Abstract

Objective: To evaluate group differences in social adjustment in survivors of pediatric ALL compared to survivor siblings, and controls; identify disease-related predictors of social adjustment in survivors; and explore whether executive functioning explained differences in social adjustment across groups and between disease-related predictors. Methods: Survivors of pediatric ALL (n =38, average age at diagnosis=4.27 years [SD =1.97]; average time off treatment=4.83 years [SD =1.52]), one sibling (if available, n=20), and one parent from each family were recruited from a long-term survivor clinic. Healthy age- and sex-matched controls (n =38) and one parent from each family were recruited from the community. Parents completed the Behavioral Assessment System for Children, Parent Rating Scale (BASC-3) Social Withdrawal subscale as a measure of social adjustment and the Behavior Rating Inventory of Executive Functions (BRIEF-2) as a measure of executive function for each of their children. Results: Parents reported that survivors had significantly worse social adjustment compared to controls (b =6.34, p =.004), but not survivor siblings. Among survivors, greater time off treatment (b =2.06, p =.058) and poorer executive functioning (b =0.42, p =.006) were associated with worse social adjustment. Executive function did not mediate differences in social withdrawal between survivors and controls or the relationship between time off treatment and social withdrawal among survivors. Conclusions: Survivors of pediatric ALL presenting to follow-up programs should be screened for difficulties with social adjustment. Future research should examine treatment- and non-treatment-related factors contributing to poorer social outcomes.

Keywords: ALL, Late effects, Pediatric oncology, Psychology, Psychosocial

Social Adjustment in Survivors of Pediatric ALL

Pediatric ALL is a major medical success story. Advances in treatment for ALL have resulted in one of the most impressive increases in cancer survival over the last 35 years, from 60% in 1975 to approximately 80-90% today in North America.¹ The number of survivors is growing rapidly. Given the dramatically improved survival rates, efforts were made in the early 1990’s to reduce the toxicity of treatment to the central nervous system (CNS) in ALL. Modern treatments for pediatric ALL rely less on cranial radiation therapy (CRT) for CNS prophylaxis and instead focus on intermediate or high dose intravenous methotrexate and intrathecal chemotherapies, intended to maximize CNS drug exposure while reducing systemic drug toxicity.²ALL is one of few pediatric cancers to receive both intravenous methotrexate and intrathecal chemotherapy. Despite efforts to reduce CNS toxicity, negative effects of these therapies on the developing brain persist.^3-5

Survivors of pediatric ALL experience difficulties with social adjustment.^6-8 Social adjustment is defined as the extent to which children attain socially desirable and developmentally appropriate goals.⁹ The social adjustment difficulties that have been reported in the literature for survivors of pediatric ALL include being more withdrawn, socially isolated, lonely, and bullied compared to their siblings and classmates.^8,10Survivors of ALL have been found to engage in less than half the number of social activities than their peers.^8,10-12 As adults, survivors of ALL are much less likely to marry or live independently compared to their siblings.^6,13-16 Tied to these enduring social difficulties, adult survivors of pediatric ALL are 1.7 times more likely to report mental health problems compared to their siblings, placing a significant burden on our health, economic, and social welfare systems.¹⁵ The majority of studies describing these specific social outcomes, however, involved patients treated with older protocols from the late 1970s through the mid-1980s that included CRT. Moreover, many of these studies reported the outcomes of long-term survivors of ALL. We do not yet know what effect modern therapies, which include higher doses of intravenous methotrexate and intrathecal chemotherapies, have on social adjustment, particularly in the early survivorship period (e.g., 2-7 years post treatment).

CNS-directed chemotherapies impair cognitive-executive processes.^17-21 Despite the effort to reduce toxicity to the developing brain by eliminating CRT, treatment with methotrexate and intrathecal chemotherapy alone has been linked to the presence of cognitive deficits in 40-60% of survivors of ALL.^3,19-21 Cognitive deficits experienced by survivors include difficulties with tasks related to processing speed, attention, working memory, and executive function. Consistent with the Social Competence Model developed by Yeates and colleagues,⁹ these same cognitive processes may play a role in social adjustment. The ‘Social Competence Model’ is a theoretical framework examining correlates of social adjustment in children with acquired brain injuries.⁹ This model takes a multilevel approach to understanding social competence, distinguishing among three key levels: 1) social adjustment; 2) social interaction; and 3) social information processing, comprised of social-cognitive and cognitive-executive function and assumes significant associations among these levels. Indeed, attention has been found to be uniquely associated with social adjustment in survivors of pediatric ALL relative to other known demographic- and treatment-related risk factors.²² The social competence model has been validated in research examining social outcomes among a variety of pediatric brain disorders, including traumatic brain injury (TBI),^23,24 stroke,²⁵epilepsy,²⁶ and survivors of pediatric brain tumor.²⁷ The contribution of cognitive-executive processes to social adjustment in survivors of ALL requires further investigation.

Thus, the specific aims of this study were to evaluate: 1) potential group differences in social adjustment across three groups of children (survivors of ALL, survivor siblings, age- and sex-matched controls); 2) disease-related factors (age at diagnosis, time off treatment) and executive functioning as predictors of social adjustment in survivors; 3) whether executive functioning mediates the differences in social adjustment across groups that were identified in the first aim (i.e., executive functioning as a mediator of the relationship between group and social adjustment); and 4) whether executive functioning mediates the relationship between the disease-related predictors (that were identified in the second aim) and social adjustment in survivors (i.e., executive functioning as a mediator of the relationship between disease-related predictors and social adjustment). We hypothesized that survivors of ALL would demonstrate significantly more social adjustment difficulties compared to their siblings and controls and that disease-related predictors of social adjustment would include diagnostic risk status with survivors diagnosed with high-risk disease being more likely to report social adjustment difficulties. Finally, we hypothesized that executive functioning would explain the differences in social adjustment across groups and disease-related predictors.