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REQUITE Report Summary

Project ID: 601826
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 2 - REQUITE (Validating predictive models of radiotherapy toxicity to improve quality-of-life and reduce side-effects in cancer survivors)

Project Context and Objectives:
Approximately half of the ~28 million cancer survivors worldwide received radiotherapy as part of their cancer treatment. However, patients vary in how they react to radiation. Up to 5% of patients are sensitive and at risk of having long-term side-effects (radiation toxicity) that impact on their health and quality-of-life. Predictive clinical models for radiotherapy side-effects are being developed to try to identify before the start of treatment those patients who are most sensitive. Some biomarkers show promise for incorporation into clinical models. However, the models and biomarkers are not yet ready to use in the clinic so radiation doses for all patients are currently limited by the risk of side-effects in the most sensitive patients.

The REQUITE project brings together clinicians, basic research scientists, patient advocates and clinical research teams from across Europe and the US. The consortium aims to: (1) develop validated clinical models incorporating biomarkers to identify before treatment cancer patients who are at risk of developing long-term side-effects from radiotherapy; and (2) design interventional trials aimed at improving the quality-of-life of cancer survivors who underwent radiotherapy. If successful, then in future it would be possible to identify the ‘radiosensitive’ patients before the start of treatment and move towards biologically personalised radiotherapy.

The REQUITE consortium objectives are to: (1) Carry out an observational study recruiting prospectively a cohort of 5,300 patients undergoing radiotherapy for breast, prostate or lung cancer, and collect longitudinal, standardised radiotherapy toxicity and quality of life data. (2) Produce a centralised database and a DNA biobank for patients enrolled in the observational study. (3) Validate published biomarkers of radiotherapy toxicity (SNPs, an apoptosis assay). (4) Validate published clinical models of radiotherapy toxicity using the REQUITE cohort for final testing and incorporating biomarker data if validation is successful. (5) Design interventional trials that can use the validated models and biomarkers to personalise radiotherapy based on risk of side-effects. (6) Provide a resource for dissemination and exploitation to the radiotherapy community.

Project Results:
WP1: Project Management & Co-ordination
This WP is dedicated to the efficient and timely management of the operational aspects of REQUITE, enabling all deliverables and milestones to be met.

WP2: Multi-centre Observational Study
There was data and sample collection at 26 centres in 8 countries. All sites completed site initiation, and were monitored to ensure continued protocol compliance. By 30/09/2016 accrual reached 4,314 patients, split 2,070 breast (99% of target); 1,812 prostate (86%); 432 lung (39%). Lung recruitment is extended to 31/03/2017. Standardised data forms are available in multiple languages. By 30/09/2016 the bespoke centralised database held 17,525 completed data forms and patient questionnaires, and a further 4,159 anonymized files of radiotherapy imaging, dosimetry data and photos, providing a unique resource for the future.

WP3: Biobanking
The biobank team was responsible for: 1) training new staff in sample tracking; 2) preparing and shipping 5,421 validated blood sample collection kits; 3) receipting, tracking and storing 2,535 whole blood samples; 4) DNA extraction of 2,791 blood samples; 5) transfer of 1,520 DNA samples for genotyping.

WP4: Biomarker Assays
This WP is validating an assay that predicts for the risk of radiotherapy toxicity. A standard operating procedure developed in REQUITE is used to run the radiation-induced lymphocyte apoptosis (RILA) assay in 3 centres, such that this consortium achieved where previous research has faltered by implementing the RILA assay under standardised conditions across European laboratories. A paper to report the initial cross-laboratory comparison work is under review by the consortium. By 30/09/2016, the RILA assay had been run in duplicate on 1,319 patient samples, exceeding the revised target by a wide margin. A test genotyping run of 380 DNA samples was successfully completed using the OncoArray chip with the main genotyping run to conclude in ~12 months.

WP5: Validation of Clinical Predictors & Models
Breast cancer cohorts from international clinical trials were made available for validation of risk factors and clinical model validation. A biostatistical plan detailed methods to handle different datasets, and logistic regression performed (with steps taken to avoid overfitting) to select patient and treatment variables associated with late effects. These variables are used with other parameters to construct a prediction model in a training dataset, which is applied to a test dataset for validation. This showed the most important predictor of fibrosis is breast volume, however, the prediction models did not validate in the test dataset. Work is ongoing to simplify the breast model using only clinical parameters and analysis of prostate cohorts has begun.

WP6: Interventional Trial Design
Researchers working with members of the Patient Advisory Group (PAG) published their findings on the optimal design and patient selection for interventional trials using radiogenomic biomarkers (in press). This was the culmination of a review of international trial methodology where the use of predictive models had been implemented. Work will now start on in silico modelling of the most suitable study endpoints for each cancer type using results from WP4 & WP5, and writing clinical protocols.

WP7: Exploitation & Dissemination
The website is regularly updated with information on the project, current news and accrual. REQUITE is active on social media via Twitter (@RequiteProject) and Facebook (RequiteProject) allowing active engagement with users to highlight project successes and spread topical news. The consortium published 10 peer review articles (2 open access), and given 51 oral/ poster presentations across Europe & USA, including 1 poster initiated and presented by a member of our PAG. Patient questionnaires to better record standardised late effects from radiotherapy have been translated into 6 European languages and disseminated to 3 groups for use in clinic and trials.

Potential Impact:
The REQUITE consortium believes that the work undertaken in this project is achieving its goals and already having an impact in the research community. The REQUITE observational study is the largest study of its kind and has received attention as an example of the type of multi-disciplinary, multi-centre work that can and should be carried out in the radiotherapy/ radiation research field. It is likely to increase the use of standardised data collection forms for radiotherapy-related research. Furthermore, the centralised REQUITE database that includes comprehensive treatment (including physics) and outcome data will be a valuable resource for future research, e.g. exploring the relationships between different radiotherapy toxicity endpoints. The linked centralised biobank is likely to be exploited by third parties in new studies (e.g. next generation sequencing) aimed at increasing the understanding of the biological basis of radiosensitivity. Requests for access to data and samples have already been received.

The short-term impact of the project will be a better understanding of the scale of radiotherapy toxicity in a multi-national setting. The results will inform stakeholders and increase knowledge of the health burden of long-term side-effects following radiotherapy in the EU.

The long-term impact on health will be a reduction in long-term side effects and improved health-related quality-of-life in cancer survivors who received radiotherapy. Survivorship issues are particularly relevant for radiotherapy as it is an important potentially curative treatment in many cancers. This work has the potential to increase the number of patients successfully treated for their cancer.

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United Kingdom


Life Sciences
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