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Health effects of cArdiac fluoRoscopy and MOderN radIotherapy in paediatriCs

Periodic Reporting for period 1 - HARMONIC (Health effects of cArdiac fluoRoscopy and MOderN radIotherapy in paediatriCs)

Reporting period: 2019-06-01 to 2020-11-30

The use of ionising radiation (IR) with advanced technology in medicine represents a tremendous benefit for the diagnosis and treatment of pathologies in paediatric populations. While benefits to the patient largely outweigh the risk, the late effects of exposure to IR are particularly important to understand in populations of young patients who nowadays survive the disease for decades; the evidence to-date suggesting that children are more sensitive to the carcinogenic effects of ionizing radiation than adults.
HARMONIC aims at complementing recent studies on paediatric CT examinations, to improve understanding of the health effects of exposure to medical IR in children, specifically cancer patients treated with modern radiotherapy techniques, and cardiac patients treated with X-ray guided imaging procedures.
The project builds on a multi-disciplinary collaboration to provide the medical and scientific communities with instruments to investigate cancer and non-cancer outcomes (neuro & cardiovascular and endocrine system effects) in these two European paediatric cohorts and evaluate Quality of Life (QoL) and social impacts, with potential for advanced patient-specific dose reconstruction and mechanistic investigations.
So far, HARMONIC was devoted to setting-up its legal, administrative and operational framework with emphasis to allow evaluation of potential health, QoL and social impacts of medical exposures to IR in children. Activities focused on the development of procedures and protocols, procurement of ethics approvals from participating institutions and setting up the project framework:
—setting up the structure of the databases for inclusion of patients in both cohorts and starting data collection, where possible
—developing simulation models for dose reconstruction and implementing measurement sessions for validation of these models.
—pilot testing methodology and framework for analysis of biomarkers in both blood and saliva
WP2 (Radiotherapy) partners agreed on parameters that are to be collected at different points in time (baseline and follow-up). The study protocol was established to capture the procedures that need to be taken. The consortium agreed on the database and platforms used for collection, storage and processing of clinical and physical data. To ensure quality, processes are being standardised and secure transmission paths developed. The protocol was submitted for approval by ethical committees in all participating institutions and the database is being developed and tested.
WP3 (Cardiology) partners developed the study protocol to build the joint cohort of paediatric patients subjected to cardiac catherization and followed for cancer incidence. Ethics approvals were obtained or are in progress. In addition to data already collected in France and the UK, collection of new data is underway in 3 countries (Belgium, Norway, Italy)
The strategy for dose reconstruction (WP4) has been established for the 2 aspects of the project (radiotherapy and cardiology) and computational frame works have been set-up. They are currently developed further and compared with first benchmarking measurements:
—In radiotherapy, the Monte Carlo (MC) dose estimation systems and codes were adapted to the project specificities and were benchmarked against experimental data obtained either in water or from the irradiation of an anthropomorphic paediatric phantom. On-phantom measurements were performed for a proton therapy treatment, including the imaging CT. The MC simulations of most imaging devices in the project were finalized and the CT fusion algorithm for extending patient body with NCI paediatric anthropomorphic phantoms was developed and tested.
— In cardiology, a computational frame work was established for producing organ dose coefficients which will be used for rapid retrospective dose reconstruction. The structure of the supporting database was drafted, main parameters influencing dose estimates accuracy were identified and information about their characteristic distribution is currently being gathered. For that purpose, a dedicated data collection tool is currently being tested.
WP5 (biology) partners have established a detailed protocol for collection, preparation, storage and transportation of saliva and blood samples. They have established different analytical tools/methods to be used to identify biomarkers. A biobank has been registered and several pilot studies were implemented:
—Two pilot studies have been carried out to test the quality of saliva samples. Collection of fresh saliva in tubes without preservative and storing at -20°C is adequate for obtaining a good quality of DNA for anticipated analysis.
—A third pilot study was carried out to test the quantity and quality of lymphocytes for reverse phase protein array (RPPA) assay using 2 different protocols.
Communication activities (WP6) were devoted to designing logo, website and communication material and to establishing the strategy for dissemination of scientific results.
HARMONIC will 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. Our activities rely on the establishment of 2 unique cohorts.
—the first international registry of paediatric cancer patients treated with modern radiotherapy techniques to provide crucial information both from the point of view of clinical efficiency and from that of patient QoL and social impact of treatment and the risk of developing radiation-related secondary diseases. Based on improved knowledge on the risk of developing radiation-related secondary diseases, treatment guidelines will be developed.
—We also propose to pool data on approximately 100,000 paediatric patients who underwent cardiac catheterization in Europe to study the relationship between IR exposure early in life, and subsequent cancer in children treated for cardiac birth defect. This research will strengthen the epidemiological basis for assessing radiation risk in paediatric patients – a demographic group for which such data are very sparse.
Dosimetric data collection tools and software are developed to allow dose reconstruction in both interventional cardiology and radiotherapy. In cardiology, the tool will rely on table of precomputed dose coefficients to allow rapid dose estimates. In Radiotherapy, both analytical and Monte Carlo-based tools aim at estimating far-from-the-field dose distribution for conventional and proton therapy. Eventually, our dosimetric tools will be made available to the community thus supporting accurate dosimetry and dose optimisation, and fostering the research on radiation induced secondary malignancies.
With prospective design and the creation of a Biobank for the collection of biological samples, HARMONIC will provide mechanistic understanding of radiation induced adverse health effects and identify potential biomarkers indicative of vascular adverse effects and second cancer. The potential health impact of IR exposure as well as effects on quality of life (QoL) will be investigated in an integrated approach where biomarkers indicative of health effects 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