title: Assessment of repeatability and treatment response in early phase clinical trials using DCE-MRI: comparison of parametric analysis using MR- and CT-derived arterial input functions.
abstract: OBJECTIVE
  Pharmacokinetic (PK) modelling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data requires a reliable measure of the arterial input function (AIF) to robustly characterise tumour vascular properties. This study compared repeatability and treatment-response effects of DCE-MRI-derived PK parameters using a population-averaged AIF and three patient-specific AIFs derived from pre-bolus MRI, DCE-MRI and dynamic contrast computed tomography (DC-CT) data.
  
  
  METHODS
  The four approaches were compared in 13 patients with abdominal metastases. Baseline repeatability [Bland-Altman statistics; coefficient of variation (CoV)], cohort percentage change and p value (paired t test) and number of patients with significant DCE-MRI parameter change post-treatment (limits of agreement) were assessed.
  
  
  RESULTS
  Individual AIFs were obtained for all 13 patients with pre-bolus MRI and DC-CT-derived AIFs, but only 10/13 patients had AIFs measurable from DCE-MRI data. The best CoV (7.5 %) of the transfer coefficient between blood plasma and extravascular extracellular space (K (trans)) was obtained using a population-averaged AIF. All four AIF methods detected significant treatment changes: the most significant was the DC-CT-derived AIF. The population-based AIF was similar to or better than the pre-bolus and DCE-MRI-derived AIFs.
  
  
  CONCLUSIONS
  A population-based AIF is the recommended approach for measuring cohort and individual effects since it has the best repeatability and none of the PK parameters derived using measured AIFs demonstrated an improvement in treatment sensitivity.
  
  
  CONCLUSIONS
  • Pharmacokinetic modelling of DCE-MRI data requires a reliable measure of AIF. • Individual MRI-DCE-derived AIFs cannot reliably be extracted from patients. • All four AIF methods detected significant K (trans) changes after treatment. • A population-based AIF can be recommended for measuring cohort treatment responses in trials.
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Rata
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Collins
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Darcy
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Messiou
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK.
authors.forename: Nina
authors.initials: N
authors.lastname: Tunariu
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK.
authors.forename: Nandita
authors.initials: N
authors.lastname: Desouza
authors.affiliation: Early Clinical Development, AstraZeneca, Macclesfield, Cheshire, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Young
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK. Martin.Leach@icr.ac.uk.|CRUK Cancer Imaging Centre, MRI Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK. Martin.Leach@icr.ac.uk.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leach
authors.affiliation: CR-UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden Hospital, London, UK.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Orton
mesh_terms: D000008:Abdominal Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000473:pathology / Q000556:secondary; D000328:Adult; D000368:Aged; D000465:Algorithms; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001011:Aorta / Q000000981:diagnostic imaging* / Q000503:physiopathology; D003198:Computer Simulation; D003287:Contrast Media / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000627:therapeutic use; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D011799:Quinazolines; C500926:cediranib; D007211:Indoles
keywords: Clinical trials, phase 1; Comparative study; Computed tomography; Drug evaluation; Magnetic resonance imaging