title: Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.
abstract: The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high-dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract-based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H-MRS) in the left centrum semiovale (white matter) showed a reduction of N-acetylasparate/creatine indicative of axonal injury. Voxel-based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H-MRS only in the chemotherapy group. These results converge to suggest that high-dose adjuvant chemotherapy for breast cancer is associated with long-term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment.
authors.affiliation: Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. mbderuiter@gmail.com
authors.forename: Michiel B
authors.initials: MB
authors.lastname: de Ruiter
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Reneman
authors.forename: Willem
authors.initials: W
authors.lastname: Boogerd
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Veltman
authors.forename: Matthan
authors.initials: M
authors.lastname: Caan
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Douaud
authors.forename: Cristina
authors.initials: C
authors.lastname: Lavini
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
authors.forename: Frits S A M
authors.initials: FS
authors.lastname: van Dam
authors.forename: Sanne B
authors.initials: SB
authors.lastname: Schagen
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D003071:Cognition / Q000187:drug effects; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006304:Health Status; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000473:pathology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000473:pathology; D009483:Neuropsychological Tests; D011788:Quality of Life; D017741:Survivors; D013852:Thiotepa / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin
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