Periodic Reporting for period 4 - HARMONIC (Health effects of cArdiac fluoRoscopy and MOderN radIotherapy in paediatriCs)
Reporting period: 2023-12-01 to 2024-11-30
The use of ionising radiation (IR) for medical diagnosis and treatment has significantly impacted the survival rates of paediatric cancer and cardiac patients. While these techniques have undeniable benefits, it is crucial to evaluate the potential long-term health effects (cancer and non-cancer), particularly in young patients with an extended lifespan.
The HARMONIC project primary objective is to investigate cancer and non-cancer outcomes following exposure to medical IR in young cancer patients undergoing external beam radiotherapy (EBRT) and in children with cardiac defects receiving cardiac fluoroscopy procedures (CFP). Understanding the health effects together with the cellular and molecular mechanisms involved in patient exposure will contribute to the development of more effective radioprotection protection programs, optimisation of diagnostic and treatment procedures and improved individual health surveillance.
The HARMONIC project primary objective is to investigate cancer and non-cancer outcomes following exposure to medical IR in young cancer patients undergoing external beam radiotherapy (EBRT) and in children with cardiac defects receiving cardiac fluoroscopy procedures (CFP). Understanding the health effects together with the cellular and molecular mechanisms involved in patient exposure will contribute to the development of more effective radioprotection protection programs, optimisation of diagnostic and treatment procedures and improved individual health surveillance.
HARMONIC is a consortium of 25 partner institutions that have built two critical cohorts of paediatric patients exposed to ionising radiation during treatment of cancer and cardiac defects. It provides medical professionals and the radiation protection community with the necessary framework and tools to assess the effects of IR exposure on children, adolescents and young adults. By doing so, HARMONIC advances the understanding of long-term sequelae, ensuring they are considered and integrated into patient care and follow-up.
HARMONIC-RT established the first pan-European registry dedicated to paediatric patients who have undergone modern radiotherapy techniques, specifically proton or photon therapies. This initiative aims to provide valuable insights to the medical community regarding potential endocrine disorders, as well as cardio- and neurovascular sequelae, in addition to assessing the quality of life and social implications associated with contemporary radiotherapy methods. To date, more than 2,300 cancer patients treated EBRT since the year 2000 have been meticulously recorded through both prospective and retrospective data collection methods and task-specific analysis plans have been developed to guide future data assessment and research endeavours.
In parallel, the joint HARMONIC-Cardio database containing about 60 000 patients aged less than 22 years old exposed to Ionizing radiation through CFP has been built based on collection of data in 7 European countries: Belgium, France, Germany, Italy, Norway, Spain and UK. Analyses on the risk of cancer compared to thus observed in the general population has been performed, based on standardized incidence ratio (SIR). Impact of predisposing factors on the SIR estimates has been assessed.
Strategies for dose reconstruction were established for both cohorts. These rely on newly developed computational frame works and software tools, which were benchmarked against existing tools, when available, and validated against new measurements on anthropomorphic phantoms. Organ doses are estimated to further investigate the dose response relationship for each outcome of interest.
Enrolment of the patients from each of the two cohorts and collections of blood and saliva samples was achieved in Italy, France, Denmark and Belgium. A set of analyses was performed: plasma protein profiles, saliva protein profiles, miRNA analysis, telomere length measurements, determination of post translation changed of proteins using RPPA and detention of mitochondrial copy numbers. The promising first results will be verified with deep biostatistical analysis.
HARMONIC-RT established the first pan-European registry dedicated to paediatric patients who have undergone modern radiotherapy techniques, specifically proton or photon therapies. This initiative aims to provide valuable insights to the medical community regarding potential endocrine disorders, as well as cardio- and neurovascular sequelae, in addition to assessing the quality of life and social implications associated with contemporary radiotherapy methods. To date, more than 2,300 cancer patients treated EBRT since the year 2000 have been meticulously recorded through both prospective and retrospective data collection methods and task-specific analysis plans have been developed to guide future data assessment and research endeavours.
In parallel, the joint HARMONIC-Cardio database containing about 60 000 patients aged less than 22 years old exposed to Ionizing radiation through CFP has been built based on collection of data in 7 European countries: Belgium, France, Germany, Italy, Norway, Spain and UK. Analyses on the risk of cancer compared to thus observed in the general population has been performed, based on standardized incidence ratio (SIR). Impact of predisposing factors on the SIR estimates has been assessed.
Strategies for dose reconstruction were established for both cohorts. These rely on newly developed computational frame works and software tools, which were benchmarked against existing tools, when available, and validated against new measurements on anthropomorphic phantoms. Organ doses are estimated to further investigate the dose response relationship for each outcome of interest.
Enrolment of the patients from each of the two cohorts and collections of blood and saliva samples was achieved in Italy, France, Denmark and Belgium. A set of analyses was performed: plasma protein profiles, saliva protein profiles, miRNA analysis, telomere length measurements, determination of post translation changed of proteins using RPPA and detention of mitochondrial copy numbers. The promising first results will be verified with deep biostatistical analysis.
The establishment of tools and infrastructures for data collection has paved the way for the inaugural international registry focused on evaluating outcomes in children and adolescents undergoing treatment with contemporary radiotherapy techniques. This registry gathers comprehensive information concerning both clinical results and quality-of-life metrics, as well as data to quantify dose-volume effects associated with treatment protocols. HARMONIC seeks to enhance patient care and elevate treatment standards. A standardized long-term follow-up process will facilitate a deeper understanding of the factors contributing to the incidence of second primary cancers, alongside identifying individual susceptibilities to risks related to cancer treatment. HARMONIC takes a critical first step toward comparing photon and proton therapy in terms of effectiveness and health and social impact.
New insight on the dose response relationship between low doses of ionizing radiation received during CFP and cancer will be obtained in a very sensitive and specific population, paediatric patients, which is known to be more sensitive to ionizing radiation and for whom la lack of epidemiological studies has been largely pointed out. It will reinforce the knowledge in the field of radiation protection for a very sensitive population. It will alert the physicians, especially radiologists and paediatricians on the need to carefully justify use of ionizing radiation in children and to decrease as much as possible the doses delivered.
Software tools were developed to allow more accurate dose reconstruction in both cohorts potentially also allowing the routine computation of dose to in-field and out-of-field organs, thus contributing to lower the risk of late effects. In addition, data collection frame works were set up to allow better dosimetry in future epidemiology studies and a dedicated tool to support optimisation of procedures in cardiology was prototyped. Eventually, all developed tools will be made available to the community for supporting accurate dosimetry and dose optimisation, and fostering the research on radiation induced secondary malignancies.
The HARMONIC prospective data and bio-samplings will provide important knowledge on radiation-induced adverse health effects and identify potential biomarkers indicative of the health effects. The potential health impacts of ionising radiation exposure are investigated in an integrated approach where biomarkers could potentially be used for early diagnosis, progression, treatment and perhaps prevention of adverse effects.
New insight on the dose response relationship between low doses of ionizing radiation received during CFP and cancer will be obtained in a very sensitive and specific population, paediatric patients, which is known to be more sensitive to ionizing radiation and for whom la lack of epidemiological studies has been largely pointed out. It will reinforce the knowledge in the field of radiation protection for a very sensitive population. It will alert the physicians, especially radiologists and paediatricians on the need to carefully justify use of ionizing radiation in children and to decrease as much as possible the doses delivered.
Software tools were developed to allow more accurate dose reconstruction in both cohorts potentially also allowing the routine computation of dose to in-field and out-of-field organs, thus contributing to lower the risk of late effects. In addition, data collection frame works were set up to allow better dosimetry in future epidemiology studies and a dedicated tool to support optimisation of procedures in cardiology was prototyped. Eventually, all developed tools will be made available to the community for supporting accurate dosimetry and dose optimisation, and fostering the research on radiation induced secondary malignancies.
The HARMONIC prospective data and bio-samplings will provide important knowledge on radiation-induced adverse health effects and identify potential biomarkers indicative of the health effects. The potential health impacts of ionising radiation exposure are investigated in an integrated approach where biomarkers could potentially be used for early diagnosis, progression, treatment and perhaps prevention of adverse effects.