Neurocognitive late effects are common sequelae of cancer in children, especially in those who have undergone treatment for brain tumors or in those receiving prophylactic cranial radiation therapy to treat leukemia. Neurocognitive morbidity in attention, executive functioning, processing speed, working memory, and memory frequently occurs and contributes to declines in intellectual and academic abilities. Oncologists are faced with the challenge of using the most effective, often the most intense, therapy to achieve the primary goal of medical success, balanced with the desire to prevent adverse late effects. Not all children with similar diagnoses and treatment have identical neurocognitive outcomes; some do very poorly and some do well. Attention now turns to the reliable prediction of risk for poor outcomes and then, using risk-adapted therapy, to preserve neurocognitive function. Prevention of late effects through rehabilitative strategies, continuation of school, and pharmacotherapy will be explored.
Cancer Facts and Figures. Atlanta, GA: American Cancer Society; 2007.
2.
Ries LAG , Reichman ME, Lewis DR, et al. Cancer survival and incidence from the surveillance, epidemiology, and end results (SEER) program. Oncologist. 2003;8:541-552.
3.
Reddick WE, Russell JM, Glass JO, et al. Subtle white matter volume differences in children treated for medulloblastoma with conventional or reduced dose craniospinal irradiation . Magn Reson Imaging. 2000;18:787-793.
4.
Moore BDNeurocognitive outcomes in survivors of childhood cancer. J Pediatr Psychol. 2005;30:51-63.
5.
Butler RW, Mulhern RKNeurocognitive interventions for children and adolescents surviving cancer . J Pediatr Psychol. 2005;30:65-78.
6.
Palmer SL, Reddick WE, Gajjar A.Understanding the cognitive impact on children who are treated for medulloblastoma . J Pediatr Psychol. 2007;32:1040-1049.
7.
Fouladi M., Gilger E., Kocak M., et al. Intellectual and functional outcome of children 3 years old or younger who have CNS malignancies. J Clin Oncol. 2005;23:7152-7160.
8.
Lahteenmaki PM, Harila-Saari A., Pukkala EI, et al. Scholastic achievements of children with brain tumors at the end of comprehensive education-A nationwide, register-based study. Neurology. 2007;69:296-305.
9.
Ater JL, van EJ, Woo SY, et al. MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children. J Neurooncol. 1997;32:243-252.
10.
Mulhern RK, Hancock J., Fairclough D., Kun L.Neuropsychological status of children treated for brain-tumors: a critical-review and integrative analysis. Med Pediatr Oncol . 1992;20: 181-191.
11.
Mazzocco MM , Pennington BF, Hagerman RJThe neurocognitive phenotype of female carriers of fragile X: additional evidence for specificity. J Dev Behav Pediatr. 1993;14:328-335.
12.
Steen RG, Koury M., Granja CI, et al. Effect of ionizing radiation on the human brain: white matter and gray matter T1 in pediatric brain tumor patients treated with conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2001;49:79-91.
13.
Mulhern RK, Palmer SL, Reddick WE, et al. Quantitative white matter loss explains risks of young age for neurocognitive deficits in medulloblastoma survivors. Arch Clin Neuropsychol. 2000;15:791-792.
14.
Mulhern RK, Palmer SL, Reddick WE, et al. Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss. J Clin Oncol. 2001;19:472-479.
15.
Iuvone L., Mariotti P., Colosimo C., et al. Long-term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia . Cancer. 2002;95:2562-2570.
16.
Netter FHPart I.: Anatomy and physiology: nervous system, vol 1. The CIBA Collection of Medical Illustrations. Summit, NJ: Ciba-Geigy Corporation; 1983.
17.
Meyn RE, Milas L., Stephens C.Programmed cell death in normal development and disease. Cancer Bull. 1994;46:120-124.
18.
Baron IS, Fennell EB, Voeller KKS.Neurodevelopmental and genetic syndromes. In: Pediatric Neuropsychology in the Medical Setting. New York, NY: Oxford University Press; 1995:64-113.
19.
Wilson DA, Nitschke R., Bowman ME, et al. Transient white matter changes on MR images in children undergoing chemotherapy for acute lymphocytic leukemia: correlation with neuropsychological deficiencies. Radiology. 1991;180:205-209.
20.
Levin HSNeuroplasticity following non-penetrating traumatic brain injury. Brain Inj. 2003;17:665-674.
21.
Wolf H., Ecke GM, Bettin S., et al. Do white matter changes contribute to the subsequent development of dementia in patients with mild cognitive impairment? A longitudinal study . Int J Geriatr Psychiatry. 2000;15:803-812.
22.
Schultheiss TE, Kun LE, Ang KK, Stephens LCRadiation response of the central nervous-system . Int J Radiat Oncol Biol Phys . 1995;31:1093-1112.
23.
Fouladi M., Langston J., Mulhern R., et al. Silent lacunar lesions detected by magnetic resonance imaging of children with brain tumors: a late sequela of therapy. J Clin Oncol. 2000;18:824-831.
24.
Lacaze E., Kieffer V., Streri A., et al. Neuropsychological outcome in children with optic pathway tumours when first-line treatment is chemotherapy. Br J Cancer. 2003;89:2038-2044.
25.
Moore BD, Ater JL, Copeland DRImproved neuropsychological outcome in children with brain tumors diagnosed during infancy and treated without cranial irradiation. J Child Neurol. 1992;7:281-290.
26.
von der Weid N., Mosimann I., Hirt A., et al. Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences. Eur J Cancer. 2003;39:359-365.
27.
Moleski M.Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol. 2000;15: 603-630.
28.
Copeland DR , Moore BD, Francis DJ, et al. Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study. J Clin Oncol . 1996;14:2826-2835.
29.
Bleyer WA, Fallavollita J., Robison L., et al. Influence of age, sex, and concurrent intrathecal methotrexate therapy on intellectual function after cranial irradiation during childhood: a report from the Children's Cancer Study Group. Pediatr Hematol Oncol. 1990;7:329-338.
30.
Balsom WR, Bleyer WA, Robison LL, et al. Intellectual function in long-term survivors of childhood acute lymphoblastic leukemia: protective effect of pre-irradation methotrexate? A Children's Cancer Study Group. Med Pediatr Oncol. 1991;19: 486-492.
31.
Constine LS, Konski A., Ekholm S., et al. Adverse effects of brain irradiation correlated with MR and CT imaging. Int J Radiat Oncol Biol Phys. 1988;15:319-330.
32.
Paakko E., Vainionpaa L., Lanning M., et al. White matter changes in children treated for acute lymphoblastic leukemia. Cancer. 1992;70:2728-2733.
33.
Copeland DR, deMoor C., Moore BD III, Ater JLNeurocognitive development of children after a cerebellar tumor in infancy: a longitudinal study. J Clin Oncol. 1999;17:3476-3486.
34.
Radcliffe J. , Bunin GR, Sutton LN, et al. Cognitive deficits in long-term survivors of childhood medulloblastoma and other noncortical tumors: age-dependent effects of whole brain radiation . Int J Dev Neuroscience. 1994;12:327-334.
35.
Walter AW, Mulhern RK, Gajjar A., et al. Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol. 1999;17:3720-3728.
36.
Cichowski K. , Shih TS, Schmitt E., et al. Mouse models of tumor development in neurofibromatosis type 1. Science. 1999 ;286: 2172-2176.
37.
Palmer SL, Gajjar A., Reddick WE, et al. Predicting intellectual outcome among children treated with 35-40 Gy craniospinal irradiation for medulloblastoma. Neuropsychology . 2003;17:548-555.
38.
Anderson VA , Godber T., Smibert E., et al. Cognitive and academic outcome following cranial irradiation and chemotherapy in children: a longitudinal study. Br J Cancer. 2000;82: 255-262.
39.
Spiegler BJ , Bouffet E., Greenberg ML, et al. Change in neurocognitive functioning after treatment with cranial radiation in childhood. J Clin Oncol. 2004;22:706-713.
40.
Ater JL, Moore BD, Francis DJ, et al. Correlation of medical and neurosurgical events with neuropsychological status in children at diagnosis of astrocytoma: utilization of a neurological severity score. J Child Neurol. 1996;11:462-469.
41.
Khong PL, Leung LH, Fung AS, et al. White matter anisotropy in post-treatment childhood cancer survivors: preliminary evidence of association with neurocognitive function. J Clin Oncol. 2006;24:884-890.
42.
Mukherjee P.Diffusion tensor imaging and fiber tractography in acute stroke. Neuroimaging Clin N Am. 2005 ;15:655-665, xii. Review.
43.
Wilde HE, McCauley S., Hunter JV, et al. Diffusion tensor imaging of acute mild traumatic brain injury in adolescents. Neurology. 2008;70:948-955.
44.
Krajinovic M., Robaey P., Chiasson S., et al. Polymorphisms of genes controlling homocysteine levels and IQ score following the treatment for childhood ALL . Pharmacogenomics. 2005 ;6:293-302.
45.
Savitz J., Solms M., Ramesar R.The molecular genetics of cognition: dopamine, COMT and BDNF. Genes Brain Behav. 2006;5: 311-328.
46.
Mattay VS, Tessitore A., Callicott JH, et al. Dopaminergic modulation of cortical function in patients with Parkinson's disease. Ann Neurol. 2002;51:156-164.
47.
Cools R., Stefanova E., Barker R., et al. Dopaminergic modulation of high-level cognition in Parkinson's disease: the role of prefrontal cortex and basal ganglia revealed by PET. Neuroimage. 2001;13:S652.
48.
Malhotra AK , Egan M., Lipsky RH, et al. The COMT Va1158Met polymorphism and human cognitive function. Biol Psychiatry.2002;51:95S.
49.
Malhotra AK , Kestler LJ, Mazzanti C., et al. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition . Am J Psychiatry. 2002;159:652-654.
50.
Bates JA, Goldman D., Malhotra AKCOMT and neurocognition: new evidence for a role in visual memory . Schizophr Res. 2003;60:123.
51.
de Frias CM , Annerbrink K., Westberg L., et al. COMT gene polymorphism is associated with declarative memory in adult-hood and old age. Behav Genet . 2004;34:533-539.
52.
de Frias CM , Annerbrink K., Westberg L., et al. COMT gene polymorphism is associated with cognitive functioning in adult-hood and old age. Behav Genet. 2004;34:635.
Kirsch DG, Tarbell NJNew technologies in radiation therapy for pediatric brain tumors: the rationale for proton radiation therapy. Pediatr Blood Cancer. 2004;42:461-464.
55.
Merchant TE , Mulhern RK, Krasin MJ, et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma . J Clin Oncol. 2004;22:3156-3162.
56.
Schneider U. , Lomax A., Lombriser N.Comparative risk assessment of secondary cancer incidence after treatment of Hodgkin's disease with photon and proton radiation . Radiat Res. 2000;154:382-388.
57.
Suit H.The Gray Lecture 2001: coming technical advances in radiation oncology . Int J Radiat Oncol Biol Phys.2002;53:798-809.
58.
Paganetti H. , Niemierko A., Ancukiewicz M., et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys. 2002;53:407-421.
59.
Doolittle ND , Anderson CP, Bleyer WA, et al. Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium. Neurooncol. 2001;3:46-54.
60.
Mabbott DJ, Spiegler BJ, Greenberg ML, et al. Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol. 2005;23:2256-2263.
61.
Baron I., Fennell EB, Voeller Kks.Pediatric Neuropsychology in the Medical Setting. New York, NY: Oxford University Press; 1995 .
62.
Searle NS, Askins M., Bleyer WAAdolescent cancer patients' perspectives on their educational experiences: ten case studies. Psychooncol. 2003;12:S78.
63.
Copeland DR, Askins MABehavioral medicine in cancer care. Pediatric Oncology. In: Chan K, Raney RB , eds. New York, NY: Springer Science and Business Media, Inc; 2005:244-255.
64.
Nathan PC, Patel SK, Dilley K., et al. Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group. Arch Pediatr Adolesc Med. 2007;161:798-806.
65.
Butler RWAttentional processes and their remediation in childhood cancer. Med Pediatr Oncol.1998;75-78.
66.
Butler RW, Copeland DRAttentional processes and their remediation in children treated for cancer: a literature review and the development of a therapeutic approach . J Int Neuropsychol Soc. 2002;8:115-124.
67.
Sohlberg MM, Mateer CAImproving attention and managing attentional problems. Adapting rehabilitation techniques to adults with ADD. Ann N Y Acad Sci.2001;931:359-375.
68.
Meichenbaum D.Cognitive-Behavior Modification: An Integrative Approach. New York, NY: Plenum Press; 2008 .
69.
Mabbott DJ, Noseworthy MD, Bouffet E., et al. Diffusion tensor imaging of white matter after cranial radiation in children for medulloblastoma: correlation with IQ. Neurooncology . 2006;8: 244-252.
70.
Mulhern RK, White HA, Glass JO, et al. Attentional functioning and white matter integrity among survivors of malignant brain tumors of childhood. J Int Neuropsychol Soc. 2004;10: 180-189.
71.
Thompson SJ , Leigh L., Christensen R., et al. Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer . J Clin Oncol. 2001;19: 1802-1808.
72.
Mulhern RK, Khan R., Kaplan S., et al. A randomized, double-blind, placebo-controlled trial of methylphenidate for attentional problems in survivors of childhood cancer. J Clin Oncol.2004;22:801S.
73.
Conklin HM, Khan RB, Reddick WE, et al. Acute neurocognitive response to methylphenidate among survivors of childhood cancer: a randomized, double-blind, cross-over trial. J Pediatr Psychol. 2007;32:1127-1139.
74.
Biederman J. , Swanson JM, Wigal SB, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study . Pediatrics. 2005;116:E777-E784.
75.
Rugino TA, Copley TCEffects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study. J Am Acad Child Adolesc Psychiatry . 2001;40:230-235.
