With advances in technology leading to improved survival rates among cancer patients, attention has turned to quality-of-life research and the survivorship experience. This attention has largely focused on survivors of adult cancers; less is clear about the long-term fallout of surviving cancer as a child, adolescent, or young adult. An even greater dearth of research exists for survivors of rare cancers, such as sarcomas – a form of cancer that occurs in both bone and soft tissue and requires aggressive treatment. Storey et al. (Reference Storey, Fern, Martins, Wells, Bennister, Gerrand and Taylor2019) recently addressed this gap, highlighting the well-being costs of pediatric sarcoma survivorship. In addition, a longitudinal investigation by Marina et al. (Reference Marina, Liu, Donaldson, Sklar, Armstrong, Oeffinger and Ness2017) showed that many outcomes for sarcoma survivors worsen over time as survivors age. We build on these insights, recognizing pediatricFootnote 1 sarcomas as posing both immediate physical threats and long-term developmental obstacles.
We suggest that the impact of pediatric sarcoma is best conceptualized with a “developmental cascade” model (Masten & Cicchetti, Reference Masten and Cicchetti2010). Such a model highlights how particular insults or benefits in one domain, at one point in time, “cascade” or spill over into other domains and across time. This approach frames the sarcoma experience as a broad developmental threat, reverberating through multiple domains of functioning (physical, psychological, neurocognitive, and psychosocial), extending across time, and reshaping the developmental trajectory of the young person.
Thinking about pediatric sarcoma as a developmentally cascading event – one affecting seemingly unrelated intrapersonal and interpersonal constructs (e.g., executive functions, peer group interactions) and doing so into the future – provides a structure for understanding the less than optimal outcomes of long-term survivors. What follows is not an exhaustive review of the pediatric sarcoma survivor literature; rather it is a proposal to encourage researchers and clinicians to consider the long-term outcomes of survivors as a function of developmentally cascading processes that increase stress and overwhelm coping resources at developmentally sensitive moments.
Below, we discuss the utility of a developmental cascades approach, briefly contrasting it with a biopsychosocial framework. We define “developmental tasks” and “developmental transitions” that we argue are affected by sarcoma and its treatment. We then outline common physical, psychological, neurocognitive, and psychosocial correlates of sarcoma survivorship. We indicate how these costs may interact with other domains, accumulating across time, increasing the stress of developmental tasks and transitions, reducing coping strategies for managing this stress, and degrading long-term quality of life. We end by highlighting the clinical and research implications of adopting a developmental cascade understanding of pediatric sarcoma survivorship.
The Utility of a Developmental Cascades Approach
Understanding long-term outcomes related to pediatric sarcomas requires us to recognize the developmental context of the disease. Osteosarcoma and Ewing's sarcoma are predominately diagnosed in children and adolescents and are among the most common forms of bone cancer (Weber, Damron, Frassica, & Sim, Reference Weber, Damron, Frassica and Sim2008). In general, sarcomas account for roughly 15% of all pediatric malignant tumors (National Foundation for Cancer Research, 2019). Compared to more common childhood cancers, overall survivability is worse (Lim et al., Reference Lim, Yoo, Han, Cho, Kim, Ahn and Kim2015) and subsequent limitations on survivors’ physical functions and daily activities are greater (Ness et al., Reference Ness, Mertens, Hudson, Wall, Leisenring, Oeffinger and Gurney2005, Reference Ness, Gurney, Zeltzer, Leisenring, Mulrooney, Nathan and Mertens2008). Moreover, cognitive and psychosocial outcomes for sarcoma survivors are less than ideal (Tonning Olsson et al., Reference Tonning Olsson, Brinkman, Wang, Ehrhardt, Banerjee, Mulrooney, Huang, Ness, Bishop, Srivastava, Robison, Hudson and Krull2020; Storey et al., Reference Storey, Fern, Martins, Wells, Bennister, Gerrand and Taylor2019). These compromised outcomes in turn raise additional challenges, the sum of which can prove overwhelming – a recent analysis (Siracuse, Gorgy, Ruskin, & Beebe, Reference Siracuse, Gorgy, Ruskin and Beebe2017) of survivors ranging 0 and 30 years since their diagnosis indicated that they were twice as likely to die by suicide than the national average.
Biopsychosocial approaches guide clinicians and researchers in understanding contextual variables (biological, psychological, social) contributing to children's adjustment and disease outcomes during and following sarcoma treatment. Researchers informed by a biopsychosocial perspective have emphasized the importance of appreciating the developmental tasks and psychosocial milieu of adolescence and young adulthood in determining quality of life and disease outcomes (e.g., Zebrack, Santacroce, Patterson, & Gubin, Reference Zebrack, Santacroce, Patterson, Gubin, Abrams, Muriel and Wiener2016). However, profound physical threats encountered in childhood and adolescence carry developmental costs. The sequelae of sarcoma and its treatment interact to influence whether and how survivors accomplish developmental tasks and successfully manage the psychosocial milieu of developmental transitions. A developmental cascade approach extends the insights afforded by a biopsychosocial perspective; it closely examines transactions among domains which serve to enhance or impede survivors’ abilities to effectively meet the demands of typical developmental tasks and transitions.
Researchers and clinicians have long recognized “late effects” – or negative physical and psychosocial outcomes – in childhood cancer survivors (e.g., Byrd, Reference Byrd1985; Mulhern, Reference Mulhern, Bearison and Mulhern1994). The consequences of intensive therapies and these late effects have been shown to lower the life expectancy of childhood cancer survivors (Yeh et al., Reference Yeh, Ward, Chaudhry, Liu, Yasui, Armstrong and Leisenring2020), particularly that of Ewing sarcoma survivors (Yeh, Nekhlyudov, Goldie, Mertens, & Diller, Reference Yeh, Nekhlyudov, Goldie, Mertens and Diller2010). A developmental cascades approach offers a way of thinking about mechanisms involved in such late effects and their cumulative impact. This perspective recognizes that competent adulthood – one characterized by social connection, economic autonomy, and freedom from chronic mental health struggles – relies on a series of probabilistic developmental successes. With typical experiences, children often successfully assimilate an ocean of information from social and academic environments. In these environments, children acquire and practice skills necessary for navigating adulthood. They also practice retrieving and distilling insights from their knowledge base to help them manage novel environments. Children developing within more typical contexts and experiences learn social norms germane to their peer group; they form social identities and self-concepts conducive to success in adulthood.
Pediatric sarcoma, a highly atypical experience, removes children from the opportunities of developmentally normative contexts. Survivors have missed – and due to subsequent physical limitations, may continue to miss – many experiences key to successful development. Moreover, a cancer diagnosis is a traumatic stressor for children and families (Goldwin, Lee, Afzal, Drossos, & Karnik, Reference Goldwin, Lee, Afzal, Drossos and Karnik2014; Landolt, Vollrath, Ribi, Gnehm, & Sennhauser, Reference Landolt, Vollrath, Ribi, Gnehm and Sennhauser2003); it derails plans and routines, upends life narratives, and threatens structures of meaning children and families rely on to organize their lives and identity. The developmental cascade model, with its view of development as a dynamic set of processes, poses questions for researchers to pursue longitudinally, such as: how do the presence of atypical stressors (e.g., threat to life, cancer-related fatigue, chronic pain, heightened psychological distress) the absence of typical experiences (e.g., normative learning in social and academic environments), and the potential cost to coping resources (e.g., due to reduced mobility, smaller social networks, compromised executive functions), combine and accumulate to affect survivors’ well-being (e.g., stress levels, quality of life).
A developmental cascade approach also suggests to clinicians and researchers specific moments for support and intervention. For many survivors, stress related to secondary complications – and to the sarcoma experience generally – plays out endlessly across the developmental trajectory. Each typical developmental transition – to elementary, middle and high school settings, to intimate relationships, to college, to work environments, and so on – carries more stress with fewer coping resources for sarcoma survivors than for their healthy peers. A cascade approach points to this type of recurrent stress and concomitant decrements in coping, and these moments of transition, as critical foci in need of clinical and research attention. Presently, cancer-care protocols do not appear to recognize nor address the recurrent and cumulative nature of stress – and compromised coping abilities – which may contribute to the lower well-being and poorer quality-of-life outcomes of pediatric sarcoma survivors.
Developmental Tasks and Transitions
A pediatric sarcoma diagnosis during childhood and adolescence disrupts a period of intense developmental change, one which sets the stage for adult functioning. As such, sarcomas and their treatment interfere with the accomplishment of developmental tasks and the navigation of developmental transitions. Here, “developmental tasks” refers to widely recognized tasks of middle childhood, adolescence, and young adulthood; “developmental transitions” refers to common, culturally recognized movement into psychosocial spaces (e.g., the middle school, high school, college, and work milieu) that bring greater complexity of stimuli, responsibilities, and relationships, and thus place greater demands on the developing young person. That is, researchers recognize that successfully meeting typical developmental tasks and managing typical developmental transitions invariably carry a relatively typical amount of stress (Elias, Gara, & Ubriaco, Reference Elias, Gara and Ubriaco1985; Marcia, Reference Marcia and Miller2010).
Developmental tasks of middle childhood include the development of a self-concept of competence and connectedness in relation to peers (Erikson, Reference Erikson1968), forming friendships, and managing oneself behaviorally and academically within the school environment and in accordance with prosocial goals (Hartup, Reference Hartup and McGurk1992; Markus & Nurius, Reference Markus, Nurius and Collins1984). Tasks of adolescence and young adulthood include academic attainment, engagement in romantic relationships, and acquiring work competence and economic autonomy (Roisman, Masten, Coatsworth, & Tellegen, Reference Roisman, Masten, Coatsworth and Tellegen2004; Schulenberg, Bryant, & O'Malley, Reference Schulenberg, Bryant and O'Malley2004).
Researchers and theorists have emphasized the centrality of peer experiences in successfully meeting these tasks and navigating transitions. They observe that essential interpersonal and social problem-solving skills are acquired and practiced in the context of peer relationships (Connolly, Furman, & Konarski, Reference Connolly, Furman and Konarski2000; Masten, Juvonen, & Spatzier, Reference Masten, Juvonen and Spatzier2009). Further, Hay and Ashman (Reference Hay and Ashman2003) note the importance for adolescents of extrafamilial social networks, particularly insofar as the development of self-concept, coping strategies, and emotional stability are concerned.
Successfully managing developmental transitions carries a typical level of stress. We suggest that the stress encountered by pediatric sarcoma survivors, many of whom carry the sequelae of sarcoma treatment, as they encounter developmental tasks and transitions is far greater than that encountered by their non-afflicted peers. We propose that survivors confront unhealthy levels of stress, that cascade across domains of function and overwhelm efforts and abilities to cope.
In the following sections, we highlight common physical, psychological, neurocognitive, and psychosocial correlates of survivorship. We do so with an eye towards the interactive and developmentally cascading nature of these costs, noting how disruption in one domain can undermine functioning in others. For example, treatments that even slightly degrade executive functions can negatively affect a survivor's academic performance, self-concept, social functioning, and coping strategies. We then consider development, pointing to ways in which compromised functioning – related to sarcoma and its treatment – and lack of typical experiences interfere with developmental tasks and transitions, thus affecting survivors across time. Figure 1 illustrates linkages – or cascades – among domains of functioning, noting connections which have been supported by data and relations suggested by reviews. Figure 1 also highlights the increased stress and diminished coping skills and resources that may follow from disruptions within each domain.
Domains of functioning, six cross-domain interactions with contributors to unhealthy stress and insufficient coping resources/strategies with examples from prior research (Patenaude & Kupst, Reference Patenaude and Kupst2005; Wiener et al., Reference Wiener, Battles, Bernstein, Long, Derdak, Mackall and Mansky2006; Schultz et al., Reference Schultz, Ness, Whitton, Recklitis, Zebrack, Robison, Zeltzer and Mertens2007; Schwarzer, Reference Schwarzer2008; Gurney et al., Reference Gurney, Krull, Kadan-Lottick, Nicholson, Nathan, Zebrack and Ness2009; de la Haye et al., Reference De La Haye, Robins, Mohr and Wilson2011; Quesada et al., Reference Quesada, Wiemers, Schoofs and Wolf2012; Cassidy, Reference Cassidy2016; Edelmann et al., Reference Edelmann, Daryani, Bishop, Liu, Brinkman, Stewart and Krull2016; Moran, 2016; Shields et al., Reference Shields, Moons, Tewell and Yonelinas2016; McLachlan & Gale, Reference McLachlan and Gale2018; Olsson et al., Reference Tonning Olsson, Brinkman, Wang, Ehrhardt, Banerjee, Mulrooney, Huang, Ness, Bishop, Srivastava, Robison, Hudson and Krull2020).
We propose that survivors endure heightened stress as a result of both the presence of atypical stressors and the absence of typical developmental experiences, and that this stress is exacerbated by a reduced ability to cope. We suggest that both factors contribute to lower quality of life. We further propose that a developmental cascade approach is most suited to guiding research and clinical interventions aimed at documenting, understanding, and bolstering well-being in pediatric sarcoma survivors.
Common Correlates of Sarcoma Survivorship
Physical costs
Pediatric sarcoma treatment often includes a combination of surgeries, chemotherapies, and radiation sessions that – while lifesaving – are taxing, exacting both short- and long-term tolls. Gerrand and Furtado (Reference Gerrand and Furtado2017) observed that patients can be left with reduced mobility, which impedes activities of daily life (walking, dressing), reduces participation in developmentally typical activities such as sports or employment, and culminates in a lower health-related quality of life score. On average, sarcoma survivors engage in less activity and reach lower peak exertion levels compared to age/sex matched norms (Mansky et al., Reference Mansky, Arai, Stratton, Bernstein, Long, Reynolds and Mackall2007). Hamilton and colleagues (Hamilton, Carlson, Hasan, Rassekh, & Goddard, Reference Hamilton, Carlson, Hasan, Rassekh and Goddard2017) reported that 77% of their sample of long-term sarcoma survivors (≥5 years) struggled with long-term physical complications. Accordingly, a report from the Childhood Cancer Survivor Study (Gibson et al., Reference Gibson, Mostoufi-Moab, Stratton, Leisenring, Barnea, Chow and Nathan2018), found childhood sarcoma survivors to have the highest cumulative incidence for a number of chronic conditions. Pediatric sarcoma survivors are often left with pain (Gerrand & Furtado, Reference Gerrand and Furtado2017) which is resistant to amelioration (Kuo et al., Reference Kuo, Yen, Parker, Chapman, Kandikattu, Sohanpal and Williams2011), chronic health conditions such as heart disease, diabetes, kidney and endocrine-related problems, secondary malignancies (Marina et al., Reference Marina, Liu, Donaldson, Sklar, Armstrong, Oeffinger and Ness2017; Weiss & Zimel, Reference Weiss and Zimel2018), poorer sleep quality (Mulrooney et al., Reference Mulrooney, Ness, Neglia, Whitton, Green, Zeltzer and Mertens2008), infertility, and premature menopause (Mansky et al., Reference Mansky, Arai, Stratton, Bernstein, Long, Reynolds and Mackall2007) – all of which appear to speed the aging process (Baker, Reinke, Boonstra, & Antalis, Reference Baker, Reinke, Boonstra and Antalis2019).
Such health concerns are problematic in their own right. They also serve to isolate the sarcoma survivor from their non-afflicted peers – potentially removing them from playground games, team sports, and physical hobbies (e.g., dance, exercise classes, etc.) that provide rich opportunities for social learning. Even when not physically isolating, the late effects of sarcoma treatment can be psychologically isolating. Sarcoma survivors trying to create a social identity post-treatment may be “damned if they do, damned if they don't” – few peers want to be around someone consumed by health concerns; yet if such concerns are hidden from close others, one experiences a different type of loneliness and isolation (Fantozzi, personal communication, Reference Felgenhauer, Hawkins, Pendergrass, Lindsley, Conrad and Miser2019). In other words, loneliness and isolation may result from coping mechanisms aimed at protecting the survivor from social rejection rooted in compromised physical functioning and aimed at protecting close others from worry or harm. This particular hypothesis reflects developmental cascade thinking with respect to psychosocial functioning and psychological distress.
Echoing these observations, Maes et al. (Reference Maes, Noortgate, Fustolo-Gunnink, Rassart, Luyckx and Goossens2017) revealed links between chronic health conditions and loneliness in children and adolescents. Despite recent findings that social isolation degrades mental and physical health (Leigh-Hunt et al., Reference Leigh-Hunt, Bagguley, Bash, Turner, Turnbull, Valtorta and Caan2017), this area has been only minimally addressed in the oncology literature. In qualitative interviews with 30 adult survivors of childhood cancer, Howard et al. (Reference Howard, Tan de Bibiana, Smillie, Goddard, Pritchard, Olson and Kazanjian2014) found that nearly 2/3 grappled with some form of significant social isolation.
Amputation
Due to the etiology of sarcoma tumors, many patients undergo amputation of the affected extremity. Of cancer patients requiring amputation, Parsons et al. (Reference Parsons, Pimiento, Cheong, Marzban, Gonzalez, Johnson and Zager2012) noted that sarcomas are the most common cancer subtype. Studies examining outcomes associated with amputation versus limb-salvage surgeries show mixed results; investigations of diminished quality of life, material well-being, and relationship satisfaction among amputees versus limb-salvage patients have been inconclusive (Aksnes et al., Reference Aksnes, Bauer, Jebsen, Follerås, Allert, Haugen and Hall2008; Barrera, Teall, Barr, Silva, & Greenberg, Reference Barrera, Teall, Barr, Silva and Greenberg2011; Mason, Mason, Meyers, & Healey, Reference Mason, Mason, Meyers and Healey2013; Robert, Ottaviani, Huh, Palla, & Jaffe, Reference Robert, Ottaviani, Huh, Palla and Jaffe2010). Although limb-salvage patients score higher than amputee patients in social desirability measures, limb-salvage patients still score lower than non-afflicted peers, suggesting widespread self-esteem issues (Mason et al., Reference Mason, Mason, Meyers and Healey2013).
In addition to a variety of ecological variables that influence post-amputation outcomes (e.g., family support, parent education), the developmental context plays an important role as well. Amputation in a 6-year-old, versus a 16-year-old, will have very different consequences. The limited mobility and changes in physical appearance in the 6-year-old will set the stage for the developing self-concept and peer interactions. In a 16-year-old, amputation may involve a loss of activities, social interactions, and physical competencies on which the teen's self-concept rested. These losses, in turn, may threaten identity and prior peer relationships, with subsequent consequences for mental health and well-being. Thus, the impact of amputation will cascade over time, affecting each child's psychological and social domains in very different ways as a result of the developmental context.
Cancer-related fatigue and reduced physical activity
Cancer-related fatigue (CRF), defined by its impact on one's ability to participate in both mentally taxing and physically demanding sports or academic activities, pervades the pediatric sarcoma community (LaVoy, Fagundes, & Dantzer, Reference LaVoy, Fagundes and Dantzer2016). Though not as conspicuous as other physical impairments, CRF can markedly impair functioning during routine chores, recreational activities, social engagements, and vocational demands (Hofman, Ryan, Figueroa-Moseley, Jean-Pierre, & Morrow, Reference Hofman, Ryan, Figueroa-Moseley, Jean-Pierre and Morrow2007). CRF may also exacerbate preexisting conditions such as attention-deficit/hyperactivity disorder (ADHD). Because it permeates all aspects of life, CRF may undermine survivors’ ability to concentrate in the classroom, support and sustain peer relationships, and exert effort to achieve typical developmental tasks (e.g., dating, graduating from high school, becoming financially independent). Van Dijk-Lokkart et al. (Reference Van Dijk-Lokkart, Steur, Braam, Veening, Huisman, Takken and Van Litsenburg2019) noted that physical activity reduces CRF. Regrettably, such a coping strategy is less available to survivors with resected limbs, reduced mobility, and pain. CRF demands careful assessment, given its influence on academic, social, and coping processes. However, identifying causes of CRF has proven challenging because they are multifactorial, stemming from the myriad challenges related to survivorship (Tobias & Gillis, Reference Tobias and Gillis2015).
Reduced physical activity – secondary to pain, mobility issues, CRF, or a combination of all three – can degrade quality of life and well-being by limiting opportunities for peer engagement. Such a reduction compromises social development, as well as the sense of industry, autonomy, and self-confidence that accompany the participation in sports, exercise, and hobbies (Oberle et al., Reference Oberle, Ji, Magee, Guhn, Schonert-Reichl and Gadermann2019). Furthermore, diminished engagement in sports and exercise deprives survivors of a key strategy for managing stress, mood, and anxiety (Otto & Smits, Reference Otto and Smits2011; Szuhany & Otto, Reference Szuhany and Otto2019). Thus, in addition to stress generated by reduced physical activity, pain, and CRF, an effective means for coping with such distress is often unavailable to sarcoma survivors.
Again, the developmental context of pediatric sarcoma is highly relevant. As noted, physical impairments associated with sarcoma treatment readily cascade into the peer and psychological domain and do so across time. Harter (Reference Harter2012) showed that the domain of physical appearance is central to children and young adolescents’ global self-esteem, and that athletic competence is a key contributor to the developing self-concept. This is important. Disruptions in physical functioning thus cascade into disruptions in psychological and psychosocial functioning, calling into question matters of identity and where one fits in the social milieu.
Investigations into child and adolescent social experiences point to the centrality of self-concept in terms of organizing behavior (Markus & Nurius, Reference Markus, Nurius and Collins1984), quality of peer relationships (Swann, Chang-Schneider, & Larsen McClarty, Reference Swann, Chang-Schneider and Larsen McClarty2007) romantic relationships (Chen, Yuan, Yang, & Lai, Reference Chen, Yuan, Yang and Lai2020), and risky behavior (Dudovitz, Li, & Chung, Reference Dudovitz, Li and Chung2013). Recent work also suggests that over middle childhood and adolescence, self-concept becomes a stable individual-difference variable, influencing life trajectories into young adulthood (Putnick, Hahn, Hendricks, & Bornstein, Reference Putnick, Hahn, Hendricks and Bornstein2020). In sum, changes in physical appearance and/or the loss of typical social learning experiences due to the physical effects of sarcoma and its treatment, have repercussions for the developing self-concept, spilling into psychological and social domains, and doing so into the future. The physical cost of sarcoma treatment extends beyond the physical domain and into the future by altering socialization experiences, shaping the self-concept, self-esteem, and developing beliefs about self-efficacy.
Psychological costs
Pediatric sarcoma survivors are prone to experiencing chronic stress given the uncertainty of physical outcomes and the additive developmental challenges survivors must manage. In a study of long-term sarcoma survivors (averaging 17.4 years post-treatment), over threequarters met criteria for psychological distress (Wiener et al., Reference Wiener, Battles, Bernstein, Long, Derdak, Mackall and Mansky2006). Wiener et al. (Reference Wiener, Battles, Bernstein, Long, Derdak, Mackall and Mansky2006) also found that most respondents noted persistent fear and concern for their health, while a significant minority met criterion for posttraumatic stress disorder (PTSD). Zeltzer et al. (Reference Zeltzer, Recklitis, Buchbinder, Zebrack, Casillas, Tsao and Krull2009) observed that, of the various cancer subtypes in their study of survivors of childhood cancer, sarcoma survivors endorsed more psychological distress than their siblings or comparison population norms. Tang, Castle, and Choong (Reference Tang, Castle and Choong2015) corroborated these findings of significant psychological sequelae within sarcoma-specific cohorts, finding that the prevalence of depression and anxiety range from 14% to 33% and from 12% to 47%, depending on the study. Tang et al. further reported that elevated distress among survivors was correlated with poorer physical functions. In a related vein, Kosir and colleagues (Kosir, Wiedemann, Wild, & Bowes, Reference Kosir, Wiedemann, Wild and Bowes2019), in their review of psychiatric disorders in adolescent cancer survivors, note that whereas not all survivors struggle with clinically significant distress, a significant proportion do. Those at risk for developing psychiatric disorder included those burdened with greater levels of late effects. As noted, sarcoma patients are likely to encounter numerous late effects, as well as mobility and functional limitations, making them vulnerable to elevated levels of distress. Kosir et al. also raise the issue of subthreshold levels of psychopathology; that is, distress that may be elevated but not sufficiently so to receive a particular diagnosis.
Another psychological burden, particularly for adolescents, is related to struggles concerning identity, self-esteem, understanding oneself in relation to others, and the need to meet developmental milestones while carrying sarcoma-related costs (Zebrack & Zeltzer, Reference Zebrack and Zeltzer2001). The additional developmental demand to become more autonomous and competent while struggling with late effects of sarcoma and its treatment carries additional stress for the pediatric sarcoma survivor.
Neurocognitive costs
The adverse impact of the sarcoma experience on survivors’ physical and psychological well-being is clear. However, the adverse impact on neurocognitive functioning typically is not considered in understanding long-term psychosocial outcomes. Here, we raise the possibility that even subtle neurocognitive changes secondary to life-saving sarcoma treatment also increase stress and erode coping abilities.
There appear to be at least three groups of factors contributing to neurocognitive decrements among sarcoma survivors: neurotoxicity of chemotherapy agents; chronic medical conditions resulting from cancer treatment; and cancer-related fatigue, chronic pain, and mood disorders resulting from treatment. Ikonomidou (Reference Ikonomidou2018) reviewed the significant effects of chemotoxicity on neurological structures and functions, noting that chemotherapy may at times result in brain injury or disruption of typical developmental processes such as myelination, neurogenesis, or the formation of neuronal networks. Among effects of chemotherapy, Ikonomidou (Reference Ikonomidou2018) noted disruption/decline of neurogenesis in the hippocampus, reduction in white matter volume, and problems with white matter integrity. These changes appear to be related to decrements in cognitive performance. In addition to reductions in IQ, Ikonomidou (Reference Ikonomidou2018) highlights evidence of problems with executive functions, memory, and attention. Similarly, Tonning Olsson and colleagues (Reference Tonning Olsson, Brinkman, Wang, Ehrhardt, Banerjee, Mulrooney, Huang, Ness, Bishop, Srivastava, Robison, Hudson and Krull2020) reported poorer verbal reasoning, mathematics, and long-term memory in adult survivors of childhood soft tissue sarcomas. These researchers also reported links between higher cognitive performance and higher social attainment, further observing that both chemotoxicity and chronic conditions were associated with impaired cognitive functioning.
Others have reported similar links between chronic medical conditions – secondary to chemotherapy – and poorer performance on cognitive tasks. Edelmann et al. (Reference Edelmann, Daryani, Bishop, Liu, Brinkman, Stewart and Krull2016) identified lower reading scores, poorer short-term memory, attentional deficits, slower motor processing speed, and poorer cognitive fluency among adult survivors of pediatric osteosarcoma treated with high-dose methotrexate (HDMTX). This is noteworthy because HDMTX is just one drug used to treat osteosarcoma patients; HDMTX is typically administered in combination with doxorubicin, cisplatin, and ifosfamide (Hawkins, Rajendran, Conrad, Bruckner, & Eary, Reference Hawkins, Rajendran, Conrad, Bruckner and Eary2002; Miser et al., Reference Miser, Arndt, Smithson, Gilchrist, Edmonson, Sim and Conrad1994). Although some sarcoma patients (i.e., those with Ewing Sarcoma Family Tumors) do not receive HDMTX as part of their treatment protocol, they do receive a similar cocktail of medications (Felgenhauer et al., Reference Felgenhauer, Hawkins, Pendergrass, Lindsley, Conrad and Miser2000; Grier et al., Reference Grier, Krailo and Link1994; Hawkins et al., Reference Hawkins, Rajendran, Conrad, Bruckner and Eary2002), all shown to be potentially neurotoxic (Alhowail et al., Reference Alhowail, Bloemer, Majrashi, Pinky, Bhattacharya, Yongli and Suppiramaniam2019; Fortin, Mccormick, Remsen, Nixon, & Neuwelt, Reference Fortin, Mccormick, Remsen, Nixon and Neuwelt2000; Ikonomidou, Reference Ikonomidou2018). Despite the potential harm these agents hold for the developing brain, Edelmann et al. (Reference Edelmann, Daryani, Bishop, Liu, Brinkman, Stewart and Krull2016) tie the cognitive deficits of osteosarcoma survivors to the chronic medical conditions caused by cancer treatment, and not to chemotherapy. Regardless of whether the neurocognitive functions above are directly degraded by treatment, or by treatment's subsequent chronic conditions, findings indicate disruption of neurocognitive processes crucial for readily achieving developmental tasks and effectively managing developmental transitions.
The third group of factors contributing to poorer neurocognitive function includes cancer-related fatigue, chronic pain, and mood challenges secondary to treatment. In addition to the toll described earlier, CRF can also affect cognition. Feng et al. (Reference Feng, Regan, Shrader, Liwang, Ross, Kumar and Saligan2019) observed that patients with CRF were slower than healthy controls on a task of executive function. Diamond (Reference Diamond2013) observes that executive functions are the “canary in the coal mine” of cognitive function – the first of cognitive abilities to suffer in the face of organismic adversity. Moreover, chronic pain and mood challenges such as depression, anxiety, and overall psychological distress – not uncommon among sarcoma survivors – have been shown to degrade cognitive functioning in other populations (Eysenck, Derakshan, Santos, & Calvo, Reference Eysenck, Derakshan, Santos and Calvo2007; Matthews, Reference Matthews and Fink2016; Mccracken & Iverson, Reference Mccracken and Iverson2001; Moriarty, Mcguire, & Finn, Reference Moriarty, Mcguire and Finn2011; Paelecke-Habermann, Pohl, & Leplow, Reference Paelecke-Habermann, Pohl and Leplow2005; Shields, Moons, Tewell, & Yonelinas, Reference Shields, Moons, Tewell and Yonelinas2016; Van den Berg, Deeg, Lindeboom, & Portrait, Reference Van den Berg, Deeg, Lindeboom and Portrait2010).
Again, the developmental context is important for understanding the neurocognitive toll of cancer. Both the cerebellum and the frontal lobes, structures shown to be affected in long-term pediatric sarcoma survivors (Sleurs et al., Reference Sleurs, Blommaert, Batalle, Verly, Sunaert, Peeters and Deprez2020), undergo significant growth and change from childhood through young adulthood (Moore, D'Mello, McGrath, & Stoodley, Reference Moore, D'Mello, McGrath and Stoodley2017; Sowell et al., Reference Sowell, Thompson, Holmes, Batth, Jernigan and Toga1999; Sowell, Trauner, Gamst, & Jernigan, Reference Sowell, Trauner, Gamst and Jernigan2002; Tiemeier et al., Reference Tiemeier, Lenroot, Greenstein, Tran, Pierson and Giedd2010). Moreover, both structures have been implicated in multiple cognitive functions, including executive functions (Hunter & Sparrow, Reference Hunter and Sparrow2012). Given the developmentally sensitive context of pediatric sarcoma, it seems reasonable to expect that age of neural exposure to chemotoxicity will play an important role in understanding the cognitive correlates of sarcoma survivorship.
Insults to the development and functioning of cognitive – particularly executive – skills (e.g., attention regulation, working memory, cognitive flexibility, inhibitory control) undermine people's ability to manage themselves, academic and work demands, and complex social relationships (Mccracken & Iverson, Reference Mccracken and Iverson2001). In light of the role played by executive functions in emotion- and self-regulation (Liew, Reference Liew2012), a developmental cascade approach to sarcoma survivorship raises specific hypotheses, such as: survivors burdened by executive dysfunction should – all other relevant variables being held constant – demonstrate smaller social networks, greater difficulties with peers, and higher levels of loneliness than survivors not similarly burdened.
Psychosocial costs
Information is limited regarding the specific psychosocial experiences of sarcoma survivors in adolescence and young adulthood. However, we begin to get some idea in looking at work focused on the broader population of young cancer survivors. Quinn, Gonçalves, Sehovic, Bowman, and Reed (Reference Quinn, Gonçalves, Sehovic, Bowman and Reed2015) report that – compared to the general population – these adolescent and young adult survivors report worse quality of life, with concerns centered on image dissatisfaction, difficulty establishing relationships, and financial worries. Smaller studies of young cancer survivors reveal that among their peers, survivors have a social reputation of being more socially isolated (Noll, Bukowski, Davies, Koontz, & Kulkarni, Reference Noll, Bukowski, Davies, Koontz and Kulkarni1993) and enjoy markedly fewer social activities (Pendley, Dahlquist, & Dreyer, Reference Pendley, Dahlquist and Dreyer1997).
We argue that the aggregate and cascading effects of compromised physical functioning, heightened psychological distress, and decrements in neurocognition combine to interfere with the psychosocial experiences of pediatric sarcoma survivors. Storey et al. (Reference Storey, Fern, Martins, Wells, Bennister, Gerrand and Taylor2019) discovered that, among survivors, although physical functioning improved over time, psychosocial well-being did not. These researchers point out that whereas literature related to psychosocial functioning is mixed – some investigators report no differences in psychosocial outcomes despite clear differences in health-related quality of life – the preponderance of the data point to an overall reduction in well-being. A developmental cascade approach to pediatric sarcoma survivorship underscores ways in which intrapersonal domains (i.e., physical, psychological, neurocognitive), negatively impacted by sarcoma treatment, may in turn influence psychosocial attainment and subsequent wellbeing.
Stress and Coping
The challenge of moving successfully through development – accomplishing developmental tasks and navigating capably through developmental transitions – is stressful. Managing life effectively in the aftermath of pediatric sarcoma is even more stressful. We propose that the added task of managing effects related to the sarcoma experience, in the face of typical developmental demands, can readily create unhealthy stress levels in survivors. More specifically, we suggest that the presence of atypical burdens (e.g., cancer-related fatigue, post-traumatic stress symptoms, attentional difficulties), and the temporary absence from the typical social milieu as children undergo treatment, undermine coping abilities in survivors. Removal for weeks or months from the typical social milieu – in which, day to day, children build psychosocial competencies – reduces opportunities to learn and practice social skills, conflict resolution, and coping strategies. Put plainly, we argue that survivors face unhealthy levels of stress and have fewer coping resources than their unafflicted peers.
Figure 2(a) depicts how cumulative and atypical levels of stress – emerging from decrements in physical and cognitive functioning, concerns about self-efficacy, cancer-related anxieties, and so on – coupled with the typical stress of growing up, compound over time and exceed available coping strategies and resources. Figure 2(b) provides an example of how negatived developmental cascades might serve to increase stress. In this hypothetical cascade, CRF at the entry to high school subsequently undermines functioning in other domains, degrading well-being over time and increasing stress while reducing opportunities to develop coping resources and practice adaptive coping strategies.
(a) Stress and coping across developmental tasks and transitions – contrasting typical youth versus pediatric sarcoma survivor experience. (b) Possible developmental cascades resulting from cancer-related fatigue (CRF) at the high school transition.
Entry to high school requires adolescents to navigate new and more complex social hierarchies and relationships, manage increased academic expectations, and become more adept at organizing their own time. The stress of these demands can be offset by using adaptive coping strategies such as social support, attention regulation, and exercise. However, a young person burdened with CRF, may not have the energy to join extracurricular groups (a potential source of social support and identity), to regulate attention effectively (to manage academic demands and attend to less anxiety-producing events or stimuli), or to exercise (to reduce the arousal of stress or increase opportunities to form social connections). Opportunities missed and academic demands that are poorly met have consequences for self-concept and stress levels – survivors may encounter more anxiety at the realization that their participation and success in high school is not meeting the standard set by their peers. In other words, CRF may cascade into the neurocognitive and psychosocial domains, undermining competencies and reducing opportunities to develop and practice adaptive coping strategies. Figure 2 (bottom) could easily have additional arrows of influence – for example, reduced working memory might further degrade academic performance leading to avoidance of academic challenges; however, we have limited these for the sake of clarity. What we wish to highlight in Figure 2(b) are the ways in which difficulties in one domain cascade can cascade into others and broaden over time.
We acknowledge that not all pediatric sarcoma survivors will experience CRF. Similarly, not all will experience recurrent pain, reduced mobility, posttraumatic stress, or neurocognitive difficulties. In addition, not all will experience any number of the post-cancer struggles or late-effects that have been described. However, what is key to understanding and supporting survivors’ quality of life is for clinicians and researchers to consider carefully the ways in which a decrement in one domain (e.g., physical) may cascade into other domains, particularly at moments of salient developmental transitions or when confronted with typical developmental tasks. These cascades may increase stress and overwhelm – or undermine – the coping resources and strategies available to survivors. Researchers have noted that some survivors engage in passive avoidance or other “maladaptive coping.” We raise the possibility that some survivors’ coping skills may be simply ill-matched for the task at hand.
In the absence of focused efforts to prevent and relieve the considerable stressors confronting pediatric sarcoma survivors, adolescent and young adult survivors may come to manage as best they can or cannot. Siracuse et al. (Reference Siracuse, Gorgy, Ruskin and Beebe2017) noted the increased suicide rate among sarcoma survivors; however, the prevalence and potential role of maladaptive or insufficient coping behaviors in this relation have yet to be thoroughly investigated. Results from a recent study of adult cancer survivors by Hall et al. (Reference Hall, Jimenez, Perez, Rabin, Quain, Yeh and Peppercorn2019) found that the physical effects of cancer and fear of recurrence were associated with unhelpful coping behaviors, including substance abuse behaviors and social isolation.
Limitations
Readers should keep in mind the limitations of our proposal while considering our appeal. First, this is not an exhaustive review of the pediatric sarcoma literature. We framed our paper using relevant literature reviews and seminal studies, but it is likely, even certain, that we missed studies and variables at each level of the cascade. Second, we do not address important genetic factors, nor contextual factors (e.g., temperament, socioeconomic status, the parent–child relationship) which undoubtedly play a role in survivor outcomes and likely moderate many of the proposed relations we highlight. Third, and relatedly, the role of ecological and cultural factors that influence patient outcomes are only minimally addressed in this paper. Protective factors and variables that amplify negative effects such as temperament, family functioning, socioeconomic status, experiences prior to cancer, culture, and the child's macroenvironment should each be examined in future theory building and research. Finally, this application of the developmental cascade model has not been tested. Unlike other developmental cascade models (Dodge et al., Reference Dodge, Malone, Lansford, Miller, Pettit and Bates2009; Sitnick, Shaw, & Hyde, Reference Sitnick, Shaw and Hyde2014), specific tests of a developmental cascades approach with respect to pediatric sarcoma survivorship remain to be conducted. Our intention with this proposal is to highlight the utility of conceptualizing survivorship using a developmental cascades approach to capture transactional and cascading processes we think are at play in influencing survivor outcomes, and to suggest specific moments of focus – that is developmental transitions – for researchers and clinicians.
Conclusion
Although more individuals are surviving pediatric sarcoma, the path towards well-being and competent adulthood remains challenging. Conceptualizing survivorship using a developmental cascades approach highlights particular moments of increased stress and vulnerability. As a general framework, a developmental cascade approach posits that decrements in physical, psychological, neurocognitive and/or psychosocial domains, and the loss of typical day-to-day experiences, interact and function to increase stress and undermine coping resources for survivors, particularly when faced with specific developmental tasks (e.g., the need to graduate high school as part of achieving autonomous adulthood) or specific developmental transitions (e.g., the entry into middle school or high school). These relations lend themselves to specific hypotheses to be tested (e.g., survivors experience more stress during developmental transitions relative to other time points and in comparison to their non-afflicted peers) and suggest that additional support for survivors are needed at specific time points (i.e., developmental transitions). Thus, a developmental cascades approach is useful for both clinicians and researchers, shedding light on the singular outcomes of each survivor and suggesting particular moderators and mediators for the relation between a pediatric sarcoma diagnosis and reduced well-being. Historically, routine scans that detect the recurrence of disease and assessments targeting the physical side-effects have been the cornerstone of survivorship care. Careful assessment of survivors’ experiences over the last several decades suggest that late effects extend well beyond the physical domain. Adopting a developmental cascades perspective sheds light on the heterogeneity of outcomes for this population. This approach provides a useful framework for clinicians and researchers working to understand and support quality of life and well-being in pediatric sarcoma survivors.
Acknowledgment
The authors wish to express sincere appreciation to Dr. Nancy Worsham for her editorial suggestions.
Funding Statement
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Conflicts of Interest
None.
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