Combination Chemotherapy With or Without Peripheral Stem Cell Transplantation, Radiation Therapy, and/or Surgery in Treating Patients With Ewing's Sarcoma

Sarcoma Clinical Trial

Official title:

European Ewing Tumour Working Initiative of National Groups Ewing Tumour Studies 1999 (EURO-E.W.I.N.G.99)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00020566
• Other study ID #: CDR0000068608
• Secondary ID: EURO-EWING-INTER
• Status: Recruiting
• Phase: Phase 3
• First received: July 11, 2001
• Last updated: June 23, 2014
• Start date: February 2001

Study information

• Verified date: June 2012
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy use 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. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and kill more tumor cells. It is not yet known if combination chemotherapy is more effective with or without radiation therapy and/or surgery in treating Ewing's sarcoma.

PURPOSE: This randomized phase III trial is studying different combination chemotherapy regimens to see how well they work when given with or without peripheral stem cell transplantation, radiation therapy, and/or surgery in treating patients with Ewing's sarcoma.

Description:

OBJECTIVES:

Primary

• Compare the event-free and overall survival of patients with tumor of the Ewing's family treated with standard induction chemotherapy comprising vincristine, dactinomycin, ifosfamide and etoposide (VIDE) followed by consolidation chemotherapy comprising vincristine, dactinomycin, and ifosfamide versus high-dose busulfan and melphalan (Bu-Mel) followed by autologous peripheral blood stem cell (PBSC) transplantation with or without radiotherapy and/or surgery.

Secondary

• Determine the prognostic significance of EWS-Flil transcript in these patients.

• Determine the frequency and prognostic value of minimal disease in bone marrow and PBSC, as determined by the presence or absence of EWS-Flil transcript, in these patients.

• Determine the feasibility and toxicity of VIDE induction chemotherapy in these patients.

• Determine the response of these patients to VIDE induction chemotherapy.

• Determine the feasibility and toxicity of VAI consolodation chemotherapy in these patients.

• Determine the feasibility and toxicity of Bu-Mel consolodation chemotherapy in these patients.

• Determine event-free survival and overall survival of patients treated with these regimens by prognostic group analysis.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age and local treatment of the primary tumor (yes vs no).

Patients receive induction chemotherapy comprising vincristine IV on day 1 and ifosfamide IV over 3 hours, doxorubicin IV over 4 hours, and etoposide IV over 1 hour on days 1-3 (VIDE). Treatment repeats every 21 days for 4 courses in the absence of unacceptable toxicity. Peripheral blood stem cells (PBSC) are collected after course 3 and/or 4. Patients are evaluated after course 4. Patients in need of early radiotherapy due to an axial tumor or patients who require radiotherapy to the brain and/or spinal cord (at any time during study) are assigned to group 1. Patients not needing early radiotherapy are assigned to group 2.

• Group 1: Patients receive 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Patients requiring radiotherapy to the axial tumor also undergo concurrent radiotherapy 5 days a week. Some patients may then undergo surgical resection of the tumor. All patients will then receive vincristine IV on day 1 and dactinomycin IV and ifosfamide IV over 3 hours on days 1 and 2 (VAI). Treatment repeats every 21 days for 8 courses (courses 7-14). Patients requiring radiotherapy to the brain and/or spinal cord also undergo concurrent radiotherapy.

• Group 2: Patients undergo 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Some patients may then undergo surgical resection of the tumor. All patients receive VAI chemotherapy as in group 1 for 1 course. Patients are randomized to 1 of 2 consolidation therapy arms.

• Arm I: Patients receive 7 additional courses of VAI chemotherapy (courses 8-14). Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent whole-lung radiotherapy for 6-12 days.

• Arm II: Patients receive high-dose chemotherapy comprising oral busulfan every 6 hours on days -6 to -3 and melphalan IV over 30 minutes on day -2. Patients receive autologous PBSC IV on day 0. Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent radiotherapy 5 days a week for at least 5 weeks.

Patients are followed every 3 months for 4 years, every 6 months for 1 year, and then periodically thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: Approximately 1,200 patients will be accrued for this study within approximately 7 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1200
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 49 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed tumor of the Ewing's family of bone or soft tissue

• Ewing's sarcoma

• Peripheral primitive neuroectodermal tumor

• Disease meeting one of the following criteria:

• Resectable localized disease (tumor volume less than 200 mL)

• Localized disease previously resected at diagnosis

• Unresectable disease (at least 200 mL tumor volume) but radiotherapy as local control can be delayed

• Localized disease with early radiotherapy required

• Pulmonary and/or pleural metastases only

• Extrapulmonary/pleural metastases (skeleton, bone marrow, lymph nodes)

• No more than 45 days since definitive biopsy

PATIENT CHARACTERISTICS:

Age:

• Under 50

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Renal function normal

• Glomerular filtration rate at least 60 mL/min

Cardiovascular:

• Normal cardiac function

• Fractional shortening at least 29%

• Ejection fraction at least 40%

Other:

• No medical, psychiatric, or social condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• See Disease Characteristics

Study Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Sarcoma

Intervention

Biological:
• dactinomycin
Given IV

Drug:
• busulfan
Given orally and IV
• doxorubicin hydrochloride
Given IV
• etoposide
Given IV
• ifosfamide
Given IV
• melphalan
Given orally and IV
• vincristine sulfate
Given IV

Procedure:
• autologous hematopoietic stem cell transplantation
Given IV
• conventional surgery
Given to patients deemed to require it

Radiation:
• radiation therapy
Given to patients deemed to require it

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Brisbane	Queensland
Australia	Women's and Children's Hospital	North Adelaide	South Australia
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Children's Hospital at Westmead	Westmead	New South Wales
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan
Canada	Janeway Children's Health and Rehabilitation Centre	St. John's	Newfoundland and Labrador
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	Children's and Women's Hospital of British Columbia	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Starship Children's Health	Auckland
Puerto Rico	San Jorge Children's Hospital	Santurce
United States	Texas Tech University Health Sciences Center School of Medicine - Amarillo	Amarillo	Texas
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia
United States	Children's Hospital Colorado Center for Cancer and Blood Disorders	Aurora	Colorado
United States	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Mountain States Tumor Institute at St. Luke's Regional Medical Center	Boise	Idaho
United States	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Dayton Children's - Dayton	Dayton	Ohio
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	CCOP - Duluth	Duluth	Minnesota
United States	Duke Cancer Institute	Durham	North Carolina
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Hurley Medical Center	Flint	Michigan
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Greenville Hospital Cancer Center	Greenville	South Carolina
United States	Leo W. Jenkins Cancer Center at ECU Medical School	Greenville	North Carolina
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Cancer Research Center of Hawaii	Honolulu	Hawaii
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	University of Mississippi Cancer Clinic	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Children's Hospital	Knoxville	Tennessee
United States	Breslin Cancer Center at Ingham Regional Medical Center	Lansing	Michigan
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	Southern California Permanente Medical Group	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida
United States	Midwest Children's Cancer Center at Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital of New Orleans	New Orleans	Louisiana
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Lucile Packard Children's Hospital at Stanford University Medical Center	Palo Alto	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Kaiser Permanente Medical Center - Oakland	Sacramento	California
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Providence Cancer Center at Sacred Heart Medical Center	Spokane	Washington
United States	Simmons Cooper Cancer Institute	Springfield	Illinois
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	St. Louis	Missouri
United States	Children's Hospitals and Clinics of Minnesota - St. Paul	St. Paul	Minnesota
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	Mary Bridge Children's Hospital and Health Center - Tacoma	Tacoma	Washington
United States	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida
United States	Toledo Hospital	Toledo	Ohio
United States	Children's National Medical Center	Washington	District of Columbia
United States	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware
United States	Tod Children's Hospital	Youngstown	Ohio

Sponsors (10)

Lead Sponsor

Collaborator

University of Leicester

Children's Cancer and Leukaemia Group, Children's Oncology Group, EBMT Solid Tumors Working Party, European Organisation for Research and Treatment of Cancer - EORTC, Gesellschaft fur Padiatrische Onkologie und Hamatologie - Austria, Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany, National Cancer Institute (NCI), Societe Francaise Oncologie Pediatrique, Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Puerto Rico, 

References & Publications (3)

Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO — View Citation

Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O, van den Berg H, Dirksen U, Hjorth L, Michon J, Lewis I, Craft A, Jürgens H. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol. 2010 Jul — View Citation

Le Deley MC, Delattre O, Schaefer KL, Burchill SA, Koehler G, Hogendoorn PC, Lion T, Poremba C, Marandet J, Ballet S, Pierron G, Brownhill SC, Nesslböck M, Ranft A, Dirksen U, Oberlin O, Lewis IJ, Craft AW, Jürgens H, Kovar H. Impact of EWS-ETS fusion typ — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival			No
Primary	Overall survival			No
Secondary	Feasibility, toxicity, and response at 1 month following induction therapy			Yes
Secondary	Feasibility and toxicity of consolidation regimens at 1 month following consolidation therapy			Yes