Brain tumors are the second most common type of cancer in children, affecting approximately 1 in every 30 000 to 40 000 youth in the United States.1 For survivors, neurocognitive deficits are common, affecting 40% to 100% of children, depending on age at treatment and history of cranial radiation or types of chemotherapy,2 and may not become fully realized until years after treatment has ended. Neurocognitive deficits have been linked to poor educational attainment, difficulty finding employment, and behavioral and social difficulties, all of which may contribute to poor quality of life (QOL).3 Central nervous system (CNS) injury after treatment of a brain tumor can be linked to the initial presence of the tumor and resulting edema or hydrocephalus or to any therapeutic modality such as surgical intervention, cranial radiation, or chemotherapy.
More recently, investigators have studied the physiological processes involved when giving chemotherapy and radiation to eradicate or provide prophylaxis against malignancies in the CNS. Cranial radiation, the cornerstone of pediatric brain tumor therapy for years, contributed to a 5-year survival rate of approximately 66%. However, as long-term survival was achieved, radiation to the brain was also identified as an important causative factor for neurocognitive deficits, ranging from global loss of intelligence quotient (IQ) points to attention problems.4–6 More severe neurocognitive deficits, specifically difficulty with abstract thinking, correlate with younger age at treatment and higher doses of radiation.7
Cranial radiation may be more damaging to the developing brain of a child than to the fully developed adult brain.8 This issue has been so strongly recognized that many young children are now treated on protocols with chemotherapy alone.9,10 Yet, even less is known about late effects of chemotherapy on the child’s developing brain. The rapid postnatal brain development that occurs during early childhood makes children particularly vulnerable to neurocognitive damage.11,12 Multiplication of glial cells and myelination of axons begin during gestation and continue during early childhood to the age of 5 to 7 years, even extending into the third decade in certain areas of the brain such as the prefrontal cortex. If normal brain development is interrupted by an insult, such as that of neurotoxic chemotherapy or cranial radiation, the branching and myelination processes of the developing brain can be delayed or thwarted, and ultimately, brain growth and functional outcome will be limited.11 In addition, during a time of rapid brain growth, it requires less of an insult to make a more dramatic lasting effect.11,13–15
Because radiation therapy results in deleterious consequences, high-dose chemotherapy followed by autologous hematopoietic stem cell rescue (AuHCR) has become more common as a frontline treatment for brain tumors in children younger than 6 years.9 This has resulted in a 5-year survival rate (57%–79%) that is within the range achieved by radiation and chemotherapy.10 Medulloblastoma has proven to be particularly sensitive to this treatment, resulting in improved survival and neurocognitive outcomes in very young children.16 The chemotherapy agents most commonly used in high-dose regimens for childhood brain tumors are cisplatin (CDDP), cyclophosphamide (CPM), etoposide, methotrexate (MTX), thiotepa, carboplatin, and topotecan.10,17,18 Few studies have examined the neurotoxic effects of high doses of this type of chemotherapy in children, focusing instead on more acute organ toxicities and survival statistics.
This article reviews the literature on the effects of cranial radiation and chemotherapy agents used to treat brain tumors in children on healthy brain tissue and discuss outcomes after treatment. There are limitations to the interpretation of the body of clinical research available on this population. Most of the research on CNS injury and neurocognitive outcomes due to pediatric cancer therapy involves subjects treated with a combination of cranial radiation, chemotherapy, and corticosteroids, making it difficult to distinguish between direct and interaction effects of each intervention. Thus, included in this review are relevant research studies in animal models and in general pediatric oncology.
A literature search was performed in PubMed and PsycINFO for the years 2000 to 2011, using a combination of key words: neuronal injury, neuronal loss, chemotherapy, radiation, neurocognitive, quality of life, brain tumors in children, childhood, and pediatric. Inclusion criteria for in vitro and rodent studies were clinically relevant treatment, and inclusion criteria for human studies were treatment for pediatric brain tumors. Exclusion criteria included duplicate or very similar findings to other articles. Some earlier important works were also included; one, a classic early article from 1963, establishing a link between cranial radiation, CNS injury, and behavior change, and a few brain tumor studies from the 1990s to demonstrate critical findings.
As a brief review, the CNS includes the brain and spinal cord. The brain itself is made up of neurons and glial cells that differentiate from neural progenitor cells (Figure 1). Neurons have a cell body, an axon, and many dendrites, and they send (via axons) and receive (via dendrites) signals by forming synapses with other cells. Astrocytes and oligodendrocytes are types of glial cells. Astrocytes provide a supportive structure and nutrients to neurons, whereas oligodendrocytes form the myelin sheaths that surround and insulate axons, facilitating transmission of synaptic signaling.19 White matter consists of myelinated axons, whereas gray matter is largely made up of cell bodies.
Although different parts of the brain have specific functions (Figure 2), there is some overlap. Cognition, specifically, requires the interaction of thinking, memory, perception, and language. Because many brain regions are involved in this process, dysfunction in 1 area can create a disability that may or may not be overcome.20
The presence of a brain tumor alone, with or without resulting hydrocephalus, may injure normal brain tissue. Once the open sutures and fontanels of the infant’s skull close, the presence of a mass in the brain will cause increased intracranial pressure when it reaches a certain volume. Vasogenic edema, as a result, may cause damage to healthy brain tissue, if not treated in a timely manner.21 Delicate brain tissue may also be injured during surgical resection of the tumor, manifesting as either traumatic brain injury or ischemic injury.22
CNS Injury From Cranial Radiation and Chemotherapy
In Vitro and Rodent Studies of Radiation/Chemotherapy Effect on CNS
Basic science research has provided much of the evidence regarding neurotoxic effects of cancer therapies in children. It demonstrates that both cranial radiation and certain chemotherapy agents affect a variety of normal healthy brain cells, in addition to eradicating cancer cells. A summary of this literature is found in Table 1.
A major cause of cellular injury results from the process of oxidative stress and inflammation triggered by radiation and/or chemotherapy. Within hours to days after exposure to cranial radiation, ongoing release of proinflammatory cytokines from damaged cells supports a chronic state of inflammation in the rodent brain.35 During the cycle of oxidative stress and inflammation, cell membrane breakdown and cell death, apoptosis (programmed cell death), demyelination, and loss of integrity of the blood-brain barrier (BBB) are common. Disruption of the BBB also contributes to edema and cell membrane breakdown and loss, as the regulatory mechanisms that control passage through this important barrier fail, creating a cycle of continuing injury.
Pathological changes in the mouse brain after cranial radiation were noted 5 decades ago26 with the findings that extreme doses of cranial radiation (720 Gy) caused widespread destruction of a variety of brain cells that were gradually replaced with fluid-filled cavities within 7 months of treatment. Even significantly less (80 Gy) but still very high doses of cranial radiation induced signs of active inflammation in the brain at 21 days after treatment.26 Although such high radiation doses are not used today, this 1963 study provided important early information about the chronic injurious nature of radiation.
There is evidence that several chemotherapy agents cause injury in a similar manner. Administration of intrathecal and systemic MTX has been linked to the presence of oxidative stress markers in the cerebrospinal fluid of children on treatment for acute lymphoblastic leukemia.36,37 Disruption of axonal and dendritic networks appeared in neuronal cultures exposed to ifosfamide, vinblastine, cyclophosphamide, CDDP, MTX, and thiotepa.31,32 Although this may not overtly cause cell death, it renders the affected neurons dysfunctional.
Cyclophosphamide appears to be more toxic to the young, developing brain than to the adult brain, causing brain tissue loss in many more areas in younger rodents than in older ones.32 Cerebellar granule cells, tiny neurons found in the cerebellum, are similarly affected by chemotherapy, and many die within 72 hours after exposure to lomustine, CDDP, vincristine (VCR), and topotecan.33 These cells were particularly sensitive to low concentrations of VCR. In addition, VCR was toxic to astrocytes. Vincristine is a known potent peripheral neurotoxin,38 but there has been little research on its effects on cells of the CNS.
Although cranial radiation results in generalized white and gray matter loss in the brain, its effect on the hippocampus is of particular importance, because this is a primary site of neurogenesis, the generation of new neurons from progenitor cells, after the early postnatal period. Specific areas of the hippocampus where proliferating (growing and dividing) cells may be found include the subventricular zone, subgranular zone, and dentate gyrus. A single low dose of radiation to the adult rat brain (1–3 Gy) led to significantly less brain growth over time, with an acute decrease in the number of cells in the subventricular zone.24 Proliferating cells decreased markedly up to 2 months after a single 10-Gy dose of cranial radiation.25 After exposure to radiation, remaining progenitor cells have a stronger tendency to differentiate into glial cells than into neurons, which may reflect an alteration of the signaling process.25 The exact mechanism for the failure of neurogenesis is unknown but may be related to alterations in the microenvironment of the hippocampus and the presence of proinflammatory cytokines or to interference with normal molecular and cellular interactions.25 Moreover, this reduction in hippocampal proliferating cells due to radiation given early in life persisted into adulthood.27 These processes may help to explain the more severe neurocognitive effects of radiation found in children, as compared with adults.27,28 Even in adults, loss of oligoprogenitor cells, precursors to the cells that form myelin, persisted for up to 7 years after radiation therapy.23
As with radiation, chemotherapy appears to preferentially affect cells of the hippocampus. Methotrexate injures neural progenitor cells in the hippocampus,39 which is believed to account for delayed neurotoxicities (progressive cognitive dysfunction, neuropathies, cerebral atrophy, cerebellar toxicity) associated with that treatment. Systemic administration of thiotepa, an antimitotic agent that effectively crosses the BBB, resulted in significant neuronal loss in the mouse hippocampus.30,34 Cisplatin exposure caused an increase in apoptosis of cells in the dentate gyrus,30 The effects of CDDP, carmustine and cytarabine, given separately and in combination, on both quiescent brain tissue cells and cancer cell lines suggest that these agents are even more toxic to neural progenitor cells than to the cancer cells, decreasing viability by up to 90% for at least 6 weeks after chemotherapy exposure.30
In summary, the literature suggests that cranial radiation results in both acute and chronic injury to a wide variety of cells, leading to demyelination and areas of necrosis of the brain. Both chemotherapy and radiation appear to target neural progenitor cells in the hippocampus, leading to notable decreases in the number of new neurons. As a site of memory consolidation, hippocampal cell loss is detrimental to cognition. The time progression of damage to normal cells after treatment with chemotherapy indicates that CNS cell death may occur within 24 hours of treatment and continue for up to 6 weeks and may cause more widespread neuronal degeneration in the young brain than in the adult brain. The multiple mechanisms by which cell injury occurs, including cell shrinkage, axonal and dendritic disruption, and apoptosis of cerebellar granule cells and neural progenitor cells, resulting in white and gray matter loss, have also been explicated.
Pediatric Brain Tumor Studies of Radiation/Chemotherapy Effect on the CNS
A summary of the literature on the effects of CNS cellular injury and loss after brain tumor therapy in childhood is found in Table 2. One of the most commonly reported effects of cancer treatment evident on pathological examination and with certain brain imaging techniques is a loss of white matter, or demyelination. After cranial radiation, demyelination appears within 5 months, with vascular structural changes and necrosis occurring about 9 months later.43 Five years after radiation, significant structural damage to the brain appeared and continued to progress.43 After treatment with 35- to 40-Gy cranial radiation, normal-appearing white matter (NAWM) continued to decrease at a rate of 0.3 mL/y over 5 years.44
The volume of the hippocampus was also affected by radiation, continuing to decrease bilaterally on magnetic resonance imaging for 2 to 3 years after diagnosis, but then returning to a normal growth pattern.42 On autopsy examination of the hippocampi of children, a 100-fold decrease in neurogenesis after total body irradiation (13.2 Gy) and a 10-fold decrease in neurogenesis after 23.4-Gy craniospinal radiation and focal cranial radiation were observed. As is typical in most clinical samples, these patients were also treated with chemotherapy and with corticosteroids, known inhibitors of neurogenesis, so these differences may not solely be attributable to radiation.41
There is also evidence of gray and white matter loss in children treated for brain tumors with standard dose chemotherapy combined with cranial radiation.7 With higher doses of MTX and cranial radiation, an increased incidence of leukoencephalopathy (white matter changes related to endothelial cell loss and demyelination) was seen at a median 7.5 years after therapy.40 Those children with more severe changes had all received higher doses of radiation. Because both cranial radiation and MTX have been associated with leukoencephalopathy, an interaction effect of both treatments may exist.
Model of Injury of Cancer Treatment to CNS
Figure 3 demonstrates the similarities in the injurious processes of chemotherapy and radiation to healthy brain tissue. An acute cranial radiation effect is an increased expression of intracellular adhesion molecule 1 (ICAM-1) within 24 hours of exposure, which contributes to disruption of the BBB.35 The integrity of the BBB is compromised by damage to vascular endothelial cells, leading to edema, further inflammation, and tissue hypoxia.4 In response to cell injury, acute and chronic oxidative stress processes damage cellular mitochondria and result in the formation of oxidative products and enzymes such as lipid peroxidase, which contribute to continuing cell membrane breakdown.36 Like radiation, chemotherapy induces oxidative stress in the CNS45–47 through the release of cytokines such as tumor necrosis factor and interleukin 1β, contributing to demyelination35 and white matter loss.
Chronic oxidative stress secondary to radiation or chemotherapy also inhibits hippocampal neurogenesis, which appears related to memory dysfunction.30,34,48 Therefore, the 2 common mechanisms of injury from chemotherapy and radiation resulting from oxidative stress are CNS cell injury and/or death leading to white and gray matter loss, and decreased hippocampal neurogenesis leading to a drop in the development of new neurons. These 2 separate mechanisms contribute to the most common neurocognitive deficits in brain tumor survivors. Damage to the hippocampus or to its progenitor cells results in memory problems, specifically with short-term memory, which can be very detrimental to learning.49 Loss of gray and white matter in certain areas of the brain may result in attention and executive functioning problems50–52 and decreased IQ.
CNS Cell Loss and Neurobiobehavioral Outcome
It is important to investigate the impact of CNS injury on developmental and neurocognitive outcomes. The loss of cells in cortical and subcortical regions in the brain induced by chemotherapy and radiation predicts neurocognitive deficits in children with brain tumors. Life-threatening illness and aggressive treatment at a young age can affect future physical, emotional, cognitive, and psychosocial health.
Neurocognitive deficits in children with brain tumors have been almost exclusively studied in those who received a combination of radiation and chemotherapy or with radiation alone. Children treated with cranial radiation before the age of 5 years have much poorer neurocognitive outcomes than those treated in older childhood and adolescence.53 Research on rodent models of the relationship of treatment-induced CNS injury and loss to neurocognitive deficits is summarized in Table 3.
Rodent Models of Neurobiobehavioral Effects After Radiation and/or Chemotherapy
In an early study of adult rodent behavior after cranial radiation, mice treated with 80 Gy demonstrated small but significantly different behavior changes, depending on the area of the brain treated. For example, rodents who received cerebellar radiation had locomotor problems, whereas those radiated in the parietal areas had more difficulty with tasks involving memory.26 Young mice (21 days old) experienced memory retention deficits that correlated with a decrease in neurogenesis in the subgranular zone after a single 5-Gy dose of whole-brain radiation.28 Five consecutive days of 4-Gy whole-brain radiation resulted in long-term impairment of nonspatial learning in 1-month-old mice.27
Systemic high-dose MTX caused a loss of healthy neurons in the hippocampi of rats as well as concurrent changes in neurocognitive functioning, specifically, difficulties with spatial learning and object recognition tasks.54 High-dose MTX–treated adult mice had an inadequate response to fear conditioning, which represented cognitive and memory deficits.55 Mice treated with combined standard-dose MTX and 5-fluorouracil had difficulty with spatial memory tests on the day after treatment, but these deficits normalized with time.56
Pediatric Studies of Neurobiobehavioral Effects After Radiation and/or Chemotherapy
A summary of the studies of the relationship of treatment-induced CNS injury and loss to neurocognitive deficits in children is presented in Table 4.
For children, school achievement is an indirect indicator of cognitive function. A report on more than 800 Canadian childhood cancer survivors demonstrated that those with a history of a CNS tumor treated with chemotherapy and cranial radiation were significantly more likely to have utilized special educational services than were survivors of other cancers.57 The academic subject accounting for the greatest difference between survivors and controls was mathematics. Children who were older at the time of diagnosis had better reading skills and were rated more highly by their teachers for academic performance than those who were younger.61 Those with ventriculoperitoneal shunts for tumor-related hydrocephalus had significantly lower math scores than those without shunts. Math, spelling, reading scores, and attention continued to decline over time, possibly related to continuing, chronic white matter changes.52 As additional evidence of progressive deficits over time, children with medulloblastoma treated with higher doses of CRT (36–39.6 Gy neuraxis and 55.8 Gy to tumor bed) lost more IQ points per year over 5 years than did those treated with a lower dose of neuraxis cranial radiation.64
Older children with germ cell tumors treated mainly with chemotherapy, although some also received cranial radiation, scored within the average range on full-scale IQ, verbal IQ, reading, math, and spelling.67 Younger age at diagnosis was related to lower scores in math and overall IQ.67
Significant correlations between white matter volume, attention, and IQ have been noted in brain tumor survivors treated with chemotherapy and cranial radiation.52 White matter loss is strongly correlated with adverse neurocognitive outcomes.60 A decrease in white matter of just 3.3% predicted an IQ score of 85 or less, approaching borderline deficiency. Indicators of white matter loss were seen in widespread areas of the brain, including the cerebellar hemispheres, pons, medulla, frontal and parietal periventricular structure, and corona radiata in children with medulloblastoma treated with chemotherapy and radiation 1 to 6 years earlier.60 Fractional anisotropy values, indicating loss of white matter integrity, correlated significantly with younger age at diagnosis, poorer school performance and longer time off-therapy,59 and with full-scale IQ, verbal IQ and performance IQ.60 These findings have been supported using alternate indicators of tissue damage with diffusion tensor imaging. Another indicator of microstructural CNS damage, the absolute diffusion coefficient, is significantly related to decreased IQ in brain tumor survivors as compared with healthy controls.62
Attention problems are fairly common in survivors of childhood brain tumors. Total volume of NAWM after chemotherapy and radiation was a strong predictor of attention problems,51 whereas 70% of the correlation between IQ and age at cranial radiation was explained by NAWM.7 White matter lesions became evident in a sample of brain tumor survivors at a median time of 7.8 months after radiation, and many (73%) resolved within another 6 months. A decline in IQ was also significantly related to the presence of these lesions.50
There are few studies to date on the long-term outcome of children with brain tumors who were treated with only chemotherapy. One study showed no significant loss of IQ points over time after chemotherapy, as compared with those who received radiation.69 Treatment for a brain tumor with chemotherapy before the age of 3 years resulted in mean IQ and memory scores within the average range, but in executive functioning significantly below the standard mean.47 Those who underwent more than 1 surgical resection had lower IQ, memory, and executive function scores. Lower socioeconomic status was related to lower scores on IQ and memory scores.47
Children with brain tumors who were an average of 3 years’ posttreatment showed low-average to average neurocognitive functioning after high-dose chemotherapy with AuHCR.66 Mean performance was in the average range for most academic skills, whereas fine motor skills and processing speed were in the low average range.66 Another group treated in the same manner displayed similar performance on intelligence testing and academic achievement and normal scores on behavioral and social-emotional functioning at a mean of 39.7 months after therapy.18
Quality of life in survivors of childhood brain tumors may be affected by many variables, including the treatment, frequent medical procedures, and hospitalizations at a young age. Findings are mixed regarding whether impairments in specific areas of neurocognitive functioning may impact QOL. More than 80% of medulloblastoma survivors studied had impaired executive functioning, and 92% were impaired on at least 1 subtest of attention, but despite these findings, neither self-reported nor caregiver-reported QOL was significantly diminished.63 A longitudinal study found that QOL scores of children with brain tumors improved such that, at 12 months after diagnosis, there was no significant difference between subjects and healthy controls in any domain.65 This particular study is relevant to the resolution of effects of acute treatment on QOL but does not measure QOL in the long-term survivor. No significant difference was seen in QOL scores between children with brain tumors treated with multimodal therapy (surgery, cranial radiation, and chemotherapy) and those treated with surgery only.58 Older children treated with a combination of cranial radiation and chemotherapy for germ cell tumors had low-average psychosocial functioning, borderline physical functioning, and impaired self-esteem on measures of QOL. Age at diagnosis was a factor related to lower scores on psychosocial and physical domains of QOL. Studies of children with brain tumors treated on the Head Start protocols, which utilize high-dose chemotherapy regimens and AuHCR, show that QOL scores were generally positive, but younger age at diagnosis and longer time off treatment correlated with risk for behavior and attention problems.68
As noted, there is good evidence to suggest that children treated with radiation alone or both chemotherapy and radiation have poor neurocognitive outcomes. Late effects of chemotherapy on cognitive centers in the brain in children include neurocognitive deficits in the areas of visual processing, visual motor skills, and memory and executive functioning. The addition of cranial radiation therapy leads to a more global loss of IQ points. In the few studies of children with brain tumors treated with chemotherapy only, memory and executive functioning deficits were observed, but overall neurocognitive function and QOL were generally within average range.
Implications for Practice
Nurses are often sought out by family members to explain treatment regimens and acute and chronic effects of therapy. As the numbers of childhood cancer survivors increase, our involvement in long-term follow-up care is crucial. Educating families to recognize the signs of neurocognitive problems in children is just as important as teaching about signs of other toxicities. Nurses can educate parents to be aware of subtle difficulties in school and to discuss concerns with teachers and healthcare providers. These difficulties may include academic, social, mood, and behavioral problems. Interaction with education specialists and teachers by the nurse to explain the possibility of neurocognitive late effects is recommended.
Standard guidelines for children who have received cranial radiation and/or MTX or high doses of cytarabine recommend regular neuropsychological testing and follow-up as needed.70 Nurses should advocate for any child with a brain tumor to have a neuropsychological testing battery after treatment and as recommended thereafter and encourage parents to be vigilant about this. Results of testing are used to develop Individualized Education Programs at school in order to ensure the best learning environment for each child. There is a wide range of possible interventions, ranging from simple techniques to more complex cognitive behavioral therapies, computerized interventions, and medications to improve attention and memory. Early intervention, in conjunction with newer therapies, may help to mitigate neurocognitive deficits and social problems.
Summary and Conclusions
Survival of a childhood brain tumor is often the result of administration of toxic therapies that not only eradicate cancer cells but also affect the healthy tissue of the child’s developing brain both acutely and in an ongoing manner. Radiation to the brain causes a progressive loss of healthy CNS cells because of a chronic state of inflammation, oxidative stress, and a loss of neural progenitor cells. Many chemotherapeutic agents cause injury to healthy brain cells by similar mechanisms. Neurocognitive deficits, often resulting in poor academic achievement and social isolation, may interfere with QOL in this population. Educational success is directly related to social proficiency and successful transition to adulthood and independence.71 Difficulty making friends and maintaining relationships may lead to withdrawal from social situations and subsequent isolation. Survivors of childhood brain tumors are less likely to marry or to be employed than are healthy peers and more likely to experience depression and anxiety.2,3,71 Although there is evidence to suggest that young children treated with chemotherapy alone may encounter fewer neurocognitive deficits, there may be long-term difficulties in the areas of memory, attention, and executive functioning. Little is known about long-term neurobiobehavioral outcomes in children who were treated with high-dose chemotherapy and AuHCR, which is becoming more common as a frontline treatment. As this treatment technique gains popularity, it will be important to define its long-term effects.
There are several limitations to the state of the science upon review of the literature. There are no studies to document loss of healthy brain tissue in children with brain tumors who were treated solely with chemotherapy. Most brain tumor studies have examined children treated with a combination of radiation and chemotherapy. However, available results indicate improved QOL in those treated without radiation.
Because the number of children diagnosed each year with brain tumors is relatively small, and so many variables affect outcomes, multi-institutional studies are critical to achieve sample sizes with adequate power to demonstrate significance. Future research must seek to minimize variability in tumor location, pathology, and treatment among subjects as much as possible in order to attribute certain toxicities to specific agents with more confidence. This approach will allow research to progress to develop more interventions to maximize long-term neurocognitive outcomes and QOL.
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