Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Ewing's Sarcoma or Primitive Neuroectodermal Tumor

Condition(s) targeted: Ewing's Family of Tumors; Neutropenia

Intervention: amifostine trihydrate (Drug); cyclophosphamide (Drug); doxorubicin hydrochloride (Drug); etoposide (Drug); filgrastim (Drug); ifosfamide (Drug); topotecan hydrochloride (Drug); vincristine (Drug); biological therapy (Procedure); chemotherapy (Procedure); colony-stimulating factor therapy (Procedure); conventional surgery (Procedure); cytokine therapy (Procedure); low-LET cobalt-60 gamma ray therapy (Procedure); low-LET electron therapy (Procedure); low-LET photon therapy (Procedure); radiation therapy (Procedure); surgery (Procedure)

Phase: Phase 2

Status: Completed

Sponsored by: Pediatric Oncology Group

Official(s) and/or principal investigator(s):
Mark L. Bernstein, MD, FRCPC, Study Chair, Affiliation: Montreal Children's Hospital at McGill University Health Center
Paul A. Meyers, MD, Study Chair, Affiliation: Memorial Sloan-Kettering Cancer Center

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy in treating patients with newly diagnosed metastatic Ewing's sarcoma or primitive neuroectodermal tumor.

Official title: INTENSIVE THERAPY WITH GROWTH FACTOR SUPPORT FOR PATIENTS WITH EWING'S TUMOR METASTATIC AT DIAGNOSIS: A PEDIATRIC ONCOLOGY GROUP PHASE II STUDY

Study design: Interventional, Treatment

Detailed description: OBJECTIVES: I. Evaluate the response rate and duration of response of patients with newly diagnosed, metastatic Ewing's sarcoma or primitive neuroectodermal tumor treated with maximally intensified VAdrC (vincristine, doxorubicin, cyclophosphamide) alternating with IE (ifosfamide, etoposide). II. Evaluate the response to new agents (first topotecan, then topotecan with cyclophosphamide) utilized in an upfront treatment window. III. Assess the role of surgery with regard to local control of primary and metastatic sites and disease course. IV. Evaluate whether individual variability in ifosfamide and cyclophosphamide metabolism correlates with toxicity and/or response. V. Evaluate the rise in the absolute neutrophil count following one dose of filgrastim (G-CSF) given immediately prior to a chemotherapy course as an indicator of bone marrow reserve and subsequent myelosuppression. VI. Determine if amifostine provides significant chemo-radio protection, particularly against the cumulative toxicities of this intensive therapy.

OUTLINE: This is a partially randomized, multicenter study. Patients are treated on the investigational window first or proceed to induction therapy immediately, if aggressive treatment is necessary. Investigational window: Patients receive cyclophosphamide IV and topotecan IV over 30 minutes on days 1-5. Filgrastim (G-CSF) is administered subcutaneously (SQ) beginning day 6 until blood cell counts recover. Treatment is repeated at week 3. Induction therapy: Patients over 12 months old are randomized to receive amifostine or not. Patients receive etoposide IV over 45 minutes and ifosfamide IV over 2 hours on days 1-5. Amifostine IV over 15 minutes is also administered prior to ifosfamide. Patients receive G-CSF SQ (or IV over 2 hours) beginning on day 6. This course of treatment is administered on weeks 6, 12, and 18. Patients receive the VAdrC chemotherapy regimen on weeks 9 and 15. This regimen consists of vincristine IV and amifostine IV over 15 minutes on days 1, 8, and 15, cyclophosphamide IV over 30 minutes and doxorubicin IV over 48 hours on days 1 and 2, and G-CSF beginning on day 3. The VAdrC regimen is continued during local therapy on weeks 21-29 and 39-47, except the day 15 dose of vincristine is omitted, cyclophosphamide is administered on day 1 only on weeks 21, 24, 27, 39, 42, and 45, and doxorubicin is replaced with etoposide IV over 60 minutes on days 1-3 on weeks 24, 28, 42, and 45. Local therapy begins after 21 weeks of chemotherapy. Patients who respond to chemotherapy and have resectable disease undergo a complete resection with negative margins. Patients with unresectable disease or bulky lesions undergo radiotherapy. Some patients may undergo both surgery and radiotherapy. Local therapy of metastases is delayed until after week 39. Patients are followed every 3 months for 1 year, every 6 months for 2 years, then annually thereafter.

PROJECTED ACCRUAL: A total of 130 patients will be accrued to the randomized amifostine amendment over 3 years. A total of 30 patients will be accrued on the investigational window.

Maximum age: 30 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS: Newly diagnosed, pathologically confirmed Ewing's sarcoma or primitive neuroectodermal tumor (PNET) Diagnosis established from biopsy of primary tumor Light microscopy (hematoxylin and eosin stained) consistent with Ewing's sarcoma or PNET No immunohistochemical or ultrastructural characteristics inconsistent with Ewing's sarcoma or PNET or suggestive of rhabdomyosarcoma Metastatic disease required Biopsy of radiographically questionable metastases (e. g., pulmonary lesions) required Chest wall tumor with separate pleural mass considered metastatic No positive pleural fluid cytology alone

PATIENT CHARACTERISTICS: Age: 30 and under Performance status: Not specified Hematopoietic: (in the absence of marrow involvement) Absolute neutrophil count greater than 1,200/mm3 Platelet count greater than 120,000/mm3 Hepatic: Bilirubin less than 1. 5 mg/dL AST/ALT less than 3 times normal Renal: Creatinine normal for age Significant renal abnormality/disease eligible only if: Nuclear GFR is normal Study coordinator approves Cardiovascular: Echocardiogram or MUGA normal

PRIOR CONCURRENT THERAPY: No prior chemotherapy or radiotherapy Resection at diagnosis is discouraged but does not exclude

British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada

Children's Hospital Los Angeles, Los Angeles, California 90027-0700, United States

Children's Hospital of Orange County, Orange, California 92668, United States

David Grant Medical Center, Travis Air Force Base, California 94535, United States

Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095-1781, United States

Long Beach Memorial Medical Center, Long Beach, California 90806, United States

UCSF Cancer Center and Cancer Research Institute, San Francisco, California 94115-0128, United States

Children's Hospital of Denver, Denver, Colorado 80218, United States

Children's National Medical Center, Washington, District of Columbia 20010-2970, United States

Clinique de Pediatrie, Geneva 1211, Switzerland

University of Puerto Rico School of Medicine Medical Sciences Campus, San Juan 00936-5067, Puerto Rico

University of Chicago Cancer Research Center, Chicago, Illinois 60637, United States

Indiana University Cancer Center, Indianapolis, Indiana 46202-5265, United States

University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, United States

Via Christi Regional Medical Center-Saint Francis Campus, Wichita, Kansas 67214, United States

MBCCOP - LSU Medical Center, New Orleans, Louisiana 70112, United States

CCOP - Kalamazoo, Kalamazoo, Michigan 49007-3731, United States

University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0752, United States

Mayo Clinic Cancer Center, Rochester, Minnesota 55905, United States

University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, United States

Children's Mercy Hospital - Kansas City, Kansas City, Missouri 64108, United States

University of Nebraska Medical Center, Omaha, Nebraska 68198-3330, United States

Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, United States

Herbert Irving Comprehensive Cancer Center, New York, New York 10032, United States

Kaplan Cancer Center, New York, New York 10016, United States

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States

Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, North Carolina 27599-7295, United States

Memorial Mission Hospital, Asheville, North Carolina 28801, United States

CCOP - Merit Care Hospital, Fargo, North Dakota 58122, United States

Veterans Affairs Medical Center - Fargo, Fargo, North Dakota 58102, United States

IWK Grace Health Centre, Halifax, Nova Scotia B3J 3G9, Canada

Children's Hospital Medical Center - Cincinnati, Cincinnati, Ohio 45229-3039, United States

Children's Hospital of Columbus, Columbus, Ohio 43205-2696, United States

Ireland Cancer Center, Cleveland, Ohio 44106-5065, United States

Doernbecher Children's Hospital, Portland, Oregon 97201-3098, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

Montreal Children's Hospital, Montreal, Quebec H3H 1P3, Canada

Vanderbilt Cancer Center, Nashville, Tennessee 37232-6838, United States

Medical City Dallas Hospital, Dallas, Texas 75230, United States

San Antonio Military Pediatric Cancer and Blood Disorders Center, Lackland Air Force Base, Texas 78236-5300, United States

University of Texas - MD Anderson Cancer Center, Houston, Texas 77030, United States

University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284, United States

Huntsman Cancer Institute, Salt Lake City, Utah 84132, United States

Cancer Center, University of Virginia HSC, Charlottesville, Virginia 22908, United States

Children's Hospital and Regional Medical Center - Seattle, Seattle, Washington 98105, United States

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States

Princess Margaret Hospital for Children, Perth, Western Australia 6001, Australia

University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Related publications:

Souid AK, Fahey RC, Dubowy RL, Newton GL, Bernstein ML. WR-2721 (amifostine) infusion in patients with Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna: drug and thiol levels in plasma and blood cells, a Pediatric Oncology Group study. Cancer Chemother Pharmacol. 1999;44(6):498-504.

Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group Phase II Study 9457; Children's Oncology Group. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol. 2006 Jan 1;24(1):152-9.

Souid AK, Newton GL, Dubowy RL, Fahey RC, Bernstein ML. Determination of the cytoprotective agent WR-2721 (Amifostine, Ethyol) and its metabolites in human blood using monobromobimane fluorescent labeling and high-performance liquid chromatography. Cancer Chemother Pharmacol. 1998;42(5):400-6.

Starting date: April 1995
Last updated: April 9, 2007