Childhood Brain Stem Glioma Treatment (PDQ®)

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General Information

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.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.

Refer to the PDQ summary Childhood Brain and Spinal Cord Tumors Treatment Overview for information about the general classification of childhood brain and spinal cord tumors.

References:
  • Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.

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, midbrain, tectum, 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, the cervical spinal cord, and/or thalamus. The majority of childhood brain stem gliomas are diffuse, fibrillary astrocytomas that involve the pons (diffuse intrinsic pontine gliomas [DIPG]), often with contiguous involvement of other brain stem sites. The prognosis is extremely poor for these tumors. The biology of diffuse pontine glioma is limited by the lack of pathological tissue available for study, but this is slowly being remedied by occasional upfront biopsies or analysis of immediate postmortem autopsy specimens. Overexpression of epidermal growth factor receptor, platelet-derived growth factor receptor alpha, and poly (ADP-ribose) polymerase (PARP-1) have been identified. Focal pilocytic astrocytomas have a more favorable prognosis. These most frequently arise in the tectum of the midbrain, focally, within the pons, or at the cervicomedullary junction where they are often exophytic, and have a far better prognosis than diffuse intrinsic tumors.

Primary tumors of the brain stem are most often diagnosed based on clinical findings and on neuroimaging studies using magnetic resonance imaging. Histologic confirmation of presumed DIPG is usually unnecessary. Biopsy or resection may be indicated for brain stem tumors that are not diffuse and intrinsic or when there is diagnostic uncertainty based on imaging findings. New approaches with stereotactic needle biopsy may make biopsy safer.

References:
  • Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40 (2): 265-71, 1998.
  • Laigle-Donadey F, Doz F, Delattre JY: Brainstem gliomas in children and adults. Curr Opin Oncol 20 (6): 662-7, 2008.
  • Gilbertson RJ, Hill DA, Hernan R, et al.: ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res 9 (10 Pt 1): 3620-4, 2003.
  • Zarghooni M, Bartels U, Lee E, et al.: Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28 (8): 1337-44, 2010.
  • Epstein F, McCleary EL: Intrinsic brain-stem tumors of childhood: surgical indications. J Neurosurg 64 (1): 11-5, 1986.
  • 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.
  • 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.
  • 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.
  • Liu AK, Brandon J, Foreman NK, et al.: Conventional MRI at presentation does not predict clinical response to radiation therapy in children with diffuse pontine glioma. Pediatr Radiol 39 (12): 1317-20, 2009.
  • 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. 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. 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. <10% for tumors of the pons). Similarly, dorsally exophytic and cervicomedullary tumors are generally low grade and have a relatively favorable prognosis. Children younger than 3 years may have a more favorable prognosis, perhaps reflecting different biologic characteristics.

References:
  • Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40 (2): 265-71, 1998.
  • Packer RJ, Allen J, Nielsen S, et al.: Brainstem glioma: clinical manifestations of meningeal gliomatosis. Ann Neurol 14 (2): 177-82, 1983.
  • 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.
  • Epstein F, McCleary EL: Intrinsic brain-stem tumors of childhood: surgical indications. J Neurosurg 64 (1): 11-5, 1986.
  • 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.
  • 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.
  • 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.
  • Broniscer A, Laningham FH, Sanders RP, et al.: Young age may predict a better outcome for children with diffuse pontine glioma. Cancer 113 (3): 566-72, 2008.

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.

Untreated Childhood Brain Stem Glioma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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 54 Gy and 60 Gy 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 78 Gy 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, or in combination with chemotherapy. Studies evaluating the efficacy of various radiosensitizers as a means for enhancing the therapeutic effect of this modality have been undertaken but to date have failed to show any significant improvement in outcome. Radiation-induced changes may occur a few months after the completion of radiation therapy and may mimic tumor progression. When considering the efficacy of additional treatment, care needs to be taken to separate radiation-induced change from progressive disease.

The utility of chemotherapy in the treatment of patients with newly diagnosed DIPG is unproven.; [Level of evidence: 2A] Currently, no chemotherapeutic strategy—including neoadjuvant, concurrent, post-radiation survival or immunotherapy—when added to radiation therapy has led to long-term survival for children with DIPG. Similarly, studies utilizing high-dose, marrow-ablative chemotherapy with autologous hematopoietic stem cell rescue have been ineffective in extending survival. Consonant with other brain tumors, radiation therapy is often omitted for infants with DIPG and chemotherapy-only approaches are utilized.

Treatment options under clinical evaluation

Studies using new anticancer agents with alternative mechanisms of actions and brain stem radiation are ongoing.

  • PBTC-030: The Pediatric Brain Tumor Consortium (PBTC) is conducting a phase II study of capecitabine and concomitant radiation therapy.

Focal or Low-grade Brain Stem Gliomas

In general, maximal surgical resection should be attempted. Patients with residual tumors may be candidates for additional therapy including 3-dimensional conformal radiation therapy approaches with or without adjuvant chemotherapy. 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.

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. Brain stem gliomas in these children may be indolent and may require no specific treatment for years.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood brain stem glioma. 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Liu AK, Macy ME, Foreman NK: Bevacizumab as therapy for radiation necrosis in four children with pontine gliomas. Int J Radiat Oncol Biol Phys 75 (4): 1148-54, 2009.
  • 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.
  • 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.
  • 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.
  • Korones DN, Fisher PG, Kretschmar C, et al.: Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children's Oncology Group phase II study. Pediatr Blood Cancer 50 (2): 227-30, 2008.
  • Frappaz D, Schell M, Thiesse P, et al.: Preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas: final results of BSG 98 prospective trial. Neuro Oncol 10 (4): 599-607, 2008.
  • Frazier JL, Lee J, Thomale UW, et al.: Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies. J Neurosurg Pediatr 3 (4): 259-69, 2009.
  • Hargrave D, Bartels U, Bouffet E: Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7 (3): 241-8, 2006.
  • 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.
  • Vandertop WP, Hoffman HJ, Drake JM, et al.: Focal midbrain tumors in children. Neurosurgery 31 (2): 186-94, 1992.
  • Kestle J, Townsend JJ, Brockmeyer DL, et al.: Juvenile pilocytic astrocytoma of the brainstem in children. J Neurosurg 101 (1 Suppl): 1-6, 2004.
  • Bilaniuk LT, Molloy PT, Zimmerman RA, et al.: Neurofibromatosis type 1: brain stem tumours. Neuroradiology 39 (9): 642-53, 1997.
  • 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, 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, magnetic resonance spectroscopy, and single-photon emission computed tomography, have not yet been shown to be reliable in distinguishing necrosis from tumor recurrence in brain stem gliomas. Radiation-induced changes may occur a few months after the completion of radiation therapy and may mimic tumor progression. When considering the efficacy of additional treatment, care needs to be taken to separate radiation-induced change from progressive disease.

Treatment considerations at the time of recurrence or progression are dependent on prior treatment. Considerations include: further surgical resection, irradiation including 3-dimensional conformal radiation therapy, 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.

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

Treatment Options Under Clinical Evaluation

Early phase therapeutic trials may be available for selected patients. These trials may be available via Children's Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium or other entities.

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

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This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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 brain stem glioma. 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. 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 Brain Stem Glioma Treatment are:

  • Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
  • Roger J. Packer, MD (Children's National Medical Center)
  • Malcolm 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.

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The preferred citation for this PDQ summary is:

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

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