Neurocognitive domain
Intellectual/global cognitive functioning
Academic achievement
Visuospatial and motor
Attention and working memory
Memory
Processing speed
Executive functioning
Measurement instrument
WISC Full Scale IQ
WJ-Achievement
WISC Perceptual Reasoning Index
WISC Working Memory Index
CVLT
WISC Processing Speed Index
DKEFS subtests
WAIS Full Scale IQ
WIAT
Beery VMI
Conners CPT
CMS
WJ-Cognitive Processing Speed/Cognitive Efficiency
Trail Making Test B
WJ-Cognitive General Intellectual Ability
WRAT
Pegboard Tests (various)
Digit span tasks (various)
WMS
Trails Making Test A
Verbal fluency tasks (various)
30.3.1 Neurocognitive Functioning
With regard to neurocognitive changes associated with PBT treated with RT, changes in overall intellectual functioning have been well documented. A recent meta-analysis by de Ruiter et al. (2013) examined intellectual functioning in PBT patients relative to normative samples and showed moderate to large effect sizes for estimates of global, verbal, and visuo-perceptual intellectual abilities on the WISC-III. Research estimates a 2–4 point decline in IQ per year in the first 4 years post-treatment, with steeper declines shortly following treatment and some plateauing thereafter (Spiegler et al. 2004). Older children (mean age at diagnosis = 11 years) have been shown to evidence a delay before declines in IQ performance are apparent, whereas younger children (mean age at diagnosis = ~6 years) have been shown to evidence early declines followed by later stabilization (Palmer et al. 2003); however, longer follow-up is needed to fully understand this pattern. Neurocognitive declines in IQ as well as other specific cognitive domains typically reflect a slowed rate of skill acquisition relative to healthy peers rather than loss of existing abilities.
With respect to specific neurocognitive skills beyond IQ, much of the brain tumor literature has focused on measures of attention, processing speed, and executive functions in the assessment of short- and long-term neurocognitive deficits. In fact, following their review of the literature on neurocognitive functioning in individuals with pediatric MB patients, Palmer (2008) created a model that proposes that impairments in attention, processing speed, and working memory underlie the deficits in more distal areas of functioning, including intellectual abilities and academic achievement. This is consistent with literature documenting such associations in typically developing children and in survivors of ALL (Fry and Hale 1996; Schatz et al. 2000).
Studies examining attention have utilized both standardized rating scales and performance-based tests to document deficits in this patient population. Although ratings often remain below clinically significant levels, parents and teachers report greater attention problems on standardized rating scales than are reported in normative populations (Moyer et al. 2012; Willard et al. 2014). Adolescents also self-report greater attention problems than normative populations although these scores also fall within normal ranges, i.e., within one standard deviation of the mean (Beek et al. 2015). Parent-rated attention problems have been associated with worse social functioning in survivors of PBTs and ALL (Moyer et al. 2012), demonstrating a clear functional impact of attention changes post-treatment.
Meta-analytic research has indicated large effect sizes for deficits in standardized, performance-based measures of attention, including Trail Making Test A and Conners Continuous Performance Test (CPT) in comparison to normative samples (Robinson et al. 2010). An additional meta-analysis documented a large effect size for greater CPT omission errors (sustained attention) in comparison to normative samples but nonsignificant differences in CPT commission errors (disinhibition; de Ruiter et al. 2013), suggesting that treatment may result in more inattention, but not impulsivity, in survivors. However, in a study examining performance across a combination of measures tapping attention and working memory in MB survivors who had received RT and chemotherapy, scores fell in the average range at baseline and were estimated to remain in the low-average to average range 5 years post-diagnosis (Palmer et al. 2013). Thus, differences across measures exist, likely related in part to various measures assessing different aspects of attentional functioning and at varying degrees of measurement refinement. PBT research to date has generally not utilized more experimental tasks to investigate specific components of attention that map onto established models of attention (e.g., Petersen and Posner 2012). However, one study that did so documented significantly worse performance on a computerized measure of the orientating attention network in a group of 19 patients treated with surgery only for cerebellar astrocytomas relative to 48 healthy controls (Quintero-Gallego et al. 2011).
Given findings of attention problems, the question has been raised as to whether PBT survivors with such difficulties are captured within the diagnostic criteria of Attention-Deficit/Hyperactivity Disorder (ADHD). Kahalley et al. (2011) found that 9% of their sample of 100 pediatric brain tumor survivors met strict criteria for ADHD, a prevalence rate that is not significantly different than the upper limits of the estimated rate of ADHD in the United States. However, many children with significant attention difficulties and impairment were not accounted for using strict DSM-IV diagnostic criteria, suggesting that the attention difficulties seen in this patient population may differ from those experienced by children with developmentally based impairments in attention. The conceptual framework of Sluggish Cognitive Tempo (SCT) has been utilized in the literature to describe a subset of children with ADHD who demonstrate signs of lethargy, day dreaming and staring, and poor organization. Research by Willard et al. (2013) documented greater parent-rated SCT symptoms in PBT survivors (mixed diagnoses and treatments) compared with ALL survivors and healthy controls. SCT symptoms were significantly and negatively correlated with overall IQ and working memory scores, but not processing speed scores. Multiple medical variables, including tumor location, radiation field, age at radiation, age at diagnosis, time off-treatment, were not significantly related to SCT scores.
In addition to deficits in attention, PBT survivors as a group show slower processing speed. For example, lower WISC Processing Speed Index scores (in comparison to the normative group) have been recently documented in a group of survivors with multiple tumor types (Kahalley et al. 2013).Furthermore, on the WJ-III Cognitive, MB patients who were treated with surgery, risk-adapted RT, and high-dose chemotherapy with stem-cell support evidenced slower processing speed than general population norms (Palmer et al. 2013). In addition, a recent study of a diagnostically mixed sample of PBT survivors treated with RT also documented deficits in reaction times on the ImPACT test, a brief computerized assessment typically used to screen concussion, relative to sibling controls and a solid tumor control group (Conklin et al. 2013).
Executive functions refer to the cognitive abilities responsible for maintaining internal goals to perform task-relevant behaviors (Miller and Cohen 2001) and may include working memory, inhibitory control, planning, problem solving as well as other higher order cognitive functions utilized for goal-direct behaviors (e.g., sequencing, switching, monitoring). Of these, working memory is the best studied in PBT. For example, research suggests that PBT survivors score worse on a variety of standardized verbal and spatial working memory measures in comparison to both patients with other solid tumors and sibling controls (Conklin et al. 2012, 2013). Additional research suggests that children with posterior fossa tumors who received RT and/or chemotherapy perform more poorly on measures of working memory than do either children with posterior fossa tumors who underwent surgery only or healthy controls (Law et al. 2011). While deficits in working memory have been observed across multiple PBT groups, deficits in this domain are not entirely consistent across studies. For example, Mabbott et al. (2008) did not find differences in working memory between survivors who had undergone surgery and RT for posterior fossa tumors, survivors who had undergone surgery only for posterior fossa tumors, and survivors of non-CNS tumors. With respect to broader executive functioning beyond working memory, Winter et al. (2014) found that most survivors of PBTs exhibited executive functioning abilities that were broadly within normal limits for age (although at the lower end of that range); however, a sizeable subset of survivors exhibited clinically significant executive functioning deficits, which appeared to be consistent with broadly impaired abilities, affecting both higher- and lower order executive functions (i.e., processing speed and working memory).
Although attention, working memory, and processing speed have been the most frequently studied domains of neurocognition to date in pediatric brain tumor populations, there is evidence that these individuals may also show deficits in other areas, including language, visuospatial skills, memory,and fine motor control. Overall mean effect sizes across studies examining deficits on measures of language and visuospatial functioning in comparison to normative samples fall in the large range (Robinson et al. 2010). Despite earlier research documenting mixed findings that may have been related to tumor location (King et al. 2004; Spiegler et al. 2004), more recent research has also documented memory deficits in survivors of PBT on both neuropsychological tests (Jayakar et al. 2015; Özyurt et al. 2014; Riggs et al. 2014) and on the ImPACT test (Conklin et al. 2013). With regard to fine motor control, overall mean effect sizes across studies examining measures of psychomotor speed fall in the large range (Robinson et al. 2010) for PBT patients in comparison to normative samples.
30.3.2 Academic Functioning
The neurocognitive deficits often present in PBT survivors can be accompanied by academic skill difficulties though studies are mixed with regard to the extent of academic impairment in PBT survivors. For example, Mabbott et al. (2005) examined standardized reading, spelling, and math performance, as well as parent and teacher ratings of school performance, in 53 patients with posterior fossa tumors who had all undergone RT. All academic measures fell approximately one standard deviation (12–15 points) below normative means. Extent of resection, use of chemotherapy, and RT dose were not associated with academic scores or ratings. In addition, Conklin et al. (2008) found significant declines over time in standardized reading, but not spelling or math reasoning scores, in survivors of ependymomas treated with RT. Supratentorial tumor location and multiple surgeries were associated with worse reading performance at baseline, and male sex, longer symptomatic intervals, pre-RT chemotherapy, hydrocephalus, and younger age at RT (<5 years) predicted significant decline in reading scores over time. Research by Holland et al. (2014) suggests that it is academic fluency deficits (e.g., rate and accuracy of academic skill performance), rather than skill deficits per se, that are most affected in PBT survivors, likely attributable to the deficits in attention, processing speed, and working memory discussed earlier in this review. In addition to the cognitive deficits that likely contribute to the academic difficulties that many patients experience, it is important to note that other factors, such as school absence, may also contribute to difficulties across subjects.
A recent study of ependymoma survivors identified higher rates of clinically significant school competence problems (e.g., parent ratings of academic performance, participation in special education, and history of grade retention) that were identifiable relatively early following RT (6 months) and persistent throughout the 5-year study period (Willard et al. 2014). Reduced school competence has implications for long-term educational and vocational outcomes. Several studies of adult outcomes among PBT survivors have identified increased risk for “proximal” educational performance difficulties, (e.g., grade retention, special education placement, and worse proficiency test performance), as well more “distal” educational and vocational outcomes (e.g., worse graduation test performance, lower high school and college graduation rates, and increased unemployment; Barrera et al. 2005; de Boer et al. 2006; Kirchhoff et al. 2010; Lorenzi et al. 2009; Mitby et al. 2003; Pang et al. 2008).
30.3.3 Adaptive, Emotional/Behavioral, and Psychosocial Functioning
Aspects of adaptive, emotional/behavioral, and psychosocial functioning are also among the areas that can be affected in PBT survivors. With regard to adaptive functions (activities of daily living), research has documented mild weaknesses in some domains compared with normative populations, but scores remain within one standard deviation of the mean (e.g., Robinson et al. 2015). Ashford et al. (2014) found greater adaptive skill deficits in PBT survivors who had received RT compared to both sibling controls and solid tumor controls. However, there are other variables besides RT that may impact adaptive functioning. For example, Robinson et al. (2015) did not find a relationship between RT dose and parent ratings of adaptive functioning but did find an association between tumor size and overall adaptive functioning scores as well as conceptual, practical, and social skills. Furthermore, in a group of patients with ependymoma, lower baseline adaptive scores were associated with pre-RT chemotherapy, shunt placement, number and extent of surgical resections, and younger age at treatment (Netson et al. 2012). In a study of craniopharyngiomas survivors, females evidenced greater decline than males in parent-rated functional communication skills over a 5-year period (Netson et al. 2013).
Results from studies examining emotional functioning in brain tumor survivors are mixed. Mabbott et al. (2005) found that parent and teacher ratings of internalizing and externalizing symptoms on standardized behavioral rating scales fell broadly within normal limits, but clinically significant internalizing symptoms were identified in another study (Poggi et al. 2005). Post-traumatic stress symptoms that are subclinical for a diagnosable PTSD have been reported in family members of survivors and, less consistently, survivors themselves (Kazak et al. 2001, 2004a). Results from a study by Brinkman et al. (2012) suggest that parent-reported depression/withdrawal symptoms may be higher for female survivors than males. Importantly, findings from a large study by Brinkman et al. (2013a, b, c) suggest that medical professionals working with PBT survivors during childhood and into adulthood should be vigilant about assessing for mental health difficulties, as over 11% of their sample of survivors ranging from 10 to 35 years of age reported that they had experienced suicidal ideation. This is much higher than the prevalence of suicidal ideation (SI) in the general US adult population (3.7%; Crosby et al. 2011). Those who had undergone surgery were 3.5 times more likely to experience suicidal ideation than those treated with other modalities, including RT.
Multiple studies have examined social difficulties experienced by PBT survivors. Studies examining parent ratings on standardized rating scales have generally not identified clinically significant social difficulties in PBT survivors. For example, a recent study of patients treated for ependymomas found stable parent ratings of social competence from baseline to 5 years following RT (Willard et al. 2015). Still, social functioning has been shown to fall significantly below population norms in some PBT samples (Brinkman et al. 2012; Willard et al. 2014), and one study identified that a subset of survivors are at greater risk for clinically significant internalizing problems, social problems, and withdrawal, with the latter two difficulties associated with longer time since diagnosis (Poggi et al. 2005). Patients themselves may be more likely to underestimate the social difficulties they are experiencing (Radcliffe et al. 1996). In a study including PBT survivors, survivors were more likely to overestimate their leadership popularity and underestimate isolation and victimization when compared with ratings completed by their peers (Salley et al. 2014). Difficulties in social functioning may be associated with different aspects of neurocognition, including overall intellectual abilities (Brinkman et al. 2012; Holmquist and Scott 2002), attention difficulties (Moyer et al. 2012), and/or executive dysfunction (Wolfe et al. 2013a, b).
30.4 Methodological Considerations
It is necessary to view the existing literature pertaining to the neuropsychological sequelae of PBT and their associated risk factors within the context of a number of critical methodological considerations. A review of such considerations serves to highlight the unique challenges inherent in conducting neurocognitive research with the PBT population and also serves to identify important future directions in the field.
Small sample sizes are a hurdle to conducting outcome studies in PBT due to low population base rates and attrition related to survival rates. Typically, larger samples are achieved by sacrificing specificity (i.e., samples of mixed diagnostic, treatment, and/or age groups), accruing patients over longer periods of time, and/or accruing patients through collaborative organizations, such as the Children’s Oncology Group (COG). Due to variation in available resources (e.g., trained professionals, testing instruments) across member institutions within organizations like COG, the latter strategy often results in studies characterized by missing data or limitations in the cognitive domains that are assessed. While these are general limitations in the research, specialty programs have published on relatively large samples that are less mixed with respect to tumor type, and such studies are an important development in the literature.
The PBT literature comprises numerous studies that lack control groups, more typically comparing samples of PBT survivors to published test norms, “a strategy which does not effectively control potentially important factors, such as demographics or issues related to chronic illness. Furthermore, neurocognitive outcome models likely involve direct and indirect effects of a combination of medical, child-specific, and broader contextual predisposing factors (e.g., family functioning), but there is a relative lack of attention to many of these nonmedical factors. Finally, advances in PBT treatment protocols/technology typically outpace the collection of neuropsychological outcome data, resulting in research that is less applicable to the current state of the field. This is particularly true for studies that accrue large sample sizes by recruiting over extended periods of time, or for longitudinal studies that require a number of years to study neuropsychological outcomes over time in the same cohort. In fact, longitudinal studies are far outnumbered by cross-sectional designs, making it difficult to examine or account for maturational changes.
30.5 Therapeutic Interventions
Research examining the efficacy of various interventions for neuropsychological late effects in PBT survivors has begun to receive increased attention in the last 10–15 years. This is reflected in the COG Long-Term Follow-Up Guidelines (COG-LTFU Guidelines; Children’s Oncology Group 2013), which recommend neuropsychological assessment and yearly history-taking/psychosocial assessment to triage survivors to school-liaison services, community-based disability services, pharmacological interventions, direct psychological services, and cognitive rehabilitation. Occupational, physical, and speech therapies address overlapping areas of functioning with neuropsychology and are typically considered and coordinated in the neuropsychological care of PBT survivors. While some of these recommendations rely heavily upon clinical experience and established patterns of practice in the field, others have varying degrees of evidence supporting their implementation in survivors of PBT.
30.5.1 Pharmacologic Interventions
There are limited pharmacologic studies focused solely on PBT survivors, but methylphenidate (MPH) is the most extensively studied pharmacologic intervention in mixed samples of pediatric cancer patients who have received CNS-directed therapies, including RT and/or intrathecal methotrexate and cytarabine. The published studies have primarily been generated from two independent, randomized, double-blind, placebo-controlled trials and document positive, short-term outcomes on direct measures of attention and parent/teacher ratings of behavior at intervals up to 3 weeks following medication initiation (Conklin et al. 2007, 2010a; Mulhern et al. 2004a; Thompson et al. 2001). The most recent of these studies (Conklin et al. 2010a) documented that positive medication response was predicted by higher parent and teacher ratings of attention problems prior to the medication trial, and it also documented a lower overall medication response rate in the pediatric cancer sample (45%) than has been reported in the developmental ADHD literature (~75%). Possible explanations for this finding proposed by the authors included this study’s more stringent criteria for positive response through the use of reliable change indices, a higher incidence of poor prognostic factors in their sample relative to developmental ADHD samples (i.e., lower hyperactivity and more comorbid learning and neurologic issues), and a potentially different etiologies of attention problems (e.g., genetic polymorphism in pediatric ALL v. dopamine transport/reuptake in developmental ADHD). In one of two studies examining side effects of MPH in pediatric cancer survivors, Conklin et al. (2009) reported that MPH was well tolerated overall in their randomized trial, with increased side effects associated with moderate dose (0.6 mg/kg) (versus either placebo or low dose (0.3 mg/kg)), female gender, and lower IQ. Consistent with findings in the developmental ADHD literature, side effects ratings during all 3 weeks of the trial were actually lower than baseline ratings prior to MPH initiation, which has been posited to be due to “side effects” on rating scales reflecting attention problems that are responsive to MPH as opposed to adverse medication effects which are the result of MPH.
One limitation of these randomized trials has been their short follow-up periods. However, two non-randomized studies have reported on longer term outcomes examined in the final phase of Conklin and colleagues’ trial (see Conklin et al. 2007, 2010a; Mulhern et al. 2004a). Collectively, these studies demonstrate that the improvements documented at 3 weeks following initiation of medication are maintained at 12 months, as measured by direct measures of attention, parent ratings of social skills and behavioral problems, and parent, teacher, and self-report (adolescent subsample) ratings of attention (Conklin et al. 2010b; Netson et al. 2011); however, examination of the pattern of change across the 12-month period identified mild rebound in cognitive problems and inattention between months 6 and 12 of the medication trial. As part of this same 12-month trial, Jasper et al. (2009) documented significant deceleration of BMI and weight, but not height, in the MPH treatment group during the 12-month trial, but no growth deceleration was found in a case-matched, unmedicated, comparison group. Given that the rate of growth deceleration for the MPH group was modest relative to Center for Disease Control normative data, the authors contended that MPH was reasonably well tolerated with respect to short-term growth, particularly given the propensity toward obesity that is present among pediatric cancer survivors; however, longer trials remain needed to elucidate any growth effects that may emerge after 12 months of MPH treatment.
Beyond MPH, numerous studies have documented increased use of antidepressants and other psychoactive medications among pediatric cancer survivors relative to siblings, peers, and the general population (Brinkman et al. 2013b; Deyell et al. 2013; Lund et al. 2015; Portteus et al. 2006), but efficacy studies of these psychoactive medications are not available in the literature. However, Brinkman et al. (2013c) published a report from the Childhood Cancer Survivor Study (CCSS) demonstrating an association between psychoactive medications (i.e., antidepressants, anticonvulsants, CNS stimulants, and neuroleptic medications) and impaired functioning across multiple domains of neurocognition (i.e., task efficiency, organization, memory, and emotional regulation), and the effect of psychoactive medications on neurocognition was above and beyond that of established predictors of neurocognitive impairment, including RT, neurologic history, and acute psychological distress. The associational nature of this finding does not elucidate whether the relationship between psychoactive medications and neurocognition is causal or simply reflective of the underlying neurological impairment for which the medications initially were prescribed.
Donepezil, an acetylcholinesterase inhibitor, has been the focus of two studies in adult brain tumor survivors and one study in PBT survivors. Both a prospective, open-label phase-II study (n = 24; Shaw et al. 2006) and a randomized, placebo-controlled phase III trial (n = 198; Rapp et al. 2015) of adults irradiated for brain tumors documented multiple areas of cognitive improvement at the end of 24-week trials relative to baseline, and the former study also demonstrated positive changes in health-related quality of life and mood. However, the randomized, placebo-controlled trial also found that observed cognitive improvements were only significantly different between the Donepezil and placebo groups at the end of the 24-week trial for patients with more significant cognitive impairment at baseline. In the only study published in the PBT literature to date, Castellino et al. (2012) demonstrated that Donezepil was well tolerated in a sample of 11 PBT survivors who received >23.4 Gy RT and were at least 1-year status post-cancer treatment at the time of the open-label trial. Preliminary findings in support of cognitive benefits on executive functioning, visual memory, and aspects of attention and auditory/verbal working memory were documented and suggest that future trials examining the potential benefit of Donepezil in PBT survivors are warranted.
30.5.2 Cognitive Remediation
In recent years, various cognitive remediation techniques have received increasing attention as potential interventions for the neurocognitive deficits experienced by PBT survivors. This line of empirical research essentially began with the work of Butler and colleagues (Butler 1998; Butler and Copeland 2002; Butler et al. 2008), who investigated the efficacy of the Cognitive Remediation Program (CRP). This program involves a tripartite model of rehabilitation techniques (hierarchically graded, massed practice to strengthen attentional control and information processing speed), educational interventions (15 metacognitive strategies to address preparedness, task approach, on-task behavior, and generalization), and clinical psychology techniques (cognitive-behavioral interventions to improve resistance to distraction and the ability to self-coach). While preliminary studies provided early empirical support for the CRP, the results of a follow-up, multicenter, randomized controlled trial of pediatric cancer survivors with CNS-involved disease or treatments were mixed. There was significant improvement (generally small to medium effect sizes) on measures of academic achievement, self-reported metacognitive strategies use, and parent (not teacher) ratings of attention, but there was no improvement on direct measures of neurocognitive functioning. In a pilot study of a different cognitive remediation program involving a 15-session, clinic-based program to teach compensatory learning and problem-solving skills in survivors of pediatric cancers involving CNS disease or treatments (n = 12) and associated cognitive deficits, there was only qualified evidence of efficacy in two areas (social skills and writing) though parent and child satisfaction were high (Patel et al. 2009).
In contrast to the time- and resource-heavy interventions described above, online, computerized cognitive training programs have been the focus of more recent investigations, targeting working memory or broader executive functioning in particular. Conklin et al. (2015) identified a number of advantages of such programs compared to the pharmacological interventions and in-clinic cognitive remediation programs previously employed with samples of PBT survivors, including broader geographic reach due to remote administration capability, reduced time burden with scheduling flexibility, engaging interfaces for child participants, ease of progress monitoring, and reduced medical contraindications. Kesler et al. (2011) conducted a 1-arm, open trial investigating the efficacy of an online cognitive rehabilitation program developed by Lumos Labs to train cognitive flexibility, working memory, and attention in a small sample of ALL or PBT survivors who were ≥6 months status post-CNS-directed treatment. Utilizing a pre-post design, significant improvements were reported in processing speed and cognitive flexibility as well as visual and verbal declarative memory, and the program was associated with changes in fMRI activation patterns in the dorsolateral prefrontal cortex; however, associations between the cognitive and fMRI changes were not investigated. Further, only immediate post-intervention outcomes were reported, so the lasting impact of the intervention is unknown.
Following initial demonstration of feasibility and acceptability of the working memory intervention Cogmed (www.cogmed.com) in samples of ALL and infratentorial PBT survivors with a history of CNS-directed therapies (Cox et al. 2015; Hardy et al. 2013), another research group reported on the findings of a randomized, single-blind, waitlist-controlled trial to investigate the efficacy and neural correlates of change associated with Cogmed in survivors of PBT and ALL who received CNS-directed therapy (Conklin et al. 2015). After completing the 5- to 9-week Cogmed program, the intervention group demonstrated greater benefit than controls on direct measures of working memory, attention, and processing speed as well as caregiver ratings of inattention and executive dysfunction. However, improvements in processing speed did not generalize to measures of academic fluency, and thus a functional benefit associated with these preliminary findings has not been clearly evidenced. While fMRI was not completed for the waitlist controls, the intervention group evidenced training-related neuroplasticity in the left lateral prefrontal, left cingulate, and bilateral medical frontal areas; however, these activation changes were not associated with change in working memory scores. Taken together, the current body of research highlights potential promise of these techniques for the remediation of some neuropsychological late effects experienced by pediatric cancer patients with CNS disease or treatment histories, but studies investigating the maintenance and generalization of these deficits beyond very specific cognitive tasks are an essential next step before utilization of such programs should be broadly recommended for this population.
30.5.3 Educational Interventions
The COG-LTFU Guidelines recommend baseline neuropsychological evaluation upon entry into long-term follow-up (2 years post-treatment) and periodically as clinically indicated thereafter (Children’s Oncology Group 2013). More recent guidelines published as part of a collaborative effort of experts in the field (see Wiener et al. 2015) also conclude that there is support in the literature for the importance of neuropsychological evaluation but provide less clear guidance regarding the time of evaluation (Annett et al. 2015). Ultimately, the authors recommended neuropsychological evaluation upon completion of treatment and at regular 2–3-year intervals thereafter, unless otherwise clinically indicated. Empirical studies documenting the efficacy of neuropsychological evaluation for PBT survivors or even mixed pediatric cancer samples are limited. Quillen et al. (2011) reported that less than half of the recommendations in neuropsychological reports were implemented by parents in a mixed sample of pediatric cancer survivors. In another study, despite approximately 75% of a small sample of parents and teachers of PBT survivors reporting a sound understanding of the neuropsychological report, less than half of the recommendations were implemented (Cheung et al. 2014). In a sample of children treated with chemotherapy and 18 Gy cranial RT for ALL, however, Anderson et al. (2000) reported improved reading and spelling skills between initial neuropsychological evaluation at 2 years post-treatment and a follow-up evaluation 3 years later when the initial evaluation was accompanied by verbal feedback to parents and provision of written information to both parents and school. While a comprehensive neuropsychological report has the potential to be an effective intervention for PBT survivors by way of prescribing the specific school services and accommodations that should be most beneficial for a given child in the academic setting, it is an ongoing challenge to be sure that these reports are provided to the school and that the recommendations are implemented appropriately.
A formal plan for continuation of school during treatment, for school reentry, and for implementation of appropriate educational interventions is important following diagnosis and during survivorship (Mitby et al. 2003). Many specialized pediatric cancer centers utilize school liaison professionals to support such planning and to communicate information between the medical and educational teams. However, while formal educational interventions (i.e., school personnel workshops, peer education programs, comprehensive programs involving multiple educational interventions) were the subject of several empirical investigations over a decade ago, no such studies have been generated in recent years. Furthermore, none of the available studies exclusively included children with primary CNS disease or CNS-directed treatment who are at highest risk for poor school adjustment and performance, and many studies have methodological limitations that hamper their contribution to the literature. Within this context, the available studies that did not specifically exclude children with brain tumors document preliminary but qualified evidence of increased participant knowledge about the child’s medical condition, increased participant interest in interacting with a peer with cancer, and decreased personal worrying about cancer (Benner and Marlow 1991; Prevatt et al. 2000; Rynard et al. 1998; Treiber et al. 1986).
While no specific academic interventions have been investigated in survivors of PBT, one study investigated a math intervention based in Multiple Representations Theory in a sample of ALL survivors who received chemotherapy only (Moore et al. 2012). The intervention was associated with increases in calculation and applied math skills immediately following completion, but such improvements were not evident in reading and spelling, demonstrating specificity of the intervention. Improvements in applied math remained evident approximately 1-year following completion of the intervention and, overall, were larger than those following the CRP intervention studied by Butler and colleagues (Butler 1998; Butler and Copeland 2002; Butler et al. 2008), highlighting the question of whether specific academic interventions may be a more effective use of resources than broad cognitive remediation techniques when attempting to remediate specific academic skill deficits. Future interventions will be needed to directly address this question.
30.5.4 Socioemotional Interventions
Existing socioemotional intervention studies within the field of pediatric cancer have been primarily conducted in mixed diagnostic groups and, thus, may have more limited applicability to PBT survivors, for whom socioemotional risk is elevated (Zeltzer et al. 2009). The most developed programs have targeted three areas: maternal problem-solving, post-traumatic stress in the child and family members, and child social functioning. The maternal problem-solving intervention has thus far been studied with respect to its benefits for mothers of newly diagnosed pediatric cancer patients, and evidence of efficacy has been documented in three randomized controlled trials (Sahler et al. 2002, 2005). To our knowledge, no studies to date have investigated the indirect effects of this intervention on the psychosocial adjustment of survivors themselves.
In a sample of 150 adolescent cancer survivors, their parents, and their adolescent siblings, Kazak et al. (2004b) conducted a randomized wait-list control trial of a family intervention that integrates cognitive-behavioral and family systems approaches to target post-traumatic stress symptoms related to the cancer experience. The study evidenced significant post-treatment reductions in symptoms of post-traumatic stress, specifically intrusive thoughts among fathers and arousal among survivors. There were no effects demonstrated for the mothers in the sample.
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