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Childhood Ependymoma Treatment (PDQ®)

Treatment of Newly Diagnosed Childhood Ependymoma or Anaplastic Ependymoma

Standard treatment options for newly diagnosed ependymoma (WHO Grade II) or anaplastic ependymoma (WHO Grade III) include the following:

Typically, all patients undergo surgery to remove the tumor. Whether additional treatment is given depends on the extent of tumor resection and whether there is disseminated disease.

Surgery

Surgery should be performed in an attempt at maximal tumor reduction. Evidence suggests that more extensive surgical resection is related to an improved rate of survival.[1-5]; [6][Level of evidence: 3iDii] Magnetic resonance imaging (MRI) should be performed postoperatively to confirm the extent of resection. If not performed preoperatively, MRI of the entire neuraxis to evaluate disease dissemination and cerebrospinal fluid cytopathology should be performed.

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.

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.[7,8][Level of evidence: 3iiiDi]; [9,10][Level of evidence: 3iiiDiii]

Adjuvant Therapy

Treatment options for no residual disease, no disseminated disease

Radiation therapy

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.[11] It is not necessary to treat the entire CNS (whole brain and spine) because these tumors usually recur initially at the local site.[12]; [13][Level of evidence: 3iiiA] When possible, patients should be treated in a center experienced with the delivery of highly conformal radiation therapy (including intensity-modulated radiation therapy or charged-particle radiation therapy) to pediatric patients with brain tumors.

Evidence (radiation therapy):

  1. In one study, 74 patients aged 1 to 21 years were treated with radiation therapy after surgery.[14]
    • The 3-year progression-free survival (PFS) rate was 77.6% ± 5.8%.
  2. In a second series, 107 of 153 patients received conformal radiation therapy immediately after up-front resection.[5][Level of evidence: 3iA]
    • The 7-year event-free survival was 76.9% ± 13.5%.

Focal radiation therapy has been used in certain cases.[15] In a small series of children with localized ependymoma, surgery alone was compared with adjuvant radiation therapy. Adjuvant radiation therapy appeared to improve PFS, even after adjusting for the extent of resection. In fact, a PFS benefit was observed for patients who received adjuvant radiation therapy after gross-total resection, compared with those who did not receive radiation therapy.[16] Additional research will be necessary to confirm these findings.

Proton-beam radiation therapy (a type of charged-particle radiation therapy) provides a possible advantage for targeting the tumor while avoiding critical normal brain and neuroendocrine tissues, whether the tumor is supratentorial or infratentorial. Seventy children treated with involved-field, proton-beam radiation at Massachusetts General Hospital between 2000 and 2011 (median age, 33 months; range, 3 months–20 years) had 3-year local control of 83%, PFS of 76%, and overall survival (OS) of 95%, with confirmation that subtotal resection was associated with an inferior outcome. Data demonstrating an advantage in terms of intelligence, adaptive skills, neuroendocrine deficiencies, and other morbidities do not yet show an advantage over other forms of conformal radiation therapy.[17]

Chemotherapy

There is no evidence to date that adjuvant chemotherapy, including the use of myeloablative chemotherapy,[18] improves the outcome for patients with totally resected, nondisseminated ependymoma. For this reason, current treatment approaches do not include chemotherapy as a standard component of primary therapy for children with newly diagnosed ependymomas that are completely resected.

A randomized trial evaluating the efficacy of postradiation chemotherapy in children who have had a gross-total resection is underway.

Treatment options for residual disease, no disseminated disease

Second-look surgery

Second-look surgery should be considered because patients who have complete resections have better disease control.[19] In some cases, further surgery can be undertaken after the initial attempted resection if the pediatric neurosurgeon believes that a gross-total resection could be obtained by an alternate surgical approach to the tumor. In other cases, further up-front surgery is not anticipated to result in a gross-total resection, therefore, adjuvant therapy is initiated with future consideration of second-look surgery.

Radiation therapy

The rationale for radiation therapy as described in the Treatment options for no residual disease, no disseminated disease subsection above also pertains to the treatment of children with residual, nondisseminated ependymoma. In patients with a subtotal resection, treatment with radiation therapy results in 3-year to 5-year PFS in 30% to 50% of patients,[14] although the outcome for patients with residual tumor within the spinal canal may be better.[20]

Preirradiation chemotherapy

One study demonstrated a benefit of preirradiation chemotherapy in children with near-total resection (>90% resection), with outcomes comparable to children achieving a gross-total resection followed by radiation therapy.[21] The Children’s Oncology Group (COG) has completed a study of preirradiation chemotherapy in children with residual disease after up-front surgery to determine whether children treated with chemotherapy can achieve a complete response with chemotherapy or second-look surgery. Results are pending.

There is no evidence that high-dose chemotherapy with stem cell rescue is of any benefit.[22]; [23][Level of evidence: 2A]

Treatment options for CNS disseminated disease

Radiation therapy

Regardless of the degree of surgical resection, these patients generally receive radiation therapy to the 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) are also 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 are administered, with doses depending on the age of the patient and the location of the tumor. However, there are no contemporary studies published to support this approach.

Chemotherapy

The role of chemotherapy in the management of children with disseminated ependymoma is unproven.[24]

Treatment options for children younger than 3 years

Children younger than 3 years are particularly susceptible to the adverse effects of radiation on brain development.[25][Level of evidence: 3iiiC] Debilitating effects on growth and neurologic development have frequently been observed, especially in younger children.[26-28] Consequently, radiation therapy immediately after surgery in children younger than 3 years has historically been limited, with attempts to delay its administration through the use of chemotherapy.[29-32]; [33][Level of evidence: 2A]

Chemotherapy

Some, but not all, chemotherapy regimens induce objective responses in children younger than 3 years with newly diagnosed ependymoma.[29-32] Up to 40% of infants and young children with totally resected disease may achieve long-term survival with chemotherapy alone.[34][Level of evidence: 2Di]

Radiation therapy

Because of the known effects of radiation on growth and neurocognitive development, the use of radiation therapy in children younger than 3 years has been limited.

Evidence (radiation therapy):

  1. A retrospective review based on Surveillance, Epidemiology, and End Results data reported on 184 children younger than 3 years.[11]
    • 3-year OS 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.
  2. Conformal radiation therapy is an alternative approach for minimizing radiation-induced neurologic damage in young children with ependymoma. The need and timing of radiation therapy for children who have successfully completed chemotherapy and have no residual disease is still to be determined.
    • The initial experience with this approach suggested that children younger than 3 years with ependymoma have neurologic deficits at diagnosis that improve with time after conformal radiation treatment.[14]
    • 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: 3iiiC]

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.[14,35] When analyzing neurologic outcome after treatment of young children with ependymoma, it is important to consider that not all long-term deficits can be ascribed to radiation therapy because deficits may be present in young children before therapy begins.[14] For example, the presence of hydrocephalus at diagnosis is associated with lower intelligence quotient as measured after surgical resection and before administration of radiation therapy.[36]

The recently completed COG protocol (ACNS0121 [NCT00027846]) for children with ependymoma includes children aged 1 year and older. The trial is a prospective evaluation of postoperative radiation therapy. Results are forthcoming.

Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood Ependymoma or Anaplastic Ependymoma

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.

  1. COG-ACNS0831 (NCT01096368) (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 and after radiation therapy results in improved survival compared with previous studies of children who did not receive additional chemotherapy after radiation treatment.

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. 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]
  2. 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]
  3. Kothbauer KF: Neurosurgical management of intramedullary spinal cord tumors in children. Pediatr Neurosurg 43 (3): 222-35, 2007. [PUBMED Abstract]
  4. 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]
  5. 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]
  6. Cage TA, Clark AJ, Aranda D, et al.: A systematic review of treatment outcomes in pediatric patients with intracranial ependymomas. J Neurosurg Pediatr 11 (6): 673-81, 2013. [PUBMED Abstract]
  7. 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]
  8. Hukin J, Epstein F, Lefton D, et al.: Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29 (1): 40-5, 1998. [PUBMED Abstract]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. Landau E, Boop FA, Conklin HM, et al.: Supratentorial ependymoma: disease control, complications, and functional outcomes after irradiation. Int J Radiat Oncol Biol Phys 85 (4): e193-9, 2013. [PUBMED Abstract]
  16. 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]
  17. Macdonald SM, Sethi R, Lavally B, et al.: Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients. Neuro Oncol 15 (11): 1552-9, 2013. [PUBMED Abstract]
  18. 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]
  19. Massimino M, Solero CL, Garrè ML, et al.: Second-look surgery for ependymoma: the Italian experience. J Neurosurg Pediatr 8 (3): 246-50, 2011. [PUBMED Abstract]
  20. 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]
  21. Garvin JH Jr, Selch MT, Holmes E, et al.: Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (7): 1183-9, 2012. [PUBMED Abstract]
  22. 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]
  23. Venkatramani R, Ji L, Lasky J, et al.: Outcome of infants and young children with newly diagnosed ependymoma treated on the "Head Start" III prospective clinical trial. J Neurooncol 113 (2): 285-91, 2013. [PUBMED Abstract]
  24. Bouffet E, Capra M, Bartels U: Salvage chemotherapy for metastatic and recurrent ependymoma of childhood. Childs Nerv Syst 25 (10): 1293-301, 2009. [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. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  • Updated: August 12, 2014