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 are most commonly observed after treatment of malignancies that require central nervous system (CNS)–directed therapies. CNS-directed therapies include the following:
- Cranial radiation.
- Systemic therapy with high-dose methotrexate or cytarabine.
- Intrathecal chemotherapy.
- Female gender.
- Younger age at the time of treatment.
- Tumor location.
- Higher cranial radiation dose.
- Treatment with both cranial radiation and chemotherapy (systemic or intrathecal).
- Lower socioeconomic status.
It should be noted that 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.[7,8]Brain tumors
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. There is an established dose-response relationship, with patients who receive higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures.
- Tumor site.
- Shunted hydrocephalus.[9,11,12]
- Postsurgical cerebellar mutism.
- Auditory difficulties.
- History of stroke.
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; 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.[15-17] 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. 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.[16,18,19]
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).[20-23] In fact, reduced white matter integrity has been directly linked to slowed cognitive processing speed in survivors of brain tumors, while greater white matter volume has been associated with better working memory, particularly in females. 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.[12,25]
Longitudinal cohort studies have provided insight into the trajectory and predictors of cognitive decline among survivors of CNS tumors. A report from St. Jude Children’s Research Hospital showed cognitive decline after 54 Gy conformal cranial radiation therapy in 78 children younger than 20 years (mean, 9.7 years) diagnosed with low-grade glioma (refer to Figure 3). Age at time of cranial radiation was more important than was cranial radiation dose in predicting cognitive decline, with children younger than 5 years estimated to experience the greatest cognitive decline.
In a study of 126 medulloblastoma survivors treated with 23.4 Gy or 36 Gy to 39.6 Gy of cranial spinal radiation (with a conformal boost dose of 55.8 Gy to the primary tumor bed), 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 (St. Jude SJMB03 [NCT00085202]) indicated that performance was largely within the age-expected range up to 5 years postdiagnosis,[28,29] 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.
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 Childhood Cancer Survivor Study (CCSS), CNS tumor survivors (n = 802) 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). Moreover, a large proportion of CNS tumor survivors treated with cranial radiation 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.
- In a small sample of medulloblastoma survivors (N = 20; median interval since diagnosis, 15.5 years), performance in the domains of working memory, processing speed, memory, executive function, academics, and motor dexterity was significantly impaired, compared with population norms.
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.[31,32]
- CNS tumor survivors are more likely to need special education services than are survivors of other malignancies.
- Adult CNS tumor survivors are less likely to live independently, marry, and graduate from college than are survivors of other malignancies and siblings.[33-35]
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, prophylactic 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 the fewer than 20% of children who are considered at high risk for CNS relapse.
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 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 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 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.[37,38] 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.[37,39,40] Girls and children treated at a younger age are more vulnerable to cranial radiation.[41,42] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy.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.
Most studies of chemotherapy-only CNS-directed treatment report 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.[39,44-47] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[46,48] 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.[45,49,50] Risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female gender.[48,51]
Studies of neurocognitive functioning observed the following:
- In the St. Jude Total XV (NCT00137111) trial, which omitted prophylactic cranial radiation, 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.
- 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.[45,53] These differences may be attributable, in part, to the interval since diagnosis, when neurocognitive performance is assessed.
- In a large prospective study (N = 555) of neurocognitive outcomes in children with newly diagnosed ALL who were randomly assigned to receive CNS-directed therapy according to risk group (low risk: intrathecal methotrexate vs. high-dose methotrexate; high risk: high-dose methotrexate vs. 24 Gy 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.[38,42,55] According to the results of neurocognitive testing and patient reported outcomes in more than 500 adult survivors of childhood ALL at 26 years postdiagnosis, survivors demonstrated increased rates of impairment in most neurocognitive and behavioral domains. Impairment was common in survivors treated with lower doses of cranial radiation and in those treated with chemotherapy only. Impairment in executive function skills increased with time since diagnosis; impairment in intellect, academics, and memory progressively increased with younger age at treatment in a cranial radiation dose-dependent manner; and neurocognitive function was related to functional outcomes as adults, including college graduation and full-time employment. Continued monitoring by health professionals is recommended to identify neurocognitive problems that may emerge over time.
The type of steroid used for ALL systemic treatment may affect cognitive functioning. In a study that involved long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment, no meaningful differences in cognitive functioning based on corticosteroid randomization were observed.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 radiation. As a result, significant deficits in overall intellectual function were noted in comparison with those in cancer controls. Currently, most ALL treatment protocols do not specify cranial radiation 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 in the average range.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 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 and include the following:
- In a report from St. Jude Children’s Research Hospital in which 268 patients were treated with stem cell transplantation, minimal risk of late cognitive and academic sequelae was observed. Subgroups of patients were at relatively higher risk, including patients who underwent unrelated donor transplantation, received total-body radiation, 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. 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 radiation, 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.Neurologic Sequelae
Risk of neurologic complications may be predisposed by the following:
- Tumor location.
- 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.
Neurologic complications that may occur in adult survivors of childhood cancer include the following:
- Leukoencephalopathy. Clinical or radiographic leukoencephalopathy has been reported after cranial radiation and high-dose systemic methotrexate administration. Younger patients and those treated with cranial radiation doses higher than 24 Gy are more vulnerable to this complication. 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. 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.
- Stroke. A separate CCSS report revealed that survivors are at risk of stroke decades after completion of therapy. Specifically, treatment with cranial radiation was associated with increased stroke risk in a dose-dependent manner (hazard ratio [HR], 5.9 for 30–49 Gy; HR, 11.0 for ≥50 Gy). Hypertension in adult survivors increased stroke hazard fourfold.
- Other neurologic sequelae. In a report from the CCSS that compared 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 radiation for ALL and those who suffered relapse were at increased risk for late-onset neurologic sequelae.
|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 report reduced quality of life or other adverse psychosocial outcomes.
- In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome in 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 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 than were siblings in the control group.
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. 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. History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors.
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.
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%. 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 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. These data support the feasibility and importance of consistent assessment of psychosocial distress in a medical clinic setting.
(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 those in healthy comparison children. Patient and parent adaptive style are significant determinants of PTSD in the pediatric oncology setting.[73,74]
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.
- Survivors with PTSD reported more psychological problems and negative beliefs about their illness and health status than did those without PTSD.[76,77]
- 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. 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 radiation before age 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 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.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. The following early studies describe the impact of a cancer diagnosis made during adolescence:
- In 820 adult survivors of cancer diagnosed during adolescence (between ages 15 and 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 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 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.
- 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 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 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 were siblings to have symptoms of depression/anxiety and 1.7 times (99% CI, 1.3–2.2) more likely than were 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 and/or intrathecal methotrexate) were specific risk factors for adverse behavioral outcomes.
It should be noted that social withdrawal in adolescence was associated with adult obesity and physical inactivity. 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 associated with the diagnosis of an AYA cancer, this group needs to have access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.[85,86]
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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