Recommendations for the surveillance of education and employment outcomes in survivors of childhood, adolescent, and young adult cancer: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Educational achievement and employment outcomes are critical indicators of quality of life in survivors of childhood, adolescent, and young adult (CAYA) cancer. This review is aimed at providing an evidence-based clinical practice guideline (CPG) with internationally harmonized recommendations for the surveillance of education and employment outcomes in survivors of CAYA cancer diagnosed before the age of 30 years. The CPG was developed by a multidisciplinary panel under the umbrella of the International Late Effects of Childhood Cancer Guideline Harmonization Group. After evaluating concordances and discordances of 4 existing CPGs, the authors performed a systematic literature search through February 2021. They screened articles for eligibility, assessed quality, and extracted and summarized the data from included articles. The authors formulated recommendations based on the evidence and clinical judgment. There were 3930 articles identified, and 83 of them, originating from 17 countries, were included. On a group level, survivors were more likely to have lower educational achievement and more likely to be unemployed than comparisons. Key risk factors for poor outcomes included receiving a primary diagnosis of a central nervous system tumor and experiencing late effects. The authors recommend that health care providers be aware of the risk of educational and employment problems, implement regular surveillance, and refer survivors to specialists if problems are identified. In conclusion, this review presents a harmonized CPG that aims to facilitate evidence-based care, positively influence education and employment outcomes, and ultimately minimize the burden of disease and treatment-related late adverse effects for survivors of CAYA cancers. LAY SUMMARY: A multidisciplinary panel has developed guidelines for the surveillance of education and employment outcomes among survivors of childhood, adolescent, and young adult cancer. On the basis of evidence showing that survivors are at risk for lower educational achievement and unemployment, it is recommended that all survivors receive regular screening for educational and employment outcomes.

Intellectual functioning among case-matched cohorts of children treated with proton or photon radiation for standard-risk medulloblastoma.

BACKGROUND: Proton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case-matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period. METHODS: Among 88 consecutive patients with standard-risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One-way analyses of variance were performed to compare the Full-Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts. RESULTS: Neurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The median follow-up was 5.3 years (range, 1.0-11.4 years) and 4.6 years (range, 1.1-11.2 years) for the PRT and XRT cohorts, respectively (P = .193). Patients treated with PRT had significantly higher mean FSIQ (99.6 vs 86.2; P = .021), verbal (105.2 vs 88.6; P = .010), and nonverbal scores (103.1 vs 88.9; P = .011) than the XRT-treated cohort. Differences in processing speed (82.9 vs 77.2; P = .331) and working memory (97.0 vs 92.7; P = .388) were not statistically significant. CONCLUSIONS: Radiotherapy-associated cognitive effects appear to be more attenuated after proton therapy. Comprehensive prospective studies are needed to appropriately evaluate the neurocognitive advantages of proton therapy.

Impact of executive functioning on health-related quality of life of pediatric brain tumor survivors.

BACKGROUND: Brain tumor survivors are at risk for significant late effects following treatment completion that may adversely impact health-related quality of life (HRQOL). The current study examines the relationship between executive functioning (EF) and HRQOL in pediatric brain tumor survivors within a longitudinal framework. We hypothesized that early deficits in EF would be related to less optimal HRQOL in this population. PROCEDURE: The current study utilized retrospective medical chart review to identify neurocognitive correlates of HRQOL in 137 youth previously treated for a pediatric brain tumor. Participants completed the Pediatric Quality of Life Inventory (PedsQL) and neuropsychological assessment, including a well-validated measure of executive functioning (Behavior Rating Inventory of Executive Function; BRIEF). General linear regression and multivariate models were utilized to examine the relationship between child executive functioning and HRQOL. RESULTS: Multiple domains of child executive functioning, as reported by parents on the BRIEF, significantly predicted parent-proxy reported HRQOL after controlling for demographic and medical covariates, including child intellectual functioning (IF). Similarly, after controlling for covariates, the BRIEF Cognitive Regulation Index was a significant predictor of self-reported physical and school functioning domains of HRQOL. CONCLUSION: Current data demonstrate EF is a significant predictor of HRQOL during survivorship for youth previously diagnosed with a pediatric brain tumor. Results suggest that opportunities may exist to intervene and improve HRQOL of pediatric brain tumor survivors by targeting EF.

Use of Wise Device Technology to Measure Adherence to Hydroxyurea Therapy in Youth With Sickle Cell Disease.

Despite broad support for hydroxyurea (HU) therapy, suboptimal adherence is reported for youth with sickle cell disease. Valid adherence measurement is crucial to understanding the relationship between medication behavior, disease response, and patient-centered health outcomes. The current pilot study examined the feasibility of the Wise electronic device for longitudinal HU adherence measurement in a sample of 36 youths prescribed HU. The study also explored the association between HU adherence, as measured by the Wise device, with other adherence measures (ie, family report, lab values, pill count, and medication possession ratio). A measure of family-reported acceptability was also completed. Overall, results supported the feasibility of the Wise device (rate of consent=82%, device use=75%, device failure=3%) for HU adherence measurement and most families rated their experience using their device positively (favorable responses ranged from 67% to 100%). Associations between HU adherence, as measured by the Wise device, and other adherence measures were not significant. Overall, the feasibility was supported. The Wise device allows longitudinal measurement of adherence with HU from initiation as a young child (ie, with liquid formulations) through adolescence and provides a novel means of adherence measurement for both clinical and research use.

Clinic Attendance of Youth With Sickle Cell Disease on Hydroxyurea Treatment.

OBJECTIVE: The objective of this study is to describe rates of clinic attendance of youth with sickle cell disease prescribed hydroxyurea and examine potential demographic and medical factors related to consistent clinic attendance. METHODS: Participants included 148 youth diagnosed with sickle cell disease and prescribed hydroxyurea during a single calendar year. Clinic attendance and potential demographic and medical factors related to attendance were extracted via systematic retrospective medical chart review. RESULTS: Youth attended 90.3% of scheduled appointments and 85.1% of youth attended at least 80% of scheduled clinic appointments during the study window. Adjusting for other factors, multivariate analysis revealed families with fewer children in the household, families with private insurance, youth experiencing fever, and youth not experiencing pain during the calendar year were more likely to consistently attend clinic visits. CONCLUSIONS: Adherence to clinic appointments is critical to optimizing health outcomes for youth with sickle cell disease and integral for adequate monitoring of youth prescribed hydroxyurea, in particular. Findings may aid providers in appropriately identifying possible barriers to clinic attendance to develop attendance promotion interventions.

White coat adherence over the first year of therapy in pediatric epilepsy.

OBJECTIVE: To examine white coat adherence over time in children with epilepsy. STUDY DESIGN: This was a longitudinal prospective study to examine medication adherence prior to and following consecutive clinic visits over a 13-month period in 120 children with newly diagnosed epilepsy (M(age) = 7.2 ± 2.9 years; 38% female) and their caregivers. Electronic monitors were used to assess adherence and ordinal logistic regression models were employed. RESULTS: Results demonstrated white coat adherence, with adherence increasing during the 3 days preceding clinic visits. Data also revealed a significant interaction, whereby adherence increased following initial clinic visits, but decreased following the last clinic visit. CONCLUSIONS: White coat adherence occurs for children with newly diagnosed epilepsy. Increased awareness of white coat adherence has important implications for clinical decision-making and should be examined in other pediatric populations. Increased monitoring of medication patterns can help clinicians avoid unnecessary changes to the treatment regimen. Interventions targeting improved communication around adherence behaviors are necessary to maximize therapy benefits.

Preparing for transition? The allocation of oral medication regimen tasks in adolescents with renal transplants.

A mixed-methods design was utilized to examine strategies that families use to manage the post-transplant oral medication regimen of adolescents with renal transplants. Seventeen adolescents and their caregivers were administered structured interviews assessing the tasks that families identified as comprising the oral medication regimen, how tasks were allocated across family members and how the dyad decided on the allocation of tasks. Adherence was assessed via electronic pill bottles and calculated by dividing the number of doses taken by those prescribed. Patients and their caregivers identified the following tasks as part of the oral medication regimen: filling the pillbox (71%), calling for refills (65%) and verifying that the pillbox is filled correctly (47%). Adult caregivers were primarily responsible for managing the medication regimen for the majority of adolescents (70%). Secondary analyses revealed that the number of oral medication regimen tasks identified by the dyad was significantly associated with patient adherence. Our findings highlight the need to bolster efforts to develop methods to quantitatively assess and promote self-management skills among adolescents with renal transplants.

Individually tailored treatment of medication nonadherence.

OBJECTIVE: Nonadherence is a significant health care issue in pediatric inflammatory bowel disease (IBD) that requires intervention to improve outcomes. This pilot randomized controlled trial was designed to evaluate the feasibility, acceptability, and preliminary efficacy of an individually tailored behavioral treatment for nonadherence in adolescents with IBD. PATIENTS AND METHODS: Fourteen adolescents ages 14.89 ± 2.01 years were randomly assigned to immediate care or wait list control conditions and received a manualized individually tailored behavioral intervention for nonadherence. Medication adherence, measured by pill count, served as the primary endpoint. Parents provided demographic data and ratings of intervention acceptability and patients provided disease-severity data. RESULTS: Feasibility of the treatment was demonstrated by 100% treatment session attendance for all of the patients enrolled in the trial. Both parent and patient acceptability ratings were favorable. Comparison of baseline with posttreatment percent adherence across both conditions demonstrated that treatment resulted in a 4% gain in 6-mercaptopurine/azathioprine adherence (52% at baseline; 56% at posttreatment; δ = 0.07) and a 25% gain in mesalamine adherence (43% at baseline; 68% at posttreatment; δ = 0.57). CONCLUSIONS: Individually tailored treatment of nonadherence in adolescents with IBD is feasible and may result in substantial improvement in medication adherence. Differential effect of the intervention on medications requires further investigation, but it may reflect differences in regimen complexity, concerns about medication adverse effects, and/or patient/parent preference to target more complex regimens. Large-scale testing of this intervention is needed to demonstrate effect on clinical outcomes.

Treatment factors affecting longitudinal quality of life in new onset pediatric epilepsy.

OBJECTIVES: Recognizing the importance of patient-reported outcomes, this longitudinal, prospective study examined: Changes in health-related quality of life (HRQOL) over seven months following antiepileptic drug (AED) initiation and the relationship of seizures, AED side-effects, and AED type to HRQOL. METHOD: Parents of 124 children with newly diagnosed epilepsy completed measures of HRQOL and side-effects at each clinic visit. Treatment information was also collected. RESULTS: HRQOL remained stable over time; however, seizures and AED side-effects significantly affected multiple HRQOL domains. Higher seizure activity was associated with decreased Physical HRQOL. Side-effects were negatively associated with all HRQOL domains. Children taking carbamazepine who experienced higher side-effects early in therapy demonstrated declining emotional functioning compared to children experiencing no/some side-effects. CONCLUSIONS: AED side-effects, AED type, and seizure frequency were associated with longitudinal HRQOL in children with newly-diagnosed epilepsy. Routine assessment of AED side-effects and HRQOL may be useful for clinical decision making.

Explaining the family conflict-glycemic control link through psychological variables in adolescents with type 1 diabetes.

To examine whether individual psychological variables mediate the family conflict-glycemic control relationship. During three study visits spanning 9 months, 147 adolescents with type 1 diabetes completed questionnaires measuring anxiety and depressive symptoms, and diabetes-specific worry. Caregivers similarly completed a measure of diabetes-specific family conflict. Blood glucose monitoring frequency and glycemic control were also obtained during study visits. Separate mediation analyses revealed that anxiety was the only individual psychological variable that mediated the caregiver-reported family conflict-glycemic control link. Anxiety accounted for 20% of the family conflict-glycemic control link, compared to 8.5% for depression and 6% for diabetes-specific worry. Results suggest that anxiety symptoms may be promoted in a family environment characterized by conflict and these symptoms have detrimental effects on glycemic control. Continued monitoring of family functioning and adolescents' anxiety symptoms, as well as refinement of interventions, is needed to promote positive health outcomes.

Preventing Medication Nonadherence of Youth (13-24 Years) With HIV Initiating Antiretroviral Therapy.

PURPOSE: The objective of this study was to evaluate the feasibility and acceptability of a dynamic, behavioral intervention to optimize medication adherence of adolescents and young adults (AYAs) with HIV newly initiating highly active antiretroviral therapy (HAART) and explore its efficacy on adherence and disease outcomes. METHODS: The two-arm randomized controlled trial piloted a brief, individualized intervention designed for direct integration into standard clinical care. In total, 32 AYAs with a confirmed HIV diagnosis, reportedly horizontally acquired, and recommended to initiate HAART completed a two-week placebo trial before HAART initiation and were subsequently randomized to standard of care or the individualized intervention. Adherence and disease outcomes were measured over the first six months of HAART. RESULTS: Results supported the primary study aim regarding feasibility (recruitment = 89%, attendance = 81%-100%, intervention exercise completion = 100%) and acceptability (average favorable response = 89%). Data also supported the positive effect of the intervention on select HAART adherence measures and disease outcomes. Adherence (by pharmacy refill) declined in both groups; however, adherence declined more slowly in the intervention group versus standard of care (p < .001). In addition, 100% of participants receiving the intervention obtained an undetectable viral load by 3 months and maintained an undetectable viral load at 6 months (vs. 68.8% standard of care). CONCLUSIONS: This is one of the first interventions to target adherence for AYAs with HIV newly initiating HAART and designed for delivery in existing clinical care settings. Future research will help confirm efficacy and the potential utility of the intervention in promoting HAART adherence from medication initiation and preventing the decrease in adherence often observed over time.

Health-related quality of life across pediatric chronic conditions.

OBJECTIVE: To compare health-related quality of life (HRQOL) across 8 pediatric chronic conditions, including 5 understudied populations, and examine convergence between youth self-report and parent-proxy report. STUDY DESIGN: Secondary data from 589 patients and their caregivers were collected across the following conditions: obesity, eosinophilic gastrointestinal disorder, inflammatory bowel disease, epilepsy, type 1 diabetes, sickle cell disease, post-renal transplantation, and cystic fibrosis. Youth and caregivers completed age-appropriate self-report and/or parent-proxy report generic HRQOL measures. RESULTS: Youth diagnosed with eosinophilic gastrointestinal disorder and obesity had lower HRQOL than other pediatric conditions by parent report. Caregivers reported lower HRQOL by proxy report than youth self-reported across most subscales. CONCLUSIONS: Use of brief, easily administered, and reliable assessments of psychosocial functioning, such as HRQOL, may provide clinicians additional opportunities for intervention or services targeting improved HRQOL relative to the needs of each population.

Correlates of glycemic control and quality of life outcomes in adolescents with type 1 diabetes.

BACKGROUND: A major focus of pediatric multidisciplinary diabetes care is promoting glycemic control (A1c) while ensuring high quality of life (QOL). The current study investigated factors associated with A1c and QOL using a methodology that considered these variables as simultaneous outcomes. METHOD: A total of 261 adolescents (aged 13-18) with type 1 diabetes completed measures of blood glucose monitoring (BGM) frequency, diabetes-specific QOL, negative affect, and depression. Caregivers completed measures of demographic and disease characteristics, depression, and family conflict. RESULTS: A1c was negatively correlated with QOL (r = -0.18 to -0.29, p < 0.01) across all subscales. Based on clinical A1c goals and median QOL scores, adolescents fell into four glycemic control-QOL groups. Multinomial logistic regression determined correlates of group membership utilizing adolescents with suboptimal glycemic control-low QOL as the referent group. Adolescents with optimal glycemic control-high QOL reported increased BGM frequency (OR = 1.87), less negative affect (OR = 1.32), and were more likely to use CSII (OR = 5.41). Adolescents with optimal A1c-low QOL reported greater BGM frequency (OR = 1.91) and shorter disease duration (OR = 1.09). Adolescents with suboptimal glycemic control-high QOL reported greater BGM frequency (OR = 1.41), fewer depressive symptoms (OR = 1.13), and less negative affect (OR = 1.31). CONCLUSIONS: Results reveal disease, management, and psychosocial characteristics that differentiate glycemic control-QOL outcome groups and identify risk factors related to this relationship. Further appreciation of these characteristics may increase clinicians' understanding and attention to these important clinical outcomes and help tailor the most appropriate interventions (e.g., individual psychotherapy vs. family problem-solving interventions) to help adolescents achieve glycemic control without sacrificing QOL.

Barriers to oral medication adherence for adolescents with inflammatory bowel disease.

OBJECTIVE: To identify family-reported, adherence-related barriers for adolescents with inflammatory bowel disease (IBD) and examine their relationship to 6-MP/azathioprine and 5-ASA medication adherence. METHODS: Participants included 74 adolescents, aged 13-17 years, diagnosed with IBD and their caregivers. Adolescents and caregivers jointly completed a measure of barriers to medication adherence. Adherence to medication was measured by family-report, pill-count, and serum assay. RESULTS: Families endorsed one to seven total barriers to medication adherence. The most commonly reported barriers included forgetting, being away from home, and interference with an activity. Neither demographic nor disease severity variables were related to the total number of reported barriers. Fewer total reported barriers was related to better adherence by adolescent and maternal report. CONCLUSION: Most families experience at least one barrier to treatment adherence. Effective problem-solving around these barriers and its integration into future treatment protocols may help improve medication adherence in the pediatric IBD population.

Responsibility sharing between adolescents with type 1 diabetes and their caregivers: importance of adolescent perceptions on diabetes management and control.

OBJECTIVE: To analyze associations between factor scores for caregiver responsibility for direct and indirect diabetes management tasks with glycemic control and blood glucose monitoring (BGM) frequency. METHODS: Two hundred and sixty one adolescents with type 1 diabetes and their caregivers completed the Diabetes Family Responsibility Questionnaire (DFRQ). Data on diabetes management (e.g., BGM frequency) and glycemic control (e.g., A1c values) were obtained. RESULTS: Confirmatory factor analysis of the DFRQ revealed two factors-direct and indirect management tasks. Multivariate analyses demonstrated that adolescent perception of greater responsibility sharing with caregivers on direct management tasks was significantly associated with higher BGM frequency. CONCLUSIONS: Adolescents who perceive greater caregiver responsibility, particularly around direct management tasks, engage in better diabetes management. Implications of these findings include designing interventions that encourage and sustain caregiver responsibility through adolescence and make explicit the contribution of caregivers.

The impact of peer victimization, parent distress and child depression on barrier formation and physical activity in overweight youth.

OBJECTIVE: With the prevalence of childhood overweight reaching epidemic proportions, there is an increased need to identify factors which may aid in the development of successful weight intervention programs. Given that lower levels of physical activity are inversely correlated with weight status in children, research has focused on identifying and addressing reported barriers to physically activity. A relationship exists between the number of reported barriers and weight status such that children who are overweight report more barriers to being physically active. However, important demographic and psychosocial correlates of barriers have not been examined. METHODS: This study investigates the relationship among parent distress, peer victimization, childhood depression, barriers to physical activity, and physical activity among a sample of 95 clinically overweight children and adolescents. Higher levels of parent distress, peer victimization, and childhood depression are predictive of a variety of barriers to physical activity, with peer victimization emerging as the strongest predictor of barriers. Barriers to physical activity mediate the relationships between peer victimization, parent distress, child depression and physical activity. RESULTS: These findings have significant implications for the development/design of weight intervention programs. Interventions targeting increases in physical activity should not only focus on the barriers children report, but should also include a psycho-emotional component to address factors such as parent distress, peer victimization and child mood that may contribute to barrier formation/maintenance. CONCLUSION: Future interventions may benefit from the identification of additional factors that impact barrier formation and physical activity levels among children.

Use of Placebo Pills Before Treatment Initiation in Youth with HIV: Are They Ready?

Highly active antiretroviral therapy (HAART) nonadherence is related to negative health outcomes and is well-documented in adolescents and young adults (AYAs) with behaviorally acquired HIV. Few studies describe methods to improve adherence in this population. This retrospective study describes placebo pill trial use (ie, pills with inert substance prescribed to practice taking HAART) in AYAs initiating HAART and its relation to disease outcomes. Sixty-two AYAs initiated HAART during the review period. Disease outcomes during the first year of standard clinical care were abstracted from medical records. In all, 72.6% of participants received ≥1 pill trial and 27.4% received ≥2 trials. Placebo trial use was not independently related to adherence post-HAART initiation. "Prescription" of a second trial was related to less optimal disease status over the first 6 months of treatment. Placebo trials have the potential to inform clinical care, aid in identifying AYAs at risk for nonadherence, and may provide a novel intervention strategy before/after HAART initiation.

Telehealth behavioral treatment for medication nonadherence: a pilot and feasibility study.

OBJECTIVE: To evaluate an individually tailored multicomponent nonadherence treatment protocol using a telehealth delivery approach in adolescents with inflammatory bowel disease. METHODS: Nine participants, age 13.71±1.35 years, completed a brief treatment online through Skype. Medication nonadherence, severity of disease, and feasibility/acceptability data were obtained. RESULTS: Adherence increased markedly from 62% at baseline to 91% for mesalamine (δ=0.63), but decreased slightly from 61% at baseline to 53% for 6-mercaptopurine /azathioprine. The telehealth delivery approach resulted in cost savings of $100 in mileage and 4 h of travel time/patient. Treatment session attendance was 100%, and the intervention was rated as acceptable, particularly in terms of treatment convenience. CONCLUSION: Individually tailored treatment of nonadherence through telehealth delivery is feasible and acceptable. This treatment shows promise for clinical efficacy to improve medication adherence and reduce costs. Large-scale testing is necessary to determine the impact of this intervention on adherence and health outcomes.

Evaluation of a group-based behavioral intervention to promote adherence in adolescents with inflammatory bowel disease.

OBJECTIVE: To pilot test the feasibility and acceptability of a family-based group behavioral intervention and to improve medication adherence in adolescents diagnosed with inflammatory bowel disease. METHODS: Participants were 40 adolescents aged 11-18 years diagnosed with inflammatory bowel disease and their primary caregivers, who were randomized to either a four-session Family-Based Group Behavioral Treatment or Usual Care over a 6-week period. Adherence was measured using a multi-method, multi-informant assessment involving caregiver-report and patient-report, pill count data, and electronic monitoring. RESULTS: Adherence rates ranged from 66 to 89% for 6-mercaptopurine/azathioprine and 51 to 93% for mesalamine across assessment methods. The intervention was feasible, as evidenced by the 99% treatment session attendance rate, and acceptable based on patient and caregiver report. Repeated measures analysis of variance tests revealed nonsignificant differences between the conditions from baseline to post-treatment assessments for pill count, electronic monitor, and primary caregiver-reported adherence (P's>0.05). There was a statistically significant improvement in patient-reported mesalamine adherence represented by a significant main effect for Condition (F=22.24, P<0.01; δ=0.79) and Condition×Time interaction (F=13.32, P<0.05; δ=0.69). CONCLUSION: Findings suggest potential for use of behavioral intervention to improve medication adherence in this population. This intervention may be more effective with more complex regimens (e.g. multiple doses per day) such as those prescribed with mesalamine. Further research is needed to examine this type of intervention in more diverse samples with more active disease. Use of alternative adherence measurement approaches, including electronic pill boxes and/or real-time self-report (e.g. by text messaging, electronic diaries, etc.) is also recommended.