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

Phase 3

Completed

• Conditions: Sarcoma
• Interventions: 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

• Registration Number: NCT00006734
• Lead Sponsor: Children's Oncology Group

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.

Study Timeline

• Study First Submitted: 2000-12-06
• Study Start: 2001-05
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2006-08
• Study Completion: 2023-06-30
• Status Verified: 2023-08
• Last Update Submitted: 2023-08-01
• Last Update Posted: 2023-08-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 587

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen A	brachytherapy	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.
Regimen B	filgrastim	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.
Regimen A	filgrastim	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.
Regimen A	ifosfamide	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.
Regimen B	brachytherapy	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.
Regimen A	vincristine sulfate	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.
Regimen A	adjuvant therapy	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.
Regimen A	neoadjuvant therapy	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.
Regimen A	radiation therapy	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.
Regimen A	conventional surgery	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.
Regimen B	radiation therapy	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.
Regimen B	adjuvant therapy	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.
Regimen B	vincristine sulfate	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.
Regimen B	conventional surgery	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.
Regimen B	neoadjuvant therapy	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.
Regimen A	cyclophosphamide	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.
Regimen A	etoposide	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.
Regimen A	doxorubicin hydrochloride	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.
Regimen B	cyclophosphamide	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.
Regimen B	doxorubicin hydrochloride	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.
Regimen B	etoposide	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.
Regimen B	ifosfamide	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.

Primary Outcome Measures

Name	Time	Method
Event-free survival	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	Assessed using a two sided log rank test of 0.05.

Trial Locations

Locations (238)

Comprehensive Cancer Center at University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

University of South Alabama Cancer Research Institute; 🇺🇸 Mobile, Alabama, United States

Phoenix Children's Hospital; 🇺🇸 Phoenix, Arizona, United States

Arizona Cancer Center at University of Arizona Health Sciences Center; 🇺🇸 Tucson, Arizona, United States

Arkansas Cancer Research Center at University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

Southern California Permanente Medical Group; 🇺🇸 Downey, California, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

Rebecca and John Moores UCSD Cancer Center; 🇺🇸 La Jolla, California, United States

Loma Linda University Cancer Institute at Loma Linda University Medical Center; 🇺🇸 Loma Linda, California, United States

Jonathan Jaques Children's Cancer Center at Miller Children's Hospital; 🇺🇸 Long Beach, California, United States

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