Quic-Concept

Quantative imaging in cancer:connecting cellular process with therapy
QUANTITIVE IMAGING IN CANCER: CONNECTING CELLULAR PROCESSES WITH THERAPY

FACTS & FIGURES

Start Date
End Date
Call
IMI1 - Call 2
Grant agreement number
115151

Type of Action: 
RIA (Research and Innovation Action)

Contributions
IMI Funding
7 000 000
EFPIA in kind
6 602 606
Other
1 903 309
Total Cost
15 505 915

Summary

QUIC-CONCEPT investigated whether certain imaging biomarkers – signs indicating change in biology that can be observed on a medical scan - are reliable for establishing whether or not a cancer drug is having the desired effect on a tumour. If such biomarkers could be proven to be dependable, they could help oncologists make decisions more quickly about whether to continue or stop a cancer patient’s treatment. It would also help drug developers judge the effectiveness of treatments under development, allowing them to make decisions about continuing or calling off expensive clinical studies. The consortium managed to establish the relationship between imaging and underlying biology for two key imaging biomarkers. They also established standards and a 'roadmap' for future imaging biomarker studies and produced a repository of thousands of MRI and PET images and datasets.

Background

A good imaging biomarker shows evidence of a drug’s activity before the benefit to the patient is evident. Although imaging biomarkers are already used in cancer treatment and research, few are considered to be sufficiently reliable as to be used as a matter of routine. This project set out to get definitive evidence as to the usefulness of three different imaging biomarkers in determining whether a drug is having the effect of either forcing cell death (necrosis), encouraging tumour cells to shut themselves down and die (apoptosis), or reducing tumour cell proliferation. These three phenomena constitute the goal of many cancer drugs in development; if pharma companies could have confidence that imaging could offer reliable evidence of them, it would help them to make decisions about whether a treatment under development is worth pursuing. Likewise, if doctors could have confidence in the reliability of the biomarkers from a scan, they would be able to make crucial decisions about stopping ineffective drugs, often being administered to patients who don’t have long left to live.

The clinical trials

Tumours in the lung and liver were chosen as the targets for the QUIC-CONCEPT clinical trials. The reason for this is that cancer often spreads (metastasises) to these organs. Drug therapy is particularly appropriate for metastatic disease, because radiotherapy or surgery are generally less effective against metastatic tumours than primary tumours. 

The team studied three imaging biomarkers. One was studied for its ability to indicate cell death (ADC MRI, or apparent diffusion coefficient as seen via magnetic resonance imaging); another for its ability to indicate reduced rate of cell proliferation (FLT PET, using the tracer fluorothymidine F-18 and positron emission tomography scan); and finally, one that would measure apoptosis (ICMT11 PET, another tracer material used in conjunction with a PET scan). Patients underwent scans before taking a treatment and then again a set period of time afterwards, to see if the imaging could offer reliable indications of the activity of the drug.

In the case of ADC MRI, which involves watching for signs that water molecules can move freely around the tumour, suggesting the drug had caused cell death; although the ADC value did increase, as expected, with treatment, the team found weak evidence that it is a reliable or effective imaging biomarker of necrosis. The fact that it disproved the assumption that it could be used as a marker for necrosis is itself a useful finding that will of particular help to drug developers.  

The second method, which involved the injection of FLT and a PET scan, did indeed establish that this form of imaging biomarker could be used to reliably judge the effectiveness of the drug’s ability to reduce cell proliferation, as FLT uptake was found to decrease with effective treatment.

The study of the third imaging biomarker was ultimately unsuccessful. Apoptosis proved quite tricky to study as it occurs at a very specific time after the drug is given, otherwise the signal is weak and hard to measure. This work will make drug developers more cautious in deciding how to measure whether new drugs induce apoptosis.  

The team also undertook comprehensive studies in tumours in rodent models, as these are often used to help design and interpret clinical trials. One important finding was that the ADC biomarker was unexpectedly found to be a weak biomarker of necrosis (cell death), but a good biomarker of cellularity. In addition, the FLT biomarker signal quickly decreased in most cases where drugs were working, but importantly the team identified some particular types of drug which could give misleading results due to the so-called ‘flare’ effect, so FLT PET should definitely be avoided in such cases. 

Legacy of the project

At the outset of the project the team realised that, although patient scanning is almost universally used to assess whether drugs are working, only a very small variety of types of scanning are routinely used and trusted by doctors and drug developers. This is surprising because a huge variety of types of scanning, measuring different biological processes, has been developed in universities.  The team realised that in many cases these new types of scan have not been developed in the most useful way, and they developed a new ‘roadmap’ to help get these new scanning tools into use faster. This roadmap has already been widely adopted.

One of the reasons previous studies on imaging biomarkers were unreliable is that each study used its own protocol, making comparison very hard. QUIC-CONCEPT introduced standardisation of the studies across the multicentre study and across animal models and cancer patients. Regarding assets, the project left behind an imaging repository, which contained over 1,200 MRI scans, 600 PET images and datasets by the end of the project lifespan. These data still being worked on to gain new insights.

On average, it costs about one billion euro and takes about ten years to develop a cancer drug. The benefit to industry of the results of QUIC-CONCEPT is that they will help make decisions at phase one or phase two of clinical research as to whether to continue to the more expensive later phase trials. In this respect, the project achieved its goal.

For cancer patients, unfortunately, time is often quite short. Anything that helps oncologists cut down on the time spent treating patients with ineffective drugs is valuable. The project outcome can ultimately help primary care practitioners understand more about what tools can reliably be used to predict prognosis, choose the optimal treatment for each patient, and to monitor treatment to determine whether drugs, doses and schedules elicit a desired or undesired biological effect.

Achievements & News

QuIC-ConCePT biomarker tests to speed up cancer drug development
October 2017

Imaging biomarkers extracted from CT, PET and MRI scans are extremely beneficial tools for assessing if a cancer drug is working at an early stage. However, scientists are frustrated that not enough of these tests are validated for use in clinical research.### IMI’s QuIC-ConCePT project seeks to address this challenge by accelerating the validation of existing bioimaging markers so that they can reliably be used in drug research. ‘Our frustration was that there was only a small number of imaging biomarkers that drug developers could trust,’ says deputy project coordinator John Waterton, professor of translational imaging at the UK’s University of Manchester and former head of imaging at the pharmaceutical company AstraZeneca. ‘The genesis of the QuIC-ConCePT project was to add to the number of imaging biomarkers that could be used in drug development. We cherry-picked a few promising tests – and then put them through a vigorous validation process.’  ###

The project focuses on tumour cell proliferation, programmed cell death (apoptosis) and cell death due to injury, disease or lack of blood supply (necrosis) and has concentrated on two imaging biomarkers for measuring these. These include: MRI ADC (Apparent Diffusion Coefficient), a measure of diffusion of water molecules within tissue that gives information about tissue integrity; and FLT (fluorothymidine) PET scan, which measures whether tumour cells are dividing fast. The team has evaluated the two imaging biomarkers, assessing their reproducibility, effectiveness, timing, dose response and imaging in animals and humans. They are now awaiting results from two clinical trials involving a well-known cancer drug for lung and liver cancer patients to see if changes in imaging are reflected in the pathology of the cancer tumours. Results are due to be published in 2018. QuIC-ConCePT also led a consensus group that produced a set of 14 recommendations (or a ‘roadmap’) for accelerating the clinical validation of imaging biomarkers in an influential paper in the medical journal Nature Reviews Clinical Oncology.

QuIC-ConCePT scientists make recommendations on cancer clinical trials
January 2016

An international team of experts, including scientists from IMI cancer project QuIC-ConCePT, have put forward a framework to improve the way imaging is used in clinical trials of cancer drugs. Writing in The Lancet Oncology, the team explains that improvements in imaging methods are making them increasingly popular in clinical trials of cancer drugs.### Used well, imaging can show whether or not a patient is responding to treatment with days of the treatment starting. However, there are issues with the use of imaging in clinical trials; for example, the quality of data derived from imaging is variable. The researchers propose a practical, risk-based framework and recommendations on the use of imaging as a marker of how well a treatment is working. They recommend carrying out a risk assessment plan before the study starts, and reviewing and updating the risk plan throughout the trial. ‘In cancer clinical trials, we are always trying to strike the right balance between maximising data quality and minimising cost. Here, risk management can be an extremely helpful tool, because it can help us to prioritise, reduce costs, and decrease attrition rates,’ said the lead author of the paper, Dr Yan Liu of the EORTC. ‘In our study, we used a quality risk management approach to help us outline a consensus framework for imaging biomarker driven trials. This approach recognises that other stakeholders such as regulatory bodies, pharmaceutical companies, and patients also play essential roles in the conduct of these trials.’

QuIC-ConCePT standardises biomarkers for early-stage cancer drug development
June 2015

QuIC-ConCePT is working on validating imaging biomarkers for early-stage cancer drug development. In the past, such biomarkers were widely used by academia in single centre studies, but were difficult for industry to use because results from different imaging centres were not comparable.### Reproducibility is critically dependent on how imaging equipment performs for each different hospital. QuIC-ConCePT currently has 15 separate clinical trials either underway or completed to reach technical assay validation in patients with lung and liver malignancies, mainly coordinated through consortium partner EORTC and in collaboration with US colleagues at the Quantitative Imaging Biomarker Alliance of the Radiological Society of North America (US QIBA). This ground-breaking work includes repeatability, reproducibility, and advanced image analysis to overcome the challenges of scanning living, breathing patients.  QuIC-ConCePT is also working towards a unique standardisation project to ensure that the enabling work in animal models is completely valid. The scope of this work is far beyond the capabilities of even the largest cancer centre and the IMI model has ensured that the focus has remained on the needs of drug development

QuIC-ConCePT findings advance personalised cancer medicine research
July 2014

A new technology to analyse scans of cancer patients predicts how their disease will progress. This is the key outcome from a recent study published in Nature Communications that was supported in part by IMI’s QuIC-ConCePT project.### The findings could help to advance personalised treatments for cancer patients and also improve clinical trials of cancer drugs. Cancer patients regularly undergo imaging scans, yet until recently much of the exquisite detail in these scans was lost in the analysis. Recently, a new technique called radiomics has allowed researchers to put numbers to the scans, effectively creating a detailed ‘blueprint’ of the tumour. In this study, researchers used radiomics to analyse 440 aspects of over 1 000 computed tomography (CT) scans from patients with lung or head and neck cancers. Their findings demonstrate that radiomics can be used to predict far more accurately how the disease will progress in a patient, and suggest that it could be used to determine which medicines may be most appropriate for each individual patient. In addition, the results imply that radiomics could be used in clinical trials to identify the patients most likely to benefit from a new medicine and to monitor the impact of the medicine on the disease. QuIC-ConCePT is now working to confirm its findings with additional high quality data from the EFPIA companies in the project. 

QuiC-ConCePT scans for new ways of testing cancer treatment efficacy
January 2012

Scientific progress in cancer research has substantially increased our understanding of the molecular biology of cancer, paving the way to novel treatments. However, new tools to rapidly and reliably demonstrate the efficacy of novel cancer drugs are lacking.### A new paper by scientists from IMI project QuiC-ConCePT discusses how magnetic resonance imaging (MRI) could be used to assess the efficacy of new drugs. MRI scans are able to highlight differences in the way water moves in different tissues by detecting something called the apparent diffusion coefficient (ADC). This is important because the ADC of healthy tissues is different to that of cancerous tissues. Furthermore, studies have shown that the ADC of cancer cells rises sharply when the cells are killed, for example by chemotherapy. This means that ADC could potentially be used to assess whether a treatment has worked or not. However, more studies are needed before ADC can be used in studies to test the efficacy of new treatments. Writing in the European Journal of Cancer, QuiC-ConCePT scientists set out a roadmap highlighting the steps needed before ADC can be used in drug development.

Participants Show participants on map

EFPIA companies
  • Amgen, Brussels, Belgium
  • Astrazeneca AB, Södertälje, Sweden
  • Eli Lilly and Company Limited, Basingstoke, United Kingdom
  • F. Hoffmann-La Roche AG, Basel, Switzerland
  • Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
  • Merck Kommanditgesellschaft Auf Aktien, Darmstadt, Germany
  • Pfizer Limited, Sandwich, Kent , United Kingdom
  • Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
Universities, research organisations, public bodies, non-profit groups
  • Eidgenoessische Technische Hochschule Zuerich, Zurich, Switzerland
  • Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, Netherlands
  • European Organisation For Research And Treatment Of Cancer Aisbl, Brussels, Belgium
  • Imperial College Of Science Technology And Medicine, London, United Kingdom
  • Institut National De La Sante Et De La Recherche Medicale, Paris, France
  • King'S College London, London, United Kingdom
  • Stichting Katholieke Universiteit, Nijmegen, Netherlands
  • Stichting Maastricht Radiation Oncology Maastro Clinic, Maastricht, Netherlands
  • Stichting Vumc, Amsterdam, Netherlands
  • The Institute Of Cancer Research: Royal Cancer Hospital, London, United Kingdom
  • The University Of Manchester, Manchester, United Kingdom
  • Universitair Ziekenhuis Antwerpen, Edegem, Belgium
  • University of Cambridge, Cambridge, United Kingdom
  • Westfaelische Wilhelms-Universitaet Muenster, Münster, Germany
Small and medium-sized enterprises (SMEs)
  • Keosys S.A.S., Saint-Herblain, France
Project coordinator
Yan Liu
European Organisation for Research and Treatment of Cancer
Belgium
Managing entity
Eva Lindgren
AstraZeneca AB