Comparison of Combination Chemotherapy Regimens in Treating Patients With Ewing's Sarcoma or Neuroectodermal Tumor

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known which chemotherapy regimen combined with radiation therapy and/or surgery is more effective in treating Ewing's sarcoma or primitive neuroectodermal tumor. PURPOSE: Randomized phase III trial to compare the effectiveness of different chemotherapy regimens combined with radiation therapy and/or surgery in treating patients who have Ewing's sarcoma or primitive neuroectodermal tumor.

Detailed Description
-----------------
OBJECTIVES: Compare the effect of interval-compressed vs standard chemotherapy in terms of event-free survival and overall survival in patients with newly diagnosed, localized Ewing's sarcoma or peripheral primitive neuroectodermal tumor. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 18 years vs 18 years and over) and location of primary disease (pelvic vs nonpelvic). Patients are randomized to 1 of 2 treatment arms for induction and continuation therapy. Induction therapy (weeks 1-12): Arm I: Patients receive alternating courses of chemotherapy consisting of vincristine IV on day 1, doxorubicin IV continuously over 48 hours on days 1 and 2, and cyclophosphamide IV over 1 hour on day 1 for courses 1 and 3 and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 for courses 2 and 4. Beginning 24 hours after the last dose of chemotherapy for each course, patients receive filgrastim (G-CSF) subcutaneously (SC) daily until blood counts recover. Treatment continues every 3 weeks for 4 courses. Arm II: Patients receive alternating courses of chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide as in arm I for courses 1, 3, and 5 and ifosfamide and etoposide as in arm I for courses 2, 4, and 6. Patients also receive G-CSF as in arm I. Treatment continues every 2 weeks for 6 courses. After completion of induction therapy, patients in both arms receive local control treatment to the primary tumor. Patients receive continuation chemotherapy after surgery or concurrently with radiotherapy. Continuation therapy: Arm I (weeks 13-42): Patients receive additional alternating courses of chemotherapy as in arm I of induction therapy with the exception of vincristine and cyclophosphamide alone for courses 7 and/or 11 and/or 13. Patients also receive G-CSF as in induction therapy. Treatment continues every 3 weeks for 10 courses. Arm II (weeks 13-29): Patients receive additional alternating courses of chemotherapy as in arm II of induction therapy with the exception of vincristine and cyclophosphamide alone for courses 9 and/or 11 and/or 13. Patients also receive G-CSF as in induction therapy. Treatment continues every 2 weeks for 8 courses. Patients are followed every 3 months for 4 years and then every 6 months for 1 year. PROJECTED ACCRUAL: Approximately 528 patients will be accrued for this study within 4-5 years.

Official Title
-----------------
Trial of Chemotherapy Intensification Through Compression in Ewing's Sarcoma and Related Tumors

Conditions
-----------------
Sarcoma

Intervention / Treatment
-----------------
* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Drug: ifosfamide
* Drug: vincristine sulfate
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Radiation: brachytherapy
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed localized Ewing's sarcoma or peripheral primitive neuroectodermal tumor (PNET) of the bone or soft tissues Diagnostic biopsy of primary tumor within 30 days of study Paraspinal or bony skull tumors of extradural origin allowed No intradural soft tissue tumors Askin's tumor of the chest wall allowed Chest wall tumors with ipsilateral pleural effusions or ipsilateral pleural-based secondary tumor nodules allowed No contralateral pleural effusions No metastatic disease or distant node involvement One pulmonary or pleural nodule greater than 1 cm in diameter OR more than 1 nodule greater than 0.5 cm in diameter are considered pulmonary metastasis Solitary lung nodules of 0.5-1 cm OR multiple nodules of 0.3-0.5 cm allowed unless biopsy positive for tumor Light microscopic appearance (hematoxylin and eosin stained) consistent with Ewing's sarcoma or peripheral PNET No immunohistochemical or ultrastructural evidence of rhabdomyosarcoma No esthesioneuroblastoma Clinically or pathologically involved regional lymph nodes allowed No CNS involvement PATIENT CHARACTERISTICS: Age: 50 and under at diagnosis Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Bilirubin no greater than 1.5 mg/dL Renal: Creatinine normal for age Creatinine clearance or isotope glomerular filtration rate at least 75 mL/min Cardiovascular: Shortening fraction at least 28% by echocardiography OR Ejection fraction at least 55% by radionuclide angiogram Other: Not pregnant or nursing Fertile patients must use effective contraception No other prior malignancy except skin cancer diagnosed at least 5 years ago and currently in remission PRIOR CONCURRENT THERAPY: Biologic therapy: No prior immunotherapy for skin cancer No concurrent sargramostim (GM-CSF) No concurrent pegfilgrastim Chemotherapy: No prior chemotherapy Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy Surgery: Prior complete or partial excision of primary tumor allowed

Ages Eligible for Study
-----------------
Minimum Age: 0 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A<br>Test the hypothesis that chemotherapy given every two weeks (Regimen B) will produce higher event-free survival. Treatment will occur in two phases: Induction and Continuation, with 14 cycles of chemotherapy in all. Induction consists of the first twelve weeks (four cycles on Regimen A. The cycles alternate between vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, MESNA and ifosfamide, etoposide, MESNA. G-CSF (Filgrastim) is given between chemotherapy doses. Local control (Surgery, Radiation Therapy, or a combination) will begin on Week 13 which will be after four cycles of chemotherapy. | Biological: filgrastim<br>* Given IV<br>* Other names: NSC 614629;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #026271;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: IND #7038;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: ifosfamide<br>* Given IV<br>* Other names: NSC #109724;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #067574;Procedure: adjuvant therapy<br> <br> Procedure: conventional surgery<br> <br> Procedure: neoadjuvant therapy<br> <br> Radiation: brachytherapy<br> <br> Radiation: radiation therapy<br> <br> |
| Experimental: Regimen B<br>Conventional every-three-week chemotherapy for patients with Ewing sarcoma and related tumors. Treatment will occur in two phases: Induction and Continuation, with 14 cycles of chemotherapy in all. Induction consists of the first twelve weeks six cycles on Regimen B). The cycles alternate between vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, MESNA and ifosfamide etoposide MESNA. G-CSF (Filgrastim) is given between chemotherapy doses. Local control (surgery, Radiation Therapy, or a combination) will begin on Week 13, which will be after six cycles of chemotherapy. | Biological: filgrastim<br>* Given IV<br>* Other names: NSC 614629;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #026271;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: IND #7038;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: ifosfamide<br>* Given IV<br>* Other names: NSC #109724;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #067574;Procedure: adjuvant therapy<br> <br> Procedure: conventional surgery<br> <br> Procedure: neoadjuvant therapy<br> <br> Radiation: brachytherapy<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Assessed using a two sided log rank test of 0.05. | Time from study entry until disease progression, death without progression of disease, occurrence of a second malignant neoplasm or last follow-up, whichever comes first, assessed up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
localized Ewing sarcoma/peripheral primitive neuroectodermal tumor