4

Childhood Cancers and Function

As discussed in Chapter 3, advances in tumor diagnostics and treatment interventions have led to significant improvements in survivorship across the spectrum of childhood cancer diagnoses. With this increase in survivorship, morbidities due to the cancer or the interventions used to treat or manage it or prevent its progression have also increased, and include conditions that impact function throughout the lifespan and contribute to premature death. Cancers often present with symptoms and signs resulting from the anatomic or physiologic impact of the cancer itself. One of the primary goals of initial cancer treatment is to reduce this impact and subsequently alleviate the severity of these impairments, which may affect function. While improvements are often seen with cancer treatment, rehabilitation interventions, including audiology services and occupational, physical, and speech therapy, are also often necessary and instrumental in improving functional recovery. Despite treatment and rehabilitation interventions, full functional recovery may not be achieved. Long-term functional deficits come from a combination of the permanent destructive effects of the tumor itself and the detrimental effects of cancer treatment.

Unlike adults, children often tolerate the acute side effects of treatment relatively well, but the use of cancer therapy at an early age may result not only in chronic effects that persist but also in complications that can develop more than 5 years after cancer diagnosis, becoming apparent only years after the completion of treatment or as the child matures (Landier et al., 2016). Late effects and associated functional limitations vary with the primary cancer type, its location and treatment, and potential genetic or other underlying medical conditions.

The effects of cancer and its treatment manifest as impairments in body structures and functions (including psychological functions), with resulting activity limitations and restrictions on participation (WHO, 2001). Notably, the impact of childhood cancer is not limited to physical or cognitive functions but also includes psychosocial and emotional functions. Moreover, these areas of function interact such that impairments in one area (e.g., physical) may precipitate or exacerbate impairments in one or more of the others (cognitive, psychosocial, and/or emotional).

Nearly two decades ago, the Institute of Medicine recognized the need for a lifelong surveillance plan for cancer survivors that identifies risk based on therapeutic exposures, genetic predisposition, health-related behaviors, and comorbid health conditions for cancer survivors across the spectrum of ages (IOM and NRC, 2003). In response, the Children’s Oncology Group (COG) developed risk-based, exposure-related guidelines (Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers) for follow-up care of patients who have completed treatment for pediatric malignancies (COG, 2018). A decade after those guidelines were published, the International Guideline Harmonization Group issued harmonized evidence-based guidelines for long-term followup of survivors of childhood and young adult cancers (Kremer et al., 2013). Attention to these guidelines is imperative for children with cancer, both during and after therapy.

This chapter reviews what is known about the wide range of conditions that impact the functioning of survivors of childhood cancers as a result of either the cancer itself (prior to treatment or from persistent impairments in spite of treatment), the adverse effects of cancer treatments, late manifestations of the cancer or its treatments, or new cancers that may develop. It provides a description of each condition and explains its known pathogenesis, risk of impairment (where the information is available), and functional implications for survivors. In many cases, the chapter identifies which of the six U.S. Social Security Administration (SSA) functional equivalence domains are most likely to be impacted by the impairment associated with a condition. As outlined in Chapter 1, the six domains are (1) acquiring and using information, (2) attending and completing tasks, (3) interacting and relating with others, (4) moving about and manipulating objects, (5) caring for oneself, and (6) health and physical well-being.¹

Finally, of note, the literature cited in this chapter largely includes studies of pediatric patients with central nervous system (CNS) and bone tumors, reflecting the available evidence on functional impairment in this setting. Furthermore, the evidence for functional impact is uneven; only some of the sections that follow address the full range of functional deficits,

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¹ 20 CFR 416.926a.

yet all of them focus at least on the effects of cancer treatment. While treatment can be expected to reduce the symptoms related to the presence of a specific cancer in some cases, which may affect a child’s functioning, in most cases the cancer treatment itself is likely to impose barriers to function that are important to consider. For this reason, the discussion of function in this chapter follows the overview of cancer treatments provided in Chapter 3.

PHYSICAL FUNCTIONING

Deficits in physical function can be secondary to organ-specific structural changes (e.g., brain cortex in brain tumors, bone and muscle changes in sarcomas) but can also be a consequence of the multimodal treatment used to manage and potentially cure a cancer (see Chapter 3). Many survivors of childhood cancer have treatment-related neurologic or musculoskeletal issues that interfere with both the normal developmental trajectory of childhood and the expected level of participation in regular activities. In addition, therapy-induced limitations in physical performance can contribute to a sedentary lifestyle and reduced musculoskeletal function (Hoffman et al., 2013). In many cases, moreover, survivors of childhood cancer face numerous late effects that compound their challenges with physical function. The consequences of impairments in body structures and functions lead to both activity limitations and participation restrictions (WHO, 2001) that can occur acutely during treatment, subacutely following the completion of treatment, and longitudinally as a result of persistent deficits that may be unresponsive to rehabilitation therapeutics. Over time, these limitations can accumulate or worsen.

Multiple components are involved in the execution of physical functioning, and one, or often many, of these components can be affected by a specific cancer type or treatment intervention(s). For example, ambulation requires adequate range of motion (ROM) of joints, strength of muscles, peripheral sensation, balance and coordination, and aerobic endurance. When present, deficits in physical functioning impact both the basic completion of physical functional goals (such as standing from a chair, walking, or dressing) and a survivor’s level of independence in completing them successfully. As a result of this multifactorial nature of physical functioning, multiple assessment tools are often used to measure each of the individual components. Any selected method of measurement should be well validated and be supported by appropriate and relevant normative data. Annex Table 4-1 at the end of the chapter provides a list of selected representative instruments used to measure physical functioning, including pain.

Musculoskeletal Functioning

Amputation

Description

Amputation is the surgical removal of all or part of a limb or extremity, such as an arm, leg, foot, hand, toe, or finger. Amputation remains a viable option for the treatment of cancer or after failed limb-salvage procedures. The functional outcomes for patients with amputation differ considerably based on the location of the amputation, and each patient needs to be evaluated on a case-by-case basis.

Amputation is associated with the risk of immediate and long-term loss of physical function, as is limb-sparing surgery (see below). If the amputation is discussed appropriately and the patient’s expectations are addressed prior to the procedure, most patients can adapt well. However, studies have found that a number of factors affect impairment and outcome (Nagarajan et al., 2009; Robert et al., 2010; Wilson et al., 2015). Survivors with upper-extremity versus lower-extremity amputations were less likely to graduate from college, and non-White children were more likely than White children to experience functional loss, not to graduate from college, and to be unemployed. Impairment and outcome also were less positive for survivors with above-the-knee versus below-the-knee amputation and for females, those whose amputation occurred at older ages, and those with osteosarcoma tumors.

Pathogenesis and risk of impairment in childhood cancer

Amputation remains a viable option for the treatment of extremity tumors. Although used less frequently than limb-sparing surgeries, amputations continue to have an important role in the treatment of patients with bone tumors. As systemic therapy, imaging, and surgical techniques have improved, the indications for amputation have changed. The major indications for amputation are extremely small skeletal size (small medullary canal of the bone, so that a durable prosthesis could not be made to fit), progression on chemotherapy, and tumor encompassing the blood vessels and nerves of the limb. If limb salvage is not feasible with adequate margins, amputation must be considered (Hawkins et al., 2016), and amputations now account for 4–20 percent of surgeries in children (Erstad and Raut, 2017; He et al., 2017). It is interesting to note that attitudes toward amputation may be changing. As the options for external prostheses improve, the appeal of an amputation—only one surgery in the child’s lifetime and no activity restriction—is increasing.

Functional implications

Annex Table 4-2 summarizes the functional impairments associated with both amputation and limb-sparing surgery in

upper and lower extremities. One disability unique to amputation is phantom limb sensation and pain. Although this pain or sensation can occur early and then dissipate, it can also persist and cause significant morbidity and functional limitations. The other complications seen are related to the stump and the prosthesis, and include bony overgrowth, chronic skin breakdown, residual chronic osteomyelitis, and deformities that hinder wearing the prosthesis. These complications cause further disability for the patient by requiring surgical revisions or expensive prosthesis modifications and thus delay in returning to full function. However, most children who survive bone tumors adapt well to their environment and report high levels of global functioning. When surveyed, they have reported few physical limitations and only mild impairment of global functioning (Bradlyn et al., 1996; Rapkin and Schwartz, 2004). It appears further that quality of life depends on reintegration into “normal life.” Access to rehabilitation to restore function, teach the child compensatory strategies, or provide environmental adaptations to maximize function is very important to enable these children to reach their maximal function.

Childhood cancer survivors with amputation have difficulty with the following functional equivalence domains: moving about and manipulating objects, caring for oneself, interacting and relating with others, and health and physical well-being.

Limb-Sparing Surgery

Description

Limb-sparing surgery varies depending on the size and location of the limb and the reconstructive method used. The skeletally immature patient presents a unique set of surgical considerations: small size of the medullary canal, often too small to accommodate a durable prosthesis, and continued growth of the contralateral limb and ensuing limb-length discrepancy, which can result in gait abnormalities. Variables that contribute to the overall limb-length discrepancy include systemic chemotherapy, slowing of the preserved growth plate in the affected joint, muscle atrophy, muscle loss, and overgrowth of the contralateral limb. Each of these variables must be considered when estimating the final growth of a patient and the final limb-length discrepancy. In a young child who has undergone resection of the long bone, the estimated limb-length discrepancy can be quite large, and epiphysiodesis of the contralateral limb or lengthening of the ipsilateral limb often cannot achieve the length correction needed.

Limb-salvage options in the growing child fall into two categories—biological and endoprosthetic—and include intercalary allografts, intercalary autografts, distraction osteogenesis, expandable prostheses, and rotationplasty. The decision as to which option to employ is individualized and depends on the tumor location (anatomical site), the remaining growth of

the child, the current height of the child compared with parents, and the level of family support. Advances in endoprosthetic design and biological reconstructive techniques afford limb-salvage options that can be tailored to the pediatric patient’s unique anatomical and functional needs.

Pathogenesis and risk of impairment in childhood cancer

The vast majority of children and adolescents who undergo surgery for bone tumors will have limb-sparing surgery (Shehadeh et al., 2013). Among patients with primary malignant bone tumors involving the extremities, 80–85 percent can be treated safely with wide resection and limb preservation (DiCaprio and Friedlaender, 2003).

Functional implications

Overall, survivors of limb salvage adapt well to their environment and report high levels of global functioning. The types and frequencies of immediate and late physical dysfunction following limb-sparing surgery vary depending on the site and type of limb-salvage reconstruction. In general, continued physical therapy is needed even years after surgery. In one study, for example, patients who underwent lower-extremity limb salvage were compared with normative controls and were found to have persistent hip weakness in both operated and nonoperated limbs for up to 42 months after resection around the knee (Beebe et al., 2009). This global or bilateral weakness can be seen in any extremity reconstruction, and continued physical therapy can be of significant benefit in addressing it.

Psychologically, while children undergoing limb salvage are often limited in their pursuit of high-impact activities, they have been found to adapt well. However, there is a paucity of data to support the conclusion that their quality of life is superior compared with those who require or elect treatment with amputation instead of limb salvage. It is important to stress, moreover, that “measurement of [quality of life] must be from the perspective of the child, adolescent and family, and it must be sensitive to the changes that occur throughout development” (Bradlyn et al., 1996, p. 1334).

Survivors of childhood cancer with a history of limb-sparing surgery have difficulty with the following functional equivalence domains: moving about and manipulating objects, caring for oneself, interacting and relating with others, and health and physical well-being.

Osteonecrosis

Description

Osteonecrosis (ON), or avascular necrosis, results from disrupted vascular supply to the bone, which causes the death of bone marrow cells and osteocytes (mature bone cells), resulting in marrow edema and necrotic bone. This process can lead in turn to tiny breaks in the bone and

the bone’s eventual collapse (Mankin, 1992). ON most commonly affects the femoral heads, but it can occur in many joints and is often multifocal, meaning that many joints can be affected. Symptomatic ON usually affects weight-bearing joints, including the hips, knees, or ankles, and is typically located closer to a joint line than is asymptomatic ON (Niinimaki et al., 2015). Magnetic resonance imaging (MRI) is generally regarded as the most sensitive and specific image modality for identification and diagnosis of ON (Niinimaki et al., 2015). Proper management of ON includes consultation with a pediatric orthopedic surgeon given the potential for collapse of the femoral head and the potential need for surgical intervention. Nonsurgical treatments include nonsteroidal anti-inflammatory medications and physical therapy services (Crawford, 2003).

Pathogenesis and risk of impairment in childhood cancer

The incidence of ON ranges from 1–9 percent when based on clinical presentation to more than 71 percent when based on MRI screening (Landier et al., 2016; Niinimaki et al., 2015; Rao et al., 2019). It is typically diagnosed 14–25 months after the initiation of corticosteroid treatment (Rao et al., 2019). Risk factors associated with the development of ON include corticosteroid treatment and radiation therapy, hematopoietic stem cell transplantation, obesity, treatment with asparaginase, female gender, and ages 10–20 years (Arico et al., 2003; Bürger et al., 2005; Mattano et al., 2000; Niinimaki et al., 2015). Risk factors also include being pubertal or postpubertal at the time of treatment, receiving high-dose radiation to any bone, and prolonged immunosuppression (e.g., for chronic graft-versus-host disease) (COG, 2018).

Functional implications

Both children undergoing treatment and survivors of childhood cancer diagnosed with ON sustain impaired physical performance and reduced quality of life (DeFeo et al., 2020). Functional impairments resulting from ON include impaired gait mechanics, reduced endurance, and chronic pain. Symptoms and functional impairments have been shown to be persistent for a majority of patients who do not pursue surgical intervention (te Winkel et al., 2011).

Children with a history of childhood cancer complicated by ON have reduced capacity in such areas as mobility and independence in instrumental activities of daily living, which negatively impacts their ability to participate actively in academic and vocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of ON often have difficulty with the following functional equivalence domains: moving about and manipulating objects, caring for oneself, interacting and relating with others, and health and physical well-being.

Radiation-Induced Fracture

Description

High-dose radiation (≥50 Gy) may be used to treat cancer and certain noncancerous conditions (desmoids). As discussed in Chapter 3, while having a beneficial effect on the cancer, radiation can also cause significant injury to the surrounding soft tissue and bone. After radiation, a combination of direct cell injury and radiation-induced vascular injury can cause the bone to become brittle and avascular, and therefore predisposed to fracture (Lin et al., 1998). Cell death and vessel fibrosis can lead to fibrosis of the periosteum and endosteum of bone. The most commonly observed radiographic effect is radiation osteitis, which manifests as osteopenia, atrophy, and coarsening of trabeculae.

Pathogenesis and risk of impairment in childhood cancer

Fracture of bone is a well-known complication following radiation treatment. The risk and severity of fracture depend on the total radiation dose, the dose per fraction, the total volume of the bone irradiated, and the treatment schedule. It is difficult to discern a clear threshold dose of radiation that can result in bone fracture; clinically, however, fractures are seldom seen at doses <50 Gy (Dickie et al., 2009; Engleman et al., 2006; Paulino, 2004).

The current incidence of radiation-induced fracture in patients receiving radiation therapy is not well defined. Much of the literature on the subject is based on the use of orthovoltage radiation therapy. No longer in use, this type of radiation resulted in an increased dose to the bone relative to the radiation therapy used today and thus an increased fracture rate. Several studies have shown that the cumulative incidence of fracture in the pediatric population depends on the population studied and whether a weight-bearing bone was included in the field (Gortzak et al., 2010; Helmstedter et al., 2001; Krasin et al., 2010), and ranges from less than 10 percent to greater than 31 percent. Several researchers have found that periosteal stripping, female gender, chemotherapy, fractionation, and age at the time of treatment all affect the risk and incidence of radiation-induced fracture with radiation therapy.

Functional implications

Radiation-induced fractures may limit physical function and performance and participation in work, social, and recreational activities. These fractures carry a poor prognosis. The location of a postradiation fracture directly influences treatment, prognosis, and outcome. Postradiation fractures of the long bone are notoriously difficult to heal and often result in amputation.

Even with surgery, fracture healing is challenging, and the nonunion (failure) rate generally is greater than 50 percent (Cannon et al., 2008; Helmstedter et al., 2001; Lin et al., 1998). If the fracture does not heal

with intramedullary stabilization, the salvage options of bone grafting, vascularized fibula grafting, resection and endoprosthetic reconstruction, and amputation can be attempted. Each salvage option carries its own risk of complications for the child. Definitive management of radiation-induced fracture takes a considerable amount of time, and during this time the child will not have full function of the extremity, which will have both physical and psychological functional ramifications.

Childhood cancer survivors with radiation-induced fractures have difficulty with the following functional equivalence domains: moving about and manipulating objects, caring for oneself, interacting and relating with others, and health and physical well-being.

Problems with Musculoskeletal Growth and Alignment

Description

Treatment-related problems with musculoskeletal growth and alignment include abnormal vertebral growth, growth retardation, limb-length discrepancy, craniofacial deformities, and orbital hypoplasia. The COG long-term follow-up guidelines recommend that survivors of childhood and young adult cancers who received any radiation undergo yearly musculoskeletal examination with annual measurements of height, weight, sitting height (for those who underwent trunk radiation), and limb lengths (for those with a history of extremity radiation) (COG, 2018). For those survivors who underwent radiation exposure to the chest, abdomen, or spine, annual musculoskeletal examination of the back and spine is recommended, with increased interval frequency during puberty. Spine films are recommended for patients with clinically apparent curves (COG, 2018).

Pathogenesis and risk of impairment in childhood cancer

Radiotherapy, chemotherapy, and surgery are associated with musculoskeletal late effects both independently and additively (Gawade et al., 2014). Younger age and radiation doses >20 Gy influence the impact of radiation on muscle. Accordingly, there is a potentially higher risk associated with cancers diagnosed at a younger age and requiring radiation in cases of advanced disease. Radiotherapy may also affect axial alignment, presenting long after treatment as scoliosis or kyphosis (Gawade et al., 2014). The effect of radiation on spinal malalignment is influenced by younger age, higher doses, and asymmetric radiation (Gawade et al., 2014). There is also evidence to suggest an association between spine-directed radiation and abnormal vertebral growth and growth retardation (Gawade et al., 2014). Limb-length discrepancy may develop in survivors treated with extremity or abdominal radiation (Gawade et al., 2014). Craniofacial deformities and orbital hypoplasia are reported following radiotherapy for head and neck tumors,

also impacted heavily by age at the time of treatment and dose of radiation (Gawade et al., 2014).

Problems with musculoskeletal growth and alignment resulting from radiotherapy, chemotherapy, and surgical interventions contribute to potential functional impairments in childhood cancer survivors. Impairments resulting from any of the musculoskeletal complications identified above can include gait abnormalities, impairment of independence with instrumental activities of daily living, and chronic musculoskeletal pain.

Functional implications

Children with a history of childhood cancer complicated by problems with musculoskeletal growth and alignment have reduced capacity in such areas as mobility and independence with instrumental activities of daily living, which negatively impacts their ability to participate actively in academic, vocational, and avocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of problems with musculoskeletal growth and alignment may have difficulty with the following functional equivalence domains: moving about and manipulating objects, caring for oneself, interacting and relating with others, and health and physical well-being.

Reduced Bone Mineral Density, Osteopenia, and Osteoporosis

Description

Children undergoing cancer treatment, as well as survivors, are at risk of early-onset and severe deficits in bone mineral density (BMD), with attendant complications of insufficiency fractures and thoracic kyphosis with loss of height (Krishnamurthy et al., 2016). Reduced BMD is assessed through dual-energy x-ray absorptiometry (DXA) and measured in survivors less than 20 years of age utilizing a Z-score, which measures the number of standard deviations by which the measurement is above or below the age-matched mean BMD. Reduced BMD is defined as Z-score >2.0 standard deviations below the mean in survivors under age 20.

Reduced BMD can be secondary to a number of factors, including prolonged corticosteroid treatment and methotrexate (MTX) osteopathy, as well as other treatments that reduce BMD during the therapy (Mandel et al., 2004; Pfeilschifter and Diel, 2000). Alkylating agent chemotherapy can contribute to BMD deficits secondarily through impairment of gonadal function (Pfeilschifter and Diel, 2000). Decreased activity levels and nutritional deficiencies play a role in decreased BMD. Such secondary effects of treatment as hypothalamic pituitary endocrinopathies and primary hypogonadism, often secondary to radiation therapy to the sellar area,

can also lead to BMD deficits (Landier et al., 2016; Wasilewski-Masker et al., 2008).

Decreased BMD is especially common after treatment for acute lymphoblastic leukemia (ALL), allogenic hematopoietic bone marrow transplantation, or childhood brain tumors, but survivors of extracranial solid tumors are also at risk (Krishnamurthy et al., 2016). The COG’s current guidelines for long-term follow-up recommend bone density evaluation via DXA at entry into long-term follow-up, which typically occurs 2 years after completion of cancer therapy, for survivors treated with agents that predispose to BMD deficits, as well as survivors with medical conditions associated with BMD deficits, such as growth hormone (GH) deficiency, hypogonadism, delayed puberty, or hyperthyroidism (COG, 2018; Wasilewski-Masker et al., 2008).

Given that BMD in later life depends largely on the peak bone mass achieved in adolescence or young adulthood, optimizing peak bone mass is of clinical importance (van der Sluis and van den Heuvel-Eibrink, 2008). Treatment of BMD deficits in children includes increasing weight-bearing exercise as tolerated; optimizing dietary intake of calcium and vitamin D; nutrient supplementation if dietary intake is insufficient; and treatment of underlying conditions that may exacerbate BMD deficits, such as hypogonadism and GH deficiency (Wasilewski-Masker et al., 2008).

Pathogenesis and risk of impairment in childhood cancer

Both children undergoing treatment and survivors of childhood cancer diagnosed with reduced BMD are at risk for fractures. In adults and children, a reduction of 1 standard deviation in bone density is associated with at least a doubling of fracture risk (Goulding et al., 2000). Fractures can occur at any point in the care of children with cancer, from diagnosis through survivorship. Additional treatment factors and neurologic deficits, such as motor or sensory neuropathy and ataxia, can also increase fracture risk associated with decreased BMD. Both axial and appendicular bone structures are at risk for fracture.

Functional implications

Pediatric patients with cancer often have reduced BMD, osteopenia, or osteoporosis. These conditions may not only result in decreased mobility and independence with instrumental activities of daily living, but also impair the ability to participate in academic, vocational, and avocational activities during childhood and possibly into young adulthood and beyond.

Survivors of childhood cancer with a history of reduced BMD, osteopenia, or osteoporosis often have difficulty with the following functional equivalence domains: moving about and manipulating objects, caring for oneself, interacting and relating with others, and health and physical well-being.

Neurological Functioning

Neurological Motor Deficits

Description

There are many etiologies of potential motor deficits resulting from childhood cancers and their treatments. There is certainly risk of motor impairment in patients with CNS tumors and tumors that metastasize to the CNS (brain or spinal cord). Surgical disruption of motor centers or connections among the spinal cord, brainstem, cerebellum, and cerebral hemispheres are persistent and are associated with poor motor performance (Aukema et al., 2009; Huber et al., 2006; Rueckriegel et al., 2009). Tumor location, tumor progression, associated neurological conditions (e.g., edema, hydrocephalus), and surgical management of CNS tumor diagnoses can all impact motor function.

Focal motor weakness and subsequent gross- and fine-motor deficits are often associated with supratentorial tumors in the CNS. In infratentorial tumors, ataxia describes the predominant and most disabling collective of motor clinical signs affecting children both before and following treatment interventions. From 58 to 90 percent of children with posterior fossa tumors present with ataxia, frequently describing either balance or gait impairment, tremor, speech disturbance, or incoordination, and a considerable proportion of children will continue to present with long-term mobility problems following treatment interventions (Hartley, 2019). Cranial nerve dysfunction, associated with mass encroachment upon cranial nerve nuclei, most often occurring in infratentorial tumors, also can be associated with motor impairment in the areas of vision, communication, mastication, and swallowing.

Motor deficits are also commonly seen in cancers other than CNS tumors, including solid tumors and leukemias; motor deficits due to amputation or limb-sparing surgery are discussed above. Motor deficits can result subsequent to many of the treatment interventions utilized for childhood cancer, including radiation (CNS radiation necrosis, radiation plexopathy), chemotherapy (peripheral neuropathy, CNS neurotoxicity), and surgical intervention (focal neuropathies).

Pathogenesis and risk of impairment in childhood cancer

Motor deficits in childhood cancer can be variable depending on the location and focality of the cancer and on the potential for functional recovery with treatment interventions (tumor resection, use of steroids, physical therapy, and occupational therapy). Some motor deficits will demonstrate good recovery with treatment intervention, but even significant recovery may not translate to an equivalent state of safety and precision with functional activity; that is, strength recovery is not synonymous with motor ability and efficiency,

given that functional capability requires multidimensional input, including strength, coordination, and motor planning.

Functional implications

Children with a history of childhood cancer complicated by motor deficits have reduced functional capacity in such areas as mobility and independence with instrumental activities of daily living, which negatively impacts their ability to participate actively in academic, vocational, and avocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of motor deficits may have difficulty with the following functional equivalence domains: moving about and manipulating objects, caring for oneself, interacting and relating with others, and health and physical well-being.

Seizures

Description

Seizures are transient involuntary alterations of consciousness, behavior, motor function, sensation, or autonomic function. Factors predisposing to seizures in CNS tumors include tumor pathology (low/high-grade glioma, glioneuronal tumor), cortical location, and subtotal resection (Ullrich et al., 2015). Although most common in children with brain tumors or metastases of other cancers to the brain, seizures can occur in other cancers as well, as effects of antineoplastic therapy (intrathecal [IT] chemotherapy, radiation therapy) or as the result of metabolic disturbances, or hypoxia. A seizure is a symptom of an underlying pathological process, and an investigation into potential etiologies, including detailed history of prior seizures, family history of seizures, medications, and antineoplastic treatments, should commence following initial seizure symptomatology. Bloodwork and neuroimaging should be included in the evaluation. Most children with cancer and seizures receive antiseizure medication during the evaluation process, but many are weaned from this medication if the evaluation reveals no significant abnormalities (normal electroencephalography and normal neuroimaging). Children whose first seizure is prolonged or who have repeated seizures experience an increased incidence of seizure recurrence and generally require prolonged therapy with antiepileptic medication.

Pathogenesis and risk of impairment in childhood cancer

Seizures are a frequent comorbidity in survivors of pediatric brain tumors, seen at presentation in 24 percent of patients and ongoing in 14 percent (Ullrich et al., 2015). Children who have poorly controlled seizures are at risk for functional deficits complementing the alteration in function that is associated with the seizure activity. The frequency of seizures, coupled with the

postictal symptomatology and duration associated with the seizure activity, can significantly impact the level of impairment experienced by the patient. Other important considerations with respect to impairment associated with seizures are the side effects of antiepileptic treatments, including sedation, cognitive impairment, and fatigue, among others.

Functional implications

Both patients with childhood cancer and survivors who have been diagnosed with recurrent seizures and are undergoing treatment with antiepileptic medication may demonstrate impairments in motor function and cognitive function and deficits in participation in both instrumental activities of daily living and school activities.

Survivors of childhood cancer with a history of seizures may have difficulty with the following functional equivalence domains: attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Hydrocephalus and Shunt Malfunction

Description

Acquired hydrocephalus is frequently noted at the time of presentation for newly diagnosed pediatric brain tumors, causing obstruction of the flow of cerebrospinal fluid (CSF). Obstructive tumoral hydrocephalus in children is secondary to blockage of CSF at different anatomical levels by midline or paramidline tumors. Management of tumoral obstructive hydrocephalus includes tumor resection as well as temporary external ventricular drainage, as indicated. Subsequent interventions may include endoscopic third ventriculostomy and ventriculoperitoneal shunt, with implantation of the latter being the most common definitive shunting procedure.

Pathogenesis and risk of impairment in childhood cancer

Studies have demonstrated a prevalence of hydrocephalus and shunt malfunction of more than 50 percent in cases of pediatric brain tumor at the time of diagnosis—the second most common comorbidity at presentation (Wright et al., 2016). Surgical treatment of hydrocephalus is associated with a number of risks. Immediate procedural risks include strokes, hemorrhages (intraparenchymal or subdural), catheter misplacement resulting in a nonfunctioning shunt, and need for immediate reoperation (Wright et al., 2016). Following their placement, shunts typically malfunction in one of three ways: mechanical hardware failure, infection, or overdrainage (Wright et al., 2016). Overall failure rates, defined by the need for shunt revision or replacement of new shunts within a 30-day and 1-year period, respectively, are approximately 13 percent and 29 percent (Al-Tamimi et al., 2014). Shunt malfunction presents similarly to hydrocephalus but is of a more rapid onset. Shunt infection is also a common complication of shunt-treated

hydrocephalus. Neurological and cognitive deficits are frequent complications of shunt malfunction and infection, often worsened by the frequency with which these complications occur.

Functional implications

Children with a history of childhood cancer complicated by hydrocephalus and complications related to shunting have reduced capacity in such areas as mobility and independence with instrumental activities of daily living relative to their peers, which negatively impacts their ability to participate actively in academic and vocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of hydrocephalus and complications related to shunting often have difficulty with the following functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Chemotherapy-Induced Peripheral Neuropathy (Sensory and Motor)

Description

Chemotherapy-induced peripheral neuropathy (CIPN), which can have both acute and chronic functional implications for pediatric patients with cancer, is caused by exposure to various neurotoxic chemotherapeutic agents. These drugs often disrupt axonal transport and microtubules, leading to nerve damage. Acute damage can occur in sensory, motor, or autonomic neurons, with symptoms that are rarely life-threatening but often severe enough to interfere with function both during therapy and after its completion (Bjornard et al., 2018). CIPN can be long-lasting, with multiple studies showing persistence of electrophysiologic, subjective, and/or functional dysfunction months and years after treatment (Kandula et al., 2016). Symptoms can include dampening or loss of peripheral reflexes, pain, numbness, tingling, weakness, difficulty swallowing, altered thermoregulation, poor blood pressure control, and problems with intestinal mobility (Gilchrist, 2012). Symptoms of peripheral neuropathy usually start distally and can progress proximally (Bjornard et al., 2018).

Vinca alkaloids (e.g., vincristine) cause a sensorimotor axonal neuropathy that is length-dependent (Zajaczkowska et al., 2019). The distal polyneuropathy caused by vinca alkaloids can initially be painful, affecting both sensory and motor functions (Ness et al., 2011). Loss of ankle reflexes and complaints of numbness and tingling in the feet and/or hands often precede the onset of distal weakness. Taxanes (e.g., paclitaxel) also create a length-dependent peripheral neuropathy that is often limited to small sensory nerve fibers (Zajaczkowska et al., 2019). Platinum drugs

(e.g., cisplatin) cause a sensory neuropathy in a different manner by causing accumulation of platinum in the dorsal root ganglia (Zajaczkowska et al., 2019). As a result, peripheral neuropathy induced by platinum drugs often has a patchy distribution.

With all of these agents, the neurotoxic effect is influenced by the cumulative exposure to the drug. Neuropathies typically occur acutely and may require dose reduction or cessation of chemotherapy to reduce symptomatology. In some cases, the neuropathy is reversible with dose reduction or cessation of the offending agent, but in others, symptoms can persist for years or be permanent (Adamson et al., 2016; Bakogeorgos and Georgoulias, 2017; Miltenburg and Boogerd, 2014; Zajaczkowska et al., 2019).

Children with CIPN may also present with dysesthesias and neuropathic pain, as several classes of chemotherapeutic agents, including vinca alkaloids, taxanes, and platinum agents, have effects on sensory nerves (Adamson et al., 2016). Treatment for chemotherapy-induced neuropathic pain and dysesthesias mirrors therapy for other etiologies of neuropathic pain and includes desensitization techniques, as well as pharmacologic management with such medications as gabapentin, pregabalin, or selective serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine) (Gewandter et al., 2019).

Functional testing should be completed when pronounced neuropathy or functional impairment is present and should include refined measures of strength and sensation, measurement of joint ROM, estimates of functional capacity (e.g., 6-minute walk test), balance testing, and standardized evaluation of manual dexterity (Bjornard et al., 2018). Although pharmacologic therapy can attenuate pain symptoms, research also supports the use of nonpharmacologic interventions in children with cancer who develop neuropathy, including the use of ankle/foot orthosis (bracing) and graded motor imagery (a protocol of three progressive stages—right-left laterality, imagined movements, and mirror therapy) (Casanova-Garcia et al., 2015; Tanner et al., 2015). Rehabilitation strategies for children with CIPN should focus on remediation of impairments (e.g., postural control deficits, gait abnormalities, muscle weakness, loss of fine-motor skills), support the continued development of motor control (e.g., jumping, running, stair climbing), and promote regular physical activity (Bjornard et al., 2018).

Pathogenesis and risk of impairment in childhood cancer

The functional impairment related to CIPN, both sensory and motor, is high. The development and severity of peripheral neuropathy can depend on multiple factors, including gender, age, race, genetic variants, and pharmacokinetics related to dosing and method of administration of the chemotherapeutic agent (van

de Velde et al., 2017). Risk factors for the development of CIPN include high doses of chemotherapy, long duration of therapy, current administration of azoles, and older age (Kandula et al., 2016; Kurczynski et al., 1980). In a retrospective review of six large treatment trials, severe or disabling peripheral neuropathy with vincristine was observed in 10 percent of patients receiving a lower cumulative dose and in a significant percentage of patients—20–52 percent—receiving a higher dose (Langholz et al., 2011). Children and adolescents who sustain CIPN will demonstrate significant motor impairments that affect mobility, fine-motor skills, and independence with instrumental activities of daily living. Sensory neuropathies can include tactile sensation that can impair fine-motor dexterity and subsequent attainment of instrumental activities of daily living.

Functional implications

Children with a history of childhood cancer complicated by CIPN have reduced capacity in such areas as mobility and independence with instrumental activities of daily living, which negatively impacts their ability to participate actively in academic, vocational, and avocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of CIPN have difficulty with the following functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Leukoencephalopathy

Description

Some types of chemotherapy may cause leukoencephalopathy, which refers to disorders of the white matter in the CNS. CNS prophylaxis, utilized in the treatment of ALL, is based on the premise that the CNS acts as a sanctuary site where leukemic cells, undetected at diagnosis, are protected by the blood–brain barrier from therapeutic concentrations of systemically administered antileukemic drugs (Rabin et al., 2016). CNS prophylaxis can be accomplished utilizing a variety of modalities, including radiation, IT chemotherapy, and high-dose systemic agents (MTX or cytosine arabinoside) (Rabin et al., 2016). IT MTX alone and triple IT therapy (cytarabine, MTX, and hydrocortisone) can produce a broad spectrum of acute, subacute, or chronic neurotoxic sequelae (Rabin et al., 2016). Leukoencephalopathy typically presents with fluctuating encephalopathy, stroke-like symptoms, seizures, and/or headache that develop over minutes to hours (Bhojwani et al., 2014; Inaba et al., 2008). Subacute MTX neurotoxicity may occur days to weeks following exposure to MTX and may include varying degrees of encephalopathy, myelopathy, hemiparesis,

seizures, and paraplegia. Although symptoms can improve, recovery is not always complete. Diagnostics typically include cranial imaging with brain MRI and possibly magnetic resonance angiography. Treatment is supportive, but omission of MTX from the chemotherapeutic regimen is typically not recommended given the benign course of its associated neurotoxicity (Bhojwani et al., 2014). Despite the short clinical course, acute leukoencephalopathy during chemotherapy may increase the risk for long-term neurobehavioral problems (Bhojwani et al., 2014).

Pathogenesis and risk of impairment in childhood cancer

Leukoencephalopathy is associated with IT MTX and triple IT therapy. It has been demonstrated to have an incidence of 23.3 percent in patients who have undergone routine serial surveillance screening with a brain MRI during IT treatment for ALL (Bhojwani et al., 2014).

Functional implications

Children with a history of childhood cancer complicated by leukoencephalopathy have reduced capacity in such areas as mobility and independence with instrumental activities of daily living, which negatively impacts their ability to participate actively in academic, vocational, and avocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of leukoencephalopathy have difficulty with the following functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Cerebrovascular Complications

Description

Cerebrovascular complications of treatment for childhood cancer may include stroke, moyamoya, occlusive cerebral vasculopathy, or cavernomas. Alterations in cerebrovasculature may occur as a consequence of radiation therapy. Development of arterial disease is a late phenomenon; therefore, stroke as a result of cranial radiation therapy typically occurs years after treatment initiation (Sun and Cooper, 2018). Changes to the large vessels have been noted following significant radiation doses to the circle of Willis in the parasellar region (Ullrich et al., 2007). Focal narrowing of one or more of the six major intracranial vessels is most often seen after irradiation for tumors that tend to infiltrate around or are located adjacent to the major vasculature (Ullrich et al., 2007). Occlusion of the three major vessels emanating from the circle of Willis, sometimes bilaterally, is called moyamoya syndrome (Ermoian et al., 2016). The phenomenon is most common in children irradiated before 5 years of age, particularly in

the setting of neurofibromatosis type 1 (Ullrich et al., 2007). The median time to the recognition of moyamoya syndrome is 3–4 years posttherapy, putting children and adolescents at considerable risk for stroke at a relatively young age (Ermoian et al., 2016). The use of T2 gradient recalled echo MRI is paramount in the diagnosis of late cerebrovascular complications, as indicated (Passos et al., 2015). The COG’s current long-term follow-up guidelines recommend that survivors of childhood and young adult cancers who received ≥40 Gy to the neck region undergo yearly neurological examination and assessment for diminished carotid pulses and the presence of carotid bruits (COG, 2018).

Pathogenesis and risk of impairment in childhood cancer

The reported incidence of late cerebrovascular complications in patients who have undergone radiation treatment for childhood primary CNS tumors is 36 percent (Passos et al., 2015). Regardless of optimization of radiation therapy, damage to surrounding normal brain tissue will occur (Partap, 2012). Radiation therapy is an established cause of endothelial dysfunction (Fajardo, 2005) and a risk factor for such late cerebrovascular complications as cavernoma, moyamoya syndrome, microbleeds, and stroke (Passos et al., 2015). The interaction of irradiation with specific host factors, such as neurofibromatosis and the presence of an underlying cardiovascular risk profile, can catalyze adverse outcomes (Morris et al., 2009).

Functional implications

Children with a history of childhood cancer complicated by cerebrovascular complications raise concern for cognitive impairments, as well as reduced capacity in such areas as mobility and independence with instrumental activities of daily living, which negatively impacts their ability to participate actively in academic, vocational, and avocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of cerebrovascular complications often have difficulty with the following functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Cancer-Related Pain

Description

Pain is a common and distressing symptom associated with cancer, and children with cancer frequently report pain across the disease trajectory, from diagnosis to end of life or into survivorship (Tutelman et al., 2018). There are many potential etiologies for cancer-related pain, including medical interventions and treatments (chemotherapy and radiation

therapy), procedural factors (postoperative discomfort, venipuncture, lumbar puncture), and pain from the cancer itself. Many children with cancer undergo surgery, and several of the most common surgeries, such as amputation, limb-sparing surgery, and thoracotomy, have the greatest incidence of chronic postsurgical pain due to associated nerve damage, thereby increasing the risk of developing chronic pain into survivorship (Alberts et al., 2018). Studies have documented numerous adverse outcomes of unmanaged pain in children with cancer, including declines in health-related functioning, body image, and quality of life; difficulty with sleep; increased sensitivity to pain and procedural distress; restriction of social activities; and the development of emotional and behavioral problems (e.g., anxiety, depression) (Alberts et al., 2018; Tutelman et al., 2018).

Pathogenesis and risk of impairment in childhood cancer

The prevalence of pain in survivors of childhood cancer ranges from 5–59 percent in studies evaluating pain as an outcome measure, highlighting the potential for unreported pain in this population of patients (Alberts et al., 2018). Not only is pain common and significant among children completing active cancer treatment, but parents and health care providers often undertreat children’s pain (Fortier et al., 2014). This has implications for survivors because early injury to the developing nociceptive system (e.g., undertreated pain) can permanently impact subsequent pain processing, including sensitization to future painful stimuli (Fitzgerald, 2005).

Functional implications

Survivors reporting pain are also likely to show symptoms of emotional distress, demonstrate fear about the future, and experience increased anxiety (Alberts et al., 2018). There is a bidirectional relationship between psychological distress and pain, such that heightened levels of emotional distress in the child or parent may be associated with increased and more persistent pain (Hedén et al., 2013; Hedström et al., 2003; Linton and Shaw, 2011), which can also diminish independent functioning. Compared with sibling controls, survivors have been demonstrated to have increased suicidal ideation, and cancer-related pain and pain severity have been observed to be significant predictors of suicidal ideation (Recklitis et al., 2006, 2010).

Patients with childhood cancer and survivors who have experienced cancer-related pain may demonstrate disabilities in terms of motor function, cognitive function, and psychosocial interactions, as well as deficits in the independent execution of instrumental activities of daily living and difficulty participating in school activities.

Survivors of childhood cancer with a history of cancer-related pain may have difficulty with the following functional equivalence domains: attending and completing tasks, interacting and relating with others, moving

about and manipulating objects, caring for oneself, and health and physical well-being.

Fatigue/Sleep Problems

Description

Fatigue is a subjective experience of tiredness, exhaustion, and lack of energy that is not proportional to recent activities and interferes with usual functioning (Stone and Minton, 2008). Fatigue may be stratified as acute or chronic, with chronic fatigue being defined as lasting for 6 months or more and after the stimuli that caused it have ended (Fukuda et al., 1994). Long-term survivors of childhood cancer with persistent chronic fatigue versus those without it are characterized by more depressive symptoms, anxiety, pain, and insomnia and less physical activity.

Pathogenesis and risk of impairment in childhood cancer

Chronic fatigue has emerged as a significant late effect in survivors of childhood cancer, and a prevalence of up to 30 percent has been reported (Zeller et al., 2014). Etiologies of sleep disorders in children with cancer and survivors are multidimensional. These disorders can derive from cancer-related factors that may include the direct result of brain injury (brain tumor, neurosurgery, cranial radiation therapy, hydrocephalus) or an indirect result of the tumor itself (chemotherapy, cancer-related fatigue, pain, seizures, obesity, endocrinopathies, heart failure, blindness, medication) (Kaleyias et al., 2012). Stress on the child and the family resulting from such life-threatening disease may contribute to or exacerbate sleep disorders (Kaleyias et al., 2012).

Excessive daytime sleepiness (EDS), defined as sleepiness that occurs when an individual would usually be expected to be awake and alert, is the most common manifestation of sleep disorder in children with cancer, particularly those with neoplasms involving the CNS, and more specifically involving the hypothalamus and the brainstem (Kaleyias et al., 2012). The etiology of EDS is multifactorial and includes (1) insufficient nighttime sleep (such as insomnia and circadian rhythm sleep disorders); (2) fragmented nighttime sleep (contributed to by behavioral disorders including anxiety and depression, sleep-onset association disorder, movement disorders, parasomnias, and environmental causes); and (3) an increased drive for sleep, such as temporary hypersomnia associated with increased intracranial pressure or with drug-related (chemotherapy) or secondary narcolepsy affecting the pons or hypothalamus (Kothare and Kaleyias, 2008). Aside from EDS, other potential etiologies for fatigue and sleep disorders in children with cancer and survivors can include sleep dysfunction due to medical therapy (dexamethasone, cranial radiation therapy), insomnia, cancer-related fatigue, and sleep-disordered breathing (most prominently obstructive sleep apnea) (Witmans and Young, 2011).

Functional implications

Both fatigue and sleep disorders can carry a significant risk of functional impairment, particularly in the area of cognitive function and precision with fine- and gross-motor activities. For a child with additional underlying deficits, such as peripheral neuropathy or motor deficits, fatigue can further amplify these functional impairments and result in additional difficulty in attaining independence and accuracy with these activities.

Children with a history of childhood cancer complicated by chronic fatigue or sleep disorders have reduced capacity in such areas as mobility and independence with instrumental activities of daily living, which negatively impacts their ability to participate actively in academic, vocational, and avocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of chronic fatigue or sleep disorders may have difficulty with the following functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Paraneoplastic Neurologic Syndromes

Description

Paraneoplastic syndromes are defined as clinical syndromes that are not related to direct tumor invasion or compression but are secondary to tumor secretion of functional peptides and hormones or related to immune cross-reactivity with normal host tissue (Pelosof and Gerber, 2010). In some instances, they present before the primary malignancy or tumor recurrence is diagnosed, and they often mimic subtypes of syndromes that occur in the absence of malignancy (Ma et al., 2019).

Paraneoplastic syndromes can be categorized as neurologic, endocrine, and dermatologic/rheumatologic conditions (Ma et al., 2019; Rutherford et al., 2007). Paraneoplastic neurologic syndromes frequently develop before underlying cancer becomes clinically apparent (Ma et al., 2019). Most result from the production of tumor-directed antibodies (onconeural antibodies), which, as a result of antigenic similarity (immune cross-reactivity) with host nervous system tissues, attack components of the host nervous system (de Beukelaar and Sillevis Smitt, 2006; Pelosof and Gerber, 2010). Paraneoplastic neurologic syndromes can involve different parts of the CNS and the neuromuscular junction, and include opsoclonus-myoclonus syndrome (OMS), limbic encephalitis, N-Methyl-D-aspartate encephalitis, Anti-Ma2 encephalitis, and myasthenia gravis.

The most common paraneoplastic neurologic syndrome in children is OMS, associated most typically with neuroblastoma. Symptoms include unsteady gait, body jerks, twitching eye movements, irritability, sleep

disturbance, and cognitive impairment. Treatment consists of multimodal immune suppression (de Alarcon et al., 2018; Galstyan et al., 2017).

Pathogenesis and risk of impairment in childhood cancer

Paraneoplastic syndromes are rare in children, affecting fewer than 1/10,000 patients with cancer (Alavi, 2013). Up to 50 percent of cases of OMS are related to neuroblastoma in children, while 2–3 percent of neuroblastoma patients present with OMS (Alavi, 2013; Brunklaus et al., 2012). The prognosis for OMS with aggressive treatment is improving, although some children are left with long-term neurological and cognitive disability.

Functional implications

Children with a history of childhood cancer complicated by paraneoplastic neurologic syndromes have reduced capacity in such areas as mobility and independence with instrumental activities of daily living, which negatively impacts their ability to participate actively in academic, vocational, and avocational activities during childhood, impacts that persist into young adulthood and beyond.

Survivors of childhood cancer with a history of paraneoplastic neurologic syndromes will have difficulty with the following functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Sensory Impairments

Hearing impairment

Description

Hearing impairment is defined as difficulty hearing and may range in severity from mild to severe. It can be apparent on physical exam and is diagnosed with audiogram or audiological testing.

Pathogenesis and risk of impairment in childhood cancer

Hearing impairment is associated with cisplatin chemotherapy, other platinum agents, and radiation therapy to the cochlea (Brinkman et al., 2015; Khan et al., 2018; Weiss et al., 2019). Among survivors of childhood cancer with a history of these treatments who underwent audiological testing, the prevalence of ototoxicity was 62 percent (Hudson et al., 2013).

Functional implications

Hearing impairment can be treated or partially treated with hearing aids or, in some cases, cochlear implant. Survivors may also benefit from the use of assistive listening devices and speech/language therapy. Hearing loss has the potential to reduce physical well-being and quality of life, as well as capacity for vocational or educational

activities (Brinkman et al., 2015; Weiss et al., 2019). Children with hearing impairment who qualify for an Individualized Education Program can receive additional accommodations and supports within the school setting (e.g., preferential classroom seating or instruction in sign language). See the discussion of interventions for and remediation of cognitive sequelae below for details about this program. The following functional equivalence domains can be affected: attending and completing tasks, interacting and relating with others, caring for oneself, and health and physical well-being.

Low vision, cataracts, and blindness

Description

Low vision, cataracts, and blindness are disorders of impaired visual acuity and can be diagnosed with ophthalmologic examination and vision testing.

Pathogenesis and risk of impairment in childhood cancer

Children with optic pathway glioma and orbital tumors, such as retinoblastoma and orbital rhabdomyosarcoma, are at risk for visual impairment as a result of their cancer or associated surgeries (Rakotonjanahary et al., 2019). Cataracts are also associated with radiation therapy to the orbit, temporal lobe, or posterior fossa; graft-versus-host disease; prednisone; and busulfan chemotherapy (Whelan et al., 2010). With ophthalmologic exam, the prevalence of ocular late effects in survivors of childhood cancer with a history of one of these exposures was found to be approximately 27 percent (Hudson et al., 2013).

Functional implications

Visual impairment, including low vision and cataracts, may be amenable to corrective lenses (glasses) or surgical treatment. Blindness, or complete loss of vision, is typically irreversible. For a child with a history of cancer complicated by visual toxicities, the ability to be fully mobile or to attend to vocational or educational activities is likely impacted. The following functional equivalence domains are affected: attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Medical Late Effects by Body System

Cardiac and Vascular

Carotid artery disease

Description

Carotid artery disease is atherosclerotic narrowing of the large arteries in the neck that supply blood to the brain. Its clinical manifestations include carotid insufficiency, dizziness, syncope, and cerebral vascular

accident (stroke). It is diagnosed with a carotid artery ultrasound or a carotid artery angiogram demonstrating narrowing.

Pathogenesis and risk of impairment in childhood cancer

Carotid artery disease can be caused by radiation therapy to the carotid arteries and may be caused or accelerated by such risk factors as hypertension or smoking (Meeske et al., 2009; Wilson et al., 2015). It is typically a progressive process that manifests after treatment has ended, although it may manifest acutely during treatment. In one study of survivors of childhood cancer with a history of radiation to the neck, 55 percent showed evidence of plaque or calcification on carotid ultrasound (Zaletel et al., 2018).

Functional implications

Children whose cancer is complicated by carotid artery disease may have such physical limitations as dizziness or syncope and reductions in the following functional equivalence domains: moving about and manipulating objects and health and physical well-being. In survivors who suffer a cerebral vascular accident (stroke), the following functional equivalence domains are impacted: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being. The consequence is reduced ability to participate in academic and vocational activities.

Coronary artery disease

Description

Coronary artery disease is an atherosclerotic process whereby the coronary arteries become narrowed, and insufficient blood flow is provided to the cardiac tissues. Its clinical manifestations include chest pain, shortness of breath, angina pectoris, and myocardial infarction, as well as coronary heart disease. It is diagnosed with a cardiac stress test demonstrating areas of decreased perfusion or cardiac function, or among those with a history of myocardial infarction. It can also be diagnosed posthumously, most commonly when sudden death is caused by a myocardial infarction.

Pathogenesis and risk of impairment in childhood cancer

Coronary artery disease can be caused by radiation therapy to the coronary arteries and may be caused or accelerated by chemotherapies such as anthracyclines and risk factors such as hypertension or smoking (Armenian et al., 2018; Chow et al., 2014; Mulrooney et al., 2020). It is typically a progressive process that manifests after treatment has ended, although it may manifest acutely during treatment. In one study of survivors of childhood cancer with a mean age of 33.1 years (range 18–60), the prevalence of ischemic heart disease as indicated on electrocardiogram was 5.7 percent (Hudson et al., 2013).

Functional implications

Those whose childhood cancer is complicated by coronary artery disease have difficulties in the following functional equivalence domains: attending and completing tasks, caring for oneself, moving about and manipulating objects, and health and physical well-being. These difficulties result from such physical limitations as dyspnea on exertion or angina pectoris. The consequence is reduced ability to participate in academic and vocational activities.

Congestive heart failure

Description

Congestive heart failure is the clinical manifestation of weakening of the cardiac muscle (myocardium), resulting in reduced cardiac output. Its clinical manifestations include weakness, fatigue, dyspnea on exertion, pulmonary edema, lower-extremity edema, syncope, arrhythmia, and death. It is diagnosed with an echocardiogram, multigated acquisition scan, or cardiac MRI.

Pathogenesis and risk of impairment in childhood cancer

Congestive heart failure can be caused by radiation therapy to the myocardium; radiation therapy–related coronary artery disease; or chemotherapy, such as anthracyclines (Armenian et al., 2018; Chow et al., 2014; Mulrooney et al., 2020; Wilson et al., 2015). It may be accelerated by such risk factors as hypertension or smoking and can appear during cancer treatment or at any time after treatment has ended. Among 1,214 survivors of childhood cancer with a mean age of 33.1 years, the prevalence of abnormal echocardiogram suggesting congestive heart failure was found to be 6.2 percent (Hudson et al., 2013).

Functional implications

Those whose childhood cancer is complicated by congestive heart failure have reductions in the following functional equivalence domains: attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being. These reductions result from such physical limitations as dyspnea on exertion or lower-extremity edema. The consequence is reduced ability to participate in academic and vocational activities.

Endocrine

Obesity

Description

Body mass index (BMI) is calculated as weight in kilograms over height in meters squared. In children, BMI is represented as age- and

sex-specific percentile from growth charts created by the Centers for Disease Control and Prevention. Obesity is defined as 95th percentile or higher.

Pathogenesis and risk of impairment in childhood cancer

Obesity is associated with childhood leukemia (Oeffinger et al., 2003), as well as cancer treatments that include cranial radiotherapy, sometimes used to treat leukemia, and hematopoietic stem cell transplantation (Belle et al., 2019; Tonorezos et al., 2015). In addition, children who are obese at the time of cancer diagnosis are at risk for obesity during and following treatment (Co-Reyes et al., 2012). The prevalence of obesity among long-term survivors of childhood cancer approaches 50 percent (Hudson et al., 2013).

Functional implications

Those whose childhood cancer is complicated by obesity experience reductions in the functional equivalence domains of attending and completing tasks, caring for oneself, moving about and manipulating objects, and health and physical well-being as a result of physical limitations that include poor cardiorespiratory fitness, a risk for type 2 diabetes mellitus, cardiovascular disease, and dyspnea upon exertion. The stigma of obesity may also result in challenges in the domain of interacting and relating with others.

Diabetes mellitus

Description

Diabetes mellitus is diagnosed when blood glucose is abnormally high because insulin production is insufficient or its utilization is inadequate.

Pathogenesis and risk of impairment in childhood cancer

Diabetes mellitus is associated with cancer treatments that include radiation therapy to the brain or abdomen or total body irradiation (Tonorezos et al., 2015). One study found that among long-term survivors of childhood cancer with a history of radiation to the hypothalamic-pituitary axis, the prevalence of diabetes mellitus was 7.8 percent (Hudson et al., 2013).

Functional implications

Those whose childhood cancer is complicated by diabetes mellitus have reduced capacity in the functional equivalence domain of health and physical well-being as a result of requiring medication, as well as the potential sequelae of diabetes mellitus, including cardiovascular disease, retinal vasculopathy, and peripheral neuropathy.

Gonadal failure

Description

Gonadal failure is diagnosed when the gonads (ovaries or testes) are not producing estrogen, progesterone, or testosterone, and may

be associated with failure to produce eggs or sperm. It can occur during treatment, such as in acute ovarian failure, or during survivorship, as in premature ovarian insufficiency (premature menopause).

Pathogenesis and risk of impairment in childhood cancer

Gonadal failure can be caused by radiation to the gonads, alkylating agent chemotherapy, or radiation to the hypothalamic-pituitary-adrenal axis that results in failure to stimulate the gonads (Tonorezos et al., 2015). Its prevalence can range from 11.8 percent for primary ovarian failure to 66 percent for male germ cell failure (resulting in azoospermia) (Hudson et al., 2013).

Functional implications

If untreated, gonadal failure can result in short stature, low bone density, reduced fertility/fecundity, and other sequelae of early menopause or andropause. These sequelae will affect the functional equivalence domain of health and physical well-being.

Hyperthyroidism

Description

Hyperthyroidism is defined as overproduction of thyroid hormone and can result from dysfunction of the thyroid gland (primary hyperthyroidism) or overproduction of thyroid-stimulating hormone (TSH) (secondary hyperthyroidism). It is diagnosed with a blood test used to determine serum elevated free thyroxine (T4) level.

Pathogenesis and risk of impairment in childhood cancer

Hyperthyroidism can result from radiation therapy to the thyroid gland, where T4 is produced, or the hypothalamus, which produces TSH (Tonorezos et al., 2015).

Functional implications

Those whose childhood cancer is complicated by hyperthyroidism have reduced capacity in the functional equivalence domain of health and physical well-being as a result of physical limitations that include palpitations, hyperhidrosis, weight loss, and other symptoms of hyperthyroidism or thyroid storm. In severe cases, the domains of acquiring and using information and attending and completing tasks may also be affected.

Panhypopituitarism

Description

Panhypopituitarism is defined as insufficiency of the hypothalamic-pituitary axis resulting in low levels of TSH; GH; adrenocorticotropic hormone (ACTH); follicle-stimulating hormone; luteinizing hormone; and vasopressin, also called antidiuretic hormone (ADH). It is diagnosed when

blood and urine testing reflects low levels of these hormones and low urine-specific gravity (indicating that ADH is insufficient).

Pathogenesis and risk of impairment in childhood cancer

Panhypopituitarism can result from surgery or radiation therapy to the hypothalamic-pituitary axis (Tonorezos et al., 2015). It often occurs with a history of craniopharygioma and other supratentorial brain tumors near the sella turcica.

Functional implications

Children with panhypopituitarism require lifelong hormone replacement. In times of illness or bodily stress, increased doses of mineralocorticoid are required; failure to replace it adequately can result in death. If untreated, symptoms include hypotension, dizziness, arrhythmia, electrolyte abnormalities, osteoporosis, obesity, and short stature. This condition affects the functional equivalence domain of health and physical well-being.

Hypothyroidism

Description

Hypothyroidism is defined as insufficient production of thyroid hormones triiodothyronine (T3) and T4. It may reflect either dysfunction of the thyroid gland (primary hypothyroidism) or inadequate production of TSH (secondary hypothyroidism). It is diagnosed with a blood test that identifies low serum T4 and/or T3.

Pathogenesis and risk of impairment in childhood cancer

Hypothyroidism can result from surgery on the thyroid gland or the hypothalamic-pituitary axis. It is also a common late effect of radiation therapy to the neck, spine, or nearby regions (Tonorezos et al., 2015) and is associated with immune checkpoint inhibitor therapy (Barroso-Sousa et al., 2018). Among survivors of childhood cancer with a history of radiation to the neck, the prevalence of hypothyroidism approaches 14 percent, and prevalence is even higher among those with a history of radiation to the hypothalamic-pituitary axis (Hudson et al., 2013).

Functional implications

Children with hypothyroidism require lifelong hormone replacement. If the condition is untreated, symptoms include weight gain, edema, heart failure, dizziness, and short stature. This condition affects the functional equivalence domain of health and physical well-being.

Adrenal insufficiency

Description

Adrenal insufficiency is defined as inadequate production of adrenocortical hormones. It may reflect failure of the adrenal gland

(primary adrenal insufficiency) or the inadequate production of ACTH in the hypothalamic-pituitary axis (secondary adrenal insufficiency). It is diagnosed with an ACTH or cosyntropin stimulation test, which requires taking blood cortisol levels before and after injection of synthetic ACTH; an inadequate response reflects adrenal insufficiency. Supportive but not diagnostic testing includes low morning serum cortisol level and low or inadequate serum ACTH level.

Pathogenesis and risk of impairment in childhood cancer

Adrenal insufficiency in children with cancer can be caused by removal or insufficiency of the adrenal glands or, more commonly, damage to the hypothalamic-pituitary axis, where production of ACTH occurs (Tonorezos et al., 2015). This damage is often seen in children with brain tumors and may be associated with surgery or radiation therapy to the hypothalamic-pituitary axis.

Functional implications

Adrenal insufficiency, if untreated, is a life-threatening condition. Lifetime treatment with adrenocortical hormone replacement is required. In times of illness or bodily stress, increased doses of mineralocorticoid are required; failure to replace adequately can result in death. If the condition is untreated, symptoms include hypotension, dizziness, and arrhythmia. This condition results in impairment in the functional equivalence domain of health and physical well-being.

Growth hormone deficiency

Description

GH deficiency is defined as inadequate production of GH. It reflects failure of the hypothalamic-pituitary axis, where GH is produced. While low serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are often seen in GH deficiency, they are not diagnostic. Instead, provocative stimulation testing is usually required. This procedure entails measuring serum GH after stimulation from intravenous clonidine, arginine, or glucagon.

Pathogenesis and risk of impairment in childhood cancer

GH deficiency in children with cancer is caused by damage to the hypothalamic-pituitary axis, where production of GH occurs (Tonorezos et al., 2015). This damage is often seen in children with brain tumors and may be associated with surgery or radiation therapy to the region.

Functional implications

Treatment with daily subcutaneous injection of synthetic GH is required throughout childhood. If the condition is untreated, symptoms include cardiac insufficiency, prediabetes or diabetes

mellitus, growth failure, low bone density, and short stature. This condition results in impairment in the following functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, and health and physical well-being.

Diabetes insipidus

Description

Diabetes insipidus is defined as insufficiency of ADH, also known as arginine vasopressin. It is caused by insufficient production of ADH by the pituitary gland (central diabetes insipidus) or inadequate action at the renal tubule (nephroenic diabetes insipidus). It is diagnosed when the patient is suffering from polyuria and low urine osmolality that rapidly corrects with intranasal, subcutaneous, or intravenous synthetic ADH (desmopressin).

Pathogenesis and risk of impairment in childhood cancer

Diabetes insipidus in children with cancer is caused by damage to the pituitary gland, where ADH production occurs (Tonorezos et al., 2015). This damage is often seen in children with brain tumors and may be associated with surgery or radiation therapy to the region.

Functional implications

Lifelong treatment with intranasal or oral synthetic ADH (desmopressin), up to three times per day, is required. If the condition is untreated, symptoms include severe polyuria, electrolyte abnormalities, hypotension, and dizziness. This condition affects the functional equivalence domain of health and physical well-being.

Gastrointestinal and Hepatic

Malnutrition and nutritional deficiencies

Description

Malnutrition and nutritional deficiencies are defined as a lack of adequate nutrients and may be observed in children with normal weight or normal BMI. Children with cancer may suffer from malnutrition and nutritional deficiencies before, during, and after treatment (Co-Reyes et al., 2012; Zimmermann et al., 2013). These impairments are diagnosed with serum testing demonstrating low nutrient levels, with suggestive clinical features such as low BMI (Sala et al., 2004).

Pathogenesis and risk of impairment in childhood cancer

Malnutrition and nutritional deficiencies can be due to direct effects of cancer, such as lack of appetite, prior to treatment. During and after treatment, infections, surgical manipulation of the gastrointestinal tract, graft-versus-host disease

following hematopoietic cell transplantation, and radiation-related enteritis are implicated (Co-Reyes et al., 2012; Sala et al., 2004). In addition, some children suffer from malnutrition and nutritional deficiencies as a result of inadequate intake, which can be caused by altered taste, nausea, vomiting, or food insecurity (Sala et al., 2004; Skolin et al., 2006).

Functional implications

Malnutrition and nutritional deficiencies are pervasive conditions that can impact a child’s outcomes and physical, emotional, and psychosocial well-being and the child’s ability to participate actively in academic and vocational activities. If untreated, they may result in starvation and death. The following functional equivalence domains are impacted: attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Hepatic dysfunction

Description

Hepatic dysfunction is defined as inadequate or insufficient function of the liver, gall bladder, or biliary tree. It is diagnosed when serum testing indicates elevated aspartate aminotransferase, alanine transaminase, alkaline phosphatase, or gamma-glutamyl transferase. Liver ultrasound or MRI may provide supportive evidence related to the cause or complication of hepatic dysfunction.

Pathogenesis and risk of impairment in childhood cancer

Hepatic dysfunction may be the direct result of radiation therapy or chemotherapy, such as busulfan (Green et al., 2019; Mulder et al., 2019). It can also result from viral hepatitis; vaso-occlusive crisis; lipid disorders; the metabolic syndrome; or surgery to the liver, gall bladder, or duodenum (Green et al., 2019; Mulder et al., 2019). In one study, abnormal liver function was found in 13 percent of long-term survivors of childhood cancer (Hudson et al., 2013).

Functional implications

Hepatic dysfunction can have a lasting and far-reaching effect on physical health and well-being during and after treatment for childhood cancer. Without a normally functioning liver and gallbladder, children may suffer from pain, metabolic abnormalities, jaundice, diarrhea, and liver failure. Hepatic dysfunction can also negatively impact the ability to tolerate other treatments or medications and results in an inability to meet vocational or educational expectations. The following functional equivalence domains can be impacted: attending and completing tasks, caring for oneself, and health and physical well-being.

Esophageal stricture

Description

Esophageal stricture is defined as narrowing of the esophagus and is diagnosed with endoscopy or barium esophagram. It can cause dysphagia and odynophagia, at times progressing to poor oral intake, esophageal fistula, or undernutrition.

Pathogenesis and risk of impairment in childhood cancer

Esophageal stricture is caused by radiation therapy to the esophagus or direct tumor involvement of the esophagus with candidal esophagitis; it can also occur as a complication of esophageal surgery. It typically appears several years after treatment has ended and must be treated with esophageal dilatation.

Functional implications

Children with a history of childhood cancer complicated by esophageal stricture are at risk for undernutrition and low body weight, which negatively impacts their ability to participate in academic and vocational activities. The following functional equivalence domains can be impacted: caring for oneself and health and physical well-being.

Chronic constipation or diarrhea

Description

Chronic constipation or diarrhea is diagnosed when symptoms are persistent and do not respond to first-line therapy. Symptoms of chronic constipation include infrequent bowel evacuation, hard small feces, difficult or painful evacuation of large-diameter stools, and fecal incontinence. Chronic diarrhea results in frequent soft or watery stools lasting at least 2 weeks. These conditions can result in malnutrition or malabsorption, and chronic diarrhea is associated with impaired mucosal healing.

Pathogenesis and risk of impairment in childhood cancer

Chronic constipation is associated with radiation therapy to the colon and some chemotherapies, such as vinblastine. Chronic diarrhea is also associated with radiation therapy or may be the result of an infectious process. These conditions can appear at any time during or after cancer treatment, often respond poorly to initial treatment, and can last through the lifespan.

Functional implications

Chronic constipation or diarrhea can impact both physical and psychological well-being, making it difficult for the child to sit for long periods of time or participate in vocational and academic activities. The following functional domains can be affected: interacting and relating with others, caring for oneself, and health and physical well-being.

Infectious and Immunologic

HIV/AIDS, hepatitis B or C

Description

HIV/AIDS and hepatitis B and C are bloodborne infectious diseases transmissible via transfusion of blood products before the blood supply was routinely screened for these diseases. They are diagnosed with serum antibody or viral load testing.

Pathogenesis and risk of impairment in childhood cancer

Children with a history of receiving transfusion of blood products prior to screening of the blood supply for these diseases are at risk for chronic infection. For HIV/AIDS, the risk is limited to those treated during 1977–1985; for hepatitis B, the risk is among those treated before 1972; and for hepatitis C, the risk is among those treated before 1993. In one study that tested approximately 2,000 survivors of childhood cancer treated during these periods, the prevalence of HIV/AIDS was 0.5 percent, the prevalence of hepatitis B was 3.6 percent, and the prevalence of hepatitis C was 6.8 percent (Hudson et al., 2013). These infections are life-threatening if they go untreated and in the case of HIV/AIDS, cannot be cured.

Functional implications

These serious infections have significant implications for psychological and physical well-being, with the potential to affect nearly every organ system. They may result in such chronic conditions as hepatic dysfunction, malignant neoplasm, and susceptibility to other infections, with negative impacts on vocational and academic activities. The functional equivalence domain of health and physical well-being can be affected.

Asplenia

Description

Asplenia is defined as the absence of a spleen.

Pathogenesis and risk of impairment in childhood cancer

Historically, splenectomy was included in the staging work-up for Hodgkin lymphoma, rendering the patient asplenic; however, this procedure is no longer performed routinely in the United States. Radiation therapy to the spleen can result in functional asplenia, whereby the infection-fighting properties of the spleen are not functional. In one report from the Childhood Cancer Survivor Study, 6.8 percent of survivors had a history of splenectomy, and 46 percent had received splenic radiation without splenectomy (Weil et al., 2018).

Functional implications

Asplenia and functional asplenia put a child at risk for overwhelming infection and death. Encapsulated organisms, such as pneumococcus, are often implicated, but infection from any cause may occur. Because of the risk of overwhelming infection, children with a history of childhood cancer complicated by asplenia or functional asplenia have impaired ability to participate in vocational and academic activities. The following functional equivalence domains can be affected: interacting and relating with others and health and physical well-being.

Chronic graft-versus-host disease

Description

Chronic graft-versus-host disease is a multiorgan, multisystem complication of hematopoietic stem cell transplantation that occurs when immune cells transplanted from a nonidentical donor (graft) identify the transplant recipient (host) as foreign. It is diagnosed by characteristic clinical findings or histologic findings on biopsy of affected tissue (Dignan et al., 2012; Filipovich et al., 2005).

Pathogenesis and risk of impairment in childhood cancer

Chronic graft-versus-host disease occurs only in children who undergo allogeneic hematopoietic stem cell transplantation with a nonidentical donor. In the Bone Marrow Transplant Survivor Study, which is not a fully representative sample, approximately 13 percent of survivors had chronic graft-versus-host disease at a mean of 12.9 years from treatment (range 5.1–26.1 years) (Armenian et al., 2011).

Functional implications

This is a severe, life-threatening condition. Patients often have a rash, dry mucous membranes, and hepatic dysfunction. Children with childhood cancer that is complicated by graft-versus-host disease are at risk for death as a result of this condition and must be managed closely and carefully; the ability to participate in vocational activities is negatively affected. The condition may cause reductions in the following functional equivalence domains: attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Hypogammaglobulinemia

Description

Hypogammaglobulinemia is defined as low or inadequate production of antibodies by B lymphocytes. It is diagnosed with a serum test for immunoglobulin levels, which may be low or undetectable.

Pathogenesis and risk of impairment in childhood cancer

Hypogammaglobulinemia results from inadequate recovery from cancer treatment, most often rituximab, a CD-20 specific monoclonal antibody (Barmettler et al., 2018; Rao et al., 2008).

Functional implications

Children with hypogammaglobulinemia are at risk for infection, especially bacterial infections of the sinuses and pneumonia. They require lifelong treatment with regular infusions of intravenous immunoglobulins. As a result, the ability to participate in vocational and educational activities may be reduced. The following functional equivalence domains may be affected: interacting and relating with others, caring for oneself, and health and physical well-being.

Pulmonary

Pulmonary dysfunction

Description

Pulmonary dysfunction includes fibrosis, a diffuse parenchymal lung disease characterized by interstitial fibrosis and diagnosed with computed tomography scan of the lungs, as well as obstructive or restrictive dysfunction diagnosed by pulmonary function testing.

Pathogenesis and risk of impairment in childhood cancer

Pulmonary dysfunction is associated with chemotherapy, including busulfan, carmustine, lomustine, and bleomycin; lung surgery; or radiation therapy to the lungs, or it may occur as a complication of hematopoietic stem cell transplantation. In one study, pulmonary function testing was used to diagnose abnormal lung function in more than 65 percent of survivors of childhood cancer with a history of these exposures (Hudson et al., 2013).

Functional implications

Pulmonary dysfunction causes cough; dyspnea; poor oxygenation; and, in severe cases, death. It is associated with recurrent pneumonia. Treatments include oxygen supplementation and oral medication, such as prednisone. Children with a history of childhood cancer that is complicated by pulmonary dysfunction are chronically ill with reduced mobility and decreased exercise capacity, and may have difficulty with vocational or academic activities. The following functional equivalence domains can be affected: attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Renal and Urologic

Renal dysfunction

Description

Renal dysfunction is defined as inadequate function of the kidneys and includes such disorders as glomerular filtration rate impairment, proteinuria, tubulopathy, and hypertension. It is diagnosed with blood and urine testing that identifies elevated serum creatinine, proteinuria, or cells in the urine. Renal ultrasound can be helpful in elucidating the cause of renal dysfunction.

Pathogenesis and risk of impairment in childhood cancer

Renal dysfunction can be caused by chemotherapy, such as cisplatin, carboplatin, or ifosfamide, as well as radiation therapy or nephrectomy (often seen in treatment for Wilms tumor) (Kooijmans et al., 2019). Its prevalence approaches 5 percent among those with at-risk exposures (Hudson et al., 2013).

Functional implications

Children with childhood cancer complicated by renal dysfunction can have a more complicated or difficult recovery and may require such treatment as intravenous fluid; medication, such as angiotensin-converting enzyme inhibitor; or kidney transplant. As a result, the ability to participate actively in academic and vocational activities is negatively impacted. The functional equivalence domain of health and physical well-being can be affected.

Secondary Malignant Neoplasms

Secondary malignant neoplasms (SMN), defined as new primary malignancies after an initial cancer diagnosis, cause substantial morbidity and mortality in long-term survivors of childhood cancer. Survivors of childhood cancer experience long-term increased SMN risk compared with the general population, with the greatest risk observed for cancers of the breast, kidney, and thyroid, as well as soft-tissue sarcomas (STS) (Turcotte et al., 2018). Importantly, SMN are rarely observed in the first 5 years after diagnosis of childhood cancer. The cumulative incidence of these SMN, as well as subsequent neoplasms, which also include nonmelanoma skin cancers and benign meningiomas, is less than 1 percent by 5 years in those who have survived for 5 or more years (Turcotte et al., 2017). The SMN most common in the first 5 years after diagnosis are therapy-related myelodysplastic syndrome (MDS). Yet, even these subsequent cancers are rare in the first 5 years after diagnosis, with a cumulative incidence of less than

1 percent (Hawkins et al., 1992; Rihani et al., 2010). Risk of SMN is associated with treatment exposures, potentially modified by age at exposure and genetic predisposition. Importantly, the risk of SMN has decreased by treatment era, with those treated in earlier decades demonstrating higher risk than those treated more recently (Turcotte et al., 2017).

Radiation-Associated Risk

There is a dose-dependent increased risk for solid tumors following radiotherapy, with the highest risk for tumors occurring in or near the treatment field (e.g., >5-fold increased risk for breast, brain, thyroid, skin, bone, and STS malignancies) (Inskip et al., 2016; Schaapveld et al., 2015; Turcotte et al., 2018). Female breast cancer is highly prevalent, particularly after chest/absorbed doses >10 Gy, with an established linear dose-response relationship (Inskip et al., 2009; Moskowitz et al., 2014). This risk is reduced in women with premature menopause (Inskip et al., 2009; Moskowitz et al., 2017).

Chemotherapy-Associated Risk

The best-established associations between chemotherapy and the development of SMN are for therapy-related acute myeloid leukemia (t-AML) and MDS. There is a greater than 10-fold dose-dependent risk for t-AML/MDS after administration of almost all alkylating agents, as well as topoisomerase II inhibitors (Hawkins et al., 1992; Le Deley et al., 2003; Pui et al., 1991; Travis et al., 2013). Typically, t-AML arises after exposure to alkylating agents following a latency of 5–8 years; it is frequently preceded by MDS, and often has a complex karyotype with chromosome 5/7 abnormalities. In contrast, t-AML after exposure to topoisomerase II inhibitor typically arises less than 3 years following therapy, is rarely preceded by MDS, and is most frequently characterized by 11q23 rearrangements.

Alkylating and anthracycline chemotherapy both increase the risk of several solid malignancies, risks that are often modified by other patient characteristics, such as age at exposure and, potentially, inherited genetic susceptibility. Alkylating agent exposure increases the risk for gastrointestinal, thyroid, lung, breast, and bladder cancers, as well as sarcomas (Travis et al., 2013; Turcotte et al., 2018), typically more than 10 years after exposure. Risk for breast cancer and other solid malignancies, including sarcoma, is increased after anthracycline exposure. Notably, chemotherapy can also indirectly affect SMN risk (Henderson et al., 2012, 2016; Teepen et al., 2017; Turcotte et al., 2018). Conversely, high-dose cumulative alkylator exposure has been observed to reduce breast cancer risk in survivors exposed to chest radiation.

COGNITIVE FUNCTIONING

It is well recognized that many survivors of childhood cancer experience significant cognitive sequelae from the disease itself, as well as from various modalities of therapy (Butler and Haser, 2006; Correa, 2010; Krull et al., 2018; Phillips et al., 2015; Robinson et al., 2013). Thus, although survival rates have increased, these cognitive deficits may limit the ability of survivors of childhood cancer to achieve their full academic (Aarsen et al., 2009; Butler and Haser, 2006; Mabbott et al., 2005; Mulhern et al., 1987) and vocational (Maddrey et al., 2005; Prasad et al., 2015) potential, and even functional independence (Brinkman et al., 2016a; Mulhern et al., 1988a; Palmer, 2008). Cognitive abilities encompass a wide range of skills and domains of functioning, including general intellectual abilities/intelligence, processing speed, attention, executive functioning (EF), language, visual-spatial abilities, memory, academic skills, and adaptive skills.

Many factors moderate the cognitive outcomes experienced by children with a history of cancer, including child factors, developmental factors, environmental/family factors, and disease and treatment factors (for a review, see Stavinoha et al., 2018). Regarding treatment factors, chemotherapy, radiation, and neurosurgical procedures, both independently and in combination, can impact each cognitive domain (Krull et al., 2018; Nathan et al., 2007). Notably, several areas of cognition are more frequently impacted by standard cancer interventions, as discussed in the following sections. The specific mechanisms by which these treatments impact cognition is not always fully understood; however, it is recognized that the impact is generally mediated through associated medical (e.g., cardiopulmonary or endocrine dysfunction) or neurological (e.g., hydrocephalus or leukoencephalopathy) complications, as described in other sections of this chapter. Primary brain tumors also can cause significant cognitive dysfunction simply on the basis of location within the brain and resulting surgery-related changes (Beebe et al., 2005; Grill et al., 2004; Marusak et al., 2018).

Research in childhood cancer has identified some general risk factors for cognitive sequelae that are related to the disease itself and to its various treatments. Importantly, these illness-related effects can also exacerbate any preexisting cognitive deficits a child may have at the time of diagnosis (Iuvone et al., 2011). Not surprisingly, the greatest risk for new or later cognitive deficits is experienced by those with CNS (e.g., brain or spine) disease and/or CNS-directed therapies (e.g., craniospinal radiation for ALL [Annett et al., 2015; Stavinoha et al., 2018]), and the majority of the literature examining cognitive sequelae focuses only on survivors within those categories. However, elevated risk also is associated with systemic or non-CNS-directed therapies, thought to be related to cardiopulmonary

and/or endocrine late effects. For example, cognitive dysfunction has been identified in survivors of childhood Hodgkin lymphoma (Krull et al., 2012) and even in survivors of childhood ALL who received only chemotherapy (Kanelloupoulos et al., 2016). Finally, it is known that children diagnosed and treated for cancer in early childhood bear increased risk for cognitive late effects as a result of the disruption of normal cognitive development during critical developmental windows via neurotoxic effects of treatment that alter typical neuroanatomical developmental processes (Ikonomidou, 2018) or even via simply missed developmental experiences and opportunities that result from being ill (Anderson et al., 2000; Mulhern et al., 1987). In fact, one overarching theory is that the experience of cancer and its associated treatments at any point in childhood can irreparably alter the typical neurodevelopmental trajectory for any cognitive process (Marusak et al., 2018). Moreover, in addition to the increased risk in children diagnosed in early childhood (Robinson et al., 2013), there is ample evidence for cognitive sequelae in survivors diagnosed during adolescence or early adulthood, with significant deleterious effects on functional capacity (Jim et al., 2018; Krull et al., 2018). And it is well documented that these cognitive deficits persist well into adulthood (Harila et al., 2009; Maddrey et al., 2005). Although it is important to consider the possibility of cognitive sequelae in all childhood cancer survivors, it should be noted that most of the literature examining cognitive outcomes in childhood cancer survivors focuses on those children who have experienced CNS cancers or CNS-directed treatment.

Given the high frequency of cognitive sequelae, it is essential to consider the likelihood of cognitive deficits in each individual survivor of childhood cancer. Accordingly, it is the standard of care for childhood cancer patients—especially those with CNS cancers or CNS-directed treatment (Annett et al., 2015)—to undergo thorough cognitive evaluation at various points during treatment, including baseline/pretreatment and after various interventions, to identify cognitive sequelae as soon as possible (Mulhern et al., 1998; Nathan et al., 2007). Reassessment after completion of treatment and transition into survivorship is also essential given that some cognitive late effects can emerge years after completion of therapy (Annett et al., 2015). These evaluations are often conducted by clinical neuropsychologists, who are trained to interpret scores on cognitive measures in the context of known neurological risk factors and brain–behavior relationships, although evaluations may be completed by clinical psychologists or school psychologists in some instances. Documentation of the results of these evaluations, therefore, can be found in a child’s medical or school/educational record.

Cognitive skills can be evaluated in a variety of ways, with tasks designed to assess specific domains or with a battery of tasks/measures that makes it possible to fully appreciate a child’s profile of cognitive strengths and weaknesses. Any standardized assessment measure compares an individual’s performance against that of a cohort of same-aged typically developing peers or a normative sample. The comparison results in a standardized score that describes the extent to which the individual’s performance exceeds, meets, or falls below the mean performance of the comparison group. There also are screening measures that may be useful for identifying risk for cognitive deficits, particularly in those patients who lack access to neuropsychological services. Screening tools, including simply parent report of perceived cognitive dysfunction (e.g., Pediatric Perceived Cognitive Functioning from the Patient-Reported Outcomes Measurement Information System), are adequate for indication of likely problems but not sufficient for full determination or characterization of cognitive deficits and their functional implications (Lai et al., 2014). Any selected method of measurement should be well validated and have appropriate and relevant normative data. Annex Table 4-3 provides a list of selected representative cognitive assessment instruments.

Regardless of the measurement method selected, cognitive dysfunction is common in survivors of childhood cancer. Estimates range from 30 to 60 percent of children with a history of ALL (Krull et al., 2013) and 40 to 100 percent of children with a history of CNS tumor (Correa, 2010; Glauser and Packer, 1991), with the magnitude of deficits reaching large effect sizes (Robinson et al., 2010). It is worth noting that advanced imaging techniques, such as diffusion tensor imaging, are increasingly used in presurgical planning for CNS tumors in an attempt to identify and therefore avoid injury to neural connections during tumor resection (Caras et al., 2020). The occurrence of cognitive deficits has been studied less frequently in children with non-CNS-related cancers; however, there is ample evidence of cognitive dysfunction in a variety of cancers secondary to the effects of various treatments and secondary medical conditions (Edelmann et al., 2016; Krull et al., 2012; Sleurs et al., 2016; Tonning Olsson et al., 2019). Phillips and colleagues (2015) found that approximately 35 percent of all survivors of childhood cancer have some degree of cognitive dysfunction that persists into adulthood.

Impairment in any area of cognitive functioning is likely to impact a child’s functioning within several of SSA’s functional equivalence domains. Literature regarding the impact of childhood cancers, particularly those with direct impact on the CNS, and associated treatments on relevant cognitive domains is reviewed in the following sections.

Intellectual Ability

Definition and Measurement

Intellectual ability can be defined as an individual’s general ability to understand, interpret, retain, and apply information gathered from a variety of sources. It is commonly characterized by an intelligence quotient (IQ). Although IQ was previously regarded as a unitary concept, it is now understood that, as traditionally assessed, it encompasses a number of specific cognitive processes, including attention, speed of processing, visual-spatial processing, language, and even memory, among others (Lezak, 1995). Several standardized measures can be used to assess IQ, most of which include assessment of a variety of specific skills that are then summed to describe an overall level of intellectual capacity (see Annex Table 4-3) and compared with normative datasets. IQ scores are typically reported as standard scores that have a mean of 100 and a standard deviation of 15. Children with scores of 85–115 are considered functioning within the average range, or at age-expected levels, while those with scores below 85 are considered to have some degree of intellectual dysfunction and/or impairment.

Pathogenesis and Risk of Impairment in Childhood Cancer

Most of the literature examining cognitive outcomes of childhood cancer have focused on general intelligence (IQ) (Butler and Haser, 2006). There is ample evidence that a higher proportion of survivors of childhood cancer have reduced intellectual abilities compared with their same-aged healthy peers (Armstrong et al., 2011), and it is estimated that at least 30–35 percent have some degree of cognitive dysfunction (Armstrong et al., 2011; Phillips et al., 2015). Decline in intellectual functioning over time was initially noted in early outcome studies (Duffner et al., 1988). This risk for intellectual decline is particularly significant for those treated in early childhood (e.g., prior to age 6 years [Fouladi et al., 2005; Garcia-Perez et al., 1994; George et al., 2003]). Although there has been some documentation of IQ decline in children treated with chemotherapy only (Iyer et al., 2015; Kanellopoulos et al., 2016), risk for decline in intellectual abilities is most notable in survivors of childhood cancer treated with craniospinal radiation (De Ruiter et al., 2013; Merchant et al., 2009; Palmer et al., 2003; Spiegler et al., 2004), in a dose-related pattern (Grill et al., 1999). Some early studies documented a 2- to 4-point decline per year (Spiegler et al., 2004), with evidence of a 12–14-point difference between those who were treated with radiation and those who were not (Mulhern et al., 1992). Emerging research has found reduced risk for decline when proton beam radiation is used instead of traditional craniospinal radiation therapy (Gross et al., 2019; Kahalley et al., 2016; Warren et al., 2018).

Onset and Course

The onset and course of impact on general intellectual abilities may vary based on disease and treatment characteristics. In general, however, initial demonstration of global cognitive dysfunction is often noted within the first year postdiagnosis, with potential for progression of decline in functioning over time. Although the course of decline may be more rapid in children who are diagnosed at a younger age, decline, perhaps with a slower, more protracted course, is also experienced by children diagnosed at a later age (Palmer et al., 2003; Radcliffe et al., 1994).

It is of course important to note that there have been substantial changes in treatment over the past decades, as described in preceding chapters. Unfortunately, data on long-term cognitive sequelae for novel treatments are still emerging (Duffner, 2010).

Close examination of longitudinal data reveals not a frank loss of intellectual knowledge or previously attained skills, but slowing of the typical developmental trajectory over time. That is, children treated for childhood cancer have a change in their developmental trajectory and rate of progress that results in a widening gap between their abilities and those of typically developing same-aged peers over time (Anderson et al., 2000; Mulhern et al., 2004b; Palmer, 2008; Palmer et al., 2001). Thus, their standardized IQ score decreases over time and may eventually fall into the score range indicative of intellectual disability.

Functional Implications

Regardless of the reason for lowered standardized IQ scores, the implication is the same: many children with a history of childhood cancer have lower cognitive capacity than their peers, which negatively impacts their ability to achieve their academic, vocational, and functional potential during childhood, impacts that persist into young adulthood and beyond. The intellectual abilities of a proportion of children with childhood cancer will eventually fall within the range of dysfunction characterized as intellectual disability (e.g., mental retardation), typically defined as standardized IQ scores of 70 or lower. These individuals typically require ongoing special educational and vocational supports, as well as some degree of guardianship into adulthood. At least 23 percent of survivors of childhood cancer eventually receive special education services (Mitby et al., 2003).

Even those survivors who do not end up with standardized scores in the intellectual disability range can have functional limitations related to diminished IQ compared with their premorbid or anticipated level of functioning. In fact, one study found that almost 60 percent of a cohort of survivors of brain tumor required special education services and support despite having IQ within the normal range (Aarsen et al., 2009). This outcome has been

identified in children with higher premorbid functioning or greater cognitive reserve (Kesler et al., 2010). That is, children with higher cognitive abilities at the time of diagnosis may not experience a decline sufficient to qualify as intellectual disability; however, they still exhibit a reduced rate of development that may result in a widening gap between their level of functioning and that of same-aged typically developing peers over time. Although ameliorated, this slowed developmental trajectory is observed even in children with reduced radiation exposure (Ris et al., 2001). As a result, these survivors still experience significant functional deficits that may best be characterized as specific learning disabilities or attention-deficit/hyperactivity disorder (ADHD). Although some childhood cancer survivors may meet diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for specific cognitive disorders, it is important to recognize that the cognitive sequelae of childhood cancer can vary in degree and pattern across individuals and may not fit precisely into a DSM-5 diagnostic category, or may best be characterized as a mild or major neurocognitive disorder. In general, regardless of the degree of intellectual impairment documented, survivors of childhood cancer with slowed intellectual development will have significant functional difficulties within several of the SSA functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, and caring for oneself.

Whereas initial studies on cognitive outcomes in survivors of childhood cancer focused on evaluation of the broad functional domains of intellectual abilities and academic skills, the importance of assessing and identifying the specific cognitive skill deficits underlying overall underachievement is now well recognized (Butler and Haser, 2006). Although much of the research in this area has focused on documenting the impact of slowed developmental progression on IQ, a similar impact of slowed developmental gains often is observed in other domains of cognitive functioning as well, in conjunction with IQ or in isolation. Moreover, even those survivors who demonstrate average-range or normal scores on intellectual tests may have specific cognitive deficits that will significantly negatively impact their functional capacity. In fact, it has been suggested that assessment or estimation of IQ alone underestimates the full cognitive sequelae in survivors of childhood cancer (Burgess et al., 2018). Although there will always be individual variability in cognitive outcomes from childhood cancer and associated treatments, the most common cognitive deficits observed in survivors occur in processing speed, attention/working memory, EF, and memory (Butler and Haser, 2006; Palmer et al., 2013; Schatz et al., 2000; Stavinoha et al., 2018). The following sections address these and other cognitive domains frequently impacted by childhood cancer and associated treatments.

Processing Speed

Description

Processing speed is defined as the rate at which individuals can take in, comprehend, apply, and react to information they receive (Lezak, 1995). It is recognized as an underlying cognitive skill that can impact the efficiency of any higher-level cognitive ability. Processing speed is assessed as a component skill on many IQ tests (e.g., Wechsler tests) but can also be assessed independently using specific tasks. Most measures of processing speed require some motor response (e.g., pressing a button, selecting/marking an object, writing a response). Thus, children with any residual neuropathy or deficit in motor coordination from either disease or treatment effects will likely perform poorly on many measures of processing speed.

Pathogenesis and Risk of Impairment in Childhood Cancer

The risk of deficits in processing speed in survivors of childhood cancer is exceptionally high. In fact, processing speed has been identified as one of the core cognitive components that likely underlies the IQ declines documented in many survivors (King et al., 2019). Deficits in processing speed have been associated primarily with radiation treatment and the resultant damage to white matter (Bledsoe, 2016; Partanen et al., 2018; Scantlebury et al., 2016). However, even chemotherapy (Hardy et al., 2017; Iyer et al., 2015; Krull et al., 2016) alone and isolated surgical resection, particularly within the posterior fossa with resultant disconnection of cerebellar-fronto-subcortical circuits (Aarsen et al., 2009; Ronning et al., 2005; Steinlin et al., 2003), have been identified as causal factors, specifically in childhood survivors of ALL or CNS tumors. In addition, given the way in which processing speed is generally assessed and functionally relevant, survivors may have deficits secondary to treatment-related neuropathy or fine-motor deficits (Grill et al., 2004). Emerging evidence suggests that use of proton beam radiation rather than traditional photon radiation may result in less significant deficits in processing speed and related cognitive functions (Antonini et al., 2017; Kahalley et al., 2016; Warren et al., 2018); however, processing speed is impacted negatively in general by the volume or dose of radiation and the amount of tissue exposed.

Onset and Course

The timing of the onset of deficits in processing speed varies significantly in survivors of childhood cancer. Evidence indicates that some children, particularly those with posterior fossa tumors and associated

hydrocephalus, may demonstrate these deficits at the time of diagnosis (Di Rocco et al., 2010), while others may experience acute onset following surgical intervention or initiation of treatment. The association between deficits in processing speed and radiation treatment is perhaps the most well studied, with rapid onset typically noted within 1–3 years posttreatment (Spiegler et al., 2004). There also is evidence of decline in processing speed over time (Anderson et al., 2000), which, as noted previously, is believed to underlie the well-documented slowed general cognitive developmental trajectory in survivors of childhood cancer (Palmer, 2008; Schatz et al., 2000).

Functional Implications

As noted, deficits in processing speed are now considered one of the primary factors underlying the apparent intellectual decline observed in survivors of childhood cancer (Mabbott et al., 2008). Moreover, children with slowed processing speed often are characterized as having a “sluggish cognitive tempo” and diagnosed as having ADHD, predominantly inattentive type (Jacobson et al., 2018). Survivors of childhood cancer with deficits in processing speed have difficulty with the following functional equivalence domains: acquiring and using information, attending and completing tasks, moving about and manipulating objects, and interacting and relating with others.

Attention and Working Memory

Description

Attention encompasses a variety of skills related to one’s ability to direct and sustain focus to a task or set of stimuli while simultaneously suppressing irrelevant stimuli. In addition, ability to inhibit or monitor responses is often considered part of attention. Finally, attention is closely related to working memory, or one’s ability to take in, manipulate, make sense of, and immediately apply novel information. Both attention and working memory are discussed in this section.

Attention can be assessed directly or indirectly. Working memory tasks are embedded in many of the Wechsler intelligence measures, as well as specific independent tasks. Direct assessment of attention often relies on computerized tasks used to monitor patterns of response to prescribed stimuli over a period of time. Attentional problems are assessed indirectly using self- or proxy (e.g., parent or teacher) report on standardized behavioral questionnaires. The latter may be more ecologically valid than direct assessment using computerized tasks as these questionnaires will reflect an individual’s attentional capacity in a typical work or school

environment, rather than performance on an artificial task in a one-on-one testing setting.

Pathogenesis and Risk of Impairment in Childhood Cancer

Deficits in attention and working memory have been identified as commonly as have deficits in processing speed in survivors of childhood cancer (Cheung and Krull, 2015; Stavinoha et al., 2018), and deficits have been associated with various clinical and treatment factors. Attention problems are commonly identified in children with a history of posterior fossa tumors, presumably secondary to disconnection of the cerebellar-fronto-subcortical network (Ronning et al., 2005; Steinlin et al., 2003), as well as due to the impact of cranial radiation on white matter circuitry in general (Brinkman et al., 2012; Kiehna et al., 2006). Deficits in working memory have been identified as well in children with a history of ALL (Van Der Plas et al., 2018) and brain tumor, even in the context of average general intellectual abilities (Conklin et al., 2012) and in the context of treatment with chemotherapy alone, particularly when MTX is administered (Buizer et al., 2009; Cheung and Krull, 2015; Kanellopoulos et al., 2016). Treatment with CNS radiation also has been associated with deficits in attention and working memory. These attention problems have been found to be correlated with decreased volume of normal-appearing white matter on brain MRI in survivors of childhood cancer (Mulhern et al., 2004c). In some children, however, attention problems exist prior to radiation treatment and can be attributed to the presence of brain tumor and treatment other than radiation (Merchant et al., 2002). Although attention deficits are most commonly attributed to the effects of radiation treatment, they also have been associated with certain chemotherapeutic agents alone in both animal (Huo et al., 2018) and human (Cheung and Krull, 2015; Iyer et al., 2015; Pierson et al., 2016) studies.

Onset and Course

Problems with attention and working memory can be identified acutely at the time of diagnosis or initiation of treatment, but often evidence progression and persistence over time. One study, for example, found that pediatric and adolescent and young adult (AYA) survivors of various primary brain tumors demonstrated attention problems at diagnosis, with an increase in inattention and deficits in sustained attention following treatment that persisted for years (Kiehna et al., 2006). The same is true of survivors of ALL with and without a history of CNS radiation treatment, although those with cranial radiation have demonstrated an increase in attention problems in a dose-related manner that persisted for decades after

treatment (Jacola et al., 2016; Krull et al., 2013). Given varying baseline levels of functioning, it may be that some survivors do not demonstrate sufficient deficits in skills on formal measures at an initial assessment, but will still experience functional impact or exhibit increasing difficulties over time as demands increase.

Functional Implications

Reddick and colleagues (2003) found that attentional impairments, in combination with associated reductions in white matter volume, explained 60–80 percent of academic underachievement in survivors of childhood brain cancer. Many children with a history of cancer and associated treatments can meet diagnostic criteria for ADHD, predominantly either inattentive or combined type (APA, 2013). ADHD is well known to be associated with academic and vocational underachievement and is identified as an independent disability category. Given the frequency of attentional deficits in survivors of childhood cancer, even those who do not receive a formal diagnosis of ADHD will demonstrate deficits in the functional equivalence domains of acquiring and using information, attending and completing tasks, interacting and relating with others, and caring for oneself.

Executive Functioning

Description

EF is an umbrella label that encompasses several important core cognitive abilities, including planning, organization, cognitive flexibility, and problem solving, as well as broader capacities for emotional and behavioral regulation (Lezak, 1995). Frequently, attention, processing speed, and particularly working memory are also included under the umbrella of EF. Thus, much of the above discussion of attention and working memory is applicable to EF as well. It is well recognized that typical EF development occurs over a protracted time course beginning in childhood and persisting through early adulthood. Moreover, it is important to note that the expectations for independent demonstration of EF skills are limited in early childhood, but increase exponentially throughout later childhood and adolescence, with full application of these skills not expected until the late adolescent/young adult age range.

Formal assessment of EF is challenging. A number of published measures utilize a variety of paper-and-pencil or other interactive tasks to evaluate various EF functions. Several of these tasks are listed in Annex Table 4-3. However, it is recognized that formal EF measures may lack ecological validity; that is, these structured tasks may not fully assess EF as

it is required in daily life. For this reason, EF is sometimes assessed using parent- or self-report questionnaires, which may better capture the impact of specific EF deficits on daily life.

Pathogenesis and Risk of Impairment in Childhood Cancer

The risk of EF dysfunction is comparable to that identified for deficits in attention/working memory and processing speed, and EF deficits are evident in many survivors of childhood cancer, particularly those with a history of ALL or brain tumor (Cheung and Krull, 2015; Stavinoha et al., 2018). EF deficits can result from various treatments, including surgical resection alone (Aarsen et al., 2009); chemotherapy alone (Buizer et al., 2009; Cheung and Krull, 2015; Krull et al., 2016); and particularly radiation (Spiegler et al., 2004), presumably as a result of degradation of cortical white matter (Brinkman et al., 2012). Some evidence suggests that children who receive proton beam radiation may experience less EF dysfunction relative to those who receive the traditional photon radiation (Antonini et al., 2017). It is important to note that survivors of childhood cancer may exhibit deficits in EF even though their functioning in other domains, including general intellectual abilities, remains intact (Ward et al., 2009).

Onset and Course

Given the typical developmental course for EF, it is often difficult to identify EF deficits in early childhood. Additionally, as a result of the later age at which independent EF skills are expected, survivors of childhood cancer with EF dysfunction often “grow into” their deficits and exhibit greater impairment once expectations exceed their threshold of functioning. This is particularly true for children who are exposed to the known risk factors in early childhood. Thus, although the impact of various cancer treatment on EF development may occur acutely, it is likely that the full effect will not be observed for some time. There also is evidence that EF deficits increase in severity over the years since diagnosis and treatment, well into the AYA period (Krull et al., 2013).

Functional Implications

As noted above, EF functions are considered core cognitive skills, which means that EF underlies one’s demonstration of general cognitive skills. More specifically, individuals with significant EF deficits will be unable to plan, organize, problem solve, or manage emotional or behavioral functioning regardless of the degree to which other cognitive skills are

intact. EF deficits in survivors of childhood cancer are associated with significant academic underachievement and poor employment outcomes in adulthood (Brinkman et al., 2016a). Survivors of childhood cancer with deficits in EF will demonstrate difficulties in the functional equivalence domains of acquiring and using information, attending and completing tasks, interacting and relating with others, and caring for oneself.

Memory Deficits

Definition and Measurement

Assessment of memory involves evaluation of an individual’s ability to learn, encode, and retrieve novel information over extended periods of time (Lezak, 1995). Working memory, sometimes referred to as short-term memory, is a separate cognitive function, covered in a preceding section. Although there are several theoretical models of different types of memory, discussion of all types of memory is beyond the scope of this chapter. The most clinically relevant type for survivors of childhood cancer is long-term declarative or explicit memory for facts and events. Declarative memory can be broken down into underlying processes that include learning (i.e., perceiving, attending to, and understanding novel information); encoding (i.e., conversion of perceived stimuli into a construct that can be recalled later); consolidation (i.e., transfer of construct from recent recall into long-term memory storage); and retrieval (i.e., the process of recalling and restating or using previously encoded information). Disruption of any of these processes can result in memory dysfunction.

Assessment of memory should address learning and memory for both verbal and visual stimuli, as memory impairment may vary with the type of stimuli presented. Additionally, assessment needs to consider sensory deficits, such as hearing or vision impairment, whether primary or secondary to treatment, that may affect an individual’s reception of a particular type of stimuli. It also is possible to have an isolated deficit in memory in the context of otherwise intact cognitive skills. Numerous well-standardized measures are available with which to fully assess the specific underlying processes of declarative memory of learning, encoding, and retrieval (see Annex Table 4-3).

Pathogenesis and Risk of Impairment in Childhood Cancer

Specific memory impairment is observed less frequently than deficits in processing speed, attention, or working memory. However, it is important to recognize that deficits in any of those domains, as well as sensory deficits, may result in memory dysfunction. Survivors of childhood cancer

at greatest risk for memory impairment are those in whom tumor location or treatment involves neuroanatomical structures involved within the memory network. Thus, memory impairment is most commonly observed in individuals with any midline brain tumor that results in injury to or mass effect on structures in Papez circuit (e.g., fornix, mamillary bodies) and/or medial (e.g., hippocampus) temporal structures (Aarsen et al., 2009). Memory impairment can also occur as a result of treatment-related damage to these regions or secondary neurological complications (e.g., seizures or hydrocephalus) (Brinkman et al., 2016a; Harila et al., 2009). However, there is neurobiological evidence that critical memory structures may be particularly vulnerable to disruption and altered neurodevelopmental trajectories (Marusak et al., 2018). Children who are treated at younger ages also appear to be at increased risk for memory deficits (Di Pinto et al., 2012; George et al., 2003). Memory impairment has been documented even in children who demonstrate otherwise intact or average general cognitive abilities or IQ (Aarsen et al., 2009).

Onset and Course

The onset and course of memory deficits can vary significantly. Children with large midline brain tumors may experience memory problems, change, or decline at the time of diagnosis, with some initial improvement following surgical resection. However, others may exhibit memory impairment as a late effect of treatment. For example, George and colleagues (2003) identified significant memory deficits, particularly in verbal memory, in a sample of childhood survivors of posterior fossa tumors evaluated approximately 11 years posttreatment, with greater impairment noted in those treated prior to age 6 years. Numerous studies have identified nonmaterial specific memory deficits in survivors of childhood cancer that persist for years after treatment has been completed (Aarsen et al., 2009; Harila et al., 2009; Mulhern et al., 1988b).

Functional Implications

The degree of memory impairment will have a direct impact on an individual’s educational attainment, which may lead to underemployment and nonindependent living status (Brinkman et al., 2016a). Intact memory is necessary to obtain full functional independence in adulthood, as one must be able to encode and retrieve information essential for the completion of tasks and decision making. As a result, survivors of childhood cancer with memory deficits will exhibit difficulties in the functional equivalence domains of acquiring and using information, attending and completing tasks, interacting and relating with others, and caring for oneself.

Focal Cognitive Deficits

Description

Focal cognitive deficits are isolated impairments in specific domains of cognitive functioning that are known to be supported by particular neuroanatomical networks or brain regions. Any focal intervention, whether surgery or radiation, has the potential to negatively impact the skills within that region. Assuming typical functional neuroanatomical organization, focal treatment within the left cerebral hemisphere could impair language and communication abilities, while focal treatment within the right cerebral hemisphere could impair visual-spatial abilities.

Language or verbal abilities include being able to understand aurally presented information and convey one’s thoughts or communicate with others verbally. Deficits in language skills are different from simple speech deficits, which are typically associated with motor control problems. Language deficits may encompass comprehension; naming abilities; vocabulary knowledge; semantic knowledge, including grammar and syntax; and repetition of verbal stimuli. Any thorough language evaluation will address each of these specific verbal skills. Language abilities can be assessed in numerous ways. While this assessment can be accomplished as part of a comprehensive neuropsychological evaluation, it can also be part of a speech/language or psychoeducational evaluation.

Visual-spatial abilities encompass the ability to understand information presented via visual stimuli and underlie one’s ability to navigate one’s environment and understand how different objects are spatially related to each other. Numerous standardized measures can be used to assess visual-spatial skills, some embedded within standardized IQ measures and others consisting of specific isolated tasks. Assessment of these skills often involves some degree of motor response; thus, any child with distal motor weakness or even persistent neuropathy may demonstrate increased visual-spatial deficits that are due to motor impairment rather than direct cortical dysfunction in primary visual-spatial areas.

Pathogenesis and Risk of Impairment in Childhood Cancer

Relatively few studies have examined the prevalence of specific or focal cognitive deficits in survivors of childhood cancer, although Robinson and colleagues (2010) found in their meta-analysis of pediatric brain tumor studies substantial evidence of persistent broad and focal cognitive deficits in survivors regardless of CNS tumor type or location. It is broadly understood that any child who undergoes surgical resection of a lesion within the cerebral hemispheres is at risk for focal cognitive deficits (Aarsen et

al., 2009). Although current surgical techniques are designed to minimize functional morbidity, the risk remains. Surgery within the posterior fossa or cerebellum, and even in subcortical structures (Nass et al., 2000), also can result in acute and persistent cognitive deficits (Robinson et al., 2013). Studies have identified visual-spatial deficits in survivors of posterior fossa surgery, with some indication of greater impairment following left cerebellar resection (Starowicz-Filip et al., 2017), but also language deficits such as those associated with cerebellar cognitive affective syndrome (CCAS) (described more fully in the following section). As described throughout this section, various treatments other than surgery can also result in acute and persistent focal cognitive deficits (Anderson et al., 2000). The impact of focal radiation to regions of the cerebral cortices is similar to that of focal resection. In survivors of both CNS cancers and non-CNS cancers, specific chemotherapeutic agents may also lead to focal deficits in language or visual-spatial impairments secondary to resultant sensory (e.g., auditory or visual) deficits.

Onset and Course

Focal deficits related to surgical resection will most likely have an acute onset immediately following surgery, while cognitive deficits may emerge over time during the course of treatment with radiation or chemotherapy. In the case of surgically induced deficits, the impact may be transient, with progressive improvement over the course of days, weeks, or months. In many instances, however, particularly in the context of additional treatment, these deficits will be permanent, and the impact of this specific deficit may increase over time as functional demands in related areas increase (Anderson et al., 2000; De Ruiter et al., 2013; Robinson et al., 2010; Stavinoha et al., 2018).

Functional Implications

Any deficit within a specific cognitive functional domain has the potential to impact a child’s overall level of cognitive functioning. Language deficits will impact a child’s communication and social skills. Visual-spatial deficits can also negatively impact a child’s social skills as a result of difficulty recognizing and interpreting nonverbal social cues. In addition, language or visual-spatial deficits may result in specific learning deficits in the areas of reading, writing, or mathematics. As noted previously, up to 60 percent of survivors of childhood cancer require some degree of special education support throughout their academic career (Aarsen et al., 2009). Moreover, it is well documented that learning disabilities typically result in

academic underachievement, negatively impacting eventual vocational attainment and functional capacity. Children with focal cognitive deficits will exhibit difficulties within the functional equivalence domains of acquiring and using information, attending and completing tasks, and interacting and relating with others.

Cerebellar Cognitive Affective Syndrome

Description

CCAS was first described by Schmahmann and Sherman (1998). CCAS is also referred to as posterior fossa syndrome or cerebellar mutism syndrome, the latter of which was first described in 1985 (Rekate et al., 1985). Whereas previous descriptions characterized the impact of cerebellar resection as being confined to mutism or speech deficit, additional behavioral symptoms are now recognized. CCAS is characterized by a set of neurobehavioral symptoms that include mutism/diminished speech output, ataxia, significant emotional/behavioral dysregulation or lability, and apathy. There is no gold standard measure of CCAS; rather, it is a diagnosis based on clinical observation of the constellation of neurobehavioral symptoms.

Pathogenesis and Risk of Impairment in Childhood Cancer

Up to 30 percent of children who undergo surgical resection of an infratentorial tumor will exhibit symptoms of CCAS within 24–48 hours of surgery (Avula et al., 2016; Korah et al., 2010). This constellation of symptoms is most commonly observed in children in whom the initial lesion and subsequent resection involved the posterior lobe or vermis of the cerebellum (Puget et al., 2009; Schmahmann and Sherman, 1998; Steinlin et al., 2003). The symptoms are thought to be related to surgical disruption of the fronto-subcortical-cerebellar pathways (Avula et al., 2016; Schmahmann and Sherman, 1998).

Onset and Course

As noted above, the onset of symptoms of CCAS is typically within hours to days of surgery. Symptoms typically resolve over the course of days to weeks (Gelabert-González and Fernández-Villa, 2001); however, there is evidence of some residual frontal/subcortical dysfunction that typically is most consistent with the attention, processing speed, and EF deficits described above (Palmer et al., 2010; Schreiber et al., 2017). Many children who experience CCAS demonstrate persistent ataxia or cranial nerve

paresis that impacts general motor and sensory functioning (Steinbok et al., 2003). Additionally, evidence suggests that children who experience CCAS have worse general cognitive outcomes relative to children who do not show these initial symptoms (Palmer et al., 2010; Schreiber et al., 2017; Steinbok et al., 2003).

Functional Implications

Within the acute timeframe, the disability associated with CCAS is significant. Any affected individual is unable to communicate effectively or engage in typical activities of daily living independently because of behavioral and emotional lability. Although the overt mutism resolves in most patients, some continue to demonstrate persistent atypical speech patterns (Steinbok et al., 2003). Additionally, most children who have experienced CCAS will exhibit persistent significant cognitive deficits that will impact functioning in several cognitive domains, particularly attention, processing speed, and EF (Steinlin et al., 2003). These cognitive deficits have been found to persist with progression in some cases (Schreiber et al., 2017). Thus, although the acute CCAS symptoms may improve, children with this clinical diagnosis will likely experience ongoing impairment in several functional equivalence domains, including acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, and caring for oneself.

Adaptive Functioning

Description

Adaptive functioning is defined as the ability to complete activities of daily living independently at an age-expected level. Any definition of adaptive functioning generally encompasses skills within the broad domains of cognition, social interaction, physical mobility, self-care, and community functioning. Importantly, the American Psychiatric Association has redefined diagnostic criteria for intellectual disability in the most recent edition of the DSM (APA, 2013) to emphasize an individual’s adaptive functioning rather than intellectual capacity. More specifically, individuals may demonstrate cognitive skills on a formal IQ test that are above the standard identified threshold for intellectual disability (i.e., >70 standard score) and yet still be unable to care for themselves or live and function independently. Thus, in many respects, adaptive skills may be the most important domain to assess for any survivor of childhood cancer to determine disability status. Adaptive functioning is generally assessed through self- or parent-reported questionnaires, although some structured

clinician-directed interviews can be used as well. (See Annex Table 4-3 for a list of standard tools.)

Pathogenesis and Risk of Impairment in Childhood Cancer

Although not frequently assessed in outcome studies, deficits in adaptive functioning are commonly observed in survivors of childhood CNS cancers (Beebe et al., 2005). However, it also has been documented that survivors of any type of cancer (e.g., including non-CNS cancers) were twice as likely as their siblings to be unable to live independently as adults, indicating that the cancer experience does play a role in this outcome (Kunin-Batson et al., 2011). Numerous factors are known to affect adaptive outcomes in survivors of childhood cancer, including neurological complications, cognitive dysfunction, psychological factors, parenting factors, and general family functioning (Hile et al., 2014; Kunin-Batson et al., 2011; Stargatt et al., 2006). There also is evidence that various cognitive deficits, such as executive dysfunction, attention problems, and language difficulties, are strongly correlated with deficits in adaptive functioning (Ashford et al., 2014; King et al., 2015; Papazoglou et al., 2008b). Additionally, those whose CNS cancer is diagnosed at earlier ages are at increased risk for adaptive deficits (Stargatt et al., 2006).

Onset and Course

Aspects of adaptive functioning may be impacted both acutely at the time of cancer diagnosis and in the midst of treatment, secondary to physical symptoms that include illness, fatigue, reduced stamina, and pain. Acute onset with persistence of difficulties for the first 6 months is observed as well in children who experience surgical resection alone (Vago et al., 2011). As children recover physically, many will also return to baseline levels of adaptive functioning. However, evidence shows that some will have persistent deficits in adaptive functioning, and some will experience a progressive decline in these skills that may vary depending on the presence of cognitive difficulties or even solely on the type of brain tumor. For example, evidence of even mild attention problems or visual-spatial dysfunction is predictive of difficulties with adaptive functioning 3–5 years postdiagnosis of a brain tumor (Papazoglou et al., 2008a). Importantly, Netson and colleagues (2013) conducted serial evaluations over 5 years of children with a history of craniopharyngioma or low-grade glioma (LGG). Results indicated that although those with craniopharyngioma did not evidence adaptive deficits at initial evaluation, they showed decline in these skills, particularly in the areas of communication and social skills. In contrast, children with

a history of LGG demonstrated adaptive deficits at initial evaluation that persisted over time.

Functional Implications

Adaptive functioning is perhaps the domain of functioning of greatest importance for consideration of disability as it by definition characterizes the ability to achieve a developmentally appropriate level of independent functioning across various types of activities. Any degree of impaired adaptive functioning is likely to have substantial negative impacts on the functional capacity of survivors of childhood cancer throughout their lifetime. Moreover, as demands for independence increase over time, deficits in adaptive functioning are likely to become more profound and noticeable across the survivor’s lifetime. Individuals with deficits in adaptive functioning will undoubtedly evidence ongoing impairment in all six functional equivalence domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for oneself, and health and physical well-being.

Interventions for and Remediation of Cognitive Sequelae

Given the increasing number of survivors of childhood cancer with cognitive sequelae that impact their functional abilities into adulthood, there has been a push to investigate and develop interventions that may improve cognition and general quality of life for survivors, particularly survivors of CNS cancers or CNS-directed therapies (for a review, see Castellino et al., 2014; Stavinoha et al., 2018). The most effective “intervention” to date has been treatment modifications, as described in other sections of this report, which have focused on reducing neurotoxicity and risks associated with specific chemotherapy and radiation regimens (Butler and Mulhern, 2005; Castellino et al., 2014).

The most typical interventions are those provided in academic settings, through either special education instruction or other classroom accommodations specified in an Individualized Education Plan. It is estimated that up to 60 percent of children with a history of childhood cancer require special education services (Aarsen et al., 2009; Mitby et al., 2003), and evidence indicates that specific remediation strategies may be beneficial for some children (Anderson et al., 2000). Obviously, the accommodations needed by each survivor will vary; in general, however, accommodations for deficits in attention and processing speed will yield the greatest benefit. A multidisciplinary team approach, in collaboration with the student and family, is necessary to develop the most successful educational support plan (Hay et al., 2015).

In addition to traditional academic accommodations, various computerized cognitive rehabilitation programs have been studied. Hardy and colleagues (2013) conducted a trial of such a program, which provided adapted training that increased in difficulty over time. The group that was trained with this program demonstrated improved visual working memory skills. Trials of other programs have shown modestly improved attention, working memory, and EF, with some impact on academic achievement but not general cognitive functioning (Butler et al., 2008; Conklin et al., 2016; Kesler et al., 2011). Longitudinal follow-up on at least one program indicated that the attentional gains were no longer evident at 6 months after program completion (Conklin et al., 2016). Challenges with any such cognitive remediation program include markedly limited access (e.g., available only at specific sites), lack of family compliance with the training, and maintenance of benefit once the program is discontinued.

The use of pharmacological interventions to address persistent cognitive deficits has been investigated. Initial data on the efficacy of use of stimulant medication in survivors of childhood cancer were mixed. Gleason and colleagues (2007) found no treatment effect of methylphenidate in a placebo-controlled, double-blind prospective, randomized clinical trial. However, other studies have identified benefit in general cognition and functioning (Meyers et al., 1998), as well as specifically in attention skills and social functioning, but not in academic achievement (Conklin et al., 2010; Kesler et al., 2011; Mulhern et al., 2004a). Relatively recent meta-analyses have confirmed the efficacy of this type of medication in a subset of survivors of childhood cancer, specifically males, those who were older at time of treatment, and those with higher baseline cognitive skills (Smithson et al., 2013). Improved EF and memory in response to the acetylcholinesterase inhibitor donepezil has also been documented (Castellino et al., 2012). Unfortunately, there are medical contraindications regarding use of these medications in some survivors of childhood cancer, as well as some hesitancy among parents about using medication for cognitive symptoms.

PSYCHOSOCIAL AND EMOTIONAL FUNCTIONING

The impact of childhood cancer on the psychosocial and emotional development of young survivors (18 years of age and younger) has been studied by several researchers; reported by survivors themselves, their parents, their school peers, and their teachers; and documented by diverse measures. The majority of studies of survivors of childhood cancer have either been conducted in adults whose late effects have presented years after their cancer treatment has been completed (e.g., Bingen et al., 2012; Gabriel

et al., 2019; Huang et al., 2018a), or been inclusive of age groups both up to and exceeding the age of 18 (e.g., Bradford and Chan, 2017; Feuz, 2014; Schwartz et al., 2012; Stone et al., 2017). Nonetheless, the limited literature specific to survivors of childhood cancer younger than 18 shows consistently that, regardless of type of cancer treatment (chemotherapy, surgery, radiotherapy, hematopoietic stem cell transplantation, etc.), adverse psychosocial and emotional effects can result (Bingen et al., 2012; Gabriel et al., 2019; Twitchell et al., 2019). Indeed, childhood cancer is defined in one report as a type of childhood adversity, as it is a form of early threat to existence (Marusak et al., 2018). The consensus is that long-term followup assessment of psychosocial status is merited for this group of survivors (Feuz, 2014). A second consensus is that there is a subgroup of young survivors (including some who experienced higher treatment intensity, such as bone marrow transplantation, and those treated for CNS tumors) that is most affected psychosocially and emotionally, demonstrating more than one disruptive adverse effect secondary to the cancer experience (Bingen et al., 2012; Kazak et al., 2010; Yi and Syrjala, 2020). This section examines the psychosocial and emotional impact of childhood cancer with respect to school and vocational outcomes, social competence and isolation, mood and other behavioral outcomes, sexual development, and involvement in risky behaviors, as well as the role of the family in those sequelae for survivors less than 18 years of age.

A review of the literature by Peterson and Drotar (2006) reveals that impacts in the first three of these areas have been well studied. Although measured at different times and using different methods, the outcomes observed across these studies (e.g., difficulties with peer relationships, greater likelihood of mood disturbance) are quite similar. The latter two areas—sexual development and involvement in risky behaviors—are acknowledged but far less extensively addressed in the literature. The review by Peterson and Drotar shows clearly that, regardless of the type or number of psychosocial and emotional effects of cancer treatment, the quality of life of survivors is significantly adversely affected. In one study of 193 survivors of childhood cancer (aged 2–34 years), the concerns most frequently reported by the survivors or their parents were emotional functioning (47.6 percent), school functioning (43.3 percent), behavioral functioning (40.9 percent), and social functioning (30.8 percent). Children who had experienced a transplant as one of their therapies consistently reported higher concerns in a majority of these categories (Bingen et al., 2012). However, these concerns were reported in varying degrees by survivors of different forms of childhood cancer and treatment. Annex Table 4-4 provides information on selected instruments used to measure psychosocial and emotional functioning in survivors of childhood cancer and to measure parental stress.

School and Vocational Outcomes

In one study, survivors of childhood cancer were found to be more likely to make use of special education services and had lower educational attainment (Zheng et al., 2018). In addition, parents of young survivors report not being prepared to support their child’s return to school (social readiness) and not knowing (1) to anticipate learning difficulties, (2) about educational interventions that could help reduce their child’s learning gaps, or (3) their legal rights to school services designed to address their child’s learning needs (Ruble et al., 2019). Without such knowledge, parents are not positioned to advocate for their child’s educational attainment, which in turn will influence the survivor’s future educational and vocational attainment.

Social Competence and Isolation

Social competence—defined as the ability to achieve personal goals through social interaction while having positive social interactions and relationships across situations (Hocking et al., 2015; Yeates et al., 2007)—can be a challenge for young survivors of childhood cancer with the most frequently identified group being survivors of CNS tumors. Reports from young survivors themselves, their school-age peers, and their classroom teachers indicate that male survivors younger than age 10 are likely to be perceived as having few friends, being socially isolated, and less liked by peers (Vannatta et al., 2007). Parents likewise provide low ratings of social competence for young survivors, including in the areas of social adjustment and interactions over time (Hocking et al., 2015), potentially indicating that these children may lose social standing over time. Older adolescent survivors representing diverse oncologic diagnoses participating in a qualitative study reported an ongoing perception of being socially isolated (Jones et al., 2011). Therefore, reassessments of social competence over time are warranted.

Mood and Other Behavioral Outcomes

The impact of social isolation is directly linked to mood and other behavioral outcomes. In a large international study based on adolescent self-reports, 49.7 percent of the adolescents reported experiencing one or more types of peer exclusion in school. This experience was directly predictive of depressive symptoms (age- and gender-controlled for in the analysis) (Kim et al., 2018). Survivors that are less accepted socially have been found to be more likely to engage in risky behaviors, such as substance abuse (see below), in addition to having worse psychological and academic functioning.

In one study (Zheng et al., 2018), compared with well siblings (age- and sex-adjusted analyses) and by parent report, survivors of childhood cancer (neuroblastoma) had a statistically significantly higher prevalence of depression and anxiety (p = 0.003), more anger or headstrong behavior (p <0.001), greater attention deficits (p <0.001), difficulties with peer relationships/social withdrawal (p <0.001), and more antisocial behavior (p <0.01). Although inconsistently noted in studies of young survivors of childhood cancer, anxiety is reported to have a prevalence of up to 22 percent and tends to be higher in female survivors (Huang et al., 2018b; McDonnell et al., 2017; Tremolada et al., 2016).

Sexual Development

Sexual development is not addressed as a type of health threat in the literature on survivors of childhood cancer less than 18 years of age. However, two or more discrete types of sexual dysfunction have been reported by young adult survivors (aged 18–25) of childhood cancer (Bober et al., 2013; Frederick et al., 2016). If this slightly older age group of survivors reports dysfunctions in sexual development, it appears likely that such concerns exist in the slightly younger group of survivors under 18 but have not been studied or otherwise well documented. Of note, radiation therapy affecting male endocrine function can lead to testosterone deficiencies in adolescents (Twitchell et al., 2019). Also, young female survivors aged 13–18 and their parents participating in a small study (26 survivors, 23 parents) reported concerns about fertility, with the great majority of survivors acknowledging a desire to have a baby in the future (Sandheinrich et al., 2018).

Involvement in Risky Behaviors

The expectation of clinicians is that children and adolescents who have been treated for cancer will be more mindful of health protective behaviors and less likely to engage in behaviors that may put their health at risk. Although data regarding risky behaviors in adolescent survivors of cancer less than 18 years of age are minimal, the available data indicate that this clinical expectation is not supported. Indeed, data indicate instead that adolescent survivors are as likely as their siblings or peers to engage in risky sexual behaviors and use of tobacco, alcohol, and illicit drugs (Brinkman et al., 2018; Klosky et al., 2012, 2014). Monitoring engagement in such behavior and intervening to diminish its likelihood are needed with this young group of survivors of childhood cancer, especially because some of these behaviors put them at increased risk for negative late effects or secondary diagnoses.

The Role of the Family

Just as the family influences the well-being of a member who is a survivor of childhood cancer, the survivor influences family well-being (Peterson and Drotar, 2006). Parents’ psychological distress contributes to overall family psychological risk, which can directly affect the child’s health-related quality of life (Racine et al., 2018), especially for survivors of female gender and for those undergoing more intense treatment. Levels of parental stress and adaptation have been found to predict functional impairment in survivors of childhood cancer, specifically with respect to school functioning, interpersonal behaviors, work roles, self-care/self-fulfillment, and community activities (Hile et al., 2014).

Combined Late Effects in Young Survivors

A young survivor will rarely experience a single late effect. For example, cognitive effects are associated with fatigue, sleep alterations, and mood (Cheung et al., 2017). More specifically, higher fatigue is associated with slower processing speed and less cognitive flexibility and self-reported inattentiveness, hyperactivity, and learning problems, as well as aggression. Certain of these associations have been reported at significantly higher rates by female survivors (Cantrell and Posner, 2014); for example, sleep alteration was found to be associated with poorer EF and being female (Cheung et al., 2017).

Psychological Late Effects

Survivors of childhood cancer are at increased risk of psychological late effects that can impair their functioning for years after the initial cancer diagnosis (CureSearch, 2020). While many survivors are able to cope well with the emotional and physical late effects of cancer, some may experience such negative psychological outcomes as depression, anxiety, posttraumatic stress, or suicidal thoughts. Treatment and diagnostic factors increasing the likelihood of emotional health problems and psychological late effects include treatment with high-dose anthracyclines, cranial irradiation, diagnoses of sarcoma or CNS tumors, and ongoing physical ill health. In addition, demographic and historical factors that increase risk for psychological late effects in survivors of childhood cancer include female gender; being adolescent or young adult; prior trauma; mental health or learning problems prior to diagnosis of childhood cancer; low levels of social support; and parental history of depression, anxiety, or posttraumatic stress disorder (PTSD) (CureSearch, 2020).

Psychological late effects have not been as well studied as physical late

effects, and there is some disagreement about the prevalence of psychological symptoms and diagnoses in survivors. One of the issues with reporting true rates of psychological symptoms is that some studies simply report distress, while others specify actual psychiatric diagnoses. Although it is common for most child and adolescent survivors to demonstrate distress and psychological or behavioral symptoms, it appears that risk of more significant impairment is due to exposure to such treatments as cranial radiation therapy and its physical sequelae (see below) (Brinkman et al., 2016b; Mertens et al., 2015). Several factors, including low income, lower education, impaired functional status, obesity, disability, pain, and unmarried status, can also contribute to poor mental health in survivors.

A recent systematic review found that up to 34 percent of adolescent survivors of cancer met criteria for PTSD, 13 percent for clinical depression, and 8 percent for anxiety. Higher distress was associated with increased number of late effects, having survived brain tumor, relapse, poor family functioning, and parental distress (Kosir et al., 2019). According to some studies, as many as 50 percent of childhood cancer survivors reported psychiatric symptoms; approximately 56 percent reported at least one psychiatric diagnosis at some point since treatment, and approximately 35 percent reported having a current psychiatric diagnosis (Bagur et al., 2015). As noted, a frequently reported risk for negative psychological late effects is receiving cranial radiation therapy. Brinkman and colleagues (2016b) found that among children who had received this therapy, 31 percent had symptoms of anxiety, depression, attention problems, and social withdrawal or peer conflict (i.e., internalizing symptoms), compared with only 16 percent of those not receiving the therapy.

Posttraumatic stress syndrome (PTSS) and PTSD can be more likely to occur based on subjective factors associated with the cancer and its severity (e.g., perceived level of threat to life and intensity of treatment), less time from the end of treatment, lack of social support and difficult family relationships, and presence and severity of physical late effects (Koutná et al., 2017; Langeveld et al., 2004; Stuber et al., 1997). The incidence of PTSD among survivors of childhood cancer may also depend on age. Stuber and colleagues (1997) found a higher prevalence of PTSD among young adult than among child and adolescent survivors, and an increased risk of PTSD associated mainly with intensive treatment, lower education, being unmarried, lower income, and unemployment.

Assessment and Treatment

The Psychosocial Standards of Care evidence-based recommendations for care of children and families suggest that survivors of childhood cancer confront psychosocial consequences of cancer, including anxiety,

depression, and PTSS/PTSD, as well as school and social issues, during and after treatment (Lown et al., 2015; Wiener et al., 2015). Annual assessment of psychosocial well-being is therefore recommended for survivors of childhood cancer to assess their functional status (Lown et al., 2015).

For such psychological disorders as anxiety and depression, the standard of care often includes psychotherapy, such as cognitive-behavioral therapy, with a licensed professional and/or medication management under the supervision of a physician. Some studies (Brinkman et al., 2016b; Lown et al., 2015) suggest short-term benefits of group social skills training for survivors of pediatric brain tumors, and educational interventions have been used to increase survivors’ awareness of the risk of certain health behaviors, such as drinking, smoking, and excessive sun exposure. Individuals who present with more vulnerabilities and higher risk indices should be assessed routinely to address the psychological, social, and economic burden associated with poor mental health in this population.

SUMMARY

Significant improvements in survival across the spectrum of childhood cancer have resulted in an increased incidence of chronic and late adverse effects of the cancer or the interventions used to treat, manage, or prevent progression of the disease. These adverse effects not only may negatively impact function throughout an individual’s lifespan but also may contribute to premature death. Cancer- and treatment-related impairments in body structures and functions (including psychological functions) can cause activity limitations and restrict the individual’s ability to participate in such activities as school, sports, and work.

FINDINGS AND CONCLUSIONS

Findings

4-1 Improved survival in childhood cancer over the past several decades has increased attention to associated functional deficits, the nature and severity of which depend on a number of factors, including cancer type, cancer treatments that are given, and rehabilitation interventions that are pursued.

4-2 Functional deficits resulting from cancer and its treatment can demonstrate improvement with intervention, but long-term impairments are expected that may impact performance in the educational, vocational, social, self-care, and avocational arenas.

4-3 The use of cancer treatments at an early age may result in

complications that may not become apparent until years later as the child matures.

4-4 The functional impact of childhood cancer and its treatments is not limited to physical and cognitive function, but includes psychosocial and emotional facets as well.

4-5 Functional deficits from neurologic or musculoskeletal conditions almost uniformly cause impairments in mobility and independence in the completion of activities of daily living, and many also cause impairment in communication and cognition skills.

4-6 Despite advances in treatment protocols, as well as treatment modifications, neurologic and musculoskeletal complications and late effects continue to occur and lead to activity limitations and participation restrictions.

4-7 Rehabilitation strategies can improve a child’s level of independence and interaction with skills and activities, but persistent measurable deficits remain for the majority of neurologic and musculoskeletal late effects.

4-8 Given the multimodal treatment of many cancers, involving combinations of surgical intervention, chemotherapy, and radiation therapy, as well as immunotherapies and hematopoietic stem cell transplantation, children with cancer diagnoses will likely be at risk for multiple treatment-related complications and late effects. Thus, it is likely that overall functional impairment and disability result from not just one but often multiple exposures to different treatments that can lead to complications and late effects.

4-9 As demands for independence increase over time for the survivor of childhood cancer, deficits in adaptive functioning are likely to become more profound and noticeable across the survivor’s lifetime.

4-10 Medical side effects of therapy are common and can impact every organ system.

4-11 Diagnosis of these conditions may require serum testing, echocardiogram, electrocardiogram, or other testing.

4-12 Secondary malignant neoplasms (SMN) in survivors of childhood cancer are rare in the first 5 years after cancer diagnosis, but cause significant morbidity and mortality in long-term survivors.

4-13 Risk of SMN is associated with exposure to treatments including radiotherapy and certain chemotherapy classes, but this risk can be modified by age at exposure and genetic predisposition.

4-14 Strategies for identifying survivors at high risk of SMN and implementing surveillance to identify SMN earlier have been established to improve morbidity and mortality, although few such strategies are implemented in survivors 18 years of age or younger.

4-15 Cognitive dysfunction is commonly observed in survivors of childhood cancer, particularly those with a history of central nervous system (CNS) cancer or CNS-directed therapies, including radiation and chemotherapy. Most research regarding cognitive sequelae focuses on those with acute lymphoblastic leukemia and brain tumor. However, there is sufficient research regarding the impact of specific treatments (e.g., systemic chemotherapy) to indicate this risk for acute and chronic cognitive sequelae for all childhood cancers, although studies are fewer and may be based on animal models.

4-16 Evaluation of IQ alone may underestimate the full cognitive sequelae experienced by survivors of childhood cancer. Survivors of cancers and treatments affecting the CNS most commonly experience deficits in attention, working memory, processing speed, executive functioning, and memory that have significant negative impacts on adaptive, educational, and vocational outcomes into adulthood, resulting in persistent functional impairment and reduced independence.

4-17 The onset of cognitive sequelae, particularly among survivors of CNS tumors or other cancers involving CNS-directed treatment, may occur at the time of diagnosis or initiation of treatment, but these sequelae often persist and may progress in severity over time. Additionally, the onset of some cognitive deficits (e.g., processing speed) may occur at a later date or not be evident until a later developmental stage of functional demands. As a result, repeated screening and risk-based assessment of cognitive functions over time is essential to accurately characterize cognitive sequelae in survivors of childhood cancer.

4-18 Certain late effects are unlikely to be detected by the affected child or adolescent and also may not be detected by the parent. Instead, specialized testing or exams are required.

4-19 Parental stress/parental psychological adaptation and functional impairment in children who are survivors of childhood cancer have a bidirectional relationship.

4-20 Although all survivors are at risk for experiencing the psychosocial and emotional functioning effects of cancer and its treatment, there is a subgroup (heavily pretreated, bone marrow transplant, certain CNS tumor diagnoses) who are most likely to experience these effects and to a greater degree.

4-21 A young survivor is likely to experience not a single psychosocial or emotional late effect but a combination of late effects.

4-22 Anxiety, depression, and posttraumatic stress occur in a significant subset of survivors of childhood cancer.

Conclusions

4-1 Many survivors of childhood cancer experience treatment-related medical, cognitive, and psychosocial impairments that interfere with both the normal developmental trajectory of childhood and the expected level of participation in regular activities. Survivors often experience numerous late effects that compound their functional challenges.

4-2 The consequences of impairments (physical and psychological) in body structures and functions lead to both activity limitations and participation restrictions that can occur acutely during treatment, subacutely following the completion of treatment, and longitudinally as a result of persistent deficits that may be unresponsive to rehabilitation therapeutics. Over time, these limitations can accumulate and worsen.

4-3 Functional deficits resulting from the complications and late effects of childhood cancer and its treatment can be persistent issues that affect survivors and their families.

4-4 Survivors of childhood cancer require lifelong surveillance and appropriate interventions for physical, cognitive, psychological, and emotional treatment-related toxicities and late effects.

4-5 Screening and surveillance need to occur on a regular, ongoing basis and incorporate multidimensional evaluation of physical, adaptive, cognitive, emotional, and psychosocial functioning. Current U.S. and international guidelines can be used to guide this surveillance.

4-6 Survivors of childhood cancer often require educational and vocational modifications and accommodations.

4-7 It is important to evaluate and support the family structure and environment during and after treatment.

4-8 For young survivors, ongoing assessment of shorter-term and intermediate effects of cancer treatment may promote the use of rehabilitative interventions that could have large positive effects on the survivor’s overall quality of life.

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ANNEX TABLE 4-1
Selected Instruments Used to Measure Physical Functioning in Survivors of Childhood Cancer

* Balance, coordination, dexterity, functional mobility, gait, strength, upper-extremity function, vestibular.

ANNEX TABLE 4-2
Functional Impairments Associated with Amputation and Limb-Sparing Surgery

SOURCES: Burger and Marincek, 1994; Carter et al., 1969; Datta et al., 2004; Milstein et al., 1985; NASEM, 2017; Raichle et al., 2008.

ANNEX TABLE 4-3
Selected Standardized Measures of Cognitive Functioning

NOTES: All measures listed in the table are well-developed published measures with acceptable validity and reliability and available for review in associated manuals. All cognitive tasks/batteries have standardized administration protocols. All tests and questionnaires listed require those administering the measure to have level B or C qualifications (Pearson, 2020).

ANNEX TABLE 4-4
Selected Instruments Used to Measure Psychosocial and Emotional Functioning in Survivors of Childhood Cancer and to Measure Parental Stress

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