Treatment of Newly Diagnosed Childhood Ependymoma

Postsurgical Treatment Options
        Standard treatment options
        Treatment options under clinical evaluation
Subependymoma
Myxopapillary Ependymoma
Current Clinical Trials

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.

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 to treat the entire CNS (whole brain and spine) because these tumors usually recur initially at the local site.[2,6,7]; [8][Level of evidence: 3iiiA] When possible, patients should be treated in a center experienced with the delivery of conformal radiation therapy to pediatric patients with brain tumors. There is no evidence that adjuvant 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%.[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%.[11][Level 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.[12][Level of evidence: 3iiiDi]; [13,14][Level 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 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 spine) because these tumors usually recur at the local site.[7][Level 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,[10,16] although the outcome for patients with residual tumor within the spinal canal may be better.[17] There is no evidence that adjuvant chemotherapy, including high-dose chemotherapy with 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.[19-22]; [23][Level 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.[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.[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.[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.

  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.[25][Level of evidence: 3iiiC] The need and timing of radiation therapy for children who have successfully completed chemotherapy and 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,[19-21] 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.[26][Level of evidence: 2Di]

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.

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.

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]

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.

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, Garrè 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, Villà 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]