Psychological Outcomes, Health-Related Quality of Life, and Neurocognitive Functioning in Survivors of Childhood Cancer and Their Parents.

Childhood cancer disrupts the lives of patients and their families and affects acute and long-term psychological health. This article summarizes (1) psychological challenges, including depression, anxiety, worries, and posttraumatic stress, as well as positive outcomes such as benefit finding and posttraumatic growth in young survivors and parents; (2) health-related quality of life; (3) interventions to support survivors and parents with psychological difficulties; and (4) neurocognitive problems and interventions to help alleviate them. Although many survivors and parents fare well in the long term, many survivors may benefit from interventions. Interventions should be further evaluated and integrated into routine clinical care.


INTRODUCTION
Childhood cancer is a severe disease striking children and their families unexpectedly. In developed countries, 5-year survival currently exceeds 80% 1 ; however, cancer remains the most common disease-related cause of death among children. 2 Treatment of childhood cancer can last several years and often disrupts normal developmental experiences and family home-life routines. These disruptions, in the context of disease-related events and experiences, may leave survivors and family members vulnerable to psychological distress both during and after treatment. Moreover, the effects of cancer-directed therapies may affect survivors' neurocognitive health and health-related quality of life (HRQOL) many years following the completion of treatment.
This article reviews potential psychological and neurocognitive consequences of young survivors (through 21 years of age, and who were diagnosed with cancer before the age of 18 years) and their families, as well as interventions developed to address these late effects. The authors searched PubMed for reviews on the topics of psychological distress, HRQOL, neurocognitive functioning, family/parents, and interventions in survivors of childhood cancer, and complemented these findings with studies identified by experts in the field.

PSYCHOLOGICAL HEALTH AND HEALTH-RELATED QUALITY OF LIFE Psychological Health in Survivors
Psychological health problems in survivors of childhood cancer encompass a variety of outcomes, including depression, anxiety, externalizing behavioral problems, and posttraumatic stress symptoms (PTSS). Psychological health also includes reference to positive outcomes such as benefit finding and posttraumatic growth (PTG; benefit finding and PTG reflect positive outcomes that can be experienced after highly stressful events, such as closer relationships and greater appreciation of life).
Two early reviews showed few psychological difficulties in young survivors of childhood cancer, 3,4 and reported similar outcomes for childhood cancer survivors and children from the general population. 4 Overall, these findings were confirmed in a later review showing that up to 80% to 90% of survivors are psychologically well. 5 However, many survivors do report both negative and positive outcomes after cancer treatment. 6 A considerable number of survivors report psychological problems, and, even if symptoms are not severe enough to warrant a clinical diagnosis, they might impair HRQOL, and many survivors benefit from support or interventions. An overview of included reviews is provided in Table 1 and summarized here.
General distress: overall, reviews show that around 6% to 30% of young survivors report symptoms of psychological distress. 5,7 Survivors report decreased positive mood and self-esteem and increased sleeping difficulties and problem behaviors,

Continued
Neurocognitive problems are highly prevalent, particularly among survivors who received central nervous system-directed therapies. Pharmacologic and nonpharmacologic treatment approaches should be considered. Various interventions to help survivors and their families to cope with and adapt to the cancer experience have been developed, but there is a lack of rigorous evidence on their effectiveness and few are implemented into routine care.    with overall generally small to medium effects. 6 A large study using data from almost 4000 adolescent survivors of childhood cancer participating in the Childhood Cancer Survivor Study (CCSS) showed that around two-third of survivors had no significant parent-reported behavioral, social, or emotional symptoms. However, around 16% showed increased externalizing behaviors (eg, aggressive or antisocial behavior), 9% showed increased internalizing behaviors (eg, symptoms of depression, anxiety, or social withdrawal), and 5% experienced increased global symptoms (both internalizing and externalizing) compared with siblings. Internalizing problems were especially prevalent among survivors who had been treated with cranial radiotherapy, with 31% showing these problems (although none showed externalizing problems only). 8 Survivors of leukemia or central nervous system (CNS) tumors, survivors who were older at diagnosis, women, those self-reporting late effects, and those whose parents experienced distress were shown to be at higher risk for psychological distress. 5,6 Anxiety: There are mixed results regarding the experience of anxiety after childhood cancer. 9 This finding might be caused by changes in anxiety with increasing time posttreatment. Shortly after end of treatment, survivors report experiencing more anxiety, which then decreases by 2 to 3 years posttreatment. 6 Higher anxiety can be experienced when children are returning to school and might interfere with school-entry. 9 Studies have also shown that social anxiety might increase with time after treatment and can be particularly associated with perceived illness impact and poor body image. 9 Also, adolescent survivors are at particularly high risk for experiencing anxiety, rather than other forms of distress. 9 Related to anxiety are worries. Survivors commonly report worries about relapse, disclosing their illness to peers and potential romantic partners, fertility, and potential cancer risk for their children. 9 Worries may increase the likelihood of risky behavior (eg, alcohol consumption) and decrease positive health behavior (eg, exercise). 9 However, many survivors also report feeling less worried about headaches, body image, being tired, minor illnesses, and dying. 9 Risk factors for reporting more worries depend on the type of worries but include older age, female sex, diagnosis (CNS tumor, lymphoma, Wilms tumor, other tumors), risk awareness, and perceiving the illness as not being caused by chance. 9 Depression: similar to anxiety, results are mixed with respect to the experience of depression in young survivors of childhood cancer. Some studies indicate that survivors are less depressed than peers, 3 or show small effects for risk of increased depression and emotional instability. 6 However, subgroups of survivors do seem to be at increased risk of depression. For example, 1 review of 8 studies on children with craniopharyngioma indicated that 40% of these survivors reported affective dysfunction, mainly depression. 10 In addition, reports on antidepressant use among survivors generally suggest that survivors are more likely to be prescribed antidepressants than the general population, with survivors treated with stem-cell transplant and solid tumors in the extremities at highest risk. 11 PTSS seem to be common among adolescent survivors of childhood cancer, with a current prevalence of 2% to 20% and a lifetime prevalence of 21% to 35%. 5,12,13 However, the prevalence is not as high as in adolescents who have experienced other forms of trauma. 13 In contrast with other traumas, there is some indication that PTSS do not decrease with increasing time following cancer diagnosis. 12,13 A recent study found that, although PTSS are common, posttraumatic stress disorder (PTSD) is rare in young survivors. 14 Risk factors for PTSS among cancer survivors include female sex, poor family functioning, parental PTSS, experiencing late effects of treatment, relapse, anxiety, perceived life threat, and greater treatment intensity. 9,13 However, other studies have found that objective disease and treatment severity are not associated with experience of PTSS. 12,13 Many survivors also report positive outcomes such as increased sense of selfworth, good behavioral conduct, and psychosocial hardiness after childhood cancer. 6 Posttraumatic growth (PTG) 15 is a frequently reported positive outcome of childhood cancer, not only in survivors but in the family as a whole. Childhood cancer survivors often report positive outcomes related to making sense of the cancer experience (meaning making), appreciation of life, greater self-knowledge, positive attitudes toward the family, and desire to give back to society. 16 In childhood cancer survivors, PTG seems to be associated with older age at diagnosis and at measurement. 17 It seems that a certain developmental stage (and cognitive capacity) is necessary to experience PTG; however, with increasing time following diagnosis, there may be a decrease in the experience of PTG. 17 More social support and higher optimism have been shown to be associated with higher levels of PTG. 17

Psychological Outcomes in Parents of Childhood Cancer Survivors
Parents experience high levels of distress when their child is diagnosed with cancer, 18 which remain increased throughout treatment. 19 With increasing time after diagnosis, overall parents' distress tends to decrease, although there is a substantial subgroup of parents who experience persistent psychological distress in the long term. Reviews summarizing psychological outcomes in parents are shown in Table 2. 18,20,21 At particular risk are mothers 19 and parents who experienced high levels of distress, problematic coping, and adjustment difficulties shortly after diagnosis and in early treatment. 20,21 With end of treatment, positive feelings such as relief predominate, but at the same time uncertainty can increase. 20 Parents become aware about the possibility of relapse and worry about the child's health, social life, and possible infertility. 20,21 Some report high levels of anxiety, anger, guilt, or self-blame. 20,21 A subgroup of parents also experience posttraumatic stress. Concurrent prevalence of PTSD is estimated at 6% to 30% and lifetime prevalence at 27% to 54%, which is higher than among parents in the general population. 12,13,21 PTSS also seem to be more frequent in parents than in survivors 13 and are more prevalent in mothers than in fathers. 18 Additional risk factors are low social support, problems with family functioning, and prior stressful life events. Parents' subjectively experienced severity of the cancer diagnosis and treatment is associated with PTSS, whereas the objective severity is not. 13 Also, the presence of PTSS in one partner is associated with PTSS in the other parent. 12 Similar to survivors, parents also report psychological growth. 22 Mothers report positive experiences, such as improved relationships and a change in values, whereas fathers tend not to report these experiences. 16,21 One recent review indicated that social support and access to psychological counseling starting after diagnosis of cancer in the child and continuing during treatment can help parents in the long term. 21 Nonetheless, psychosocial support systems should also be available to parents in need after their child's cancer treatment completion. 23

Health-Related Quality of Life
The World Health Organization defines childhood HRQOL as "a child's goals, expectations, standards or concerns about their overall health and health-related domains." 24,25 With a growing number of children with cancer surviving, HRQOL has gained increasing attention in pediatric oncology research. When measuring HRQOL, it is important to take into account generic versus disease-specific questionnaires,   age-specific questionnaires with a narrow versus a wide age range, self-report versus proxy report, and paper-pencil versus online questionnaires. 26 The number of questionnaires being used is large, with the Pediatric Quality of Life Inventory (PedsQL) among the most often used in children, 27,28 and questionnaires such as the Short Form-36 (SF-36) 29 in adults. HRQOL of survivors has mostly been examined in comparison with healthy peers or siblings.

Survivors of Childhood Cancer and Their Parents
Although results of single studies are mixed, the overall picture indicates that children experience reduced HRQOL during treatment, which then returns to normal or even improves after completion of therapy and into survivorship. 30,31 Pediatric CNS tumor survivors experience worse HRQOL compared with both general population norms as well as survivors of other types of cancer. [32][33][34] Acute lymphoblastic leukemia (ALL) survivors tend to report lower HRQOL compared with healthy controls, but better HRQOL than survivors of other cancer types. 35 However, some studies have shown that survivors may report better quality of life than their peers, 30,31 which may be caused by response shift (being able to compare with a time in life when HRQOL was worse) or PTG. 30 It is important to monitor and discuss HRQOL, symptoms, and psychosocial functioning in daily clinical practice, which can be facilitated by portals such as the evidence-based KLIK PROM portal. 36 Medical factors are the most frequently studied risk factors and include characteristics of the disease (diagnosis) and treatment (intensity). Results have been mixed, but fairly consistent risk factors associated with low HRQOL in survivors include certain cancer and treatment types 30 and presence of medical late effects. 27,31,35 CNS tumor survivors are at risk for poor HRQOL if they had an infratentorial tumor, cranial radiation therapy, or hydrocephalus. 34 CNS tumor survivors with lower intelligence quotient and behavioral problems are also at increased risk of poor HRQOL. 34 Among bone tumor survivors, meta-analyses showed no differences in HRQOL between patients who underwent limb-sparing surgery versus amputation. 37 Many determinants have been studied in relation to HRQOL, but these show conflicting results, likely because of the small number of studies per determinant and different HRQOL questionnaires used. 27 Just as with healthy peers, women are at higher risk for reduced HRQOL. 27,30,37 Other risk factors include older age at diagnosis 27,30,31,33,37 and socioeconomic disadvantage. 27,30 Studies have thus far rarely focused on more personal protective family and child factors, 27 although some positive results have been shown for positive coping or social support. 31

Psychological Interventions for Young Childhood Cancer Survivors and Their Parents
There is an increasing focus on developing interventions to attempt to improve outcomes for families affected by childhood cancer. 38 Table 3 summarizes interventions that have been trialed for young childhood cancer survivors and/or their parents.
The Surviving Cancer Competently Intervention Program (SCCIP) is the intervention that has been trialed most extensively to date. SCCIP is a family-focused intervention underpinned by cognitive-behavioral principles and family systems approaches, aiming to reduce PTSS in survivors, parents, and siblings. 39 The 1-day manualized SCCIP program is delivered via 4 sessions to 6 to 8 families together. One randomized trial reported that survivors who participated in SCCIP had fewer arousal symptoms than controls, whereas fathers in SCCIP experienced fewer intrusive thoughts than control fathers. 40 There were no significant effects of SCCIP on mothers or siblings, and the program did not affect anxiety for any group. A subsequent trial including families at the time of cancer diagnosis (SCCIP newly diagnosed) did not result in    significant differences in the measured outcomes. 41 An e-health version of SCCIP has recently been piloted, suggesting that eSCCIP may be acceptable, feasible, and usable. 42 Also focused on provision of psychosocial support to whole families is the more recent Family-oriented Support (FAMOS) intervention. 43 The 6-module intervention is delivered in families' homes, which may have enabled a large number of fathers (60 fathers from 68 families) to participate in a randomized controlled trial (RCT). The FAMOS feasibility and acceptability data are promising, with most invited families agreeing to participate and 93% of parents completing all FAMOS sessions. Evaluation revealed largely positive acceptability data, with parents also reporting that they learnt useful cognitive skills (73%) and that they used cognitive behavior therapy (CBT) skills since completing the intervention (47%). 43 Psychosocial outcomes data are forthcoming.

Survivors of Childhood Cancer and Their Parents
Three interventions have focused on survivors directly, rather than whole families. The 6-session OK Onco program is designed to improve information seeking, relaxation, social competence, and positive thinking. 44 The pilot reported positive outcomes, particularly on social competence and positive thinking. Qualitative focus group data suggested that the intervention was appropriate for young survivors. A pilot of an online version (OK Onco Online) reported high levels of satisfaction and low dropout rate. 45 Focusing on survivors in the adolescent and young adult (AYA) age range, Heros Plus 46 offered AYAs 7 30-minute telephone sessions to develop skills to cope with uncertainty in illness. An RCT reported promising findings (particularly for benefit finding), although the small sample size precluded significance testing. A recent 3-arm randomized trial 47 of the online Recapture Life program reported that Recapture Life was acceptable to survivors, feasible to deliver, and did not increase participants' distress across the 6-week program. 48 In addition, 2 interventions have focused on delivering psychological support directly to parents to improve coping skills and reduce distress. In Iceland, Bragadottir 49 offered a 4-month computer-mediated support group intervention, reporting declines over time in mothers' depression and fathers' anxiety symptoms. Fathers also experienced an improvement in perceived stress over time. In Australia, Wakefield and colleagues 50 offered parents an online group videoconferencing intervention (Cascade [cope, adapt, survive, life after cancer]), reporting that the intervention was feasible to deliver and acceptable to parents. However, there were no significant differences in quality of life between parents who participated in Cascade compared with wait-listed parents immediately postintervention or after 6 months. An enhanced version of Cascade is currently being assessed in a 3-arm RCT. 51 Although the data discussed earlier seem promising, they are not conclusive with regard to effectiveness. Reported effect sizes are typically small and several interventions have not reported significant effects on any measured outcomes. There may be several factors driving the modest findings reported to date. Most trials recruited small samples 44,46,[48][49][50] or did not use a control group. 44,49 Interventions included heterogeneous groups (eg, survivors with all types of tumors) and did not prescreen participants for existing distress. Given the emerging evidence that tailored interventions for more distressed participants can yield stronger effects than standardized interventions, 52 there is a clear need to evaluate tailored interventions for patients most at risk. It is also possible that current trials have not selected the most appropriate outcome variables, suggesting a need to adopt measures that sensitively assess clinically important outcomes. 52 There are also several other trials, not included in this review, that used marginally different eligibility criteria, 53,54 related domains such as social skills, 55,56 health knowledge/perceptions, 57 or sleep, 58,59 or included families of children with chronic illness. [60][61][62] There are multiple opportunities to improve future intervention trials. Conducting larger studies using more standardized intervention approaches and research designs would enable pooling of results to test effectiveness more rigorously. 63 There is a lack of evidence regarding whether psychological interventions can achieve long-term change for this population, with most studies to date focusing on short-term impacts (with the exception of FAMOS 43 and Recapture Life 50 ). There is also a need to consider how best to provide support for men, especially fathers, who are currently underrepresented in research studies. 40,50 As e-health interventions become increasingly prevalent, future studies need to carefully consider the potential benefits and challenges of delivering online psychological support to families of childhood cancer survivors. 63 In addition, to date, few (if any) interventions have been successfully integrated into routine clinical care. An ongoing challenge will be to identify sustainable strategies to enable interventions to continue to be offered to families into the long term.

NEUROCOGNITIVE FUNCTIONING Neurocognitive Problems
Survivors of childhood cancer are at risk for developing neurocognitive impairments secondary to their disease and treatment. Although prevalence estimates vary across studies, more than 35% of survivors may experience neurocognitive late effects. 64 Survivors of CNS tumors are at the greatest risk of developing neurocognitive impairments. 65 Beyond deficits in general intelligence, impairments are often observed in processing speed, executive functions (eg, verbal fluency, cognitive flexibility), memory, and attention. 64,66,67 The most salient risk factors for impairment in CNS tumor survivors include higher dose of cranial radiation therapy (CRT), larger brain volume irradiated, and younger age at diagnosis. 65 In addition, female sex, obstructive hydrocephalus, posterior fossa syndrome, and seizures have been identified as risk factors for neurocognitive impairment. 64,65 The risk of impairment following CRT often increases in a dose-dependent manner; however, younger age at CRT remains the most important risk factor even at a lower CRT dose. 67 Importantly, advances in CRT techniques have resulted in significant dose and target volume reductions to healthy brain tissue and have been shown to reduce neurocognitive morbidities. 66,68,69 Proton CRT minimizes dose exposure to normal brain tissue, and early studies suggest improved outcomes following treatment with proton CRT, [70][71][72][73] although long-term follow-up data are needed.
Increased rates of neurocognitive impairment also have been reported in survivors of childhood leukemia. 65,74 Historically, CRT prophylaxis was a critical component of curative therapy for ALL and was strongly associated with neurocognitive impairment, with higher doses of CRT conferring greater risk for poorer outcomes. 74 Contemporary treatment protocols, which consist of intensified intravenous and intrathecal chemotherapies (ie, methotrexate, cytarabine) for standard-risk patients, have resulted in reduced neurocognitive morbidities. 65,75,76 However, survivors of ALL remain at heightened risk for neurocognitive impairment compared with population norms and healthy controls. 75,77 Risk factors include female sex, younger age at diagnosis, and longer time since diagnosis. 65 Among survivors treated with chemotherapy only, longitudinal data suggest that many ALL survivors develop attention problems by the end of therapy 78,79 and present with executive dysfunction and processing speed deficits more than 5 years after diagnosis. 78 Neurocognitive impairments can have a significant impact on educational and functional outcomes for survivors. 80 A recent meta-analysis reported that childhood cancer survivors are significantly less likely to complete secondary or tertiary level Survivors of Childhood Cancer and Their Parents education compared with their classmates without cancer and more likely to require special education services. 81 Moreover, among survivors of ALL and CNS tumors, neurocognitive deficits have been associated with reduced rates of college graduation, employment, and independent living in adulthood. 66,75 Interventions for Neurocognitive Problems Educational accommodations are among the most routinely provided interventions to survivors of childhood cancer. Common accommodations provided in the classroom include shortened or modified assignments, extended test-taking time, copies of class notes, modified seating within the classroom, and specialized instruction. 65 Researchers have investigated several targeted treatment approaches focused on the remediation of specific neurocognitive deficits. Early pharmacologic studies investigated the short-term and long-term efficacy of the psychostimulant methylphenidate in survivors of CNS tumors and ALL. 82,83 In 1 study, methylphenidate was associated with improved attention and social skills in survivors, but similar gains in academic performance were not observed. 82 A 24-week trial of the acetylcholinesterase inhibitor donepezil was associated with improvements in executive functioning and visual memory in brain tumor survivors. 84 Promising nonpharmacologic intervention approaches have included home-based computerized cognitive training such as Cogmed. [85][86][87] Improvements have been observed in the cognitive skills targeted by the interventions (eg, working memory), with maintenance of gains observed at 6months after the intervention. 87 More recently, investigators have examined the impact of physical activity interventions on neurocognitive functioning in childhood cancer survivors. A 12-week group-based exercise intervention was associated with improved reaction time and increased white matter and hippocampal volume in brain tumor survivors, 88 whereas a 24-week Web-based physical activity intervention was associated with improved inhibitory control in a heterogeneous group of survivors; however, the observed improvement was not maintained at a 6-month follow-up. 89 In contrast, a recent examination of neurofeedback in brain tumor survivors did not show positive effects on attention, memory, processing speed, or executive function. 90

SUMMARY
Despite largely positive outcomes for survivors of childhood cancer and their families, there remains a substantial group who have psychological, HRQOL-related, and neurocognitive problems. If untreated, these problems can persist into adulthood and verylong-term survivorship. 91 Several interventions have been developed and tested, with promising findings reported in pilot studies and small-scale RCTs. There is a critical need to offer survivors and their families targeted support, starting with the diagnosis of cancer and continuing through treatment and into survivorship. Recently published psychosocial standards of care for childhood cancer survivors 92 can be used as a framework to implement and evaluate the efficacy of interventions in the future.

DISCLOSURE
The authors have nothing to disclose.