As survival among children treated for cancer continues to improve, more attention is being focussed on the late effects of cancer treatment. In children treated for brain tumours, chronic neurocognitive effects are especially challenging. Deficits in cognitive development have been described most thoroughly among children treated for posterior-fossa tumours, specifically medulloblastomas and ependymomas, which account for about 30% of all newly diagnosed cases of brain tumours in children. Most children who have survived brain tumours have required surgical resection and focal or craniospinal radiotherapy (irradiation of the entire subarachnoid volume of the brain and spine), with or without systemic chemotherapy. Historically, intelligence quotient (IQ) scores have provided a benchmark against which to measure changes in cognitive development after treatment. Observed declines in IQ are most likely a result of failure to learn at a rate that is appropriate for the age of the child, rather than from a loss of previously acquired knowledge. The rate of IQ decline is associated with a several risk factors, including younger age at time of treatment, longer time since treatment, female sex, as well as clinical variables such as hydrocephalus, use of radiotherapy and radiotherapy dose, and the volume of the brain that received treatment. Loss of cerebral white matter and failure to develop white matter at a rate appropriate to the developmental stage of the child could partly account for changes in IQ score. Technical advances in radiotherapy hold promise for lowering the frequency of neurocognitive sequelae. Further efforts to limit neurocognitive sequelae have included design of clinical trials to test the effectiveness of cognitive, behavioural, and pharmacological interventions.

Late neurocognitive sequelae in survivors of brain tumours in childhood.

Survivors of childhood and adolescent cancer are one of the higher risk populations seen by health care professionals. The curative therapy administered for the cancer also affects growing and developing tissues. Following chemotherapy, radiation therapy, and surgery, many survivors will experience chronic or late-occurring health problems, often not becoming clinically apparent until decades after therapy. Survivors face an increased risk of morbidity, mortality, and diminished quality of life associated with their previous cancer therapy. Risk is further modified by the survivor's genetics, lifestyle habits, and comorbid health conditions. Over their lifetime, survivors will see health care professionals from an array of specialties and disciplines. The aim of this review is threefold: (1) to convey a sense of the risk faced by survivors to clinicians unfamiliar with the population; (2) to provide an up-to-date tool for clinicians, regardless of specialty or discipline, when providing care for a survivor; and (3) to complement the recently completed recommendations for screening, prevention, and management of childhood cancer survivors.

Long-term Complications Following Childhood and Adolescent Cancer: Foundations for Providing Risk-based Health Care for Survivors

Purpose This prospective, longitudinal study examined the effects of risk-adapted craniospinal irradiation (CSI) dose and the interactions of dose with age and time from diagnosis on intelligence quotient (IQ) and academic achievement (reading, spelling, and math) among patients treated for medulloblastoma (MB). Patients and Methods Patients received serial neurocognitive testing spanning from 0 to 6.03 years after diagnosis (median, 3.14 years). The multi-institutional study included 111 patients, who were 3 to 20 years of age at diagnosis (median age, 7.4 years), treated for MB with risk-adapted CSI followed by four cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, and vincristine) with stem-cell support. High-risk patients (HR; n = 37) received CSI to 36 to 39.6 Gy and conformal boost treatment of the primary site to 55.8 to 59.4 Gy. Average-risk patients (AR; n = 74) received CSI to 23.4 Gy and conformal boost treatment of the posterior fossa to 36.0 Gy and primary site to 55.8 Gy. Result...

Neurocognitive Consequences of Risk-Adapted Therapy for Childhood Medulloblastoma

To assess neurocognitive functioning in adult survivors of childhood Central Nervous System (CNS) malignancy, a large group of CNS malignancy survivors were compared to survivors of non-CNS malignancy and siblings without cancer on a self-report instrument (CCSS-NCQ) assessing four factors, Task Efficiency, Emotional Regulation, Organization and Memory Additional multiple linear regressions were used to assess the contribution of demographic, illness, and treatment variables to reported neurocognitive functioning in CNS malignancy survivors and the relationship of reported neurocognitive functioning to socioeconomic indicators Survivors of CNS malignancy reported significantly greater neurocognitive impairment on all CCSS-NCQ factors than non-CNS cancer survivors or siblings (p < 01) Within the CNS malignancy group, medical complications (hearing deficits, paralysis and cerebrovascular incidents) resulted in a greater likelihood of reported deficits on all CCSS-NCQ factors Total or partial brain irradiation and ventriculoperitoneal (VP) shunt placement was associated with greater impairment on Task Efficiency and Memory Female gender was associated with a greater likelihood of impaired scores on Task Efficiency and Emotional Regulation, while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p < 01), less household income (p < 001), less full time employment (p < 001), and fewer marriages (p < 001) Survivors of childhood CNS malignancy were found to be at significant risk for neurocognitive impairment that continues to adulthood and is correlated with lower socioeconomic achievement

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Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study.

Purpose To evaluate academic and behavioral outcome in radiated survivors of posterior fossa (PF) tumors. Patients and Methods Fifty-three patients (36 males) treated for malignant PF tumors were seen for evaluation of academics and/or behavioral functioning. Forty-six patients were treated for medulloblastoma, and seven patients were treated for ependymoma. Fourteen patients were treated with reduced-dose cranial radiation, and 34 patients were treated with standard-dose cranial radiation (dose was not available for four patients). All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized achievement tests and behavioral questionnaires were administered at different times after diagnosis for each child. First, the influence of demographic and medical variables on outcome was examined. Second, the rate of change in scores was determined using mixed model regression for patients seen for serial assessment. Results The presence of hydrocephalus was rel...

Serial Evaluation of Academic and Behavioral Outcome After Treatment With Cranial Radiation in Childhood

BACKGROUND

The primary objective of this study was to test the hypothesis that, among survivors of pediatric brain tumors, the association between reduced volumes of normal-appearing white matter (NAWM) and intellectual/academic achievement deficits can be explained by patient problems with memory and attention.



METHODS

Quantitative tissue volumes from magnetic resonance imaging scans and neurocognitive assessments were obtained for 40 long-term survivors of pediatric brain tumors. They were treated with radiotherapy (RT) with or without chemotherapy 2.6–15.3 years earlier (median, 5.7 years) at an age of 1.7–14.8 years (median, 6.5 years). Neurocognitive assessments included standardized tests of intellect (intelligence quotient [IQ]), attention, memory, and academic achievement.



RESULTS

Analyses revealed significant impairments in patients' neurocognitive test performance on all measures. After statistically controlling for age at RT and time from RT, significant associations were found between NAWM volumes and both attentional abilities and IQ, and between attentional abilities and IQ. Subsequent analyses supported the hypothesis that attentional abilities, but not memory, could explain a significant amount of the relationship between NAWM and IQ. The final developmental model predicting academic achievement based on NAWM, attentional abilities, and IQ explained approximately 60% of the variance in reading and spelling and almost 80% of the variance in math.



CONCLUSIONS

The authors demonstrated that the primary consequence of reduced NAWM among pediatric patients treated for brain tumors was decreased attentional abilities, leading to declining IQ and academic achievement. Cancer 2003;10:2512–9. © 2003 American Cancer Society.



DOI 10.1002/cncr.11355

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.11355

Laurie Leigh

Papers

Developmental model relating white matter volume to neurocognitive deficits in pediatric brain tumor survivors.