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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3649-3656 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.2486 Behavioral and Social Outcomes in Adolescent Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
From the Department of Pediatrics, University of Minnesota, Minneapolis, MN; Fred Hutchinson Cancer Research Center, Seattle, WA; Dana-Farber Cancer Institute, Boston, MA; University of Southern California School of Social Work; UCLA Medical Center, Los Angeles, CA; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN; and the Department of Pediatrics, Emory University, Atlanta, GA Address reprint requests to Ann C. Mertens, PhD, Department of Pediatrics, Emory University, 2015 Uppergate Dr, Atlanta, GA 30322; e-mail: Ann.Mertens{at}choa.org
Purpose: Adolescents, regardless of medical history, may face behavioral and social challenges. Cancer and related treatments represent additional challenges for teens navigating the transition from childhood to adulthood. This study was conducted to evaluate behavioral and social outcomes of adolescent childhood cancer survivors using data from the Childhood Cancer Survivor Study. Patients and Methods: We evaluated 2,979 survivors and 649 siblings of cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence). Outcomes were determined by calculating parent-reported scores to questions from the behavior problem index. Results: Survivors and siblings were similar in age at the time of interview (mean: 14.8, survivors; 14.9, siblings; range, 12 to 17 years). Overall, multivariate analyses showed that survivors were 1.5 times (99% CI, 1.1 to 2.1) more likely than siblings to have symptoms of depression/anxiety and 1.7 times (99% CI, 1.3 to 2.2) more likely to have antisocial behaviors. Scores in the depression/anxiety, attention deficit, and antisocial domains were significantly elevated in adolescents treated for leukemia or CNS tumors when compared with siblings. In addition, survivors of neuroblastoma had difficulty in the depression/anxiety and antisocial domains. Treatments with cranial radiation and/or intrathecal methotrexate were specific risk factors. Conclusion: Adolescent survivors of childhood cancer, especially those with a history of leukemia, CNS tumors, or neuroblastoma, may be at increased risk for adverse behavioral and social outcomes. Increased surveillance of this population, in combination with development of interventional strategies, should be a priority.
In 2000, the overall 5-year survival rate was higher than 80% for children and adolescents diagnosed with cancer before age 20.1 The growing number of adolescent and adult survivors of childhood cancer mandates an assessment of issues faced by survivors and the development of strategies to minimize the long-term morbidities associated with cancer and its treatment. During adolescence, individuals begin to form many of the behavior patterns that will influence the course of their adult lives. The cancer experience complicates the challenges faced by adolescents—increasing independence, the formation of relationships, the need to make decisions about educational and career paths—and may exert its effects in different ways at different time points in an adolescent survivor's life.2 Age at cancer diagnosis, sex, current age, socioeconomic status, and life transitions may all affect social outcomes and long-term health status of childhood cancer survivors.3,4,5 Some studies in childhood cancer survivors have found an association between treatment intensity and diminished psychosocial function. In particular, intrathecal methotrexate and cranial radiation, therapies that directly affect the CNS, have been associated with increased neuropsychologic problems among survivors of acute lymphoblastic leukemia and childhood brain tumors.6,7 Studies focusing on adult survivors of pediatric cancer have analyzed measures such as marital status, education, career status, and resulting access to insurance coverage, all of which may be affected by poor social functioning.8,9 These measures are less applicable in adolescence where both survivors and age-matched controls are unlikely to be married, to have completed their education, to be seeking full-time employment, or to have separate insurance coverage from their parents. It is important to measure behavioral and social skills during adolescence as poor functioning in these areas may affect the transition to adulthood. Observation of variations in behavioral responses, whether by age, sex, or other factors, will lead to targeted interventions for survivors. We report the results of analyses utilizing the unique resource of the Childhood Cancer Survivor Study (CCSS). These findings have the potential to guide the development of appropriate and targeted interventions for subgroups of adolescent cancer survivors at risk for adverse behavioral and social outcomes.
Subject Selection and Contact The CCSS is a multi-institutional study (Appendix Table A1, online only) of individuals who survived for 5 or more years after treatment for cancer, and met the following eligibility criteria: diagnosis of leukemia, CNS malignancies (all histologies), Hodgkin's disease, non-Hodgkin's lymphoma, malignant kidney tumor, neuroblastoma, soft tissue sarcoma, or malignant bone tumor; diagnosis and initial treatment at one of the 26 collaborating institutions; diagnosis date between January 1, 1970, and December 31, 1986; age younger than 21 years at diagnosis; and survival 5 or more years from diagnosis. The CCSS protocol and contact documents were approved by the human subjects committee at each participating institution. Details of study design and cohort characteristics have been described elsewhere.10 Briefly, baseline data were collected for members of the study cohort using a 24-page baseline questionnaire designed to capture a wide range of demographic and medical information. For survivors younger than 18 years of age at contact, this questionnaire was completed by a parent. Information regarding the original cancer diagnosis and treatment was obtained from the treating institution for all eligible survivors. The baseline survey and medical record abstraction form used in data collection are available for review.11 Of the 20,602 eligible 5-year survivors, 3,035 were lost to follow-up. Of those contacted 14,307 (82%) agreed to participate and completed a questionnaire. Of these, 2,979 survivors were alive and between the ages of 12 and 17 years at contact, and were the focus of this analysis. Nearest-age siblings (regardless of sex) of randomly selected participants were invited to participate as comparison subjects; 649 of these were between 12 and 17 years old at time of interview.
Outcome Measures
We evaluated the behavioral and social outcomes of the study participants using six domains: depression/anxiety, headstrong, attention deficit, peer conflict/social withdrawal, and antisocial and social competence.14 Construct validity for the five domains obtained using the BPI questions was determined by conducting a principal components analysis using data from the cancer survivors and the sibling comparison group, first separately and then together. The number of domains was determined by retaining factors with Eigenvalues equal to or greater than 1.00. Factor loadings were determined for each by orthogonal rotation (varimax). Questions with factor loadings greater than 0.30 were included in the scale for each domain (Table 1). We examined the correlation of the questions within each factor and between each factor and quantified the scales’ internal consistency using Cronbach's alpha (  ). values were .87 for depression/anxiety, .89 for headstrong, .86 for peer conflict/social withdrawal, .80 for attention deficit, and .87 for antisocial. The sixth domain of social competence was determined by summing the scores to six questions about friendships and social interactions. The components of the depression/anxiety domain included such statements as is "is too fearful or anxious," "is unhappy, sad or depressed," and "worries too much." The headstrong domain included "argues too much" and "has a very strong temper and loses it easily." The attention deficit domain included factors characterizing both hyperactive and inattentive behaviors such as "has difficulty concentrating, cannot pay attention" as well as "is restless or overly active, cannot sit still." The peer conflict/social withdrawal domain included 10 statements including "is disobedient at school." The antisocial domain included factors such as "has trouble getting along with other children" and "is not liked by other children." Each question was scored on a scale of 1 to 3, where 1 indicated no observation and 3 frequent observation of a particular behavior. Scores for each domain were determined by calculating the mean of the questions that contributed to that domain, so that domain scores would be in similar dimensions for comparison purposes. Subjects were classified as having significant elevation in a domain if their score was 1.3 standard deviations (approximating 10% of the sibling population) or more above the sibling group's mean score in that domain.
Independent Variables Cancer treatment information, obtained from medical records, was categorized as chemotherapy (yes/no), radiation therapy (yes/no), and surgery (yes/no). Based on previous literature outlining the behavioral effects of intrathecal methotrexate and/or cranial radiation,4,15,16 participants were also classified into four mutually exclusive treatment groups depending on their exposure to CNS cancer therapies: intrathecal methotrexate; cranial radiation; intrathecal methotrexate and cranial radiation; neither intrathecal methotrexate nor cranial radiation.
Data Analysis
Characteristic of the Study Participants Table 2 presents characteristics of the survivor and sibling groups. The sex distribution of survivors and siblings was similar, with slightly more than one half of the study participants being male. Siblings were less likely than survivors to be of black race and were similar in age to survivors at the time of interview (mean ± standard deviation, 14.9 ± 1.6 siblings, 14.8 ± 1.6 survivors; range, 12 to 17 years). Survivors were slightly more likely to have a household income of lower than $20,000 per year (14.8% v 9.1%; P < .01). Nearly one third (29%) of survivors were diagnosed before the age of 2 and 45% were treated for leukemia. The survivor population had a mean age of 3.2 years at the time of their cancer diagnosis (standard deviation, 1.9; range, 0 to 9.9 years) with a mean time from diagnosis to survey of 11.5 years. A combination of chemotherapy and radiation, with or without surgery, was the most common cancer treatment (42%). Of those who received radiation, 60% had CNS directed radiation. With regard to CNS therapy, more than one half of survivors (54%) received intrathecal methotrexate, cranial radiation, or both. Parents were more likely to report disfigurement in survivors than siblings.
Mean Scores Table 3 presents means and standard deviations for survivors by cancer type and treatment characteristics. When compared with siblings, survivors scored poorer in all measured domains. In all domains, those at greatest risk for problems were individuals who had been diagnosed with leukemia, CNS tumors, non-Hodgkin's lymphoma, neuroblastoma, or Wilms’ tumor. For treatment characteristic comparisons, only survivors were considered. Survivors who received any radiation as part of their treatment were reported to have more behaviors indicating depression/anxiety, attention deficit, antisocial behaviors, and diminished social competence than those in the surgery-only group. Within the CNS treatment group, those who received cranial radiation either alone or with intrathecal methotrexate scored higher on the depression/anxiety, attention deficit, and antisocial scales than those who received neither methotrexate nor cranial radiation. Mean scores indicated increased difficulties among survivors with disfigurement although this difference reached statistical significance only in the domains of depression/anxiety, attention deficit, and antisocial behaviors.
Multiple Variable Models In comparing survivors and siblings, we adjusted for sex, age, race/ethnicity, and annual household income (Table 4). Overall, survivors were 1.4 to 1.7 times more likely than siblings to have behavioral and social difficulties in the areas of depression/anxiety, attention deficit, and antisocial domains. Survivors diagnosed with leukemia, CNS tumor, and neuroblastoma had significant elevations in depression/anxiety and antisocial behaviors. In addition, survivors with a history of leukemia or CNS tumors demonstrated attention deficit behaviors and diminished social competence. Survivors of CNS tumors were at 2.6 times the risk of demonstrating increased antisocial behaviors and at nearly twice the risk of having diminished social competence.
Table 5 presents the results of multivariate analyses of survivors for each domain. When compared with survivors who did not receive CNS treatment, those who were treated with cranial radiation or both intrathecal methotrexate and cranial radiation were at increased risk of depression/anxiety, attention deficit, antisocial behaviors, and diminished social competence. Multivariate analyses for siblings were also completed, but without treatment variables (data not shown). Among siblings, limb disfigurement was associated with depression/anxiety (RR, 2.7; 95% CI, 1.3 to 5.5) and antisocial (RR, 2.2; 95% CI, 1.3 to 5.5).
The resources of CCSS have given us the opportunity to examine behavioral and social outcomes of adolescent survivors. We found that most survivors were perceived by parents to be functioning well; however, this comprehensive analysis demonstrates that more survivors have behaviors consistent with difficulties than a comparable sibling group. Survivors of leukemia, CNS tumors, or neuroblastoma are at increased risk. The primary difficulties noted in survivors in this analysis were in the areas of depression/anxiety, attention deficit, and antisocial behaviors. Each of these domains included a number of statements that represent internalizing difficulties such as "worries too much." These internalizing symptoms may cause significant distress to survivors yet may be less apparent to health care practitioners than externalizing symptoms such as impulsive behaviors that may reach clinical attention when they interfere with classroom activities. Previous studies have found that brain tumor survivors exhibit an increased prevalence of social and behavioral problems compared with survivors of other childhood cancers. Mabbott and Spiegler7 found difficulties with social skills and attention in survivors of posterior fossa tumors who received cranial radiation. Survivors of brain tumors have also been found to have increased difficulties with social competence and elevated scores on measures of internalizing, externalizing, and somatic complaints.19 Vannatta and Gartstein found that children who were treated for CNS malignancies were described as socially isolated by teacher-, peer-, and self-report.20 Likewise, we found that survivors of CNS tumors had increased depression/anxiety and antisocial behaviors as well as diminished social competence. Several studies have analyzed neuropsychological outcomes after cranial radiation. Butler et al6 found decreased cognitive efficiency and susceptibility to distraction in survivors who were treated with cranial radiation, especially when combined with intrathecal methotrexate. Similarly, our study found an increase in hyperactivity/attention problems in individuals who received cranial radiation. Hill and Kornblith16 reported survivors who received cranial radiation had worse overall adjustment by self-report on the Psychosocial Adjustment to Illness Scale. Similarly, in a study of 101 adult survivors of childhood cancer, Recklitis et al21 reported that cranial radiation treatment was a significant predictor of distress measured by the Symptom Checklist 90 revised (SCL-90) even after adjusting for other risk factors. In contrast, Noll and MacLean found few differences in behavioral and social functioning (assessed by parental and teacher report) among survivors of acute lymphoblastic leukemia who were 5 to 18 years of age despite varying levels of CNS treatment intensity.22 In our analysis, a history of neuroblastoma was found to be an independent risk factor for adverse behavioral and social outcomes. Previous studies23-26 have associated the opsoclonus-myoclonus syndrome with adverse psychiatric and developmental sequelae. Our medical record abstraction did not assess for this uncommon syndrome, nor did it assess for auditory dysfunction that could also affect the adjustment of neuroblastoma survivors. Survivors with a history of neuroblastoma have been found to have an increased rate of utilization of special education services27 and difficulties with school and friendships.28 Conversely, other studies have shown resiliency29 and even higher intellectual functioning30 in this population. We found that survivors with disfigurement had increased problems with depression/anxiety, attention deficit, and antisocial behaviors. This finding may represent a direct effect of the disfigurement or may reflect the original diagnosis or treatment intensity. Disfigurement has been described as a risk factor for impaired social adjustment in those patients with a history of traumatic injuries such as burns31 as well as in the context of disfiguring head and neck cancers in adults.32 Mulhern33 described moderate to severe disfigurement as a risk factor for decreased social competence in a group of children with brain tumors; however, few other studies have examined this issue among childhood cancer survivors. In our analysis, low household income was associated with increased difficulty in the headstrong, attention deficit, peer conflict/social withdrawal, and antisocial domains. Low household income and the presence of a chronic medical condition have both been described as risk factors for elevated scores on the BPI.14 Studies the CCSS cohort have found household income lower than $20,000 to be associated with increased self-reported psychological distress among adult survivors of brain tumors,34 solid tumors,35 leukemia, and lymphoma.3 Our results cannot be interpreted without taking into account certain limitations. First, our analysis was based on parents’ reports of their child's behavior. Parents might be more attentive to children who have undergone treatment and may worry more about their adjustment compared with their siblings. Parents may be overly sensitive to a perceived lack of friends, fearing that the cancer experience has made it difficult for their child to form friendships. Carpentieri36 found that although parents’ and teachers’ reports provided evidence of psychosocial morbidity among 32 survivors of brain tumors, the adolescents themselves reported minimal difficulties. Parent proxy has been found to be a reliable measure of health-related quality of life for children ages 8 to 11 years37; however, use of parental proxy in adolescents may lead to varying results. Survivors are also more likely to have frequent visits within the medical system that may lead to more prompt or frequent diagnosis difficulties. Our analysis is also unable to determine the underlying cause of specific behaviors. For example, attention deficit behaviors may be related to either underlying cognitive or underlying social or behavioral issues. The demographics of our study population (individuals between the ages of 12 and 17 who survived at least 5 years after a cancer diagnosis) limits the number of survivors of cancers more commonly diagnosed during late childhood or adolescence, such as Hodgkin's lymphoma and bone tumors. Because of the large number of adolescent survivors and siblings available through CCSS, we were able to conduct principal components analysis in the survivor and sibling populations and compare survivors with siblings rather than with previously established population norms. We used a score within the highest tenth percentile of siblings as our threshold of clinical concern. Other studies have used the highest tenth percentile of the normative population as a threshold and have found a correlation with referral for mental health services.14 While some authors report that siblings may be affected by the cancer diagnosis,38 they are similar to the survivor population with respect to possible confounding variables such as socioeconomic status, ethnicity, and family environment. Siblings thus make an appropriate comparison group because results are likely less affected by these extraneous variables than would be the case in a comparison with normative data. Results from this study show a consistent trend of increased difficulty related to specific diagnoses (eg, leukemia and CNS tumors) and treatment factors (eg, CNS treatment), suggesting the need to evaluate survivors for difficulties in these areas during clinical encounters. Symptoms of behavioral and social difficulties in survivors may relate to childhood cancer and its treatment and warrant the evaluation of a multidisciplinary team, including psychologists with experience in the area of childhood cancer survivorship. As therapies for childhood cancer evolve, follow-up studies such as this one will be important in assessing the impact of treatment protocols on survivors’ behavioral and social outcomes.
The author(s) indicated no potential conflicts of interest.
Conception and design: Kris Ann P. Schultz, Kirsten K. Ness, Christopher Recklitis, Brad Zebrack, Lonnie Zeltzer, Ann C. Mertens Financial support: Leslie L. Robison Administrative support: Leslie L. Robison, Ann C. Mertens Provision of study materials or patients: Lonnie Zeltzer, Ann C. Mertens Collection and assembly of data: John Whitton, Lonnie Zeltzer, Ann C. Mertens Data analysis and interpretation: Kris Ann P. Schultz, Kirsten K. Ness, John Whitton, Christopher Recklitis, Brad Zebrack, Lonnie Zeltzer, Ann C. Mertens Manuscript writing: Kris Ann P. Schultz, Kirsten K. Ness, Christopher Recklitis, Brad Zebrack, Leslie L. Robison, Ann C. Mertens Final approval of manuscript: Kris Ann P. Schultz, Kirsten K. Ness, John Whitton, Christopher Recklitis, Brad Zebrack, Leslie L. Robison, Lonnie Zeltzer, Ann C. Mertens
Supported by Grant No. U24 CA55727 (L.L.R.) from the National Cancer Institute, Bethesda, MD, and support provided to the University of Minnesota from the Children's Cancer Research Fund (Minneapolis, MN). Presented in abstract format at the 7th International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, Ontario, Canada, June 9-10, 2006. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Support Care Cancer 7:302-320, 1999[CrossRef][Medline] Submitted September 19, 2006; accepted June 15, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 statistics. Comparisons between survivors and siblings were performed with generalized estimating equations, using a Poisson distribution and a log link. Standardized risk ratios were adjusted for multiple comparisons using a Bonferonni correction for six outcomes,
