Requite

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Project title: Validating predictive models of radiotherapy toxicity to improve quality-of-life and reduce side-effects in cancer survivors

Project coordinator (PC):West, Catharine (UNIMAN) Code: FP7-601826-2
Call: 7th Framework Programme for Research, technological Development and Demonstration.

FP7-HEALTH-2013-INNOVATION-1

Total budget: 5,997.408,00€ Total granted:info not available (NA)
Term: 5 years Starting date: 01/01/2014
Project abstract: Long-term side-effects of radiotherapy impact on the quality-of-life (QoL) of cancer survivors. These side-effects could be reduced if predicted in advance. Previous work identified clinical and biological predictors but a major, coordinated approach is needed to validate them so they can be used clinically. The EU has ~17.8 million people living with a prior diagnosis of cancer of whom ~7 million received radiotherapy. In the long-term, potentially 20% of those suffering with mild to severe side-effects (~1.4 million) might benefit from alleviation of symptoms, with resulting reductions in the cost of care in the EU.

REQUITE aims to develop validated clinical models and incorporate biomarkers to identify before treatment cancer patients at risk of side-effects and use the models to design interventional trials aimed at reducing side-effects and improving QoL in cancer survivors who underwent radiotherapy.

REQUITE will:

1. carry out a multi-centre, longitudinal, observational study to collect standardised data and samples in breast, prostate and lung cancer patients;

2. validate biomarkers with published evidence of predictive value;

3. replicate published clinical models and incorporate replicated biomarkers to create validated predictive algorithms;

4. use the prospectively validated models and biomarkers to design interventional trial protocols aiming to reduce sideeffects and improve QoL in high-risk patients.

REQUITE builds on collaborations with a proven history of data sharing, enlarged to a consortium with expertise in patient recruitment, knowledge management, biomarker testing and predictive model development. SME involvement for biomarker assays will facilitate future clinical implementation and commercial exploitation. The outcome of this project will be validated predictive models for three common cancers and trial protocols using the models to investigate interventions aimed at reducing long-term side-effects and improving the QoL of cancer survivors.

Key Words: radiotherapy, cancer survivors, quality-of-life (QoL), long-term symptoms of treatment, side- effects, toxicity, predictive model, biomarkers, personalised medicine, breast cancer, prostate cancer, lung cancer, multi-centre observational study, commertial exploitation

TEAM

Surname Name Title/ Position Entity
West Catharine Translational Radiobiology, Prof./ PC Institute of Cancer Sciences

(ICC, UNIMAN)

Chang-Claude Jenny Unit Head of Epidemiology, Prof./ PI DEUTSCHES KREBSFORSCHUNGSZENTRUM (DKFZ)
Thierens Hubert Basic Medical Sci., Head of department, Prof./ PI Faculty of Medicine (UGent)
Talbot Chris Medical Genetics, Lecturer/ PI College of Medicine (ULEIC)
De Ruysscher Dirk Radiation Oncology, Full Prof./ PI Lab of Experimental Radiotherapy  (KU Leuven)
Dunning Alison Oncology, Senior Research Associate/ PI Center for Cancer Genetic Epidemiology (CCGE, UCAM)
Azria David Radiation Oncology, Head of department/ PI CRLC Val d’Aurelle (UMONT)
Lozza Laura Radiation Oncology 1, Dr./ PI Istituto Nazionale Tumori
Vega Ana Cancer Genetic Diagnosis, Dr./ PI Molecular Medicine section (FPGMX)
Davidson Susan Clinical Oncology, Dr./ PI The Christie Hospital
Burr Tom Sr. Sci. Bioinformatic, Dr./ PI Life Sciences (SOURCE)
Rosenstein Barry Radiation Oncology , Prof./ PI Icah School of Medicine (MSSM)
Lambin Philippe Medical Director/ PI MAASTRO Clinic
PC: Project CoordinatorPI: Principal Investigator

PARTICIPATING ENTITIES

Partner Nr. Name Acronym Type/ Category
1 University of Manchester(UK) UNIMAN Public/ higher education & research
2 Deutsches Krebsforschungszentrum (DE) DKFZ Public reseach/ national institution
3 University of Gent (BE) UGent Public/ higher education & research
4 University of Leicester (UK) ULEIC Public/ higher education & research
5 Katholieke Universiteit Leuven (BE) KU Leuven Public/ higher education & research
6 University of Cambridge (UK) UCAM Public/ higher education & research
7 Universite Montpellier (FR) UMONT Public/ higher education & research
8 Fondazione IRCCS IstitutoNazionaledeiTumori (IT) INT Public reseach/ national institution
9 Fundación Pública de Medicina Xenómica (SP) FPGMX Public foundation/ reseach institution
10 The Christie NHS Foundation Trust (UK) The Christie Public hospital/ Trust
11 Source Bioscience plc (UK) SOURCE Private company/ SME
12 Mount Sinai School of Medicine (USA) MSSM Public/ higher education
13 STICHTING MAASTRICHT RADIATION ONCOLOGY MAASTRO CLINIC (NL) MAASTRO Public hospital/ reseach organization

Background to the project.

There were an estimated 3,566 people per 100,000 with a past diagnosis of any type of cancer in the European Union in 2003, equivalent to a prevalence of ~17.8 million [3]. With increasing life expectancies and improvements in diagnosis and treatment, the number of cancer patients and survivors is expected to continue to rise. For example, the estimated number of cancer survivors in the United States increased from 9.8 million in 2001 to 11.7 million in 2007 with 22% accounted for by breast and 19% by prostate cancers [4]. As the illness increasingly becomes a chronic disease, cancer patients’ quality-of-life needs to be addressed in a systematic manner in order to enhance their participation in society, including the workplace.

Being Radiotherapy an important curative treatment for cancer,however, (unavoidable) irradiation of surrounding healthy tissue will cause toxic side effects. This toxicity varies in severity, from minor to severe, nature (psychological or, for example, rectal bleeding in prostate cancer survivors) and in duration, from weeks to a lifetime. These long-term side-effects have been shown to impairQoLof cancer survivors [9].

The field also suffers from a lack of standardization in data collection [6,7] and, at present, it is not yet possible to predict who will develop long-term side-effects. Therefore a prospective multi-centre observational study is/ will be the best way of developing and validating both clinical models and biomarkers that predict for risk of long-term side-effects following radiotherapy.This requires systematic reviews to identify approaches for ameliorating those and the design of interventional clinical trials to reduce them.

Finally, although a number of approaches have been explored, no biomarker has been validated for clinical use. Involvement of SMEs is important in this context to bring in technical expertise in assay validation and  in development of marketable clinical tests.

Objectives.

The main goal, and central concept of REQUITE, is to develop validated clinical models incorporating biomarker data to identify before treatment those cancer patients who are at risk of developing long-term side-effects from radiotherapy, to identify the best interventions for reducing the side-effects and to design interventional trials aimed at improving the quality-of-life of cancer survivors who underwent radiotherapy.

The specific objectivesare to:

  1. Perform a multi-centre, longitudinal, observational cohort study collecting: pre-treatment blood samples, epidemiologydata at the start of treatment (e.g. age, weight, height, information on existing health problems such as diabetes,smoking history), treatment data at the end of treatment (radiotherapy dose delivered, fractionation regimen, radiationdoses and volumes to surrounding healthy tissue, additional treatment received), longitudinal side-effect and quality-of-life data (before treatment, end of treatment, year 1, year 2).
  2. Produce a centralisedbiobank of DNA from 5,300 patients enrolled in the observational study and a centralised datamanagement system for secure collection, integration, mining, sharing, and archiving of all project data in link-anonymisedform.
  3. Validate published biomarkers of individual radiosensitivity.
  4. Validate clinical predictors of radiotherapy toxicity in breast, prostate and lung cancer and incorporate biomarker dataif validation is successful.
  5. Design interventional trials to reduce long-term side-effects in survivors of breast, prostate and lung cancer by:carrying out systematic reviews to identify the best interventions for the primary endpoints for the three cancers; exploring interventional trial designs; and producing protocols using the validated models and biomarkers.
  6. To provide a resource for dissemination and exploitation within the radiotherapy research community.

All of them, and the corresponding WPs, can be seen at figure 1 below:

requite1

Figure 1

To fully appreciate the strength and meaningfulness of the project’ goals, the current state-of-the-art vs the progress to be made is summarized in table 1:

State-of-the-art Progress to be made
Fragmented databases containing different information Large centralised, easily accessible database withstandardised data collection.
Fragmented biobanks using different methodologies Large centralised, easily accessible biobank with samplescollected, processed, stored under SOPs.

Biobank linked to a comprehensive clinical database forexploitation in future studies.

Knowledge that nr. of factors increase risk of side effects but no validation. Relationships between side-effects not well understood.

Limited information on relationship between radiotherapy side-effects and QoL.

Known to impact on the health of cancer survivors but the extent of the health burden unknown.

Increased understanding of relationships between side-effectendpoints to ID those most informative.

Improved understanding of the relationship between sideeffectsand quality-of-life. Detailed information on the extentof the health burden due to radiotherapy side-effects incancer survivors.

Increasing nr. of clinical models (risk prediction of long-term side effects) but none validated for its use.The data show their clinical utility (AUC>0.70). Increasing nr. of approaches used inmodel development. Systematic comparison of models for primary endpoints(and secondary endpoints) to identify the best modellingapproach.

Validated clinical models ready for clinical implementation.

Promising biomarkers  but often retrospective studies, no standardisation of assays and differing clinical endpoints used.

No biomarker validated for clinical use.

First cross- EU standardisation assay formeasuring radiosensitivity. Evidence on whether anapoptosis assay has clinical utility. Validated genetic markersassociated with increased risk of side-effects.
Early stage or animal model-based research on interventions to lower radiation toxicity.

No pre-treatment targeting toxicity prone patients.

Interventional trial protocols aimed at reducing long-termradiotherapy side-effects targeted to those with high risk oftoxicity.

Table 1

Work Plan and cronogram.

Details on the WPs and interrelations within the project are shownin the chart below (figure 2):

requite2

Figure 2

The work-packages of the ReQuiTe form part of a tightly integrated project with a clear long-term focus on improving quality-of-lifeof cancer survivors. The project builds on existing evidence of clinical factors and biomarkers that may affect risk for long-termside-effects following radiotherapy, validating them in the new cohorts to create statistical models which can be applied inclinical practice for patient benefit. The leads of each WP have an existing track record of working together through theRadiogenomics Consortium, so are ideally placed to co-ordinate the different strands into an effective whole leading to asuccessful outcome.

The list of activities (WP and sub- WP; figure 2) have been scheduled as shown in the cronogram below:

requite3

Figure 3

Partner 1 is responsible for overall management and scientific oversight of the project; co-ordination with patient advocates, theethics group, the steering committee and the external advisory group; budgetary control and monitoring of project progressand milestones; co-ordination between work-packages and organisation of annual meetings. Management will be based atUNIMAN.

Ethical aspects

Ethical aspects are important for the multi-centre observational study, biobanking, biological assays and the design of interventional studies aimed at improving the quality-of-life of cancer survivors. Local ethics committees for each partner organisation must approve the project. An Ethical Review Group, formed within the consortium, will review and provide advice on ethical aspects of the project in liaison with a Patient Advisory Group. The project’s Steering Committee ensures partners adhere to ethical rules, as described in the Consortium Agreement. Copies of ethical permission have been requested in anticipation and filed in the Management Office.

Key features of the Ethical Review Group are that comprises the clinical leads for the enrolling centres for the interventional study and other clinical and scientific members nominated by the Steering Committee and the Patient Advisory Group. The chair was elected democratically. The roles are/ will be to:

  • Oversee the production of patient information sheets
  • Provide input into the project from an ethical perspective
  • Review ethical issues and comment on consent forms
  • Advise on dissemination and implementation of a trial design to improve quality-of-life in radiotherapy survivors.

Project impacts in relation with EU- horizon2020 agenda

In order to emphasize how ReQuiTe objectives align with the h2020 flagship initiatives on Health [i.e. Innovation Unit, Digital Agendas (new skills and jobs) and Platform against Poverty], the expected project impacts are summarized in the table below:

Nr. Re-Qui-Te objective Short-term impacts Long-term impacts
1 Perform a multi-centre observationallongitudinal study to collectstandardised side-effect, quality-of-life, treatment and epidemiologic data Harmonized data collection acrossEurope and internationallyCentralised e-data capture forpatient reported outcomes established e-Tools for multi-centre electronic patient reported data capture Information on the health burden of long-term side-effects in cancer survivors across the EU Long-termfollow-up of patients will

allow prediction of late side-effects, e.g. cardiovascular disease,creating a health impact. Establishment of a framework forfuture combined studies on radio/chemotherapy long-term sideeffects

2 Produce a centralised biobank and database as a resource for future use Centralised, publically advertised, fairlyaccessible DNA biobank linked toradiotherapy outcome data for exploitation in future studies such as those involving next generation sequencing and RNA profiling. Full characterisation of genetic and biological underpinnings to radiation induced tissue damage
3 Validation of biomarkers predicting risk of long-term side-effects Validated biomarkers Decision on whether an apoptosis assay has clinical utility A commercialisable biomarker panel which provides economic benefits to SME SOURCE
4 Validation of clinical models predictingrisk of long-term side-effects Proof-of-principle confirmed. Foundation forclinical interventional trials established. A new market for commercial radiotherapy outcome prediction
5 Design of interventional clinical trial protocols Enables application for funding to runclinical trials Evidence of patient benefit leads to change in clinical practice, lowering long-term side-effects in cancer survivors
6 Resource for dissemination &exploitation Increased awareness amongst oncologistsand patients that risk prediction could guidetherapeutic decisions Therapeutic decisions routinely incorporate toxicity prediction

Table 2

Literature (state of the art prior to project’s start and progress beyond).

The literature search and revision done for the occasion indicates that, although currently unclear as to what interventions are appropriate, there is a recognized need to developapproaches for identifying patient sub-populations most likely to benefit. Systematic reviews will help identify the most appropriate interventions as will additional evidence that emerges in the next 4-5 years, which can be taken into account in the interventional trials that will be designed in REQUITE.

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Current status.

Project is on- going. Planned project term is 31/12/2018

Derived publications and/ or otherproject contributions (by 01/08/2014).

WoS