Health Effects of CArdiac FluoRoscopy and MOderN RadIotherapy in PediatriCs - Radiotherapy

Study Overview
=================
Brief Summary
-----------------
The goal of the HARMONIC-RT study is to evaluate late health and social outcomes of modern external beam radiotherapy techniques in paediatric patients, based on the setting-up of a European, long-term registry complemented by a biobank.

Detailed Description
-----------------
Specific objectives: To develop the infrastructure and instruments for setting-up a European, long-term registry of paediatric patients treated with modern external radiotherapy techniques ; To assess the incidence and severity of late health outcomes, primarily endocrine dysfunctions, cardiovascular toxicities, neurovascular damages, and subsequent primary neoplasms, in relation to the dose-volume distribution to non-targeted organs and tissues, radiation delivery technique and beam quality factors, and potential modifying factors (i.e. age at exposure, genetic predispositions, comorbidities, and systemic treatments including chemotherapy, targeted therapy, immunotherapy and hormonal drugs) that may underlie differences in individual susceptibility for these outcomes ; To assess societal aspects of advances in radiotherapy, primarily health-related quality of life and academic achievement, in paediatric patients treated with modern external radiotherapy techniques. Secondary scientific objectives: To assess multidimensional fatigue in paediatric patients treated with modern external radiotherapy techniques, and identify clinical and therapeutic determinants of fatigue; To improve estimation of patient-specific doses to the whole body and non-targeted organs and substructures from different radiotherapy delivery techniques; To investigate radiation-induced cellular responses and biological mechanisms related to the occurrence of vascular diseases and subsequent primary neoplasms in samples of blood and saliva ; to identify biomarkers of susceptibility and health effects ; to evaluate differences in disease biomarkers in relation to the radiation delivery technique and beam quality factors ; to explore the relevance of the use of saliva as a biosampling method for paediatric cohorts regarding feasibility and the quality and reproducibility for different measured biomarkers. Secondary strategic objectives: To promote sustained collaborative research activities for improvement of patient care, and inform health care providers and policy makers on the clinical and social impact of advances in radiotherapy in paediatric settings; To serve as a pilot for a future long-term pan-European registry of children and adolescents treated with particle and photon beam therapy, including a biobank of saliva and blood samples collected before and after treatment; To contribute in future collaborative projects with existing cohorts or registries in Europe To contribute in future international research studies on late outcomes of modern radiotherapy techniques for management of paediatric cancers Funding: The HARMONIC project has received funding from the Euratom research and training programme 2014-2018 under grant agreement No 847707.

Official Title
-----------------
Health Effects of CArdiac FluoRoscopy and MOderN RadIotherapy in PediatriCs - Radiotherapy (HARMONIC-RT)

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Other: No intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Retrospective inclusion of study participants Inclusion Criteria: First external beam radiation therapy (EBRT) started in 2000 or after for management of a first primary neoplasm Age under 22 years at the time of first EBRT initiation Radiation treatment plan (first EBRT) stored in DICOM format Usual residency in the country of EBRT to enable a long-term follow-up Exclusion Criteria: Patients with poor prognosis (e.g. diffuse pontine glioma or high grade glioma) at first EBRT initiation Prior external or internal radiation therapy Patients who refused to participate in the study Prospective inclusion of study participants Inclusion Criteria: Scheduled first EBRT for management of a first primary neoplasm Age under 22 years at the time of scheduled first EBRT Radiation treatment plan stored in DICOM format Affiliate or beneficiary of health insurance (or any required equivalent as defined in applicable national law) Usual residency in the country of EBRT to enable a long-term follow-up Signed informed consent/assent Exclusion Criteria: Patients with poor prognosis (e.g. diffuse pontine glioma or high grade glioma) Prior external or internal radiation therapy; Protected adults (persons under curatorship, tutorship / individuals under guardianship by court order, persons deprived of their liberty) Adult/parent(s)/legal representative(s) who cannot read or understand the informed consent in the applicable language(s) in the country of EBRT

Ages Eligible for Study
-----------------
Maximum Age: 22 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: No intervention|No intervention|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endocrinopathies | Late health outcomes | up to 20 years after RT | 
| Cardiovascular diseases | Late health outcomes Neurovascular diseases Second and subsequent primary neaoplasms | up to 20 years after RT | 
| Neurovascular diseases | Late health outcomes | up to 20 years after RT | 
| Second and subsequent primary neaoplasms | Late health outcomes | up to 20 years after RT | 
| Health-related quality of life (physical, emotional, social, and school functioning) assessed by the PedsQL™ core scale (validated questionnaire) | Late social outcomes | up to 10 years after radiation therapy or attained age 25 years, whichever occurs first | 
| Academic achievement | Late social outcomes | up to 10 years after radiation therapy or attained age 25 years, whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dysfunctions in endocrine hormone levels | measured as: insulin-like growth factor-1, anterior pituitary hormones (GH, ACTH, TSH, LH, FSH), thyroid hormones (fT3, fT4), sexual hormones | up to 10 years after radiation therapy | 
| Changes in blood markers of cardiovascular diseases | measured as blood markers (incl. troponin, BNP, CPK) | up to 10 years after radiation therapy | 
| Changes in imaging markers of cardiovascular diseases | measured as cardiac echography parameters (incl. ejection fraction, diastolic function) | up to 10 years after radiation therapy | 
| Changes in imaging markers of neurovascular damages | measured as scoring of large and small vessel damages | up to 5 years after radiation therapy | 
| Changes in blood/saliva markers of protein activation relating to vascular damages | measured as signal quality of protein activity | up to 1 year after radiation therapy | 
| Changes in blood/saliva markers of oxidative stress response | measured as markers of oxidative stress (incl. 8-oxo-dG, SOD2, DNA repair enzymes) | up to 1 year after radiation therapy | 
| Changes in blood/saliva markers of inflammatory response | Inflammatory markers (incl. PTX3, CRP, NF-kB, IL-1 and IL10) | up to 1 year after radiation therapy | 
| Changes in blood/saliva markers of carcinogenesis | Markers of carcinogenesis (incl. leukocyte telomere length, mitochondrial DNA copy number, circulating microRNA) | up to 1 year after radiation therapy | 
| Multidimensional fatigue (general, sleep/rest, and cognitive fatigue) | PedsQL™ multidimensional fatigue scale (validated questionnaire) | up to 10 years after radiation therapy or attained age 25 years, whichever occurs first | 
| Clinical events other than those mentioned as primary outcomes | Late morbidity | up to 20 years after radiation therapy | 
| All-cause and cause-specific mortality | Late mortality | up to 20 years after radiation therapy | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Radiotherapy, Oncology, Paediatrics, Late toxicities, Radiation-induced neoplasms, Radiation-induced vascular damages, Radiation-induced cardiac damages, Radiation-induced endocrine damages, Quality of life, Social outcomes, External beam radiotherapy, Photon therapy, Proton therapy, Cohort, Registry