By 1980, 24 Gy CRT for children with ALL resulted in 5-year survival rates of over 50 % [26]. As survival rates increased, so did reports of cognitive difficulty among survivors. In a meta-analysis conducted during the late 1970s to 1987, Cousens et al. [26] reported 16 of 31 studies showed significant deficits in IQ among irradiated patients. Further, in their review of 21 studies meeting criteria for having a healthy control group with both baseline and repeated full-scale IQ measurement, they found a 10-point average reduction in IQ from baseline. Presently only those children who are considered high risk ALL are treated with CRT, and modern dose levels have been reduced from 24 to 18 Gy. Despite reduced levels of CRT, reductions in global IQ are reported, with one study reporting a loss of 3.65 IQ points per year treated with 18 Gy CRT [64]. Declines have been reported on measures of visuomotor integration, processing speed, attention, and immediate memory [65]. In some studies, verbal and language abilities appear to less likely decline [66].

Effect of CRT Dose Reduction. Moore et al. [67] compared two groups of children aged 9–14 years who were treated with a similar protocol of corticosteroids and two doses of intrathecal methotrexate (IT MTX); however, one group was administered 24 Gy of CRT, the other with 18 Gy CRT. Both groups were in the average range on measures of full-scale, performance, and verbal IQ (utilizing the Wechsler Intelligence Scale for Children—WISC). The mean full-scale IQ of the 24 Gy group was ten points below the average of the 18 Gy group, largely due to a reduction on verbal subtests. Scores on the Beery-Buktenica Visual-Motor Integration Test (VMI) were similar in both groups, each ranking within the lower third of the normative sample. On a measure of academic performance, the Wide Range Achievement Test (WRAT), those who received 24 Gy scored ten points lower than the 18 Gy group on measures of spelling, arithmetic, and reading. All standard scores (SS) on the WRAT were in the average range with the exception of the arithmetic subtest, which was below average (SS = 85.83). However, time-since-treatment appeared to have the largest effect size in this study. When the authors used time-since-treatment (within 2-months or greater than 2-months) as a covariate, the dose of CRT did not have a significant effect on IQ, academic functioning, or visual-motor integration.

When compared directly to chemotherapy-only regimens, a recent meta-analysis of 28 empirical studies between 1980 and 2004 demonstrated uniformly lower IQ, academic and neurocognitive (including fine motor, memory, processing and visuospatial) scores in all treated children regardless of treatment. Effect sizes in nine neurocognitive domains ranged from −0.34 to −0.71. All groups receiving CRT performed more poorly than those that did not. Reductions in memory ability as well as academic achievement were also more pronounced relative to chemotherapy only. However, inconsistent impairment across studies and other moderating variables limited the conclusions of the differential impact of CRT [68].

Administration of CRT in conjunction with IT-MTX resulted in 70 % survival rates by the mid-1990s [21]. In a study of demographically matched children aged 7–16 years at least 2 years post-treatment, Anderson et al. [21] compared a group receiving CRT + MTX and a group receiving methotrexate alone. Results showed group differences across intellectual and academic domains. Mean IQ scores in both groups were in the average range. Differences between the groups were mild but significant, with the most significant reductions in the CRT + MTX group on verbal subtests and those tapping attentional skills, such as Digit-Span. Compared to the chemotherapy alone group, the CRT + chemotherapy group were generally 10 points lower on reading, spelling, and mathematical tests, with all scores in the below average range.

In a 7 year follow-up of 201 children receiving a standardized chemotherapy regimen which included corticosteroids and MTX, plus 18 Gy of CRT, an 82 % overall survival rate was reported after 5 years. Among the survivors, performance on measures of intellectual ability and memory were in the average range. However, 51 % of these children had low performance on the Rey Complex Figure Copy task, suggesting difficulties with executive function, particularly organization and management of complex novel information [69].

When chemotherapy is used without CRT, there is some degree of variability in the literature in terms of cognitive outcome. This is to be expected due to the use of different treatment protocols, which also combined glucocorticoids and multiple anti-metabolites [62]. It is more common now than in the past to use one chemotherapy agent, typically MTX. In terms of cognitive effects during the acute phase of treatment, motor speed and working memory are the most commonly affected cognitive domains [62, 70]. Long-term changes among children 2–5 years post remission have shown no lasting deficits in IQ, but negative trends do occur consistently in domains of visuomotor integration and math ability. IQ typically remains average relative to controls [71]. Among the anti-metabolites, MTX is thought to be the most damaging to the CNS, and to white matter tracts in particular [72]. MTX has been shown to reduce cerebral glucose metabolism, resulting in cellular damage and demyelination [72, 73]. As the peak age of ALL onset occurs during a sensitive period of brain myelination within the prefrontal cortex, the timing of MTX administration and brain maturation are one explanation for reductions in frontal white matter and associations with executive deficits [71]. The relationship between cognitive deficits and methotrexate appears to be dose-dependent. Both the number of doses and cumulative dose has been associated with deficits in visuomotor and global IQ reductions [62]. The proposed effect of MTX to vascular structures will be reviewed briefly in the section on radiological findings.

Glucocorticoids inhibit glucose metabolism/utilization by neurons and glia resulting in an increase of glutamate, causing neural excitotoxicity and cell death. Neural toxicity occurs regularly in the hippocampus (a high-concentration corticosteroid binding site) [74]. Thus, it is not surprising that memory deficits result as a late effect of treatment with glucocorticoids [75]. There are differences in CNS affinity among glucocorticoids. Dexamethasone more readily penetrates the CNS and has a longer half life than prednisone and prednisolone [76]. Waber et al. report poorer memory and visuospatial organization in children treated with dexamethasone instead of prednisone [75].

Overall, neurocognitive deficits are common, but vary from mild to severe, and are moderated by a number of variables related to the patient (i.e., age and gender) and the treatment protocol (i.e., level of methotrexate and/or use and dose of CRT).

Moleski [80] conducted the most extensive review of studies conducted in the 1980s and 1990s of ALL patients treated with IT MTX and/or CRT. Two thirds of the 33 studies found declines in one or more areas of intellectual functioning in ALL patients treated with CNS prophylaxis chemotherapy and/or CRT [80]. Roughly half of the studies employed some healthy control group including siblings or non-CNS cancer patients. Several studies reported no differences between ALL patients receiving MTX with or without CRT though all studies using siblings as controls reported significant lower scores in ALL patients. These studies highlight the need to employ matched controls as opposed to reliance on normative data from the test manual [80]. In the best well-controlled studies [81], ALL patients demonstrated an average of 12 points lower than siblings and non-CNS cancer groups. The latter finding is also significant as non-CNS control groups often still endure the disruptions of day-to-day life and education seen in ALL children and these types of controls aid in our understanding of the impact these disruptions may have on IQ and cognitive development, if any.

Langer, Martus, Ottensmeier, Hertzberg, Beck, & Meier [82] investigated the long term outcomes of ALL children treated with either the German BFM-ALL (ALL-relapse-Berlin/Frankfurt/Münster-Study-Group) or COALL (Cooperative study with modified BFM protocols) protocols. The subjects were medium and standard risk patients and were divided into MTX only and MTX with CRT. Patients with encephalitis, secondary malignancies and preexisting neurological or mental health conditions were excluded. Participants included 121 patients (63 females) who were off-therapy for at least 4.5 years (mean = 7.2 years, maximum = 10.6 years). The average age at initial diagnosis was 5.8 years (range = 0.3–16.1 years), the age at investigation was 14.8 years (range = 8.0–27.8 years). No pretreatment data were available for comparison. Subjects were administered the Hamburg-Wechsler Intelligence Scale for Children-Revised in addition to several other neurocognitive measures. Results indicated that patients in the MTX + CRT group scored 8.7 points lower on the Full Scale IQ (FSIQ) than patients receiving MTX alone (109.9 vs. 101.2). Significant differences also were found with the Verbal IQ (VIQ) (7.4 points), Freedom from Distractibility (8.6 points) and non-significant (but similar magnitude) in the Performance IQ (PIQ) (8 points). All results indicated higher performance in the MTX only group. CRT had a differentially negative impact on males in this study. Males with MTX only scored 17 points higher on FSIQ than males with MTX + CRT (115.6 and 98.6, respectively). No gender differences were seen in corresponding female samples. No relationship was found between the amount of CRT (range 12–18 Gy) nor the amount of MTX (range 26 and 156 mg). Results support the conclusion that preventive CRT usage is associated with lower (though still average) IQ scores compared to MTX alone.

The presence of comparison groups is critical as declines in overall IQ scores are modest and often continue to fall in the average range. Waber et al. [69] evaluated children treated for high-risk ALL on the Dana-Farber Cancer Institute Protocol 87–01, which included 18-Gy CRT as a component of CNS treatment. Their results indicated excellent 5-year overall survival (82 %) and disease recurrence (<1 %) rates in the CNS. WISC-III scores 7 years after diagnosis were generally average (FSIQ = 98–102) and did not vary based on age at diagnosis, gender, or MTX dosing. However, no pre-treatment data, sibling control or chemotherapy only groups were utilized.

In a recent study conducted in Norway, Lofstad, Reinfjell, Hestad & Diseth [83] examined the long-term impact of 35 ALL children treated with chemotherapy (NOPHO-ALL 1992 Protocol) only. Inclusion criteria allowed for examination of a small group of high-risk children and apart from severity and age, most other factors were controlled yielding a homogenous sample of ALL children. Normal controls (N = 35) were recruited for comparison and matched for age, gender and SES. However, no pre/post treatment data were collected on the ALL children. Results indicated significantly lower scores for the ALL group on six of the seven WISC-III scales including Full Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ), Vverbal Comprehension Index (VCI), Perceptual Organization Index (POI) and Freedom from Distractibilty Index (FDI) and Processing Speed Index (PSI). The POI also trended lower. ALL children were 9–16 IQ points or more below healthy controls, though all mean scores fell within the average range except the PSI (SS = 88.8). The authors note the high correlations between global measures within the entire sample, which suggests lower overall cerebral functions. Thus, the majority of the lower scores on subtests are the result of deficits in higher mental or frontal lobe functions, which the authors contend may represent a shared factor. However, processing speed was also significantly lower in the ALL group and was not significantly correlated with global measures in the ALL group and could represent a focal deficit related to chemotherapy in this study. No comparison of risk groups with ALL on WISC-III scores was made [83].

Kingma, et al. [84] conducted one of the few studies utilizing MRI, serial neuropsychological evaluations at 3 months following treatment and then 5 years later. In addition, MRIs were conducted at the 5-year follow-up. Parents of these children also were asked to completed questionnaires of school performance for their ALL child and their siblings at the 10-year post treatment mark. Forty-five (45 %) of the children completed both evaluations. Seventeen (17) received chemotherapy only and 28 received chemotherapy and CRT. The healthy controls consisted of 225 community-recruited children matched for age, SES and geographic region. The CRT group had lower scores than the MXT group on all measures. However, neither the CRT nor MTX-only group had significant changes in IQ scores from time one to time two. In addition, 63 % of the CRT children showed MRI abnormalities as opposed to 38 % of MTX-only treatment. Finally, school performance rating scales indicated no difference between MTX-only group and their siblings; but significant differences between CRT and siblings were noted with the CRT group scoring lower. When compared to themselves, no differences in FSIQ were noted (MTX-only 103.6 and healthy controls 107.0) in the MTX-only group at follow up [84]. These findings suggest that baseline data and serial follow-up studies may be more useful in quantifying actual loss in IQ from late-stage effects of cancer-related treatments.

In one of the largest study to date on neuropsychological outcomes of ALL, Halsey et al. [85] assessed 866 children (555 patients and 311 controls). No significant differences were seen between patients and healthy controls at baseline. However, significant differences were seen between groups at 3 years (ALL = 97.7 and Controls = 104.8) and at 5 years (ALL = 100.0 and Controls at 105.3). It is worth noting, however, that ALL patients showed no appreciable drop in IQ scores from baseline (5 months) to the 5-year mark. The investigators were also able to compare low risk ALL randomized to IT MTX or high dose systemic MTX at 3-year and 5-year intervals and no significant differences were noted. High risk ALL patients were treated with IT MTX and then randomized into additional treatment using high dose systemic MTX or CRT. No differences were seen between groups in the high-risk sample though larger differences (favoring high dose MTX) were seen. All IQ scores at all points in time were in the average range. There were no gender differences seen in either the high or low risk groups in this study and the impact of age at the time of onset treatment (above or below 5 years) was associated with higher probability of IQ score under 80 (17 vs. 7 %). The authors predicted that improvements in neuropsychological outcomes for children with ALL would depend more on the individualized therapy for children at high risk of CNS morbidity than on avoidance of specific CNS-directed therapy regimens in unselected patient cohorts [85].

Several studies have looked at subjective and objective measures of academic functioning in children with ALL treated with chemotherapy with and without CRT. Many of these studies also included IQ measures. Early studies found specific deficits in areas of arithmetic [86]. However, unlike innate abilities, academic skills also can be affected by the multiple life stressors associated with cancer treatment such as frequent hospitalizations, protracted medical treatment, fatigue, etc. Many of the complications surrounding treatment of ALL co-occur with the child’s initial foray into the school setting with average diagnoses coming at or near kindergarten.

Anderson et al. [21] attempted to control for the impact of life stress from cancer treatment in general through the inclusion of a non-CNS cancer group in their study of 100 children with ALL treated with MTX and CRT (18–24 Gy). Fifty [53] children with acute myeloid or lymphoblastic leukemia, or non-CNS tumor treated with chemotherapy alone and 100 healthy controls stratified to control for demographic factors including SES were assessed. All subjects were administered the WISC-R, Wide Range Achievement Test (WRAT) and Child Behavior Checklist (CBCL). Significantly lower FSIQ were found in the IT MTX + CRT group (SS = 94.9, SD = 13.1) from the MTX only cancer group (SS = 102.3, SD = 13.5) or healthy controls (SS = 101.7, SD = 12.3). As with other studies, FSIQ was still within the average range for all groups. However, WRAT scores for the IT MTX + CRT were significantly lower in all areas (Reading, Spelling and Math) than either the non-CNS cancer or healthy control groups. In addition, all three domains fell into the low average range (Reading SS = 88.0, Spelling SS = 87.8, Math SS = 88.3). The other groups averaged nearly 10 points higher in all areas. The authors concluded that children treated with chemotherapy alone (with or without CNS involvement) showed no declines in IQ or academics [21]. Finally, CBCL data comparing the two cancer groups revealed significantly higher scores on measures of anxiety, social functioning and attention problems and significantly lower scores on school functioning compared to healthy controls. Overall, these findings did suggest lower academic functioning and increased psychosocial stress in children treated with MTX and CRT compared to cancer and healthy controls. The inclusion of the chemotherapy-only cancer group also suggests these differences could not be explained by life stressors alone. Findings indicate children treated with non-CNS chemotherapy did not differ from normal controls.

While Anderson et al. [21] collapsed children receiving 18 and 24 Gy CRT, other authors [87] evaluated the impact of higher dose CRT on WISC-R and WRAT scores in ALL compared to a cancer control group (Wilms’ tumor). Children receiving the 18 Gy dose scored significantly higher than the 24 Gy group and at the same level as cancer control groups. In fact, the 18 Gy group and cancer control group average 10–15 points higher an all IQ and academic measures. The 24 Gy group fell into the low 90s on all scores except Math, which was a mean standard score of 86 [87]. Sample sizes were small but results suggested significant differences based on level of whole brain CRT on all IQ and academic measures. Other authors using larger samples [88] did not find declines in overall IQ comparing 18 and 24 Gy children; however, academic performance was not considered.

Brown et al. [89] conducted a prospective analysis of 38 ALL/AML children treated with IT MTX (Australia–New Zealand Children’s Cancer Study Group Protocols) to 25 matched non-CNS cancer children treated with a variety of protocols not involving IT MTX. Subjects were between 2–15 years old at time of treatment and follow up was conducted over 3 years. This study is unique in that no differences were found between age, gender, father’s occupational rating, or survival rates. In addition, attendance was tracked throughout the study to provide an estimate of the impact or CNS and non-CNS prophylactic cancer treatment. Subjects receiving IT MTX missed more days of school in the 3-year period, with significant differences in year 2 accounting for most of the days missed. The increased absentee rate is due to the longer duration of IT MTX treatment protocols and suggests a longer active state of potential neurotoxic impact. Full Scale IQ estimates based on (McCarthy Scales of Children’s Abilities and WISC-R) increased slightly from baseline to year 3 in the non-CNS group (SS = 106.7 to 116.2) but not for the CNS group (SS = 106.6–105.1). This trend was true for the Verbal and Performance scales as well. Academic achievement was assessed using the WRAT-R. Non-CNS subjects showed similar level and patterns of improvement over time from baseline (Reading SS = 102.6, Spelling SS = 99.7; Arithmetic SS = 99.5) to year 3 (Reading SS = 112.7; Spelling SS = 107.6; Arithmetic SS = 101.4). The reverse trend was seen in the CNS group from baseline (Reading SS = 114.3, Spelling SS = 110.0; Arithmetic SS = 107.1) to year 3 (Reading SS = 94.0; Spelling SS = 92.4; Arithmetic SS = 87.0). Thus, while no declines was seen in any IQ scales over time, the CNS group showed significant declines in the rate of academic achievement and by year 3 and were approximately one standard deviation below their non-CNS peers. The authors concluded that the prolonged nature of IT chemotherapy treatment and insidious neurotoxicity of the treatment were possible factors in the declining performance in academics over time. This study highlights the need for aggressive tutoring in early and late stages of cancer treatment [89]. These authors provided year 4 data in a 1998 study on these same children [90]; however, samples sizes were much smaller for both groups. Results continued to suggest a near one standard deviation drop in academics in the CNS group.

Problems with attention have been consistently reported among the late cognitive effects of pediatric ALL. However, the precise nature of attentional dysfunction has been difficult to characterize, likely due to different assessment techniques across studies. Some studies have attempted to categorize the attention deficits in ALL survivors according to DSM-IV criteria for ADHD, while other studies have utilized a more in-depth cognitive battery to assess sub-domains of attention, such as working memory and processing speed.

Kahalley et al. [91] assessed a group of 100 survivors of childhood cancer (50 ALL, 50 Brain Tumor), ranging from ages 12–17. The authors sought to determine the percentage of the sample, which would be classified as having a DSM-IV diagnosis of ADHD or Secondary ADHD. Participants were given a structured clinical interview, the Conners’ Continuous Performance Test (CPT), and behavior rating scales. Nine out of 100 survivors met criteria for ADHD or Secondary ADHD. Of these, eight out of nine were characterized solely by inattentive symptoms. On the Conners’ CPT, slow response time (Hit RT) was significantly slower among survivors meeting criteria for ADHD. However, the authors note that elevated ratings on behavior scales were common throughout the entire group of ALL survivors, including those not meeting a formal ADHD diagnosis. The authors conclude that a DSM diagnosis of ADHD is not useful for characterizing the deficits found in those childhood cancer survivors. Anderson & Mullens [92], in their review of the aforementioned study, agree with the conclusion that it is inaccurate to liken the late effects seen in survivors of ALL to the diagnosis of ADHD. They note that key differences in etiology between late effects and ADHD appear to lead to different expectations in terms of symptom severity, prognosis, and treatment.

Schatz et al. [93] used a measure of broad cognitive functioning (Kaufman Brief Intelligence Test [K-BIT]) and stand-alone measures of processing speed (PS) and working memory (WM) in children following CRT + chemotherapy and chemotherapy alone. Twenty-seven participants age 9 or older in at least 30 months of continuous remission were matched by age and gender to 27 healthy controls. Fifteen received 18 Gy of CRT in addition to a chemotherapy regimen, three received 24 Gy, and nine received chemotherapy only. Working memory deficits were most profound in the CRT group when compared to age matched healthy controls. The chemotherapy only group was found to have lower WM, PS, and over all IQ compared to controls, though not to the degree of the CRT group. The difference between the CRT and chemotherapy group in overall IQ was accounted for primarily by reduced working memory scores. Processing speed did not fully account for the differences, suggesting a moderating effect of CRT directly on working memory ability. Working memory difficulties were found primarily on tasks requiring verbal span and spatial span while including interference, with intact performance on verbal span without interference. Thus, all spatial tasks and verbal tasks with interference appeared to characterize the working memory deficit. Studies, which utilize neuroimaging, have recently found a relationship between white matter changes in the right hemisphere and reductions in attention and spatial abilities [71].

In terms of treatment for the attention-related late effects of pediatric ALL, there is some evidence to support the use of methylphenidate (MPH). Mulhern et al. [65] studied the short-term effect of methylphenidate at 3 weeks in a randomized, double blind, placebo controlled trial among survivors of childhood cancer. Results indicated significant improvements across teacher and parent reports of attention and cognition. The low dose of MPH on the Conners’ Parent and Teacher Rating Scales inattention and cognitive problems index resulted in effect sizes of 0.42 and 0.62, respectively. The moderate dose yielded effect sizes of on symptoms of inattention (0.52) and cognitive problems (0.53) on the Conners’ Parent and Teacher Rating Scales. On the social skills rating scales, no change was found on the parent report. However, on the teacher report, effect sizes were reported on indices of social skills (LD = 0.49, MD = 0.68), problem behaviors (LD = NS, MD = 0.37), and academic competence (LD = .55, MD = .73). Side effects were tolerated among most of the sample, with symptoms including irritability, crying, and hyper vigilance. Five percent of the sample had dose-limiting side effects, and tended to be those in the brain tumor group.

Conklin et al. [94] studied the long-term effectiveness of MPH over a 12-month period. Though effect sizes were not reported, significant differences were reported in a MPH group on CPT indices, parent teacher and self-report ratings of attention, and parent ratings of social and behavioral problems. On the Conners’ CPT, significant differences within the MPH group were found on omissions, Hit reaction time, Reaction time variability, and d′ (difference between the signal and noise distributions, a measure of the ability to distinguish and detect targets from non-targets). When compared to the clinical control group, significant improvement from baseline was found on the overall CPT index, reaction time variability, d′, and commissions.

Mulhern and Butler [95] suggest that metacognitive strategies, which teach children to monitor their own thinking approach may be useful in improving attentional processes in survivors of ALL, based upon promising studies, which have utilized this approach in children with brain injuries. Contingency management, problem solving skills training, social skills training, relaxation training, anger management and working with parents are components of metacognitive strategies. Please see Chap. 27 for a more detailed review of cognitive remediation strategies for survivors of cancer.

There have been few studies that have investigated the impact of fine and gross motor skills in children with ALL. Many of these studies are limited in terms of sample sizes [96–98]. However, deficits in fine motor abilities, tactile-perceptual skills, and perceptual-motor skills are consistent findings across outcome literature [99–103]. However, many of these studies are limited by the length of longitudinal follow up data points.

Hockenberry et al. [104] conducted a longitudinal study with ALL children with low, standard and high-risk protocols. A total of 82 children participated in repeated neuropsychological testing including IQ, the Developmental Test of Visual-Motor Integration (VMI) and Purdue Pegboard Test. Testing was conducted at baseline and years 1 and 2 of treatment. Mean age at baseline was 7.2 years. Results indicated significant reductions in fine motor speed at baseline in chemotherapy treated patients regardless of risk protocol and these deficits persisted through the 2 years of the study. In addition, visual-motor integration deficits were not evident at baseline but emerged by year 1 and continued to decline at year 2. These deficits were not related to overall declines in IQ; but VMI scores were correlated with baseline deficits on the Purdue Pegboard Test, suggesting fine motor speed deficits related to vincristine and methotrexate toxicity. Acute changes in white matter were proposed as the causal factor in fine motor and VMI deficits in ALL and may suggest specific points of intervention for children during and after treatment [104].

To evaluate the long-term impact, Copeland et al. [97] conducted a study of 99 children (51 received IT chemotherapy, 48 treated systemically with chemotherapy) with various types of cancers who did not receive CRT. These children were evaluated on 4 occasions during and after treatment with long-term follow up as late as 5–11 years post diagnosis. Gender, age, ethnicity and SES were included in the analyses. A full battery of neuropsychological tests was administered at each assessment period. Fine motor control and speed (Finger Tapping and Grooved Pegboard) were assessed along with visuomotor integration (VMI). Results indicated that IT chemotherapy group showed significant declines in VMI scores relative to the non-CNS chemotherapy group at early (<3 years) and late (5–11 years) stages. These results were present even when SES was controlled. In addition, younger age of diagnosis was associated with increased impairment in VMI scores. However, while these differences in VMI scores were robust when other demographical and medical variables were controlled, the overall scores were still within the average range.

Studies of executive functioning (EF) in children with ALL have frequently focused on aspects of working memory, behavioral inhibition, self-monitoring, and mental flexibility using a variety of instruments. In a meta-analysis conducted by Campbell et al. [68], researchers found differences between groups on objective measures of working memory (WISC-IV/WAIS-III WMI); but not on measures from the D-KEFS, including Color-Word Interference, Sorting Test and Tower Test. In addition, subjective complaints of EF deficits were obtained by parent completed Behavior Rating Inventory of Executive Functions (BRIEF) scales and no differences between groups were found. ALL children scored within the average range on all measures, though a modest effect size (Cohen’s d = −0.75) was found on the WMI of the WISC-IV/WAIS-III.

In the Copeland et al. [101] study, serial assessments of ALL children treated with IT chemotherapy were completed at baseline and three subsequent intervals. Patients with ALL or lymphomas and IT chemotherapy (N = 51) were compared to other cancer groups treated systemically (N = 48). Measures of phonemic fluency and Trails A and B were completed. Patients with CRT were eliminated from the study. Results from the long term (5–11 years) follow up indicated no significant differences in EF measures used between groups at baseline or any follow up point. However, among those patients from either group, a modest decline in EF skills was noted over time with both groups declining slightly less than 0.5 SD over the ≥5 interval. No other interactions with other demographic variables were found [101].

A chemotherapy-only, prospective study of children with ALL was conducted by Kingma et al. [25] in which some specific measures of EF were included. Twenty patients underwent a series of three evaluations with a median range of follow up lasting 7 years. Results from the ALL patients were compared to a cohort of 225 Dutch control students demographically matched. Results indicated that the ALL group scored in the normal range and did not differ significantly from the NC group on Trails A & B. However, by the third evaluation, the ALL group scored significantly lower than NC on Trails B (NC = 38.2 s, ALL = 47.0 s, p = 0.009) and 3 out of 20 patients scored below the 5th percentile on the test. No significant demographic factors were noted. Although limited in subject size and test selection, declines were evident in EF from baseline. All other neuropsychological measures in this study were non-significant except a slight drop in VIQ on the WISC-R [25].