Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma

PRIMARY OBJECTIVES:

I. To determine the event free survival (EFS) and overall survival (OS) of children with
completely resected ependymoma treated with post-operative conformal radiation therapy (cRT)
and then randomized to receive or not receive four cycles of post radiation maintenance
chemotherapy (vincristine sulfate [vincristine] cisplatin, etoposide and cyclophosphamide
[VCEC]).

SECONDARY OBJECTIVES:

I. To estimate the EFS and OS of children with incompletely resected ependymoma who are
unable to achieve a complete response (CR) by post-operative induction chemotherapy or by
second surgery who will then be non-randomly assigned to cRT followed by four cycles of
maintenance chemotherapy (VCEC).

II. To further evaluate the EFS and OS of children with supratentorial classic ependymoma who
achieve a complete resection at first or second resection OR children who achieve a CR to
short course induction chemotherapy following first surgery.

III. To evaluate whether the addition of maintenance chemotherapy post-radiation therapy
contributes to neurobehavioral morbidity and reduced functional outcomes over time, compared
to patients treated with radiation therapy followed by observation alone.

IV. To examine differences in neurobehavioral outcomes and quality of life of children
treated with proton beam radiation therapy compared to children treated with conventional
radiation delivery techniques.

V. To evaluate biologic prognostic factors in childhood ependymoma by utilizing genomic
profiles via comparative genomic hybridization (CGH), single-nucleotide polymorphism arrays,
and microarray gene expression profiling analysis on initial tumor samples and correlating
this data with clinical outcome.

VI. Explore prognostic molecular signatures and genomic alterations in ependymomas.

VII. Evaluate prognostic immune-function gene expression in ependymomas. VIII. Build upon the
data derived from COG-ACNS0121 to develop genotypically based classification signatures and
to correlate these to World Health Organization (WHO) grade, location, extent of resection,
treatment, EFS, and OS.

IX. To evaluate telomere maintenance as a prognostic marker.

OUTLINE: Patients are assigned to Arm I or randomized to Arms II or III.

Arm I: Patients receive vincristine sulfate intravenously (IV) over 1 minute on days 1 and 8
of courses 1 and 2, carboplatin IV over 15-60 minutes on day 1 of courses 1 and 2, and
cyclophosphamide IV over 30-60 minutes on days 1-2 of course 1 only. Patients also receive
etoposide IV over 60-120 minutes on days 1-3 of course 2 only. Course 1 continues for 3 weeks
and course 2 continues for 4 weeks in the absence of disease progression or unacceptable
toxicity. Patients with complete response are randomized to Arm II or III. Patients achieving
stable disease, partial response, or locally progressive disease and who are deemed
potentially resectable undergo surgery within 15 days after completion of induction
chemotherapy. Patients with sub total resection are assigned to Arm II. Patients with gross
total resection undergo observation.

ARM II: Patients undergo conformal radiotherapy over 6-7 weeks. Patients then receive
vincristine sulfate IV on days 1, 8, and 15 of courses 1-3 only, etoposide IV over 60-120
minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60
minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease
progression or unacceptable toxicity.

ARM III: Patients undergo conformal radiotherapy over 6-7 weeks and then undergo observation.

After completion of study therapy, patients are followed up every 4 months for 5 years, and
then annually thereafter.

Inclusion Criteria:

- Patients must be newly diagnosed with histologically confirmed intracranial
ependymoma; patients with classic ependymoma (WHO II) or anaplastic ependymoma (WHO
III) are eligible, as are various subtypes described as clear cell, papillary,
cellular or a combination of the above

- There is no minimum performance level; children with ependymoma may suffer neurologic
sequelae as a result of their tumor or surgical measures taken to establish a
diagnosis and resect the tumor; in the majority of cases, there is neurologic
recovery; neurologic recovery is not likely to be impeded by protocol therapy

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met

Exclusion Criteria:

- Patients with evidence of metastatic disease will be excluded; any evidence of
non-contiguous spread beyond the primary site as determined by pre or post-operative
magnetic resonance (MR) imaging of brain, pre or post-operative MR imaging of the
spine, and post-operative cerebrospinal fluid (CSF) cytology obtained from the lumbar
CSF space (the requirement for lumbar CSF examination may be waived if deemed to be
medically contraindicated); CSF cytology from a ventriculostomy or permanent
ventriculoperitoneal (VP) shunt that reveals the presence of tumor cells is indicative
of metastatic disease

- Patients with a diagnosis of spinal cord ependymoma, myxopapillary ependymoma,
subependymoma, ependymoblastoma, or mixed glioma are NOT eligible

- No prior treatment other than surgical intervention and corticosteroids; patients are
allowed to have had more than one attempt at resection prior to enrollment

- Pregnant female patients are not eligible for this study

- Post-menarchal females may not participate unless a pregnancy test with a negative
result has been obtained

- Males and females of reproductive potential may not participate unless they have
agreed to use an effective contraceptive method

- Lactating females may not participate unless they have agreed not to breastfeed a
child while on this study