title: Vulnerability of white matter to insult during childhood: evidence from patients treated for medulloblastoma.
abstract: OBJECTIVE Craniospinal irradiation damages the white matter in children treated for medulloblastoma, but the treatment-intensity effects are unclear. In a cross-sectional retrospective study, the effects of treatment with the least intensive radiation protocol versus protocols that delivered more radiation to the brain, in addition to the effects of continuous radiation dose, on white matter architecture were evaluated. METHODS Diffusion tensor imaging was used to assess fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. First, regional white matter analyses and tract-based spatial statistics were conducted in 34 medulloblastoma patients and 38 healthy controls. Patients were stratified according to those treated with 1) the least intensive radiation protocol, specifically reduced-dose craniospinal irradiation plus a boost to the tumor bed only (n = 17), or 2) any other dose and boost combination that delivered more radiation to the brain, which was also termed the "all-other-treatments" group (n = 17), and comprised patients treated with standard-dose craniospinal irradiation plus a posterior fossa boost, standard-dose craniospinal irradiation plus a tumor bed boost, or reduced-dose craniospinal irradiation plus a posterior fossa boost. Second, voxel-wise dose-distribution analyses were conducted on a separate cohort of medulloblastoma patients (n = 15). RESULTS The all-other-treatments group, but not the reduced-dose craniospinal irradiation plus tumor bed group, had lower fractional anisotropy and higher radial diffusivity than controls in all brain regions (all p < 0.05). The reduced-dose craniospinal irradiation plus tumor bed boost group had higher fractional anisotropy (p = 0.05) and lower radial diffusivity (p = 0.04) in the temporal region, and higher fractional anisotropy in the frontal region (p = 0.04), than the all-other-treatments group. Linear mixed-effects modeling revealed that the dose and age at diagnosis together 1) better predicted fractional anisotropy in the temporal region than models with either alone (p < 0.005), but 2) did not better predict fractional anisotropy in comparison with dose alone in the occipital region (p > 0.05). CONCLUSIONS Together, the results show that white matter damage has a clear association with increasing radiation dose, and that treatment with reduced-dose craniospinal irradiation plus tumor bed boost appears to preserve white matter in some brain regions.
authors.affiliation: Program in Neuroscience and Mental Health and |Departments of 2 Psychology.|Pediatric Oncology Group of Ontario, Toronto; and.
authors.forename: Iska
authors.initials: I
authors.lastname: Moxon-Emre
authors.affiliation: Divisions of 4 Hematology/Oncology.
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.affiliation: Neurosurgery, and.|Neurosurgery.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Radiation Oncology, and.|Radiation Oncology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Normand
authors.initials: N
authors.lastname: Laperriere
authors.affiliation: Radiation Oncology, and.|Radiation Oncology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sharpe
authors.affiliation: Diagnostic Imaging, Hospital for Sick Children, Toronto; 
authors.forename: Suzanne
authors.initials: S
authors.lastname: Laughlin
authors.affiliation: Divisions of 4 Hematology/Oncology.
authors.forename: Ute
authors.initials: U
authors.lastname: Bartels
authors.affiliation: Program in Neuroscience and Mental Health and 
authors.forename: Nadia
authors.initials: N
authors.lastname: Scantlebury
authors.affiliation: Program in Neuroscience and Mental Health and |Departments of 2 Psychology.
authors.forename: Nicole
authors.initials: N
authors.lastname: Law
authors.affiliation: Divisions of 4 Hematology/Oncology.|Paediatrics, University of Toronto;|Pediatric Oncology Group of Ontario, Toronto; and.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.affiliation: Program in Neuroscience and Mental Health and 
authors.forename: Jovanka
authors.initials: J
authors.lastname: Skocic
authors.affiliation: Program in Neuroscience and Mental Health and |Departments of 2 Psychology.
authors.forename: Logan
authors.initials: L
authors.lastname: Richard
authors.affiliation: Program in Neuroscience and Mental Health and |Departments of 2 Psychology.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Mabbott
mesh_terms: D000293:Adolescent; D016880:Anisotropy; D002528:Cerebellar Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy; D002648:Child; D015331:Cohort Studies; D061888:Craniospinal Irradiation / Q000009:adverse effects* / Q000639:trends; D056324:Diffusion Tensor Imaging / Q000639:trends; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000000981:diagnostic imaging* / Q000532:radiotherapy; D012189:Retrospective Studies; D016896:Treatment Outcome; D066127:White Matter / Q000000981:diagnostic imaging* / Q000528:radiation effects*
keywords: AD = axial diffusivity; CSI = craniospinal irradiation; CSI+PF = CSI plus posterior fossa; CSI+TB = CSI plus tumor bed; DTI = diffusion tensor imaging; FA = fractional anisotropy; FOV = field of view; FSL = Functional MRI of the Brain Software Library; MD = mean diffusivity; MNI = Montreal Neurological Institute; RD = radial diffusivity; ROI = region of interest; TBSS = tract-based spatial statistics; craniospinal irradiation; diffusion tensor imaging; dose-response relationship; medulloblastoma; oncology; white matter