Hodgkin and Non-Hodgkin Lymphoma:Using routine data to identify recurrence, and variation in the use of radiotherapy ( ODR1920_011 )

University of Oxford requires access to NHS England data for the purpose of the following research project: Hodgkin and Non-Hodgkin Lymphoma: Using routine data to identify recurrence, and variation in the use of radiotherapy.

The following is a summary of the aims of the research project provided by University of Oxford:

Lymphoma is a form of cancer which is very sensitive to treatment, both with chemotherapy and radiotherapy. Significant variation in the use of radiotherapy was identified in a report in 2015, which may be more related to geographical and organisational factors rather than patient or disease factors.

This project has two main aims:

• undertake analysis of radiotherapy usage in England, to understand the causes and clinical impact of any variation on patient outcomes,

• use the routine datasets available within NHS England to further understand subsequent relapse and recurrence of lymphoma. Factors predicting recurrence will be identified and used to develop a model to help predict those patients who may experience recurrence of their lymphoma following standard treatment.

The final aspect of analysis will be to look at what long-term side-effects survivors of lymphoma develop. In particular to analyse the incidence of heart disease, stroke and subsequent cancers.

The data accessed from NHS England will form the foundation of improving understanding into the use of radiotherapy, recurrence rates of lymphoma, and late-toxicity in an English population. Having access to population-based data spanning decades will allow the identification of trends which may not otherwise be seen. The large cohort size of the NHS England data will allow statistical analysis to identify any significant predictors of recurrence, or factors associated with variations in radiotherapy usage in the UK.

The following NHS England data will be accessed:

• Hospital Episode Statistics

- Accident & Emergency (HESAE)

- Inpatient (HESAPC)

- Outpatients (HESOP)

• Cancer Registry

• Diagnostic Imaging Dataset (DIDS)

• Systemic Anti-Cancer Therapy Dataset (SACT)

• National Cancer Waiting Times Dataset (CWT

• Radiotherapy Dataset (RTDS)

The quantum of Data requested is necessary to determine treatment patterns, patterns of presentation, co-morbidities, initial treatment, recurrence, and investigation. The Cancer Registry data is necessary to provide a cohort of unique individuals, to allow analyses by age, sex, ethnicity, and vital status and to allow ascertainment of the index diagnosis including multiple prognostic factors and help determine the treatments used.

The level of the data will be pseudonymised and will be minimised as follows:

• Limited to data indexing between 01st January 1997 to 31st December 2020 ;

• Limited to approximately 264,443 records

• Limited to the following geographic areas: England

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

Hodgkin Lymphoma, Follicular and non Follicure Lymphoma Mature T/NK-cell lymphomas, Other specified and unspecified types of non-Hodgkin lymphoma, Other specified types of T/NK-cell lymphoma, Malignant immunoproliferative diseases, Hodgkin’s disease, Lymphosarcoma and reticulosarcoma and other specified malignant tumours of lymphatic tissue. morphology codes.

University of Oxford is the research sponsor and the data controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

The University of Oxford rely on Article 6(1)(e) - the processing is necessary for you to perform a task in the public interest or for your official functions, and the task or function has a clear basis in law. The public interest in this circumstance is research to increase medical knowledge for the benefit of all and to improve public health.

The University of Oxford rely on Article 9(2)(j) - processing is necessary for archiving purposes in public interest, scientific or historical research purposes. The legitimate need for processing special category data under 9(2)(j) as: "necessary for scientific research purposes to increase medial knowledge for the benefit of all and to improve public health".

The funding is provided by a grant from Cancer Research UK. The funding is specifically for the study described. Funding is in place for 12 months. Funding to continue the work described will be sought on an ongoing basis via an annual grant cycle.

University of Oxford is the sole data controller and sole data processor.

There are no other organisation(s) involved or accessing the NHS England data, including organisations acting in an advisory capacity or as part of an oversight or steering committee.

The design of the proposed use of the data has been discussed with and supported by a Project Advisory Group comprised of 4 individuals previously treated for lymphoma, contacted via the Oxford Blood Group patient involvement group ( https://oxfordbrc.nihr.ac.uk/ppi/oxford-blood-group).

In line with the National data opt-out policy, opt-outs are not applied because the data is not Confidential Patient Information as defined in section 251(10) and (11) of the National Health Service Act 2006

Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out

No data will flow to NHS England for the purposes of this Agreement.

NHS England will provide the relevant records from the HES A&E, HES IP, HES OP, CANCER Registry, DIDS, SACT, CWT and RTDS datasets to University of Oxford.

The data will contain no direct identifying data items but will contain a unique person ID which can be used to link the data with other older record level data already held by the recipient within the scope of this study and Data Sharing Agreement. Data will not be linked to other datasets out of scope of this agreement.

The data will not be transferred to any other location.

Within Nuffield Department of Population Health (NDPH) department in Oxford University, electronic data files are kept on password-protected network servers behind a local firewall. Servers are kept in a locked room with access restricted to IT staff.

Access to data is restricted via user identification. No data are moved or copied from these servers. The primary data received from NHS England are also stored on the secure NDPH network behind a firewall. The IT department have setup a special permissions compliant folder to receive and hold data securely. The PI of the group controls who can access this folder and the list is reviewed every 6 months. Data are not copied but can be accessed by analysis programs. Receipt of data is recorded in The University of Oxford asset register. When data are to be deleted a request is made to the IT department who provide a deletion certificate which the study team enter into the asset register (any backups resulting from the 28-day back-up cycle are also deleted).

Backups are held for 6 months on internal servers spread over three locations within the Old Road Campus, at The University of Oxford. Backed up data is encrypted both in transit and at rest. After 6 months, any expired data is deleted from the server. Access to data is restricted via user identification. No data are moved or copied from these servers.

The data will be accessed by authorised personnel via remote access. The data will remain on the servers at University of Oxford at all times. Personnel are prohibited from downloading or copying data to local devices.

The data will not leave England/Wales at any time.

Data processing and access will be carried out by substantive employees of the data processor/controller (University of Oxford) who have authorisation from the PI who is working within University of Oxford under honorary contract. All individuals have been appropriately trained in data protection and confidentiality.

No other organisation is permitted to access the data.

There will be no requirement and no attempt to reidentify individuals when using the data. Analysts from the University of Oxford will process the data only for the purposes described above.

The expected outputs of the processing will be:

• Abstracts and presentations at national and international conferences

• Submissions to peer reviewed journals anticipating 1 publication per year over the next 3 years.

• Provision of results to other researchers to help in the development of their research studies and in clinical trials

• Results will also be shared directly with people affected by lymphoma at Lymphoma Action’s National Conference and their Lymphoma Matters publication.

• Planned that these data will be used as part of a further PhD project over the next 4 years.

The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The results of analyses of lymphoma outcomes and late effects will be presented using standard epidemiology measures such as Overall Survival (OS), cause-specific mortality (CSM), standardized mortality ratios (SMR), standardized incidence ratios (SIR), absolute excess risk (AER) and cumulative incidences and mortality. These analyses will be completed, presented and published as a number of smaller projects over the next 4+ years, coinciding with the study’s current programme grant funding cycle from CRUK.

Methods to infer recurrence of lymphoma from routinely collected data will be developed over the next 4+ years as part of a Clinical Research Fellow post funded within our CRUK programme. It is hoped that this work will form a component of a PhD thesis and will also be presented and published separately.

The study research group has a strong record of achieving previous research goals, have an excellent publication record and have maintained continuous programmatic funding from CRUK for >10 years. The study team envisage continuing research using these data into the future, requesting renewals and data up-dates every 2-3 years.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• Journals

• Public events such as conferences

• Publication and citation record originating from the programme

• Contribution through informing national (and international) clinical guidelines

• Contribution through the development of clinical trials

The results of analyses of radiotherapy usage will be presented using the proportion of cases receiving radiotherapy and assessing variation by factors including geography, travel time from nearest radiotherapy centre and multiple deprivation index. This analysis will be completed and presented within the next year and subsequently prepared for appropriate publication.

The study’s CRUK programme grant (‘Benefits and Risks of Cancer Treatment’) utilises data from a variety of different sources (also including clinical trials, large cohort studies and radiation dosimetry studies) to provide relevant information to clinicians and patients and allow optimal treatment decisions to be made. The data provided to The University of Oxford by NHS England is another important source of data that contributes towards the overall project aims. It is therefore in the public interest for this data to be released, processed and the results disseminated.

Specifically, the data provided by NHS England will allow:

• Analysis of variation in radiotherapy use across the country and the possible reasons behind this variation.

• Assessment of the long-term risks (e.g. cause-specific mortality and second cancer incidence) following lymphoma diagnosis and treatment.

• Development of an algorithm to detect lymphoma recurrence in routinely collected data to give population-based indications of how recurrence risk has varied by treatment strategies.

The results of this work will contribute towards an improved understanding of the optimal management of different sub-types of lymphoma to further improve the observed outcomes.

Approximately 16,500 people are diagnosed with lymphoma in the UK each year, making it the 6th most common cancer type overall (after breast, prostate, lung, bowel and melanoma skin cancer). Improvements in the management of, and the long-term outcomes after, lymphoma therefore stand to make a substantial benefit to public health.

The study teams record of delivering planned outputs in this area is evidenced by the publication and citation record originating from the programme. In addition the study contributes through informing national (and international) clinical guidelines and the development of clinical trials.

This study is not in direct support of an individual PhD project, but this study has already formed part of a successful PhD thesis (the original data applicant, Dr Rebecca Shakir) and it is planned that these data will be used as part of a further PhD project over the next 4 years.

Data for this study has previously been shared when the data were controlled and managed by Public Health England (PHE). As such there are some yielded benefits to be observed from the access to the data for the study prior to NHS England becoming data controller. It should be noted, as the study is, by definition, focused on the long-term outcomes of cancer treatments it is not possible to directly assess the benefits of the research as these would not become measurable for many years following any influence on clinical practice. However, some of examples of this study’s research (the late effects of cancer treatments) have been cited and referenced in clinical guidelines and policy documents nationally and internationally over the past 5.

The inclusion of research in multiple clinical guidelines and policy documents, for example recent research on the same themes (long term effects of cancer treatments) from the study has been cited in:

• 2022 ESC Guidelines on Cardio-Oncology (10.1093/eurheartj/ehac244)

• 2022 Update to NCCN Guidelines: Hodgkin Lymphoma, Version 2.2023

• 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure (10.1016/j.cardfail.2022.02.010)

• 2022Position paper of the Heart Failure Working Group of the Austrian Society of Cardiology

• 2022 Radiation Therapy Across Pediatric Hodgkin Lymphoma Research Group Protocols: A Report From the Staging, Evaluation, and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) Group (10.1016/j.ijrobp.2021.07.1716)

• 2021 Stratification and management of cardiovascular risk in cancer patients. A consensus document of the SEC, FEC, SEOM, SEOR, SEHH, SEMG, AEEMT, AEEC, and AECC (10.1016/j.rec.2020.11.020)

• 2021 Cardiovascular Manifestations From Therapeutic Radiation: A Multidisciplinary Expert Consensus Statement From the International Cardio-Oncology Society (10.1016/j.jaccao.2021.06.003)

• 2021 Coronary artery disease surveillance among childhood, adolescent and young adult cancer survivors: A systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group (10.1016/j.ejca.2021.06.021)

• 2020 Fondazione Italiana Linfomi (FIL) expert consensus on the use of intensity-modulated and image-guided radiotherapy for Hodgkin’s lymphoma involving the mediastinum (10.1186/s13014-020-01504-8)

• 2020 Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology (10.1007/s00392-020-01636-7)

• 2020 Guidelines for Long-Term Follow-Up after Childhood Cancer: Practical Implications for the Daily Work (10.1159/000504200)

• 2020 Long-Term Follow-Up Guidelines and Organization of Long-Term Follow-Up Care for Childhood and Young Adult Cancer Survivors (10.1007/978-3-030-49140-6_44)

• 2019 Evidence-based recommendations for the organization of long-term follow-up care for childhood and adolescent cancer survivors: a report from the PanCareSurFup Guidelines Working Group (10.1007/s11764-019-00795-5)

• 2019 Cardio-Oncology Rehabilitation to Manage Cardiovascular Outcomes in Cancer Patients and Survivors: A Scientific Statement From the American Heart Association (10.1161/CIR.0000000000000679)

• 2018 Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines (10.1182/blood-2018-03-837633)

• 2018 Bone sarcomas: ESMO–PaedCan–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up (10.1093/annonc/mdy310)

• 2018 Proton therapy for pediatric malignancies: Fact, figures and costs. A joint consensus statement from the pediatric subcommittee of PTCOG, PROS and EPTN (10.1016/j.radonc.2018.05.020)

Additionally, examples cited include how the data is being used in the development of clinical studies with examples included below.

• Citation in: 2019 The Evolving Design of NIH-Funded Cardio-Oncology Studies to Address Cancer Treatment-Related Cardiovascular Toxicity (10.1016/j.jaccao.2019.08.007)

• Use of data to inform the development of the PROSPERITY trial (‘A randomised multi-centre phase II study of protons versus photons to deliver intensity modulated radiotherapy with deep inspiration breath hold for the treatment of mediastinal lymphoma’)

• Use of data to inform the development of a study of lung cancer screening in Hodgkin lymphoma survivors (led by Dr Kim Linton, Christie Hospital, Manchester)

• Use of data to inform the development and analysis and interpretation of a study of Response Adapted incorporation of Tislelizumab into the Front-line treatment of older patients with Hodgkin lymphoma (RATIFTY) – Funded will open soon

These activities were sufficient over the past 5 years for the study team to obtain an extension of CRUK’s programme grant for a further 5 years (from April 2022) to continue research and yield further such benefits.