Treatment of childhood cancer is a highly stressful experience, challenging and disruptive to children and their family members. It is therefore assumed that children undergoing cancer treatment are at significantly higher risk for depression, anxiety, and other indicators of psychological distress. However, the empirical evidence to support this assumption is weak. Overall, studies suggest that children treated for cancer and children who are long-term survivors of cancer experience few significant psychological adjustment problems.[1-3]
There is evidence that children experience distress during the cancer treatment process. Distress appears to be most significant early in therapy, typically when frequent hospitalizations are necessary, with a pattern of less distress occurring over time.[4,5] One group of 39 families of children newly diagnosed with leukemia was compared with a group of 49 families of healthy children. While parents and the children treated for cancer reported higher levels of distress immediately following diagnosis, these levels of distress decreased over 4 years of follow-up, and there were no significant differences in psychological distress compared with the healthy comparison cohort. Similar findings have been reported across cultures.
The validity of obtaining accurate reports of psychologic distress in this population has been questioned. One investigation of whether psychological defensiveness might mask the reporting of depression and other symptoms of psychological distress studied 107 children treated for cancer and 422 healthy controls who completed a series of measures of depression and anxiety.[Level of evidence: II] Children treated for cancer reported significantly fewer depressive symptoms than did healthy children, and defensive style was not related to report of depression. Another study of 205 children and 321 parents of children with either cancer, asthma, or no significant health problem also found no significant levels of depression in children treated for cancer. However, parents of children with cancer attributed more cheerful characteristics to their children than did the parents of children in the other groups.[Level of evidence: II]
Studies have reported no differences from controls on the following measures:
One group of investigators  found that teachers perceived children with cancer as more social and less aggressive, and peers rated them as less aggressive and having greater social acceptance than other peers. It may make a difference who is reporting: parents of children report more limitations in their children than the children themselves report, although children do report lower satisfaction with athletic competence than do their peers.
Differences in Adjustment
Diagnosis and type of treatment appear to make a difference in adjustment in specific subgroups of children with cancer.
Children treated for solid tumors not involving the central nervous system (CNS) appear to have minimal psychological distress, and this is maintained after treatment.
Acute lymphoblastic leukemia or lymphoma
Children treated for acute lymphoblastic leukemia (ALL) or lymphoma report poorer emotional functioning, cognitive skills, autonomy, and family interaction than do children treated for non-CNS solid tumors.
For children whose disease or treatment directly involves the CNS, the risk of developing social and emotional problems appears much greater. Children with brain tumors are seen by their peers as being sick, fatigued, absent from school, and socially isolated and are less likely to be endorsed as friends by their peers.
Stem cell transplantation
Children receiving hematopoietic stem cell transplantation (HSCT) are likely to experience declines in both social competence and self-concept over time.
Ethnicity can also play a role in quality of life.
Family factors appear to play a large role in child adjustment, with family cohesion and expressiveness associated with better outcomes and family conflict associated with poorer outcomes, particularly for children experiencing more-intensive treatment. Younger (pre-school) children are more likely to experience higher levels of externalizing behavior problems (e.g., aggression, impulsivity, or disruptive behavior) during treatment than do adolescents, but overall health-related quality of life (HRQL) reported by parents is better for younger children than for adolescents. Age may also serve as a mediator in the approach to coping and perceived level of control experienced by children being treated for cancer. While one group of researchers found that children with cancer reported significantly more use of avoidant coping strategies than did healthy children, regardless of age, another group found that the relationship between perceived control and problem-focused or emotion-focused coping (problem-focused coping related to higher appraisals of control) was mediated by age. A limited number of studies has been conducted in this area, and there are likely a number of additional mediators of adjustment-coping relationships that have not yet been examined.
Childhood Cancer Survivor Study
The Childhood Cancer Survivor Study (CCSS) is a large, ongoing, multicenter study of more than 10,000 long-term survivors of childhood cancer and a comparison sibling control population. Using extensive survey methodology that links reports of current functioning to diagnosis, types of treatment, and other health factors associated with cancer and its treatment, the CCSS has selectively looked at long-term adjustment in large samples of young adults treated for similar childhood cancers. In one CCSS report, 2,778 survivors of solid tumors diagnosed in childhood and 2,925 siblings were surveyed using a standardized long-term follow-up questionnaire. Symptoms associated with depression, somatization, and anxiety were reported, along with demographic, health, and medical information. Few, if any, symptoms of psychological distress were reported by the cancer survivors, although survivors of solid-tumor cancers reported higher levels of global distress than did their siblings. There were no differences on these measures from population norms. For both cancer survivors and their siblings, female gender, lower education and income attainment, perceived poor health status, and reports of current health problems were all associated with higher levels of psychological distress symptoms.[Level of evidence: II]
Positive findings also have been reported by the CCSS for young adults who are survivors of leukemias and lymphomas. Follow-up questionnaires about psychological adjustment were administered to 5,736 young adult survivors of leukemia, non-Hodgkin lymphoma, and Hodgkin disease and to 2,565 adult siblings. Survivors reported higher levels of depressive symptoms and somatic distress than did siblings, but scores for neither group fell within the clinically significant range for the general population. Sociodemographic factors such as gender and socioeconomic status were associated with reports of depressive symptoms, regardless of treatment status. The only disease-related factor associated with psychological distress was intensive chemotherapy, which was associated with an increase in somatic complaints.[Level of evidence: II] Similar outcomes were reported for survivors of brain cancers. Brain tumor survivors reported higher levels of depressive symptomatology than did siblings, but the rates for both groups were similar to rates for the general population.[Level of evidence: II] A summary of the main psychosocial outcomes reported by the CCSS is available.[Level of evidence: II] Other reports from the CCSS address alcohol consumption, the role of physical limitations on HRQL,[Level of evidence: II] fatigue, and sleep.
Depression and Suicide
Young adult survivors of childhood cancer may have an elevated risk for suicidality. A report from Eastern Europe compared the responses of 228 long-term survivors of childhood cancer with those of 127 controls to the Center for Epidemiologic Studies Depression Scale (CES-D) and the Suicidal Ideation and Behaviour Questionnaire. The rates of depressive symptoms reported by the childhood cancer survivors were three times the rates reported by the controls, with 13% indicating some level of suicidal ideation. Similarly, 226 adult survivors of childhood cancer seen in a survivor clinic completed the Short Form-36 (SF-36), the Beck Depression Inventory (BDI), and suicide items from the Symptom Checklist-90-Revised (SCL-90-R) and the Beck Scale for Suicide Ideation (BSS). The measures assessed whether the survivors had ever attempted suicide or whether they had experienced significant suicidal ideation within the past week; 29 participants (12.83%) reported suicidality. Suicidality was associated with younger age at diagnosis, longer time since diagnosis, cranial radiation therapy, a diagnosis of leukemia, pain, and concerns about physical appearance. Current physical condition, including pain, was associated with suicidality.[Level of evidence: II] These studies represent relatively small samples with small comparison groups and may reflect a reporting bias represented in individuals who actively attend follow-up clinics. Nonetheless, while these results are inconsistent with other findings related to psychological distress, they do suggest the need for ongoing monitoring and surveillance of adults who are survivors of childhood cancer.
Significant concern about the potential for suicide as a side effect of selective serotonin reuptake inhibitors (SSRIs) has led the U.S. Food and Drug Administration (FDA) to issue a caution about their use that includes the importance of careful monitoring of potential risks. Before this FDA Health Advisory was issued, clinical experience and the results of small clinical trials suggested that antidepressants can be safely administered to adult cancer patients, although there are no controlled clinical trials to support this position. The risk/benefit ratio for use of SSRIs may not be as favorable for children and adolescents. Several multicenter, double-blind, randomized, placebo-controlled clinical trials using SSRIs with children and adolescents with major depressive disorder but not cancer found modest improvements for fluoxetine,[28,29] paroxetine, and sertraline.[Level of evidence: I] Balancing these improvements were reports of serious adverse events that included worsening of psychiatric symptoms, increased suicidal ideation and gestures, increased conduct problems or hostility with paroxetine, and suicide and suicide attempts with sertraline.[Level of evidence: I]
None of these clinical trials have included or focused on children and adolescents being treated for cancer. Risk/benefit concerns have reached the level of international regulatory concern. The Medicines and Healthcare Products Regulatory Agency of Great Britain has recommended that most of the drugs in the SSRI category not be used with children and adolescents, and the FDA raised similar concerns in a Talk Paper and subsequently issued a “black box” warning. A major meta-analysis published in the Journal of the American Medical Association reanalyzed the data from the child and adolescent studies [Level of evidence: I] (including seven studies not included in the initial meta-analysis [Level of evidence: I]) using a random-effects model. While this reanalysis found an overall increased risk of suicidal ideation/suicide attempt consistent with the initial meta-analysis, the pooled risk differences were found to be smaller and statistically insignificant. Furthermore, another study examining the U.S. and Dutch data suggests a drop in SSRI prescriptions for children and adolescents and a simultaneous increase in suicide rates in this patient population since the FDA Health Advisory was issued.
In summary, the risk/benefit equation favors appropriate use of antidepressants with careful monitoring for suicidality. The British Committee on Safety of Medicines considered only one of the SSRIs (fluoxetine) to have a favorable balance of risks and benefits, but it is only considered beneficial in approximately one in ten patients. Consistent with this finding, age-stratified analyses of the child and adolescent studies found that for children younger than 12 years who have major depression, only fluoxetine showed benefit over placebo.
As noted, none of the children or adolescents in these studies had cancer, so there are no reports available that address whether there are additional increased risks of adverse events associated with the use of SSRIs following exposure to different chemotherapeutic agents and/or CNS radiation treatment. Frontline, alternative, effective, behavioral, and pharmacologic treatments for depression should be used for children and adolescents being treated for cancer. However, if the risks of depression are significant and SSRIs are considered, consultation with a child psychiatrist or neurologist is essential, and close monitoring of potential adverse events is crucial.
Post-traumatic Stress Disorder and Post-traumatic Stress Symptoms
The cancer treatment experience may be considered a significant traumatic event, given the nature of diagnosis, the number of invasive and painful procedures, and the often long hospitalizations that children and their families must experience. On the basis of this exposure model, a number of studies have examined whether children treated for cancer are at a significantly higher risk for the development of symptoms of post-traumatic stress disorder (PTSD). The results of these studies have been mixed. One study reported that children and adolescents who were undergoing treatment reported some symptoms of post-traumatic stress; however, for most children these symptoms did not meet the criteria for a diagnosis of PTSD, and the symptoms diminished over time.[Level of evidence: II]
Other studies suggest that survivors of childhood cancer have an increased risk for post-traumatic stress symptoms and PTSD after treatment is finished. In a study of 78 adults aged 18 to 41 years who had been treated for childhood cancer, 20.5% met the criteria for a diagnosis of PTSD at some time since the end of their treatment. Clinically significant events of intrusive symptoms (9%) and avoidant symptoms (16.7%) were reported in the sample, and the symptoms were associated with elevated reports of anxiety and other measures of psychologic distress.[Level of evidence: II] Survivors who report higher levels of uncertainty about their disease and future appear to be more likely to have elevated reports of post-traumatic stress symptoms.[Level of evidence: II] A study of 182 adolescent and young adult cancer survivors who were more than 5 years from diagnosis and more than 2 years from completion of cancer treatment also found that 16% met the criteria for PTSD. A relationship between PTSD and higher levels of other psychological problems was also reported. When survivors meet the criteria for PTSD, they are more likely to experience depression and negative affect, lower satisfaction with life, and poorer reported HRQL, as well as difficulty performing developmental tasks.[Level of evidence: II]
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