Impact of Chemotherapy for Childhood Leukemia on Brain Morphology and Function

Abstract

ObjectiveUsing multidisciplinary treatment modalities the majority of children with cancer can be cured but we are increasingly faced with therapy-related toxicities. We studied brain morphology and neurocognitive functions in adolescent and young adult survivors of childhood acute, low and standard risk lymphoblastic leukemia (ALL), which was successfully treated with chemotherapy. We expected that intravenous and intrathecal chemotherapy administered in childhood will affect grey matter structures, including hippocampus and olfactory bulbs, areas where postnatal neurogenesis is ongoing.MethodsWe examined 27 ALL-survivors and 27 age-matched healthy controls, ages 15–22 years. ALL-survivors developed disease prior to their 11th birthday without central nervous system involvement, were treated with intrathecal and systemic chemotherapy and received no radiation. Volumes of grey, white matter and olfactory bulbs were measured on T1 and T2 magnetic resonance images manually, using FIRST (FMRIB’s integrated Registration and Segmentation Tool) and voxel-based morphometry (VBM). Memory, executive functions, attention, intelligence and olfaction were assessed.ResultsMean volumes of left hippocampus, amygdala, thalamus and nucleus accumbens were smaller in the ALL group. VBM analysis revealed significantly smaller volumes of the left calcarine gyrus, both lingual gyri and the left precuneus. DTI data analysis provided no evidence for white matter pathology. Lower scores in hippocampus-dependent memory were measured in ALL-subjects, while lower figural memory correlated with smaller hippocampal volumes.InterpretationFindings demonstrate that childhood ALL, treated with chemotherapy, is associated with smaller grey matter volumes of neocortical and subcortical grey matter and lower hippocampal memory performance in adolescence and adulthood.

Central nervous system acute lymphoblastic leukemia: role of natural killer cells

“…[2][3][4][5] However, these therapies are associated with substantial acute and long-term neurotoxicity. [6][7][8][9] Moreover, CNS relapse remains a major therapeutic obstacle in ALL, accounting for 30% of the relapses. [10][11][12][13][14][15] Despite its clinical importance, little is known about the mechanisms that cause CNS leukemia.…”

Neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on contemporary treatment protocols: A systematic review

“…(Von der Weid,2001; Langer et al,2002; Hill et al,2004; Spiegler et al,2006; Mahone et al,2007; Aukema et al,2009; Kadan-Lottick et al,2009; Kadan-Lottick et al,2010; Robinson et al,2010; Daams et al,2012; Krawczuk-Rybak et al,2012; Edelmann et al,2013; Genschaft et al,2013; Krull et al,2013; Lewis et al,2013; Ross et al,2013; Schuitema et al,2013; Edelmann et al,2014; Elalfy et al,2014) There were only 4 longitudinal studies that evaluated survivors’ neurocognitive changes from active treatment to post-treatment survivorship phase. (Kingma et al,2001; Harila et al,2009; Halsey et al,2011; Lewis et al,2013) Most studies focused on a pure sample of survivors who received chemotherapy-only treatment protocols while others included separate populations of ALL survivors who received CRT(Kingma et al,2001; Von der Weid,2001; Langer et al,2002; Spiegler et al,2006; Harila et al,2009; Kadan-Lottick et al,2010; Halsey et al,2011; Krull et al,2011; Daams et al,2012; Krull et al,2013; Schuitema et al,2013; Edelmann et al,2014) or patients of other cancer types.…”

“…(Kingma et al,2001; Harila et al,2009; Halsey et al,2011; Lewis et al,2013) Most studies focused on a pure sample of survivors who received chemotherapy-only treatment protocols while others included separate populations of ALL survivors who received CRT(Kingma et al,2001; Von der Weid,2001; Langer et al,2002; Spiegler et al,2006; Harila et al,2009; Kadan-Lottick et al,2010; Halsey et al,2011; Krull et al,2011; Daams et al,2012; Krull et al,2013; Schuitema et al,2013; Edelmann et al,2014) or patients of other cancer types. (Aukema et al,2009; Kadan-Lottick et al,2010) The majority of the included studies had sample sizes between 10 to 50 subjects,(Kingma et al,2001; Langer et al,2002; Hill et al,2004; Mahone et al,2007; Aukema et al,2009; Harila et al,2009; Daams et al,2012; Krawczuk-Rybak et al,2012; Edelmann et al,2013; Genschaft et al,2013; Schuitema et al,2013; Edelmann et al,2014) with the exception of 4 studies with a larger cohort of more than 100 subjects(Von der Weid,2001; Kadan-Lottick et al,2010; Halsey et al,2011; Krull et al,2013) and 3 studies with less than 10 subjects. (Lewis et al,2012; Lewis et al,2013; Ross et al,2013) Most the studies reported survivors’ mean duration of time since diagnosis, which ranged between 5 and 22 years.…”

“…Eighteen studies included a population of non-cancer controls or a normative healthy sample for comparative purposes. (Kingma et al,2001; Hill et al,2004; Spiegler et al,2006; Mahone et al,2007; Aukema et al,2009; Harila et al,2009; Kadan-Lottick et al,2010; Robinson et al,2010; Halsey et al,2011; Daams et al,2012; Lewis et al,2012; Edelmann et al,2013; Genschaft et al,2013; Krull et al,2013; Lewis et al,2013; Schuitema et al,2013; Edelmann et al,2014; Elalfy et al,2014) All patients in the included studies received customized chemotherapy-only contemporary protocols (referred to as “contemporary protocols” thereafter) that originated from the Berlin-Frankfurt-Münster (BFM) Study Group, Children’s Oncology Group (COG), Dana-Farber Cancer Institute ALL Consortium, Dutch Childhood Leukemia Study Group (DCLSG) and St. Jude Children's Research Hospital (SJCRH). The most commonly administered drugs were vincristine, corticosteroid (hydrocortisone, dexamethasone or prednisone), L-asparaginase, and anthracycline (either doxorubicin or daunorubicin).…”

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

“…A previous study by Edelmann et al (2014) in slightly older ALL survivors demonstrated a primarily left lateralized profile of alterations in FA in comparison between chemotherapytreated patients and healthy controls. Given that others have shown bilateral alteration of FA (Morioka et al, 2013) as well as no group differences in FA (Genschaft et al, 2013), the significance, if any, of left lateralized findings remains unclear. However, increased left hemisphere susceptibility has been consistently noted in several other neurological conditions.…”