Periodic Reporting for period 3 - HARMONIC (Health effects of cArdiac fluoRoscopy and MOderN radIotherapy in paediatriCs)
Reporting period: 2022-06-01 to 2023-11-30
The use of ionising radiation (IR) for medical diagnosis and treatment has significantly impacted the survival rates of pediatric cancer and cardiac patients. While these techniques have undeniable benefits, it is crucial to evaluate the potential long-term health effects, particularly in young patients with an extended lifespan. Previous understanding of radiation exposure effects in children relied on large epidemiological studies, such as those involving A-bomb survivors. Recent studies, including the EPI-CT cohort, have revealed increased risks of leukemia, lymphoma, and brain tumors in children and adolescents exposed to IR from computed tomography (CT) scanning.
The HARMONIC project aims to better understand the elevated cancer risk and non-cancer effects resulting from exposure to medical IR in young cancer patients undergoing external beam radiotherapy (EBRT) and children with cardiac defects receiving cardiac fluoroscopy procedures (CFP). Through four scientific work packages, the project focuses on establishing two distinct cohorts/registries for long-term follow-up of patients who have been exposed to varying doses of photons, protons, and secondary neutrons as part of their treatment. Advanced patient-specific dose reconstruction strategies are being developed to accurately estimate the delivered dose to organs of interest and investigate dose-effect associations. Mechanistic investigations are also being conducted to enhance understanding of the molecular pathways triggering cellular responses leading to acute or late adverse health effects.
The HARMONIC project aims to better understand the elevated cancer risk and non-cancer effects resulting from exposure to medical IR in young cancer patients undergoing external beam radiotherapy (EBRT) and children with cardiac defects receiving cardiac fluoroscopy procedures (CFP). Through four scientific work packages, the project focuses on establishing two distinct cohorts/registries for long-term follow-up of patients who have been exposed to varying doses of photons, protons, and secondary neutrons as part of their treatment. Advanced patient-specific dose reconstruction strategies are being developed to accurately estimate the delivered dose to organs of interest and investigate dose-effect associations. Mechanistic investigations are also being conducted to enhance understanding of the molecular pathways triggering cellular responses leading to acute or late adverse health effects.
Setting up registries and cohorts requires considerable effort, including implementation of the legal and ethical framework. Since the beginning of the project and after the protocols were finalised, the legal framework was implemented in parallel with the scientific framework. More specifically, during the reporting period:
The clinical database established by WP2 (Radiotherapy) is fully operational and data collection is ongoing in all countries. Alongside the clinical database, RT images are being uploaded to a secure platform tailored to the consortium's needs: nomenclature, organs at risk (OAR) and dose constraints.
WP3 (Cardiology) has developed and tested a structured database for data collection, though some delays occurred due to legal and ethical framework implementation. Data collection started in all countries and is expected to be completed in early 2024, although it has already been completed in Norway, where linkage with national cancer registries has been performed. Despite efforts to include as many patients as possible, the target population will not be reached, although some countries such as France are trying to include additional patients. However, the number of patients available will still enable necessary analyses. The statistical analysis plan has been developed and discussed with all partners.
The dose reconstruction strategy (WP4) has been established for both IC and RT patients, employing newly developed computational frameworks and software tools. For radiotherapy, the framework includes various Monte Carlo and analytical codes, validated for both photon and proton therapy scenarios and associated imaging modalities. In cardiology, a rapid dose reconstruction tool and supporting database structure have been developed, with key parameters influencing dose estimates identified and information on their characteristic distribution is being collected. For this purpose, a dedicated data collection tool was developed and is currently being used in some of the participating hospitals.
In WP5 (Biology), detailed protocols for the collection, preparation, storage and transport of saliva and blood samples have been developed and published, and a biobank has been established. Patient enrolment and biosample collection are ongoing in Italy, France, Denmark and Belgium. Preliminary analyses of the samples from 6 proton therapy patients and 17 cardiac patients includes plasma protein profiling, miRNA screening, telomere lengths measurements, determination of stress marker 8-oxo-dG, RPPA analysis and mitochondrial DNA copy numbers. In France, 30 additional patients were enrolled to contribute to WP5 which was at the start of the project only anticipated in Italy.
The second newsletter of the project was prepared and sent to the list of stakeholders established earlier in the project (WP6). An area of the website dedicated to patients participating in the project is now available for general information on the project, contacts and relevant documents in all languages.
The clinical database established by WP2 (Radiotherapy) is fully operational and data collection is ongoing in all countries. Alongside the clinical database, RT images are being uploaded to a secure platform tailored to the consortium's needs: nomenclature, organs at risk (OAR) and dose constraints.
WP3 (Cardiology) has developed and tested a structured database for data collection, though some delays occurred due to legal and ethical framework implementation. Data collection started in all countries and is expected to be completed in early 2024, although it has already been completed in Norway, where linkage with national cancer registries has been performed. Despite efforts to include as many patients as possible, the target population will not be reached, although some countries such as France are trying to include additional patients. However, the number of patients available will still enable necessary analyses. The statistical analysis plan has been developed and discussed with all partners.
The dose reconstruction strategy (WP4) has been established for both IC and RT patients, employing newly developed computational frameworks and software tools. For radiotherapy, the framework includes various Monte Carlo and analytical codes, validated for both photon and proton therapy scenarios and associated imaging modalities. In cardiology, a rapid dose reconstruction tool and supporting database structure have been developed, with key parameters influencing dose estimates identified and information on their characteristic distribution is being collected. For this purpose, a dedicated data collection tool was developed and is currently being used in some of the participating hospitals.
In WP5 (Biology), detailed protocols for the collection, preparation, storage and transport of saliva and blood samples have been developed and published, and a biobank has been established. Patient enrolment and biosample collection are ongoing in Italy, France, Denmark and Belgium. Preliminary analyses of the samples from 6 proton therapy patients and 17 cardiac patients includes plasma protein profiling, miRNA screening, telomere lengths measurements, determination of stress marker 8-oxo-dG, RPPA analysis and mitochondrial DNA copy numbers. In France, 30 additional patients were enrolled to contribute to WP5 which was at the start of the project only anticipated in Italy.
The second newsletter of the project was prepared and sent to the list of stakeholders established earlier in the project (WP6). An area of the website dedicated to patients participating in the project is now available for general information on the project, contacts and relevant documents in all languages.
The risks of late effects of medical radiation exposure in populations with long life expectancy are important to investigate. HARMONIC aims to provide medical professionals and the radiation protection community with tools to better assess the effects of IR exposure in children, adolescents and young adults, and thus improve the basis for radiation protection in medicine. The project targets two distinct populations: pediatric cancer patients treated with modern radiotherapy and patients with congenital and acquired heart defects undergoing cardiac fluoroscopy procedures. The structured cohorts and registries are meant to be maintained for the long-term follow-up and might be expanded (subject to funding availability) to treatment centres in other European countries.
The data provided by HARMONIC’s RT registry (WP2) on quality of life, clinical outcomes (endocrine dysfunction, cardiac toxicity, neurovascular events, and cancer risk), and assessment of dose-volume effects will facilitate decision-making, improve patient care and treatment, and allow comparison of the effectiveness of photon and proton therapy. HARMONIC’s cohort of cardiac patients (WP3) will help to better understand and assess the cancer risk associated with exposure to ionizing radiation from cardiac catheterization. It will study if the highest incidence of cancer reported in this population might be partially explained by radiation exposure during the cardiac procedures. The data collection framework developed in the project will facilitate radiological data collection and improve dose reconstruction in future epidemiology studies.
The project also improves organ dose reconstruction (WP4) in interventional cardiology and individualized dose estimation in radiotherapy. The novel dosimetric tools developed during the project have the potential to be automatised for wider use in the clinics thus supporting accurate dosimetry and dose optimisation, and fostering research on radiation induced health effect. Additionally, HARMONIC collaborates with cardiologists to develop an Augmented Reality Computer System to aid in the preparation of complicated interventions. The prospective data and biospecimens (WP5) will provide important insights into radiation-induced adverse health effects and potential biomarkers for early diagnosis and treatment and possibly prevention or mitigation of adverse effects.
In summary, HARMONIC aims to better understand the biological and health effects of radiation exposure during childhood, especially considering the increased radiosensitivity of pediatric patients compared with adults. The project´s results will benefits clinicians, patients, parents, and healthcare professionals by providing improved information on radiation-related risks and enhancing radiation protection measures in the medical sector.
The data provided by HARMONIC’s RT registry (WP2) on quality of life, clinical outcomes (endocrine dysfunction, cardiac toxicity, neurovascular events, and cancer risk), and assessment of dose-volume effects will facilitate decision-making, improve patient care and treatment, and allow comparison of the effectiveness of photon and proton therapy. HARMONIC’s cohort of cardiac patients (WP3) will help to better understand and assess the cancer risk associated with exposure to ionizing radiation from cardiac catheterization. It will study if the highest incidence of cancer reported in this population might be partially explained by radiation exposure during the cardiac procedures. The data collection framework developed in the project will facilitate radiological data collection and improve dose reconstruction in future epidemiology studies.
The project also improves organ dose reconstruction (WP4) in interventional cardiology and individualized dose estimation in radiotherapy. The novel dosimetric tools developed during the project have the potential to be automatised for wider use in the clinics thus supporting accurate dosimetry and dose optimisation, and fostering research on radiation induced health effect. Additionally, HARMONIC collaborates with cardiologists to develop an Augmented Reality Computer System to aid in the preparation of complicated interventions. The prospective data and biospecimens (WP5) will provide important insights into radiation-induced adverse health effects and potential biomarkers for early diagnosis and treatment and possibly prevention or mitigation of adverse effects.
In summary, HARMONIC aims to better understand the biological and health effects of radiation exposure during childhood, especially considering the increased radiosensitivity of pediatric patients compared with adults. The project´s results will benefits clinicians, patients, parents, and healthcare professionals by providing improved information on radiation-related risks and enhancing radiation protection measures in the medical sector.