Cancer Registry-wide study in infants with neuroblastoma; Task 11.4 of the ENNCCA Network of Excellence

University College London (UCL) requires access to NHS England data for the purpose of the following research project: The ENCCA (European Network for Cancer Research in Children and Adolescents

The ENCCA (European Network for Cancer Research in Children and Adolescents, www.encca.eu) Network of Excellence aims to accelerate clinical and translational research in paediatric and adolescent oncology and to promote evaluation of and access to innovative therapies. The ENCCA network of 34 partners spans 11 European countries and includes 27 eminent paediatric oncology institutions. ENCCA links all the multinational clinical trial groups and national childhood cancer professional societies across Europe in an ENCCA European Clinical Research Council. It is structured as a consortium that will carry out 18 working packages. Work package 11 aims to establish methods of linkage of the population-based cancer registries with other forms of routine health care data to conduct future research in childhood cancers where the overall population has a good prognosis. Work package 10 aims to develop risk-adapted therapies in solid tumours, mainly neuroblastoma.

The work of the ENCCA network, including the European Clinical Research Council, is now continued under the auspices of the SIOP Europe, (European Society for Paediatric Oncology) (https://siope.eu/european-research-and-standards/clinical-research-council/ ).

The following is a summary of the aims of the research project provided by UCL

1. Primary objective: To analyse long term event-free and overall survival of infants (defined as age <1yr) with neuroblastoma with comparisons with other European countries contributing a similar data set direct to IARC from their cancer registries (England, France, Germany, Italy (Piedmont region), Spain (selected regions) and Switzerland).

2. Secondary objective: To compare distribution of tumour stage, tumour biology (MYCN amplification) and types of treatments given where these data are provided by each contributing country.

This project will develop mechanisms and methods of collaborative work between the population-based cancer registries and the clinical databases across the participating European countries and clinical registries. The aim will be to link the series of cases arising in a well-defined (by age at diagnosis) population of infants with neuroblastoma and registered in cancer registries, enhanced with the detailed information held in the clinical databases/hospital records at the patient's treatment centres.

The objective is to understand the reasons for the observed decline in overall survival rates for infants diagnosed with neuroblastoma in England in the 2000s- hypotheses that will be explored include whether it is due to poorer compliance with the international 'best practice standards of diagnosis and treatment following the ending of the SIOPEN INES 99 study in 2004. There has since been no open clinical trial in the UK for neuroblastoma in this age group. The project involves international benchmarking of detailed patient and tumour demographic data collated from 6 European countries (England, Spain, France, Germany, Italy, Switzerland) and received directly by the processor at the International Agency for Research on Cancer (IARC) in 2019.

UCL requires access and continued retention by its processor, IARC and the addition of one individual based at University Hospitals Southampton, to NHS England Data in order to achieve the study objectives.

This being an international collaborative study, dataset receipt from all partners and analysis has taken longer than expected. Therefore, the original agreement has been extended to allow for analysis of the complete international cohort and for preparation of a publication and a reserve time in case follow-up needed after the publication.

The addition of University Hospital Southampton as data processor will allow a Paediatric Oncologist and Research Registrar with the requisite expertise to access the data extract for this study. This will enable a detailed clinical understanding and descriptive analysis of the English patients such as the outcomes of current treatments for neuroblastoma in infants, the reasons for lack of improvement in recent overall survival rates compared to other childhood cancers and to identify and understand any differences in outcomes for children in the UK compared to other countries in Europe.

The following NHS England Dataset is accessed:

- NDRS Cancer Registrations

The level of the Data will be Pseudonymised.

The Data will be minimised as follows:

• The dataset is limited to a cohort of children diagnosed with neuroblastoma between 01.01.1999 and 31.12.2010 and aged less than 365 days (1 year) at diagnosis.

• Follow up for survival extends to the most recent date each patient has a known vital status documented in NCRAS

• Limited to conditions relevant to the study identified by specific ICD or OPCS codes

• Only neuroblastoma and ganglioneuroblastoma

• Limited to the geographical area of England

UCL is the Controller and the research sponsor as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller;

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This research is deemed to be in the public interest as this research explores rare tumours neuroblastoma and ganglioneuroblastoma in children (infants) with an aim to understand variations in treatment and outcomes.

This research historically received European funding. Prospective funding will be provided by UCL.

IARC (Lyon, France) is the processor acting under the instructions of the controller UCL. Data will only be accessed by individuals who hold substantive employment contracts with the named processors.

Two individuals substantively employed at University Hospitals Southampton (a paediatric oncologist and research registrar) also requires access to the data for the purposes outlined in this application.

The project has been presented and discussed at several national and international meetings held in conjunction with parents and survivors of childhood cancer during 2019. The study have an active parent-patient involvement group working with the study team on disseminating research related to routine health care data analyses. The study team will produce appropriate lay language versions of research papers in parallel with writing up and publishing the main results of the project, so that the parent and patient community are well-informed of the findings and their potential significance for childhood cancer patients with neuroblastoma in the UK. The study team will work with the CCLG (Children’s Cancer and Leukaemia Group) to ensure full dissemination of relevant information to this audience.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA). Historically data was collected from clinical centres in England and identifying data items were sent directly to the National Disease Registration Service (NDRS) at Public Health England in 2019 (now part of NHS England) for linkage. NDRS then linked these data with the NDRS cancer registrations data based on a set of inclusion criteria previously agreed with the NDRS analysis team to define the cohort. A pseudonymised extract was sent directly to the processor (IARC), in Lyon, France. A copy of the pseudonymised extract will be transferred securely from NHSE to University Hospitals Southampton.

The controller (UCL) has never received any data for this project and does not access the data.

The Data will not be transferred to any other location.

IARC has conducted statistical analyses on the data provided to fulfil the study's aims and objectives. Training for all Data Users is organised by the Information Security Officer and the Director for Administration and Finance on a periodic basis.

Data is kept in a safe and secure environment, available only to authorized users with a legitimate need to access them, and protected against unauthorised access. IARC's System Level Security Policy enforces the following controls:

Access Control:

Physical and logical access controls must be established in order to protect the Data at all times. The Data is stored in a secure location requiring either badge or key access to its physical location. Logical access will be controlled with Access Controls Lists (ACL), username and strong password combinations and file and share level permissions.

User Access:

Access to the Data will only be granted by the Principal Investigator (PI). A central log of users having access to the Data will be maintained.

Passwords:

All passwords will be strong in nature. Passwords must never be written down or shared.

Virus Protection:

All IT equipment storing or accessing the Data will have up-to-date anti-virus protection.

Operating System Management:

All IT equipment storing or accessing the data must be updated automatically on a regular basis with the operating system and security patches in order to avoid potential security breaches.

Backup:

The Data will be backed up on a regular basis and stored in a separate location from the original data in order to allow the recovery of the data after a major incident.

Logging:

Logging of access to the Data will be put in place in order to allow a clear audit trail to be maintained of access and modifications made by each authorised User.

Network Security:

The network where the data is stored will be secured to avoid unauthorized access to the information. Network segregation and firewalls should be implemented to increase the safety of the data.

The Data will not leave the EEA at any time.

Access is restricted to one employee of the International Agency for Research on Cancer (IARC) who has authorisation from the Principal Investigator and two individual substantively employed at University Hospitals Southampton (a paediatric oncologist and research registrar) also requires access to the data for the purposes outlined in this application all of whom have authorisation by the principal investigator.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The 6 contributing countries (England, France, Germany, Switzerland, Spain, and Italy) have contributed regional data to this research. The individual countries each shared their dataset directly with IARC who did the processing.

The Data will not be linked with any other data.

There will be no requirement and no attempt to reidentify individuals when using the Data.

Analysts/researchers from the Cancer Surveillance section of the IARC and University Hospitals Southampton will only process the Data for the purposes described above.

It is anticipated that the study findings will be published in peer-reviewed journals and will also be presented at relevant conferences.

Should the opportunity arise, the study may publish findings on the SIOP Europe and Children’s Cancer and Leukaemia Group (CCLG) webpages, and hold open lectures or engage with the press. This will aid the dissemination of the findings and will reach interested groups in civil society.

Update under v1:

Results of the international comparative study (analysis performed at IARC) have been presented orally during the International Society of Paediatric Oncology (SIOP) 2022 congress (Barcelona, Oct 2022). The results of the analysis of the full English dataset (analysis performed at NCRAS) was presented as a poster at the SIOP 2019 congress (Lyon, Oct 2022).

Both analyses are in the process of final analysis to include all data variables collected and preparation of the full publications for submission to peer reviewed journals.

The data were presented in poster format in November 2023 at the European Network of Cancer Registries (ENCR) / International Association of Cancer Registries (IACR) congress, held in Granada, Spain.

The aim of this study is to better understand the outcomes of current treatments for neuroblastoma in infants in relation to the success of first-line therapy (event-free survival) and the burden of treatment received by the individual child and reasons for any differences between countries. Carrying out this research may assist in identifying optimal practice in the clinical care of children with neuroblastoma, and therefore has the potential to benefit the provision of health and social care in England.

The international comparative analysis that includes 6 countries (England, France, Germany, Switzerland, Spain, Italy) shows that the proportion of infants diagnosed with stage 4 disease is highest in England. This suggests that we need to focus improvement efforts on earlier diagnosis compared to other Western European countries. The prevalence of the adverse biomarker, MYCN amplification, was also the highest % in England - which may reflect differences in tumour biology or, again, later presentation with tumour evolution. Finally, there are differences in the proportions of patients treated first line by the different therapeutic approaches available - analyses of these differences are still underway. Note the IARC analyses only included cases diagnosed in the time period 2000-2009 for which all 6 countries sent data.

The English dataset includes all cases on which additional data items were collected by NCRAS and covers a slightly longer time period of incidence compared to the dataset included in the IARC analyses. This permits us to perform a much more detailed analysis including data items that were not available to the cancer registries in all countries. Hence, we intend to analyse numbers of lines of therapy received by each patient as part of planned first line therapy, and to estimate relapse-free and event-free survival, which will give an indication of the success of first line therapy for infants with neuroblastoma diagnosed in England during the period 1999 - 2010. This is important for comparison with the event-free and relapse-free survival rates achieved by the European LINES trial (Localised and Infant Neuroblastoma European Study) in which the UK was unable to participate. This analysis will be performed within the NCRAS environment with clinical support for data cleaning from the research team, who only have access to pseudonymised data to resolve relevant queries

An extensive list of publications published by ENNCA can be found at the following link: http://worldspanmedia.s3.amazonaws.com/media/siope/wp-content/uploads/2013/06/SIOPE-ENCCA-Scientific-Articles.pdf. Information on how the research has so far benefitted the provision of health and social care can be found within these publications.

Update under v1:

Two publications in abstract form have been published:

1. Irvine L et al, Learning from Clinically-Linked Population-based Cancer Registry Data on Infant Neuroblastomas for Comparative Cancer Outcomes Research. Pediatr Blood Cancer (2019) SIOP congress abstract supplement. DOI: 10.1002/pbc.27989 abstract number V339 SIOP19-0815 p 328

2. Steliarova-Foucher E et al, Prognosis of infants diagnosed with neuroblastoma during 2000-2009 in six European countries. Pediatr Blood Cancer (2022) SIOP congress abstract supplement. DOI: 10.1002/pbc.29952 abstract number O217 / #393 p 106

Further update (April 30 2025) - The English data set on these infants with neuroblastoma is currently being written up for publication under the supervision of Prof Juliet Gray, University Hospitals Southampton.

The international dataset is still pending completion of the full analysis and write up by the team at IARC, Lyon, France, under the supervision of Dr Eva STeliarova-Foucher. This expected to be completed within the 2025 calendar year.