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Epidemiological study to quantify risks for paediatric computerized tomography and to optimise doses.

Periodic Report Summary 4 - EPI-CT (Epidemiological study to quantify risks for paediatric computerized tomography and to optimise doses.)

Project Context and Objectives:
Diagnostic radiation represents an indispensable, sometimes life-saving, tool in modern medicine. However, the growing use of computerized tomography (CT) scans is a topic of concern in radiological protection, especially for children and adolescents. Children are generally more sensitive to the carcinogenic effects of ionizing radiation than adults. In addition, they have a longer life-span to express any effect and, because of their smaller mass, they may receive higher radiation doses from a CT exam than an adult.
Following concerns raised by the first interpolation studies, several epidemiological studies were set-up in the early 2000s to assess the cancer risk associated with CT examinations performed on children. Two large recently published studies have linked CT-radiation dose to cancer risk: leukaemia and brain tumour risk was associated with CT radiation in a UK cohort of over 175,000 young people (Pearce et al, 2012); a linkage study of 680,211 young people in Australia (Mathews et al, 2012), also suggested a relationship between CT-radiation dose and subsequent cancer risk. The UK study estimated that per 10,000 head CT scans at ages below 10 years, one extra case of leukaemia and one case of brain tumour will occur within 10 years after the CT scan.
Despite the consistent results, the two studies have received criticism for several reasons. There were concerns over potential organ-dose errors, and the possible inclusion of patients with cancer predisposing syndromes (such as Down syndrome) and benign conditions with malignant transformation potential. Since information on the reason for CT scan in both studies was unavailable, reverse causation was raised as a likely explanation for the observed associations.
It is worth mentioning that two recent smaller studies of nearly 70,000 children in France and nearly 45,000 children in Germany (both are included in the current EPI-CT project) tried to make adjustments for conditions that initiated the scan or other predisposing factors known to be associated with increased cancer and leukaemia risk. In the German study, the standardised incidence ratio (SIR) for lymphomas decreased substantially when subjects with predisposing conditions were excluded from the analyses while the SIR for leukaemia changed only marginally. The French study suggested a possible increased risk of leukaemia and lymphoma with increasing dose from CT. Interestingly, for leukaemia, the risk estimate among subjects without predisposing factors was higher than that in the entire cohort.
The observed ERRs per radiation dose are difficult to interpret based on substantial uncertainties in organ doses associated with type of CT scanner, type of procedure, changes in scanners and technique over calendar year and missed examinations. An accurate dosimetry and thorough assessment of related uncertainties and potential biases is therefore needed to ensure the validity of the resulting risk estimates. Compared to the UK and Australian studies, the EPI-CT is designed to derive improved individual organ-dose estimates for each cohort member and subsequently to more precisely quantify the associated health risks.
Scientists with multidisciplinary expertise from 10 EU member states and one associated state composed a consortium for the conduct of the international cohort study in order to directly quantify possible cancer risks from CT doses, particularly leukaemia and brain cancer. The present multi-national collaborative study aims to bring together the national paediatric CT patients’ studies already ongoing in Europe and to set-up additional studies in five other countries (Belgium, Denmark, the Netherlands, Spain and Norway).
In each participating hospital, for each eligible patient, computerized data is abstracted from the Radiological Information System (RIS) and, for recent periods, individual machine settings are extracted automatically from the Picture Archiving and Communication System (PACS).
Specific objectives of the project are to:
• Establish a large multinational cohort of paediatric patients who received CT scans;
• Describe patterns of use of CTs over time and between countries;
• Develop individual estimates of organ-specific doses from paediatric CT scans using improved methods for dose estimation for paediatric patients;
• Evaluate the radiation-related risk of cancer in this cohort and pilot test biological markers of CT-irradiation effects;
• Develop methods to characterize quality of CT images in relation to the corresponding examination dose;
• Provide recommendations for a “harmonized” approach to CT dose optimisation for paediatric patients in Europe.

Project Results:
The main efforts were undertaken in the reporting period to achieve the following:
• To compile national data sets and to validate them;
• To finalise the automated software for individual dose estimation and to reconstruct individual doses and related uncertainties for cohort members;
• To finalise statistical analysis plan.
Overall, 1,163,571 patients are included in the pooled cohort with over 2 million CT examinations. PACS data are available for over 173,000 patients in the study. Within EPI-CT, cohort members are followed-up passively through linkage to cancer, mortality and other national/regional registries (e.g. centralised hospital discharge databases), to determine incidence and mortality from leukaemia and non-cancer diseases. Overall, 48,568 patients developed a tumour during the follow-up period: 7,545 were haematological malignancies, 24,674 – solid tumours, including 9,981 brain tumours. Information on indication of the CT is very important to address a potential bias by indication but is difficult to obtain in all countries. Various approaches have been chosen according to what information is available in each country and simulation studies are being conducted to assess potential impact of various confounding factors and biases.
During the fourth reporting period, the following steps in the dose reconstruction process were further improved and finalised:
1) Modification of the dose calculation software (NCICT) to be in adequacy with ICRP recommendations;
2) Finalization of a harmonised data treatment and automated dose calculation;
3) Implementation of the new 2DMC paradigm to reconstruct doses and evaluate the related uncertainties.
Preliminary dose calculations were carried out and results provided to statisticians to help finalisation of analyses strategy.
All the main tasks within WP on biological mechanisms have been accomplished in the previous reporting periods and results and achievements presented in the earlier reports. The results of the feasibility study demonstrated that cellular repair in young children is impaired at high doses (1 Gy) as detected by increased cytogenetic damage in umbilical cord blood and young children compared to adults. However, for low dose CT exposure (0.04 Gy), no clear statement can be given due to lack of statistical power in this pilot study. The results show that there is an urgent need to organize an in vitro study with sufficient statistical power to investigate low dose radiation sensitivity of children by using dicentric aberrations as a reliable and sensitive biomarker. Results of the in vitro inter-comparison showed that it is feasible to develop a working protocol to resolve damage response in the low dose range (10-100 mGy CT X-ray) by gammaH2AX foci analysis in an automatic manner which is suitable for a large molecular epidemiological study. Work also focused on the different approaches and the results of whole genome analysis of in vitro x-irradiated samples. Whole blood samples were collected from healthy donors and irradiated with low (0.05 Gy) and high (1 Gy) doses of irradiation. RNA was isolated and hybridized to microarrays. Additional testing of saliva collection devices for analysis of oxidative stress markers, for DNA and RNA extraction was performed to identify optimal non-invasive methods suitable for application in large scale paediatric studies. The work also focused on publishing study results in peer reviewed literature and supervision of completion of theses of a PhD student.
In the Optimisation WP, the electronic tool to score image quality developed in the previous reporting period was circulated to different EPI-CT partners, together with the instruction manual. Participating radiologists scored images, evaluated the quality of collected data and reported the results. Very useful comments were made by the radiologists who filled electronic forms for each examination. All these remarks will be taken into account for developing the final version of the tool.

Potential Impact:
While physicians see benefits of using CT scanning in their clinical practice, concerns about the possible harmful effects of exposure to radiation from diagnostic radiologic procedures have existed for many decades. EPI-CT will help us better understand what these risks actually are. EPI-CT has been designed from the start to identify and characterise the potential magnitude of factors that may affect the precision of risk estimates so that they can be taken into account. It will therefore provide important information to assess the adequacy of current radiation risk estimates derived from studies of children with moderate to high doses received at high dose-rates from atomic bombings or radiotherapy to the generally lower doses received by CT patients.
The study will also provide a surveillance tool to monitor changes in exposures associated with these rapidly evolving technologies. Evaluating associations between the CT scan types, frequency, estimated bone marrow dose and leukaemia incidence have potentially important implications for the protection of paediatric patients.
A report detailing how to develop guidelines and recommendations for the optimal use of CT scans in paediatric patients will be prepared and presented to national and international radiation protection authorities.
Project results could be used as a basis for training radiologists and other technical personnel in how to optimise image quality and lower CT dose by adjusting scanning parameters.
There is no doubt that the use of CT imaging is beneficial for millions of patients annually. However, the results of this study jointly with CT paediatric protocol optimisation may help limit the radiation dose delivered to children and therefore reduce any potential risk arising from CT. At the same time it may be an important component to empower physicians and parents for informed decision making.

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