title: Imaging biomarker dynamics in an intracranial murine glioma study of radiation and antiangiogenic therapy.
abstract: OBJECTIVE
  There is a growing need for noninvasive biomarkers to guide individualized spatiotemporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI).
  
  
  METHODS
  Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhanced T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K(trans), K(ep)).
  
  
  RESULTS
  Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K(trans) reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K(ep) reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of -0.878 (P=.002) and -0.80 (P=.01), respectively.
  
  
  CONCLUSIONS
  Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future.
authors.affiliation: Department of Radiation Oncology, University Health Network-Princess Margaret Hospital, Toronto, Ontario, Canada. caroline.chung@rmp.uhn.on.ca
authors.forename: Caroline
authors.initials: C
authors.lastname: Chung
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Jalali
authors.forename: Warren
authors.initials: W
authors.lastname: Foltz
authors.forename: Kelly
authors.initials: K
authors.lastname: Burrell
authors.forename: Petra
authors.initials: P
authors.lastname: Wildgoose
authors.forename: Patricia
authors.initials: P
authors.lastname: Lindsay
authors.forename: Christian
authors.initials: C
authors.lastname: Graves
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: David
authors.initials: D
authors.lastname: Jaffray
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ménard
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011758:Pyrroles / Q000627:therapeutic use*; D020266:Radiotherapy, Conformal; D000077210:Sunitinib; D047368:Tumor Burden
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib