Recent research has demonstrated that survivors of childhood cancer are at risk for a myriad of late effects that affect physical and mental quality of life. We discuss the patterns and prevalence of neurocognitive problems commonly experienced by survivors of CNS tumors and acute lymphoblastic leukemia, the two most commonly researched cancer diagnoses. Research documenting the direct effects of tumor location and treatment type and intensity is presented, and patient characteristics that moderate outcomes (eg, age at diagnosis and sex) are discussed. Potential biologic mechanisms of neurotoxic treatment exposures, such as cranial irradiation and intrathecal and high-dose antimetabolite chemotherapy, are reviewed. Genetic, brain imaging, and neurochemical biomarkers of neurocognitive impairment are discussed. Long-term survivors of childhood cancer are also at risk for physical morbidity (eg, cardiac, pulmonary, endocrine) and problems with health behaviors (eg, sleep); research is reviewed that demonstrates these health problems contribute to neurocognitive impairment in survivors with or without exposure to neurotoxic therapies. We conclude this review with a discussion of literature supporting specific interventions that may be beneficial in the treatment of survivors who already experience neurocognitive impairment, as well as in the prevention of impairment manifestation.

PURPOSE Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT. METHODS Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups. RESULTS Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose ( P < .001) and boost margin ( P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed ( P = .003). CONCLUSION To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Purpose Compared with photon radiation (XRT), proton beam radiation therapy (PBRT) reduces dose to normal tissues, which may lead to better neurocognitive outcomes. We compared change in intelligence quotient (IQ) over time in pediatric patients with brain tumors treated with PBRT versus XRT. Patients and Methods IQ scores were available for 150 patients (60 had received XRT, 90 had received PBRT). Linear mixed models examined change in IQ over time since radiation therapy (RT) by RT group, controlling for demographic/clinical characteristics. Craniospinal and focal RT subgroups were also examined. Results In the PBRT group, no change in IQ over time was identified (P = .130), whereas in the XRT group, IQ declined by 1.1 points per year (P = .004). IQ slopes did not differ between groups (P = .509). IQ was lower in the XRT group (by 8.7 points) versus the PBRT group (P = .011). In the craniospinal subgroup, IQ remained stable in both the PBRT (P = .203) and XRT groups (P = .060), and IQ slopes did not differ (P = .890). IQ was lower in the XRT group (by 12.5 points) versus the PBRT group (P = .004). In the focal subgroup, IQ scores remained stable in the PBRT group (P = .401) but declined significantly in the XRT group by 1.57 points per year (P = .026). IQ slopes did not differ between groups (P = .342). Conclusion PBRT was not associated with IQ decline or impairment, yet IQ slopes did not differ between the PBRT and XRT groups. It remains unclear if PBRT results in clinically meaningful cognitive sparing that significantly exceeds that of modern XRT protocols. Additional long-term data are needed to fully understand the neurocognitive impact of PBRT in survivors of pediatric brain tumors.

Background We compared proton beam therapy (PBT) with intensity-modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity. Methods We reviewed records from 52 children treated with PBT (n=21) or IMRT (n=31) at two institutions in 1996−2012. Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity. Results At 59.6 months’ median follow-up ( PBT 33 mo vs. IMRT 106 mo, P < 0.001), the 3 year outcomes were 96% for OS, 95% for nodular failure-free survival (NFFS) and 76% for cystic failure-free survival (CFFS). Neither OS nor disease control differed between treatment groups (OS P=0.742; NFFS P=0.546; CFFS P=0.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs. 19% PBT, P=0.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT, P=0.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=0.009 and 0.04). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=0.017 and 0.024) dysfunction. Conclusions Survival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, as it contributes to late toxicity. Delaying RT until recurrence may result in worse visual and endocrine function.

Background ALL and brain tumor (BT) survivors are at risk for post-treatment IQ declines. The extent to which lower scores represent global cognitive decline versus domain-specific impairment remains unclear. This study examined discrepancies between processing speed and Estimated IQ (EIQ) scores and identified clinical characteristics associated with score discrepancies in a sample of pediatric cancer survivors. Procedure Survivors (50 ALL, 50 BT) ages 12–17 completed cognitive testing. The Wechsler Abbreviated Scale of Intelligence provided an untimed measure of general reasoning ability (EIQ). The age-appropriate Wechsler Intelligence Scale provided a Processing Speed Index (PSI) score. Scores were examined and compared. Results Survivors’ PSI scores were lower than their EIQ scores (BT t(45)=6.3, p<0.001; ALL t(49)=6.9, p<0.001). For BT survivors, lower PSI scores were associated with history of craniospinal irradiation, t(44)=3.3, p<0.01. For ALL survivors, lower PSI scores were associated with male gender, grade retention, and time since diagnosis, F(3,46)=10.1, p<0.001. Clinically significant EIQ-PSI score discrepancies were identified in 41.3% of BT and 14.0% of ALL survivors. Conclusions Many pediatric BT and ALL survivors exhibit slower processing speed than expected for age while general reasoning ability remains largely intact. Risk factors associated with larger EIQ-PSI discrepancies include: BT diagnosis, craniospinal irradiation (BT only), male gender and younger age at diagnosis (ALL only). Grade retention was frequent and associated with lower EIQ scores (both groups) and PSI scores (ALL only). Describing post-treatment cognitive declines using global measures of intellectual ability may underestimate dysfunction or fail to isolate specific underlying deficits contributing to impairment.

Objectives To describe the psychological needs of adolescent survivors of acute lymphoblastic leukemia (ALL) or brain tumor (BT), we examined: (a) the occurrence of cognitive, behavioral, and emotional concerns identified during a comprehensive psychological evaluation, and (b) the frequency of referrals for psychological follow-up services to address identified concerns. Methods Psychological concerns were identified on measures according to predetermined criteria for 100 adolescent survivors. Referrals for psychological follow-up services were made for concerns previously unidentified in formal assessment or not adequately addressed by current services. Results Most survivors (82%) exhibited at least one concern across domains: behavioral (76%), cognitive (47%), and emotional (19%). Behavioral concerns emerged most often on scales associated with executive dysfunction, inattention, learning, and peer difficulties. CRT was associated with cognitive concerns, χ2(1,N=100)=5.63, p<0.05. Lower income was associated with more cognitive concerns for ALL survivors, t(47)=3.28, p<0.01, and more behavioral concerns for BT survivors, t(48)=2.93, p<0.01. Of survivors with concerns, 38% were referred for psychological follow-up services. Lower-income ALL survivors received more referrals for follow-up, χ2(1,N=41)=8.05, p<0.01. Referred survivors had more concerns across domains than non-referred survivors, ALL: t(39)=2.96, p<0.01, BT: t(39)=3.52, p<0.01. Trends suggest ALL survivors may be at risk for experiencing unaddressed cognitive needs. Conclusions Many adolescent survivors of cancer experience psychological difficulties that are not adequately managed by current services, underscoring the need for long-term surveillance. In addition to prescribing regular psychological evaluations, clinicians should closely monitor whether current support services appropriately meet survivors’ needs, particularly for lower-income survivors and those treated with CRT.

Background and purpose This study examines attention, processing speed, and executive functioning in pediatric brain tumor survivors treated with proton beam radiation therapy (PBRT). Material and methods We examined 39 survivors (age 6–19 years) who were 3.61 years post-PBRT on average. Craniospinal (CSI; n = 21) and focal (n = 18) subgroups were analyzed. Attention, processing speed, and executive functioning scores were compared to population norms, and clinical/demographic risk factors were examined. Results As a group, survivors treated with focal PBRT exhibited attention, processing speed, and executive functioning that did not differ from population norms (all p > 0.05). Performance in the CSI group across attention scales was normative (all p > 0.05), but areas of relative weakness were identified on one executive functioning subtest and several processing speed subtests (all p < 0.01). Conclusions Survivors treated with PBRT may exhibit relative resilience in cognitive domains traditionally associated with radiation late effects. Attention, processing speed, and executive functioning remained intact and within normal limits for survivors treated with focal PBRT. Among survivors treated with CSI, a score pattern emerged that was suggestive of difficulties in underlying component skills (i.e., processing speed) rather than true executive dysfunction. No evidence of profound cognitive impairment was found in either group.

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