Title: Calibration of whOle-body apparent diffusion coefficient: enabling multi-centRe studies for assessment of REsponse to Cancer Therapy (CORRECT)
Funder: Health Education England

Abstract: Positron emission tomography (PET) has the standardised uptake values (SUV) and computed tomography X-ray Hounsfield Units (HU), but the signal recorded from magnetic resonance imaging (MRI) has no direct quantitative equivalent. MRI uses magnetic fields and radio frequency irradiation to manipulate the magnetic moments of nuclei (usually the protons of the hydrogen atom in water molecules) to visualise their distribution and magnetic microenvironment and thus generate a high resolution image of anatomical structure. However, this signal is sensitive to fluctuations in the main magnetic field introduced by the presence of the patient and although it can be compensated for on a patient to patient basis it cannot be entirely removed leaving residual, difficult to predict fluctuations across the image and between imaging sessions. Therefore using the MRI signal intensity as a quantitative marker for clinical assessment is complicated by the uncalibrated nature of the data acquired. In addition to anatomical imaging, MRI signal can be sensitised to microstructural and physiological properties of tissue. For example diffusion weighted imaging (DWI) allows the interrogation of the microscopic translational motion of water molecules within image pixels, a property often altered by tissue pathology. The myriad of recent publications highlight the power of DWI for assessment of cancer, inflammatory and neurological disease; and many provide quantitative (apparent diffusion coefficient (ADC)) thresholds of water diffusion for differentiating significant pathologies. The focus of this application is on tumour imaging, where ADC has shown promise for assessing tumour stage, predicting response and informing treatment selection. Despite promising results, and despite all the major MRI scanner manufacturers offering a commercial software for DWI, the technique is considered difficult to apply in the clinic as a robust and reliable quantitative metric remains elusive, mainly due to the difficulties with standardising the diffusion signal between institutions, scanner manufacturers and diffusion techniques. This proposal describes a multi-centre calibration study' for whole body DWI to facilitate adoption of quantitative ADC assessments for cancer staging. The work integrates with and brings together leading clinical and physics experts previously and presently conducting trials within the field (Padhani, Koh, Punwani, Taylor, Collins, Atkinson, Leach); and by a co-ordinated approach led by the applicant seeks to define and tackle the problem of ADC calibration. Previous efforts (including my own contributions) to calibrate MR signal in general mainly concentrated on brain imaging (grey matter maps, BOLD-fMRI task and resting state time series). By employing travelling phantoms and cohorts of healthy volunteers, and focusing on development of standardised acquisition protocols and data processing pipelines we have successfully enabled multi-centre brain imaging studies. Our calibration work used the general linear model to understand sources of variances associated with multi-centre/scanner studies. The present proposal will adapt and refine previously successful approaches to investigate sources of variance and bias to whole body DWI and ADC maps. The explicit aim will be to develop, test and provide a calibration factor to reduce variance and enable multi-centre application and adoption of DWI ADC for whole body cancer imaging. It is intended that the final outcome will for the first time enable reliable multi-centre quantitative longitudinal imaging of individual patients; facilitate the pooling of ADC research data for the purposes of Big Data' analysis of evaluation of ADC as a biomarker for prediction and evaluation of cancer therapies; and finally enable all NHS hospital sites to benefit from the advances in MRI currently restricted to NHS university sites.

Lay abstract: Imaging is playing an ever more important role in the management of patients with cancer. Many patients have repeated CT studies to look for shrinkage in the size of tumours with treatment. However, this method of assessment is sometimes insensitive and it doesn't work for treatments that do not change the size of a lesion. Whole-body diffusion weighted imaging (DWI) can offer an improvement over standard methods, as it can detect changes in cellular composition (tissue microstructure) but for it to be adopted widely it needs to be standardised. This proposal describes a calibration study' for standardisation of DWI.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS