Late Effects of the Central Nervous System
Acute lymphoblastic leukemia (ALL)
Stem cell transplantation
Post-traumatic stress after childhood cancer
Psychosocial outcomes among adolescent cancer survivors
Neurocognitive late effects most commonly follow treatment of malignancies that require central nervous system (CNS)-directed therapies, such as cranial radiation, systemic therapy with high-dose methotrexate or cytarabine, or with intrathecal chemotherapy. Children with brain tumors or acute lymphoblastic leukemia are most likely to be affected. Risk factors for the development of neurocognitive side effects are female gender, young age at the time of treatment, supratentorial tumor location, higher radiation dose, treatment with both cranial radiation and chemotherapy (systemic or intrathecal), and lower socioeconomic status.[1-5]Brain tumors
Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects due to their illness and associated treatments are emerging. In childhood and adolescent brain tumor survivors, tumor site, treatment of hydrocephalus with a shunt, paralysis, postsurgery mutism, auditory difficulties, or history of a stroke have emerged as risk factors for adverse neurocognitive effects.[6-9]
Cranial radiation therapy has been associated with the highest risk of long-term cognitive morbidity particularly in younger children. There is an established dose-response relationship with those getting higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures.
The negative impact of radiation treatment has been characterized by changes in intelligence quotient (IQ) scores, which have been noted to drop about 2 to 5 years after diagnosis with an attenuation of the decline 5 to 10 years afterward, followed by stabilization of the IQ scores 20 to 40 years after diagnosis.[11-13]
The decline over time is typically reflective of the child’s failure to acquire new abilities or information at a rate similar to peers, rather than a progressive loss of skills and knowledge. Affected children may experience information-processing deficits resulting in academic difficulties and are prone to problems with receptive and expressive language, attention span, and visual and perceptual motor skills.[12,14-16]
These changes in intellectual functioning may be partially explained by radiation-induced or chemotherapy-induced reduction of normal white matter volume as evaluated through magnetic resonance imaging (MRI).[17-19] Using lower doses of radiation and more targeted volumes have demonstrated improved results in neurocognitive effects of therapy.[8,20]
Longitudinal cohort studies have provided insight into predictors of cognitive decline among long-term survivors of CNS tumors. A report from St. Jude Children’s Research Hospital showed cognitive decline after conformal radiation therapy in 78 children younger than 20 years (mean, 9.7 years) with low-grade glioma treated with 54 Gy (see Figure 3). Age at time of irradiation was more important than radiation dose in predicting cognitive decline with children younger than 5 years showing the most cognitive decline. Neurocognitive deficits have also been linked to poor social outcomes including poor social adjustment, problems with peer relationship, and withdrawn/depressed behaviors among survivors of pediatric embryonal tumors.
Glutathione S-transferase M1 and T1 gene polymorphisms may predict patients with medulloblastoma who are more likely to experience neurocognitive toxicity secondary to radiation.Acute lymphoblastic leukemia (ALL)
One of the great medical success stories of the past generation is how advances in the treatment of ALL have dramatically improved survival. With the recognition that CNS relapse was common among children in bone marrow remission, presymptomatic CNS radiation and intrathecal chemotherapy were introduced into the treatment of children with ALL in the 1960s and 1970s. 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. Patients are stratified for treatment according to their risk of relapse. Cranial radiation is reserved for children (less than 20%) considered at high risk for CNS relapse.
Although low-, standard-, and most high-risk patients currently are treated with chemotherapy-only protocols, the described neurocognitive effects for ALL patients are based on a heterogeneous treatment group of survivors in the past who were treated with combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation, and high-dose chemotherapy making it difficult to differentiate the impact of the individual components. In the future, more accurate data will be available about the neurocognitive effects on survivors of childhood ALL treated with chemotherapy only.
In a large prospective study (N = 555) of neurocognitive outcomes in children with newly diagnosed ALL randomly assigned to CNS-directed therapy according to risk group (low: intrathecal methotrexate vs. high-dose methotrexate; high: high-dose methotrexate vs. cranial radiation therapy), a significant reduction in IQ scores (4 to 7 points) was observed between all patient groups when compared with controls (P < .002), regardless of the CNS treatment delivered. Children younger than 5 years at diagnosis were more likely than children older than 5 years at diagnosis to have IQs below 80 at 3 years posttherapy, irrespective of treatment allocation, suggesting that younger children are more vulnerable to treatment-related neurologic toxic effects.
In the St. Jude Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed 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 gender. These results underscore the need for longitudinal follow-up to better characterize the prevalence and magnitude of cognitive deficits after CNS-directed therapy with chemotherapy alone.ALL and cranial radiation
In survivors of ALL, cranial radiation therapy does lead to identifiable neurodevelopment late sequelae. Although these abnormalities are mild in some patients (overall IQ fall of approximately 10 points), those who have received higher doses at a young age may have significant learning difficulties.[27,28] 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.[29-31] Girls and younger children are more vulnerable to cranial irradiation.[32-34] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy.[35,36] When the neurocognitive outcome of radiation therapy and chemotherapy-only CNS regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone although some studies show no significant difference.[37-39]
The phenotype of attention problems in ALL survivors appears to differ from developmental attention-deficit disorder in that few survivors demonstrate significant hyperactivity/impulsivity. By contrast, impairments in cognitive efficiency (information processing and short-term memory) and executive functioning (organization and planning) have been more often observed among ALL survivors treated with cranial radiation therapy, and have been observed in children at lower frequency among those treated with chemotherapy alone.ALL and chemotherapy–only CNS therapy
Most studies of chemotherapy-only CNS-directed treatment display good neurocognitive long-term outcomes. However, one review suggests modest effects on processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, and visual-motor functioning; global intellectual function was found to be preserved.[29,37,41-43] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[42,44] 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.[37,45,46] Further risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female gender.[44,47] Time since diagnosis or treatment does not appear to have a similar influence on neurocognitive functioning as observed after cranial irradiation.
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 and combined with radiation therapy can lead to an infrequent but well-described leukoencephalopathy, in which severe neurocognitive deficits are obvious.Other factors
The type of steroid used for ALL systemic treatment does not affect cognitive functioning. This is based on long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment that observed no meaningful differences in cognitive functioning based on corticosteroid randomization.
Treatment intensity and duration can also adversely affect cognitive performance, because of absences from school and interruption of studies. In the Childhood Cancer Survivor Study (CCSS), treatment-related neurocognitive impairment resulted in decreased educational attainment and greater utilization of special education services. Those ALL survivors who were provided with special educational services had comparable educational attainment to siblings, whereas those not reporting use of special education had lower educational attainment.Infants with ALL
Infants with ALL are considered to be at high risk for CNS disease. In the past, infants diagnosed before age 2 years were treated with cranial irradiation. As a result, significant deficits in overall intellectual function were noted compared with those in cancer controls. Currently, most ALL treatment protocols do not specify cranial irradiation for infants or very young children. When cranial radiation is avoided, neurodevelopmental outcome improves. One long-term study of infants who received high-dose systemic methotrexate combined with intrathecal cytarabine and methotrexate for CNS leukemia prophylaxis and were tested 3 to 9 years posttreatment showed cognitive function was in the average range.Other cancers
Neurocognitive abnormalities have been reported in other groups of cancer survivors besides patients with CNS tumors and ALL. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors had impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that in the sibling comparison. Factors such as diagnosis before age 6 years, female gender, cranial radiation therapy, and hearing impediment were associated with impairment.Stem cell transplantation
Cognitive and academic consequences of stem cell transplantation in children have also been evaluated. In a report from the St. Jude Children’s Research Hospital in which 268 patients were treated with stem cell transplant, minimal risk of late cognitive and academic sequelae was seen. Subgroups of patients were at relatively higher risk, including those undergoing unrelated donor transplantation, receiving total-body irradiation, and developing graft-versus-host disease (GVHD). However, these differences were small relative to differences in premorbid functioning, particularly those associated with socioeconomic status.
Neurocognitive function of pediatric patients with hematologic malignancies who had undergone hematopoietic stem cell transplantation (HSCT) was evaluated before HSCT and then at 1, 3, and 5 years post-HSCT. In this series of 38 patients who had all received intrathecal chemotherapy as part of their treatment, significant declines in visual motor skills and memory test scores were noted within the first year posttransplant. By 3 years posttransplant, there was an improvement in the visual motor development scores and memory scores, but there were new deficits seen in long-term memory scores. By 5 years posttransplant, there were progressive declines in verbal skills, performance skills, and new deficits 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 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 associated with white matter was compared with performance on measures associated with gray matter. Composite white matter scores were significantly lower than composite gray matter scores.Neurologic Sequelae
Neurologic complications may be predisposed by tumor location, neurosurgery, radiation therapy, or 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 such secondary effects as seizures and cerebrovascular complications.
Clinical or radiographic leukoencephalopathy has been reported after cranial irradiation and high-dose systemic methotrexate administration. Younger patients and those given radiation doses greater than 24 Gy are more vulnerable to this complication. White matter changes may be accompanied by such neuroimaging abnormalities as dystrophic calcifications, cerebral lacunae, and cerebral atrophy.
Vinca alkaloid agents (vincristine and vinblastine) and cisplatin may cause peripheral neuropathy. This condition presents during treatment and appears to clinically resolve after completion of therapy. 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. 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. 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.
In a report from the CCSS that compared 4,151 adult survivors of childhood ALL with their siblings, survivors were at an 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 radiation for ALL and those who suffer relapse were at increased risk for late-onset neurologic sequelae.Table 3. Central Nervous System Late Effects
|Predisposing Therapy||Neurologic Effects||Health Screening|
|IQ = intelligence quotient; IT = intrathecal; IV = intravenous.|
|Platinum agents (carboplatin, cisplatin)||Peripheral sensory neuropathy||Neurologic exam|
|Plant alkaloid agents (vinblastine, vincristine)||Peripheral sensory or motor neuropathy (areflexia, weakness, foot drop, paresthesias)||Neurologic exam|
|Methotrexate (high dose IV or IT); cytarabine (high dose IV or IT); radiation impacting the brain||Clinical leukoencephalopathy (spasticity, ataxia, dysarthria, dysphagia, hemiparesis, seizures); headaches; seizures; sensory deficits||History: cognitive, motor, and/or sensory deficits, seizures|
|Radiation impacting cerebrovascular structures||Cerebrovascular complications (stroke, moyamoya, occlusive cerebral vasculopathy)||History: transient/permanent neurological events|
|Neurosurgery–brain||Motor and/or sensory deficits (paralysis, movement disorders, ataxia, eye problems [ocular nerve palsy, gaze paresis, nystagmus, papilledema, optic atrophy]); seizures||Neurologic exam|
|Neurosurgery–brain||Hydrocephalus; shunt malfunction||Abdominal x-ray|
|Neurosurgery–spine||Neurogenic bladder; urinary incontinence||History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream|
|Neurosurgery–spine||Neurogenic bowel; fecal incontinence||History: chronic constipation, fecal soiling|
|Predisposing Therapy||Neuropsychological Effects||Health Screening|
|Methotrexate (high-dose IV or IT); cytarabine (high-dose IV or IT); radiation impacting the brain; neurosurgery–brain||Neurocognitive deficits (executive function, memory, attention, processing speed, etc.); learning deficits; diminished IQ; behavioral change||Assessment of educational and vocational progress|
|Formal neuropsychological evaluation|
Many childhood cancer survivors have adverse quality of life or other adverse psychological outcomes. 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 those 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, in whom rates of psychological maladjustment range from 25% to 93%. In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome indicators of successful adult adaptation (educational attainment, income, employment, and marital status) were most likely in survivors who report neurocognitive dysfunction. Collectively, studies evaluating psychosocial outcomes among CNS tumor survivors indicate deficits in social competence in the level of social adjustment that worsen over time. 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 compared with a sibling control group. The presence of chronic health conditions can also impact other aspects of psychological health. In a study that evaluated psychological outcomes among long-term survivors treated with hematopoietic cell transplantation (HCT), 22% of survivors and 8% of sibling controls reported adverse outcomes. Somatic distress was the most prevalent among the domains studied and affected 15% of HCT survivors, representing a threefold higher risk compared with siblings. HCT survivors with severe/life-threatening conditions and active chronic GVHD had a twofold increased risk for somatic distress.
The CCSS has shown that adolescents who are long-term survivors of childhood cancer demonstrate significantly higher rates of inattention, social withdrawal, emotional problems, and externalizing problems than their siblings. Social withdrawal was associated with adult obesity and physical inactivity. As a result, these psychological problems may increase future risk for chronic health conditions and subsequent neoplasms and support the need to routinely screen and treat psychological problems after cancer therapy. 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 radiation. In this study, the instrument was shown to be feasible in the setting of a clinic visit because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to result in distress on the part on the survivors in 80% of cases. These data support the feasibility and importance of consistent assessment of psychosocial distress in a medical clinic setting. However, further study is needed to evaluate the true prevalence of suicidality among a representative cohort of long-term childhood cancer survivors. (Refer to the PDQ summary on Adjustment to Cancer: Anxiety and Distress for more information about psychological distress and cancer patients.)Post-traumatic stress after childhood cancer
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 healthy comparison children. Patient and parent adaptive style are significant determinants of PTSD in the pediatric oncology setting.[65,66]
The incidence of PTSD and post-traumatic stress symptoms has been reported in 15% to 20% of young adult survivors of childhood cancer, with prevalence varying based on criteria used to define these conditions. Survivors with PTSD reported more psychological problems and negative beliefs about their illness and health status than those without PTSD.[68,69] 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 significantly more frequently than sibling control subjects. 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 underwent cranial radiation therapy at younger than 4 years were at particularly high risk for PTSD. Intensive treatment 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 perceived 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. (Refer to the PDQ summary on Post-traumatic Stress Disorder for more information about PTSD in cancer patients.)Psychosocial outcomes among adolescent 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. In 820 survivors of cancer during adolescence (diagnosed between ages 15–18 years), when compared with an age-matched sample from the general population and a control group of adults without cancer, female survivors of adolescent cancers had achieved fewer developmental milestones in their psychosexual development, such as having their first boyfriend, or 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 had children. Compared with their age-matched samples, survivors were significantly older at their first marriage and at the birth of their first child. Survivors in this cohort were also significantly less satisfied with their general and health-related life compared with 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.
In a survey of 4,054 adolescent and young adult (AYA) cancer survivors and 345,592 respondents who had no history of cancer, AYA cancer survivors were more likely to smoke (26% vs. 18%), be obese (31% vs. 27%), and have chronic conditions including 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 be receiving medical care because of cost (24% vs. 15%).
The CCSS evaluated outcomes of 2,979 adolescent survivors and 649 siblings of 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). Survivors were 1.5 times (99% confidence interval [CI], 1.1–2.1) more likely than siblings to have symptoms of depression/anxiety and 1.7 times (99% CI, 1.3–2.2) more likely 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 and/or intrathecal methotrexate) were specific risk factors for adverse behavioral outcomes.
Because of the challenges associated with the diagnosis of an AYA cancer, it is important for this group to have access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.[76,77]
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for CNS and psychosocial late effects information including risk factors, evaluation, and health counseling.References
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