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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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 and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a Spanish version.
This summary will be available soon in a patient version, which is written in less technical language, and in a Spanish version.
The NCI provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. The PDQ Childhood brain tumor treatment summaries are organized primarily according to the World Health Organization classification of nervous system tumors. [1] [2]
In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. 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.
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors for information about the general classification of childhood brain and spinal cord tumors.
The pathologic classification of pediatric brain tumors is a specialized area that is undergoing evolution; review of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.
Childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are histologically graded from grade I to IV according to the World Health Organization’s (WHO) histologic typing of central nervous system (CNS) tumors. [1] Tumor types are based on the glial cell type of origin: astrocytomas (astrocytes), oligodendroglial tumors (oligodendrocytes), mixed gliomas (cell types of origin include oligodendrocytes, astrocytes, and ependymal cells) and neuronal tumors (with or without an astrocytic component).
WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (see Table 1).
| WHO Histologic Grade | Grade Classification |
|---|---|
| I | Low-grade |
| II | Low-grade |
| III | High-grade |
| IV | High-grade |
In 2007, the WHO further categorized astrocytomas, oligodendroglial tumors, and mixed gliomas according to histopathologic features and biologic behavior. In 2004, it was determined that the pilomyxoid variant of pilocytic astrocytoma may be a more aggressive variant and may be more likely to disseminate, and it was reclassified by the WHO as a grade II tumor (see Table 2). [1] [2] [3]
| Type | WHO Histologic Grade |
|---|---|
| Astrocytic Tumors: | |
| Pilocytic astrocytoma: | I |
| Pilomyxoid astrocytoma | II |
| Pleomorphic xanthoastrocytoma | II |
| Subependymal giant cell astrocytoma | I |
| Diffuse astrocytoma: | |
| Gemistocytic astrocytoma | II |
| Protoplasmic astrocytoma | II |
| Fibrillary astrocytoma | II |
| Anaplastic astrocytoma | III |
| Glioblastoma multiforme | IV |
| Oligodendroglial Tumors: | |
| Oligodendroglioma | II |
| Anaplastic oligodendroglioma | III |
| Mixed Gliomas: | |
| Oligoastrocytoma | II |
| Anaplastic oligoastrocytoma | III |
Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have preferential CNS locations (see Table 3).
| Tumor Type | Preferential CNS location |
|---|---|
| Pilocytic astrocytoma | Optic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, brain stem, spinal cord (rare) |
| Pleomorphic xanthoastrocytoma | Superficial location in cerebrum (temporal lobe preferentially) |
| Diffuse astrocytoma (including fibrillary) | Cerebrum (frontal and temporal lobes), brain stem, spinal cord, optic nerve, optic chiasm, optic pathway, hypothalamus, thalamus |
| Anaplastic astrocytoma, glioblastoma | Cerebrum, occasionally cerebellum, brain stem and spinal cord |
| Oligodendrogliomas | Cerebrum (frontal lobe preferentially followed by temporal, parietal and occipital lobes), cerebellum, brain stem, spinal cord |
| Oligoastrocytoma | Cerebral hemispheres (frontal lobe preferentially followed by the temporal lobe) |
| Gliomatosis cerebri | Cerebrum with or without brain stem involvement, cerebellum, spinal cord |
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 has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location. [4]
Children with neurofibromatosis type 1 (NF1) have an increased propensity to develop WHO grade I and II astrocytomas in the visual pathway; approximately 20% of all patients with NF1 will develop a visual 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, and when biopsies have been performed, these tumors have been found to be predominantly pilocytic (grade I) rather than fibrillary (grade II) astrocytomas. [2] [3] [5] [6] [7] In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment. [8]
Gliomatosis cerebri is a diffuse glioma that involves widespread involvement of the cerebral hemispheres in which it may be confined, but it often extends caudally to affect the brainstem, cerebellum and/or spinal cord. [1] It rarely arises in the cerebellum and spreads rostrally. [9] The neoplastic cells are most commonly astrocytes, but in some cases, they are oligodendroglia. Although they occur primarily in adults, more than 100 cases have been observed in children. [10] They may respond to treatment initially, but overall have a poor prognosis.
Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly if complete excision is possible. [11] [12] [13] [14] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other central nervous system (CNS) sites is uncommon. [15] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with neurofibromatosis type 1.
High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium. [11] [12] [14] 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. Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas. [3] [16] [17] MIB-1 labeling index, a marker of cellular proliferative activity, is predictive of outcome in childhood malignant brain tumors. Both histologic classification and proliferative activity evaluation have been shown to be independently associated with survival. [18] Although high-grade astrocytoma carries a generally poor prognosis in younger patients, those with anaplastic astrocytoma and those in whom a gross total resection is possible may fare better. [19] [20]
Presenting symptoms for childhood astrocytomas depend not only on central nervous system location, but also size of tumor, rate of growth, and chronologic and developmental age of the child.
There is no generally recognized staging system for childhood astrocytomas. For the purposes of this summary, childhood astrocytomas will be described as low-grade astrocytoma (pilocytic astrocytomas and diffuse fibrillary astrocytomas) or high-grade astrocytoma (anaplastic astrocytomas and glioblastoma multiforme) and as untreated or recurrent.
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 those that were previously obtained with 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. To determine and implement optimum treatment, treatment planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in that area in order to ensure optimal results.
Debilitating effects on growth and neurologic development have frequently been observed following radiation therapy, especially in younger children. [1] [2] [3] There are also other less common complications of radiation therapy, including cerebrovascular accidents. [4] For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, and sometimes obviate, the need for radiation therapy in children with benign and malignant lesions. [5] Long-term management of these patients is complex and requires a multidisciplinary approach.
The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.
To determine and implement optimum treatment, treatment planned by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required.
In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in the 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. [1] Because the location of these tumors makes a surgical approach difficult, biopsies are not always done. This is especially true in patients with neurofibromatosis type 1 (NF1). [2] When associated with NF1, tumors may be of multifocal origin.
For children with low-grade optic tract astrocytomas, treatment options should be considered not only to improve survival but also to stabilize visual function. Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the visual pathway. [1] [2] [3] [4] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening. [3] Observation is an option for patients with NF1 or nonprogressive masses. [1] [3] [5] [6] Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1. [7] [8] [9]
Surgical resection is the primary treatment for childhood low-grade astrocytoma [1] [2] [3] and surgical feasibility is determined by tumor location. For example, complete or near complete removal can be obtained in 90% to 95% of patients with pilocytic tumors that occur in the cerebellum. Similarly, hemispheric tumors are often amenable to complete surgical resection. [10] [11] For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection or local radiation therapy may result in prolonged progression-free survival. [12] Diffuse astrocytomas may be less amenable to total resection, and this may account for the poorer outcome. The extent of resection necessary for cure is unknown because patients with microscopic and even gross residual tumor after surgery may experience long-term progression-free survival without postoperative therapy. [2] [5]
Low-grade astrocytomas that occur in midline structures (e.g. hypothalamus, thalamus, brain stem, and spinal cord) can also be aggressively resected, with resultant long-term disease control; [7] [8] [13] however, such resection may result in significant neurologic sequelae, especially in children younger than 2 years at diagnosis. [7] Because of the infiltrative nature of some deep-seeded lesions, extensive surgical resection may not be appropriate and biopsy only should be considered. Treatment options for patients with incompletely resected tumor must be individualized and may include observation, a second resection, chemotherapy, and/or radiation.
Following 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 of this is uncertain. [1] In selected patients in whom a portion of the tumor has been resected, the patient may also be observed without further disease-directed treatment, particularly if the pace of tumor regrowth is anticipated to be very slow.
Radiation therapy is often reserved until progressive disease is documented, [2] [3] and its use may be further delayed through the use of chemotherapy, a strategy that is commonly employed in young children. [4] [5] 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, and possibly an increased risk of secondary tumors. [6] [7] [8] [9] An alternative to immediate radiation therapy is subtotal surgical resection, but it is unclear how many patients will have stable disease and for how long. [6] Radiation and alkylating agents are used as a last resort for patients with neurofibromatosis type 1 (NF1), given the theoretical risk of inducing neurotoxicity and second malignancy in this population. [10] Children with NF1 may be at higher risk for radiation-associated secondary tumors and morbidity due to vascular changes.
For those children with low-grade glioma for whom radiation therapy is indicated, conformal radiotherapeutic approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality. [11] [12] [13]
Given the side effects associated with radiation therapy, chemotherapy may be particularly appropriate for patients with NF1 and for younger children.
Chemotherapy may result in objective tumor shrinkage and will delay the need for radiation therapy in most patients. [4] [5] [14] [15] [16] 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. [17] The most widely used regimen to treat progression or symptomatic nonresectable, low-grade gliomas is a combination of carboplatin and vincristine. [4] [5] Other chemotherapy approaches have been employed to treat children with progressive low-grade astrocytomas, including multiagent platinum-based regimens [5] [14], nitrosourea-based regimens, [15] and temozolomide. [18] [19]
Reported 5-year progression-free survival rates have ranged from approximately 35% to 60% for children receiving platinum-based chemotherapy for optic pathway gliomas, [5] [14] but most patients ultimately require further treatment.
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. [5] [14] [20]
The COG completed a randomized phase III trial, COG-A9952, that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas on one of two regimens: carboplatin and vincristine or thioguanine (6-thioguanine), lomustine, and procarbazine hydrochloride given with vincristine. Children with NF1 were treated only on the carboplatin and vincristine arm. Study results are pending.
The following are examples of national and/or institutional clinical trial that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood low-grade cerebellar astrocytoma and childhood low-grade cerebral astrocytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Childhood low-grade astrocytomas may recur many years after initial treatment. Recurrent disease is usually at the primary tumor site, though multifocal or widely disseminated disease to other intracranial sites and to the spinal leptomeninges has been documented. [1] [2] Most children whose low-grade fibrillary astrocytomas recur will harbor low-grade lesions; however, malignant transformation is possible. [3]
At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated. 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. The need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the mass lesion, and the clinical picture.
An individual plan needs to be tailored on the basis of patient age, tumor location, and prior treatment. If patients have not received radiation therapy, local radiation therapy is the usual treatment. [4] For those children with low-grade glioma for whom radiation therapy is indicated, conformal radiotherapeutic approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality. [5] [6] In patients treated with surgery alone whose disease progresses, chemotherapy and radiation therapy are options. If recurrence takes place after irradiation, chemotherapy should be considered. Chemotherapy may result in relatively long-term disease control. [7] [8] Temozolomide alone or drug combinations, such as carboplatin and vincristine, may be useful at the time of recurrence for children with low-grade gliomas. [7] [8] [9]
Patients with low-grade astrocytomas who relapse after being treated with surgery alone should be considered for another surgical resection. [10] If this is not feasible, local radiation therapy is the usual treatment. [11] If there is recurrence in an unresectable site after irradiation, chemotherapy should be considered. [11]
Entry into studies of novel therapeutic approaches should be considered for patients with recurrent brain tumors. [12] [13] Information about ongoing clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood cerebral astrocytoma and recurrent childhood cerebellar astrocytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
To determine and implement optimum therapy, treatment planned by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required.
The therapy for both children and adults with supratentorial high-grade astrocytoma includes surgery, radiation therapy, and chemotherapy. Outcome in high-grade gliomas occurring in childhood may be more favorable than that in adults, but it is not clear if this difference is caused by biologic variations in tumor characteristics, therapies used, tumor resectability, or other factors that are presently not understood. [1] The ability to obtain a complete resection is associated with a better prognosis. [2] Radiation therapy is administered to a field that widely encompasses the entire tumor. Alternatively, it can be administered to the entire brain with a cone down to the tumor volume. [3] The radiation therapy dose to the tumor bed is usually at least 5,400 cGy. Despite such therapy, overall survival rates remain poor. Among patients treated with surgery, radiation therapy and nitrosourea (lomustine)-based chemotherapy, 5-year progression-free survival was 19% ± 3%; survival was 40% in those who had total resections. [4] In one trial, children with glioblastoma multiforme who were treated on a prospective randomized trial with adjuvant lomustine, vincristine, and prednisone fared better than children treated with radiation therapy alone. [5] In adults, the addition of temozolomide during and after radiation therapy resulted in improved 2-year event-free survival as compared with treatment with radiation therapy alone. Adult patients with glioblastoma multiforme with a methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not. [6] [7] The role of temozolomide given concurrently with radiation therapy for children with supratentorial high-grade gliomas has not yet been demonstrated but is under clinical evaluation. Younger children may benefit from chemotherapy to delay, modify, or, in selected cases, obviate the need for radiation therapy. [8] [9] [10] Clinical trials that evaluate chemotherapy with or without radiation therapy are ongoing. Information about ongoing clinical trials is available from the NCI Web site.
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood high-grade cerebellar astrocytoma and childhood high-grade cerebral astrocytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Most patients with high-grade astrocytomas or gliomas will eventually have tumor recurrence, usually within 3 years of original diagnosis but perhaps 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 is rare but may occur. 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. The need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the mass lesion, and the clinical picture.
Patients for whom initial treatment fails may benefit from additional treatment. High-dose chemotherapy with hematopoietic stem cell transplant may be effective in a subset of patients with minimal residual disease at time of treatment. [1] [2] Such patients should also be considered for entry into trials of novel therapeutic approaches. Information about ongoing clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood cerebellar astrocytoma and recurrent childhood cerebral astrocytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood astrocytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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Added text to state that the summary will be available soon in patient and Spanish versions.
Added Louis et al. [WHO Classification of Tumors of the Central Nervous System 2007] and Louis et al. [Acta Neuropathol 2007] as references 1 and 2, respectively.
Added gliomatosis cerebri to Table 3.
Revised text to state that the presence of certain histologic features has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location (cited Tibbetts et al. as reference 4).
Added text describing gliomatosis cerebri (cited Rorke-Adams et al. and Armstrong et al. as references 9 and 10, respectively).
Added Fisher et al., Pfister et al., and Civitello et al. as references 13, 14, and 15 respectively.
Added Villano et al. as reference 20.
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This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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