title: Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry.
abstract: BACKGROUND
  Isocitrate dehydrogenase 1 (IDH1) mutations have been linked to favorable outcomes in patients with glioblastoma multiforme (GBM). Recent in vitro experiments suggest that IDH1 mutation sensitizes tumors to radiation damage. We hypothesized that radiographic treatment response would be significantly different between IDH1 mutant versus wild-type GBMs after radiotherapy (RT) and concurrent temozolomide (TMZ).
  
  
  METHODS
  A total of 39 newly diagnosed GBM patients with known IDH1 mutational status (10 IDH1 mutants), who followed standard therapy and had regular post-contrast T1W (T1+C) and T2W/ fluid-attenuated inversion recovery (FLAIR) images in the 6-month period after starting RT, were enrolled. The volume of contrast-enhancing and FLAIR hyperintensity were calculated from each scan. Linear and polynomial regression techniques were used to estimate the rate of change and temporal patterns in tumor volumes.
  
  
  RESULTS
  IDH1 mutant GBMs demonstrated a favorable response to RT/TMZ in the study period, as demonstrated by 10 of 10 mutants showing radiographic response (decreasing V(T1+C)), compared with 13 of 29 wild-types (P < .001). During the study period, V(T1+C) and V(FLAIR) changed at -3.6% per week and +0.6% per week in IDH1 mutant tumors, respectively, as compared with +0.8% per week and +5.2% per week in IDH1 wild-type tumors (P = .0076 and P = .0118, respectively). Amongst the radiographic responders, IDH1 mutant GBMs still demonstrated significant progression-free and overall survival benefit. Aggregated tumor kinetics by group showed significant lower rate in IDH1 mutant GBMs in specific periods: >105 days for V(FLAIR) and 95-120 and >150 days for V(T1+C) from starting RT/TMZ.
  
  
  CONCLUSIONS
  The current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.
authors.affiliation: Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore (A.N.T.); Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (A.T., W.B.P., S.T., R.J.H., D.C.W., P.L.N., B.M.E.); Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (A.N.T., A.L., S.L., P.L.N., T.F.C.); Department of Biomedical Physics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (R.J.H., D.C.W., B.M.E.); Department of Bioengineering, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E.).
authors.forename: Anh N
authors.initials: AN
authors.lastname: Tran
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.forename: Sichen
authors.initials: S
authors.lastname: Li
authors.forename: Whitney B
authors.initials: WB
authors.lastname: Pope
authors.forename: Stephanie
authors.initials: S
authors.lastname: Teixeira
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harris
authors.forename: Davis C
authors.initials: DC
authors.lastname: Woodworth
authors.forename: Phioanh L
authors.initials: PL
authors.lastname: Nghiemphu
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Ellingson
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009154:Mutation; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D000077204:Temozolomide
keywords: IDH1 mutation; MRI; glioblastoma; radiochemotherapy; volumetry