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Primary brain tumors, including astrocytomas, are a diverse group of diseases that together constitute the most common solid tumors of childhood. Brain tumors are classified according to histology and molecular features, but tumor location and extent of spread are also important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are used in tumor diagnosis and classification.
Gliomas are thought to arise from glial precursor cells that are present in the brain and spinal cord. Gliomas are named according to their presumed clinicopathologic and histologic subtype. Astrocytoma is the most commonly diagnosed type of glioma in children.
According to the World Health Organization (WHO) classification of brain tumors, gliomas are classified further as low-grade (grades I and II) or high-grade (grades III and IV) tumors. Children with low-grade tumors have a relatively favorable prognosis, especially when the tumors can be completely resected. Children with high-grade tumors generally have a less favorable prognosis, but this is somewhat dependent on subtype.
The PDQ childhood brain tumor treatment summaries are organized primarily according to the WHO classification of nervous system tumors.[1,2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
Childhood astrocytomas can occur anywhere in the central nervous system (CNS) (refer to the Figure). Refer to Table 3 for the most common CNS location for each tumor type. Anatomy of the inside of the brain, showing the cerebrum, cerebellum, brain stem, spinal cord, optic nerve, hypothalamus, and other parts of the brain.
Presenting symptoms for childhood astrocytomas depend on the following:
In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.
The diagnostic evaluation for astrocytoma includes magnetic resonance imaging (MRI) of the brain or spine. For brain primary tumors, spinal MRI is usually performed in conjunction with the initial brain MRI to exclude neuraxis metastases.
Lumbar punctures examining the cerebrospinal fluid for circulating tumor cells are not commonly performed in children with this disease.
Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
The pathologic classification of pediatric brain tumors is a specialized area that is evolving. Examination of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.
Tumor types are based on the putative glial cell type of origin, as follows:
WHO histologic grade for astrocytic tumors
According to the WHO histologic typing of CNS tumors, childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are graded (grade I to IV).
WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (refer to Table 1).
The 2016 WHO criteria began to utilize molecular data in the diagnosis of some tumors because of the accumulation of published evidence supporting that tumor behavior is typically driven by common biological alterations (refer to Table 2). Within glial CNS tumors, this was most evident in changes in the classification of the diffuse gliomas, which were grouped together based on genetic driver mutations rather than histopathological similarities. Two types of diffuse gliomas are no longer considered distinct entities: fibrillary astrocytoma and protoplasmic astrocytoma. Epithelioid glioblastoma is a new, provisionally included variant that is categorized as one subtype of IDH–wild-type glioblastoma.
Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have common CNS locations (refer to Table 3).
More than 80% of astrocytomas located in the cerebellum are low grade (pilocytic grade I) and often cystic; most of the remainder are diffuse grade II astrocytomas. Malignant astrocytomas in the cerebellum are rare.[1,2] The presence of certain histologic features (e.g., MIB-1 rate, anaplasia) has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location.[6,7,8]
Astrocytomas arising in the brain stem may be either high grade or low grade, with the frequency of either type being highly dependent on the location of the tumor within the brain stem.[9,10] Tumors not involving the pons are overwhelmingly low-grade gliomas (e.g., tectal gliomas of the midbrain), whereas tumors located exclusively in the pons without exophytic components are largely diffuse midline gliomas (e.g., diffuse intrinsic pontine gliomas with the H3 K27M-mutant genotype).[9,10] (Refer to the PDQ summary on Childhood Brain Stem Glioma Treatment for more information.)
High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium in the cerebrum. Spread via the subarachnoid space may occur. Metastasis outside of the CNS has been reported but is extremely infrequent until multiple local relapses have occurred.
Gliomatosis cerebri is no longer considered a distinct entity, but rather to be a growth pattern found in some diffuse astrocytic tumors and, occasionally, oligodendroglial tumors. The growth pattern encompasses widespread involvement of the cerebral hemispheres, often extending caudally to affect the brain stem, cerebellum, and/or spinal cord. This pattern rarely arises in the cerebellum and spreads rostrally. Patients with gliomatosis cerebri may respond to treatment initially, but overall have a poor prognosis.
Neurofibromatosis type 1 (NF1)
Children with NF1 have an increased propensity to develop WHO grade I and grade II astrocytomas in the visual (optic) pathway; as many as 20% of all patients with NF1 will develop an optic pathway glioma. In these patients, the tumor may be found on screening evaluations when the child is asymptomatic or has apparent static neurologic and/or visual deficits.
Pathologic confirmation is frequently not obtained in asymptomatic patients; when biopsies have been performed, these tumors have been found to be predominantly pilocytic (grade I) rather than diffuse astrocytic tumors.[2,5,14]
In general, treatment is not required for incidental tumors found with surveillance neuroimaging. Symptomatic lesions, often causing vision impairment, or those that have radiographically progressed may require treatment.
Patients with tuberous sclerosis have a predilection for low-grade glioma development, especially subependymal giant cell astrocytomas. Mutations in either TSC1 or TSC2 cause pathway alterations that impact the mammalian target of rapamycin (mTOR) pathway, leading to increases in proliferation. Subependymal giant cell astrocytomas have been sensitive to targeted approaches via inhibition of the mTOR pathway.
Molecular features of low-grade gliomas
Genomic alterations involving activation of BRAF and the ERK/MAPK pathway are very common in sporadic cases of pilocytic astrocytoma, a type of low-grade glioma.
BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF-KIAA1549 gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[17,18,19,20,21] This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[17,18,22,23,24,25,26,27] Other genomic alterations in pilocytic astrocytomas that can activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[18,20,21,28]
Presence of the BRAF-KIAA1549 fusion predicted a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) in one report that described children with incompletely resected low-grade gliomas. However, other factors such as CDKN2A deletion, whole chromosome 7 gain, and tumor location may modify the impact of the BRAF mutation on outcome.; [Level of evidence: 3iiiDiii] Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.
BRAF activation through the BRAF-KIAA1549 fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[25,26]
BRAF V600E point mutations are occasionally observed in pilocytic astrocytoma; the mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytomas.[33,34,35] Studies have observed the following:
As with neurofibromatosis type 1 (NF1) deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.
Activating mutations in FGFR1, PTPN11, and in NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas. In pediatric grade II diffuse astrocytomas, the most common alterations reported (up to 53% of tumors) are rearrangements in the MYB family of transcription factors.[39,40]
Most children with tuberous sclerosis have a germline mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in activation of the mammalian target of rapamycin (mTOR) complex 1. These children are at risk of developing subependymal giant cell astrocytomas, cortical tubers, and subependymal nodules. Because subependymal giant cell astrocytomas are driven by mTOR activation, mTOR inhibitors are active agents that can induce tumor regression in children with these tumors.
Angiocentric gliomas: Angiocentric gliomas typically arise in children and young adults as cerebral tumors presenting with seizures. Two reports in 2016 identified MYB gene alterations as being present in almost all cases diagnosed as angiocentric glioma, with QKI being the primary fusion partner in cases where fusion-partner testing was possible.[42,43] While angiocentric gliomas most commonly occur supratentorially, brain stem angiocentric gliomas with MYB-QKI fusions have also been reported.[44,45]
Astroblastomas: Astroblastomas are defined histologically as glial neoplasms composed of GFAP-positive cells and contain astroblastic pseudorosettes that often demonstrate sclerosis. Astroblastomas are diagnosed primarily in childhood through young adulthood. Multiple reports have described genomic alterations associated with astroblastoma.
These reports suggest that the histologic diagnosis of astroblastoma encompasses a heterogeneous group of genomically defined entities; astroblastomas with MN1 fusions represent a distinctive subset of histologically diagnosed cases.
Molecular features of high-grade gliomas
Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[51,52,53,54]
Pediatric high-grade gliomas can be separated into distinct subgroups on the basis of epigenetic patterns (DNA methylation), and these subgroups show distinguishing chromosome copy number gains/losses and gene mutations in the tumor.[55,56,57] Particularly distinctive subtypes of pediatric high-grade gliomas are those with recurring mutations at specific amino acids in histone genes, and together these account for approximately one-half of pediatric high-grade gliomas. The following pediatric high-grade glioma subgroups were identified on the basis of their DNA methylation patterns, and they show distinctive molecular and clinical characteristics:
Pediatric glioblastoma multiforme high-grade glioma patients whose tumors lack both histone mutations and IDH1 mutations represent approximately 40% of pediatric glioblastoma multiforme cases.[57,61] This is a heterogeneous group, with higher rates of gene amplifications than other pediatric high-grade glioma subtypes. The most commonly amplified genes are PDGFRA, EGFR, CCND/CDK, and MYC/MYCN;[55,56] MGMT promoter methylation rates are low in this group. One report divided this group into three subtypes. The subtype characterized by high rates of MYCN amplification showed the poorest prognosis, while the subtype characterized by TERT promoter mutations and EGFR amplification showed the most favorable prognosis. The third group was characterized by PDGFRA amplification.
Infants and young children with a glioblastoma multiforme diagnosis appear to have tumors with distinctive molecular characteristics when compared with tumors of older children and adults. The application of DNA methylation analysis to pediatric glioblastoma multiforme tumors identified a group of patients (representing approximately 7% of pediatric patients with a histologic diagnosis of glioblastoma multiforme) whose tumors had molecular characteristics consistent with low-grade gliomas. The median age for this group of patients was 1 year, with eight of ten infants showing a low-grade glioma–like profile. The low-grade glioma–like subtype had a favorable prognosis (3-year OS rate, approximately 90%).[56,57]BRAF V600E mutations were observed in 4 of 13 low-grade glioma–like tumors and in 3 of 15 tumors from patients aged 3 years and younger.
A second report investigated gene copy number gains and losses and mutation status of selected genes for glioblastoma multiforme tumors from children younger than 36 months. Molecular alterations observed at appreciable rates in older children (e.g., K27M, CDKN2A loss, PDGFRA amplification, and TERT promoter mutations) were rare in the tumors of these young children, and novel abnormalities (e.g., loss of SNORD on chromosome 14q32) were observed in some cases.
The distinctive molecular characteristics of gliomas arising in infants (aged <12 months) were further defined in a study of 118 infants who had tumor tissue available for genomic characterization. Approximately 75% of the cases were classified as low grade, but the diminished utility of histologic classification in this age group was illustrated by the relatively low OS rate for the low-grade cohort (71%) and the relatively favorable survival for the high-grade cohort (55%). Genomic characterization divided the infant glioma population into the following three groups:
Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 of 14 cases (57%).
High-grade gliomas can arise in children with neurofibromatosis type 1 (NF1), although low-grade gliomas are much more common. When a high-grade tumor occurs, it is most often in adulthood. Genomic characterization of 23 patients with NF1-associated high-grade gliomas (median age, 38.8 years) showed higher rates of mutations compared with NF1 patients who had low-grade gliomas (21.5 vs. 6 mutations, respectively). The vast majority of patients showed NF1 germline mutations with either loss of heterozygosity or with an inactivating mutation in the second NF1 allele. In contrast to NF1-associated low-grade gliomas, genomic alterations associated with high-grade gliomas were common (CDKN2A [58%], ATRX [38%], and TP53 [29%]).
Neuronal and mixed neuronal-glial tumors
Molecular features of neuronal and mixed neuronal-glial tumors
Neuronal and mixed neuronal-glial tumors are generally low-grade tumors, with an exception of the grade III anaplastic gangliogliomas. The histologies recognized by the 2016 World Health Organization (WHO) classification include the following:
Ganglioglioma: Ganglioglioma presents during childhood and into adulthood. It most commonly arises in the cerebral cortex, in association with seizures, but also presents in other sites, including the spinal cord.[65,66] The unifying theme for the molecular pathogenesis of ganglioglioma is genomic alterations leading to MAPK pathway activation.[43,67]BRAF alterations are observed in approximately 50% of ganglioglioma cases, with V600E being by far the most common alteration; however, other BRAF mutations and gene fusions are also observed. Other less commonly altered genes in ganglioglioma include KRAS, FGFR1/2, RAF1, NTRK2, and NF1.[43,67]
Dysembryoplastic neuroepithelial tumor (DNET): DNET presents in children and adults, with the median age at diagnosis in mid-to-late adolescence. It is characterized histopathologically by the presence of columns of oligodendroglial-like cells and cortical ganglion cells floating in mucin. The temporal lobe is the most common location, and it is associated with drug-refractory epilepsy.[66,68]FGFR1 alterations have been reported in 60% to 80% of DNETs, and include FGFR1 activating point mutations, internal tandem duplication of the kinase domain, and activating gene fusions.[43,69,70]BRAF mutations are uncommon in DNET.
DNET of the septum pellucidum: Septal DNET generally presents with symptoms related to obstructive hydrocephalus.[71,72] Septal DNET has an indolent clinical behavior, with most tumors not requiring treatment other than surgery. In a single-institution series that incorporated other literature-reported cases, the median age at presentation was in the adolescent age range.
Mutations that are common in low-grade gliomas (e.g., BRAF V600E) and in cortical DNETs (FGFR1 mutations) are uncommon in septal DNET.[72,73,74] Instead, mutations in PDGFRA at the K385 residue typify most cases of septal DNET. A report of the molecular characterization of 18 septal DNETs showed that 14 had a PDGFRA mutation, with all but one being a mutation at the K385 residue, which is in the extracellular region of PDGFRA that mediates the receptor-receptor interaction required for dimerization and activation upon binding of PDGFs. Among the remaining four cases, three had FGFR1 mutations in line with those observed in cortical DNET. A second report observed PDGFRA mutations at K385 in each of four cases of septal DNET; combined, the two reports indicate that septal DNET is a distinct entity characterized by a stereotypic anatomic location and, in most cases, a PDGFRA mutation. Low-grade glioneuronal tumors with the K385 PDGFRA mutation have also been identified as arising in the corpus callosum and periventricular white matter of the lateral ventricle, leading to the proposal that myxoid glioneuronal tumor, PDGFRA p.K385-mutant be considered as a distinct central nervous system (CNS) tumor entity.
Desmoplastic infantile astrocytomas (DIA) and desmoplastic infantile gangliogliomas (DIG): DIA and DIG most often present in the first year of life and show a characteristic imaging appearance in which a contrast-enhancing solid nodule accompanies a large cystic component.[76,77] DIG is more common than DIA, and by methylation array analysis, both diagnoses cluster together. Survival outcome is generally favorable with surgical resection.
The most commonly observed genomic alterations in DIA and DIG are BRAF mutations involving V600; gene fusions involving kinase genes are observed less frequently.
Rosette-forming glioneuronal tumor (RGNT): RGNT presents in adolescents and adults, with tumors generally located infratentorially, although tumors can arise in mesencephalic or diencephalic regions. The typical histological appearance shows both a glial component and a neurocytic component arranged in rosettes or perivascular pseudorosettes. Outcome for patients with RGNT is generally favorable, consistent with the WHO grade I designation. DNA methylation profiling shows that RGNT has a distinct epigenetic profile that distinguishes it from other low-grade glial/glioneuronal tumor entities. A study of 30 cases of RGNT observed FGFR1 hotspot mutations in all analyzed tumors. In addition, PIK3CA activating mutations were concurrently observed in 19 of 30 cases (63%). Missense or damaging mutations in NF1 were identified in 10 of 30 cases (33%), with 7 tumors having mutations in FGFR1, PIK3CA, and NF1. The co-occurrence of mutations that activate both the MAPK pathway and the PI3K pathway makes the mutation profile of RGNT distinctive among astrocytic and glioneuronal tumors.
Diffuse leptomeningeal glioneuronal tumor (DLGNT): DLGNT is a rare CNS tumor that has been characterized radiographically by leptomeningeal enhancement on magnetic resonance imaging (MRI) that may involve the posterior fossa, brain stem region, and spinal cord. Intraparenchymal lesions, when present, typically involve the spinal cord; localized intramedullary glioneuronal tumors without leptomeningeal dissemination and with histomorphologic, immunophenotypic, and genomic characteristics similar to DLGNT have been reported. DLGNT showed a distinctive epigenetic profile on DNA methylation arrays, and unsupervised clustering of array data applied to 30 cases defined two subclasses of DLGNT: methylation class (MC)-1 (n = 17) and MC-2 (n = 13). Of note, many of the array-defined cases had originally been diagnosed as other entities (e.g., primitive neuroectodermal tumors, pilocytic astrocytoma, and anaplastic astrocytoma). Patients with DLGNT-MC-1 were diagnosed at an earlier age than were patients with DLGNT-MC-2 (5 years vs. 14 years, respectively). The 5-year overall survival was higher for patients with DLGNT-MC-1 than for those with DLGNT-MC-2 (100% vs. 43%, respectively). Genomic findings from the 30 methylation array–defined DLGNT cases are provided below:
Extraventricular neurocytoma: Extraventricular neurocytoma is histologically similar to central neurocytoma, consisting of small uniform cells that demonstrate neuronal differentiation, but it arises in the brain parenchyma rather than in association with the ventricular system. It presents during childhood through adulthood. In a study of 40 tumors histologically classified as extraventricular neurocytoma and subjected to methylation array analysis, only 26 formed a separate cluster distinctive from reference tumors of other histologies. Among cases with an extraventricular neurocytoma methylation array classification for which genomic characterization could be performed, 11 of 15 (73%) showed rearrangements affecting members of the FGFR family, with FGFR1-TACC1 being the most common alteration.
Papillary glioneuronal tumor: Papillary glioneuronal tumor is a low-grade biphasic neoplasm with astrocytic and neuronal differentiation that primarily arises in the supratentorial compartment. The median age at presentation is in the early 20s, but it can be observed during childhood through adulthood. The primary genomic alteration associated with papillary glioneuronal tumor is a gene fusion, SLC44A1-PRKCA, that is associated with the t(9:17)(q31;q24) translocation.[86,87] In one study of 28 cases diagnosed histologically as papillary glioneuronal tumor using methylation arrays, 11 of the cases clustered in a distinctive methylation class, while the remaining cases showed methylation profiles typical for other tumor entities. Molecular analysis of the cases in the distinctive methylation cluster showed that all of them had the SLC44A1-PRKCA gene fusion except for a single case with a NOTCH1-PRKCA gene fusion. This suggests that molecular methods for identifying the presence of a PRKCA fusion are less susceptible to misclassification in diagnosing papillary glioneuronal tumor than are morphology-based methods.
Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly for well-circumscribed lesions where complete excision may be possible.[11,89,90,91,92] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[93,94] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.
Unfavorable prognostic features for childhood low-grade astrocytomas include the following:[95,96,97,98]
In patients with pilocytic astrocytoma, elevated MIB-1 labeling index, a marker of cellular proliferative activity, is associated with shortened PFS. A BRAF-KIAA fusion, found in pilocytic tumors, confers a better clinical outcome.
In children with tumors of the visual pathway, outcome is not only assessed by radiographic disease control or survival but also by visual outcome. Children with isolated optic nerve tumors have a better prognosis than do children with lesions that involve the chiasm or that extend along the optic pathway.[100,101]; [Level of evidence: 3iiC] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening. Better visual acuity at diagnosis, older age at diagnosis, and presence of NF1 are associated with better visual outcomes.
Although high-grade astrocytomas generally carry a poor prognosis in younger patients, those with anaplastic astrocytomas in whom a gross-total resection is possible may fare better,[90,105,106] as well as those with non-H3 K27M–mutant tumors.
Molecular subtypes of pediatric glioblastoma multiforme show prognostic significance. Patients whose tumors have histone K27M mutations have the poorest prognosis, with 3-year survival rates below 5%. In the thalamus, wild-type high-grade gliomas have a somewhat better prognosis than do those harboring an H3.3 mutation. For high-grade gliomas in the thalamus, patients with H3 wild-type tumors have a somewhat better prognosis (2-year overall survival [OS], 71%) than do patients who harbor H3 K27M mutations (2-year OS, 13%). Patients whose tumors have IDH1 mutations appear to have the most favorable prognosis among pediatric glioblastoma multiforme cases, while those with histone G34 mutations and those lacking both histone and IDH1 mutations have an intermediate prognosis (3-year OS, approximately 30%). In a multivariate analysis that included both molecular and clinical factors, the presence of gene amplifications and K27M mutations were associated with a poorer prognosis, while the presence of IDH1 mutations was associated with a more favorable prognosis.
There is no recognized staging system for childhood astrocytomas. For the purposes of this summary, childhood astrocytomas will be described as follows:
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Many of the improvements in survival in childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with previously obtained results that assessed an existing therapy. Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.
To determine and implement optimal treatment, planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Irradiation of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in that area to ensure optimal results.
Long-term management of patients with brain tumors is complex and requires a multidisciplinary approach. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Table 4 describes the standard treatment options for low-grade and high-grade childhood astrocytomas.
To determine and implement optimal management, treatment is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.
For children with low-grade optic pathway astrocytomas, treatment options should be considered not only to improve survival but also to stabilize visual function.[1,2]
Treatment of Newly Diagnosed Childhood Low-Grade Astrocytomas
Standard treatment options for newly diagnosed childhood low-grade astrocytomas include the following:
Observation without intervention
Observation, in the absence of any intervention, is an option for patients with neurofibromatosis type 1 (NF1) or incidentally found, asymptomatic masses. Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1.[4,5]
Surgical resection is the primary treatment for childhood low-grade astrocytoma [6,7] and surgical feasibility is determined by tumor location. In infants and young children, low-grade astrocytomas presenting in the optic chiasm/hypothalamus make surgery difficult; consequently, biopsies are not always done. This is especially true in patients with NF1. When associated with NF1, tumors may be of multifocal origin. Diffuse astrocytomas (World Health Organization [WHO] grade II) may be less amenable to total resection, and this may contribute to a poorer outcome in these patients.
After resection, immediate (within 48 hours of resection per Children's Oncology Group [COG] criteria) postoperative magnetic resonance imaging is obtained. Surveillance scans are then obtained periodically for completely resected tumors, although the value following the initial 3- to 6-month postoperative period is uncertain.; [Level of evidence: 3iiDiii]
Factors related to outcome for children with low-grade gliomas treated with surgery followed by observation were identified in a COG study that included 518 evaluable patients. Overall outcome for the entire group was a 78% progression-free survival (PFS) rate at 8 years and 96% overall survival (OS) rate at 8 years. The following factors were related to prognosis:
The extent of resection necessary for cure is unknown because patients with microscopic and even gross residual tumor after surgery may experience long-term PFS without postoperative therapy.[6,7]
The long-term functional outcome of cerebellar pilocytic astrocytomas is relatively favorable. Full-scale mean IQs of patients with low-grade gliomas treated with surgery alone are close to the normative population. However, long-term medical, psychological, and educational deficits may be present in these patients.; [17,18][Level of evidence: 3iiiC]
Adjuvant therapy following complete resection of a low-grade glioma is generally not required unless there is a subsequent recurrence of disease. Treatment options for patients with incompletely resected tumor must be individualized and may include one or more of the following:
A shunt or other cerebrospinal fluid diversion procedure may be needed.
Observation after surgery
In patients in whom a portion of the tumor has been resected, the patient may be observed without further disease-directed treatment, particularly if the pace of tumor regrowth is anticipated to be very slow. Approximately 50% of patients with less-than-gross total resection may have disease that remains progression-free at 5 to 8 years, supporting the observation strategy in selected patients.
Given the long-term side effects associated with radiation therapy, postoperative chemotherapy may be initially recommended.
Chemotherapy may result in objective tumor shrinkage and delay the need for radiation therapy in most patients.[19,20,21,22] Chemotherapy is also an option that may delay or avoid radiation therapy in adolescents with optic nerve pathway gliomas.[Level of evidence: 3iiDii] Chemotherapy has been shown to shrink tumors in children with hypothalamic gliomas and the diencephalic syndrome, resulting in weight gain in those who respond to treatment.
The most widely used regimens to treat tumor progression or symptomatic nonresectable, low-grade gliomas are the following:
The COG reported the results of a randomized phase III trial (COG-A9952) that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas but without NF1 using one of two regimens: carboplatin and vincristine (CV) or TPCV. The 5-year event-free survival (EFS) rate was 39% (± 4%) for the CV regimen and 52% (± 5%) for the TPCV regimen. Toxicity rates between the two regimens were relatively comparable. In the same study, children with NF1 were nonrandomly assigned to receive treatment with CV. The 5-year EFS rate for children with NF1 was markedly better, at 69% (± 4%), than it was for children without NF1 who received CV. In multivariate analysis, NF1 was an independent predictor of better EFS but not OS.
A multicenter, prospective, randomized trial that compared treatment with vincristine/carboplatin with vincristine/carboplatin plus etoposide in children with low-grade glioma failed to demonstrate a difference in PFS and OS between the two regimens.[Level of evidence: 1iiD]
Other chemotherapy approaches have been employed to treat children with progressive or symptomatic nonresectable, low-grade astrocytomas, including the following:
Among children receiving chemotherapy for optic pathway gliomas, those without NF1 have higher rates of disease progression than those with NF1, and infants have higher rates of disease progression than do children older than 1 year.[20,21,30,35] Visual status (including acuity and field) is an important measure of outcome and improvement after treatment, and it is variable even in patients with radiographic responses. Children with sporadic visual pathway gliomas have poorer visual outcomes than do children with NF1.; [38,39][Level of evidence: 3iiiC] Better initial visual acuity, older age, and absence of postchiasmatic involvement are associated with improved or stable vision after chemotherapy.
Radiation therapy is usually reserved until progressive disease is documented [41,42] and may be further delayed through the use of chemotherapy.[19,20]
For children with low-grade gliomas for whom radiation therapy is indicated, approaches that contour the radiation distribution to the tumor and avoid normal brain tissue (3-D conformal radiation therapy, intensity-modulated radiation therapy, stereotactic radiation therapy, and proton radiation therapy [charged-particle radiation therapy]) all appear effective and may potentially reduce the acute and long-term toxicities associated with these modalities.[43,44]; [Level of evidence: 3iDiii] Radiation doses of 54 Gy in 1.8 Gy fractions are typically used.[46,47]
Subsequent to radiation administration, care must be taken in distinguishing radiation-induced imaging changes from disease progression, that usually occurs during the first year after radiation, but may occur even after the first year, especially in patients with pilocytic astrocytomas.[48,49,50,51]; [Level of evidence: 2A]; [Level of evidence: 2C]; [Level of evidence: 3iiiDi]; [Level of evidence: 3iiiDii]; [12,56][Level of evidence: 3iiiDiii]
Radiation therapy results in long-term disease control for most children with chiasmatic and posterior pathway chiasmatic gliomas, but may also result in substantial intellectual and endocrinologic sequelae, cerebrovascular damage, late death, and possibly an increased risk of secondary tumors.[57,58,59]; [Level of evidence: 2C] A population-based study identified radiation therapy as the most significant risk factor associated with late mortality, although the patients who required radiation therapy may have reflected a higher-risk population.
Radiation therapy and alkylating agents are used as last resorts for patients with NF1, given the theoretically heightened risk of inducing neurologic toxic effects and second malignancy in this population. Children with NF1 may be at higher risk of radiation-associated secondary tumors and morbidity resulting from vascular changes.
For children with symptomatic subependymal giant cell astrocytomas (SEGAs), agents that inhibit mammalian target of rapamycin (mTOR) (e.g., everolimus and sirolimus) have been studied.
Evidence (treatment of SEGA with mTOR inhibitor):
Treatment options under clinical evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Treatment of Progressive/Recurrent Childhood Low-Grade Astrocytomas
Childhood low-grade astrocytomas may progress or recur many years after initial presentation and treatment.
An individual plan needs to be tailored on the basis of the following:
Recurrent disease is usually at the primary tumor site, although multifocal or widely disseminated disease to other intracranial sites and to the spinal leptomeninges has been documented.[67,68] Most children whose low-grade diffuse fibrillary astrocytomas recur will harbor low-grade lesions; however, transformation into a higher grade tumor is possible. Surveillance imaging will frequently identify asymptomatic recurrences.
At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated. The need for surgical intervention must be individualized on the basis of the following:
Standard treatment options for progressive/recurrent childhood low-grade astrocytomas include the following:
Patients with low-grade astrocytomas who relapse after being treated with surgery alone may be candidates for another surgical resection. Utility of second surgery is impacted by site of recurrence and the probability of obtaining a near-total resection/gross-total resection without significant neurologic injury.
The rationale for the use of radiation therapy is essentially the same when utilized as first-line therapy or at the time of recurrence (refer to the Radiation therapy subsection of the Treatment of Newly Diagnosed Childhood Low-Grade Astrocytomas section of this summary). If the child has never received radiation therapy, local radiation therapy may be a treatment option, although chemotherapy in lieu of radiation may be considered, depending on the child's age and the extent and location of the tumor.[Level of evidence: 3iA]; [Level of evidence: 3iiiDi]
For children with low-grade gliomas for whom radiation therapy is indicated, conformal radiation therapy approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality.[46,47,49,53]
If there is recurrence at an unresectable site, chemotherapy should be considered.
Chemotherapy may result in relatively long-term disease control.[20,74] The choice of regimen depends on whether previous chemotherapy has been utilized. Numerous options can be considered, including CV; TPCV; vinblastine alone; temozolomide alone; or temozolomide in combination with carboplatin and vincristine.[20,35,36,74]
Targeted therapy with or without chemotherapy
Antitumor activity has also been observed for bevacizumab given in combination with irinotecan, which, in some cases, also results in clinical or visual improvement.
Evidence (targeted therapy [bevacizumab]):
With the identification of BRAF mutations driving a significant proportion of low-grade gliomas, inhibition of various elements of this molecular pathway (e.g., MEK and BRAF) are actively being tested in ongoing clinical trials, with early reports suggesting substantial activity. While first-generation BRAF inhibitors like vemurafenib and dabrafenib are active against BRAF V600E–mutated tumors, they are contraindicated for tumors with BRAF gene fusions because of the potential for paradoxical activation of the MAPK pathway.[80,81]
Studies of BRAF and MEK inhibitors include the following:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
To determine and implement optimal management, treatment of childhood high-grade astrocytomas is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.
Treatment of Newly Diagnosed Childhood High-Grade Astrocytomas
Outcomes in high-grade gliomas occurring in childhood are often more favorable than that in adults. It is not clear whether this difference is caused by biologic variations in tumor characteristics, therapies used, tumor resectability, or other factors.
The therapy for both children and adults with supratentorial high-grade astrocytoma includes surgery, radiation therapy, and chemotherapy.
Standard treatment options for newly diagnosed childhood high-grade astrocytomas include the following:
The ability to obtain a complete resection is associated with a better prognosis.[1,2] Among patients treated with surgery, radiation therapy, and nitrosourea (lomustine)-based chemotherapy, the 5-year progression-free survival rate was 19% (± 3%); the survival rate was 40% in those who had total resections. Similarly, in a trial of multiagent chemoradiation therapy and adjuvant chemotherapy in addition to valproic acid, the 5-year event-free survival (EFS) rate was 13%, but for children with a complete resection of their tumor, the EFS rate was 48%.[Level of evidence: 2A]
Radiation therapy is routinely administered to a field that widely encompasses the entire tumor. The radiation therapy dose to the tumor bed is usually at least 54 Gy. Despite such therapy, overall survival (OS) rates remain poor. Similarly poor survival is seen in children with spinal cord primaries and children with thalamic high-grade gliomas (i.e., diffuse midline gliomas, H3 K27M-mutant tumors) treated with radiation therapy.[5,6]; [7,8][Level of evidence: 3iiiA]
In one trial, children with glioblastoma who were treated on a prospective randomized trial with adjuvant lomustine, vincristine, and prednisone fared better than children treated with radiation therapy alone. Furthermore, children who received lomustine in addition to temozolomide for subtotally-resected tumors, especially glioblastoma with methylated O-6-methylguanine-DNA-methyltransferase (MGMT) overexpression, had a slightly improved outcome. Patients with IDH1 mutations had an improved 1-year OS rate (100%) when compared with IDH1–wild-type tumors (1-year OS rate, 81%), highlighting the potential importance of underlying biological characteristics.
The use of temozolomide to treat glioblastoma was initially investigated in adults. In adults, the addition of temozolomide during and after radiation therapy resulted in improved 2-year EFS compared with treatment with radiation therapy alone. Adult patients with glioblastoma with an MGMT promoter benefitted from temozolomide, whereas those who did not have a methylated MGMT promoter did not benefit from temozolomide.[12,13] The role of temozolomide given concurrently with radiation therapy for children with supratentorial high-grade glioma appears comparable to the outcome seen in children treated with nitrosourea-based therapy  and again demonstrated an EFS advantage for those children without MGMT overexpression. The use of adjuvant bevacizumab after radiation therapy does not prolong OS or progression-free survival in pediatric patients with newly diagnosed high-grade gliomas.
Younger children may benefit from chemotherapy or consolidation with high-dose chemotherapy to delay, modify, or, in selected cases, obviate the need for radiation therapy.[16,17,18]
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Treatment of Recurrent Childhood High-Grade Astrocytomas
Most patients with high-grade astrocytomas or gliomas will eventually have tumor recurrence, usually within 3 years of original diagnosis, but some patients recur many years after initial treatment. Disease may recur at the primary tumor site, at the margin of the resection/radiation bed, or at noncontiguous central nervous system sites. Systemic relapse rarely occurs.
At the time of recurrence, a complete evaluation for extent of relapse is indicated for all malignant tumors. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence.
Treatment options for recurrent childhood high-grade astrocytomas include the following:
The utility of surgical intervention must be individualized on the basis of the following:
Patients for whom initial treatment fails may benefit from additional treatment, including entry into clinical trials of novel therapeutic approaches. High-dose, marrow-ablative chemotherapy with hematopoietic SCT may be effective in a highly selected subset of patients with minimal residual disease at time of recurrence.[Level of evidence: 3iiiA] However, the results of previous clinical trials that tested various targeted and combination chemotherapies have largely failed to demonstrate convincing benefits for enrolled patients.[22,23,24]
Molecular targets for recurrent high-grade gliomas are limited. BRAF V600E mutations are present in a small subset of these patients, and a small number of cases have responded to BRAF inhibitors. A case report documented a complete response to the BRAF inhibitor vemurafenib in a patient with recurrent BRAF V600–mutated glioblastoma. A phase I study reported in an abstract that eight children with progressive BRAF V600E high-grade gliomas were treated with dabrafenib and demonstrated three complete responses, three partial responses, and two progressive disease responses.
The role of immune checkpoint inhibition in the treatment of children with recurrent high-grade astrocytoma is currently under study. Children with biallelic mismatch repair deficiency have a very high mutational burden and neoantigen expression and are at risk of developing a variety of cancers, including hematologic malignancies, gastrointestinal cancers, and brain tumors. The high mutation and neoantigen load has been correlated with improved response to immune checkpoint inhibition. Early case reports have demonstrated clinical and radiographic responses in children who are treated with an anti–programmed death-1 (anti–PD-1) inhibitor.
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Astrocytomas Treatment are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Astrocytomas Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389382]
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Last Revised: 2020-01-16
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