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Health effects of cArdiac fluoRoscopy and MOderN radIotherapy in paediatriCs

Periodic Reporting for period 2 - HARMONIC (Health effects of cArdiac fluoRoscopy and MOderN radIotherapy in paediatriCs)

Reporting period: 2020-12-01 to 2022-05-31

Medical applications of ionising radiation (IR) represent a key component of diagnosis and treatment of many diseases, guaranteeing efficient health care. The use of IR in medicine, the largest source of general population radiation exposure, is potentially associated with increased risk of cancer and non-cancer diseases, which needs to be evaluated to provide evidence-based input for risk-benefit considerations, optimization of treatment protocols and implementation of preventive actions. The HARMONIC project aims at improving understanding of the biological and health effects of exposure to medical IR in children, specifically cancer patients treated with modern radiotherapy techniques, and cardiac patients treated with cardiac fluoroscopy procedures.
We are setting-up two cohorts of children exposed to IR as a consequence of their treatment in both oncology and cardiology. HARMONIC builds on a multi-disciplinary collaboration to investigate long-term outcomes (endocrine dysfunction, cardiovascular and neurovascular damage, quality of life and social impacts, and secondary cancers) of paediatric cancer patients after modern radiotherapy. With its cardiac component, HARMONIC also contributes to investigate the relationship between early-life exposure to low and moderate doses of IR and the development of cancer.
Since the beginning of the project, activities were devoted to implementation of the legal framework, finalisation of the infrastructure of the databases and launching data collection (demographic, clinical, radiological, biological, dosimetric and social data), which is anticipated to continue in 2023. The consortium also developed simulation models for patient-specific dose reconstruction and pilot tested analyses for identification of potential biomarkers of health effects in blood and saliva.
WP2 (Radiotherapy) built a database-structure for harmonized data collection at specific time points in order to assess the late-effects of children treated with modern radiotherapy techniques. Standardised workflows for data collection and contouring were defined amongst centres in order to ensure data quality.
Based on the common French and UK framework, WP3 (Cardiology) protocol was further elaborated accounting for specificities in the joining countries (Belgium, Germany, Italy, Norway and Spain) to estimate the dose response relationship between IR exposure and health effects and to investigate modifiers of this association. The majority of the ethics approvals have been obtained and half of the target population has already been included.
The strategy for dose reconstruction with WP4 (Dosimety) has been established for radiotherapy and cardiology patients. In both contexts, models rely on newly developed computational frame works, which are benchmarked against measurements on anthropomorphic phantoms.
—In Radiotherapy: simulations of out-of-field doses with both Monte-Carlo and analytical models were published together with their validation. In addition, a method to calculate imaging doses has been elaborated for patient specific dose estimation relying on both the patient morphology and the specific imaging protocol used during radiotherapy.
—In Cardiology: a large library of organ dose coefficients was computed with Monte Carlo simulations. This is embedded in a rapid dose reconstruction tool. The main parameters influencing dose estimates accuracy were identified and information about their characteristic distribution is being gathered with a dedicated data collection tool developed to support participating hospitals.
Within WP5 (Biology), protocols for collection, preparation, storage and transportation of saliva and blood samples have been established and a biobank has been set up. Two pilot studies have been carried out to test the quality of saliva samples. A third pilot study tested the quantity and quality of lymphocytes for RPPA assay using 2 different protocols. Enrolment of patients with biosamples collection is ongoing in Italy, Denmark and Belgium.
Communication activities (WP6) were mainly devoted to publishing our first newsletter which could be found on the project website. A dedicated area of the website is currently being designed for patients participating in the project to find relevant information.
HARMONIC is a strong consortium which could expand and pursue collaboration to provide the medical and radiation protection communities with pan-European infrastructures and instruments for long term follow-up of paediatric patients treated with IR in the context of very rapid technology evolution. The main objective of the project is to improve knowledge on the biological and health effects of medical exposure to IR in childhood, exploring potential effects of exposure at very early ages, exposure to a wide range of doses from photons, protons and secondary neutrons radiation with a view to optimising therapeutic and diagnostic protocols.
—The creation of tools and infrastructures for data collection set the foundation for the first international registry of paediatric cancer patients treated with modern radiotherapy techniques, which can potentially be extended to treatment centres in all European countries and be linked with registries in North America and Asia. The registry will provide information for clinical and quality-of-life-outcomes as well as quantification of dose-volume effects. The standardised long-term follow-up will result into a better understanding of the factors underlying the incidence of second primary cancers and the factors underlying the individual susceptibility to cancer treatment-related risks.
—The Multinational cohort of Paediatric Cardiac Patients is the largest cohort to study the long-term risks from cardiac catheterisation in paediatrics and to estimate the dose response relationship between exposure to ionizing radiation in cardiac catheterization and cancer risk. It will establish whether radiation related risks from these procedures are being correctly predicted by existing risk models, considering the few paediatric populations available until now in the field of low to moderate doses radiation epidemiology. It will also help to explain the highest incidence of cancer reported in this target population. Long term follow-up of the patients is essential and sustainability of the database is a key element in full exploitation of results.
HARMONIC Dosimetry Software tools were developed to allow more accurate dose reconstruction in both radiotherapy and cardiology. These tools are expected to be automatized to allow routine computation of dose to in-field organs (in cardiology) and out-of-field organs (in radiotherapy). In addition, a data collection frame work was set up to strengthen dose reconstruction for future large-scale epidemiology studies. Eventually, all these tools will be made available to the community thus supporting accurate dosimetry and dose optimisation, and fostering the research on radiation induced malignancies.
The HARMONIC data design and biological samplings will provide important knowledge on radiation induced adverse health effects and identify potential biomarkers indicative of the health effects. The potential health impact of IR exposure as well as effects on quality of life will be investigated in an integrated approach where biomarkers will be a complementary part for early diagnosis, progression, treatment and perhaps prevention of adverse effects.
The tab of the whole body dose creation. After completing this step and saving to the database the
The user interface for the creation of the whole-body representation. On the right side the whole-bo