-dose based prescriptions were reported for 90Y microsphere treatments in the liver (64% and 96% of responses for resin and glass, respectively), 131I-NaI treatment of benign thyroid diseases (38% of responses), and for 131I-mIBG treatment of neuroblastoma (18% of responses). CONCLUSIONS: There is a wide variation in MRT practice across Europe and for different therapies, including the extent of medical-physicist involvement and the implementation of dosimetry-guided treatments.

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

BACKGROUND: The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented. RESULTS: A brief review of five of the most common therapy procedures is included in the current text, focused on the potential to perform patient-specific dosimetry. In the full report, 11 different therapeutic procedures are included, allowing additional considerations of effectiveness, references to specific literature on quantitative imaging and dosimetry, and existing evidence for absorbed dose-effect correlations for each treatment. Individualized treatment planning with tracer diagnostics and verification of the absorbed doses delivered following therapy is found to be scientifically feasible for almost all procedures investigated, using quantitative imaging and/or external monitoring. Translation of this directive into clinical practice will have significant implications for resource requirements. CONCLUSIONS: Molecular radiotherapy is undergoing a significant expansion, and the groundwork for dosimetry-based treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of the treatments, although must be adequately resourced.