Childhood Astrocytomas Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Childhood Astrocytomas Treatment

General Information About Childhood Astrocytomas

The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (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.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality decreased by more than 50%.[3] 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.

Gliomas arise from glial cells that are present in the brain and spinal cord. Gliomas are named according to their clinicopathologic and histologic subtype. For example, astrocytomas originate from astrocytes, oligodendroglial tumors from oligodendrocytes, and mixed gliomas from a mix of oligodendrocytes, astrocytes, and ependymal cells. Astrocytoma is the most commonly diagnosed type of glioma in children. According to the WHO classification of brain tumors, gliomas are further classified into low-grade (grades I and II) and 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 poor prognosis, unless the tumor is an anaplastic astrocytoma that can be completely resected.

Anatomy

Childhood astrocytomas can occur anywhere in the central nervous system (CNS). Refer to Table 3 for the preferential CNS location for each tumor type.

Drawing of the inside of the brain showing the lateral ventricle, third ventricle, and fourth ventricle, cerebrum, choroid plexus, hypothalamus, pineal gland, pituitary gland, optic nerve, tentorium, cerebellum, brain stem, pons, medulla, and spinal cord.
Anatomy of the inside of the brain, showing the cerebrum, cerebellum, brain stem, spinal cord, optic nerve, hypothalamus, and other parts of the brain.

Clinical Features

Presenting symptoms for childhood astrocytomas depend on CNS location, size of tumor, rate of growth, and chronologic and developmental age of the child.

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.[4]

Diagnostic Evaluation

The diagnostic evaluation for astrocytoma is often limited to a magnetic resonance imaging (MRI) of the brain or spine. Additional imaging, when clinically indicated, would consist of an MRI of the remainder of the neuraxis.

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 glial cell type of origin:

  • Astrocytomas (astrocytes).
  • Oligodendroglial tumors (oligodendrocytes).
  • Mixed gliomas (cell types of origin include oligodendrocytes, astrocytes, and ependymal cells).
  • Mixed neuronal-glial tumors.

WHO histologic grade

Childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are histologically graded (grade I to IV) according to the WHO histologic typing of CNS tumors.[1]

WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (refer to Table 1).

Table 1. World Health Organization (WHO) Histologic Grade and Corresponding Classification for Tumors of the Central Nervous System

WHO Histologic Grade Grade Classification
I Low grade
II Low grade
III High grade
IV High grade

Table 2. Histologic Grade of Childhood Astrocytomas and Other Tumors of Glial Origin

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 IV
Oligodendroglial Tumors:  
Oligodendroglioma II
Anaplastic oligodendroglioma III
Mixed Gliomas:  
Oligoastrocytoma II
Anaplastic oligoastrocytoma III

In 2007, the WHO further categorized astrocytomas, oligodendroglial tumors, and mixed gliomas according to histopathologic features and biologic behavior. It was determined that the pilomyxoid variant of pilocytic astrocytoma may be an aggressive variant that is more likely to disseminate, and it was reclassified as a grade II tumor (refer to Table 2) by the WHO.[1,2,5]

CNS location

Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have preferential CNS locations (refer to Table 3).

Table 3. Childhood Astrocytomas and Other Tumors of Glial Origin and Preferential Central Nervous System (CNS) Location

Tumor Type Preferential CNS Location
Pilocytic astrocytoma Optic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, and brain stem; and 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, and 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, and spinal cord
Oligoastrocytoma Cerebral hemispheres (frontal lobe preferentially followed by the temporal lobe)
Gliomatosis cerebri Cerebrum with or without brain stem involvement, cerebellum, and 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 (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 high-grade gliomas (e.g., diffuse intrinsic pontine gliomas).[9,10]

High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium in the cerebrum.[11,12] 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 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 brain stem, cerebellum, and/or spinal cord.[1] It rarely arises in the cerebellum and spreads rostrally.[13] The neoplastic cells are most commonly astrocytes, but in some cases, they are oligodendroglia. They may respond to treatment initially, but overall have a poor prognosis.[14]

Neurofibromatosis type 1 (NF1)

Children with NF1 have an increased propensity to develop WHO grade I and grade 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.[2,5,15,16,17]

In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment.[18]

Genomic alterations

Low-grade gliomas

Genomic alterations involving BRAF activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the ERK/MAPK pathway. These include the following:

  • BRAF activation in pilocytic astrocytoma occurs most commonly through a gene fusion between KIAA1549 and BRAF, producing a fusion protein that lacks the BRAF regulatory domain.[19,20,21,22,23] This fusion is seen in the majority of infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[19,20,24,25,26,27,28] Presence of the BRAF-KIAA1549 fusion predicted for better clinical outcome (progression-free survival [PFS] and overall survival) in one report that described children with incompletely resected low-grade gliomas.[28] However, other factors such as p16 deletion and tumor location may modify the impact of BRAF mutation on outcome.[29]BRAF activation through the KIAA1549-BRAF fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[27,28]
  • Other genomic alterations in pilocytic astrocytomas that can also activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[20,22,23,30]BRAF point mutations (V600E) are observed in nonpilocytic pediatric low-grade gliomas as well, including approximately two-thirds of pleomorphic xanthoastrocytoma cases and in ganglioglioma and desmoplastic infantile ganglioglioma.[31,32,33]

As expected, given the role of NF1 deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.[26]

Activating mutations in FGFR1 and PTPN11, as well as NTRK2 fusion genes, have also been identified in noncerebellar pilocytic astrocytomas.[34] In pediatric grade II diffuse astrocytomas, the most common alterations reported are rearrangements in the MYB family of transcription factors in up to 53% of tumors.[35,36]

High-grade astrocytomas

Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[37,38,39,40] Pediatric high-grade gliomas, compared with adult tumors, less frequently have PTEN and EGFR genomic alterations, and more frequently have PDGF/PDGFR genomic alterations and mutations in histone H3.3 genes. Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondary glioblastoma multiforme tumors in which there is stepwise transformation from lower-grade into higher-grade gliomas and in which most tumors have IDH1 and IDH2 mutations, the latter mutations are rarely observed in childhood glioblastoma multiforme tumors.[41,42,43]

Based on epigenetic patterns (DNA methylation), pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups with distinctive chromosome copy number gains/losses and gene mutations.[43] Two subgroups have identifiable recurrent H3F3A mutations, suggesting disrupted epigenetic regulatory mechanisms, with one subgroup having mutations at K27 (lysine 27) and the other group having mutations at G34 (glycine 34).

  • H3F3A mutation at K27: The K27 cluster occurs predominately in mid-childhood (median age, approximately 10 years), is mainly midline (thalamus, brainstem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have TP53 mutations.
  • H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis. The G34 clusters also have TP53 mutations and widespread hypomethylation across the whole genome.

The H3F3A K27 and G34 mutations appear to be unique to high-grade gliomas and have not been observed in other pediatric brain tumors.[44] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[41,42,43,44,45]

Other pediatric glioblastoma multiforme subgroups include the RTK PDGFRA and mesenchymal clusters, both of which occur over a wide age range, affecting both children and adults. The RTK PDGFRA and mesenchymal subtypes are comprised predominantly of cortical tumors, with cerebellar glioblastoma multiforme tumors being rarely observed; they both carry a poor prognosis.[43]

Oligodendroglioma

The molecular profile of pediatric patients with oligodendroglioma does not demonstrate deletions of 1p or 19q, as found in 40% to 80% of adult cases. Pediatric oligodendroglioma harbors MGMT gene promoter methylation in the majority of tumors.[46]

Prognosis

Low-grade astrocytomas

Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly for circumscribed, grade I lesions where complete excision may be possible.[11,12,47,48,49,50] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[51,52] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.

Unfavorable prognostic features include the following:[53]

  • Young age.
  • Fibrillary histology.
  • Inability to obtain a complete resection.

Elevated MIB-1 labeling index, a marker of cellular proliferative activity, is associated with shortened PFS in patients with pilocytic astrocytoma.[8] A BRAF-KIAA fusion, found in pilocytic tumors, confers a better clinical outcome.[28]

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.[54,55,56,57]; [58][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.[54,59]

High-grade astrocytomas

Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas.[5,60,61] MIB-1 labeling index 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.[62]

Although high-grade astrocytoma generally carries a poor prognosis in younger patients, those with anaplastic astrocytoma in whom a gross-total resection is possible may fare better.[49,63,64]

Oligodendrogliomas

Oligodendrogliomas are rare in children and have a relatively favorable prognosis; however, children younger than 3 years who have less than a gross-total resection have a less favorable prognosis.[65]

References:

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19. Bar EE, Lin A, Tihan T, et al.: Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 67 (9): 878-87, 2008.
20. Forshew T, Tatevossian RG, Lawson AR, et al.: Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 218 (2): 172-81, 2009.
21. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008.
22. Jones DT, Kocialkowski S, Liu L, et al.: Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28 (20): 2119-23, 2009.
23. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008.
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27. Lin A, Rodriguez FJ, Karajannis MA, et al.: BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol 71 (1): 66-72, 2012.
28. Hawkins C, Walker E, Mohamed N, et al.: BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17 (14): 4790-8, 2011.
29. Horbinski C, Nikiforova MN, Hagenkord JM, et al.: Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol 14 (6): 777-89, 2012.
30. Janzarik WG, Kratz CP, Loges NT, et al.: Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 38 (2): 61-3, 2007.
31. Dougherty MJ, Santi M, Brose MS, et al.: Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol 12 (7): 621-30, 2010.
32. Dias-Santagata D, Lam Q, Vernovsky K, et al.: BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One 6 (3): e17948, 2011.
33. Schindler G, Capper D, Meyer J, et al.: Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121 (3): 397-405, 2011.
34. Jones DT, Hutter B, Jäger N, et al.: Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45 (8): 927-32, 2013.
35. Zhang J, Wu G, Miller CP, et al.: Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45 (6): 602-12, 2013.
36. Ramkissoon LA, Horowitz PM, Craig JM, et al.: Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 110 (20): 8188-93, 2013.
37. Paugh BS, Qu C, Jones C, et al.: Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28 (18): 3061-8, 2010.
38. Bax DA, Mackay A, Little SE, et al.: A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res 16 (13): 3368-77, 2010.
39. Ward SJ, Karakoula K, Phipps KP, et al.: Cytogenetic analysis of paediatric astrocytoma using comparative genomic hybridisation and fluorescence in-situ hybridisation. J Neurooncol 98 (3): 305-18, 2010.
40. Pollack IF, Hamilton RL, Sobol RW, et al.: IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst 27 (1): 87-94, 2011.
41. Schwartzentruber J, Korshunov A, Liu XY, et al.: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482 (7384): 226-31, 2012.
42. Wu G, Broniscer A, McEachron TA, et al.: Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44 (3): 251-3, 2012.
43. Sturm D, Witt H, Hovestadt V, et al.: Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22 (4): 425-37, 2012.
44. Gielen GH, Gessi M, Hammes J, et al.: H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas. Am J Clin Pathol 139 (3): 345-9, 2013.
45. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al.: K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124 (3): 439-47, 2012.
46. Suri V, Jha P, Agarwal S, et al.: Molecular profile of oligodendrogliomas in young patients. Neuro Oncol 13 (10): 1099-106, 2011.
47. Hoffman HJ, Berger MS, Becker LE: Cerebellar astrocytomas. In: Deutsch M, ed.: Management of Childhood Brain Tumors. Boston: Kluwer Academic Publishers, 1990, pp 441-56.
48. Fisher PG, Tihan T, Goldthwaite PT, et al.: Outcome analysis of childhood low-grade astrocytomas. Pediatr Blood Cancer 51 (2): 245-50, 2008.
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50. Wisoff JH, Sanford RA, Heier LA, et al.: Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group. Neurosurgery 68 (6): 1548-54; discussion 1554-5, 2011.
51. von Hornstein S, Kortmann RD, Pietsch T, et al.: Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatr Blood Cancer 56 (7): 1046-54, 2011.
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56. Due-Tønnessen BJ, Helseth E, Scheie D, et al.: Long-term outcome after resection of benign cerebellar astrocytomas in children and young adults (0-19 years): report of 110 consecutive cases. Pediatr Neurosurg 37 (2): 71-80, 2002.
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Stage Information for Childhood Astrocytomas

There is no generally recognized staging system for childhood astrocytomas. For the purposes of this summary, childhood astrocytomas will be described as follows:

  • Low-grade astrocytoma (pilocytic astrocytomas and diffuse fibrillary astrocytomas).
    • Newly diagnosed.
    • Recurrent.
  • High-grade astrocytoma (anaplastic astrocytomas and glioblastoma).
    • Newly diagnosed.
    • Recurrent.

Treatment Option Overview for Childhood Astrocytomas

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.

To determine and implement optimum 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 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] Also, there are 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.

Table 4. Standard Treatment Options for Childhood Astrocytomas

Grade/Stage Standard Treatment Options
Childhood low-grade astrocytomas:  
  Newly diagnosed childhood low-grade astrocytomas Observation
Surgery
Adjuvant therapy(for tumors that are incompletely resected):
  Observation
Radiation therapy
Second surgery
Chemotherapy
  Recurrent childhood low-grade astrocytomas Second surgery
Radiation therapy
Chemotherapy
Childhood high-grade astrocytomas:  
  Newly diagnosed childhood high-grade astrocytomas Surgery
Adjuvant therapy:
  Radiation therapy
Chemotherapy
  Recurrent childhood high-grade astrocytomas High-dose, marrow-ablative chemotherapy with hematopoietic stem cell transplant(not considered standard treatment)
Novel therapeutic approaches(not considered standard treatment)

References:

1. Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70 (5): 707-13, 1989.
2. Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80 (6): 1004-10, 1994.
3. Packer RJ, Sutton LN, Goldwein JW, et al.: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74 (3): 433-40, 1991.
4. Bowers DC, Mulne AF, Reisch JS, et al.: Nonperioperative strokes in children with central nervous system tumors. Cancer 94 (4): 1094-101, 2002.
5. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993.

Treatment of Childhood Low-Grade Astrocytomas

To determine and implement optimum management, treatment is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.

In infants and young children, low-grade astrocytomas presenting in the hypothalamus make surgery difficult; consequently, biopsies are not always done. This is especially true in patients with neurofibromatosis type 1 (NF1).[1] When associated with NF1, tumors may be of multifocal origin.

For children with low-grade optic pathway astrocytomas, treatment options should be considered not only to improve survival but also to stabilize visual function.[2,3]

Treatment of Newly Diagnosed Childhood Low-Grade Astrocytomas

Standard treatment options for newly diagnosed childhood low-grade astrocytomas include the following:

1. Observation.
2. Surgery.
3. Adjuvant therapy.
  • Observation.
  • Radiation therapy.
  • Second surgery.
  • Chemotherapy.

Observation

Observation is an option for patients with NF1 or nonprogressive masses.[4,5,6,7] Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1.[8,9,10]

Surgery

Surgical resection is the primary treatment for childhood low-grade astrocytoma [1,4,5,11] and surgical feasibility is determined by tumor location.

  • Cerebellum: Complete or near-complete removal can be obtained in 90% to 95% of patients with pilocytic tumors that occur in the cerebellum.[11]
  • Optic nerve: For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection, while curative, generally results in blindness in the affected eye.
  • Midline structures (hypothalamus, thalamus, brain stem, and spinal cord): Low-grade astrocytomas that occur in midline structures can be aggressively resected, with resultant long-term disease control;[8,9,12]; [13][Level of evidence: 3iiiA] however, such resection may result in significant neurologic sequelae, especially in children younger than 2 years at diagnosis.[8]; [14][Level of evidence: 3iC] Because of the infiltrative nature of some deep-seated lesions, extensive surgical resection may not be appropriate and biopsy only should be considered.[15][Level of evidence: 3iiiDiii]
  • Cerebrum: Circumscribed, grade I hemispheric tumors are often amenable to complete surgical resection.[16]
  • Diffuse: Diffuse astrocytomas may be less amenable to total resection, and this may contribute to the poorer outcome.

Factors related to outcome for children with low-grade gliomas treated with surgery followed by observation were identified in a Children's Oncology Group study that included 518 evaluable patients.[11] Overall outcome for the entire group was 78% progression-free survival (PFS) at 8 years and 96% overall survival (OS) at 8 years. The following factors were related to prognosis:[11]

  • Histology: Approximately three-fourths of patients had pilocytic astrocytoma; PFS and OS were superior for these patients when compared with children with nonpilocytic tumors.
  • Extent of resection: Patients with gross-total resection had 8-year PFS exceeding 90% and OS of 99%. By comparison, approximately one-half of patients with any degree of residual tumor (as assessed by operative report and by postoperative imaging) showed disease progression by 8 years, although OS exceeded 90%.

    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.[1,6,11]

  • Age: Younger children (age <5 years) showed higher rates of tumor progression but there was no significant age effect for OS in multivariate analysis.
  • Tumor location: Cerebellar and cerebral tumors showed higher PFS at 8 years compared with patients with midline and chiasmatic tumors (84% ± 1.9% versus 51% ± 5.9%).

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]

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 following the initial 3- to 6-month postoperative period is uncertain.[19]; [20][Level of evidence: 3iiDiii]

Adjuvant therapy

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 observation, radiation therapy, a second resection, and/or chemotherapy. A shunt or other cerebrospinal fluid diversion procedure may be needed.

Observation

In selected 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.[11]

Radiation therapy

Radiation therapy is usually reserved until progressive disease is documented [16,21] and may be further delayed through the use of chemotherapy, a strategy that is commonly employed in young children.[22,23] For children with low-grade gliomas for whom radiation therapy is indicated, conformal radiation therapy, intensity-modulated radiation therapy, or stereotactic radiation therapy approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with these modalities.[24]; [25][Level of evidence: 3iDiii] Care must be taken in separating radiation-induced imaging changes from disease progression during the first year after radiation, especially in patients with pilocytic astrocytomas.[26,27,28]; [29][Level of evidence: 2A]; [30][Level of evidence: 2C]; [31][Level of evidence: 3iiiDi]; [32][Level of evidence: 3iiiDii]; [15,33][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, and possibly an increased risk of secondary tumors.[8,34,35,36]; [30][Level of evidence: 2C]

Radiation therapy and alkylating agents are used as a last resort for patients with NF1, given the theoretically heightened risk of inducing neurologic toxic effects and second malignancy in this population.[37] Children with NF1 may be at higher risk for radiation-associated secondary tumors and morbidity due to vascular changes.

Second surgery

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.[8]

Chemotherapy

Given the 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.[22,23,38,39] Chemotherapy is also an option that may delay or avoid radiation therapy in adolescents with optic nerve pathway gliomas.[40][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.[41]

The most widely used regimens to treat tumor progression or symptomatic nonresectable, low-grade gliomas are carboplatin with or without vincristine [22,23,42] or a combination of thioguanine, procarbazine, lomustine, and vincristine (TPCV).[39]; [43][Level of evidence: 1iiA] 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 using one of two regimens: carboplatin and vincristine (CV) or TPCV. The 5-year event-free survival rate was 39% ± 4% for the CV regimen and 52% ± 5% for the TPCV regimen.[43]

Other chemotherapy approaches have been employed to treat children with progressive low-grade astrocytomas, including multiagent, platinum-based regimens [23,38,44]; [45][Level of evidence: 2Diii] and temozolomide.[46,47] Reported 5-year PFS rates have ranged from approximately 35% to 60% for children receiving platinum-based chemotherapy for optic pathway gliomas,[23,38] but most patients ultimately require further treatment. This is particularly true for children who initially present with hypothalamic/chiasmatic gliomas that have neuraxis dissemination.[48][Level of evidence: 3iiiDiii]

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.[23,38,44] Whether vision is improved with chemotherapy is unclear.[49,50][Level of evidence: 3iiiC]

Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in an overexpression of the mTOR complex 1. These children are at risk of developing subependymal giant cell astrocytomas (SEGA), in addition to cortical tubers and subependymal nodules. For children with symptomatic SEGAs, agents that inhibit mTOR (e.g., everolimus and sirolimus) have been shown in small series to cause significant reductions in the size of these tumors, often eliminating the need for surgery.[51]; [52][Level of evidence: 2C]; [53][Level of evidence: 3iiiC] A multicenter, phase III, placebo-controlled trial of 117 patients confirmed these earlier findings; 35% of the patients in the everolimus group had at least a 50% reduction in the size of the SEGA, versus no reduction in the placebo group.[54][Level of evidence: 1iDiv] Whether reduction in size of the mass is durable, obviating the need for future surgery, is currently unknown.

Treatment options under clinical evaluation

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.

  • PBTC-029 (NCT01089101) (Selumetinib in Treating Young Patients With Recurrent or Refractory Low-Grade Glioma): This is a clinical trial to determine the side effects and the best dose of the MEK inhibitor selumetinib in children with low-grade astrocytoma (phase I component). Based on activity observed in the phase I component (now completed), the study has been modified to include phase II expansion cohorts for patients with pilocytic astrocytoma and other low-grade astrocytomas with BRAF genomic alterations and for NF1 patients with recurrent low-grade astrocytomas.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood low-grade untreated astrocytoma or other tumor of glial origin. 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.

Treatment of Recurrent Childhood Low-Grade Astrocytomas

Childhood low-grade astrocytomas may recur many years after initial treatment. 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.[55,56] Most children whose low-grade fibrillary astrocytomas recur will harbor low-grade lesions; however, malignant transformation is possible.[57] Surveillance imaging will frequently identify asymptomatic recurrences.[58]

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 following:

  • Initial tumor type.
  • Length of time between initial treatment and the reappearance of the mass lesion.
  • Clinical picture.

An individual plan needs to be tailored based on the following:

  • Patient age.
  • Tumor location.
  • Prior treatment.

Standard treatment options for recurrent childhood low-grade astrocytomas include the following:

1. Second surgery.
2. Radiation therapy.
3. Chemotherapy.

Second surgery

Patients with low-grade astrocytomas who relapse after being treated with surgery alone should be considered for another surgical resection.[59]

Radiation therapy

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.[60][Level of evidence: 3iA]; [61][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.[27,30]

Chemotherapy

If there is recurrence at an unresectable site that has been previously irradiated, chemotherapy should be considered.[62]

In patients previously treated with surgery and radiation therapy, chemotherapy should be considered. Chemotherapy may result in relatively long-term disease control.[23,63] Vinblastine alone, temozolomide alone, or temozolomide in combination with carboplatin and vincristine may be useful at the time of recurrence for children with low-grade gliomas.[23,46,63]

Antitumor activity has also been observed for bevacizumab given in combination with irinotecan. In a phase II study of bevacizumab plus irinotecan for children with recurrent low-grade gliomas, sustained partial response was observed in only two patients (5.7%), but the 6-month PFS was 85.4% (standard error [SE] ± 5.96%) and the 2-year PFS was 47.8% (SE ± 9.27%).[64] A pilot study of 14 patients with recurrent low-grade gliomas also evaluated bevacizumab plus irinotecan and observed 12 patients (86%) with objective responses.[65][Level of evidence: 3iiDi]; [66][Level of evidence: 3iiiDiv] No patients progressed on therapy (median treatment duration, 12 months), but 13 of 14 progressed after stopping bevacizumab at a median of 5 months.

Treatment options under clinical evaluation

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.

  • ACNS1022 (NCT01553149) (Low-Dose or High-Dose Lenalidomide in Treating Younger Patients With Recurrent, Refractory, or Progressive Pilocytic Astrocytoma or Optic Pathway Glioma): This is a randomized phase II clinical trial comparing low-dose to high-dose lenalidomide to see how well each works in treating children with recurrent, refractory, or progressive juvenile pilocytic astrocytomas or optic nerve pathway gliomas. This clinical trial is based on results of a phase I study that observed tumor responses and long-term stable clinical disease for lenalidomide across a range of dose levels for children with recurrent low-grade gliomas.[67]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood astrocytoma or other tumor of glial origin. 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.

References:

1. Due-Tønnessen BJ, Helseth E, Scheie D, et al.: Long-term outcome after resection of benign cerebellar astrocytomas in children and young adults (0-19 years): report of 110 consecutive cases. Pediatr Neurosurg 37 (2): 71-80, 2002.
2. Nicolin G, Parkin P, Mabbott D, et al.: Natural history and outcome of optic pathway gliomas in children. Pediatr Blood Cancer 53 (7): 1231-7, 2009.
3. Kramm CM, Butenhoff S, Rausche U, et al.: Thalamic high-grade gliomas in children: a distinct clinical subset? Neuro Oncol 13 (6): 680-9, 2011.
4. Campbell JW, Pollack IF: Cerebellar astrocytomas in children. J Neurooncol 28 (2-3): 223-31, 1996 May-Jun.
5. Schneider JH Jr, Raffel C, McComb JG: Benign cerebellar astrocytomas of childhood. Neurosurgery 30 (1): 58-62; discussion 62-3, 1992.
6. Hayostek CJ, Shaw EG, Scheithauer B, et al.: Astrocytomas of the cerebellum. A comparative clinicopathologic study of pilocytic and diffuse astrocytomas. Cancer 72 (3): 856-69, 1993.
7. Listernick R, Ferner RE, Liu GT, et al.: Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 61 (3): 189-98, 2007.
8. Wisoff JH, Abbott R, Epstein F: Surgical management of exophytic chiasmatic-hypothalamic tumors of childhood. J Neurosurg 73 (5): 661-7, 1990.
9. Albright AL: Feasibility and advisability of resections of thalamic tumors in pediatric patients. J Neurosurg 100 (5 Suppl Pediatrics): 468-72, 2004.
10. Piccirilli M, Lenzi J, Delfinis C, et al.: Spontaneous regression of optic pathways gliomas in three patients with neurofibromatosis type I and critical review of the literature. Childs Nerv Syst 22 (10): 1332-7, 2006.
11. Wisoff JH, Sanford RA, Heier LA, et al.: Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group. Neurosurgery 68 (6): 1548-54; discussion 1554-5, 2011.
12. Tseng JH, Tseng MY: Survival analysis of 81 children with primary spinal gliomas: a population-based study. Pediatr Neurosurg 42 (6): 347-53, 2006.
13. Milano MT, Johnson MD, Sul J, et al.: Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study. J Neurooncol 98 (1): 83-92, 2010.
14. Scheinemann K, Bartels U, Huang A, et al.: Survival and functional outcome of childhood spinal cord low-grade gliomas. Clinical article. J Neurosurg Pediatr 4 (3): 254-61, 2009.
15. Sawamura Y, Kamada K, Kamoshima Y, et al.: Role of surgery for optic pathway/hypothalamic astrocytomas in children. Neuro Oncol 10 (5): 725-33, 2008.
16. Pollack IF, Claassen D, al-Shboul Q, et al.: Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases. J Neurosurg 82 (4): 536-47, 1995.
17. Turner CD, Chordas CA, Liptak CC, et al.: Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only. Pediatr Blood Cancer 53 (3): 417-23, 2009.
18. Daszkiewicz P, Maryniak A, Roszkowski M, et al.: Long-term functional outcome of surgical treatment of juvenile pilocytic astrocytoma of the cerebellum in children. Childs Nerv Syst 25 (7): 855-60, 2009.
19. Sutton LN, Cnaan A, Klatt L, et al.: Postoperative surveillance imaging in children with cerebellar astrocytomas. J Neurosurg 84 (5): 721-5, 1996.
20. Dorward IG, Luo J, Perry A, et al.: Postoperative imaging surveillance in pediatric pilocytic astrocytomas. J Neurosurg Pediatr 6 (4): 346-52, 2010.
21. Fisher BJ, Leighton CC, Vujovic O, et al.: Results of a policy of surveillance alone after surgical management of pediatric low grade gliomas. Int J Radiat Oncol Biol Phys 51 (3): 704-10, 2001.
22. Packer RJ, Ater J, Allen J, et al.: Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86 (5): 747-54, 1997.
23. Gnekow AK, Falkenstein F, von Hornstein S, et al.: Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol 14 (10): 1265-84, 2012.
24. Paulino AC, Mazloom A, Terashima K, et al.: Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma. Cancer 119 (14): 2654-9, 2013.
25. Müller K, Gnekow A, Falkenstein F, et al.: Radiotherapy in pediatric pilocytic astrocytomas. A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH). Strahlenther Onkol 189 (8): 647-55, 2013.
26. Chawla S, Korones DN, Milano MT, et al.: Spurious progression in pediatric brain tumors. J Neurooncol 107 (3): 651-7, 2012.
27. Marcus KJ, Goumnerova L, Billett AL, et al.: Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial. Int J Radiat Oncol Biol Phys 61 (2): 374-9, 2005.
28. Combs SE, Schulz-Ertner D, Moschos D, et al.: Fractionated stereotactic radiotherapy of optic pathway gliomas: tolerance and long-term outcome. Int J Radiat Oncol Biol Phys 62 (3): 814-9, 2005.
29. Merchant TE, Kun LE, Wu S, et al.: Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 27 (22): 3598-604, 2009.
30. Merchant TE, Conklin HM, Wu S, et al.: Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27 (22): 3691-7, 2009.
31. Kano H, Niranjan A, Kondziolka D, et al.: Stereotactic radiosurgery for pilocytic astrocytomas part 2: outcomes in pediatric patients. J Neurooncol 95 (2): 219-29, 2009.
32. Hallemeier CL, Pollock BE, Schomberg PJ, et al.: Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma. Int J Radiat Oncol Biol Phys 83 (1): 107-12, 2012.
33. Mansur DB, Rubin JB, Kidd EA, et al.: Radiation therapy for pilocytic astrocytomas of childhood. Int J Radiat Oncol Biol Phys 79 (3): 829-34, 2011.
34. Jenkin D, Angyalfi S, Becker L, et al.: Optic glioma in children: surveillance, resection, or irradiation? Int J Radiat Oncol Biol Phys 25 (2): 215-25, 1993.
35. Tao ML, Barnes PD, Billett AL, et al.: Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome. Int J Radiat Oncol Biol Phys 39 (3): 579-87, 1997.
36. Khafaga Y, Hassounah M, Kandil A, et al.: Optic gliomas: a retrospective analysis of 50 cases. Int J Radiat Oncol Biol Phys 56 (3): 807-12, 2003.
37. Grill J, Couanet D, Cappelli C, et al.: Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 45 (3): 393-6, 1999.
38. Laithier V, Grill J, Le Deley MC, et al.: Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology. J Clin Oncol 21 (24): 4572-8, 2003.
39. Prados MD, Edwards MS, Rabbitt J, et al.: Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen. J Neurooncol 32 (3): 235-41, 1997.
40. Chong AL, Pole JD, Scheinemann K, et al.: Optic pathway gliomas in adolescence--time to challenge treatment choices? Neuro Oncol 15 (3): 391-400, 2013.
41. Gropman AL, Packer RJ, Nicholson HS, et al.: Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control. Cancer 83 (1): 166-72, 1998.
42. Gururangan S, Cavazos CM, Ashley D, et al.: Phase II study of carboplatin in children with progressive low-grade gliomas. J Clin Oncol 20 (13): 2951-8, 2002.
43. Ater JL, Zhou T, Holmes E, et al.: Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol 30 (21): 2641-7, 2012.
44. Massimino M, Spreafico F, Cefalo G, et al.: High response rate to cisplatin/etoposide regimen in childhood low-grade glioma. J Clin Oncol 20 (20): 4209-16, 2002.
45. Massimino M, Spreafico F, Riva D, et al.: A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J Neurooncol 100 (1): 65-71, 2010.
46. Gururangan S, Fisher MJ, Allen JC, et al.: Temozolomide in children with progressive low-grade glioma. Neuro Oncol 9 (2): 161-8, 2007.
47. Khaw SL, Coleman LT, Downie PA, et al.: Temozolomide in pediatric low-grade glioma. Pediatr Blood Cancer 49 (6): 808-11, 2007.
48. von Hornstein S, Kortmann RD, Pietsch T, et al.: Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatr Blood Cancer 56 (7): 1046-54, 2011.
49. Moreno L, Bautista F, Ashley S, et al.: Does chemotherapy affect the visual outcome in children with optic pathway glioma? A systematic review of the evidence. Eur J Cancer 46 (12): 2253-9, 2010.
50. Shofty B, Ben-Sira L, Freedman S, et al.: Visual outcome following chemotherapy for progressive optic pathway gliomas. Pediatr Blood Cancer 57 (3): 481-5, 2011.
51. Franz DN, Agricola KD, Tudor CA, et al.: Everolimus for tumor recurrence after surgical resection for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. J Child Neurol 28 (5): 602-7, 2013.
52. Krueger DA, Care MM, Holland K, et al.: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363 (19): 1801-11, 2010.
53. Franz DN, Leonard J, Tudor C, et al.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59 (3): 490-8, 2006.
54. Franz DN, Belousova E, Sparagana S, et al.: Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381 (9861): 125-32, 2013.
55. Perilongo G, Carollo C, Salviati L, et al.: Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region. Cancer 80 (1): 142-6, 1997.
56. Leibel SA, Sheline GE, Wara WM, et al.: The role of radiation therapy in the treatment of astrocytomas. Cancer 35 (6): 1551-7, 1975.
57. Giannini C, Scheithauer BW: Classification and grading of low-grade astrocytic tumors in children. Brain Pathol 7 (2): 785-98, 1997.
58. Udaka YT, Yeh-Nayre LA, Amene CS, et al.: Recurrent pediatric central nervous system low-grade gliomas: the role of surveillance neuroimaging in asymptomatic children. J Neurosurg Pediatr 11 (2): 119-26, 2013.
59. Austin EJ, Alvord EC Jr: Recurrences of cerebellar astrocytomas: a violation of Collins' law. J Neurosurg 68 (1): 41-7, 1988.
60. Scheinemann K, Bartels U, Tsangaris E, et al.: Feasibility and efficacy of repeated chemotherapy for progressive pediatric low-grade gliomas. Pediatr Blood Cancer 57 (1): 84-8, 2011.
61. de Haas V, Grill J, Raquin MA, et al.: Relapses of optic pathway tumors after first-line chemotherapy. Pediatr Blood Cancer 52 (5): 575-80, 2009.
62. Garcia DM, Marks JE, Latifi HR, et al.: Childhood cerebellar astrocytomas: is there a role for postoperative irradiation? Int J Radiat Oncol Biol Phys 18 (4): 815-8, 1990.
63. Packer RJ, Lange B, Ater J, et al.: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol 11 (5): 850-6, 1993.
64. Gururangan S, Fangusaro J, Poussaint TY, et al.: Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study. Neuro Oncol 16 (2): 310-7, 2014.
65. Hwang EI, Jakacki RI, Fisher MJ, et al.: Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas. Pediatr Blood Cancer 60 (5): 776-82, 2013.
66. Packer RJ, Jakacki R, Horn M, et al.: Objective response of multiply recurrent low-grade gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer 52 (7): 791-5, 2009.
67. Warren KE, Goldman S, Pollack IF, et al.: Phase I trial of lenalidomide in pediatric patients with recurrent, refractory, or progressive primary CNS tumors: Pediatric Brain Tumor Consortium study PBTC-018. J Clin Oncol 29 (3): 324-9, 2011.

Treatment of Childhood High-Grade Astrocytomas

To determine and implement optimum management, treatment 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

Outcome in high-grade gliomas occurring in childhood may be more favorable than that in adults, but it is not clear whether this difference is caused by biologic variations in tumor characteristics, therapies used, tumor resectability, or other factors that are presently not understood.[1]

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:

1. Surgery.
2. Adjuvant therapy.
  • Radiation therapy.
  • Chemotherapy.

Surgery

The ability to obtain a complete resection is associated with a better prognosis.[2,3] 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] Similarly, in a trial of multiagent chemoradiation therapy and adjuvant chemotherapy in addition to valproic acid, 5-year event-free survival (EFS) was 13%, but for children with a complete resection of their tumor, the EFS was 48%.[5][Level of evidence: 2A]

Adjuvant therapy

Radiation therapy

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 rates remain poor. Similarly poor survival is seen in children with spinal cord primaries and children with thalamic high-grade gliomas.[6,7]; [8,9][Level of evidence: 3iiiA]

Chemotherapy

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.[10]

In adults, the addition of temozolomide during and after radiation therapy resulted in improved 2-year EFS as compared with treatment with radiation therapy alone. Adult patients with glioblastoma with a methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not benefit from temozolomide.[11,12] 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 [13] and again demonstrated a survival advantage for those children with a methylated MGMT promoter.

Younger children may benefit from chemotherapy to delay, modify, or, in selected cases, obviate the need for radiation therapy.[14,15,16]

Clinical trials that evaluate chemotherapy with or without radiation therapy are ongoing. Information about ongoing clinical trials is available from the NCI Web site.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted or is under analysis. Information about ongoing clinical trials is available from the NCI Web site.

  • ACNS0822 (NCT01236560) (Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma): The Children's Oncology Group is conducting a randomized phase II/III study of vorinostat and local radiation therapy, temozolomide and local radiation therapy, or bevacizumab and radiation therapy followed by maintenance bevacizumab and temozolomide in newly diagnosed high-grade glioma.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood high-grade untreated astrocytoma or other tumor of glial origin. 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.

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 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 following:

  • Initial tumor type.
  • Length of time between initial treatment and the reappearance of the mass lesion.
  • Clinical picture.

Patients for whom initial treatment fails may benefit from additional treatment.[17] High-dose, marrow-ablative chemotherapy with hematopoietic stem cell transplant may be effective in a subset of patients with minimal residual disease at time of recurrence.[18]; [19][Level of evidence: 3iiiA] Such patients should also be considered for entry into trials of novel therapeutic approaches.

Treatment options under clinical evaluation

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group, the Pediatric Brain Tumor Consortium, or other entities. Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood astrocytoma or other tumor of glial origin. 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.

References:

1. Rasheed BK, McLendon RE, Herndon JE, et al.: Alterations of the TP53 gene in human gliomas. Cancer Res 54 (5): 1324-30, 1994.
2. Wisoff JH, Boyett JM, Berger MS, et al.: Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group trial no. CCG-945. J Neurosurg 89 (1): 52-9, 1998.
3. Yang T, Temkin N, Barber J, et al.: Gross total resection correlates with long-term survival in pediatric patients with glioblastoma. World Neurosurg 79 (3-4): 537-44, 2013 Mar-Apr.
4. Fouladi M, Hunt DL, Pollack IF, et al.: Outcome of children with centrally reviewed low-grade gliomas treated with chemotherapy with or without radiotherapy on Children's Cancer Group high-grade glioma study CCG-945. Cancer 98 (6): 1243-52, 2003.
5. Wolff JE, Driever PH, Erdlenbruch B, et al.: Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol. Cancer 116 (3): 705-12, 2010.
6. Kramm CM, Butenhoff S, Rausche U, et al.: Thalamic high-grade gliomas in children: a distinct clinical subset? Neuro Oncol 13 (6): 680-9, 2011.
7. Tendulkar RD, Pai Panandiker AS, Wu S, et al.: Irradiation of pediatric high-grade spinal cord tumors. Int J Radiat Oncol Biol Phys 78 (5): 1451-6, 2010.
8. Wolff B, Ng A, Roth D, et al.: Pediatric high grade glioma of the spinal cord: results of the HIT-GBM database. J Neurooncol 107 (1): 139-46, 2012.
9. Ononiwu C, Mehta V, Bettegowda C, et al.: Pediatric spinal glioblastoma multiforme: current treatment strategies and possible predictors of survival. Childs Nerv Syst 28 (5): 715-20, 2012.
10. Sposto R, Ertel IJ, Jenkin RD, et al.: The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neurooncol 7 (2): 165-77, 1989.
11. Stupp R, Mason WP, van den Bent MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10): 987-96, 2005.
12. Hegi ME, Diserens AC, Gorlia T, et al.: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352 (10): 997-1003, 2005.
13. Cohen KJ, Pollack IF, Zhou T, et al.: Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group. Neuro Oncol 13 (3): 317-23, 2011.
14. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993.
15. Duffner PK, Krischer JP, Burger PC, et al.: Treatment of infants with malignant gliomas: the Pediatric Oncology Group experience. J Neurooncol 28 (2-3): 245-56, 1996 May-Jun.
16. Dufour C, Grill J, Lellouch-Tubiana A, et al.: High-grade glioma in children under 5 years of age: a chemotherapy only approach with the BBSFOP protocol. Eur J Cancer 42 (17): 2939-45, 2006.
17. Warren KE, Gururangan S, Geyer JR, et al.: A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. J Neurooncol 106 (3): 643-9, 2012.
18. McCowage GB, Friedman HS, Moghrabi A, et al.: Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas. Med Pediatr Oncol 30 (2): 75-80, 1998.
19. Finlay JL, Dhall G, Boyett JM, et al.: Myeloablative chemotherapy with autologous bone marrow rescue in children and adolescents with recurrent malignant astrocytoma: outcome compared with conventional chemotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 806-11, 2008.

Changes to this Summary (01 / 31 / 2014)

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 and extensively revised.

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.

About This PDQ Summary

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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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:

  • Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
  • Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
  • Karen J Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Roger J. Packer, MD (Children's National Medical Center)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Astrocytomas Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/child-astrocytomas/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Last Revised: 2014-01-31

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