Late Effects of Treatment of Pediatric Central Nervous System Tumors.

Topical Review Article

Late Effects of Treatment of Pediatric Central Nervous System Tumors

Journal of Child Neurology 1-19 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815587944 jcn.sagepub.com

Erika Roddy, BA1, and Sabine Mueller, MD, PhD2,3,4

Abstract Central nervous system tumors represent the most common solid malignancy in childhood. Improvement in treatment approaches have led to a significant increase in survival rates, with over 70% of children now surviving beyond 5 years. As more and more children with CNS tumors have longer survival times, it is important to be aware of the long-term morbidities caused not only by the tumor itself but also by tumor treatment. The most common side effects including poor neurocognition, endocrine dysfunction, neurological and vascular late effects, as well as secondary malignancies, are discussed within this article. Keywords brain tumor, late effect, chemotherapy, radiation therapy, stroke Received December 22, 2014. Received revised April 03, 2015. Accepted for publication April 21, 2015.

Brain and other central nervous system tumors represent the most common solid childhood tumors, with a yearly incidence of 5.3 cases per 100 000 (ages 0-19).1 As of 2005, there were an estimated 51 650 adult survivors of childhood brain tumors in the United States, representing 1 in 670 adults ages 20 to 39.2 Increasingly sophisticated and targeted treatment modalities have led to an increase in the average 5-year survival rate for children with central nervous system tumors as a group to 73%1 from less than 60% in 1975 to 1979. However, there is a range, and some tumor types such as pediatric high-grade gliomas including diffuse intrinsic pontine glioma remain incurable whereas pure germinomas have an almost 100% cure rate.3 Continuing advances in neuroimaging, radiation delivery, chemotherapy, and other treatments mean that this rate will likely further increase. This increase in survival is great cause for celebration. However, it also represents an increasingly important challenge for neuro-oncologists and other providers who care for childhood brain tumor survivors: minimizing and managing the late effects of tumor diagnosis and treatment. The term ‘‘late effects’’ is broad; however, most investigators agree that it refers to complications that begin or persist well after tumor diagnosis. Many of these late effects arise as a result of tumor treatment. Treatment for pediatric brain tumors is variable and dependent on patient age as well as tumor size, location, and histology. However, standard protocols commonly include resection, chemotherapy, and radiation—all potentially invasive and toxic modalities. Additionally, although these treatments often come with acute side effects such as hair loss, nausea and vomiting, and weight loss, many of their most significant and debilitating consequences become apparent only months to years following the conclusion of treatment.

The majority of acute side effects typically resolve while late effects can occur insidiously and last for a lifetime. Late effects of treatment include both medical and nonmedical complications and can be divided into several categories, including (1) neurocognitive, (2) endocrine, (3) neurologic/sensory, (4) cerebro- and cardiovascular, (5) secondary malignancies, and (6) psychological and social (see Figure 1). Late effects in survivors of childhood cancers are common: 62% report at least 1 ill effect, whereas one-third report 3 or more.4 Almost one-third of these are graded as life-threatening or severe. The cumulative incidence of a severe or life-threatening condition is 42.4% at 30 years after diagnosis.4 Importantly, these results are based on self-reported health outcomes, which may significantly underestimate the true prevalence of late effects in adult survivors of childhood cancers. Recently, Hudson et al5 described the results of in-person medical assessments conducted in 1713 long-term survivors of pediatric cancer. The estimated prevalence of at least 1 chronic health condition was 95.5% by 45 years of age, whereas the prevalence of a disabling or life-threatening condition by the

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School of Medicine, University of California, San Francisco, CA, USA Department of Neurology, University of California, San Francisco, CA, USA 3 Department of Pediatrics, University of California, San Francisco, CA, USA 4 Department of Neurosurgery, University of California, San Francisco, CA, USA 2

Corresponding Author: Sabine Mueller, MD, PhD, Department of Neurology, Pediatrics and Neurosurgery, University of California, San Francisco, Helen Diller Cancer Center, 1450 3rd Street, San Francisco, CA 94143, USA. Email: [email protected]

Downloaded from jcn.sagepub.com at University of Birmingham on June 10, 2015

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Journal of Child Neurology

Neurocognition Education IQ Living independently

School programs, pharmacological interventions

Psychosocial Mental health Employment Social Interactions Marriage Sibling and parental mental health

Counseling, support groups

Fertility preservation, assisted reproductive techniques, hormone replacement therapy

Cancer Survivor

Screening, hormone replacement, riskreducing behaviors

Organ Systems Fertility and Reproduction Infertility Premature menopause

Cerebrovascular disease Endocrinopathies Peripheral neuropathy Ototoxicity

Screening, riskreducing behaviors

Cancer Secondary malignancy Primary recurrence

Figure 1. Late effects encompass numerous and diverse domains of life. Potential interventions to minimize the risk or ameliorate the burden of late effects are described.

same age was 80.5%.5 These results are concerning not only for underreporting of late effects in this population but also for the high prevalence of diseases such as cardiovascular disease and neurocognitive deficits. Risk factors contributing to the likelihood of late effects include tumor location, increased doses of chemotherapy and radiation, and young age at time of diagnosis and treatment.6-8 Generally, late effects from treatment are additive, with increased treatment modalities and doses leading to more significant and severe late effects. Survivors of childhood central nervous system tumors suffer from numerous challenges related to their tumors and treatments.9 Moreover, likely due to the highly vulnerable developing brain and neuraxis, it is well recognized that their burden is significantly greater than those of survivors of other pediatric malignancies.10,11 The frequency and severity of these late effects renders it imperative that the medical team is aware of the unique challenges that survivors of central nervous system pediatric tumors face, as more and more pediatric patients survive and enter adulthood. By anticipating these late effects, medical providers play an essential role in helping patients (1) navigate problems as they arise and (2) mitigate or reduce late effects by proactive screening, implementation of novel therapies or interventions, and encouragement of health-promoting behavior.

Neurocognition Childhood is a time of exquisite brain sensitivity and the period during which the majority of brain development

occurs. It is therefore not surprising that survivors of childhood central nervous system tumors commonly experience a myriad of neurocognitive late effects. Neurocognitive late effects range from mild deficits in academic functioning to severe deficits in intellectual ability and language. Unfortunately, studies examining the effect of radiation on cognitive decline are limited by varying lengths of follow-up. A recent quantitative meta-analysis of 39 studies found that adult survivors of pediatric brain tumors were nearly 1 full standard deviation below normative means in verbal and nonverbal global cognitive ability.12 Types of impairment. Measurement of neurocognitive functioning has traditionally been conducted through assessment of IQ. A meta-analysis of 22 studies found that survivors of childhood brain tumors decline on average 12 to 14 points in IQ after treatment.13 Moreover, this decline is progressive: with increasing time from treatment, decline is both more prevalent and more severe.14-17 Studies of survivors of childhood acute lymphoblastic leukemia who received cranial radiation therapy have similarly reported progressive decline in IQ at 25 years following treatment.18,19 More recently, researchers have focused on elucidating specific areas of deficit. The most frequently impaired domains include executive function and its components: attention, working memory, and processing speed.6,7,12,20,21 These functional impairments are hypothesized to represent the mechanism behind the declines seen in IQ and academic performance in childhood central nervous system tumor


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survivors.22,23 The typical gains in IQ seen with increasing age are largely attributed to age-related improvements in processing speed, working memory, and attention.15,22,24 Failure to make these improvements at an appropriate rate will manifest as declines in measured IQ. Therefore, it is reasonable to hypothesize that the neurocognitive decline seen in central nervous system tumor survivors may not be predominantly due to the result of loss of learned information but rather the failure to achieve age-related gains in cognitive function and subsequently impaired ability to acquire new information. Risk factors for neurocognitive impairment. Younger age at time of treatment, increased radiation field, increased radiation dose, length of time from treatment, female gender, and supratentorial tumors are all associated with increased likelihood of neurocognitive impairment.7,25 Among these, the most important risk factors appear to be age at treatment and dose and volume of radiation therapy.

Radiation Therapy: Age and Radiation Dose Treatment with cranial radiation therapy is associated with a 15- to 25-point decline in IQ compared to children who do not receive cranial radiation therapy, although some children show very minimal change and these earlier data were obtained when conformal radiation therapy was not available.26-28 Younger children not only may be more sensitive to radiation but are at increased risk for complications such as shunt infections and associated multiple surgeries, which may compound their risk for neurocognitive decline.8,29,30 One study showed that very young children are also more likely to present with hydrocephalus at diagnosis and to require more aggressive surgery than older children.6 Hydrocephalus may compress and damage white matter tracts.31 Other common treatment modalities such as chemotherapy and surgery are also associated with increased risk of neurocognitive decline, but cranial radiation therapy seems to be by far the most significant contributor. It is well established that whole brain or craniospinal radiation causes greater impairment of intellectual functioning than focal radiation.13,32-34 In one study comparing patients receiving tumor bed radiation only for ependymoma with those receiving craniospinal radiation for medulloblastoma, at 5 and 10 years after treatment 60% of ependymoma patients had IQ scores above 90. The same was true for only 20% and 10% of the medulloblastoma patients at 5 and 10 years, respectively.33 Netson et al35 recently showed that ependymoma patients receiving focal radiation alone had stable intellectual outcomes at 5 years following treatment. Additionally, Merchant et al36 found that pediatric low-grade glioma patients receiving focal radiation alone had relatively preserved cognitive function at 5 years posttreatment. Younger age at radiation is also known to confer increased risk of cognitive decline.34,37-39 Indeed, age at radiation of 3 years or younger is a guarantee of later profound neurocognitive deficits34,40,41; however, even children who receive radiation at age 6 or 7 exhibit increased deficits. In one study, all

patients who received radiation at or before age 6 had subnormal IQ on follow-up assessments.42 In the previously cited meta-analysis of 22 studies, younger age at radiation was associated with a 14-point difference in IQ compared to those who received radiation at a later age.13 Reports are conflicting regarding the contribution of the radiation dose to neurocognitive decline. In a cohort of pediatric medulloblastoma patients, decreased craniospinal dose of 23.4 Gy resulted in a 10- to 15-point mitigation in IQ decline compared to patients who received 36 Gy28; however, the differences were not statistically significant. Further, cognitive impairment and progressive decline still occur at reduced doses of 23.4 Gy26,43 and still lead to poor academic performance, just as seen in children treated with 36 Gy.44 These results are confounded, however, by the fact that the patients in these studies continued to receive full boost doses to the tumor bed (typically 54 Gy). An exciting recent report of 113 medulloblastoma patients found that children receiving lower-dose craniospinal radiation (18-23.4 Gy) plus a reduced volume boost to the tumor bed (45-55.4 Gy) showed stable cognitive outcomes at 5 years after treatment, whereas children receiving standard craniospinal radiation (30.6-39.4 Gy) or full-volume posterior fossa boost showed progressive decline in IQ.45 Chemotherapy and neurocognition. Evidence exists that chemotherapy also contributes to neurocognitive decline. Specific data regarding the precise role of chemotherapy is less clear, however, as very few brain tumor treatment protocols rely on chemotherapy alone in the absence of adjuvant radiation and/or surgery. Moreover, most protocols require the administration of multiple chemotherapeutic agents, rendering it difficult to tease out the specific contributions of individual agents. Some evidence suggests that deficits from chemotherapy alone are less severe than conferred by cranial radiation therapy, and may be limited to specific functions including attention, visual processing, and visual-motor functioning.46-50 Certain chemotherapy agents, including methotrexate, BCNU, CDDP, and cytosine arabinoside are known to be neurotoxic.46,51,52 Importantly, it seems that neurotoxic effects are in large part doserelated,46 pointing to the need for further research into the effects of chemotherapy on the central nervous system, especially as tumor treatment turns more and more toward targeted chemotherapeutic drugs. Posterior fossa syndrome. Posterior fossa syndrome occurs in up to 29% of children who receive posterior fossa surgery53 and is characterized by loss of speech after surgery, giving this syndrome its other name: cerebellar mutism syndrome. This syndrome occurs at a mean of 1.5 days following surgery. These patients do not experience any change in consciousness; however, in addition to hypotonia and ataxia, they exhibit deficits in attention, working memory, verbal fluency, executive function, and attention that can persist years after surgery.54-56 Although these patients often receive other neurotoxic treatments such as radiation and chemotherapy, patients with posterior fossa syndrome have significantly


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lower performance in measurements of executive function compared to treatment, diagnosis, and age-matched controls.54 These neurocognitive sequelae are thought to arise due to damage to white matter tracts in the cerebellarthalamic-cerebral pathway.57-59 Reduced fractional anisotropy in these pathways is correlated with lower working memory.58,60 Additionally, atrophy and gliosis of the cerebellum are more severe in medulloblastoma patients with cerebellar mutism syndrome versus those without 1 year following surgery.61 Although the frontal lobes have been strongly implicated in executive function, the cerebellum has also been implicated, particularly in mechanisms of anticipation and control: focusing attention, decision making, and suppressing extraneous thoughts or impulses.62-66 Hypoperfusion in the neural circuits connecting the cerebellum to the prefrontal cortex may mediate some of the executive function deficiencies seen in pediatric central nervous system tumor survivors. Mechanism of neurocognitive impairment/pathophysiology. The mechanism through which central nervous system tumor treatment causes neurotoxicity and neurocognitive decline is not fully understood. Generally, it is thought to be secondary to microvascular damage or decrease in white matter volume.67-69 Most is known about the role of radiation-induced damage to the brain. Radiation therapy damages and causes apoptosis of neuronal cells, oligodendrocytes, and endothelial cells. Damage to the latter can cause microvascular injury and lead to further secondary ischemic axonal and oligodendrocytic death that may mediate long-term neurocognitive impairment. Blood-brain barrier breakdown occurs both acutely and late after radiation, with corresponding inflammation, vasogenic edema, hypoxia, and reactive oxygen species.70-72 Additional studies have examined the role of damage to specific brain areas. Hippocampal areas have been found to be especially radiosensitive, and radiation to the hippocampus is associated with neurocognitive deficits.73,74 Specifically, radiation dose to the hippocampus is significantly correlated with declines in IQ and poor neurocognitive performance.75,76 Structural changes in the hippocampus may mediate this decline: reduced hippocampal volume after cranial radiation is associated with lower cognitive performance.77 The hippocampus is a site within the central nervous system that continues to experience neurogenesis throughout life and is intimately involved in memory formation and consolidation; damage to these cells from radiation may result in decreased ability to learn and retain information, a major area of deficit seen in survivors.72,78 Survivors of childhood brain tumors treated with radiation exhibit decreased white matter volume compared to those who did not undergo radiation23,79,80 as well as compared to healthy controls.81 Radiographically, demyelination and necrosis are seen.82 Investigations into the association between white matter volume posttreatment and neurocognitive functioning have found that decreases in white matter volume after radiation may explain between 60% and 80% of the neurocognitive decline seen in brain tumor survivors.37 Recent studies have used fractional anisotropy to look not only at white matter

volume but more subtle changes in white matter microstructure and integrity. Fractional anisotropy is a quantitative index generated from diffusion tensor imaging and is thought to reflex axonal degeneration or decreased integrity of myelin.83,84 These studies found reduced fractional anisotropy in brain tumor survivors.85,86 Moreover, the reduction in fractional anisotropy was significantly correlated with decline in school performance, processing speed, and IQ.19,86-89 Areas of reduced fractional anisotropy in these studies include the corpus callosum and frontal lobes.81,88,90 Most studies in this area have been cross-sectional or retrospective; however, a recent prospective study of 383 survivors of childhood cancer lent additional support to this theory, confirming not only the effects of radiation therapy on white matter loss and neurocognitive decline, but showing that decline in white matter is progressive with time.91 Whether the decreased white matter volume is due to loss of white matter or to failure to undergo appropriate maturation of white matter (ie, myelination) is still unknown. However, it is notable that myelination is completed last in the frontal and prefrontal lobes, which are implicated in many of the areas of deficit seen in survivors: executive function, working memory, as well as planning and attention.92-95 This correlation, along with studies showing reduced fractional anisotropy specifically in survivors’ frontal lobes, suggests that failure to complete normal developmental myelination may represent an important mechanism. Gray matter volume is a newer area of interest, as previous studies reported no differences in gray matter volume between survivors and controls.96 However, a recent study using advanced imaging techniques found that medulloblastoma patients who had undergone cranial radiation therapy had significantly thinner cortices than matched controls,97 suggesting a relationship between radiation, cortical volume, and neurocognitive function. Recently, Armstrong et al18 reported that among survivors of childhood acute lymphoblastic leukemia who received cranial radiation, thinner parietal and frontal cortices were associated with impairments in memory. Functional consequences and proposed mechanisms to reduce risk for poor neurocognitive function in pediatric brain tumor survivors. These neurocognitive deficits are significant for their ability to impact survivors’ quality of life and functioning in innumerable areas, including the ability to live independently, drive a car, and achieve socioeconomic success.11,16,98 Medical providers have adopted a number of strategies to decrease the risk of developing neurocognitive decline. For example, generally children under the age of 3 are not irradiated. Efforts to delay the use of radiation include utilizing chemotherapy alone until patients are older; unfortunately, the increased doses of chemotherapy are still neurotoxic.99,100 Additionally, many protocols have attempted to reduce the volume and dose of radiation given to patients while maintaining acceptable tumor control outcomes. Other strategies involve improved and targeted radiotherapy protocols and methodologies, such as conformal or intensity-modulated radiation therapy. Conformal or intensity-modulated radiation


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therapy is a more targeted form of radiation therapy that allows avoidance of healthy brain structures, with more radiation given to the tumor bed and less to surrounding healthy tissue. When possible, intensity-modulated radiation therapy is used to minimize radiation to structures such as the hippocampus, an important structure of neurogenesis.101 Other techniques include hyperfractionated radiotherapy, proton beam therapy, and more recently, radiogenomics. Radiation therapy strategies. Hyperfractionated radiotherapy involves increasing the frequency of radiation delivery but decreasing the dose of each fraction, which allows for decreased radiation to healthy brain tissue and increased radiation to the tumor bed. Some early evidence suggests that cognitive decline from this method may be reduced compared to conventional radiation.102 Proton beam therapy is a relatively new treatment that utilizes protons instead of traditional photons. Protons are unique in that they slow down and deposit most of their energy in 1 point upon entering tissue, allowing for more precise radiation delivery and avoiding radiation to neighboring healthy tissue.103 Evidence is as yet lacking, however, as to whether this technique will result in more favorable neurocognitive outcomes. Finally, radiogenomics is an exciting new field that uses genome sequencing to determine a tumor’s sensitivity to radiation in order to individualize treatment parameters for each individual patient.104 School programs. Other interventions to reduce rate or severity of neurocognitive decline include ensuring that survivors utilize available resources to promote school performance, such as educational interventions and special education that can help address specific deficits. Recently there has been much excitement surrounding the use of cognitive training programs designed to prevent and ameliorate cognitive difficulties. These interventions, modeled after programs for adult traumatic brain injury patients, involve 3 main domains. First, participants perform mass practice and drill tasks to promote attention skills; second, participants are taught strategies to organize their work and improve academic performance; third, cognitive-behavioral principles are taught to promote positive attitudes. Results from these programs have shown statistically significant improvements in IQ, although not in academic performance, and the impact on survivors’ overall function in daily life remains unknown.105,106 Stimulants. Attention is one of the major functional domains in which survivors consistently experience deficits. Methylphenidate is a stimulant used to improve the attention skills of children diagnosed with attention-deficit hyperactivity disorder (ADHD). Some researchers have examined the role of methylphenidate in treating these children and have found that methylphenidate is positively associated with improvements in attention and processing speed compared to placebo in a cohort of acute lymphoblastic leukemia and brain tumor survivors.107 Two other pharmaceutical therapies have been proposed to improve cognition in survivors of pediatric central

nervous system tumors: modafinil and donzepil. Modafinil is a dopaminergic central nervous system stimulant used to treat adult patients with Alzheimer disease and has been shown to improve cognition and mood in adult patients with central nervous system tumors. The Children’s Oncology Group is currently testing the ability of modafinil to improve attention, memory, and fatigue among survivors of pediatric brain tumors (NCT0138171). Donepezil is an acetylcholinesterase inhibitor used in the treatment of Alzheimer disease and vascular dementia. In adult patients with brain tumors, donepezil has been shown to improve attention, memory, and concentration.108 A small pilot study including 11 survivors of childhood brain tumors found improvements in memory and executive function at 24 and 36 weeks after treatment with donepezil109; a clinical study evaluating the effect of donepezil in a larger cohort is ongoing (NCT00452868).

Endocrinology Not surprisingly, survivors of childhood central nervous system tumors are at significant risk for late endocrine complications. Gurney et al110 reported a 43% prevalence of endocrine dysfunction in childhood brain tumor survivors; others111 estimate that endocrinopathies may occur in as many as 80% of survivors. The most common endocrine complications are growth hormone deficiency and hypothyroidism, but can include any of the hormones associated with the hypothalamic/pituitary axis as well as the endocrine organs throughout the body. In pediatric central nervous system tumor treatment, insults from the tumor itself, radiation, chemotherapy, as well as surgery may all adversely affect the developing and vulnerable endocrine neuraxis. The frequency, time to event, risk factors, and treatment of the most common tumor-associated endocrine dysfunctions are described below. Growth hormone. Growth hormone deficits are extremely common in survivors of childhood brain tumors, occurring in as many as 97% of survivors.112 Isolated growth hormone deficiency commonly appears after radiation doses to the hypothalamus of 50 Gy are associated with additional endocrinopathies or panhypopituitarism.113,114 Radiation therapy bestows the highest risk of growth hormone dysfunction. Increased radiation dose, fewer radiation fractions, and younger age at time of diagnosis are all associated with increased risk.114 Increased radiation dose is associated with faster time to development115; however, doses as low as 18 Gy have resulted in deficits.116,117 Treatment for growth hormone deficiency is growth hormone replacement. Growth hormone replacement is essential for improving growth to adequate levels, although it is usually not sufficient to entirely mitigate treatment effects.118 Prompt and timely diagnosis and treatment of any deficiency, however, is essential to optimize linear growth and bone health; however, because growth hormone is a mitogen, some studies have questioned if growth hormone replacement therapy is associated with a higher risk of tumor recurrence. The current consensus is that growth


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hormone replacement in survivors of childhood cancers does not lead to a higher risk of tumor recurrence. A study of 361 survivors of childhood cancer treated with growth hormone (including 172 survivors of brain tumors) found no increased risk of tumor recurrence compared to survivors who did not receive growth hormone therapy.119 Failure to diagnose and treat deficiency can lead to problems with skeletal growth, osteopenia, and metabolic disturbances. Thyroid function. Thyroid hormone dysfunction is common in pediatric central nervous system tumor survivors. Although the thyrotropin-releasing hormone– and thyroid-stimulating hormone–producing cells of the hypothalamus and pituitary are relatively insensitive to radiation, many patients receive craniospinal irradiation. Unfortunately, the thyroid gland, located anterior to the cervical spine, is in this field. The prevalence of primary hypothyroidism in brain tumor survivors has been reported to be 20% to 60% depending on the diagnosis criteria.120-123 Central hypothyroidism is relatively rare.123,124 Treatment with both chemotherapy and radiation increases the risk for hypothyroidism.121 Hypothyroidism is associated with poor growth, lack of energy, and impaired school performance and thus may contribute to both poor academic outcomes and continued reduced growth even in children treated with exogenous growth hormone. Survivors of childhood cancers are also at increased risk for subsequent primary thyroid carcinomas, most commonly papillary carcinomas.125 In particular, with 20 to 29 Gy radiation to the thyroid gland, risk of carcinoma increases in a dose-dependent manner; however, at 30 Gy and higher, the risk of thyroid cancer actually declines. This threshold likely represents the point at which thyroid cells experience irreparable damage.126 Gonads and reproductive system. Of significant concern to patients and parents are the effects of central nervous system tumor diagnosis and treatment on future fertility. Many survivors of childhood tumors will experience difficulties with reproductive health, including infertility or precocious or delayed puberty.127-129 Many of these cases are due to the effects of radiation on the hypothalamus; studies in the 1980s and 1990s estimated the cumulative incidence of gonadotropin deficiency following cranial radiation to be 20% to 50%.130,131 Gonadotropin deficiency is the second most common pituitary hormone deficiency in many series, after growth hormone deficiency.132 Risks are elevated with cranial radiation dose greater than 40 Gy.114 Patients who receive cranial radiation are also at increased risk for precocious puberty, thought to be due to the loss of cerebral disinhibition of the hypothalamus.132 These patients can be treated with GnRH antagonists to suppress endogenous gonadotropin production. Risk for direct gonadal damage is conferred both by radiotherapy and chemotherapy; however, the risks are different for males and females. In females, alkylating chemotherapeutic agents are strongly associated with increased risk of premature ovarian failure133-135 and are known to cause ovarian fibrosis and follicular destruction.136,137 In one study, 65% of females who received craniospinal irradiation alone had signs of

premature ovarian failure as assessed by elevated gonadotropin levels, suggesting that scatter from craniospinal irradiation is enough to cause gonadal damage.138 By contrast, in males, craniospinal radiation appears not to be a risk factor for direct gonadal damage, probably because of the anatomical location of the testes. Alkylating agents are associated with impaired spermatogenesis and increased risk of oligospermia or azospermia.139 In both males and females, increased dose of alkylating chemotherapeutic agents as well as the post-pubertal state contribute to increased risk of infertility. Other chemotherapeutic agents associated with infertility include vinblastine, cytarabine, cisplatin, and procarbazine among others.140 Sex hormone dysfunction may range from subclinical to severe impairment; the medical team should be aware of this range of outcomes and provide appropriate screening and counseling, possibly including referral for fertility preservation. Among survivors of pediatric cancers, misconceptions regarding the impact of cancer diagnosis on the health of future children are prevalent. More than 50% of males in one study indicated that they were concerned that any children they fathered would have a higher risk of health problems.141 With the exception of the rare patients with germline tumor mutations, most tumors arise as a result of sporadic somatic genetic mutations, and despite the toxicities of cancer treatment, children born to these survivors are not at higher risk for birth defects or cancer.142-145 Patients with germline cancer-predisposing mutations, such as neurofibromatosis types 1 and 2, tuberous sclerosis, and Gorlin syndrome, should be given appropriate genetic counseling as to their risk of passing these genes to their offspring. Importantly, the misconceptions surrounding this concept are not limited to patients. In one study, almost 50% of medical providers were unaware that patients with sporadic tumors had no greater risk of having children with special health concerns.146 These surveys point to the importance of patient and medical provider education surrounding this issue, so as to prevent any further psychological distress to survivors as well as to allow them to make fully informed decisions surrounding their reproductive choices. Options for fertility preservation prior to treatment currently include sperm and oocyte cryopreservation. Experimental methods for prepubescent children are emerging, and include ovarian or testicular cryopreservation and grafting.147 With the advent of these techniques, survivors’ reproductive options posttreatment may change. Hypothalamic-pituitary-adrenal axis. Adrenocorticotropic hormone (ACTH) dysfunction is rarely described in survivors of central nervous system tumors. However, a few studies have reported the prevalence of ACTH deficiency to be 20%.148,149 Moreover, some evidence suggests that dysfunction may begin as late as 15 years or more after treatment, and so studies with shorter follow-up may fail to capture this effect. One study of patients who received cranial radiation reported an incidence of 19% of ACTH dysfunction at 15 years.122 Symptoms of ACTH deficiency include anorexia, decreased energy, hypoglycemia, and decreased weight gain.


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Obesity and hypothalamic obesity. Survivors of childhood brain tumors may be at increased risk of obesity as well as hyperinsulinemia and dysplidemia compared to their peers.150-152 Causes of this obesity are multifactorial and include growth hormone deficiency and hypothalamic obesity. Cranial radiation, increased dose of radiation, and younger age at diagnosis are associated with increased risk for obesity.150,152,153 Endocrinopathies, including untreated growth hormone deficiency, have also been found to be associated with increased weight gain.151,154 Additionally, tumor- or radiation-induced damage to the hypothalamus may play a role in inducing hypothalamic obesity. The ventromedial hypothalamus is responsible for integrating endocrine signals including the hunger-regulators leptin, ghrelin, and insulin. Damage to this structure can cause dysregulated satiety and hunger signaling, and lead to hypothalamic obesity.155 Unfortunately, hypothalamic obesity is challenging to treat, but treatment with octreotide has shown success in a placebo-controlled trial.156 The common use of high-dose glucocorticoids in brain tumor treatments may also promote obesity by affecting appetite and regulation of energy intake and expenditure.157 Finally, sensory and motor neurologic complications are prevalent in brain tumor survivors.158 These complications often serve as barriers to engaging in physical activity, further contributing to increased risk of obesity.159,160 The high rate of obesity in survivors points to the necessity for regular screening for and counseling regarding common concomitant comorbidities of obesity such as hyperinsulinemia and dyslipidemia, and corresponding risk for cardiovascular and atherosclerotic disease.

Neurologic/Sensory Late Effects Although the majority of brain tumor patients present with acute neurologic defects that will resolve following treatment, some patients experience persistent deficits. Moreover, tumor treatments cause a variety of late effects, including neurosensory hearing loss, ataxia/motor disturbances, and peripheral neuropathies. Sensory and neurologic deficits are common during tumor presentation but some persist following treatment. A large study of 1607 pediatric brain tumor survivors reported that 4.6% had late persistent motor problems.158 Treatments play a large role in contributing to neurologic and sensory deficits. The most common side effects associated with surgical resection and standard chemotherapeutic agents are described below. Ototoxicity. Ototoxicity is most commonly a result of treatment with the platinum analogs, especially cisplatin. Despite the strong association between cisplatin and sensorineural hearing loss, cisplatin is still a mainstay of treatment for many tumors, including medulloblastoma. Cisplatin causes direct cochlear damage, possibly due to reactive oxygen species–induced cellular destruction.161 The incidence of cochlear damage following cisplatin treatment in children is 35% to 60%, and risk is dependent on age and cumulative dose.162-164 Age younger than 5 is associated with increased severity and likelihood of

hearing loss.162 Risk for ototoxicity is compounded with cranial radiation therapy treatment; with doses above 32 Gy, the risk of ototoxicity increases in a dose-dependent manner.165 Peripheral neuropathy. Peripheral neuropathy is a common side effect of platinum analogs and vinca alkaloids (such as vincristine).166,167 Often neuropathic symptoms resolve following treatment, but in some they persist for years after therapy.168 Vincristine causes a sensorimotor neuropathy, characterized by loss of deep tendon reflexes and paresthesias, most commonly affecting distal extremities leading to foot drop, muscle weakness, and cramps.169,170 Proximal neuropathies including oculomotor paresis and vocal cord dysfunction have also been described.171,172 Autonomic neuropathies can result in abdominal pain and constipation. In its most severe manifestation, autonomic neuropathy of the enteric system can result in paralytic ileus and obstipation. Other autonomic neuropathies such as urinary voiding dysfunction and postural hypotension have also been reported.173 Cisplatin causes a purely sensory neuropathy and is neurotoxic after a cumulative dose of 250 to 350 mg/m2.174

Cerebrovascular and Cardiovascular Late Effects The effects of central nervous system tumor treatments on the vascular system are substantial. Cardiovascular disease is the third leading cause of death in pediatric central nervous system cancer survivors, following cancer recurrence and secondary malignancies.10,175,176 These late effects are the direct result of damage to both central nervous system vasculature and the heart itself. Pediatric central nervous system tumor survivors are at significantly increased risk for cerebrovascular disease, including stroke and large and small vessel disease. They are also at increased risk for cardiovascular disease, including myocardial infarct, congestive heart disease, arrhythmias, and valvular heart disease. Vasculopathies in pediatric central nervous system tumor survivors. Vasculopathies are more and more recognized in survivors of pediatric brain tumors. Moyamoya, which is a specific form of vasculopathy of mainly the large vessels, has been shown to be more prevalent in children with brain tumors who undergo cranial radiation therapy.177 Risk factors for development of radiation-induced moyamoya include history of neurofibromatosis type I, radiation therapy to the parasellar region and circle of Willis (associated with midline, parasellar, or optic pathway tumors), and younger age (5 years after cancer diagnosis) stratified by maximum cranial radiation therapy in childhood brain tumor survivors followed by the Childhood Cancer Survivor Study. Source: Adapted from Mueller et al.

presenting symptom. We recently reported the results of a retrospective cohort study of 365 adult survivors of brain tumors, finding a cumulative incidence of cavernous malformations of 3% at 10 years post cranial radiation therapy and 14% at 15 years. The median time to detection of cavernous malformations was 12 years post cranial radiation therapy.185 Increasingly sensitive neuroimaging techniques have recently revealed that cerebral microhemorrhages, traditionally associated with Alzheimer disease and neurocognitive decline, are present in some pediatric brain tumor survivors.186,187 These first appear 2 years after the conclusion of cerebral radiation therapy in adult brain tumor survivors.188 Multiple studies have linked cerebral microhemorrhages to decreased cognitive function in elderly patients.186,189,190 Thus, although much is still unknown about the clinical significance of these cerebral microhemorrhages in survivors of pediatric brain tumors, they may represent a mechanism for the proposed vascular damage–mediated neurocognitive decline seen in brain tumor survivors who underwent cranial radiation. Furthermore, a recent study found that cerebral microhemorrhages were present in survivors of childhood lymphoma who did not undergo cranial radiation therapy. Brain magnetic resonance images (MRIs) of these patients revealed hemosiderin deposits, which correlated with decreased performance on multiple neurocognitive measures. Cardiac dystolic function was impaired in many survivors.191 These results suggest that cerebrovascular disease from cardiovascular damage due to non–cranial radiation treatment modalities may further contribute to survivors’ risk of neurocognitive decline. Future studies should investigate the relationship between microbleed distribution and number, and emergence of specific neurocognitive deficits in pediatric brain tumor survivors. Stroke in pediatric central nervous system tumor survivors. Stroke is increasingly recognized as an important late effect in pediatric brain tumor survivors. In the Childhood Cancer Survivor Study cohort (a multi-institutional cohort of more than 14 000

survivors of pediatric cancer who survived at least 5 years who were treated from 1970 to 1985), we reported a stroke incidence rate of 292 (95% CI 207.9-408.9) per 100 000 person-years among brain tumor survivors compared to 9.3 (95% CI 3.7-23.1) in the sibling control group.192 This represents a 30-fold increase in the relative risk of stroke in brain tumor survivors compared to the sibling control group. The most important risk factor for stroke is treatment with cranial radiation, which increases the risk of stroke in a dose-dependent manner193 (see Figure 2). Within the Childhood Cancer Survivor Study cohort, stroke outcome is self-reported and remains a limitation of this study. However, in a similar analysis, we found an overall rate of first stroke of 625 per 100 000 person years and strokes were confirmed by imaging analysis similar to results reported by the Children’s Hospital of Philadelphia.193,194 The underlying pathology is thought to be a radiation-induced vasculopathy. A large cohort study of children with stroke showed that those with an underlying vasculopathy carry an extremely high risk of stroke recurrence: 66% at 5 years.195 In pediatric brain tumor survivors, the risk of recurrent stroke is understudied but early evidence suggests that brain tumor survivors are also at high risk of recurrent stroke: 38% at 5 years and 59% at 10 years after first stroke.194 We reported that atherosclerotic risk factors such as hypertension increase stroke risk in pediatric brain tumor survivors by almost 3-fold. These findings were surprising as several studies have shown that atherosclerotic risk factors generally do not contribute to the stroke risk in young adults.192,196,197 However, radiation is thought to contribute to arterial injury by accelerating atherosclerosis, the most common etiology of stroke in adults. Radiation therapy in hypercholesterolemic mice and rabbits leads to accelerated atherosclerotic plaque formation.198,199 Recent investigations on coronary endothelial cells have shown that radiation therapy causes changes that are indistinguishable from natural age-related pro-atherosclerotic effects. Further, cervical radiation therapy is well known to cause accelerated atherosclerosis in head and neck cancer


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patients.200 It is therefore possible that radiation leads to premature aging, promoting early atherosclerosis and increased stroke risk.201 Although the direct effects of chemotherapy on stroke risk are unknown, patients who receive adjuvant treatment after cranial radiation therapy with alkylating agents might have a higher stroke risk.202 Stroke is an event with devastating further consequences; medical providers should be aware of this risk and counsel their patients to avoid or control risk factors that may lead to stroke, such as dyslipidemia, obesity, and diabetes. Many patients receive routine surveillance MRI to monitor for tumor recurrence; this regular follow-up presents a tremendous opportunity to screen for evidence of vasculopathies. We are currently conducting a prospective study with dedicated vascular imaging to determine vasculopathy rates and stroke risk in brain tumor patients who received radiation therapy. Cardiac dysfunction in pediatric central nervous system tumor survivors. The vascular risks conferred by central nervous system tumor treatments are not limited to the cranium. Patients who receive craniospinal radiation may receive scattered radiation to the mediastinum and heart, placing them at higher risk for late effects due to cardiac toxicity. Radiation-induced cardiac injury is known to induce increased risk of congestive heart failure, cardiomyopathy, myocardial infarction, arrhythmia, atherosclerotic heart disease, valvular disease, pericarditis, and pericardial fibrosis.203 Endocrinopathies can also contribute to increased cardiac disease. Specifically, growth hormone deficiency, which is common in pediatric brain tumor survivors, may contribute to increased risk of cardiovascular disease by causing metabolic dysfunction leading to excess body fat, reduced muscle mass, decreased bone density, and insulin resistance and dyslipidemia.204,205 Gurney et al110 reported that brain tumor survivors had twice the rate of angina-like symptoms as compared to sibling controls. A large study including 1876 pediatric brain tumor survivors found that these patients were 5.0 times more likely to experience myocardial infarct than siblings.203 Although studies of pediatric cancer survivors have found increased rates of cardiac disease in these patients, most analyses have reported on risk of toxicity stemming from anthracycline treatment or mediastinal radiation. These modalities are rare in pediatric central nervous system tumor treatments, though common in lymphoma treatment.206-210 However, Tukenova et al211 recently reported an increased risk of cardiovascular disease in all survivors who received more than 5 Gy to the heart, suggesting that brain tumor patients who received craniospinal irradiation are not spared. Additionally, Lipshultz et al212 found that even survivors of pediatric cancers who did not receive chest irradiation or anthracyclines are at increased risk for cardiovascular disease, including myocardial infarction, stroke, or coronary death compared to sibling controls. These results are consistent with reports that metabolic syndrome and obesity are prevalent among pediatric cancer survivors.151,152 Even long-term (>5 years) survivors who are still children have increased rates of insulin resistance and higher

low-density lipoprotein, triglyceride, and total cholesterol levels than sibling controls.213 Ultimately, these data overwhelmingly point to the importance not only of long-term screening for and awareness of cardiovascular disease among survivors and their medical providers but also of encouraging avoidance of behaviors that are known to increase cardiovascular disease risk, such as smoking and alcohol consumption.

Secondary Malignancies A rare but devastating late effect of tumor treatment is the development of a secondary malignancy. Secondary malignancies represent the second most common cause of death among adult survivors of pediatric central nervous system cancers, following death due to the primary cancer.176 In patients who are 10 or more years beyond treatment, they are the leading cause of death.214 Secondary malignancies are tumors unrelated to the initial primary malignancy and are estimated to comprise 6% to 10% of cancer diagnoses in the United States.215 A recent analysis of the Childhood Cancer Survivor Study cohort reported an incidence of secondary malignant neoplasms of 7.9% at 30 years in all pediatric cancer survivors.216 Specifically among survivors of childhood central nervous system tumors, the incidence of either a benign or malignant secondary neoplasm is 10.7% at 25 years.9 The most important risk factors for the development of a secondary malignancy are treatment with chemotherapy or radiation. Chemotherapy most commonly induces leukemia and rarely causes solid tumors, whereas radiation is associated with solid malignancies. These 2 types of secondary malignancies fall into a bimodal distribution: risk of chemotherapy-induced leukemia occurs at a median of 5 years after primary tumor diagnosis, whereas radiation-induced solid malignancies tend to occur more than 10 years after initial diagnosis. The most common secondary solid malignancies in survivors of childhood brain tumors are central nervous system tumors (with gliomas and meningiomas the most prevalent among these), sarcomas, and thyroid cancer.217 In the Childhood Cancer Survivor Study cohort among patients who received radiation, 7.1% subsequently developed a secondary central nervous system malignancy, compared to 1.0% in patients who did not.218 Of note, whereas gliomas develop at a median of 9 years following treatment, meningiomas occur later, at a median of 17 years following treatment.219 Importantly, the incidence of secondary neoplasms does not plateau with time. Leukemia is a late effect of treatment with topoisomerase inhibitors such as etoposide and alkylating agents such as cyclophosphamide.220-222 Topoisomerase inhibitors cause leukemias that appear a few months to 5 years following therapy, whereas alkylating agents are associated with leukemias within 2 to 10 years following therapy cessation.220 The incidence of secondary leukemias is 3% to 7% following treatment with high-risk chemotherapy agents, most commonly acute myeloid leukemia.223,224 Alkylator-associated acute myeloid leukemia is often associated with a prodromal myelodysplastic phase and abnormalities in chromosomes 5 and 7.222


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Despite the relatively lower incidence compared to other late effects, secondary malignancies are a significant cause of death in the survivor population. It is imperative that the medical team ensures patients are aware of their increased risk and encourage risk-reducing behaviors and prevention strategies. The role of rigorously screening patients for secondary central nervous system malignancies is still a matter of debate, however. Earlier detection of high-grade gliomas does not influence the poor prognosis and survival rates for these tumors, whereas later detection of meningiomas (which typically have good outcomes) similarly may not adversely affect survival.225

Psychological, Educational, and Social Outcomes Deficits in neuropsychological, social, and behavioral functioning and outcomes are common in adult survivors of childhood cancers. Moreover, studies have consistently reported that among this high-risk cohort, central nervous system tumor survivors have the highest rates of chronic health conditions.4,226 Among central nervous system tumor survivors, the rate of at least 1 chronic health condition at only 5 years after diagnosis is 82%.218 Given the higher rates of endocrine, neurocognitive, neurologic, and other organ system dysfunction in brain tumor survivors, it is hardly surprising that within this group of survivors, brain tumor survivors record the worst health-related and psychological life outcomes. Many studies have reported that survivors of pediatric cancers report few problems of psychological distress.227,228 In fact, despite the high prevalence of chronic health conditions in this group, fewer than 10% rate their overall health as ‘‘poor.’’4 Surviving cancer may lead to a more positive attitude irrespective of health status.16,42,229,230 Brain tumor survivors, however, are a unique exception. These patients report higher rates of depression, global and somatic distress than siblings, and score lower than population norms in measures of healthrelated quality of life.226,231 They also report more problems than their siblings in the domains of physical function, mental function, and general health.218 Interestingly, treatment- or tumor type–related variables are not associated with increased distress.218 Rather, the risk factors for increased psychological distress in the general population are the same in brain tumor survivors, including female sex, poor physical health, and lower socioeconomic status as measured by income, educational attainment, and employment status.228 Indeed, survivors of pediatric central nervous system tumors are less likely to be employed, have an income greater than $20 000, to be married, and graduate college as compared to sibling controls.11,218,232 Brain tumor survivors are also more likely to suffer from lack of close friends and less likely to use friends as confidants.233 They report fewer friends overall, and spend less of their free time with friends.234 In general, they achieve psychosocial development milestones at later ages than expected,234 and are less likely to ever have been married compared to age-matched controls in US Census data.235 Again, increased risk is conferred by cranial radiation therapy treatment.236

Zeltzer et al227,231 found that brain tumor survivors stood out among all survivors of pediatric cancer for being the only population to report lower expected future life satisfaction as well as decreased present life satisfaction. Within the survivor population, those with long-term physical late effects, learning problems, and other life stressors also report lower selfesteem, adjustment scores, and quality of life.237 Importantly, psychological distress is a risk factor for risky health behaviors such as smoking and alcohol use, and in fact, psychological distress is positively associated with engagement in these behaviors.227 Although overall, cancer survivors appear to engage in risky health behaviors at or slightly below rates in the population,238 medical providers should screen patients for psychological distress and provide appropriate counseling regarding health-related behaviors because these behaviors put them at additional risk for cardiovascular disease and other adverse health outcomes. Employment is more difficult for survivors of childhood cancers. In a study of Childhood Cancer Survivor Study survivors (median age 26) and siblings (median age 29), 5.6% of survivors reported a lack of employment history, compared to 1.2% of siblings. Moreover, the risk of current unemployment was highest among brain tumor survivors.239 In another report, de Boer found that pediatric cancer survivors were twice as likely as controls to be unemployed, with the highest risk again in brain tumor survivors, who were 5 times as likely to be unemployed.240 Other risk factors for unemployment include high cranial radiation dose, young age at diagnosis, female sex, and chronic medical conditions.218 Unsurprisingly, survivors also report lower income levels compared to sibling controls.98,232 Although childhood cancer survivors are less likely than their siblings to attend college, brain tumor survivors are especially so—11% less likely than sibling controls.241 In a report by Ness et al242 of brain tumor survivors, physical limitations were specifically associated with the inability to live independently as well as failure to attend college. These data indicate the importance for the medical team to maintain awareness of survivors’ increased risk for a wide variety of social and psychological challenges, many of which affect the ability to live independently. These results also highlight important areas for intervention to maximize longterm adjustment. For instance, the relationship between physical health and psychological health points to the need for minimizing the treatment-related toxicities and ill effects described in this paper. Further, many of the disparities seen in social outcomes between brain tumor and other cancer survivors appear to be driven by the increased rates of neurocognitive deficit seen in brain tumor survivors. Thus, there is a huge need to both prevent/minimize and ameliorate such neurocognitive decline, if possible. Potential areas of intervention include targeted interventions to receive specialized cognitive, educational, as well as vocational services. There has been some research into cognitive remediation programs, with promising initial results. The applicability of the gains seen by participants to academic performance, however, is still unknown. Finally, the relationship between lower educational


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achievement and income, and psychosocial problems drives home the crucial need for services that maximize cognitive functioning and educational achievement.

Sibling Health Of utmost importance to many families are the effects of a child’s cancer diagnosis on siblings. Past research on this topic has been limited mostly to descriptive studies, which indicate increased rates of anxiety, distress, academic problems, and isolation in this population.243 And although it might be expected that survivors will inevitably miss significant amounts of school, this absenteeism extends to their siblings as well; in one study, there was no difference in rates of absenteeism between siblings and survivors.244 Recently, increasing attention has been directed toward measures of siblings’ psychological functioning as well as their healthrelated behaviors. In particular, one study found that more than half of children with a sibling diagnosed with cancer within 38 months scored either ‘‘moderate’’ or ‘‘severe’’ in measures of posttraumatic stress, and a full 22% had symptoms consistent with PTSD.245 Furthermore, multiple studies have found that siblings are at increased risk for heavy and risky alcohol consumption compared to age-matched peers.246,247 Risk factors for increased drinking among siblings are similar to those in the general population and include depressive symptoms, global psychiatric distress, anxiety, and lower educational attainment.247 These results suggest failure of medical providers to meet the health needs of siblings of pediatric cancer survivors. Future interventions and increased attention to this population is warranted. Additionally, the family and home environment play crucial roles in shaping the outcomes of both survivors and siblings. Ach et al248 showed that survivors in families with higher levels of support and functioning had improved academic outcomes.

Future Directions/Clinical Implications Although outcomes for children with brain tumors have significantly improved for some tumor types, it is clear that for patients, the news that they are ‘‘cured’’ is concomitant with the knowledge that the same therapies that saved their lives have put them at substantial risk for functional deficits in multiple domains of life. Medical providers and researchers continue to seek new interventions to decrease the risk and rates of these deficits by employing novel risk-reducing therapies in timing and dose of radiation and chemotherapy. The creation of behavioral and therapeutic interventions to minimize the incidence of these outcomes is of equal importance. It is imperative that the medical team translates new evidence into clinical practice to ensure the best outcomes possible. Unfortunately, a recent study revealed that only 33% of pediatric oncologists correctly answered questions about the surveillance recommendations for cardiomyopathy, breast cancer, and thyroid function.249 Among family medicine practitioners, the rate of correct response was only 2%, and the

majority indicated their preference to care for survivors in conjunction with a cancer treatment center or late effects program.250 Similarly, in one report of more than 8500 long-term survivors of pediatric cancer, only 18% reported receiving risk-based and survivor-focused medical care (screening for late effects or counseling on risk reduction) during the past 2 years; moreover, the frequency of medical visits related to previous cancer as well as visits to a cancer center decreased with time from treatment.251 However, with time from treatment, risk for late effects increases. These results are emblematic of the need for the medical system as an entity to improve the delivery of continuous care, and perhaps indicate a role for developing better standards around transition of care as patients move from pediatric to adult clinics. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number KL2TR000143 (SM).

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Cytogenetic analysis of 39 pediatric central nervous system tumors.

Late effects in survivors of central nervous system tumors: reports by patients and proxies.

Early and late endocrine effects in pediatric central nervous system diseases.

Late effects following central nervous system radiation in a pediatric population.

Late side effects of treatment: skeletal, genetic, central nervous system, and oncogenic.

Rare primary central nervous system tumors.

Added value of diffusion weighted imaging in pediatric central nervous system embryonal tumors surveillance.

Multidrug resistance gene expression in pediatric primitive neuroectodermal tumors of the central nervous system.

Is the polio virus responsible for late central nervous system tumors?

Central nervous system side effects of ganciclovir.

Intraoperative consultation on pediatric central nervous system tumors by squash cytology.

Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors.

International incidence of central nervous system tumors in children.

Mesenchymal, non-meningothelial tumors of the central nervous system.

Early development of endocrine and metabolic consequences after treatment of central nervous system tumors in children.

Impact of treatment site in adolescents and young adults with central nervous system tumors.

Environmental effects on the central nervous system.

Corticosteroid-related central nervous system side effects.

Radiotherapy, hyperthermia, and phototherapy for central nervous system tumors.

Central nervous system germ cell tumors: an update.

Germ cell tumors masquerading as central nervous system sarcoidosis.

Rare Primary Central Nervous System Tumors Encountered in Pediatrics.

Central nervous system tumors: Radiologic pathologic correlation and diagnostic approach.

Pediatric central nervous system solitary fibrous tumor: case report.