title: Reducing radiation dose to normal brain through a risk adapted dose reduction protocol for patients with favourable subtype anaplastic glioma.
abstract: OBJECTIVE
  In patients with isocitrate dehydrogenase (IDH) mutated anaplastic glioma determine the dosimetric benefits of delivering radiation therapy using a PET guided integrated boost IMRT technique (ib-IMRT) compared with standard IMRT (s-IMRT) in reducing dose to normal brain.
  
  
  METHODS
  Ten patients with anaplastic glioma, identified as a favourable molecular subgroup through presence of IDH mutation, and managed with radiation therapy using an ib-IMRT were enrolled into a dosimetric study comparing two RT techniques: s-IMRT to 59.4Gy or ib-IMRT with 59.4/54Gy regions. Gross Tumour volume (GTV) and Clinical Target Volumes (CTV) were determined by MRI, 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET imaging. A standard risk Planning Target Volume (PTVsr) receiving 59.4Gy (PTV59.4) in the s-IMRT technique was determined by MRI T2Flair and FET PET. For the ib-IMRT technique this PTVsr volume was treated to 54Gy, and the high-risk PTV (PTVhr) receiving 59.4Gy was determined as a higher risk region by FDG PET and MRI gadolinium enhancement. Standard dosimetric criteria and normal tissue constraints based on recent clinical trials were used in target delineation and planning. Normal Brain was defined as Brain minus CTV. Endpoints for dosimetric evaluation related to mean Brain dose (mBrainDose), brain volume receiving 40Gy (Brainv40) and 20Gy (Brainv20). The variation between the dosimetric endpoints for both techniques was examined using Wilcoxon analysis.
  
  
  RESULTS
  The 10 patients had tumours located in temporal (1), parietal (3), occipital (2) and bifrontal (4) regions. In ib-IMRT technique the median volume of PTVhr was 25.5 cm3 compared with PTVsr of 300.0 cm3. For dose to PTVhr the two treatments were equivalent (p = 0.33), and although the ibIMRT had a prescribed 10% dose reduction from 59.4Gy to 54Gy the median reduction was only 5.9%. The ib-IMRT dosimetry was significantly improved in normal brain endpoints specifically mBrainDose (p = 0.007), Brainv40 (p = 0.005) and Brainv20 (p = 0.001), with a median reduction of 9.3%, 19.0 and 10.8% respectively. After a median follow-up of 38 months two patients have progressed, with no isolated relapse in the dose reduction region.
  
  
  CONCLUSIONS
  An approach using ib-IMRT for anaplastic glioma produces significant dosimetric advantages in relation to normal brain dose compared with s-IMRT plan. This is achieved without a significant reduction to the target volume dose despite the reduction in prescribed dose. This technique has advantages to minimise potential late neurocognitive effects from high dose radiation in patients with favorable subtype anaplastic glioma with predicted median survival beyond ten years.
authors.affiliation: Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia. michael.back@health.nsw.gov.au.|Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW, Australia. michael.back@health.nsw.gov.au.|Sydney Medical School, University of Sydney, Sydney, Australia. michael.back@health.nsw.gov.au.|Sydney Neuro-Oncology Group, Sydney, NSW, Australia. michael.back@health.nsw.gov.au.|Department of Radiation Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia. michael.back@health.nsw.gov.au.
authors.forename: M
authors.identifier: http://orcid.org/0000-0003-2363-8333
authors.initials: M
authors.lastname: Back
authors.affiliation: Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia.|Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: LeMottee
authors.affiliation: Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Crasta
authors.affiliation: Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW, Australia.|Department of PET and Nuclear Medicine, Royal North Shore Hospital, Sydney, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Bailey
authors.affiliation: Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.|Sydney Neuro-Oncology Group, Sydney, NSW, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Wheeler
authors.affiliation: Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Guo
authors.affiliation: Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia.|Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Eade
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000532:radiotherapy*; D005260:Female; D005910:Glioma / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*
keywords: Anaplastic glioma; Dosimetry; Intensity modulated radiation therapy; Neurocognitive