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Ependymomas are relatively uncommon glial tumors
accounting for approximately 10 percent of all pediatric CNS tumors. 1 Like many other
CNS malignancies in children, management of ependymomas remain a challenge.
Historically, the 5-year survival has been reported as 50 percent to 64 percent with progression
free survival of 23 percent to 45 percent. 2,4,5 Ependymomas arise from within or next to the
ependymal lining of the ventricular system of the brain or the central canal of
the spinal cord. They are typically intracranial (90percent) with 60 percent occurring in the
posterior fossa, arising from the floor or roof of the fourth ventricle. In
patients 3 years of age and younger, up to 85 percent of tumors are within the
posterior fossa. 3 Ependymomas in the spinal cord account for 25
percent of all spinal
cord tumors.
Pathology
Ependymomas are typically well-demarcated tumors with a range of histological
grades. The ependymal rosette, if present is a diagnostic microscopic feature.
However pseudorosettes are more commonly observed. Ependymomas are classified as
either benign (low grade) or malignant/anaplastic (high grade) tumors. Tumors
arising from the conus medullaris and filum terminale are usually called
myxopapillary ependymomas and they have unique histological features and
biological behavior.6 Ependymoblastomas are highly malignant tumors, and are now
classified as primitive neuroectodermal tumors (PNET). Current WHO
classification grades tumors as follows: sub-ependymoma and myxopapillary tumors
as grade 1, ependymoma as grade 2 and anaplastic ependymoma as grade 3.
Histological grade has been controversial as a predictor of both behavior and
prognosis in ependymomas. More recent studies suggest that anaplastic ependymoma
may have a poorer outcome.7 Continued efforts are needed to understand the
biology of these tumors and their variable clinical behavior in order to improve
therapy and clinical outcomes. Most recently, the radial glia cells have been
identified as the likely cell of origin of ependymoma.8 Further research in
this area may lead to identification of more targeted therapies.
Clinical Presentation
Clinical presentation in patients with ependymoma varies with tumor location.
Patients with posterior fossa tumors may present with signs and symptoms of
increased intracranial pressure, such as headache, nausea, vomiting, ataxia and
papilledema. Cranial nerve (CN) palsies involving CN VI to X are also common.
Seizures and focal neurological deficits are more common with supratentorial
tumors. Patients with spinal cord tumors present with symptoms related to cord
compression.
On CT imaging, these tumors often display areas of calcification, hemorrhage and
cysts. Preoperatively patients should have MRI imaging of both the brain and
spinal cord. CSF should be obtained postoperatively to evaluate for the presence
of metastatic disease, which is seen in less than 10 percent of patients.
Prognostic Factors
Identification of prognostic factors has been limited by single institution
reports and retrospective reviews. Multiple studies have demonstrated that the
most important prognostic factor in ependymoma is the extent of surgical
resection with patients with complete surgical resection having the best
outcomes.5,9 Some studies have demonstrated that tumor location and young age
are also poor prognostic factors.5,10,9 Histological grade remains a
controversial prognostic predictor, with some reports suggesting well
differentiated tumors do better than anaplastic. A recent report showed
that histological grade was related to PFS after irradiation. Patients with
anaplastic ependymoma had 2 year EFS of 32 percent +/- 14 percent vs. 84 percent +/- 7
percent in
differentiated.7
Surgery
Gross total resection (GTR) is the desired surgical outcome since it has been
associated with improved survival in multiple studies. However, given the
location of many tumors in the posterior fossa, attempt at GTR can leave the
patient with significant neurological dysfunction, including CN injury.
Postoperative morbidity is high and patients are also at risk for posterior
fossa syndrome in addition to other neurological deficits. Because extent of
surgical resection is so important, a second-look surgery may be attempted,
often this occurs after a brief course of chemotherapy. This method was recently
evaluated in the COG ACNS 0121 study, results of which are not yet available.13
Radiation
Radiation is considered the standard adjuvant therapy for ependymoma.
Historically all patients received cranio-spinal (CS) radiation. Review of
retrospective data, however, did not demonstrate clear benefit, and it is
no longer considered the standard therapy for patients with local disease.14 CS
radiation is indicated for patients with metastatic disease. Patients who
undergo complete resection of well-differentiated tumors in the supratentorial
region may not require any further therapy. Such patients treated with surgery
followed by observation are being evaluated prospectively in the COG ACNS 0121
study.13
Radiation dose has been another area of controversy in the treatment of
ependymoma, with efforts being made to reduce the dose in an attempt to decrease
side effects. Current doses utilized range from 45 to 60 Gy. The POG 9132 trial
used hyper-fractionated RT of 69.6 Gy in 58 fractions delivered at a twice daily
dose of 1.2 Gy BID for 6 weeks in patients with infratentorial tumors. They
demonstrated 4 yr EFS of 70 percent in patients with GTR vs. 50 percent in subtotal resection.
While there was no difference in EFS from a prior trial, POG 8532 in the GTR
group, (70 percent), there did seem to be a difference in STR group (50 percent vs. 24
percent).15
Other studies, however, have not supported the finding that hyper-fractionated
radiation therapy is beneficial.16 Long-term effects of radiation are in part
dependent on the age of the patient and the location of the tumor. The side
effects with the greatest long-term morbidity include: abnormal endocrine
function; changes in cognitive function and behavior; and neurological sequelae.
Chemotherapy
The role of adjuvant chemotherapy in the treatment of ependymoma remains
controversial. Agents that have demonstrated some activity include: carboplatin,
cisplatin, etoposide, cyclophosphamide and vincristine. Adjuvant chemotherapy is
most commonly employed following surgery in children less than 3 years of age as
a means of delaying radiation therapy. In a study conducted by the Pediatric
Oncology Group, 48 patients less than 3 years old received postoperative
chemotherapy with delayed radiation. Children ages 0 to23 months received
chemotherapy for 2 years, and children 24 to 36 months received chemotherapy for
one
year, followed by radiation therapy for all children. Chemotherapy consisted of
alternating cycles of vincristine, cyclophosphamide, and cisplatin and etoposide.
Five-year survival was significantly better in the older patients at 63.3
percent vs.
25.7 percent, suggesting that radiation should not be delayed more than a year. Multiple studies have demonstrated no further benefit from chemotherapy after
radiation, including a study from the Children’s Cancer Group, which found the
10-year failure-free survival to be 36 percent and overall survival 39 percent, with no
differences between patients who received radiation therapy alone and those who
received radiation therapy followed by chemotherapy.17 Many other groups have
found similar outcomes with no additional benefit of improved survival with
chemotherapy. However, Needle et al., reported 5-year PFS for patients with
residual tumor treated with radiation and multi-alkylator therapy to be 74
percent,
which was higher than previously published reports. Of note, some of the
patients in this study received hyperfractionated radiation, at the discretion
of the provider. Chemotherapy may play a role in reducing the tumor burden
following initial subtotal resection, facilitating complete tumor removal at the
time of second-look surgery after several courses of chemotherapy. This is
currently being evaluated in the Children’s Oncology Group trial ACNS 0121.13
Recurrent Tumors
Prognosis for patients with recurrent ependymoma is poor. In a review completed
by POG of phase II trials over a 10-year period, 153 patients with ependymoma
were treated with either single or combination chemotherapy with a PR/CR of
14.5 percent and a 5-year PFS of 25 percent.18 There has been no clear benefit demonstrated
by single or multiple institution trials of either conventional dose or
myeloablative dose therapy in this setting.
Summary
Continued efforts need to be made to identify effective treatment for
ependymomas. A better understanding of the molecular biology and genetics may
help in identifying effective therapies and improve clinical outcomes compared
to the use of surgery and radiation therapy alone.
About the Authors
Patricia Baxter, M. D., is a fellow in the Baylor College of Medicine
Pediatric Hematology/Oncology Fellowship/Faculty Training Program at the Texas
Children’s Cancer Center. Dr. Baxter’s research interest is in the area of Medulloblastoma and Glioma cancer stem cells.
Murali Chintagumpala, M.D., is a Professor of
Pediatrics at Baylor College of Medicine and serves as Clinical Director of the
Brain Tumor Program at the Texas Children’s Cancer Center.
Dr. Chintagumpala’s research interests are in the area of brain tumors,
Retinoblastoma, Osteosarcoma and Wilms tumors.
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