Childhood Cancer and Post-Traumatic Stress Disorder: A Review of Conceptions, Interventions Controversies and Future Directions Catherine MacLean

Wesleyan University: Psychology of Stress and Health, Professor Quillen

Abstract A life-threatening illness is considered a qualifying stressor for a diagnosis of PTSD as of the 1994 edition of the DSM-IV (Bruce, 2006; Kangas et al., 2002; Stuber et al., 2011; Hobbie et al., 2000). Childhood cancer, while advances in treatment have been made, still represents a significant life threat to a child. In addition, extensive and invasive treatments can be a source of trauma. Many studies have investigated the incidence and correlated factors in post-traumatic stress disorder and post-traumatic stress symptoms in survivors of childhood cancer. While rates of PTSD/PTSS vary across studies, they are not markedly higher than those of the average population. What is notable is the apparent late onset and independence from objective medical measures of these symptoms in childhood cancer survivors. These findings may be due to difficulties and controversies in applying PTSD criteria to cancer, or in applying it to young children. Due perhaps to methodological, conceptual, and logistical difficulties, there is a dearth of work in interventions for such symptoms, but several very promising avenues for such treatment exist. This is a critical area of research given the health and quality of life implications of this type of psychopathology in childhood cancer survivors.

Childhood Cancer and PTSD Childhood cancer generally describes a group of cancers commonly seen in children,

including leukemias, brain tumors, and less commonly, lymphoma and bone and soft tissue tumors (Taieb et al., 2003; Bruce, 2006; Hobbie et al., 2000). Until fairly recently, the vast majority of childhood cancer patients did not survive, but enormous improvements in treatment in the past two to three decades has brought the overall survival rates for childhood cancer to 70% (Bruce, 2006; Hobbie, et al. 2000; McDougall & Tsonis, 2009). These advances nevertheless involve severe treatments such as high-dose chemotherapy, surgery, cranial radiation and bone marrow transplantation. These interventions, and the diagnosis itself, can be a trauma (Patenaude et al., 2005; Hobbie et al., 2000; Bruce, 2006; Stuber et al., 2011). Post-traumatic stress disorder (PTSD) is a documented diagnosis that first appeared in the DSM in 1980. It has several criteria: a life-threatening traumatic event as a precipitator and symptoms of re-experiencing, avoidance, and arousal. For a clinical diagnosis x criteria must be met within x amount of time, and of a severity that is limiting to daily functioning. Posttraumatic stress symptoms (PTSS) can be seen in individuals who meet some but not all of the criteria for PTSD (4th ed., Diagnostic and Statistical Manual; American Psychiatric Association, 1994). In 1994, life-threatening illness of ones self or ones child was added to the list of precipitating traumatic events (4th ed., DSM: APA; Bruce et al., 2006; Stuber et al. 2011; Hobbie et al., 2000). PTSD and PTSS have been documented in adult survivors of cancer to further this point (Kangas et al., 2002).

PTSD/PTSS Incidence and Symptoms A large number of studies and systematic review articles have been published looking at childhood cancer survivors and the incidence of PTSD/PTSS among them. The challenge in evaluating these articles is the varied life points at which the survivors are assessed, and the

varied measures with which they are assessed. Some studies look at children and adolescents (Patenaude & Kupst, 2005; Kazak et al., 2007) while others look at adolescents (Hobbie et al., 2000; Kazak et al 2004; Langeveld et al., 2004b), young adults (Taylor et al., 2012; Hobbie et al., 2000; Meeske et al., 2001; Rourke et al., 2007; Stuber et al., 2011; Lee & Santacroce, 2007; Santacroce & Lee, 2006), or adults (Zeltzer et al., 2008; Recklitis et al., 2003; Langeveld et al., 2004a; Stuber et al., 2010) . Systematic reviews considering these groups all together list the lifetime range for full official PTSD diagnosis between 2 and 20% (Bruce, 2006; Taieb et al. 2003; McDougall &Tsonis, 2009). Rates for PTSS in at least one PTSD criterion have been reported to be as high as 78% (Kazak et al., 2004). In general, the rates of PTSD are not found to be higher than the general population for younger survivors, though when comparisons are made to groups such as the siblings of the survivors, or victims of a natural disaster, the rates in cancer survivors are measurably higher (Bruce, 2006; Zeltzer et al., 2008; McDougall & Tsonis, 2009). This difference in findings may be due to different measures being used. Depending on questionnaire type, the correspondence of survivors results to comparison populations can vary. Some studies used only PTSD-RI questionnaires or an Impact of Event Scale (IES) while others added additional measures such as the Basic Symptom Inventory (BSI) or the RAND SF-36 measure of quality of life (Meeske et al., 2001; Stuber et al., 2011; Langeveld et al., 2004a; McDougall & Tsonis, 2009). As Meeske et al. point out, the type of questionnaire is highly relevant to the results obtained (2001). Indeed, Recklitis et al. found relatively low levels of PTSD in their study, but use of the BSI revealed significant clinical levels of distress in some survivors (2003). This may be indicative of survivors who have PTSS or cormorbid psychopathologies but do not qualify for full PTSD diagnosis. It is also posited that given that the large majority of survivors do not display clinically significant symptoms, their results will

mask those survivors who do in relatively small studies being conducted (Meeske et al., 2001). The rates of PTSD are in some cases markedly higher, sometimes reaching significance as compared to the general population, in young adult survivors, especially as compared to rates for child survivors (Hobbie et al., 2000; Meeske et al., 2001; Rourke et al., 2007; Stuber et al., 2011). This is a finding unique to cancer survivors, as victims of other types of trauma show a decrease in rates of PTSD or PTSS as the time since the trauma increases. This result is not consistent however (McDougall & Tsonis 2009; Zeltzer et al 2009). There are several proposed explanations for this anomaly. The most prevalent is the potential for variations in the effect of trauma as development occurs. It is possible that the measures used to document PTSD do not perform adequately for children, and indeed they have been shown to display characteristically different symptoms of PTSD, including sleepwalking and generalized anxiety (Bruce, 2006). It may be that the measures developed for adults do not detect PTSD in children or adolescents. Possibly children do not have the awareness to express their PTSD symptoms prior to a certain age or developmental stage (Meeske et al., 2001). It has also been posited that the challenges of young adulthood force survivors to fully confront their history and its implications for the first time, which triggers the symptomology (Hobbie et al., 2000; Lee & Santacroce, 2007; Santacroce & Lee, 2006) There are other controversies in applying the PTSD model to childhood cancer survivors. There are not child-specific measurement tools for PTSD in children, and the unique features of the disorder in children make broad applications of the adult criteria difficult. Furthermore, the application of cancer to a usual PTSD model presents additional complications (Bruce, 2006). Generally precipitating traumas are categorized as either one-time (Type 1) or recurring (Type 2). In cancer, the diagnosis is a one-time occurrence, but it is not well known if it is the diagnosis

itself, or the subsequent treatment, which is very traumatic in and of itself, that is the stressor. This can make study of periods of reexperiencing and avoidance difficult, and similarly can make the determination of post difficult (Bruce, 2006; Kangas et al., 2002, Taieb et al., 2003). Additional methodological difficulties in studying PTSD in childhood cancer survivors include the difficulty of finding suitable numbers of subjects. Some studies reviewed contained only 28 subjects (Bruce, 2006). In the past, recruitment for studies was difficult due to very small numbers of survivors and difficulties in identifying and reaching those who could participate. Due to increases in survival rates, and higher rates of participation in survivorship care at specialized clinics, this is becoming less of a problem. Those participants who did join studies may have had an element of self-selection, and some findings have indicated that those who opt out of such studies have higher levels of PTSS (Kazak et al., 2004). Furthermore, the difficulty of performing longitudinal surveys on such populations is considerable and therefore the vast majority of projects are cross-sectional. Further, many studies conducted are based on patient questionnaires, which can generate inaccurate reports, with survivors over- or under-reporting symptoms. Finding proper controls for such studies is also difficult due to the nature of the cancer experience. Many studies use siblings of survivors, but exposure to the cancer experience may have contributed to symptoms in the siblings (Zeltzer et al., 2008; Stuber et al., 2011; Stuber et al., 2010). Survivors of other traumas may be a basis for comparison, but due to the aforementioned differences in cancer as a traumatic experience, this may be problematic. Further, this and the differences in childrens experience of PTSD makes comparisons to the general population potentially inaccurate, though they are generally the best basis for comparison.

Despite all of this, there is great indication that survivors of childhood cancer experience PTSD and PTSD-like symptom clusters, especially of reexperiencing and depression, at clinically and statistically significant levels. This, along with knowledge of comorbidities makes PTSD/PTSS in childhood cancer survivors a necessary and important area of study.

Predictors Several predictors of PTSD have been reported in the literature previously, including female gender, younger age, lower education and SES, appraisals and lack of social support, avoidant coping. In the literature concerning childhood cancer survivors and PTSD, it has been found that female gender and low social support did indeed serve as a predictor that a patient would develop PTSD (Bruce, 2006; Stuber et al., 2011). However, the other predictors found were different than those reported in general PTSD literature, and there was a great deal of variance in findings. Many studies found that patients had higher levels with increased age, while others did not (Stuber et al., 2011; Hobbie et al., 2000). Additionally, findings on SES correlations were contradictory, with some finding that higher SES corrletated to PTSD while other studies found that low SES was correlated (Bruce, 2006). Low levels of education, unmarried status, and unemployment were found to be predictive of PTSD young adult populations (Bruce, 2006; Stuber et al., 2011; Zeltzer et al., 2009; Zeltzer et al., 2008; Stuber et al., 2010) One of the most significant findings of the studies, which was nearly universally reported, was that little correlation was found between objective intensity of treatment and life threat, but there were correlations between patients perception of life threat and intensity of treatment (Bruce, 2006; Zeltzer et al., 2008; Stuber et al., 2011; McDougall & Tsonis 2009).

Additionally, some studies measured and found that the presence of current health issues, cancerrelated or not, also correlated to the presence of PTSD symptoms (Stuber et al., 2010; Patenaude & Kupst, 2005; Zeltzer et al., 2008). This is a critical finding with important implications for practitioners, because it means that risk for PTSD cannot be adequately attained from medical history but rather must be assessed through interview or questionnaire with the patients. The contradictory findings of different studies may indicate that the measures or methodologies used were insufficient, or that the populations of patients being compared may not have been entirely comparable. Predictors of PTSD in childhood cancer survivors are certainly at variance to those documented in the general PTSD literature in several areas, again indicating that this is a critical area of investigation. This incongruence may be illustrative of the very different nature of cancer-related PTSD from more classically described cases of PTSD.

Health and Quality of Life Implications Studies conducted of young adult childhood cancer survivors analyzing quality of life and PTSD found that those survivors who qualified for a diagnosis of PTSD demonstrated markedly lower quality of life and higher psychological distress (Meeske et al., 2001). This is consistent with other studies of traumatized populations, and demonstrates the serious consequences of such conditions. Several studies looking at factors other than PTSD/PTSS which found few significant differences between survivors and comparison groups. Langeveld et al. assessed quality of life and worries in young adult survivors, and found that they generally had similar QoL scores and actually tended to worry less about current health, but had many more worries about issues such

as employment and health insurance (2004b). A review of studies looking at quality of life found no few significant differences between peers and survivors (Cantrell, 2011; Klassen et al., 2011). This may be demonstrative of the effects Meeske et al. posited: given the majority of survivors demonstrating high functioning, the effects of the minority experiencing distress could be masked, especially if PTSD/PTSS is not directly studied (2001). In general, these studies found slightly lower physical quality of life in survivors, and that female gender, low income, physical functioning and unemployment contributed to overall lover quality of life scores (Cantreall, 2011, Klassen et al., 2011, McDougall & Tsonis, 2009). Stam et al investigated the general HRQoL of young adult childhood cancer survivors as compared to healthy peers (2006). They found overall lower HRQoL scores among the survivors. The survivors health perceptions and expectations for the future influenced mental health QoL. This does reflect findings of PTSD/PTSS studies, and HRQoL was also shown to be correlated to current health problems and treatment intensity for mental HRQoL, while PTSD/PTSS results on this measure were mixed based on results in other studies (Patenaude & Kupst, 2005; Stuber et al., 2011; Bruce, 2006 Hobbie et al., 2000; Zeltzer et al., 2008). Regardless of this difference, lower HRQoL for survivors does indicate that the plethora of issues that survivors face ought to be addressed in order to improve these outcomes. Specifically, the mental HRQoL is a locus on which to focus improvement, as it has been shown that PTSD/PTSS can have negative impacts on HRQoL (Stam et al 2006). Given the findings of significant distress and PTSD in young adults, at even higher rates than in children, this is an important age cohort at which to target interventions. Given all the task of young adulthood including identity-forming, and attaining educational, social, and occupational goals, it is important that survivors are able to meet these challenges despite the

additional impact of their medical history. Finally, health behavior as related to uncertainty and PTSS was explored by Santacroce and Lee. The results demonstrated that uncertainty was a major contributor to the development of PTSS and that this led to a lack of health-promoting behaviors (2006). This is perhaps one of the strongest arguments for interventions to reduce PTSD/PTSS in childhood cancer survivors. The avoidance characteristic of PTSD/PTSS can lead directly to survivors neglecting health care needs so as to avoid potential triggers connected to health-related trauma. Given that current and future health is major contributor to quality of life, worries, and PTSS, it is critical that survivors continue to effectively manage their health and develop a positive outlook in health beliefs. However, the PTSS may directly inhibit these efforts, making interventions potentially difficult to administer but critical for survivors health and well-being.

Interventions Overall, very little work has been done in the area of creating interventions for PTSD/PTSS in childhood cancer survivors. This may be because of the difficulties still present in studying the incidence and symptoms of PTSD/PTSS in this population and the disagreements that exist in the literature. Nevertheless, as the health and quality of life implications illustrate, this is an important area for intervention. An important first step is to analyze the feasibility of incorporating this type of screening and intervention into the follow-up care that most survivors now receive in specialized clinics within cancer treatment centers. Recklitis et al conducted a study to this end, and found that the questionnaires administered had a fairly high participation rate and were not rated as highly burdensome or troubling by the survivors (2003). Additionally, the questionnaire did identify a

segment of survivors with serious clinical distress and PTSD/PTSS. These results show that these questionnaire methods could be used to identify survivors who might require further treatment. The most prolific work in this area comes from the Kazak group in Philadelphia. In addition to studying and developing interventions, they have made substantial recommendations for the administration of psychological interventions for cancer survivors and their patients. Their 2007 paper outlined a comprehensive system that would be involve universal, targeted and clinical levels depending on the familial factors and indications of distress. The universal interventions would be based in promoting competence and adaptive coping skills for an entire family. All three levels of intervention would have components that could be applied immediately after diagnosis, during treatment, and on a long-term basis. Early interventions may be able to reduce the levels of PTSD/PTSS exhibited by survivors and their families. The longterm interventions are also important given the increases in levels of PTSD/PTSS shown in young adult survivors, even many years after completion of treatment. One of the interventions developed by Kazak et al is called the Surviving Cancer Competently Intervention Program. The program is based in cognitive-behavioral and family therapy principles to promote adaptive health beliefs and coping skills so that survivors and families can demonstrate competence and resiliency in the face of the cancer experience. This has been shown in studies to increase the chances of distress-free survivorship. In a preliminary study, it was shown to be effective and useful for the parents of recently-diagnosed children. In a randomized clinical trial involving adolescent survivors and their families, it was found to reduce PTSD/PTSS symptoms (2004). Despite the dearth of interventions research, those studies that are being conducted are

showing promising results for the potential of interventions to be easily and successfully implemented for survivors and their families.

Conclusions and Future Directions As can be illustrated by the references in this review, the body of literature for this area is large, though the number of professionals contributing to it is small. In recent years, there has been a major shift of attention towards the long-term sequelae of pediatric cancer survivors, though emphasis is still placed on physical over emotional and psychosocial. As the literature demonstrates, however, there is ample evidence that a persistent and significant minority of survivors experience marked long term psychological effects which are serious enough to warrant intervention. Studies of PTSD in childhood cancer survivors are complicated by the difficulties in applying PTSD models to both children and the cancer experience, which may explain some incongruence in incidence studies, and the lack of research into interventions for this population. However some very effective interventions have been developed and demonstrated efficacy, both in preventative and treatment modalities (Kazak et al., 2005; Kazak et al., 2004; Kazak et al., 2007). Hopefully, these interventions will be expanded and applied at more treatment centers. In addition, the feasibility of administering assessments of PTSD and other distress symptoms within the survivor clinic setting has been explored in a limited fashion (Recklitis et al., 2003). It would seem that this is a critical locus to direct efforts at implementation as it will hopefully lead to identification of patients and further referrals (Taylor et al., 2012). Future research ought to be focused in a few directions. First, it ought to attempt to

characterize and establish reliable characteristics and measures of PTSD/PTSS in children and to determine if such a separate set of measures and definitions is necessary or possible for cancer. Next, further research needs to be focused in developing interventions that can contribute to reduction and prevention of PTSD/PTSS. These interventions also need to be clinically tested such that they can be easily implemented in treatment centers (Taylor et al., 2012; Kazak et al., 2005; Kazak et al., 2004; Kazak et al., 2007). The indications from current research are that the impact of PTSD/PTSS affects a small segment of childhood cancer survivors, but that those affected are significantly impacted in health and quality of life, and are often affected many years after cessation of treatment and in ways that cannot be predicted from medical information. Thus, it is critical to implement screening and intervention tools as broadly as possible so that all childhood cancer survivors can be restored to full mental and physical health, and can achieve full quality of life after their treatment has been curative.

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