PRIMARY OBJECTIVE:

      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, cisplatin, etoposide and cyclophosphamide [VCEC]).

      EXPLORATORY 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 studying molecular
      groups as defined by deoxyribonucleic acid (DNA) methylation profiling and
      immunohistochemistry, copy number variants to identify 1q gain in posterior fossa
      ependymomas, CDKN2A loss (homozygous deletion) in supratentorial ependymomas and specific
      genetic alterations such as RELA fusions, YAP1 fusions and the H3 K27M mutation on initial
      tumor samples and correlating these data with clinical outcome.

      Va. To explore prognostic molecular signatures and genomic alterations in ependymomas by
      building upon the data derived from ACNS0121 to correlate biomarkers listed above with World
      Health Organization (WHO) grade, location, extent of resection, treatment, EFS and OS.

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

      Arm I: Patients receive vincristine intravenously (IV) over 1 minute on days 1 and 8 of
      cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and
      cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive
      etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks
      and cycle 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 IV on days 1, 8, and 15 of cycles 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.