A Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma

The primary purpose of this study is to investigate whether surgery and re-irradiation will help treat ependymoma that has come back after initial treatment. The combined doses of the first and second courses of radiation are higher than what is usual standard of care. The investigators will study the effects and side effects of surgery and re-irradiation. They will also evaluate and study tumor tissue and blood to learn more about the tumor and how it does or does not respond to treatments and will use magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to see if they can predict tumor response and tumor recurrence. Participants will be followed for up to 5 years following enrollment. Evaluations during radiation therapy will be done weekly while receiving therapy for up to 7 weeks. Other evaluations will be done at enrollment, every 4 months from enrollment through 3 years, and every 6 months during the 4th and 5th year.

Stratification for treatment will be determined when radiation therapy planning is initiated. Patients will be stratified for outcome according to diagnosis and prior therapy. Stratum 1 (initial pattern of failure is local); disease confined to primary site; age >12 months at time of enrollment to < 21 years. Treatment: focal irradiation. Stratum 2 (initial pattern of failure is metastatic); neuraxis metastatic disease without equivocal evidence of local failure; age > 36 months at time of enrollment to < 21 years. Treatment: craniospinal irradiation. Stratum 3 (Initial pattern of failure is both local and metastatic): neuraxis metastatic disease with unequivocal evidence of local failure; age > 36 months at time of enrollment to < 21 years. Treatment: craniospinal irradiation. Stratum 4 (initial pattern of failure is local): disease confined to primary site, age >36 months at time of enrollment to <21 years; tumor shows presence of 1g gain. Treatment: craniospinal irradiation (optional). PRIMARY OBJECTIVE: To prospectively estimate the progression-free and overall survival distributions for children and young adults with recurrent ependymoma treated with a second course of irradiation while monitoring for excessive central nervous system necrosis. SECONDARY OBJECTIVES: To explore potential associations of clinical and treatment factors with the incidence and severity of neurological, endocrine and cognitive deficits in children and young adults with ependymoma treated with a second course of irradiation. Using specific measures of sleep quality, excessive daytime sleepiness, daytime activity, fatigue, symptom distress, and quality of life, explore associations of sleep, fatigue and quality of life with other measures of CNS effects, clinical and treatment factors in children and young adults with ependymoma treated with a second course of irradiation. To evaluate and explore differences in physical performance and movement in children and young adults with ependymoma treated with a second course of irradiation. Estimate and compare the response of residual tumor and the incidence and severity of structural, physiological, and vascular effects of normal brain in children and young adults with ependymoma after treatment with a second course of irradiation using specific methods of diffusion, contrast-enhancement, magnetization transfer, vascular and functional neuroimaging, and explore the association between these and other measures of CNS effects and clinical and treatment factors. Determine the time course of gray matter and white matter tract injury and recovery post irradiation and the association between imaging metrics derived from serial quantitative neural imaging and radiation dosimetry as well as neuro-cognitive outcomes. Other Pre-Specified (Exploratory) Objectives: Estimate the avidity of ependymoma to 18F-fluorodeoxyglucose (FDG) and 11C-methionine positron emission tomography (IND # 104987) prior to radiation therapy and correlate change in avidity 12, 24 and 36 months after a second course of irradiation with tumor progression. Measure growth factor and cytokine responses in children and young adults with ependymoma after treatment with a second course of irradiation, and explore associations between these and other measures of CNS effects and clinical and treatment factors. Descriptively compare findings for patients treated with an initial course of irradiation. To conduct a variety of exploratory molecular analyses on tumor samples (and blood where a germline control is required), including but not limited to broad (genome-wide / array-based) or focused (gene-specific) analyses at the DNA, RNA, or protein level and next generation (whole genome, exome, transcriptome) sequencing in an effort to improve the investigators understanding of ependymoma biology, and to explore associations between molecular findings and treatment response and various side effects including vasculopathy, hearing loss, cognitive deficits, and growth hormone deficiency and other measures as appropriate. To explore the association of chemotherapy given prior to re-irradiation with progression-free survival and overall survival distributions To compare the progression-free and overall survival distributions for children (age >3 years) and young adults with recurrent ependymoma and 1g gain treated with a second course of irradiation (focal or craniospinal) while monitoring for excessive central nervous system necrosis.

Participants exhibit an initial pattern of failure that is local (disease confined to primary site). Treatment is surgery and a second course of focal irradiation. The total dose for the second course of irradiation will be 54Gy. Participants may receive one or both: Photon therapy or proton therapy. Participants receive ^1^8F-fluorodeoxyglucose and ^1^1C-methionine to aid in tumor visualization.

Participants exhibit an initial pattern of failure that is metastatic (neuraxis metastatic disease without equivocal evidence of local failure). Treatment is surgery and craniospinal irradiation. Craniospinal irradiation (36-39.6Gy) will include focal boost treatment of metastatic sites (54-59.4Gy) depending on location, extent of resection and target volume. Participants may receive one or both: Photon therapy or proton therapy. Participants receive ^1^8F-fluorodeoxyglucose and ^1^1C-methionine to aid in tumor visualization.

Participants exhibit an initial pattern of failure that is both local and metastatic (neuraxis metastatic disease with equivocal evidence of local failure). Treatment is surgery and craniospinal irradiation. Participants may receive one or both: Photon therapy or proton therapy. Participants receive ^1^8F-fluorodeoxyglucose and ^1^1C-methionine to aid in tumor visualization.

Local Failure Participants exhibit an initial pattern of failure that is local (disease confined to primary site). Age is >36 months at time of enrollment to <21 years. Tumor shows presence of 1q gain. Treatment is optional craniospinal irradiation. Participants may receive one or both: Photon therapy or proton therapy. Participants receive ^1^8F-fluorodeoxyglucose and ^1^1C-methionine to aid in tumor visualization.

Radiation therapy on this protocol will be based on extent of disease, extent of resection and location. The allowed treatment modalities include conformal or intensity-modulated radiation therapy using photons or proton therapy using double-scattering or spot-scanning methods. The general goal is to initiate radiation therapy within 12 weeks of last surgery performed at the time of recurrence.

When applicable, surgery will be used to remove metastases. The goal of surgery is to achieve gross total resection of all imaging visible residual tumor.

Evaluation will be in children and young adults with ependymoma treated with a second course of irradiation. Outcomes will be reported by p-values.

Evaluation will be in children and young adults with ependymoma treated with a second course of irradiation. Outcome will be reported with p values.

Evaluation will be in children and young adults with ependymoma treated with a second course of irradiation. Outcome will be reported with p-values.

Evaluation will be in children and young adults with ependymoma treated with a second course of irradiation. Outcome will be reported with p-values.

Baseline is defined as day 1 of radiation therapy. Measured task sets: BOT2 (4-21 years old) and PPT (≥22 years old). BOT2 outcome: total motor composite, a standardized score range from 20 to 80, with a mean of 50 and a standard deviation of 10. PPT (7-item questionnaire) outcome: a score range from 0 to 28. The normative data is available from the human performance lab. The above scores will be standardized into z-scores/T-scores for data analysis based on normative data.

Baseline is defined as day 1 of radiation therapy. Self-reported instruments (PROMIS): Three questionnaires. Pediatric Physical Function - Mobility - SF1: 8-item questionnaire with the score range from 0 to 32. Pediatric Physical Function - Upper Extremity - SF1: same as above. Physical Function - SF1: 10-item questionnaire with the score range from 0 to 50. The above scores will be standardized into z-scores/T-scores for data analysis based on normative data

Baseline is defined as day 1 of radiation therapy. Ankle dorsiflexion active and passive range of motion: measured by goniometer, and recorded as an angle (degree).

Baseline is defined as day 1 of radiation therapy. Overall flexibility: measured by sit and reach test, and recorded as a length (cm).

Baseline is defined as day 1 of radiation therapy. Balance measured by Measured by sensory organization test (SOT), and the result from the test is the equilibrium score, a percentage range from 0% to 100%, with the higher percentage, the better balance. The outcome is a binary variable with a cutoff score of < 70% indicates future risk for a fall.

Baseline is defined as day 1 of radiation therapy. Fine motor coordination (finger and hand coordination). Measured by Composite Cerebellar Functional Severity Score (CCFS), and the outcome is an age-adjusted z-score and log transformed.

Baseline is defined as day 1 of radiation therapy. Overall coordination measured by brief ataxia rating scale (five-item questionnaire). The outcome is a total scale range from 0 to 22.

Baseline is defined as day 1 of radiation therapy. Lower extremity strength measured by BiodexIII. The outcomes are peak torque value/body weight ratios at different speeds of motion. The scores will be standardized into z-scores for data analysis based on normative data.

Baseline is defined as day 1 of radiation therapy. Hand grip strength is measured by a Jamar hand held dynamometer and recorded in kilograms (kg). The scores will be standardized into z-scores for data analysis based on normative data.

Baseline is defined as day 1 of radiation therapy. Resting energy expenditure is measured with indirect calorimetry after an overnight fast and recorded as REE (kcal/day). The scores will be standardized into z-scores for data analysis based on normative data.

Baseline is defined as day 1 of radiation therapy. Cardiopulmonary exercise test (CPET) will be completed on a treadmill using the Balke protocol or cycle ergometer using an incremental ramping protocol. The outcome is recorded as VO2max (ml/kg/min). The scores will be standardized into z-scores for data analysis based on normative data.

Longitudinal change of avidity of ependymoma to 18F-fluorodeoxyglucose and 11C-methionine PET prior to radiation therapy

Correlation of avidity of ependymoma to 18F-fluorodeoxyglucose and 11C-methionine PET prior to radiation therapy with progression-free survival will be reported

Association between necrosis measured with MET/FDG vs. MRI Baseline is defined as day 1 of radiation therapy (RT).

Evaluate will be of genetic variations in germline associated with treatment response and side effects. P-values will be reported. Baseline is defined as day 1 of radiation therapy.

Inclusion Criteria: Progressive intracranial ependymoma after prior focal irradiation Patients aged 1-21 years at the time of enrollment Adequate performance status (ECOG < 3) and research participant does not require mechanical ventilation Interval from start of initial radiation therapy to enrollment > 9 months Exclusion Criteria: Prior craniospinal irradiation Pregnant women are excluded from enrollment on this study because radiation therapy is an agent with the potential for teratogenic or abortifacient effects Any patient with both metastatic ependymoma and age < 3 years at the time of enrollment