title: Monitoring early response to anti-angiogenic therapy: diffusion-weighted magnetic resonance imaging and volume measurements in colon carcinoma xenografts.
abstract: OBJECTIVE
  To evaluate the use of diffusion-weighted MRI (DW-MRI) and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model.
  
  
  METHODS
  23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29) were examined before and after 6 days of treatment with regorafenib (n = 12) or placebo (n = 11) in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10-800 s/mm2) was used. The apparent diffusion coefficient (ADC) was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC) analysis individually and combined using Fisher's linear discriminant analysis (FLDA).
  
  
  RESULTS
  All ADCs and volumes are stated as median±standard deviation. Tumor ADC increased significantly in the therapy group (0.76±0.09×10(-3) mm2/s to 0.90±0.12×10(-3) mm2/s; p<0.001), with significantly higher changes of tumor ADC than in the control group (0.10±0.11×10(-3) mm2/s vs. 0.03±0.09×10(-3) mm2/s; p = 0.027). Tumor volume increased significantly in both groups (therapy: 347.8±449.1 to 405.3±823.6 mm3; p = 0.034; control: 219.7±79.5 to 443.7±141.5 mm3; p<0.001), however, the therapy group showed significantly reduced tumor growth (33.30±47.30% vs. 96.43±31.66%; p<0.001). Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%; and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%.
  
  
  CONCLUSIONS
  Regorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and control group. The combination of both parameters using FLDA substantially improved diagnostic accuracy, thus highlighting the potential of multi-parameter MRI as an imaging biomarker for non-invasive early tumor therapy monitoring.
authors.affiliation: Josef Lissner Laboratory for Biomedical Imaging, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
authors.forename: Moritz Jörg
authors.initials: MJ
authors.lastname: Schneider
authors.affiliation: Laboratory for Experimental Radiology, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
authors.forename: Clemens Christian
authors.initials: CC
authors.lastname: Cyran
authors.affiliation: Laboratory for Experimental Radiology, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Munich, Germany; Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Nikolaou
authors.affiliation: Laboratory for Experimental Radiology, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Hirner
authors.affiliation: Josef Lissner Laboratory for Biomedical Imaging, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Munich, Germany; Laboratory for Experimental Radiology, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Reiser
authors.affiliation: Josef Lissner Laboratory for Biomedical Imaging, Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Dietrich
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D005260:Female; D019073:HT29 Cells; D064593:Heterografts / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011923:Rats, Nude; D047368:Tumor Burden
chemical_list: D020533:Angiogenesis Inhibitors; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib