Testing Safe Doses of Anti-Cancer Medicines, 5-Flurouracil (5-FU) and Tretinoin (ATRA), Added to the Usual Cancer Treatment of Ependymoma

Inclusion Criteria:

* PRE-ENROLLMENT: Patients must be \> 12 months and \< 21 years of age at the time of enrollment
* PRE-ENROLLMENT: Patient has newly diagnosed posterior fossa ependymoma based on institutional pathologic diagnosis
* PRE-ENROLLMENT: The patient and/or their parents or legal guardians must have signed informed consent for APEC14B1 Part A - Eligibility Screening
* PRE-ENROLLMENT: If relying on APEC14B1-MCI for molecular characterization, required specimens for molecular characterization should be submitted as soon as possible, preferably within 5 calendar days of definitive surgery
* Patients must be \> 12 months and \< 21 years at the time of study enrollment
* Patients must be newly diagnosed, localized and have eligibility confirmed by central review of molecular reports
* Histologically confirmed diagnosis of Posterior fossa ependymoma, group PFA
* Molecular high risk features including Chromosome 1q gain and/or chromosome 6q loss
* Patients must be enrolled on study within 56 days of definitive surgical resection. If applicable, the day of subsequent resection to remove residual tumor will be regarded as the day of definitive surgery and must be within a month (31 days) of the initial resection
* Patients must have negative lumbar CSF cytology.

  * Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF. Ideally, CSF should be obtained between Day 14 and Day 21 to allow for final staging status before enrollment onto the study. Patients with positive lumbar CSF cytology obtained 0 to 14 days after surgery should have lumbar cytology repeated to determine eligibility and final CSF status. Patients with negative CSF lumbar cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated. Patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively.
  * CSF cytology does not need to be repeated if within 87 days prior to enrollment regardless of timing
* Patients must have localized disease. Pre and post-operative whole brain MRI with and without gadolinium and spine MRI with gadolinium must be performed

  * Disease/staging imaging studies, including MRI brain (post operative) and spine (pre or post-operative), must be obtained within 31 days prior to enrollment and start of protocol therapy (repeat if necessary)
* No prior treatment other than surgical intervention and corticosteroids. Patients are allowed to have had more than one surgical resection prior to enrollment. For patients who have subsequent surgery, the day of the subsequent resection to remove residual tumor will be regarded as the day of definitive surgery and must be within a month (31 days) of initial resection
* Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* Peripheral absolute neutrophil count (ANC) ≥ 1000/ µL (performed within 7 days prior to enrollment)
* Platelet count ≥ 100,000/µL (transfusion independent) (performed within 7 days prior to enrollment)
* Hemoglobin ≥ 8 g/dL (may receive red blood cell \[RBC\] transfusions) (transfusion independent) (performed within 7 days prior to enrollment)
* Adequate Renal Function Defined As:

  * A serum creatinine based on age/sex as follows (performed within 7 days prior to enrollment) OR

    * 1 to \< 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female)
    * 2 to \< 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female)
    * 6 to \< 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female)
    * 10 to \< 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female)
    * 13 to \< 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
    * \>= 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female)

      * The threshold creatinine values in this Table were derived from the Schwartz formula for estimating glomerular filtration rate (GFR) utilizing child length and stature data published by the Center for Disease Control (CDC)
  * a 24-hour urine Creatinine clearance ≥ 50 mL/min/1.73 m\^2 (performed within 7 days prior to enrollment) OR
  * a GFR ≥ 50 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard) (performed within 7 days prior to enrollment)

    * Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable if using GFR for determine eligibility
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (performed within 7 days prior to enrollment)
* Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) ≤ 135 U/L\* (performed within 7 days prior to enrollment)

  * Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* Central nervous system function defined as:

  * Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
  * Patients must not be in status epilepticus, a coma or assisted ventilation at the time of study enrollment
* Adequate cardiac function

  * Shortening fraction of ≥ 27% by echocardiogram, or
  * Ejection fraction of ≥ 50% by echocardiogram, cardiac MRI, or radionuclide angiogram, AND
  * For Patients ≥ 18 years:

    * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
* Test result showing no evidence of complete or partial absence of dihydropyrimidine dehydrogenase (DPYD) activity. This genetic test can be obtained at any time prior to enrollment at a College of American Pathology (CAP)/Clinical Laboratory Improvement Act (CLIA) certified laboratory. Patients with DPYD variants that result in complete or partial DPD deficiency are not permitted to enroll on this study

Exclusion Criteria:

* Patients with metastatic disease by either MRI evaluation or lumbar CSF cytology are not eligible. Patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible
* Hypersensitivity to fluorouracil, tretinoin, other retinoids, or any component of the formulation
* Personal history of Torsades de pointes, atrial fibrillation, supraventricular tachycardia (SVT), or heart failure; personal history of prolonged QT Syndrome; other uncontrolled arrhythmia in the past 6 months prior to study enrollment
* Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation. Patients who could become pregnant should use effective contraception during treatment and 1 month following the last dose of tretinoin or for 3 months following last dose of fluorouracil, whichever is longer. Patients with partners who could become pregnant should also use effective contraception during treatment and for 1 week after the last dose of tretinoin or 3 months after the last dose of fluorouracil, whichever is longer