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NCI/PDQ^® Health professionals: Childhood Ependymoma Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 2 de noviembre del 2012

TABLE OF CONTENTS

• General Information
  • Incidence and Molecular Determinants

• Histopathologic Classification of Childhood Ependymal Tumors

• Stage Information

• Treatment Option Overview

• Treatment of Newly Diagnosed Childhood Ependymoma
  • Postsurgical Treatment Options
    • Standard treatment options
    • Treatment options under clinical evaluation
  • Subependymoma
  • Myxopapillary Ependymoma
  • Current Clinical Trials

• Treatment of Recurrent Childhood Ependymoma
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Changes to This Summary (11/02/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
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General Information

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

Incidence and Molecular Determinants

Childhood ependymoma comprises approximately 9% of all childhood brain tumors representing approximately 200 cases per year in the United States. 4 5

Molecular determinants of outcome for ependymomas are just being identified. Studies have identified numerous chromosomal aberrations and related molecular genetic changes. Gain of 1q25, overexpression of EGFR, hTERT expression, high levels of nucleolin, activation of the Notch pathway or Tenascin C, and others have been related to poorer prognosis. 6 7 8 9 10 11 12 In contrast, gains of 9, 15q, and 18, and loss of chromosome 6 were associated with improved prognosis. 13

References:

1. Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007. [PUBMED Abstract]
2. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]
3. 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. [PUBMED Abstract]
4. Gurney JG, Smith MA, Bunin GR: CNS and miscellaneous intracranial and intraspinal neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., Chapter 3, pp 51-63. Also available online [PUBMED Abstract]
5. Central Brain Tumor Registry of the United States.: Statistical Report: Primary Brain Tumors in the United States, 1997-2001. Hinsdale, Ill: Central Brain Tumor Registry of the United States, 2004. Also available online [PUBMED Abstract]
6. Tabori U, Ma J, Carter M, et al.: Human telomere reverse transcriptase expression predicts progression and survival in pediatric intracranial ependymoma. J Clin Oncol 24 (10): 1522-8, 2006. [PUBMED Abstract]
7. Mendrzyk F, Korshunov A, Benner A, et al.: Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12 (7 Pt 1): 2070-9, 2006. [PUBMED Abstract]
8. Pezzolo A, Capra V, Raso A, et al.: Identification of novel chromosomal abnormalities and prognostic cytogenetics markers in intracranial pediatric ependymoma. Cancer Lett 261 (2): 235-43, 2008. [PUBMED Abstract]
9. Preusser M, Heinzl H, Gelpi E, et al.: Ki67 index in intracranial ependymoma: a promising histopathological candidate biomarker. Histopathology 53 (1): 39-47, 2008. [PUBMED Abstract]
10. Tabori U, Wong V, Ma J, et al.: Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma. Br J Cancer 99 (7): 1129-35, 2008. [PUBMED Abstract]
11. Puget S, Grill J, Valent A, et al.: Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas. J Clin Oncol 27 (11): 1884-92, 2009. [PUBMED Abstract]
12. Ridley L, Rahman R, Brundler MA, et al.: Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. Neuro Oncol 10 (5): 675-89, 2008. [PUBMED Abstract]
13. Korshunov A, Witt H, Hielscher T, et al.: Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 (19): 3182-90, 2010. [PUBMED Abstract]

Histopathologic Classification of Childhood Ependymal Tumors

In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into four main subtypes: 1

• Subependymoma (WHO Grade I).
• Myxopapillary ependymoma (WHO Grade I).
• Ependymoma (WHO Grade II). Variants include cellular, papillary, tanycytic, clear cell, and mixed.
• Anaplastic (also known as malignant) ependymoma (WHO Grade III).

The subependymoma is a slow-growing benign neoplasm, typically attached to the ventricle wall, and is composed of glial tumor cell clusters embedded in a fibrillary matrix. The myxopapillary ependymoma arises almost exclusively in the location of the conus medullaris, cauda equina, and filum terminale of the spinal cord, and is characterized histologically by tumor cells arranged in a papillary manner around vascularized myxoid stromal cores.

The ependymoma, which is considered a Grade II neoplasm originating from the walls of the ventricles or from the spinal canal, is composed of neoplastic ependymal cells. Ependymomas are subdivided, based on histological findings, into four subtypes:

• Cellular ependymoma the most common subtype; usually demonstrates significant cellularity without an increase in mitotic activity.
• Papillary ependymoma forms linear, epithelial-like surfaces along cerebrospinal fluid exposures.
• Clear cell ependymoma displays an oligodendroglial-like appearance with perinuclear halos; this variant is preferentially located in the supratentorial compartment of the brain.
• Tanycytic ependymoma the rarest form of Grade II ependymoma; most commonly found in the spinal cord; tumor cells are arranged in fascicles of variable width and cell density and poorly intertwined.

The anaplastic ependymoma is considered a malignant glioma of ependymal differentiation and, compared to the Grade II ependymomas, shows increased cellularity and increased mitotic activity, often associated with microvascular proliferation and pseudopalisading necrosis.

In children, approximately 65% to 75% of ependymomas arise in the posterior fossa. Believed to arise from radial glia cells, supratentorial and infratentorial ependymomas have different genomic, gene expression, and immunohistochemical signatures. 2 3 4 Supratentorial tumors are characterized by neuronal differentiation. 3

Subependymomas and myxopapillary ependymomas are usually considered to be different than the Grade II and Grade III ependymomas. In Grade II and Grade III ependymomas, the relationship between histological features and survival has varied between studies, although most recent larger studies and meta-analyses have demonstrated that histological grade is an independent predictor of event-free survival. 5 6 7 8 9 10 11 A single institution study suggests that patients with clear-cell ependymomas may be at higher risk for treatment failure than patients with other forms of Grade II ependymomas; 12 however, confirmation is required in the larger group of unselected patients.

Ependymoblastomas, which generally behave more like medulloblastomas or cerebral neuroectodermal tumors, are considered separate entities from ependymomas and are now classified with the embryonal tumors. 1 5 (Refer to the PDQ® summary on Childhood Central Nervous System Embryonal Tumors for more information.)

The pathologic classification of pediatric brain tumors is a specialized area that is undergoing evolution; review of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.

References:

1. Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007. [PUBMED Abstract]
2. Taylor MD, Poppleton H, Fuller C, et al.: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8 (4): 323-35, 2005. [PUBMED Abstract]
3. Andreiuolo F, Puget S, Peyre M, et al.: Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol 12 (11): 1126-34, 2010. [PUBMED Abstract]
4. Grill J, Bergthold G, Ferreira C: Pediatric ependymomas: will molecular biology change patient management? Curr Opin Oncol 23 (6): 638-42, 2011. [PUBMED Abstract]
5. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]
6. Goldwein JW, Leahy JM, Packer RJ, et al.: Intracranial ependymomas in children. Int J Radiat Oncol Biol Phys 19 (6): 1497-502, 1990. [PUBMED Abstract]
7. Rousseau P, Habrand JL, Sarrazin D, et al.: Treatment of intracranial ependymomas of children: review of a 15-year experience. Int J Radiat Oncol Biol Phys 28 (2): 381-6, 1994. [PUBMED Abstract]
8. Chiu JK, Woo SY, Ater J, et al.: Intracranial ependymoma in children: analysis of prognostic factors. J Neurooncol 13 (3): 283-90, 1992. [PUBMED Abstract]
9. Pollack IF, Gerszten PC, Martinez AJ, et al.: Intracranial ependymomas of childhood: long-term outcome and prognostic factors. Neurosurgery 37 (4): 655-66; discussion 666-7, 1995. [PUBMED Abstract]
10. Tihan T, Zhou T, Holmes E, et al.: The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod Pathol 21 (2): 165-77, 2008. [PUBMED Abstract]
11. Shu HK, Sall WF, Maity A, et al.: Childhood intracranial ependymoma: twenty-year experience from a single institution. Cancer 110 (2): 432-41, 2007. [PUBMED Abstract]
12. Fouladi M, Helton K, Dalton J, et al.: Clear cell ependymoma: a clinicopathologic and radiographic analysis of 10 patients. Cancer 98 (10): 2232-44, 2003. [PUBMED Abstract]

Stage Information

Although there is no formal staging system, ependymomas can be divided into supratentorial, infratentorial, and spinal tumors. In children, approximately 30% of childhood ependymomas arise in supratentorial regions of the brain and 70% in the posterior fossa. 1 2 3 They usually originate in the ependymal linings of ventricles or central canal or ventriculus terminalis of the spinal cord, and have access to the cerebral spinal fluid (CSF). Therefore, these tumors may spread throughout the neuraxis, although dissemination is noted in less than 10% of patients with Grade II and Grade III ependymomas. Myxopapillary ependymomas are more likely to disseminate to the nervous system early in the course of illness. Every patient with ependymoma should be evaluated with diagnostic imaging of the spinal cord and whole brain. This is ideally done prior to surgery to avoid confusion with postoperative blood. The most sensitive method available for evaluating spinal cord subarachnoid metastasis is spinal magnetic resonance imaging (MRI) performed with gadolinium. If MRI is used, the entire spine is generally imaged in at least two planes with contiguous MRI slices performed after gadolinium enhancement. In addition, CSF cytological evaluation should be conducted. While a number of factors have sometimes been associated with an unfavorable outcome (younger age at diagnosis, lower doses of radiation, anaplastic histology, subtotal resection, higher proliferation marker, MIB-1 labeling index), age, histology, and extent of resection have consistently been the most important factors. 1 4 5 6 7 8 9 10 11; 12[Level of evidence: 3iiiDi]; 13[Level of evidence: 3iiiDii] Primary spinal cord ependymomas have a more favorable outcome than cranial variants. 14

References:

1. Goldwein JW, Leahy JM, Packer RJ, et al.: Intracranial ependymomas in children. Int J Radiat Oncol Biol Phys 19 (6): 1497-502, 1990. [PUBMED Abstract]
2. Kovnar E, Kun L, Burger J, et al.: Patterns of dissemination and recurrence in childhood ependymoma: preliminary results of Pediatric Oncology Group protocol #8532. Ann Neurol 30(3): 457, 1991. [PUBMED Abstract]
3. Vanuytsel LJ, Bessell EM, Ashley SE, et al.: Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 313-9, 1992. [PUBMED Abstract]
4. Shaw EG, Evans RG, Scheithauer BW, et al.: Postoperative radiotherapy of intracranial ependymoma in pediatric and adult patients. Int J Radiat Oncol Biol Phys 13 (10): 1457-62, 1987. [PUBMED Abstract]
5. Merchant TE, Jenkins JJ, Burger PC, et al.: Influence of tumor grade on time to progression after irradiation for localized ependymoma in children. Int J Radiat Oncol Biol Phys 53 (1): 52-7, 2002. [PUBMED Abstract]
6. Wolfsberger S, Fischer I, Híftberger R, et al.: Ki-67 immunolabeling index is an accurate predictor of outcome in patients with intracranial ependymoma. Am J Surg Pathol 28 (7): 914-20, 2004. [PUBMED Abstract]
7. Kurt E, Zheng PP, Hop WC, et al.: Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas. Cancer 106 (2): 388-95, 2006. [PUBMED Abstract]
8. Horn B, Heideman R, Geyer R, et al.: A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors. J Pediatr Hematol Oncol 21 (3): 203-11, 1999 May-Jun. [PUBMED Abstract]
9. Pollack IF, Gerszten PC, Martinez AJ, et al.: Intracranial ependymomas of childhood: long-term outcome and prognostic factors. Neurosurgery 37 (4): 655-66; discussion 666-7, 1995. [PUBMED Abstract]
10. Bouffet E, Perilongo G, Canete A, et al.: Intracranial ependymomas in children: a critical review of prognostic factors and a plea for cooperation. Med Pediatr Oncol 30 (6): 319-29; discussion 329-31, 1998. [PUBMED Abstract]
11. Korshunov A, Golanov A, Sycheva R, et al.: The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients. Cancer 100 (6): 1230-7, 2004. [PUBMED Abstract]
12. Tihan T, Zhou T, Holmes E, et al.: The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod Pathol 21 (2): 165-77, 2008. [PUBMED Abstract]
13. Tamburrini G, D'Ercole M, Pettorini BL, et al.: Survival following treatment for intracranial ependymoma: a review. Childs Nerv Syst 25 (10): 1303-12, 2009. [PUBMED Abstract]
14. McGuire CS, Sainani KL, Fisher PG: Both location and age predict survival in ependymoma: a SEER study. Pediatr Blood Cancer 52 (1): 65-9, 2009. [PUBMED Abstract]

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 previously obtained with existing therapy.

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

Treatment for childhood ependymoma has included surgery followed by standard fractionated radiation therapy. There is evidence to suggest that more extensive surgical resections are related to an improved rate of survival. 1 2 3 4 5 6 7 In addition, in a small series of children with localized ependymoma, adjuvant radiation therapy appeared to improve progression-free survival (PFS), even after adjusting for the extent of resection. In fact, a benefit in PFS was observed for patients who received adjuvant radiation therapy after gross total resection compared with those who did not receive radiation therapy. Additional research will be necessary to confirm these findings. 8 Chemotherapy has been shown to be active in patients with recurrent ependymoma. 9 One relatively small, prospective, randomized trial suggests that chemotherapy activity in newly diagnosed cases is limited, 10 and current treatment approaches do not include chemotherapy as a component of primary therapy for most children with newly diagnosed ependymomas that are completely resected. Children younger than 3 years are particularly susceptible to the adverse effect of radiation on brain development. 11[Level of evidence: 3iiiC] Debilitating effects on growth and neurologic development have frequently been observed, especially in younger children. 12 13 14 For this reason, conformal radiation approaches, such as 3-dimensional conformal radiation therapy, that minimize damage to normal brain tissue and charged-particle radiation therapy, such as proton beam therapy, are under evaluation for infants and children with ependymoma. 15 16 Long-term management of these patients is complex and requires a multidisciplinary approach.

There is evidence that surveillance neuroimaging in childhood ependymoma will identify tumors that have recurred when the patient is asymptomatic; however, it is unclear whether this detection will change the ultimate prognosis of the patient. 17

References:

1. Pollack IF, Gerszten PC, Martinez AJ, et al.: Intracranial ependymomas of childhood: long-term outcome and prognostic factors. Neurosurgery 37 (4): 655-66; discussion 666-7, 1995. [PUBMED Abstract]
2. Horn B, Heideman R, Geyer R, et al.: A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors. J Pediatr Hematol Oncol 21 (3): 203-11, 1999 May-Jun. [PUBMED Abstract]
3. van Veelen-Vincent ML, Pierre-Kahn A, Kalifa C, et al.: Ependymoma in childhood: prognostic factors, extent of surgery, and adjuvant therapy. J Neurosurg 97 (4): 827-35, 2002. [PUBMED Abstract]
4. Abdel-Wahab M, Etuk B, Palermo J, et al.: Spinal cord gliomas: A multi-institutional retrospective analysis. Int J Radiat Oncol Biol Phys 64 (4): 1060-71, 2006. [PUBMED Abstract]
5. Kothbauer KF: Neurosurgical management of intramedullary spinal cord tumors in children. Pediatr Neurosurg 43 (3): 222-35, 2007. [PUBMED Abstract]
6. Zacharoulis S, Ji L, Pollack IF, et al.: Metastatic ependymoma: a multi-institutional retrospective analysis of prognostic factors. Pediatr Blood Cancer 50 (2): 231-5, 2008. [PUBMED Abstract]
7. Merchant TE, Li C, Xiong X, et al.: Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 10 (3): 258-66, 2009. [PUBMED Abstract]
8. Pejavar S, Polley MY, Rosenberg-Wohl S, et al.: Pediatric intracranial ependymoma: the roles of surgery, radiation and chemotherapy. J Neurooncol 106 (2): 367-75, 2012. [PUBMED Abstract]
9. Goldwein JW, Glauser TA, Packer RJ, et al.: Recurrent intracranial ependymomas in children. Survival, patterns of failure, and prognostic factors. Cancer 66 (3): 557-63, 1990. [PUBMED Abstract]
10. Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, et al.: Adjuvant chemotherapy of childhood posterior fossa ependymoma: cranio-spinal irradiation with or without adjuvant CCNU, vincristine, and prednisone: a Childrens Cancer Group study. Med Pediatr Oncol 27 (1): 8-14, 1996. [PUBMED Abstract]
11. von Hoff K, Kieffer V, Habrand JL, et al.: Impairment of intellectual functions after surgery and posterior fossa irradiation in children with ependymoma is related to age and neurologic complications. BMC Cancer 8: 15, 2008. [PUBMED Abstract]
12. 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. [PUBMED Abstract]
13. 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. [PUBMED Abstract]
14. 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. [PUBMED Abstract]
15. Merchant TE, Mulhern RK, Krasin MJ, et al.: Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 22 (15): 3156-62, 2004. [PUBMED Abstract]
16. MacDonald SM, Safai S, Trofimov A, et al.: Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys 71 (4): 979-86, 2008. [PUBMED Abstract]
17. Good CD, Wade AM, Hayward RD, et al.: Surveillance neuroimaging in childhood intracranial ependymoma: how effective, how often, and for how long? J Neurosurg 94 (1): 27-32, 2001. [PUBMED Abstract]

Treatment of Newly Diagnosed Childhood Ependymoma

In the newly diagnosed patient, careful evaluation to fully determine the extent of disease must precede the treatment of ependymoma. Surgery should be performed in an attempt at maximal tumor reduction; children have improved progression-free survival (PFS) if there is minimal residual disease present after surgery. 1 2 Postoperatively, magnetic resonance imaging (MRI) should be performed to determine the extent of resection, although the rate of dissemination is low. If not performed preoperatively, MRI of the entire neuraxis should be obtained to evaluate for disease dissemination. Myxopapillary ependymomas, considered to be a benign histologic subtype of ependymoma, have a relatively high incidence of central nervous system (CNS) tumor dissemination at diagnosis and at follow-up, and require imaging of the complete cranial spinal axis at the time of diagnosis and during follow-up. 3 4 Patients with residual tumor or disseminated disease should be considered at high risk for relapse and should be treated on protocols specifically designed for them. Those with no evidence of residual tumor still have an approximate 20% to 40% relapse risk in spite of postoperative radiation therapy.

Postsurgical Treatment Options

Standard treatment options

Ependymoma (World Health Organization [WHO] Grade II) and anaplastic (WHO Grade III)
• No residual disease; no disseminated disease:

  The traditional postsurgical treatment for these patients has been radiation therapy consisting of 54 Gy to 55.8 Gy to the tumor bed for children aged 3 years and older. 5 It is not necessary It is not necessary to treat the entire CNS (whole brain and spine) because these tumors usually to treat the entire CNS (whole brain and spine) because these tumors usually recur initially at the local site.recur initially at the local site. 2 6 7; ; 8[[Level of evidence: 3iiiALevel of evidence: 3iiiA] When possible, patients should be treated in a ] When possible, patients should be treated in a center experienced with the delivery of center experienced with the delivery of conformal radiation therapy to pediatric patients with brain tumors. There is no evidence that adjuvant to pediatric patients with brain tumors. There is no evidence that adjuvant chemotherapy, including the use of myeloablative chemotherapy,chemotherapy, including the use of myeloablative chemotherapy, 9 improves the outcome for patients with totally resected, nondisseminated ependymoma. The 3-year PFS rate in 74 patients aged between 1 and 21 years treated with radiation therapy following surgery was 77.6% 5.8%. improves the outcome for patients with totally resected, nondisseminated ependymoma. The 3-year PFS rate in 74 patients aged between 1 and 21 years treated with radiation therapy following surgery was 77.6% 5.8%. 10 In a second series of 153 patients, 107 received conformal irradiation immediately following up-front resection, the 7-year event-free survival was 76.9% 13.5%. In a second series of 153 patients, 107 received conformal irradiation immediately following up-front resection, the 7-year event-free survival was 76.9% 13.5%. 11[[Level of evidence: 3iALevel of evidence: 3iA] Anecdotal experience suggests that surgery alone for completely resected supratentorial nonanaplastic tumors, and intradural spinal cord ependymomas may, in select cases, be an appropriate approach to treatment.] Anecdotal experience suggests that surgery alone for completely resected supratentorial nonanaplastic tumors, and intradural spinal cord ependymomas may, in select cases, be an appropriate approach to treatment. 12[[Level of evidence: 3iiiDiLevel of evidence: 3iiiDi]; ]; 13 14[[Level of evidence: 3iiiDiiiLevel of evidence: 3iiiDiii]]

• Residual disease; no disseminated disease:

  Second-look surgery should be considered because patients who have complete resections have better disease control. 15 The traditional postsurgical treatment The traditional postsurgical treatment for children aged 3 years and older has been radiation therapy consisting of 54 Gy to 55.8 Gy to for children aged 3 years and older has been radiation therapy consisting of 54 Gy to 55.8 Gy to the tumor bed. It is not necessary to treat the entire CNS (whole brain and the tumor bed. It is not necessary to treat the entire CNS (whole brain and spine) because these tumors usually recur at the local site.spine) because these tumors usually recur at the local site. 7[[Level of evidence: 3iiiALevel of evidence: 3iiiA] In subtotally resected patients, treatment with radiation therapy results in 3-year to 5-year PFS in 30% to 50% of patients,] In subtotally resected patients, treatment with radiation therapy results in 3-year to 5-year PFS in 30% to 50% of patients, 10 16 although the outcome for patients with residual tumor within the spinal canal may be better. although the outcome for patients with residual tumor within the spinal canal may be better. 17 There is There is nno evidence that adjuvant chemotherapy, including high-dose chemotherapy with o evidence that adjuvant chemotherapy, including high-dose chemotherapy with stem cell rescue, is of any benefit.stem cell rescue, is of any benefit. 18

• CNS disseminated disease:

  In children with disseminated disease, long-term survivors have been reported and aggressive therapy is warranted. Regardless of degree of surgical resection, these patients require radiation therapy to the entire CNS (whole brain and spine) along with boosts to local disease and bulk areas of disseminated disease. The traditional local postsurgical radiation doses in these patients have been 54 Gy to 55.8 Gy. Doses of approximately 36 Gy to the entire neuraxis (i.e., the whole brain and spine) should also be administered, but may be modulated depending on the age of the patient. Boosts between 41.4 Gy and 50.4 Gy to bulk areas of spinal disease should be administered, with doses depending on the age of the patient and the location of the tumor. When possible, patients should be treated in a center experienced with this therapy. Trials are ongoing to evaluate the possible role of radiation therapy and chemotherapy in these patients.

• Management of children younger than 3 years:

  Because of the known effects of radiation on growth and neurocognitive development, radiation therapy immediately after surgery in children younger than 3 years has traditionally been limited, with attempts to delay its administration through the use of chemotherapy. 19 20 21 22; ; 23[[Level of evidence: 2ALevel of evidence: 2A] When analyzing neurologic outcome following treatment of young children with ependymoma, it is important to consider that not all long-term deficits can be ascribed to radiation therapy, as deficits may be present in young children before therapy is begun.] When analyzing neurologic outcome following treatment of young children with ependymoma, it is important to consider that not all long-term deficits can be ascribed to radiation therapy, as deficits may be present in young children before therapy is begun. 10 For example, the presence of hydrocephalus at diagnosis is associated with lower intelligence quotient as measured following surgical resection and prior to administration of radiation therapy. For example, the presence of hydrocephalus at diagnosis is associated with lower intelligence quotient as measured following surgical resection and prior to administration of radiation therapy. 24

  In a retrospective review based on Surveillance Epidemiology and End Results data of 184 children younger than 3 years, 3-year overall survival was shown to be significantly better for children who received postoperative radiation therapy (81%) than for those who did not (58%, P = .005), even when adjusting for tumor location or degree of resection. = .005), even when adjusting for tumor location or degree of resection. 5 The recently completed Children's Oncology Group protocol for children with ependymoma included children aged 1 year and older. The trial is a prospective evaluation of this same issue and results are forthcoming. The recently completed Children's Oncology Group protocol for children with ependymoma included children aged 1 year and older. The trial is a prospective evaluation of this same issue and results are forthcoming.

  Conformal radiation therapy is an alternative approach for minimizing radiation-induced neurologic damage in young children with ependymoma. The initial experience with this approach suggests that children younger than 3 years with ependymoma have neurologic deficits at diagnosis that improve with time following conformal radiation treatment. 10 However, another study suggested that there was a trend for intellectual deterioration over time even in older children treated with localized radiation therapy. However, another study suggested that there was a trend for intellectual deterioration over time even in older children treated with localized radiation therapy. 25[[Level of evidence: 3iiiCLevel of evidence: 3iiiC] The need and timing of ] The need and timing of radiation therapy for children who have successfully completed chemotherapy and radiation therapy for children who have successfully completed chemotherapy and have no residual disease is still to be determined. have no residual disease is still to be determined.

  Chemotherapy is able to induce objective responses in some children younger than 3 years with newly diagnosed ependymoma, 19 20 21 although not all chemotherapy regimens induce objective responses. although not all chemotherapy regimens induce objective responses. 22 Up to 40% of infants and young children with totally resected disease may achieve long-term survival with chemotherapy alone. Up to 40% of infants and young children with totally resected disease may achieve long-term survival with chemotherapy alone. 26[[Level of evidence: 2DiLevel of evidence: 2Di] ]

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.

• COG-ACNS0831 (Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Younger Patients With Newly Diagnosed Ependymoma): The purpose of this phase III trial is as follows:
  No Residual Disease; No Disseminated Disease
  • The trial will determine whether adding chemotherapy after radiation therapy results in improved survival over radiation therapy alone.
  • The trial will determine whether children with supratentorial nonanaplastic ependymoma who receive a complete resection or who achieve a complete remission after being treated with chemotherapy can be successfully treated without radiation therapy.
  Residual Disease; No Disseminated Disease
  • The trial will determine whether adding chemotherapy before radiation therapy and then adding chemotherapy after radiation therapy results in improved survival, compared with previous studies of children who did not receive additional chemotherapy after radiation treatment.

Subependymoma

The true incidence of subependymomas is difficult to determine, because these tumors are frequently asymptomatic and may be found incidentally at autopsy. They probably comprise less than 5% of all ependymal tumors. Occasionally, subependymomas cause ventricular obstruction and, in these cases, treatment is indicated. Spontaneous intratumoral hemorrhage has also been observed. 27 In those cases requiring therapy, complete surgical removal is often curative.

Myxopapillary Ependymoma

Historically, the management of myxopapillary ependymoma (WHO Grade I) consisted of an attempt at en bloc resection of the tumor with no further treatment in the case of a gross total resection. 28; 29[Level of evidence: 3iiiDi] However, based on the finding that dissemination of these tumors to other parts of the neuraxis can occur, particularly when completed resection is not obtained and evidence that focal irradiation may improve progression-free survival, many practitioners now favor the use of irradiation following surgical resection of the primary mass. 3 28; 30[Level of evidence: 3iiiDiii]; 31[Level of evidence: 3iiiDi]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with newly diagnosed childhood ependymoma. 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. Hukin J, Epstein F, Lefton D, et al.: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29 (1): 40-5, 1998. [PUBMED Abstract]
2. Horn B, Heideman R, Geyer R, et al.: A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors. J Pediatr Hematol Oncol 21 (3): 203-11, 1999 May-Jun. [PUBMED Abstract]
3. Fassett DR, Pingree J, Kestle JR: The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients. Report of five cases and review of the literature. J Neurosurg 102 (1 Suppl): 59-64, 2005. [PUBMED Abstract]
4. Bagley CA, Kothbauer KF, Wilson S, et al.: Resection of myxopapillary ependymomas in children. J Neurosurg 106 (4 Suppl): 261-7, 2007. [PUBMED Abstract]
5. Koshy M, Rich S, Merchant TE, et al.: Post-operative radiation improves survival in children younger than 3 years with intracranial ependymoma. J Neurooncol 105 (3): 583-90, 2011. [PUBMED Abstract]
6. Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, et al.: Adjuvant chemotherapy of childhood posterior fossa ependymoma: cranio-spinal irradiation with or without adjuvant CCNU, vincristine, and prednisone: a Childrens Cancer Group study. Med Pediatr Oncol 27 (1): 8-14, 1996. [PUBMED Abstract]
7. Combs SE, Kelter V, Welzel T, et al.: Influence of radiotherapy treatment concept on the outcome of patients with localized ependymomas. Int J Radiat Oncol Biol Phys 71 (4): 972-8, 2008. [PUBMED Abstract]
8. Schroeder TM, Chintagumpala M, Okcu MF, et al.: Intensity-modulated radiation therapy in childhood ependymoma. Int J Radiat Oncol Biol Phys 71 (4): 987-93, 2008. [PUBMED Abstract]
9. Zacharoulis S, Levy A, Chi SN, et al.: Outcome for young children newly diagnosed with ependymoma, treated with intensive induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer 49 (1): 34-40, 2007. [PUBMED Abstract]
10. Merchant TE, Mulhern RK, Krasin MJ, et al.: Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 22 (15): 3156-62, 2004. [PUBMED Abstract]
11. Merchant TE, Li C, Xiong X, et al.: Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 10 (3): 258-66, 2009. [PUBMED Abstract]
12. Volpp PB, Han K, Kagan AR, et al.: Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiat Oncol Biol Phys 69 (4): 1199-204, 2007. [PUBMED Abstract]
13. Little AS, Sheean T, Manoharan R, et al.: The management of completely resected childhood intracranial ependymoma: the argument for observation only. Childs Nerv Syst 25 (3): 281-4, 2009. [PUBMED Abstract]
14. Venkatramani R, Dhall G, Patel M, et al.: Supratentorial ependymoma in children: to observe or to treat following gross total resection? Pediatr Blood Cancer 58 (3): 380-3, 2012. [PUBMED Abstract]
15. Massimino M, Solero CL, Garrí ML, et al.: Second-look surgery for ependymoma: the Italian experience. J Neurosurg Pediatr 8 (3): 246-50, 2011. [PUBMED Abstract]
16. Pollack IF, Gerszten PC, Martinez AJ, et al.: Intracranial ependymomas of childhood: long-term outcome and prognostic factors. Neurosurgery 37 (4): 655-66; discussion 666-7, 1995. [PUBMED Abstract]
17. Wahab SH, Simpson JR, Michalski JM, et al.: Long term outcome with post-operative radiation therapy for spinal canal ependymoma. J Neurooncol 83 (1): 85-9, 2007. [PUBMED Abstract]
18. Grill J, Kalifa C, Doz F, et al.: A high-dose busulfan-thiotepa combination followed by autologous bone marrow transplantation in childhood recurrent ependymoma. A phase-II study. Pediatr Neurosurg 25 (1): 7-12, 1996. [PUBMED Abstract]
19. Duffner PK, Horowitz ME, Krischer JP, et al.: The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience. Neuro-oncol 1 (2): 152-61, 1999. [PUBMED Abstract]
20. 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. [PUBMED Abstract]
21. Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005. [PUBMED Abstract]
22. Grill J, Le Deley MC, Gambarelli D, et al.: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 19 (5): 1288-96, 2001. [PUBMED Abstract]
23. Massimino M, Gandola L, Barra S, et al.: Infant ependymoma in a 10-year AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) experience with omitted or deferred radiotherapy. Int J Radiat Oncol Biol Phys 80 (3): 807-14, 2011. [PUBMED Abstract]
24. Merchant TE, Lee H, Zhu J, et al.: The effects of hydrocephalus on intelligence quotient in children with localized infratentorial ependymoma before and after focal radiation therapy. J Neurosurg 101 (2 Suppl): 159-68, 2004. [PUBMED Abstract]
25. von Hoff K, Kieffer V, Habrand JL, et al.: Impairment of intellectual functions after surgery and posterior fossa irradiation in children with ependymoma is related to age and neurologic complications. BMC Cancer 8: 15, 2008. [PUBMED Abstract]
26. Grundy RG, Wilne SA, Weston CL, et al.: Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 8 (8): 696-705, 2007. [PUBMED Abstract]
27. Waldron JS, Tihan T: Epidemiology and pathology of intraventricular tumors. Neurosurg Clin N Am 14 (4): 469-82, 2003. [PUBMED Abstract]
28. Akyurek S, Chang EL, Yu TK, et al.: Spinal myxopapillary ependymoma outcomes in patients treated with surgery and radiotherapy at M.D. Anderson Cancer Center. J Neurooncol 80 (2): 177-83, 2006. [PUBMED Abstract]
29. Bagley CA, Wilson S, Kothbauer KF, et al.: Long term outcomes following surgical resection of myxopapillary ependymomas. Neurosurg Rev 32 (3): 321-34; discussion 334, 2009. [PUBMED Abstract]
30. Jeibmann A, Egensperger R, Kuchelmeister K, et al.: Extent of surgical resection but not myxopapillary versus classical histopathological subtype affects prognosis in lumbo-sacral ependymomas. Histopathology 54 (2): 260-2, 2009. [PUBMED Abstract]
31. Pica A, Miller R, Villí S, et al.: The results of surgery, with or without radiotherapy, for primary spinal myxopapillary ependymoma: a retrospective study from the rare cancer network. Int J Radiat Oncol Biol Phys 74 (4): 1114-20, 2009. [PUBMED Abstract]

Treatment of Recurrent Childhood Ependymoma

Recurrence is not uncommon in both benign and malignant childhood brain tumors and may develop many years after initial treatment. 1 For ependymoma, late recurrence beyond 10 to 15 years has been reported. 2 3 Disease generally recurs at the primary tumor site, even in children with malignant ependymomas. 4 5 Systemic relapse is extremely rare. At time of relapse, a complete evaluation for extent of recurrence is indicated for all patients. The need for surgical intervention must be individualized on the basis of the extent of the tumor, the length of time between initial treatment and the reappearance of the recurrent lesion, and the clinical picture. Patients with recurrent ependymomas who have not previously received radiation therapy and/or chemotherapy should be considered for treatment with these modalities. 6[Level of evidence: 3iiiB] In addition, patients may be candidates for focal retreatment with various radiation modalities, including stereotactic radiosurgery. 7[Level of evidence: 3iiiA]; 8 9[Level of evidence: 3iiiDi] Active agents include cyclophosphamide, cisplatin, carboplatin, lomustine, and etoposide. Regardless of treatment strategy, the prognosis for patients with recurrence is poor. 1 Entry into studies of novel therapeutic approaches should be considered.

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