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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood ependymoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version, which is written in less technical language, and in Spanish.
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.
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 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.
Refer to the PDQ summary Childhood Brain and Spinal Cord Tumors Treatment Overview for information about the general classification of childhood brain and spinal cord tumors.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary Levels of Evidence for more information.)
Childhood ependymoma comprises approximately 9% of all childhood brain tumors representing approximately 200 cases per year in the United States. [1] [2]
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. [3] [4] [5] [6] [7] [8] [9]
In the most recent World Health Organization (WHO) classification of brain tumors, ependymal tumors are classified into four main subtypes: [1]
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:
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.
Subependymomas and myxopapillary ependymomas are usually considered different tumors 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. [2] [3] [4] [5] [6] [7] [8] 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; [9] 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] [2] For more information, refer to the PDQ summary Childhood Central Nervous System Embryonal Tumors.
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.
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 ventriculous terminalis of the spinal cord, and have access to the cerebral spinal fluid (CSF). Therefore, these tumors may spread throughout the neuroaxis, 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] Primary spinal cord ependymomas have a more favorable outcome than cranial variants. [13] Molecular diagnostics are evolving, but have yet to be validated in a prospective manner. [14] [15] 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. [16] These prognostic variables must be evaluated in the context of the treatment received.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary Levels of Evidence for more information.)
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] Chemotherapy has been shown to be active in patients with recurrent ependymoma. [8] One relatively small, prospective, randomized trial suggests that chemotherapy activity in newly diagnosed cases is limited, [9] 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. [10][Level of evidence: 3iiiC] Debilitating effects on growth and neurologic development have frequently been observed, especially in younger children. [11] [12] [13] For this reason, conformal radiation approaches that minimize damage to normal brain tissue and proton beam therapy are under evaluation for infants and children with ependymoma. [14] [15] 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. [16]
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary Levels of Evidence for more information.)
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.
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 and is under evaluation for children younger than 3 years. It is not necessary to treat the entire CNS (whole brain and spine) because these tumors usually recur initially at the local site. [2] [5] [6] [7][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, [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%. [9] 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%. [10][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. [11][Level of evidence: 3iiiDiii]; [12][Level of evidence: 3iiiDi]
Second-look surgery should be considered because patients who have complete resections have better disease control. 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. [6][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, [9] [13] although the outcome for patients with residual tumor within the spinal canal may be better. [14] There is no evidence that adjuvant chemotherapy, including high-dose chemotherapy with stem cell rescue, is of any benefit. [15]
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.
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. [16] [17] [18] [19] 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. [9] 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. [20]
Chemotherapy is able to induce objective responses in some children younger than 3 years with newly diagnosed ependymoma, [16] [17] [18] though not all chemotherapy regimens induce objective responses. [19] Up to 40% of infants and young children with totally resected disease may achieve long-term survival with chemotherapy alone. [21][Level of evidence: 2Di] The need and timing of radiation therapy for children who have successfully completed chemotherapy and have no residual disease is still to be determined.
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. [9] However, another study suggested that there was a trend for intellectual deterioration over time even in older children treated with localized radiation therapy. [22][Level of evidence: 3iiiC] The recently completed Children's Oncology Group protocol for children with ependymoma includes young children aged 12 to 36 months and is closed to patient accrual and the analysis is pending.
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. [23] 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. [24]; [25][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] [24]; [26][Level of evidence: 3iiiDiii]; [27][Level of evidence: 3iiiDi]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
Recurrence is not uncommon in both benign and malignant childhood brain tumors and may develop many years after initial treatment. For ependymoma, delays beyond 10 to 15 years have been reported. [1] [2] Disease generally recurs at the primary tumor site, even in children with malignant ependymomas. [3] [4] 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. [5][Level of evidence: 3iiiB] In addition, patients may be candidates for focal retreatment with various radiation modalities, including stereotactic radiosurgery. [6] [7][Level of evidence: 3iiiDi] Active agents include cyclophosphamide, cisplatin, carboplatin, lomustine, and etoposide. Entry into studies of novel therapeutic approaches should be considered.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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.
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