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Childhood Brain Stem Glioma

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood brain stem glioma.


Childhood Brain Stem Glioma

General Information

This cancer treatment information summary provides an overview of the diagnosis, classification, treatment, and prognosis of childhood brain stem gliomas.

The National Cancer Institute 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. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

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 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.

The classification of childhood brain tumors is based not only on histology, but also on location. Tumors are classically categorized as being infratentorial, sellar or suprasellar, or cortical based. Common infratentorial (posterior fossa) tumors include the following:

  1. Cerebellar astrocytomas (usually pilocytic but also fibrillary and, less frequently, high grade).
  2. Medulloblastomas (primitive neuroectodermal tumors [PNET]).
  3. Ependymomas (cellular, papillary, clear cell, tanycytic, or anaplastic).
  4. Brain stem gliomas are typically diffuse intrinsic pontine gliomas or diffuse intrinsic high-grade tumors that are diagnosed neuroradiographically without biopsy. Focal, tectal, and cervicomedullary tumors are generally low-grade tumors.
  5. Atypical teratoid/rhabdoid tumors (AT/RT).

Tumors that occur supratentorially include the following:

  1. Low-grade cerebral hemispheric astrocytomas (grade 1 [pilocytic] or grade 2).
  2. High-grade or malignant astrocytomas (anaplastic astrocytomas, glioblastoma multiforme [grade 3 or grade 4]).
  3. Mixed gliomas (low grade or high grade).
  4. Oligodendrogliomas (low grade or high grade).
  5. Primitive neuroectodermal tumors (including cerebral neuroblastomas, pineoblastomas, ependymoblastomas).
  6. AT/RT.
  7. Ependymomas (cellular or anaplastic).
  8. Meningiomas.
  9. Choroid plexus tumors (papillomas and carcinomas).
  10. Pineal parenchymal tumors (pineocytomas or mixed pineal parenchymal tumors).
  11. Neuronal and mixed neuronal glial tumors (gangliogliomas, desmoplastic infantile gangliogliomas, dysembryoplastic neuroepithelial tumors).
  12. Metastasis (rare) from extraneural malignancies.

In addition to those tumors that occur supratentorially, other tumors that most commonly occur in the sellar or suprasellar region are:

  1. Craniopharyngiomas.
  2. Diencephalic astrocytomas (central tumors involving the chiasm, hypothalamus, and/or thalamus) that are generally low grade (including astrocytomas, grade 1 [pilocytic] or grade 2).
  3. Germ cell tumors (germinomas and nongerminomatous).

Important general concepts that should be understood by those caring for a child with a brain tumor include the following:

  1. Selection of an appropriate therapy can only occur if the correct diagnosis is made and the stage of the disease is accurately determined.
  2. Children with primary brain tumors represent a major therapy challenge that, for optimal results, requires the coordinated efforts of pediatric specialists in fields such as neurosurgery, neuropathology, radiation oncology, pediatric oncology, neuro-oncology, neurology, rehabilitation, neuroradiology, endocrinology, and psychology, who have special expertise in the care of patients with these diseases.1,2,3,
  3. More than one half of children diagnosed with brain tumors will survive 5 years after diagnosis. In some subgroups of patients, an even higher rate of survival and cure is possible. Each child’s treatment should be approached with curative intent, and the possible long-term sequelae of the disease and its treatment should be considered before therapy begins.
  4. For most childhood brain tumors, the optimal treatment regimen has not been determined. Children who have brain tumors should be considered for enrollment in clinical trials when an appropriate study is available. Such clinical trials are being carried out by institutions and cooperative groups.
  5. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.4,
  6. The cause of most childhood brain tumors remains unknown.5,6,

This summary discusses the treatment of childhood brain stem glioma.

Information about ongoing clinical trials is available from the NCI Web site.



1 Strother DR, Poplack IF, Fisher PG, et al.: Tumors of the central nervous system. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins, 2002, pp 751-824.

2 Pollack IF: Brain tumors in children. N Engl J Med 331 (22): 1500-7, 1994.

3 Cohen ME, Duffner PK, eds.: Brain Tumors in Children: Principles of Diagnosis and Treatment. 2nd ed. New York: Raven Press, 1994.

4 Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

5 Kuijten RR, Bunin GR: Risk factors for childhood brain tumors. Cancer Epidemiol Biomarkers Prev 2 (3): 277-88, 1993 May-Jun.

6 Kuijten RR, Strom SS, Rorke LB, et al.: Family history of cancer and seizures in young children with brain tumors: a report from the Childrens Cancer Group (United States and Canada). Cancer Causes Control 4 (5): 455-64, 1993.

Cellular Classification

Brain stem gliomas are classified according to their location, radiographic appearance, and histology (when obtained). Brain stem gliomas may occur in the pons, the midbrain, the tectum, the dorsum of the medulla at the cervicomedullary junction, or in multiple regions of the brain stem. The tumor may contiguously involve the cerebellar peduncles, cerebellum and/or thalamus. The majority of childhood brain stem gliomas are diffuse, intrinsic tumors that involve the pons (diffuse intrinsic pontine gliomas [DIPG]), often with contiguous involvement of other brain stem sites.1,2,3,4 The prognosis is poor for these tumors. A prognostically more favorable subset of tumors are focal pilocytic astrocytomas. These most frequently arise in the tectum of the midbrain, focally, within the pons, or at the cervicomedullary junction, and have a far better prognosis than diffuse intrinsic tumors.2,3,5,6,7,

Primary tumors of the brain stem are most often diagnosed based on clinical findings and on neuroimaging studies,8 and there is a substantial amount of histologic variability within an individual tumor. DIPGs are generally fibrillary astrocytomas. However, histologic confirmation is usually unnecessary. Biopsy specimens of intrinsic brain stem gliomas may be misleading because of sampling error. Biopsy or resection may be indicated for brain stem tumors that are not diffuse and intrinsic. New approaches with stereotactic needle biopsy may make biopsy safer.9



1 Cohen ME, Duffner PK, Heffner RR, et al.: Prognostic factors in brainstem gliomas. Neurology 36 (5): 602-5, 1986.

2 Albright AL, Guthkelch AN, Packer RJ, et al.: Prognostic factors in pediatric brain-stem gliomas. J Neurosurg 65 (6): 751-5, 1986.

3 Halperin EC, Wehn SM, Scott JW, et al.: Selection of a management strategy for pediatric brainstem tumors. Med Pediatr Oncol 17 (2): 117-26, 1989.

4 Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40 (2): 265-71, 1998.

5 Epstein F, McCleary EL: Intrinsic brain-stem tumors of childhood: surgical indications. J Neurosurg 64 (1): 11-5, 1986.

6 Edwards MS, Wara WM, Ciricillo SF, et al.: Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases. J Neurosurg 80 (1): 20-5, 1994.

7 Pollack IF, Pang D, Albright AL: The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. J Neurosurg 80 (4): 681-8, 1994.

8 Albright AL, Packer RJ, Zimmerman R, et al.: Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children's Cancer Group. Neurosurgery 33 (6): 1026-9; discussion 1029-30, 1993.

9 Cartmill M, Punt J: Diffuse brain stem glioma. A review of stereotactic biopsies. Childs Nerv Syst 15 (5): 235-7; discussion 238, 1999.

Stage Information

There is no generally applied staging system for childhood brain stem gliomas.1,2,3 It is uncommon for these tumors to have spread outside the brain stem itself at the time of initial diagnosis. Spread of malignant brain stem tumors is usually contiguous; metastasis via the subarachnoid space has been reported in up to 30% of cases diagnosed antemortem.4 Such dissemination may occur prior to local relapse but usually occurs simultaneously with or after local disease relapse.

The less common tumors of the midbrain, especially in the tectal plate region, have been viewed separately from those of the brain stem because they are more likely to be low grade and have a greater likelihood of long-term survival (approximately 80% 5-year progression-free survival vs. less than 20% for tumors of the pons and medulla).1,2,3,5,6,7,8,9 Similarly, dorsally exophytic and cervicomedullary tumors are generally low grade and have a relatively favorable prognosis.



1 Cohen ME, Duffner PK, Heffner RR, et al.: Prognostic factors in brainstem gliomas. Neurology 36 (5): 602-5, 1986.

2 Albright AL, Guthkelch AN, Packer RJ, et al.: Prognostic factors in pediatric brain-stem gliomas. J Neurosurg 65 (6): 751-5, 1986.

3 Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40 (2): 265-71, 1998.

4 Packer RJ, Allen J, Nielsen S, et al.: Brainstem glioma: clinical manifestations of meningeal gliomatosis. Ann Neurol 14 (2): 177-82, 1983.

5 Halperin EC, Wehn SM, Scott JW, et al.: Selection of a management strategy for pediatric brainstem tumors. Med Pediatr Oncol 17 (2): 117-26, 1989.

6 Epstein F, McCleary EL: Intrinsic brain-stem tumors of childhood: surgical indications. J Neurosurg 64 (1): 11-5, 1986.

7 Edwards MS, Wara WM, Ciricillo SF, et al.: Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases. J Neurosurg 80 (1): 20-5, 1994.

8 Pollack IF, Pang D, Albright AL: The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. J Neurosurg 80 (4): 681-8, 1994.

9 Mandell LR, Kadota R, Freeman C, et al.: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 43 (5): 959-64, 1999.

Treatment Option Overview

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 (including 3-dimensional conformal 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 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.4,5 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.



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 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.

5 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.

Untreated Childhood Brain Stem Glioma

Diffuse Intrinsic Pontine Gliomas

Conventional treatment for children with diffuse intrinsic pontine glioma (DIPG) is radiation therapy to involved areas. Such treatment will result in transient benefit for most patients, but over 90% of patients will die within 18 months of diagnosis. The conventional dose of radiation therapy ranges between 5,400 cGy and 6,000 cGy given locally to the primary tumor site in single daily fractions.

Hyperfractionated (twice daily) radiation therapy techniques have been used to deliver a higher dose, and studies using doses as high as 7,800 cGy have been completed. Evidence demonstrates that these increased radiation therapy doses do not improve the duration or rate of survival for patients with DIPG whether given alone,1,2 or in combination with chemotherapy.3 Studies evaluating the efficacy of various radiosensitizers as a means for enhancing the therapeutic effect of this modality are under study but to date have failed to show significant improvement in outcome.2,3,4,5,6,

The utility of chemotherapy in the treatment of patients with newly diagnosed DIPG is unproven.2,3,5,6,7,8,9,10 To date, neither adjuvant or neoadjuvant chemotherapy, nor immunotherapy when added to radiation therapy has been demonstrated to improve survival for children with DIPG. Similarly, studies utilizing high-dose therapy with stem cell rescue have been ineffective in extending survival.11 Studies using new anti-cancer agents with alternative mechanisms of actions and brain stem radiation are ongoing.

Treatment options under clinical evaluation

  • The Children’s Oncology Group recently completed a phase II study of low-dose temozolomide during irradiation followed by adjuvant temozolomide on a 5-day schedule (ACNS0126).12 Results are pending. The current COG trial is a phase I/II study of topotecan and concomitant radiation therapy (ANCS0224).13,
  • The Pediatric Brain Tumor Consortium is coordinating multiple studies, including a phase II study (PBTC-014) 14 of an oral farnesyl protein transferase inhibitor (tipifarnib) administered during and after radiation therapy, which is closed and results are pending; a phase II study (PBTC-006) 15 of imatinib mesylate after radiation therapy; and a phase II study (PBTC-007) 16 of an anti-epidermal growth factor receptor (EGFr) agent (gefitinib) during and after radiation therapy.

Focal or Low-grade Brain Stem Gliomas

In general, maximal surgical resection should be attempted.17 Patients with residual tumors may be candidates for additional therapy including radiation or adjuvant therapy including 3-dimensional conformal approaches. Information about ongoing clinical trials is available from the NCI Web site.

Patients with small tectal lesions and hydrocephalus but no other neurological deficits may be treated with cerebrospinal fluid diversion alone and have follow-up with sequential neuroradiographic studies unless there is evidence of progressive disease.17,

Neurofibromatosis

Children with neurofibromatosis type I and brain stem gliomas may have a different prognosis than other patients who have intrinsic lesions. Patients with neurofibromatosis may present with a long history of symptoms or be identified on screening tests; a period of observation may be indicated before instituting any treatment.18 Brain stem gliomas in these children may be indolent and may require no specific treatment for years.19,



1 Freeman CR, Krischer JP, Sanford RA, et al.: Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys 27 (2): 197-206, 1993.

2 Mandell LR, Kadota R, Freeman C, et al.: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 43 (5): 959-64, 1999.

3 Allen J, Siffert J, Donahue B, et al.: A phase I/II study of carboplatin combined with hyperfractionated radiotherapy for brainstem gliomas. Cancer 86 (6): 1064-9, 1999.

4 Freeman CR, Kepner J, Kun LE, et al.: A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas? Int J Radiat Oncol Biol Phys 47 (3): 561-4, 2000.

5 Broniscer A, Leite CC, Lanchote VL, et al.: Radiation therapy and high-dose tamoxifen in the treatment of patients with diffuse brainstem gliomas: results of a Brazilian cooperative study. Brainstem Glioma Cooperative Group. J Clin Oncol 18 (6): 1246-53, 2000.

6 Doz F, Neuenschwander S, Bouffet E, et al.: Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d'Oncologie Pédiatrique. Eur J Cancer 38 (6): 815-9, 2002.

7 Jenkin RD, Boesel C, Ertel I, et al.: Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Childrens Cancer Study Group. J Neurosurg 66 (2): 227-33, 1987.

8 Blaney SM, Phillips PC, Packer RJ, et al.: Phase II evaluation of topotecan for pediatric central nervous system tumors. Cancer 78 (3): 527-31, 1996.

9 Jennings MT, Sposto R, Boyett JM, et al.: Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group. J Clin Oncol 20 (16): 3431-7, 2002.

10 Wolff JE, Westphal S, Mölenkamp G, et al.: Treatment of paediatric pontine glioma with oral trophosphamide and etoposide. Br J Cancer 87 (9): 945-9, 2002.

11 Bouffet E, Raquin M, Doz F, et al.: Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer 88 (3): 685-92, 2000.

12 Cohen KJ, Children's Oncology Group: Phase II Pilot Study of Adjuvant Temozolomide Concurrently With Postoperative Radiotherapy and Then Alone As Maintenance Therapy in Children With Newly Diagnosed Anaplastic Astrocytoma, Glioblastoma Multiforme, Gliosarcoma, or Diffuse Intrinsic Pontine Glioma, COG-ACNS0126, Clinical trial, Closed.

13 Robertson PL, Children's Oncology Group: Phase I/II Study of Topotecan, Filgrastim (G-CSF), and Radiotherapy in Young Patients With Newly Diagnosed Malignant Intrinsic Pontine Brain Stem Glioma, COG-ACNS0224, Clinical trial, Active.

14 Haas-Kogan DA, Pediatric Brain Tumor Consortium: Phase I/II Study of Tipifarnib and Radiotherapy in Pediatric Patients With Non-Disseminated Intrinsic Diffuse Brainstem Gliomas (Phase I Closed to Accrual as of 1/3/06), PBTC-014, Clinical trial, Active.

15 Pollack I F, Pediatric Brain Tumor Consortium: Phase I/II Study of Imatinib Mesylate With or Without Radiotherapy in Children With Newly Diagnosed Poor Prognosis Brainstem Glioma or Recurrent High-Grade Intracranial Glioma (Phase I, strata I and IIA closed to accrual as of 5/10/04.), PBTC-006, Clinical trial, Closed.

16 Geyer JR, Pediatric Brain Tumor Consortium: Phase II Study of Gefitinib and Brain Irradiation in Children With Newly Diagnosed Brain Stem Tumors or Incompletely Resected Supratentorial Malignant Gliomas, PBTC-007, Clinical trial, Closed.

17 Vandertop WP, Hoffman HJ, Drake JM, et al.: Focal midbrain tumors in children. Neurosurgery 31 (2): 186-94, 1992.

18 Bilaniuk LT, Molloy PT, Zimmerman RA, et al.: Neurofibromatosis type 1: brain stem tumours. Neuroradiology 39 (9): 642-53, 1997.

19 Molloy PT, Bilaniuk LT, Vaughan SN, et al.: Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology 45 (10): 1897-902, 1995.

Recurrent Childhood Brain Stem Glioma

Diffuse Intrinsic Pontine Gliomas

Given the dismal prognosis for patients with diffuse intrinsic pontine glioma (DIPG), progression of the pontine lesion is anticipated generally within 1 year from initial radiation therapy. In most cases, biopsy at the time of clinical or radiologic progression is neither necessary nor recommended. To date, no salvage regimen has been shown to extend survival. Patients should be considered for entry into trials of novel therapeutic approaches because there are no standard agents that have demonstrated a clinically significant activity. Concomitant palliative care should be provided for these patients whether or not disease-directed therapy is administered.

Focal or low-grade brain stem gliomas

At the time of recurrence, a complete evaluation to determine the extent of the relapse may be indicated for selected low-grade lesions. Biopsy or surgical resection should be considered for confirmation of relapse when other entities such as secondary tumor and treatment-related brain necrosis, which may be clinically indistinguishable from tumor recurrence, are in the differential. Other tests, such as positron-emission tomography and single-photon emission computed tomography, have not yet been shown to be reliable in distinguishing necrosis from tumor recurrence in brain stem gliomas.

Treatment considerations at the time of recurrence or progression are dependent on prior treatment. Considerations include: further surgical resection, irradiation including 3-dimensional conformal approaches, or chemotherapy. The need for surgical intervention must be individualized on the basis of the initial tumor type, the location within the brain stem, the length of time between initial treatment and the appearance of the mass lesion, and the clinical picture.1

Chemotherapy with agents such as a carboplatin and vincristine may be effective in children with recurrent low-grade exophytic gliomas. 2,3,



1 Bowers DC, Krause TP, Aronson LJ, et al.: Second surgery for recurrent pilocytic astrocytoma in children. Pediatr Neurosurg 34 (5): 229-34, 2001.

2 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.

3 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.

Changes to This Summary (06/22/2006)

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.

Stage Information

Added text to state that dorsally exophytic and cervicomedullary tumors are generally low grade and have a relatively favorable prognosis.

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Important:

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2006-06-22







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