Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - 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.

REQUITE aims to: (1) Carry out an observational study recruiting 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 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 using 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
Patient recruitment at 26 centres in 8 countries ended 31/03/2017 with accrual of 4,438 patients: 2,069 breast (99% of target), 1,808 prostate (86%) and 561 lung (51%). Longitudinal side-effect data were available for 100% at baseline and at the primary endpoints of 24 months (56% breast, 58% prostate) or 12 months (50% lung). By the end of the reporting period the centralised database stored anonymized files of radiotherapy imaging (n=4,184), dosimetry (n=4,184) data and breast photos (n=2,037 at baseline and n=1,121 at 24 months). A data quality control check of 70,776 data entry identified only minor and a low level of errors (<0.62%).

WP3: Biobanking
The biobank team completed its primary objective of building the REQUITE Biobank. In this reporting period 1,585 EDTA bloods and 3,039 PAXgene bloods were received from REQUITE recruitment sites, along with 169 EDTA bloods and 132 DNA aliquots from ‘additional lung cohorts’ that will be genotyped alongside the REQUITE cohorts. The EDTA blood samples, along with bloods from the previous reporting periods, were processed and stored following validated Standard Operating Procedures (SOPs) in compliance with ISO9001:2008. DNA extraction was successful on 99.9% of samples received, with just six failing due to insufficient blood sample volume. DNA was sent for genotyping at REQUITE partners.

WP4: Biomarker Assays
WP4 completed the genotyping of DNA for all patients enrolled in REQUITE using the Illumina OncoArray 500K beadchip on 11th May 2018. Radiation Induced Lymphocyte Assay (RILA) biomarker data generated in RP2 were analysed in relation to acute side-effects because the data entry for the short time-point was already available. Previous finding of a lack of relationship with acute side-effects was mainly validated. A novel finding was that low RILA scores were associated with worse pain, similar to that reported previously with late side-effects.

WP5: Validation of Clinical Predictors & Models
WP5 previously focused on breast cancer cohorts but during RP3 validation of models reported in the literature was completed for lung and prostate cancer cohorts. Furthermore, software was developed to integrate dose-volume histogram (DVH) data in prediction models with clinical and genetic variables (SNPs). In the next reporting period these models will be validated using data from patient cohorts collected in WP2.

WP6: Interventional Trial Design
During RP3 a review was undertaken of possible interventions for breast, prostate and lung cancer that could be used to reduce the side-effects of radiotherapy in those identified as high-risk using the models and biomarkers validated in REQUITE. WP6 also completed its work designing interventional trial protocols.

WP7: Exploitation & Dissemination
REQUITE consortium members increased their dissemination activities during this reporting period with presentations and posters at a number of conferences including two by members of the Patient Advisory Group. The REQUITE website continues to be well visited with 3,284 views during the period. There were 13 publications in peer reviewed journals, two of which were co-authored by members of the Patient Advisory Group. Requests for access to the study documentation set developed by REQUITE were received from 8 centres across four continents (Europe, North America, Asia, Australia). Successful patient participation events have been held providing feedback and further contact with REQUITE study participants.

Potential Impact:
Work undertaken in REQUITE is achieving its goals and 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 increased during this reporting period.

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.

The long-term impact on health will be reduced 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.

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United Kingdom


Life Sciences
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