Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning

PURPOSE To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose–volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure–informed RT planning may mitigate neurocognitive impairment. Scores on tests of memory and processing speed are correlated with dose to the hippocampus and corpus callosum/frontal white matter, respectively, for children with medulloblastoma.

[1]  Jennifer L. Hadley,et al.  Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  S. Acharya,et al.  Radiation therapy to the developing brain: advanced technology is ready for robust optimization parameters. , 2021, Neuro-oncology.

[3]  T. Merchant,et al.  Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03). , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  T. Gupta,et al.  Hippocampal radiotherapy dose-constraints for predicting long-term neurocognitive outcomes: Mature data from a prospective trial in young patients with brain tumors. , 2020, Neuro-oncology.

[5]  P. Brown,et al.  Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  T. Merchant,et al.  Association between hippocampal dose and memory in survivors of childhood or adolescent low-grade glioma: a 10-year neurocognitive longitudinal study , 2019, Neuro-oncology.

[7]  P. Northcott,et al.  Medulloblastoma , 2019, Nature Reviews Disease Primers.

[8]  T. Merchant,et al.  Attainment of Functional and Social Independence in Adult Survivors of Pediatric CNS Tumors: A Report From the St Jude Lifetime Cohort Study. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  H. Sair,et al.  Association of Neuronal Injury in the Genu and Body of Corpus Callosum After Cranial Irradiation in Children With Impaired Cognitive Control: A Prospective Study. , 2018, International journal of radiation oncology, biology, physics.

[10]  M. Boldrini,et al.  Human Hippocampal Neurogenesis Persists throughout Aging. , 2018, Cell stem cell.

[11]  David T. W. Jones,et al.  DNA methylation-based classification of central nervous system tumours , 2018, Nature.

[12]  W. Reddick,et al.  Disrupted development and integrity of frontal white matter in patients treated for pediatric medulloblastoma , 2017, Neuro-oncology.

[13]  G. Tseng,et al.  Hydrocephalus compacted cortex and hippocampus and altered their output neurons in association with spatial learning and memory deficits in rats , 2017, Brain pathology.

[14]  Jeremy D. Schmahmann,et al.  Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results , 2016, Child's Nervous System.

[15]  T. Merchant,et al.  Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma. , 2014, International journal of radiation oncology, biology, physics.

[16]  T. Merchant,et al.  Effects of Surgery and Proton Therapy on Cerebral White Matter of Craniopharyngioma Patients. , 2014, International journal of radiation oncology, biology, physics.

[17]  J. Gurney,et al.  Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. , 2014, Neuro-oncology.

[18]  M. Herk,et al.  Multiple comparisons permutation test for image based data mining in radiotherapy , 2013, Radiation oncology.

[19]  A. Gajjar,et al.  Processing speed, attention, and working memory after treatment for medulloblastoma: an international, prospective, and longitudinal study. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  C. Limoli,et al.  Cranial irradiation compromises neuronal architecture in the hippocampus , 2013, Proceedings of the National Academy of Sciences.

[21]  Yue Cao,et al.  Regional Variation in Brain White Matter Diffusion Index Changes following Chemoradiotherapy: A Prospective Study Using Tract-Based Spatial Statistics , 2013, PloS one.

[22]  K. Evankovich,et al.  Parent-reported social outcomes after treatment for pediatric embryonal tumors: a prospective longitudinal study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  W. Reddick,et al.  Cerebral white matter integrity and executive function in adult survivors of childhood medulloblastoma. , 2012, Neuro-oncology.

[24]  W. Reddick,et al.  White matter integrity is associated with cognitive processing in patients treated for a posterior fossa brain tumor. , 2012, Neuro-oncology.

[25]  K. Duff.  Evidence-based indicators of neuropsychological change in the individual patient: relevant concepts and methods. , 2012, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[26]  L. Massimi,et al.  Cerebellar mutism: review of the literature , 2011, Child's Nervous System.

[27]  K. Schmiegelow,et al.  Cerebellar mutism , 2011, Child's Nervous System.

[28]  F. Gage,et al.  New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? , 2010, Nature Reviews Neuroscience.

[29]  Silun Wang,et al.  Longitudinal diffusion tensor magnetic resonance imaging study of radiation-induced white matter damage in a rat model. , 2009, Cancer research.

[30]  Huiru Zheng,et al.  Permutation – based statistical tests for multiple hypotheses , 2008, Source Code for Biology and Medicine.

[31]  K. Ligon,et al.  Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies , 2007, Annals of neurology.

[32]  B. Postle,et al.  The cognitive neuroscience of working memory. , 2007, Annual review of psychology.

[33]  P. Robertson,et al.  Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children's Oncology Group. , 2006, Journal of neurosurgery.

[34]  R. Mulhern,et al.  Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  M. Monje,et al.  Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. , 2003, Cancer research.

[36]  S. Dudoit,et al.  Multiple Hypothesis Testing in Microarray Experiments , 2003 .

[37]  M. Monje,et al.  Irradiation induces neural precursor-cell dysfunction , 2002, Nature Medicine.

[38]  L. Rorke,et al.  Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[40]  N. Jacobson,et al.  Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. , 1991, Journal of consulting and clinical psychology.

[41]  Nancy Mather,et al.  Woodcock-Johnson III Tests of Cognitive Abilities. , 2009 .

[42]  P. Luetmer,et al.  Corpus callosal signal changes in patients with obstructive hydrocephalus after ventriculoperitoneal shunting. , 2001, AJNR. American journal of neuroradiology.