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Keywords:

  • childhood acute lymphoblastic leukemia;
  • anxiety;
  • depression;
  • family functioning

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

The authors prospectively assessed anxiety, depression, and behavior in children with standard-risk acute lymphoblastic leukemia (SR-ALL) during the first year of therapy and identified associated risk factors.

METHODS

A cohort study was performed of 159 children (aged 2 years-9.99 years) with SR-ALL who were enrolled on Children's Oncology Group protocol AALL0331 at 31 sites. Parents completed the Behavior Assessment System for Children, the General Functioning Scale of the Family Assessment Device, and the Coping Health Inventory for Parents at approximately 1, 6, and 12 months after diagnosis.

RESULTS

Overall, mean scores for anxiety, depression, aggression, and hyperactivity were similar to population norms. However, more children scored in the at-risk/clinical range for depression than the expected 15% at 1 month (21.7%; P = .022), 6 months (28.6%; P < .001), and 12 months (21.1%; P = .032). For anxiety, more children scored in the at-risk/clinical range at 1 month (25.2% vs 15%; P = .001), but then reverted to expected levels. On adjusted analysis, unhealthy family functioning was found to be predictive of anxiety (odds ratio [OR], 2.24; P = .033) and depression (OR, 2.40; P = .008). Hispanic ethnicity was associated with anxiety (OR, 3.35; P = .009). Worse physical functioning (P = .049), unmarried parents (P = .017), and less reliance on social support (P = .004) were found to be associated with depression. Emotional distress at 1 month predicted anxiety (OR, 7.11; P = .002) and depression (OR, 3.31; P = .023) at 12 months.

CONCLUSIONS

Anxiety is a significant problem in a subpopulation of patients with SR-ALL immediately after diagnosis, whereas depression remains a significant problem for at least 1 year. Children of Hispanic ethnicity or those with unhealthy family functioning may be particularly vulnerable. These data suggest that clinicians should screen for anxiety and depression throughout the first year of therapy. Cancer 2014;120:1417–1425. © 2014 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Greater than 90% of children with acute lymphoblastic leukemia (ALL) with standard risk (SR) features will be cured.[1] The improved survival rate is, in part, due to more intensive therapies with durations of 2.5 to 3.5 years.[2] These therapies involve multiple different chemotherapeutic agents that can affect the child's emotional functioning. In particular, corticosteroids, a key component of therapy for ALL, affect mood, behavior, and cognition.[3]

To our knowledge, the current study is the first prospective, longitudinal study of emotional and behavioral functioning in a large sample of children receiving active treatment for SR-ALL who did not receive cranial radiation.[4] Information regarding the behavioral and emotional health of children with cancer is largely based on studies of children after therapy, rather than those receiving active treatment.[5] Those studies have used cross-sectional designs and yielded mixed results regarding emotional distress in patients with ALL.[4, 6, 7] The few longitudinal studies that are available were small, included diverse cancer populations, and/or excluded patients with ALL who were aged < 5 years.[8-10] Variables associated with children's psychosocial adjustment include older age,[11, 12] female sex,[13, 14] lower household income,[14] parental distress,[14] and more intensive treatment.[12]

The contribution of family functioning and coping behaviors to children's emotional functioning is of particular interest because there are emerging data that suggest these factors may be modifiable. For example, a randomized clinical trial among adolescent survivors of childhood cancer and their families found that a 1-day family-based intervention improved symptoms of posttraumatic stress.[15] In addition, there is compelling evidence of the efficacy of family interventions in other childhood illness populations such as in type 1 diabetes.[16]

We prospectively evaluated the emotional and behavioral functioning of a large representative sample of children with ALL who were enrolled on a frontline Children's Oncology Group (COG) therapeutic study during the first year of therapy. We sought to: 1) describe the longitudinal trajectory of the psychological adjustment of children during their first year of therapy by measuring symptoms of anxiety, depression, and behavioral disturbances; and 2) identify factors associated with worse psychological functioning in children, including potentially modifiable variables related to family functioning and coping that could be targeted in future interventions.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Population

We conducted a prospective, longitudinal study of emotional and behavioral outcomes in children with SR-ALL who were enrolled on the COG AALL0331 protocol between 2005 and 2009 at 31 sites. We focused on a subset of children who were classified as having average-risk ALL, defined as SR by National Cancer Institute criteria (initial white blood cell count < 50,000/μL and aged 1.0-9.99 years) without central nervous system or testicular leukemia who had a good early response to therapy based on bone marrow morphology and minimal residual disease burden at end induction, and other variables.[17, 18] Additional eligibility requirements for this study of emotional and behavioral outcomes included age ≥ 2 years and at least 1 parent with reading comprehension of English or Spanish, the languages for which validated surveys exist. The participating sites were chosen from all COG sites to include a combination of community-based and tertiary care centers with available staffing for this ancillary study.

Patients received a 3-drug, 4-week induction with vincristine, pegaspargase, and dexamethasone (at a dose of 6 mg/m2/day × 28 days), as well as intrathecal chemotherapy. No patient received cranial radiation. There were 2 therapeutic randomizations: 1) standard consolidation versus intensified consolidation, which added 2 doses of cyclophosphamide and pegaspargase; and 2) standard interim maintenance with oral methotrexate versus augmented interim maintenance with escalating intravenous methotrexate as postconsolidation therapy. In 2008, the second randomization was halted based on the results of the Children's Cancer Group-1991 SR-ALL trial.[2]

A total of 194 patients who were enrolled on AALL0331 at the participating sites met the eligibility criteria for this ancillary study. Of these, 24 patients declined and 170 consented to participate. Of those who consented, 4 patients withdrew from the AALL0331 protocol before the first required survey evaluations and 7 were not given the evaluations because of errors at the study sites. The 159 participants (82% of eligible participants) were similar to the 35 eligible nonparticipants in terms of age at diagnosis and sex, with some differences in ethnicity noted (Table 1).

Table 1. Comparison of Participants With Eligible Nonparticipants
CharacteristicParticipants (n = 159)Eligible Nonparticipants (n = 35)P
  1. Abbreviation: CS, consolidation; DI, delayed intensification; IM, interim maintenance.

Age group at diagnosis, no.  .134
Preschool (ages 2-4 y)86 (54.1%)24 (68.6%) 
School age (ages 5-9 y)73 (45.9%)11 (31.4%) 
Sex, no.  .576
Female76 (47.8%)19 (54.3%) 
Male83 (52.2%)16 (45.7%) 
Child ethnicity, no.  .011
White, non-Hispanic108 (67.9%)16 (45.7%) 
Black, non-Hispanic11 (6.9%)1 (2.9%) 
Hispanic26 (16.4%)9 (25.7%) 
Other14 (8.8%)9 (25.7%) 
Marital status of parents, no.
Married105 (66.0%)  
Not married45 (28.3%)  
Missing data9 (5.7%)  
Maternal highest level of education, no.
Less than college92 (57.9%)  
At least some college55 (34.6%)  
Missing data12 (7.5%)  
Family income, no.   
<$50,00072 (45.3%)  
$50,000-$79,99925 (15.7%)  
≥$80,00030 (18.9%)  
Missing data32 (20.1%)  
Therapeutic randomization, no.   
Standard CS/standard IM-DI42 (26.4%)  
Intensified CS/standard IM-DI51 (32.1%)  
Standard CS/augmented IM-DI37 (23.3%)  
Intensified CS/augmented IM-DI29 (18.2%)  

Procedures

The Institutional Review Board of each participating center as well as the Yale University Human Investigation Committee approved the current study. Informed consent, and assent when indicated, was obtained for all participants. The identified primary caregiver (the child's mother in 84% of instances) completed surveys at 3 selected timepoints during the first year of therapy: day 1 of consolidation (approximately 1 month after diagnosis), the end of the delayed intensification (approximately 6 months after diagnosis), and 6 months after the initiation of maintenance (approximately 12 months after diagnosis). Of the 159 participants, 145 individuals, 131 individuals, and 136 individuals completed the evaluations at the first, second, and third timepoints, respectively.

Measures

Emotional and behavioral functioning was assessed by the Behavioral Assessment System for Children, Second Edition: Parent Report Scale (BASC-2 PRS), a valid and reliable instrument that has been used successfully in pediatric oncology populations.[19, 20] Children aged ≥ 8 years also completed the BASC-2 Self-Report of Personality. However, only 17 of the children in the current study (10.7%) were aged at least 8 years at the time of diagnosis, and therefore there were inadequate data with which to compare their self-report outcomes. The BASC-2 PRS yields standardized T-scores on a variety of clinical scales. Scores of 60 to 69 represent the at-risk range and scores ≥ 70 represent the clinically significant range. The BASC-2 PRS has been standardized on normative data obtained from a random sample of 12,350 children who are representative of the US population based on sex, ethnicity, socioeconomic status, geographic region, and culture.[21] Expected frequencies of elevated scores in the normative (ie, healthy comparison) population of children are available in the BASC manual.[19] For the current study, the hyperactivity, aggression, anxiety, and depression scales were analyzed. Anxiety and depression are often comorbid conditions, but in this instrument there are discrete scales for each.

Family functioning was evaluated using the General Functioning Scale of the Family Assessment Device (FAD-GF).[22] In this 12-item scale, parents indicate the degree to which they believe each statement describes their family (eg, “We are able to make decisions about how to solve problems”). Possible scores range from 1 to 4. Scores ≥ 2 reflect unhealthy family functioning.[22]

Family coping was assessed using the Coping Health Inventory for Parents (CHIP), which has been validated for children with a variety of chronic illnesses.[23] In this 45-item checklist, parents rate how helpful a specific coping behavior is on a 4-point scale ranging from “not helpful” to “extremely helpful.” A higher score on each of the 3 subscales (ie, 1) maintaining family integration and optimism; 2) maintaining social support and self-esteem; and 3) understanding the medical situation) indicates a greater reliance on that particular coping pattern, but there are no normative scores.

Physical functioning was measured by the “pain and hurt” and “nausea” subscales of the Pediatric Quality of Life Inventory (PedsQL) 3.0 Cancer Module.[24] In this questionnaire, parents rate how much of a problem each symptom has been within the past month. Scores are transformed on a scale from 0 (worst health) to 100 (best health).

A parent demographic survey included questions regarding ethnicity, household income, marital status, maternal education, and family size.

Statistical Analysis

Patient characteristics, including age at diagnosis, sex, race, and ethnicity, were summarized and compared between participants and eligible nonparticipants using an exact chi-square test to evaluate the potential for response bias.

The primary outcomes of interest were the BASC-2 PRS subscales for anxiety and depression. The percentages of patients in the “at least at-risk” and clinical ranges were compared with the corresponding percentages in the normative population, a comparison group of healthy children, using a 1-sided binomial exact test.

Both univariate and multivariate longitudinal analyses were conducted. For univariate analysis, a logistic regression model was tested with the dichotomized BASC-2 PRS scores (ie, elevated vs not elevated scores) for anxiety and depression as dependent variables, taking into consideration the dependence of repeated measurements at 3 timepoints for each subject. The following independent variables were analyzed: age at diagnosis, sex, race and ethnicity, household income, maternal education, marital status, family size, pain and hurt subscale and nausea subscale, as well as repeated measures of general family functioning and coping behaviors. The multivariate regression modeling included the patient and family factors that were found to be associated with elevated anxiety and depression scores by univariate analysis at P < .1. All analyses were performed using SAS statistical software (version 9.2; SAS Institute Inc, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Participants

The participants had a mean age of 4.9 ± 2.2 years at the time of diagnosis; 16.4% were of Hispanic ethnicity and 66.0% had married parents (Table 1).

Frequency of Emotional and Behavioral Problems

Mean scores for parental report of anxiety, depression, aggression, and hyperactivity symptoms were stable and in the average range at all 3 timepoints. However, the frequency of anxiety and depression scores in the at-risk or clinically significant range was greater than expected compared with the normative population of children (Fig. 1). At 1 month after diagnosis, a greater percentage of children scored in the at-risk or clinically significant range for anxiety (25.2% vs 15%; P = .001) compared with the normative population, but then reverted to expected levels at 6 months (17.5% vs 15%; P = .253) and 12 months (14.2% vs 15%; P = .542) after diagnosis. The frequency of anxiety scores that were elevated to the clinically significant range was greater than expected at 1 month (10.4% vs 4%; P = .001) and 6 months (8.7% vs 4%; P = .013) after diagnosis, but then declined to expected levels by 12 months after diagnosis (4.5% vs 4%; P = .448).

image

Figure 1. Prevalence of elevated anxiety and depression scores in the first year after diagnosis of acute lymphoblastic leukemia are shown.

Download figure to PowerPoint

For depression, a higher percentage of children had scores in the at-risk or clinically significant range than expected throughout the first year of therapy (1 month: 21.7% vs 15% [P = .022]; 6 months: 28.6% vs 15% [P < .001]; and 12 months: 21.1% vs 15% [P = .038]). However, the frequency of depression scores in the clinically significant range was not significantly different from expected levels at any timepoint (1 month: 5% vs 4% [P = .316]; 6 months: 6.4% vs 4% [P = .133]; and 12 months: 6.8% vs 4% [P = .087]).

At the 3 timepoints, the percentage of children with both anxiety and depression scores in the at-risk/clinically significant range was 12.6%, 15.1%, and 8.3%, respectively. The frequency of elevated hyperactivity and aggression scores was similar to that expected in a normative population (data not shown).

Longitudinal Analysis

Compared with children with anxiety scores in the average range, those with anxiety scores in the at-risk/clinically significant range 1 month after diagnosis were 7.70 times as likely to have elevated scores 6 months after diagnosis (95% confidence interval [95% CI], 2.39-24.85; P < .001) and 7.11 times as likely to have elevated scores 12 months after diagnosis (95% CI, 2.08-24.30; P = .002). Children with scores in the at-risk/clinically significant range 6 months after diagnosis were 20.64 times as likely to have scores in the at-risk/clinically significant range 12 months after diagnosis (95% CI, 6.02-70.74; P < .001).

Compared with children with depression scores in the average range, those with depression scores in the at-risk/clinically significant range 1 month after diagnosis were 3.51 times as likely to have scores in the at-risk/clinically significant range 6 months after diagnosis (95% CI, 1.33-9.26; P = .015) and 3.31 times as likely to have scores in the at-risk/clinically significant range 12 months after diagnosis (95% CI, 1.20-9.10; P = .023). Children with scores in the at-risk/clinically significant range 6 months after diagnosis were 5.11 times as likely to have scores in the at-risk/clinically significant range 12 months after diagnosis (95% CI, 1.94-13.48; P < .001) (data not shown).

Predictors of Anxiety and Depression

Table 2 displays the results of the univariate analysis adjusted for time elapsed since diagnosis. Significant predictors of anxiety and depressive symptoms by parental report included unhealthy family functioning and less reliance of each of the 3 coping patterns measured by the CHIP. Hispanic ethnicity was associated with worse anxiety symptoms, but not depressive symptoms. Conversely, worse physical functioning as measured by the pain and hurt subscale of the PedsQL was associated with depression, but not anxiety. There were no differences detected among the 4 treatment groups.

Table 2. Univariate Association Between Patient and Family Factors and Anxiety and Depression
CharacteristicAnxietyDepression
OR (95% CI)POR (95% CI)P
  1. Abbreviations: 95% CI, 95% confidence interval; AIM-ADI, augmented interim maintenance and augmented delayed intensification; IC, intensified consolidation; SC, standard consolidation; OR, odds ratio; SIM-SDI, standard interim maintenance and standard delayed intensification.

  2. a

    Measured by the General Functioning Scale of the Family Assessment Device (FAD-GF).

  3. b

    Measured by the Coping Health Inventory for Parents (CHIP) subscale 1.

  4. c

    Measured by the CHIP subscale 2.

  5. d

    Measured by the CHIP subscale 3.

  6. e

    Measured by the Pediatric Quality of Life Inventory (PedsQL) 3.0 Cancer Module pain and hurt subscale.

  7. f

    Measured by the PedsQL 3.0 Cancer Module nausea subscale.

Age group at diagnosis    
Preschool (ages 2-4 y)Reference group Reference group 
School age (ages 5-12 y)0.62 (0.37-1.05).0760.78 (0.49-1.26).314
Sex    
MaleReference group Reference group 
Female1.62 (0.97-2.72).0671.27 (0.79-2.02).325
Race/ethnicity    
White, non-HispanicReference group Reference group 
Hispanic3.32 (1.80-6.15).0001.36 (0.73-2.53).335
Black, non-Hispanic0.83 (0.23-2.96).7691.22 (0.46-3.25).696
Other1.61 (0.68-3.83).2771.59 (0.75-3.37).226
Annual family income    
≥$50,000Reference group Reference group 
<$50,0001.11 (0.63-1.98).7201.17 (0.68-2.01).564
Maternal education    
At least some collegeReference group Reference group 
Less than college1.15 (0.64-2.04).6421.24 (0.74-2.09).410
Marital status of parents    
MarriedReference group Reference group 
Not married1.30 (0.74-2.29).3541.65 (0.99-2.75).054
General family functioninga    
Healthy family functioningReference group Reference group 
Unhealthy family functioning3.01 (1.76-5.15)<.0012.37 (1.45-3.85).001
Maintaining family integration coping behaviorsb0.97 (0.94-0.99).0090.96 (0.94-0.98).001
Maintaining social support coping behaviorsc0.96 (0.94-0.99).0050.95 (0.93-0.97)<.001
Understanding the medical situation coping behaviorsd0.95 (0.90-1.00).0380.93 (0.89-0.98).003
Pain and hurt by parental reporte0.99 (0.98-1.00).0620.99 (0.98-1.00).016
Nausea by parental reportf0.99 (0.97-1.01).1860.99 (0.98-1.01).230
Therapeutic randomization    
SC/SIM-SDIReference group Reference group 
IC/SIM-SDI1.20 (0.60-2.40).5980.95 (0.50-1.78).862
SC/AIM-ADI1.23 (0.59-2.57).5851.00 (0.51-1.95).991
IC/AIM-ADI1.02 (0.45-2.28).9701.14 (0.56-2.33).713

Table 3 displays the results of a multivariate model, which included the patient and family factors that were found to be at least marginally significant (P ≤ .1) on univariate analysis. In this adjusted analysis, Hispanic ethnicity (odds ratio [OR], 3.35; 95% CI, 1.36-8.24) and unhealthy family functioning (OR, 2.24; 95% CI, 1.07-4.70) remained significant predictors of worse anxiety symptoms.

Table 3. Multivariate Analysis of the Association Between Patient and Family Factors and Anxiety and Depression
CharacteristicAnxietyDepression
OR (95% CI)POR (95% CI)P
  1. Abbreviations: 95% CI, 95% confidence interval; OR, odds ratio.

  2. a

    Measured by the General Functioning Scale of the Family Assessment Device (FAD-GF).

  3. b

    Measured by the Coping Health Inventory for Parents (CHIP) subscale 1.

  4. c

    Measured by the CHIP subscale 2.

  5. d

    Measured by the CHIP subscale 3.

  6. e

    Measured by the Pediatric Quality of Life Inventory (PedsQL) 3.0 Cancer Module pain and hurt subscale.

Age group at diagnosis    
Preschool (ages 2-4 y)Reference group Reference group 
School age (ages 5-12)0.49 (0.24-1.01).0530.77 (0.42-1.40).387
Sex    
MaleReference group Reference group 
Female1.57 (0.79-3.16).2061.24 (0.68-2.25).478
Race/ethnicity    
White, non-HispanicReference group Reference group 
Hispanic3.35 (1.36-8.24).0090.52 (0.20-1.39).192
Black, non-Hispanic0.85 (0.16-4.54).8460.86 (0.25-2.99).815
Other1.39 (0.42-4.52).5921.10 (0.42-2.87).849
Marital status of parents    
MarriedReference group Reference group 
Not married1.15 (0.49-2.56).7972.36 (1.17-4.75).017
General family functioninga    
Healthy family functioningReference group Reference group 
Unhealthy family functioning2.24 (1.07-4.70).0332.40 (1.26-4.56).008
Maintaining family integration coping behaviorsb0.99 (0.94-1.05).7711.04 (0.99-1.10).085
Maintaining social support coping behaviorsc0.98 (0.94-1.03).3660.94 (0.91-0.98).004
Understanding the medical situation coping behaviorsd1.00 (0.90-1.10).9640.95 (0.88-1.04).283
Pain and hurt by parental reporte0.99 (0.98-1.00).1520.99 (0.98-1.0).049

The significant predictors of worse depressive symptoms by adjusted analysis were unhealthy family functioning (OR, 2.40; 95% CI, 1.26-4.56), unmarried parents (OR, 2.36; 95% CI, 1.17-4.75), worse physical functioning (P = .049), and less reliance on maintaining social support coping behaviors (P = .004).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

To the best of our knowledge, the current study is the first prospective, longitudinal study of emotional and behavioral functioning in a large sample of children receiving active treatment for SR-ALL who did not receive cranial radiation. Although the majority of children had anxiety and depression scores similar to those of controls, a significant subpopulation of children displayed symptoms that merit intervention. We found that depressive symptoms were a significant problem from the end of the first month of therapy to 12 months after diagnosis. In contrast, the frequency of anxiety was elevated at the end of the first month of therapy, but then declined to levels expected in a normative population at 6 months and 12 months after diagnosis. Anxiety and depression scores at 1 month after diagnosis significantly predicted persistence of symptoms throughout the first year of therapy. In adjusted analysis, unhealthy family functioning and self-reported Hispanic ethnicity were the variables that were found to have the strongest association with emotional functioning. Children with unhealthy family functioning were 2.24 times as likely to have anxiety symptoms and 2.40 times as likely to have depressive symptoms. Hispanic children were 3.35 times as likely as white non-Hispanic children to have anxiety symptoms, but were not at an increased risk of depressive symptoms. Age, sex, family socioeconomic status, and therapeutic randomization did not predict emotional functioning. We did not find behavioral changes to be a significant problem.

The current study is unique in that our sample was a homogeneous group of patients with ALL with a high expected cure rate who were also enrolled on a randomized clinical trial. Thus, we were able to account for any differences due to therapeutic randomization. Because we enrolled patients at 31 sites from a range of community and tertiary care centers and rural and urban regions, the results of the current study can be generalized more than single-institution studies. Furthermore, we had a high participation rate (82% of eligible), which greatly reduced the potential for selection bias.

Limited published data are available regarding the longitudinal psychosocial functioning of children currently receiving chemotherapy. The results of the current study can be most closely compared with the prospective cohort study of 38 patients by Sawyer et al, who also found that children experience considerable emotional distress in the immediate postdiagnosis period.[9, 25] However, in contrast to the current study, Sawyer et al concluded that by 1 year after diagnosis, children treated for cancer had psychological functioning similar to that of children in the community. This other study had a smaller sample size and included a heterogeneous group of patients with childhood cancer. A more recent study by Furlong et al prospectively assessed quality of life in children with SR and high-risk ALL, some of whom received cranial radiation. Although their outcomes included global quality-of-life health utilities instead of clinical measures of psychological functioning, Furlong et al found that meaningful distress improved throughout therapy in a pattern similar to the results presented herein.[10] This study also differed from the current one in that the instrument used (the Health Utilities Index) was only validated for children aged ≥ 5 years, which excluded > 50% of the SR-ALL sample. The most recent longitudinal report measured the prevalence and distress of cancer-related symptoms in children throughout therapy.[8] This study, which included parents of 89 children with different cancer diagnoses, also found that psychological distress improved throughout therapy, but was still an issue for a subset of children at the end of therapy.

We found that family functioning was an important predictor of emotional functioning among children with cancer. To the best of our knowledge, the majority of previous research has focused on family functioning as an outcome variable. Maurice-Stam et al studied off-therapy children and found both positive and negative correlations between family functioning and quality of life, depending on the age of the child.[26] In patients with pediatric asthma, family dysfunction has been associated with children's mental health.[27] The current study used the FAD-GF, which measures perceived family cohesion and the ability of family members to communicate with each other. The results of the current study suggest that families who demonstrate worse cohesion and communication should be considered to be at higher risk and be offered more psychosocial support. There are available psychosocial risk screening measures such as the validated Psychosocial Assessment Tool (PAT2.0), which can integrate assessments of family functioning.[28] Furthermore, family functioning may be a modifiable variable, and thus the results of the current study support developing family-based interventions that target family functioning.

An important conclusion of the current study is that anxiety and depression at 1 month after diagnosis significantly predict the persistence of symptoms throughout the first year of therapy. Clinicians have long advocated the importance of addressing acute symptoms as part of multidisciplinary supportive care during cancer therapy.[29] The results of the current study further highlight the importance of the early identification of and intervention among distressed children to avoid long-term emotional distress. Previous studies in the general population have suggested that anxiety in children may result in the later development of depressive disorders and substance abuse.[30] Studies in non-cancer pediatric populations have also found that there are inherited factors that contribute to an individual's risk of responding to adversity in early life with depression and anxiety.[31] Such stressors can result in changes in the corticotropin-releasing factor system in genetically predisposed individuals.

Although symptoms of anxiety and depression may lessen throughout therapy, it is important to recognize the distress they cause and provide appropriate psychosocial interventions. The National Institutes of Health State-of-the-Science Conference on Symptom Management in Cancer: Pain, Depression, and Fatigue concluded that: “All patients with cancer should have optimal symptom control from diagnosis throughout the course of illness, regardless of personal and cultural characteristics.”[32] A wealth of psychosocial interventions exists for children with cancer, including cognitive behavioral therapy, social and recreational activities, and psychoeducational interventions.[33] Many interventions use family-based methods, which have been associated with beneficial outcomes for children.[34] Understanding the efficacy of various interventions is an ongoing area of research.[33]

The association between Hispanic ethnicity and anxiety is novel in children with ALL. To make sure this was not due to a methodological error in using an inappropriate comparison group, we verified that the frequencies of Hispanic children in the BASC-2 PRS normative comparison group (16.5%-20%) were similar to that in the current study population group (16.4%).[19] There is a single report that demonstrated poorer emotional functioning in Hispanic children with cancer, but it only addressed the off-treatment period.[35] There are other differences between Hispanic and non-Hispanic children with ALL, including inferior survival rates in Hispanic children.[1, 36] We do not currently have the data available to explain how Hispanic ethnicity leads to worse psychological functioning; but given these differences, this area of study deserves further attention.

The current study has some methodological characteristics that should be considered in interpreting the results. First, some patients enrolled in the study did not complete the evaluations at all the required timepoints due to withdrawals from the therapeutic study, administrative errors at study sites, and/or incomplete forms. Second, only parent report was available for the majority (89.3%) of children in the current study because there was no self-report option of the BASC-2 available for children aged < 8 years. In fact, to the best of our knowledge, there are no validated, objective self-report assessment tools for emotional functioning for children aged < 5 years and few for those aged 5 to 8 years. Young children may lack the language abilities to report on and/or the cognitive capacity to reflect on one's own behaviors or feelings. Children as old as 11 years tend to report fewer psychiatric symptoms and are unreliable in reporting about time factors, such as duration or frequency of symptoms,[37] and therefore collateral information is emphasized.[38] Assessing children of preschool age is typically accomplished through parent report and observation.[39] In addition, we were able to associate family functioning with emotional functioning, but we were unable to determine the direction of the association from our data. It may be that children with better emotional functioning lessen the burden on their families.

Based on the results of this large, multisite, cohort study of children treated for SR-ALL, we conclude that symptoms of depression and anxiety are a significant problem in the immediate postdiagnosis period. Although anxiety symptoms lessen after the first month of therapy, depressive symptoms appear to persist throughout at least the first year. We also found that we can identify children at 1 month after diagnosis who are substantially more likely to have worse psychological functioning throughout the first year of therapy. These results are highly relevant to pediatric oncologists who should be screening for clinical levels of anxiety and depression starting in the early postdiagnosis period for at least 1 year after diagnosis. Furthermore, the results of the current study highlight high-risk groups who should receive additional psychosocial support, including children of Hispanic ethnicity or those with parent-reported unhealthy family functioning. Further studies are needed to develop evidence-based interventions, including those targeting family functioning and patient subgroups at greatest risk, to prevent and treat anxiety and depression in children with ALL.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

This research was supported by grants from the National Institutes of Health to the Children's Oncology Group including CA13539, CA98543, and a Community Cancer Oncology Program grant from the Division of Cancer Prevention of the National Cancer Institute to the Children's Oncology Group.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Dr. Hunger is the Ergen Family Chair in Pediatric Cancer. Dr. Kadan-Lottick is supported in part by American Cancer Society Scholar Grant 119700-RSGHP-10-107-01-CPHPS and a Team Brent St. Baldrick's Foundation Scholar award.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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