Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version
Late Effects of the Central Nervous System
Neurocognitive
Neurocognitive late effects are most commonly observed after treatment of malignancies that require central nervous system (CNS)–directed therapies. While considerable evidence has been published about this outcome, its quality is often limited by small sample size, cohort selection and participation bias, cross-sectional versus longitudinal evaluations, and variable time of assessment from treatment exposures. CNS-directed therapies include the following:
Cranial radiation therapy.
Systemic therapy with high-dose methotrexate or cytarabine.
Intrathecal chemotherapy.
Children with brain tumors or acute lymphoblastic leukemia (ALL) are most likely to be affected. Risk factors for the development of neurocognitive late effects include the following:[1-7]
Female sex.
Younger age at the time of treatment.
Tumor location.
Higher cranial radiation dose.
Treatment with cranial radiation therapy and/or chemotherapeutic agents (systemic or intrathecal).
The cognitive phenotypes observed in childhood survivors of ALL and CNS tumors may differ from traditional developmental disorders. For example, the phenotype of attention problems in ALL and brain tumor survivors appears to differ from developmental attention-deficit/hyperactivity disorder in that few survivors demonstrate significant hyperactivity/impulsivity, but instead have associated difficulties with processing speed and executive function.[8,9]
In addition to the direct effects of neurotoxic therapies like cranial radiation, Childhood Cancer Survivor Study (CCSS) investigators observed that chronic health conditions resulting from non-neurotoxic treatment exposures (e.g., thoracic radiation) can adversely impact neurocognitive function.[10] They hypothesized that chronic cardiopulmonary and endocrine dysfunction that develops after therapy mediates and may exacerbate the impact of neurotoxic exposures on neurocognitive function, underscoring the importance of promoting interventions to support healthy brain aging in long-term survivors.
Neurocognitive outcomes in brain tumor survivors
Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects caused by illness and associated treatments are a well-established morbidity in this group of survivors. In childhood and adolescent brain tumor survivors, risk factors for adverse neurocognitive effects include the following:
Cranial radiation therapy. Cranial radiation therapy has been associated with the highest risk of long-term cognitive morbidity, particularly in younger children.[11] There is an established dose-response relationship, with patients who receive higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures.[12] Radiation dose to specific regions of the brain, including the temporal lobes and hippocampi, have been shown to significantly impact longitudinal intelligence quotient (IQ) scores and academic achievement scores among children treated with craniospinal irradiation for medulloblastoma.[13]
The negative impact of radiation treatment has been characterized by changes in IQ scores, which have been noted to drop about 2 to 5 years after diagnosis; the decline continues 5 to 10 years afterward, although less is known about potential stabilization or further decline of IQ scores several decades after diagnosis.[21-23] The decline in IQ scores over time typically reflects the child’s failure to acquire new abilities or information at a rate similar to that of his or her peers, rather than a progressive loss of skills and knowledge.[12] Affected children also may experience deficits in other cognitive areas, including academic difficulties (reading and math) and problems with attention, processing speed, memory, and visual or perceptual motor skills.[22,24,25]
These changes in cognitive functioning may be partially explained by radiation-induced reduction of normal-appearing white matter volume or integrity of white matter pathways, as evaluated through magnetic resonance imaging (MRI).[26-28] In fact, reduced white matter integrity has been directly linked to slowed cognitive processing speed in survivors of brain tumors,[29] while greater white matter volume has been associated with better working memory, particularly in females.[28] It should be noted that data emerging from contemporary protocols show that using lower doses of cranial radiation and more targeted treatment volumes appears to reduce the severity of neurocognitive effects of therapy.[14,16,30]
Data are emerging regarding cognitive outcomes after proton radiation to the CNS.[31-33] To date, these studies largely describe IQ changes during early (less than 5 years from radiation) follow-up and are limited by retrospective analysis of cognitive outcomes among relatively small clinically heterogeneous pediatric brain tumor cohorts and use of historically treated photon patients or population standards as comparison groups. Study results demonstrating lack of difference in slopes of IQ change among photon- and proton-treated patients [31] and significant declines in cognitive processing speed among patients treated with proton radiation [32] underscore the importance of longitudinal follow-up to determine whether proton radiation provides a clinically meaningful benefit in sparing cognitive function compared with photon radiation.
In addition, studies are beginning to examine cognitive outcomes in histologically distinct subtypes of brain tumors. For example, data from a sample of 121 medulloblastoma patients demonstrated variation in cognitive outcomes by four distinct molecular subgroups and differences in patterns of change over time.[34] This study highlights the need for future research to consider neurocognitive outcomes across biologically distinct subtypes of childhood brain tumors.
Longitudinal cohort studies have provided insight into the trajectory and predictors of cognitive decline among survivors of CNS tumors.
Evidence (predictors of cognitive decline among survivors of CNS tumors):
St. Jude Children’s Research Hospital (SJCRH) studied 78 children younger than 20 years (mean, 9.7 years) diagnosed with low-grade glioma.[35]
Cognitive decline after 54 Gy of conformal cranial radiation therapy was noted (refer to Figure 7).
In a study of 51 children with low-grade gliomas and low-grade glioneural tumors diagnosed within the first year of life, the mean IQ score was 75.5; 75% of the children had IQ scores lower than 85. Predictors of low IQ included a supratentorial location of the primary tumor and treatment with more chemotherapy regimens, but not radiation use. The child’s ability to complete age-appropriate tasks was as affected as IQ scores.[36]
A study of 126 medulloblastoma survivors treated with 23.4 Gy or 36 Gy to 39.6 Gy of craniospinal radiation (with a conformal boost dose of 55.8 Gy to the primary tumor bed) assessed processing speed, attention, and memory performance.[37]
Processing speed scores declined significantly over time, while less decline was observed in attention and memory performance. Higher doses of radiation and younger age at diagnosis predicted slower processing speed over time.
Studies of working memory and academic achievement in patients enrolled on the same medulloblastoma trial (SJCRH SJMB03 [NCT00085202]) indicated that performance was largely within the age-expected range up to 5 years postdiagnosis,[38,39] although in both studies, posterior fossa syndrome, higher cranial radiation dose, and younger age at diagnosis predicted worse performance over time. In addition, serious hearing loss was associated with intellectual and academic decline over time.[39]
A prospective study compared 36 pediatric medulloblastoma patients who experienced posterior fossa syndrome with 36 medulloblastoma patients who did not experience posterior fossa syndrome but were matched on treatment and age at diagnosis.[40]
The posterior fossa syndrome group demonstrated lower mean scores at 1, 3, and 5 years postdiagnosis on general intellectual ability, processing speed, working memory, and spatial relations compared with the non–posterior fossa syndrome group.
The group who experienced posterior fossa syndrome showed little recovery over time and further decline over time in some domains (attention and working memory), compared with the non–posterior fossa syndrome group.
Canadian investigators evaluated the impact of radiation (dose and boost volume) and neurologic complications on patterns of intellectual functioning in a cohort of 113 medulloblastoma survivors (mean age at diagnosis, 7.5 years; mean time from diagnosis to last assessment, 6 years).[41]
Survivors treated with reduced-dose craniospinal radiation therapy plus tumor bed boost showed stable intellectual functioning.
Neurological complications, such as hydrocephalus requiring cerebrospinal fluid diversion and mutism, and treatment with higher doses and larger boost volumes of radiation resulted in intellectual declines with distinctive trajectories.
Although adverse neurocognitive outcomes observed 5 to 10 years after treatment are presumed to be pervasive, and potentially worsen over time, few empirical data are available regarding the neurocognitive functioning in very long-term survivors of CNS tumors.
Among adult survivors participating in the CCSS, CNS tumor survivors (n = 802) self-reported significantly more problems with attention/processing speed, memory, emotional control, and organization than did survivors of non-CNS malignancies (n = 5,937) and sibling controls (n = 382).[4] Moreover, a large proportion of CNS tumor survivors treated with cranial irradiation reported impairment on measures of attention/processing speed (42.9%–73.3%) and memory (14.3%–37.4%), with differences observed by diagnosis and cranial radiation dose.[42]
A study of 224 adult survivors of pediatric brain tumors participating in the St. Jude Lifetime Cohort Study revealed that 20% to 30% of the survivors demonstrated severe neurocognitive impairment (defined as at least two standard deviations below normative mean) on tests of intelligence, memory, and executive function (e.g., planning, organization, and flexibility).[14] Among adults in the general population, the expected impairment rate at this threshold is 2%. Survivors who received whole-brain cranial irradiation were 1.5 to 3 times more likely to have severe neurocognitive impairment than were survivors who did not receive any cranial irradiation. Hydrocephalus with shunt placement and seizures were also associated with increased risk of impairment. Importantly, this study relied on direct assessment of neurocognitive skills while the previous CCSS report relied on self-report of problems.[14]
The neurocognitive consequences of CNS disease and treatment may have a considerable impact on functional outcomes for brain tumor survivors.
In childhood and adolescence, neurocognitive deficits have been associated with poor social adjustment, including problems with peer relations, social withdrawal, and reduced social skills.[43,44]
CNS tumor survivors are more likely to need special education services than are survivors of other malignancies.[45]
Adult CNS tumor survivors are less likely to live independently, marry, and graduate from college than are survivors of other malignancies and siblings.[45-47]
Neurocognitive outcomes in acute lymphoblastic leukemia (ALL) survivors
The increase in cure rates for children with ALL over the past decades has resulted in greater attention to the neurocognitive morbidity and quality of life of survivors. The goal of current ALL treatment is to minimize adverse late effects while maintaining high survival rates. To minimize the risk of late sequelae, patients are stratified for treatment according to their risk of relapse. Cranial irradiation is reserved for the fewer than 20% of children who are considered at high risk for CNS relapse.[48]
Although low-risk, standard-risk, and most high-risk patients are treated with chemotherapy-only protocols, early reports of neurocognitive late effects for ALL patients were based on heterogeneously treated groups of survivors who received combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation therapy, and high-dose chemotherapy, making it difficult to differentiate the impact of the individual treatment components. However, outcome data are increasingly available regarding the risk of neurocognitive late effects in survivors of childhood ALL treated with chemotherapy only.
ALL and cranial radiation
In survivors of ALL, cranial radiation therapy may result in clinical and radiographic neurologic late sequelae, including the following:
Clinical leukoencephalopathy. Clinical leukoencephalopathy characterized by spasticity, ataxia, dysarthria, dysphagia, hemiparesis, and seizures is uncommon after contemporary ALL therapy. In contrast, neuroimaging frequently demonstrates white matter abnormalities among survivors treated with cranial irradiation and/or high-dose methotrexate. Radiographic leukoencephalopathy has been reported in up to 80% of children on some treatment regimens. Higher doses and more courses of intravenous methotrexate have been reported to increase risk of leukoencephalopathy.[49] In many patients, white matter anomalies are transient and decrease in prevalence, extent, and intensity with longer elapsed time from completion of therapy.[49] Leukoencephalopathy results in smaller white matter volumes that have been correlated with cognitive deficits. Although these abnormalities are mild among the irradiated patients (overall IQ fall of approximately 10 points), those who have received higher doses at a young age may have significant learning difficulties.[50,51]
Neuropsychological deficits. Deficits in neuropsychological functions such as visual-motor integration, processing speed, attention, and short-term memory are reported in children treated with 18 Gy to 24 Gy.[50,52,53] Females and children treated at a younger age are more vulnerable to the adverse impact of cranial radiation on the developing brain.[54] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy.[54,55] Limited studies suggest that long-term survivors of childhood ALL treated with cranial irradiation are at risk of progressive decline consistent with early-onset mild cognitive impairment; this risk is most prominent among those treated with cranial radiation doses of 24 Gy.[56,57]
ALL and chemotherapy-only CNS therapy
Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. Systemic methotrexate in high doses with or without radiation therapy can lead to an infrequent but well-described leukoencephalopathy, which has been linked to neurocognitive impairment.[49] When neurocognitive outcomes after radiation therapy and chemotherapy-only regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone, although some studies show no significant difference.[58,59] In a longitudinal analysis of 210 childhood ALL survivors, the development of acute leukoencephalopathy during chemotherapy-only CNS therapy predicted higher risks of developing long-term neurobehavioral problems (e.g., deficits in organization and task initiation [components of executive function]) and reduced white matter integrity in frontal brain regions.[60]
Compared with cranial irradiation, chemotherapy-only CNS-directed treatment produces neurocognitive deficits involving processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, visual-motor functioning, and executive functioning; global intellectual function is typically preserved.[52,58,61-64] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[62] The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling, with deficits mainly affecting arithmetic performance.[58,65,66] Risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female sex.[64,67,68]
Reduced cognitive status has been observed in association with reduced integrity in neuroanatomical regions essential in memory formation (e.g., reduced hippocampal volume with increased activation and thinner parietal cortices). However, the long-term impact of these prevalent neurocognitive and neuroimaging abnormalities on functional status in aging adults treated for childhood ALL, particularly those treated with contemporary approaches using chemotherapy alone, remains an active area of research.
Evidence (neurocognitive functioning in large pediatric cancer survivor cohorts):
The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[69]
Survivors treated with cranial irradiation had significantly higher frequency of problems in anxiety-depression, inattention-hyperactivity, and social withdrawal than did patients who were not treated with cranial irradiation.
Compared with siblings, survivors treated with chemotherapy only were more likely to demonstrate headstrong behavior (19% of survivors vs. 14% of siblings, P = .010), inattention-hyperactivity (19% vs. 14%, P < .0001), social withdrawal (18% vs. 12%, P = .002), and had higher rates of learning problems (28% vs. 14%, P < .0001).
In multivariable models among survivors, increased cumulative dose of intravenous methotrexate (i.e., >4.3 g/m2) conferred increased risk of inattention-hyperactivity (relative risk [RR], 1.53).
Adolescent survivors with cognitive or behavior problems and those with learning problems were less likely to graduate from college as young adults than adolescent survivors without cognitive or behavior problems.
Inattention and hyperactivity problems were associated with the highest risk of special education placement during adolescence. Participation in special education during adolescence did not improve adult educational attainment.
In the SJCRH Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[70]
A higher risk for below-average performance on a measure of sustained attention but not on measures of intellectual functioning, academic skills, or memory.
The risk of cognitive deficits correlated with treatment intensity but not with age at diagnosis or sex.
Prolonged follow-up (average, 7.7 years from diagnosis) of this cohort demonstrated that intelligence was within normal limits compared with population expectations, but measures of executive function, processing speed, and memory were less than population means. Higher plasma methotrexate was associated with executive dysfunction, thicker cerebral cortex, and higher activity in frontal brain regions on functional MRI.
These results underscore the need for continued follow-up as this population ages to better characterize the prevalence and magnitude of cognitive deficits after CNS-directed therapy with chemotherapy alone.[71]
In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[72]
Low-risk group: Intrathecal methotrexate versus high-dose methotrexate.
High-risk group: High-dose methotrexate versus 24 Gy of cranial radiation therapy.
A significant reduction in IQ scores (4–7 points) was observed in all patient groups when compared with controls, regardless of the CNS treatment delivered.
Children younger than 5 years at diagnosis were more likely to have IQs below 80 at 3 years posttherapy than were children older than 5 years at diagnosis, irrespective of treatment allocation, suggesting that younger children are more vulnerable to treatment-related neurologic toxic effects.
Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment.[51,54,57] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following:[51]
Survivors demonstrated increased rates of impairment across all neurocognitive domains (ranging from 28.6%–58.9% for each domain).
Rate of severe impairment increased as a function of cranial radiation dose, but was common among survivors treated with lower doses of cranial irradiation and chemotherapy only.
Impairment in executive function skills increased with time since diagnosis in a cranial radiation dose-dependent manner; impairment in intellect, academics, and memory progressively increased with younger age at treatment in a cranial radiation dose-dependent manner; and neurocognitive impairment was related to functional outcomes as adults, including reduced likelihood of college graduation and full-time employment.
Continued monitoring by health professionals is needed to identify neurocognitive problems that may emerge over time.
ALL and steroid therapy
The type of steroid used for ALL systemic treatment may affect cognitive functioning. In a study that involved long-term neurocognitive testing (mean follow-up, 9.8 years) of 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment, no meaningful differences in mean neurocognitive and academic performance scores were observed.[73] In contrast, in a study of 567 adult survivors of childhood leukemia (mean age, 33 years; mean time since diagnosis, 26 years) dexamethasone exposure was associated with increased risk of impairment in attention (RR, 2.12; 95% confidence interval [CI], 1.11–4.03) and executive function (RR, 2.42; 95% CI, 1.20–4.91), independent of methotrexate exposure. Intrathecal hydrocortisone also increased risk of attention problems (RR, 1.24; 95% CI, 1.05–1.46).[51]
Other cancers
Neurocognitive abnormalities have been reported in other groups of cancer survivors. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors reported impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that reported in the sibling comparison group. Factors such as diagnosis before age 6 years, female sex, cranial radiation therapy, and hearing impediment were associated with impairment.[53] In addition, emerging data suggest that the development of chronic health conditions in adulthood may contribute to cognitive deficits in long-term survivors of non-CNS cancers.
Neurocognitive abnormalities have been reported for the following cancers:
Osteosarcoma. In a study evaluating neurocognitive function among 80 long-term survivors of osteosarcoma (mean time since diagnosis, 24.7 years), survivors demonstrated lower mean scores in reading skills, attention, memory, and processing speed than did community controls. The presence of cardiac, pulmonary, and endocrine conditions were significantly associated with worse performance on measures of memory and processing speed.[74]
Retinoblastoma. Early studies of intellectual functioning in survivors of retinoblastoma suggested above average intelligence among bilateral survivors compared with unaffected siblings and the general population, especially those who were blind as a result of their disease.[75-77]
Later studies have yielded mixed results. For example, serial assessment of cognitive and adaptive functioning in a group of survivors younger than 6 years revealed declines in developmental functioning over time. The most pronounced declines were observed in patients with 13q deletion.[78] In contrast, a study of long-term adult survivors, who were on average 33 years postdiagnosis, demonstrated largely average cognitive functioning across domains of intelligence, memory, attention, and executive function.[79] These conflicting findings may be attributed, in part, to the low test-retest reliability of measures used to assess cognitive outcomes at a very young age, as well as temporal differences in treatment exposures.
Lymphoma. Survivors of lymphoma have not historically been considered at risk of developing neurocognitive late effects. However, reports suggest that more than two-thirds of survivors of childhood non-Hodgkin lymphoma experience at least mild neurocognitive impairment, including severe deficits in executive function (13%), attention (9%), and memory (4%).[80] Similarly, in a study of 62 adult survivors of childhood Hodgkin lymphoma, survivors demonstrated worse performance on measures of sustained attention, short- and long-term memory, and cognitive fluency when compared with national normative data.[81] Importantly, measures of cardiac and pulmonary function also were associated with neurocognitive impairment in this group of survivors.
Stem cell transplantation
Cognitive and academic consequences of stem cell transplantation in children have also been evaluated and include, but are not limited to, the following:
In a report from SJCRH in which 268 patients were treated with stem cell transplantation, minimal risk of late cognitive and academic sequelae was observed.[82]
Subgroups of patients were at relatively higher risk, including patients who underwent unrelated donor transplantation, received total-body irradiation, and developed graft-versus-host disease (GVHD). However, these differences were small relative to differences in premorbid functioning, particularly those associated with socioeconomic status.
In a series of 38 patients who underwent hematopoietic stem cell transplantation (HSCT) and received intrathecal chemotherapy, significant declines in visual motor skills and memory scores were noted within the first year posttransplant.[83]
By 3 years posttransplant, there was an improvement in visual motor development scores and memory scores, but new deficits were evident in long-term memory scores.
By 5 years posttransplant, there were progressive declines in verbal skills and performance skills, and new deficits were seen in long-term verbal memory scores.
The greatest decline in neurocognitive function occurred in patients who received cranial irradiation, either as part of their initial therapy or as part of their HSCT conditioning.
Most neurocognitive late effects after stem cell transplantation are thought to be related to white matter damage in the brain. This was investigated in children with leukemia who were treated with HSCT. In a series of 36 patients, performance on neurocognitive measures typically associated with white matter was compared with performance on measures thought to correlate with gray matter function. Composite white matter scores were significantly lower than composite gray matter scores, thereby supporting the belief that white matter damage contributes to neurocognitive late effects in this population.[84]
Neurologic Sequelae
Risk of neurologic complications may be predisposed by the following:
Tumor location.
Neurosurgery.
Cranial radiation therapy.
Specific neurotoxic chemotherapeutic agents.
In children with CNS tumors, mass effect, tumor infiltration, and increased intracranial pressure may result in motor or sensory deficits, cerebellar dysfunction, and secondary effects such as seizures and cerebrovascular complications. Numerous reports describe abnormalities of CNS integrity and function, but such studies are typically limited by small sample size, cohort selection and participation bias, cross-sectional ascertainment of outcomes, and variable time of assessment from treatment exposures. In contrast, relatively few studies comprehensively or systematically ascertain outcomes related to peripheral nervous system function.
CNS tumor survivors remain at higher risk of new-onset adverse neurologic events across their lifetimes than siblings. No plateau has been reached for new adverse sequelae, even 30 years from diagnosis, according to a longitudinal study of 1,876 5-year survivors of CNS tumors from the CCSS. The median time from diagnosis was 23 years and the median age of the patients studied was 30.3 years.[85]
Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset neurologic sequelae (seizures, focal neurologic dysfunction, and neurosensory abnormalities).
This finding supports the need to monitor these patients carefully with continued neurologic follow-up within or in close association with a multidisciplinary cancer survivor clinic.
Neurologic complications that may occur in survivors of childhood cancer include the following:
Seizures. The development of seizures may occur secondary to tumor mass effect within the CNS and/or as a result of neurotoxic CNS-directed therapies.
In 1,876 5-year survivors of CNS tumors from the CCSS, the incidence of seizures increased from 27% in survivors 5 years from diagnosis to 41% in survivors 30 years from diagnosis. Late-onset seizures were associated with frontal lobe radiation of 50 Gy (hazard ratio [HR], 1.8) and temporal lobe radiation in a dose-dependent fashion (HR, 1.9 for 1–49 Gy; HR, 2.2 for >50 Gy). Other risk factors associated with late-onset seizures included recurrence (HR, 2.3), development of meningioma (HR, 2.6), and history of stroke (HR, 2.0). The risk of seizures was elevated for survivors compared with siblings (HR, 12.7).[85]
Among survivors of childhood leukemia in the CCSS (N = 4,151; 64.5% treated with cranial irradiation), 6.1% reported the development of a seizure disorder, and seizures occurred more than 5 years after diagnosis in 51% of these patients.[86]
Leukoencephalopathy. Clinical or radiographic leukoencephalopathy has been reported after cranial irradiation and high-dose systemic methotrexate administration. Younger patients and those treated with cranial radiation doses higher than 24 Gy are more vulnerable to reduced white matter volumes associated with leukoencephalopathy.[52,57,87,88] White matter changes may be accompanied by other neuroimaging abnormalities, including dystrophic calcifications, cerebral lacunae, and cerebral atrophy.
Peripheral neuropathy. Vinca alkaloid agents (vincristine and vinblastine) and cisplatin may cause peripheral neuropathy.[89-91] This condition presents during treatment and appears to improve or clinically resolve after completion of therapy.[89] However, higher cumulative doses of vincristine and/or intrathecal methotrexate have been linked to neuromuscular impairments in long-term survivors of childhood ALL, which suggests that persistent effects of these agents may affect functional status in aging survivors.[89]
Among adult survivors of extracranial solid tumors of childhood (median time from diagnosis, 25 years), standardized assessment of neuromuscular function disclosed motor impairment in association with vincristine exposure and sensory impairment in association with cisplatin exposure.[90] Survivors with sensory impairment demonstrated a higher prevalence of functional performance limitations related to poor endurance and mobility restrictions. These studies underscore the importance of assessment and referral to rehabilitative services to optimize functional outcomes among long-term survivors.
Stroke. Childhood CNS tumor survivors have a 43-fold elevated risk of stroke compared with siblings.[42,92] Cranial radiation therapy (dose dependent), baseline atherosclerosis, hypertension, and African American ethnicity are identified risk factors.[93,94] (Refer to the Cerebrovascular disease section of this summary for information on stroke.)
Hypersomnia (daytime sleepiness) or narcolepsy. In a retrospective review of brain tumor patients treated at SJCRH, investigators identified 39 of 2,336 patients who were diagnosed with hypersomnia/narcolepsy, for a prevalence rate of 1,670 cases per 100,000, which is much higher than a prevalence rate of 20 to 50 cases per 100,000 reported in the general population. This may be an underestimate in childhood brain tumor survivors because many patients with mild-to-moderate symptoms, such as fatigue and sleep disturbances, may not be recognized or referred to a sleep specialist. Hypersomnia/narcolepsy was diagnosed at a median of 6 years (range, 0.4–13.2 years) from tumor diagnosis and 4.7 years (range, 1.5–10.4 years) from cranial radiation. Midline tumor location and antiepilepsy drug use correlated with hypersomnia/narcolepsy, while radiation dose higher than 30 Gy trended toward significance. Posterior fossa tumor location was associated with a reduced risk of hypersomnia. Treatment of hypersomnia/narcolepsy should be individualized and pharmacologic intervention with stimulants may be beneficial.[95]
Other neurologic sequelae. In a report from the CCSS that compared self-reported neurologic late effects among 4,151 adult survivors of childhood ALL with siblings, survivors were at elevated risk for late-onset coordination problems, motor problems, seizures, and headaches. The overall cumulative incidence was 44% at 20 years. Serious headaches were most common, with a cumulative incidence of 25.8% at 20 years, followed by focal neurologic dysfunction (21.2%) and seizures (7%). Children who were treated with regimens that included cranial irradiation for ALL and those who suffered relapse were at increased risk for late-onset neurologic sequelae.[86]
In a cross-sectional study that evaluated neurologic morbidity and quality of life in 162 survivors of childhood ALL (median age at evaluation, 15.7 years; median time from completion of therapy, 7.4 years) in concert with a clinical neurologic exam, neurologic symptoms were present in 83% of survivors, but symptom-related morbidity was low and quality of life was high in most survivors. The most commonly reported symptoms included neuropathy (63%), headache (46.9%), dizziness (33.3%), and back pain (22.8%). Female sex, ten doses or more of intrathecal chemotherapy, cranial irradiation, CNS leukemia at diagnosis, and history of ALL relapse were associated with neurologic morbidity.[7]
Neuroimaging studies of irradiated and nonirradiated ALL survivors demonstrate a variety of CNS abnormalities, including leukoencephalopathy, cerebral lacunes, cerebral atrophy, and dystrophic calcifications (mineralizing microangiopathy). Among these, abnormalities of cerebral white matter integrity and volume have been correlated with neurocognitive outcomes.[49,57,87,88]
Cavernomas have also been observed in ALL survivors treated with cranial irradiation. They have been speculated to result from angiogenic processes as opposed to tumorigenesis.[96]
In 1,876 5-year survivors of CNS tumors from the CCSS, the cumulative incidence of headaches increased from 38% at 5 years to 53% at 30 years from diagnosis. Similarly, coordination problems increased from 21% at 5 years to 53% at 30 years from diagnosis, and motor impairment increased from 21% to 35% during this time period. Increased risk of motor impairment was associated with tumor recurrence (HR, 2.6), development of a meningioma (HR, 2.3), and stroke (HR, 14.9). Adverse neurosensory outcomes also increased during this period; the cumulative incidence of hearing loss increased from 9% at 5 years to 23% at 30 years, cumulative incidence of tinnitus increased from 8% at 5 years to 21% at 30 years, and cumulative incidence of vertigo increased from 9% at 5 years to 17% at 30 years. Risks of motor impairment (HR, 7.6) and hearing loss (HR, 18.4) were elevated compared with siblings.[85]
Table 3 summarizes CNS late effects and the related health screenings.
Table 3. Central Nervous System Late Effectsa
Predisposing Therapy
Neurologic Effects
Health Screening
IQ = intelligence quotient; IT = intrathecal; IV = intravenous.
Many childhood cancer survivors report reduced quality of life or other adverse psychosocial outcomes. Evidence for adverse psychosocial adjustment after childhood cancer has been derived from a number of sources, ranging from patient-reported or proxy-reported outcomes to data from population-based registries. The former may be limited by small sample size, cohort selection and participation bias, and variable methods and venues (clinical vs. distance-based survey) of assessments. The latter is often not well correlated with clinical and treatment characteristics that permit the identification of survivors at high risk of psychosocial deficits.
Survivors with neurocognitive deficits are particularly vulnerable to adverse psychosocial outcomes that affect achievement of expected social outcomes during adulthood.
In a population-based study of adult survivors of CNS tumors diagnosed in childhood or adolescence, survivors had significantly poorer self-perception and self-esteem than did individuals in the general population. Female sex, persistent visible physical sequelae, specific tumor type, and treatment with cranial radiation therapy predicted poor self-perception outcomes.[97]
In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome on multiple indicators of successful adult adjustment (educational achievement, income, employment, and marital status) were most prevalent among survivors who reported neurocognitive dysfunction.[4]
Collectively, studies evaluating psychosocial outcomes among CNS tumor survivors indicate deficits in social competence that worsen over time.[98] This includes problems with peer rejection and isolation in childhood/adolescence, as well as the inability to develop friendships and romantic relationships as adults.
In a CCSS study that evaluated predictors of independent living status across diagnostic groups, adult survivors of childhood cancer with neurocognitive, psychological, or physical late effects were less likely to live independently as adults than were siblings in the comparison group.[46]
In a St. Jude Lifetime Cohort study of 224 survivors of CNS tumors (median current age, 26 years; median time from diagnosis, 18 years), neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and nonindependent living.[14]
In a series of 1,560 adolescent survivors of childhood ALL treated with chemotherapy alone, the CCSS identified a significant proportion of survivors who still experienced problems with headstrong behavior, inattention-hyperactivity, and social withdrawal, which were associated with an increased risk of special education placement and predicted reduced adult educational attainment.[69]
Childhood cancer survivors are also at risk of developing symptoms of psychological distress. In a longitudinal study of more than 4,500 survivors, subgroups of survivors were found to be at risk of developing persistent and increasing symptoms of anxiety and depression during a 16-year period. Survivors who reported pain and worsening health status were at the greatest risk of developing symptoms of anxiety, depression, and somatization over time.[99]
Adult survivors of childhood cancer are also at risk of suicide ideation compared with siblings, with survivors of CNS tumors being most likely to report thoughts of suicide. In a CCSS study that evaluated the prevalence of recurrent suicidal ideation among 9,128 adult long-term survivors of childhood cancer, survivors were more likely to report late suicidal ideation (odds ratio [OR], 1.9; 95% CI, 1.5–2.5) and recurrent suicidal ideation (OR, 2.6; 95% CI, 1.8–3.8) compared with siblings. History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors.[100] In a population-based study that evaluated suicide among adults treated for cancer before age 25 years, the absolute risk of suicide was low (24 cases among 3,375 deaths), but the HR of suicide was increased among individuals treated for cancer in childhood (0–14 years; HR, 2.5; 95% CI, 1.7–3.8) and in adolescence and young adulthood (15–24 years; HR, 2.3; 95% CI, 1.2–4.6).[101]
The presence of chronic health conditions can also impact aspects of psychological health. In a study that evaluated psychological outcomes among long-term survivors treated with HSCT, 22% of survivors and 8% of sibling controls reported adverse outcomes. Somatic distress was the most prevalent condition and affected 15% of HSCT survivors, representing a threefold higher risk compared with siblings. HSCT survivors with severe or life-threatening health conditions and active chronic GVHD had a twofold increased risk of somatic distress.[102] A report from the CCSS revealed that the presence of chronic pulmonary, endocrine, and cardiac conditions was associated with increased risk of psychological distress symptoms in a sample of 5,021 adult survivors of childhood cancer.[103]
In a CCSS investigation that evaluated long-term psychological and educational outcomes among survivors of neuroblastoma, survivors demonstrated elevated risks of psychological impairment, which was associated with the use of special education services and lower educational attainment. The presence of two or more chronic health conditions, but not common treatment exposures, predicted psychological impairment. Specifically, pulmonary disease predicted impairment in all five psychological domains, whereas endocrine disease and peripheral neuropathy each predicted impairment in three domains.[104]
Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of survivors with more difficulties, and precise prevalence rates may be difficult to establish. A review of behavioral, emotional, and social adjustment among survivors of childhood brain tumors illustrates this point, with the prevalence of psychological maladjustment ranging from 25% to 93%.[105] In a study of 101 adult cancer survivors of childhood cancer, psychological screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32 subjects had a positive screen (indicating psychological distress), and 14 subjects reported at least one suicidal symptom. Risk factors for psychological distress included subjects’ dissatisfaction with physical appearance, poor physical health, and treatment with cranial irradiation. In this study, the instrument was shown to be feasible for use in the clinic visit setting because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to cause distress in the survivors in 80% of cases.[106] These data support the feasibility and importance of consistent assessment of psychosocial distress in a medical clinic setting.
Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post-traumatic stress symptoms and post-traumatic stress disorder (PTSD) in children with cancer, typically no higher than those in healthy comparison children.[107] Patient and parent adaptive style appear to be significant determinants of PTSD in the pediatric oncology setting.[108,109]
The prevalence of PTSD and post-traumatic stress symptoms has been reported in 15% to 20% of young adult survivors of childhood cancer, with estimates varying based on criteria used to define these conditions.[110]
Survivors with PTSD reported more psychological problems and negative beliefs about their illness and health status than did those without PTSD.[111,112]
A subset of adult survivors (9%) from the CCSS reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD. This was significantly more prevalent in survivors than in sibling comparisons.[113] In this study, PTSD was significantly associated with being unmarried, having an annual income of less than $20,000, being unemployed, having a high school education or less, and being older than 30 years. Survivors who were treated with cranial irradiation before age 4 years were at particularly high risk for PTSD. Intensive cancer-directed therapy was also associated with increased risk of full PTSD.
Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceive greater current threats to their lives or the lives of their children. Other risk factors include poor family functioning, decreased social support, and noncancer stressors.[114]
Psychosocial outcomes among childhood, adolescent, and young adult cancer survivors
Most research on late effects after cancer has focused on individuals with a cancer manifestation during childhood. Little is known about the specific impact of a cancer diagnosis with an onset in adolescence or the impact of childhood cancer on adolescent and young adult (AYA) psychosocial outcomes.
Evidence (psychosocial outcomes in AYA cancer survivors):
Adult survivors of cancer diagnosed during adolescence (aged 15–18 years) (N = 825) were compared with an age-matched sample from the general population and a comparison group of adults without cancer.[115]
Female survivors of adolescent cancers achieved fewer developmental milestones related to their psychosexual development, such as having their first boyfriend, or they reached these milestones later.
Male survivors were more likely to live with their parents than were same-sex controls.
Adolescent cancer survivors were less likely to have ever married or have had children. Survivors were significantly older at their first marriage and at the birth of their first child than were their age-matched samples.
Survivors in this cohort were also significantly less satisfied with their general and health-related life than were people in a community-based control group. Impaired general and health-related life satisfaction were associated with somatic late effects, symptoms of depression and anxiety, and lower rates of posttraumatic growth.[116]
A survey of 4,054 AYA cancer survivors and 345,592 respondents who had no history of cancer reported the following:[117]
AYA cancer survivors were more likely to smoke (26% vs. 18%), be obese (31% vs. 27%), and have chronic conditions such as cardiovascular disease (14% vs. 7%), hypertension (35% vs. 9%), asthma (15% vs. 8%), disability (36% vs. 18%), and poor mental health (20% vs. 10%).
They were also less likely to receive medical care because of cost (24% vs. 15%).
The CCSS evaluated outcomes of 2,979 adolescent survivors and 649 siblings of childhood cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, being headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence).[118]
Survivors were 1.5 times (95% CI, 1.1–2.1) more likely than siblings to have symptoms of depression/anxiety and 1.7 times (95% CI, 1.3–2.2) more likely than siblings to have antisocial behaviors.
Scores in the depression/anxiety, attention deficit, and antisocial domains were significantly elevated in adolescents treated for leukemia or CNS tumors, compared with the scores in siblings.
In addition, survivors of neuroblastoma had difficulty in the depression/anxiety and antisocial domains.
CNS-directed treatments (cranial radiation therapy and/or intrathecal methotrexate) were specific risk factors for adverse behavioral outcomes.
Another CCSS study evaluated psychological and neurocognitive function in 2,589 long-term cancer survivors who were diagnosed during adolescence and young adulthood.[119]
Compared with a sibling cohort, survivors diagnosed during adolescence and young adulthood reported higher rates of depression (OR, 1.55; 95% CI, 1.04–2.30) and anxiety (OR, 2.00; 95% CI, 1.17–3.43) and reported more cognitive problems affecting task efficiency (OR, 1.72; 95% CI, 1.21–2.43), emotional regulation (OR, 1.74; 95% CI, 1.26–2.40), and memory (OR, 1.44; 95% CI, 1.09–1.89).
Survivors of lymphoma and sarcoma diagnosed during later adolescence were at reduced risk of psychosocial and neurocognitive problems than were those diagnosed before age 11 years. These outcomes did not differ by age at diagnosis among CNS tumor and leukemia survivors.
Survivors diagnosed during adolescence and young adulthood were also significantly less likely than sibling controls to have attained a post–high school education, be working full time, be married, or be living independently; inferior social outcomes were related to neurocognitive symptoms.
A follow-up CCSS study evaluated profiles of symptom comorbidities in 3,993 adolescents (aged 13–17 years) treated for cancer.[120] Latent profile analysis identified four symptom profiles:
No significant symptoms.
Elevated internalizing symptoms (anxiety and/or depression, social withdrawal, and attention problems).
Elevated externalizing symptoms (headstrong behavior and attention problems).
Elevated internalizing and externalizing symptoms.
Overall results support that behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors and are associated with treatment exposures (cranial radiation, corticosteroids, and methotrexate) and late effects (obesity, cancer-related pain, and sensory impairments).
The diagnosis of childhood cancer may also affect psychosocial outcomes and the expected attainment of functional and social independence in adulthood. Several investigations have demonstrated that survivors of pediatric CNS tumors are particularly vulnerable.[121,122]
Evidence (functional and social independence):
In a study of 665 survivors of CNS tumors (54% male; 52% treated with cranial radiation therapy; median age, 15 years; and 12 years from diagnosis), CCSS investigators observed the following:[121]
Almost 50% of survivors experienced social difficulties related to peer relationships that exceeded those of survivors of solid tumors and sibling controls.
Cranial radiation exposure predicted social and peer relationships; cognitive impairment mediated the association between all social outcomes and cranial radiation.
A St. Jude Lifetime Cohort Study investigated functional and social independence in 306 CNS tumor survivors (astrocytoma [n = 130], medulloblastoma [n = 77], ependymoma [n = 36], and other [n = 63]; median age, 25 years; and time since diagnosis, 16.8 years).[122]
Only 40% of long-term survivors in the study cohort achieved complete independence as adults.
Predictors of nonindependence included treatment with craniospinal irradiation, history of hydrocephalus with shunting, and younger age at diagnosis.
Beyond impaired IQ scores, functional limitations in aerobic capacity, flexibility, and adaptive physical function were significantly associated with nonindependence.
Social withdrawal in adolescence has been associated with adult obesity and physical inactivity.[123] As a result, these psychological problems may increase future risk for chronic health conditions and support the need to routinely screen and treat psychological problems after cancer therapy.
Because of the challenges experienced by adolescents and young adults at cancer diagnosis and during long-term follow-up, this group may benefit from access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.[124,125]
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