Brain cancer, visual pathway glioma, childhood: Treatment - Health Professional Information [NCI PDQ]

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Childhood Visual Pathway and Hypothalamic Glioma Treatment (PDQ®)

General Information

This cancer treatment information summary provides an overview of the diagnosis, classification, treatment, and prognosis of childhood visual pathway and hypothalamic 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 summary 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 the 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 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 [PNETs]).
3. Ependymomas (cellular, papillary, clear cell, tanycytic, or anaplastic).
4. Brain stem gliomas are typically diffuse intrinsic high-grade tumors that are diagnosed neuroradiographically without biopsy. Focal, tectal, and exophytic cervicomedullary tumors are generally low-grade tumors.
5. Atypical teratoid/rhabdoid tumors.

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, glioblastomas multiforme [grade 3 or grade 4]).
3. Mixed gliomas (low grade or high grade).
4. Oligodendrogliomas (low grade or high grade).
5. PNETs (including cerebral neuroblastomas, pineoblastomas, and ependymoblastomas).
6. Atypical teratoid/rhabdoid tumors.
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 or nongerminomatous).

Important general concepts that should be understood by those caring for a child who has 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 from 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 is begun.
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 visual pathway and hypothalamic gliomas.

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

References:

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

Childhood visual pathway and hypothalamic gliomas are usually low-grade (grades 1 and 2) astrocytomas. Both pilocytic astrocytomas and fibrillary astrocytomas may occur. The pilomyxoid variant of pilocytic astrocytoma occurs in the visual pathway and may be a more aggressive variant and more likely to disseminate.[1] Visual pathway gliomas include astrocytic tumors of the optic nerve, optic chiasm, and optic tract. Because of the infiltrative nature of such lesions, separation of visual pathway and hypothalamic gliomas from thalamic tumors is often difficult and arbitrary. Malignant gliomas of the visual pathway are rare. Visual pathway gliomas occur at an increased incidence in patients with neurofibromatosis type 1 (NF-1); approximately 20% of all patients with NF-1 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 1) rather than fibrillary (grade 2) astrocytomas.[2,3,4,5]

References:

1. Komotar RJ, Burger PC, Carson BS, et al.: Pilocytic and pilomyxoid hypothalamic/chiasmatic astrocytomas. Neurosurgery 54 (1): 72-9; discussion 79-80, 2004.
2. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000.
3. Listernick R, Darling C, Greenwald M, et al.: Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history. J Pediatr 127 (5): 718-22, 1995.
4. Burger PC, Scheithauer BW: Tumors of the Central Nervous System. Washington, DC: Armed Forces Institute of Pathology,1994.
5. Allen JC: Initial management of children with hypothalamic and thalamic tumors and the modifying role of neurofibromatosis-1. Pediatr Neurosurg 32 (3): 154-62, 2000.

Stage Information

There is no universally accepted staging system for visual pathway and hypothalamic gliomas. They are low-grade astrocytomas that grow slowly and may occur anywhere along the optic tracts. Visual pathway gliomas are found with increased frequency in patients with neurofibromatosis. The major clinical symptoms are visual. Tumors may also arise in the hypothalamus; in large infiltrating lesions, distinctions between optic and hypothalamic tumors are often artificial and of little clinical importance. In infants and young children, hypothalamic gliomas may result in the diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.[1] Because the location of these tumors makes a surgical approach difficult, biopsies are not always done. This is especially true in patients with neurofibromatosis type 1 (NF-1).[2] Visual pathway and hypothalamic gliomas usually spread contiguously, though subarachnoid dissemination has been reported.[1,3] Evaluation should include neuro-ophthalmological testing to carefully monitor the patient for the visual effects of tumor progression that may not be evident using computed tomography or magnetic resonance imaging. Visual-evoked responses have not, as yet, been shown to be more sensitive than clinical examination in patients with visual pathway gliomas, even in young children.

References:

1. 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.
2. Pollack IF, Mulvihill JJ: Special issues in the management of gliomas in children with neurofibromatosis 1. J Neurooncol 28 (2-3): 257-68, 1996 May-Jun.
3. Mamelak AN, Prados MD, Obana WG, et al.: Treatment options and prognosis for multicentric juvenile pilocytic astrocytoma. J Neurosurg 81 (1): 24-30, 1994.

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 upon 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 2 treatment arms, or by evaluating a single new treatment and comparing the results with previously obtained results using existing standard therapy.

Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, treatment planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy of pediatric brain tumors is technically very demanding and should be carried out in centers with experience in that area in order to ensure optimal results.

Debilitating effects on growth and neurologic development have frequently been observed following radiation therapy, especially in younger children.[1,2,3] There are also other less common complications of radiation therapy, including cerebrovascular accidents.[4] For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, and sometimes obviate, the need for radiation therapy in children with benign and malignant lesions.[5] Long-term management of these patients is complex and requires a multidisciplinary approach.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

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.

Untreated Childhood Visual Pathway and Hypothalamic Glioma

Treatment options should be considered not only to improve survival but also to stabilize visual function. Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the visual pathway.[1,2,3] Children with neurofibromatosis type 1 (NF-1) also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.[1] Observation is an option for patients with NF-1 or nonprogressive masses.[1,2,4] Spontaneous regressions of optic pathway gliomas have been reported in children both with and without NF-1.[5,6] For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection or local radiation therapy may result in prolonged progression-free survival.[1]

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.[1,3,7,8] 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.[7] For those children with low-grade glioma for whom radiation therapy is indicated, conformal radiotherapeutic approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality.[9,10,11]

Chemotherapy may result in objective tumor shrinkage and will delay the need for radiation therapy in most patients.[4,12,13,14,15] The most widely used regimen to treat progression or symptomatic nonresectable, low-grade gliomas is a combination of carboplatin and vincristine.[4,15] Other chemotherapy approaches have been employed to treat children with progressive optic pathway gliomas, including multiagent platinum-based regimens [12,16] and nitrosourea-based regimens.[13]

Reported 5-year progression-free survival rates have ranged from approximately 35% to 60% for children receiving platinum-based chemotherapy for optic pathway gliomas,[12,15] but most patients ultimately require further treatment. Among children receiving chemotherapy for optic pathway gliomas, those without NF-1 have higher rates of disease progression than those with NF-1, and infants have higher rates of disease progression than do children older than 1 year.[12,15,16] Given the side effects associated with radiation therapy, chemotherapy may be particularly appropriate for patients with NF-1 and for younger children. Younger children are at higher risk for radiation-associated intellectual and endocrinologic sequelae. Children with NF-1 may be at higher risk for radiation-associated secondary tumors and morbidity due to vascular changes. Chemotherapy has been shown to shrink tumors in children with hypothalamic gliomas and the diencephalic syndrome, resulting in weight gain in those who respond to treatment.[17]

The Children's Oncology Group (COG) completed a randomized phase III trial, COG-A9952,[18] that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas on 1 of 2 regimens: carboplatin and vincristine or thioguanine (6-thioguanine), lomustine, and procarbazine hydrochloride given with vincristine. Children with NF-1 were only treated on the carboplatin and vincristine arm. Study results are pending.

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.

• COG-ACNS0223:[19] The COG is also conducting a group-wide pilot study of vincristine, carboplatin, and temozolomide for children younger than 10 years with newly diagnosed disease (without NF-1).

References:

1. 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.
2. Kovalic JJ, Grigsby PW, Shepard MJ, et al.: Radiation therapy for gliomas of the optic nerve and chiasm. Int J Radiat Oncol Biol Phys 18 (4): 927-32, 1990.
3. 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.
4. 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.
5. Schmandt SM, Packer RJ, Vezina LG, et al.: Spontaneous regression of low-grade astrocytomas in childhood. Pediatr Neurosurg 32 (3): 132-6, 2000.
6. Parsa CF, Hoyt CS, Lesser RL, et al.: Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch Ophthalmol 119 (4): 516-29, 2001.
7. Wisoff JH, Abbott R, Epstein F: Surgical management of exophytic chiasmatic-hypothalamic tumors of childhood. J Neurosurg 73 (5): 661-7, 1990.
8. 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.
9. Merchant TE, Zhu Y, Thompson SJ, et al.: Preliminary results from a Phase II trail of conformal radiation therapy for pediatric patients with localised low-grade astrocytoma and ependymoma. Int J Radiat Oncol Biol Phys 52 (2): 325-32, 2002.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Gnekow AK, Kortmann RD, Pietsch T, et al.: Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy -- report from the multicenter treatment study for children and adolescents with a low grade glioma -- HIT-LGG 1996 -- of the Society of Pediatric Oncology and Hematology (GPOH). Klin Padiatr 216 (6): 331-42, 2004 Nov-Dec.
16. 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.
17. 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.
18. Ater J, Children's Oncology Group: Phase III Randomized Study of Carboplatin and Vincristine Versus Thioguanine, Procarbazine, Lomustine, and Vincristine in Children With Progressive Low Grade Astrocytoma, COG-A9952, Clinical trial, Closed.
19. Chintagumpala MM, Children's Oncology Group: Pilot Study of Carboplatin, Vincristine, and Temozolomide in Children With Progressive and/or Symptomatic Low-Grade Gliomas, COG-ACNS0223, Clinical trial, Closed.

Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Recurrence may take place in both benign and malignant childhood visual pathway and hypothalamic gliomas, and may develop many years after initial treatment. Recurrent disease is usually at the primary tumor site, though widely disseminated disease to other intracranial sites and to the spinal leptomeninges has been documented.[1] At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the mass lesion, and the clinical picture.

If patients have not received radiation therapy, local radiation therapy is the usual treatment.[2] For those children with low-grade glioma for whom radiation therapy is indicated, conformal radiotherapeutic approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality.[3,4] In patients treated with surgery alone whose disease progresses, however, chemotherapy and radiation therapy are options. If recurrence takes place after irradiation, chemotherapy should be considered. Chemotherapy may result in relatively long-term disease control.[5,6] Entry into studies of novel therapeutic approaches should be considered for patients with recurrent brain tumors.[7,8] Information about ongoing clinical trials is available from the NCI Web site.

References:

1. 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.
2. 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.
3. Merchant TE, Zhu Y, Thompson SJ, et al.: Preliminary results from a Phase II trail of conformal radiation therapy for pediatric patients with localised low-grade astrocytoma and ependymoma. Int J Radiat Oncol Biol Phys 52 (2): 325-32, 2002.
4. 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.
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.
6. Gnekow AK, Kortmann RD, Pietsch T, et al.: Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy -- report from the multicenter treatment study for children and adolescents with a low grade glioma -- HIT-LGG 1996 -- of the Society of Pediatric Oncology and Hematology (GPOH). Klin Padiatr 216 (6): 331-42, 2004 Nov-Dec.
7. Chamberlain MC, Grafe MR: Recurrent chiasmatic-hypothalamic glioma treated with oral etoposide. J Clin Oncol 13 (8): 2072-6, 1995.
8. Gaynon PS, Ettinger LJ, Baum ES, et al.: Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial. Cancer 66 (12): 2465-9, 1990.

Changes to This Summary (07/21/2006)

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.

UNTREATED CHILDHOOD VISUAL PATHWAY AND HYPOTHALAMIC GLIOMA

Revised text about spontaneous regressions of optic pathway gliomas reported in children both with and without NF-1 (cited Parsa et al. as reference 6).

Added Combs et al. as reference 11.

Added text about the use of multiagent platinum-based regimens and nitrosourea-based regimens to treat children with progressive optic pathway gliomas (cited Massimino et al. as reference 16).

Revised text about progression-free survival rates for children receiving platinum-based chemotherapy for optic pathway gliomas. Also added text about children with or without NF-1 who receive chemotherapy for optic pathway gliomas.

Added text about a group-wide pilot study of vincristine, carboplatin, and temozolomide for children younger than 10 years with newly diagnosed disease (without NF-1).

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Date Last Modified: 2006-07-21