Observation or Radiation Therapy and/or Chemotherapy and Second Surgery in Treating Children Who Have Undergone Surgery for Ependymoma

Study Overview
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Brief Summary
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RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving chemotherapy before surgery may shrink the tumor so that it can be removed during surgery. PURPOSE: Phase II trial to determine the effectiveness of specialized radiation therapy either alone or after chemotherapy and second surgery in treating children who have undergone surgery for localized ependymoma.

Detailed Description
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OBJECTIVES: Determine the local control and pattern of failure in children with completely resected, differentiated, supratentorial localized ependymoma after initial surgical resection alone. Determine the rate of complete resection with second surgery after chemotherapy in patients with initially incompletely resected localized ependymoma. Determine the local control and pattern of failure in patients treated with conformal radiotherapy. Determine the influence of histologic grade on the time to progression in patients after treatment with conformal radiotherapy. OUTLINE: This is a multicenter study. Patients are stratified according to extent of prior surgical resection. Group 1 (patients with supratentorial differentiated ependymoma who have undergone gross total resection and have no visible residual tumor): Patients undergo observation. Group 2 (patients with supratentorial anaplastic ependymoma or infratentorial anaplastic or differentiated ependymoma who have undergone gross total resection or near total resection): Patients undergo conformal radiotherapy to the brain once daily 5 days a week for 6-6½ weeks. Group 3 (patients with tumor of any histology or location who have undergone subtotal resection): Patients receive an initial course of chemotherapy comprising vincristine IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously or IV beginning on day 3 and continuing until blood counts recover. Patients then receive a second course of chemotherapy comprising vincristine IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and oral etoposide on days 1-21. After completion of chemotherapy, patients are evaluated for second surgery. Patients who have unresectable disease undergo conformal radiotherapy. Patients who have resectable disease undergo second surgery followed by conformal radiotherapy. Patients are followed every 4 months for 3 years, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 250-350 patients will be accrued for this study within 5 years.

Official Title
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A Phase II Trial of Conformal Radiation Therapy for Pediatric Patients With Localized Ependymoma, Chemotherapy Prior to Second Surgery for Incompletely Resected Ependymoma and Observation for Completely Resected, Differentiated, Supratentorial Ependymoma

Conditions
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Brain Tumor, Central Nervous System Tumor

Intervention / Treatment
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* Biological: filgrastim
* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: etoposide
* Drug: vincristine sulfate
* Radiation: radiation therapy
* Drug: Mesna
* Procedure: therapeutic conventional surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed intracranial ependymoma Differentiated ependymoma or anaplastic ependymoma No primary spinal cord ependymoma, myxopapillary ependymoma, subependymoma, ependymoblastoma, or mixed glioma No evidence of noncontiguous spread beyond primary site Initial surgical resection within the past 56 days PATIENT CHARACTERISTICS: Age: 1 to 21 Performance status: No restrictions Life expectancy: At least 2 months Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified Other: Able to undergo MRI Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy Endocrine therapy: Prior or concurrent corticosteroids allowed Radiotherapy: No prior radiotherapy Surgery: See Disease Characteristics More than 1 prior surgery allowed Other: No other prior treatment for ependymoma

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: GTR1 Differentiated Histology Supratentorial (Group 1)<br>Patients undergo observation. | |
| Experimental: Radiation (Group 2)<br>Supratentorial Anaplastic Ependymoma (GTR1, GTR2, NTR) and Anaplastic or Differentiated Infratentorial Ependymoma (GTR1, GTR2, NTR) and Supratentorial Differentiated Ependymoma(GTR2, NTR). Patients undergo conformal radiation therapy to the brain once daily 5 days a week for 6-6½ weeks. | Radiation: radiation therapy<br>* Given once daily 5 days a week for 6-6½ weeks<br>* Other names: irradiation, radiotherapy, therapy, radiation;|
| Experimental: Sub-Total Resection Any Histology or Location (STR) (Group 3)<br>Patients receive an initial course of chemotherapy comprising vincristine sulfate IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously or IV beginning on day 3 and continuing until blood counts recover. Patients then receive a second course of chemotherapy comprising vincristine sulfate IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and oral etoposide on days 1-21. After completion of chemotherapy, patients are evaluated for second therapeutic conventional surgery. Patients who have unresectable disease undergo conformal radiation therapy. Patients who have resectable disease undergo second surgery followed by conformal radiotherapy. | Biological: filgrastim<br>* Given IV or SC (5mcg/kg/day) start on Day 3 and continue until ANC >1500/μl given subcutaneously or intravenously.<br>* Other names: G CSF, G-CSF, granulocyte colony stimulating factor, granulocyte colony-stimulating factor;Drug: carboplatin<br>* Given IV (375 mg/m2/day) Day 1 given as an IV infusion over one hour. For patients with BSA <0.45m2 the dose is 12.5 mg/kg/day.<br>* Other names: Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA,;Drug: cyclophosphamide<br>* Given IV (1000mg/m2/day) Day 1 and 2 given as an IV infusion over one hour following carboplatin administration. For patients with BSA<0.45m2 the dose is 33mg/kg/day on Day 1 and 2.<br>* Other names: Neosar, Procytox, Sendoxan, Syklofosfamid, WR-138719, Zytoxan;Drug: etoposide<br>* Given orally (50 mg/m2/day) orally once daily on Days 1 through 21. For patients with BSA < 0.45 m2, the dosage is 1.7 mg/kg/day on Days 1 through 21.<br>* Other names: Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, epipodophyllotoxin, Lastet, Toposar, VePesid;Drug: vincristine sulfate<br>* Given IV or orally (1.5mg/m2/day) (maximum dose 2 mg) Day 1 and 8 given as IV bolus. For patients with BSA<0.45m2 the dose is 0.05mg/kg.<br>* Other names: 22-oxovincaleukoblastine, 57-22-7, leurocristine sulfate, VCR, Vincasar PFS;Radiation: radiation therapy<br>* Given once daily 5 days a week for 6-6½ weeks<br>* Other names: irradiation, radiotherapy, therapy, radiation;Drug: Mesna<br>* Mesna (200mg/m2/dose) Day 1 and 2. For patients with BSA<0.45m2 the dose is (7mg/kg/dose). Combine mesna (200mg/m2) with cyclophosphamide and administer intravenously over one hour followed by mesna (200mg/m2) in 375 cc/m2 D5-1/2NS and run intravenously over 3 hours at 125cc/m2/hr. After 3 hour mesna, administer mesna (200 mg/m2/dose) IV over 15 minutes at hour 5.<br>Procedure: therapeutic conventional surgery<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Event-free survival is calculated from the date of study enrollment to the date of disease progression, disease relapse, occurrence of second neoplasm, or death from any cause. The product-limit (Kaplan-Meier) estimate is for estimation of Event -free survival (EFS) probability at 5 years. | Up to 5 years after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) is measured from the date of study enrollment to the date to death. The product-limit (Kaplan-Meier) estimate is for estimation of OS probability at 5 years. | Up to 5 years after completion of study treatment | 
| Rate of Gross-total or Near-total Resection and Second Surgery After Chemotherapy | The Rate Of Gross-Total or Near-Total Resection With Second Surgery After Chemotherapy Treatment. | At the time of second surgery | 
| Event-free Survival (EFS) | EFS between centrally reviewed differentiated ependymoma and anaplastic ependymoma for the patients who had sub-total resection initially. The event-free survival (EFS) defined as the date of disease progression, disease relapse, occurrence of a second neoplasm, or death from any cause, measured from the start date of radiation therapy. The product-limit (Kaplan-Meier) estimate is for estimation of EFS probability. | At 5 years since the time of radiation therapy. | 
| Event-free Survival (EFS) | EFS between centrally reviewed differentiated ependymoma and anaplastic ependymoma for the patients who were treated with radiation therapy only. The event-free survival (EFS) defined as the time to disease progression, disease relapse, occurrence of a second neoplasm, or death from any cause, measured from the start of radiation therapy. The product-limit (Kaplan-Meier) estimate is for estimation of EFS probability at 5 years. | At 5 years since the time of radiation therapy | 
| Local Control and Patterns of Failure | Documented and analyzed qualitatively and quantitatively. | Up to 5 years after completion of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood supratentorial ependymoma, newly diagnosed childhood ependymoma, childhood infratentorial ependymoma