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Clinical Trials (PDQ®)

Phase III Randomized Evaluation of VAC (VCR/DOX/CTX) and VAC (VCR/DACT/CTX) with vs without IFF/VP-16 in the Treatment of Newly Diagnosed Ewing's Sarcoma and Primitive Neuroectodermal Tumors of Bone

Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted30 and underNCIPOG-8850
CCG-7881, INT-0091

Objectives

I.  Compare event-free survival and survival among patients with newly 
diagnosed localized Ewing's sarcoma or primitive neuroectodermal tumors of the 
bone randomly assigned to standard therapy with VAC (vincristine/doxorubicin 
or dactinomycin/cyclophosphamide) vs. VAC combined with ifosfamide/etoposide, 
both groups also receiving local therapy with surgery and/or radiotherapy.

II.  Determine the toxicity of an intensified regimen of 
ifosfamide/vincristine/continuous-infusion doxorubicin/cyclophosphamide with 
granulocyte colony stimulating factor in children with metastatic disease.

III.  Compare the incidence of serious toxicities and adverse orthopedic 
outcomes in these treatment groups.

IV.  Evaluate the significance of tumor site, tumor size, histologic subtype, 
and electron microscopic pattern in determining response to therapy and 
ultimate outcome.

V.  Correlate imaging features observed at diagnosis and sequentially 
throughout therapy with response to therapy, prognosis, adequacy of 
radiotherapy volume, and survival (special emphasis will be placed on MRI 
studies, where available).

VI.  Determine the prognostic value of cellular DNA content and chromosomal 
changes, including the t(11;22)(q23;q11) translocation.

Entry Criteria

Disease Characteristics:


Newly diagnosed Ewing's sarcoma, primitive neuroectodermal
tumor of a bone, or a diagnosis compatible with primitive
sarcoma of bone (as of 12/8/92, only patients with metastatic
disease are eligible)

No extraosseous tumors

Tumors must satisfy the following pathologic criteria:

  Light microscopic appearance of small round cell neoplasm
  with the primary in bone

  H and E staining under light microscopy consistent with
  Ewing's sarcoma, primitive neuroectodermal tumor of bone,
  or any other primitive sarcoma of bone

  No immunohistochemical or ultrastructural evidence to
  exclude the foregoing light microscopic diagnosis


Prior/Concurrent Therapy:


Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior radiotherapy

Surgery:
  Diagnostic biopsy within 1 month prior to registration
  Complete or partial resection discouraged but allowed


Patient Characteristics:


Age:
  No more than 30

Performance status:
  Not specified

Hematopoietic:
  ANC more than 1,200 (unless marrow involved with tumor)
  Platelets more than 150,000 (unless marrow involved with
     tumor)

Hepatic:
  Bilirubin less than 1.5 x ULN

Renal:
  Creatinine normal for age

Cardiovascular:
  Normal cardiac function


Expected Enrollment

About 400 patients will be entered over 4 years.

Outline

Randomized study.  Patients with metastatic disease at diagnosis are treated 
on Regimen A.  As of 12/8/92, the study is closed for randomized therapy and 
only Regimen A remains open.

Arm I (arm closed as of 12/8/92).

Induction:  3-Drug Combination Chemotherapy with Urothelial Protection.  VAC:  
Vincristine, VCR, NSC-67574; Doxorubicin, DOX, NSC-123127; Cyclophosphamide, 
CTX, NSC-26271; with Mesna, NSC-113891.

Local Therapy Phase:  Surgery and/or Radiotherapy plus 3-Drug Combination 
Chemotherapy with Urothelial Protection.  Appropriate surgical resection 
and/or involved-field irradiation using Co60 equipment or 4-25 MV accelerator 
beams (or electrons if indicated); plus VAC; with Mesna.

Maintenance:  3-Drug Combination Chemotherapy with Urothelial Protection.  VAC 
(with DOX or Dactinomycin, DACT, NSC-3053); with Mesna.

Arm II (arm closed as of 12/8/92).

Induction:  2-Drug Combination Chemotherapy with Urothelial Protection 
alternating with 3-Drug Combination Chemotherapy with Urothelial Protection.  
VP-16/IFF:  Etoposide, VP-16, NSC-141540; Ifosfamide, IFF, NSC-109724; with 
Mesna; alternating with VAC; with Mesna.

Local Therapy Phase:  Surgery and/or Radiotherapy plus 3-Drug Combination 
Chemotherapy with Urothelial Protection followed by 2-Drug Combination 
Chemotherapy with Urothelial Protection.  Surgical resection and/or 
involved-field irradiation as on Arm I; plus VAC; with Mesna; followed by 
VP-16/IFF; with Mesna.

Maintenance:  3-Drug Combination Chemotherapy with Urothelial Protection 
alternating with 2-Drug Combination Chemotherapy with Urothelial Protection.  
VAC (with DOX or DACT); with Mesna; alternating with VP-16/IFF; with Mesna.

Regimen A (dose-intense courses).

Induction:  3-Drug Combination Chemotherapy with Urothelial Protection and 
Hematologic Toxicity Attenuation alternating with 2-Drug Combination 
Chemotherapy with Urothelial Protection and Hematologic Toxicity Attenuation.  
VAC; with Mesna; and Granulocyte Colony Stimulating Factor (Amgen), G-CSF, 
NSC-614629; alternating with VP-16/IFF; with Mesna; and G-CSF.

Local Primary Control:  Surgery and/or Radiotherapy plus 3-Drug Combination 
Chemotherapy with Urothelial Protection and Hematologic Toxicity Attenuation 
followed by 2-Drug Combination Chemotherapy with Urothelial Protection and 
Hematologic Toxicity Attenuation.  Surgical resection and/or involved-field 
irradiation as on Arm I Local Therapy Phase; plus VAC; with Mesna; and G-CSF; 
followed by VP-16/IFF; with Mesna; and G-CSF.

Interval Therapy:  3-Drug Combination Chemotherapy with Urothelial Protection 
and Hematologic Toxicity Attenuation alternating with 2-Drug Combination 
Chemotherapy with Urothelial Protection and Hematologic Toxicity Attenuation.  
VAC (with DOX or DACT, as indicated); with Mesna; and G-CSF; alternating with 
VP-16/IFF; with Mesna; and G-CSF.

Local Metastasis Control:  Surgery and/or Radiotherapy plus 3-Drug Combination 
Chemotherapy with Urothelial Protection and Hematologic Toxicity Attenuation 
followed by 2-Drug Combination Chemotherapy with Urothelial Protection and 
Hematologic Toxicity Attenuation.  Surgical resection and/or involved-field 
irradiation as in Arm I Local Therapy Phase; plus VAC (with DACT); with Mesna; 
and G-CSF; followed by VP-16/IFF; with Mesna; G-CSF.

Maintenance:  3-Drug Combination Chemotherapy with Urothelial Protection and 
Hematologic Toxicity Attenuation alternating with 2-Drug Combination 
Chemotherapy with Urothelial Protection and Hematologic Toxicity Attenuation.  
VAC (with DACT); with Mesna; and G-CSF; alternating with VP-16/IFF; with 
Mesna; G-CSF.

Published Results

Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009.[PUBMED Abstract]

Leavey PJ, Mascarenhas L, Marina N, et al.: Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer 51 (3): 334-8, 2008.[PUBMED Abstract]

Bhatia S, Krailo MD, Chen Z, et al.: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 109 (1): 46-51, 2007.[PUBMED Abstract]

DuBois SG, Krailo MD, Cook EF, et al.: Evaluation of local control in patients with non-metastatic Ewing sarcoma of the bone: a report from the Children's Oncology Group. [Abstract] J Clin Oncol 25 (Suppl 18): A-10013, 548s, 2007.

Leavey P, Mascarenhas L, Marina N, et al.: Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence. [Abstract] J Clin Oncol 25 (Suppl 18): A-10011, 547s, 2007.

Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007.[PUBMED Abstract]

Yock TI, Krailo M, Fryer CJ, et al.: Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group. J Clin Oncol 24 (24): 3838-43, 2006.[PUBMED Abstract]

Yock TI, Krailo MD, Grier HE, et al.: A comparison of local control achieved by surgery and radiotherapy in patients with non-metastatic pelvic Ewing sarcoma enrolled on INT-0091. [Abstract] Int J Radiat Oncol Biol Phys 60 (1 Suppl 1): A-192, S247, 2004.

Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003.[PUBMED Abstract]

Grier H, Krailo M, Link MP, et al.: Improved outcome in nonmetastatic Ewing's sarcoma (EWS) and PNET of bone with addition of ifosfamide (I) and etoposide (E) to vincristine (V), Adriamycin (AD), cyclophosphamide (C), and actinomycin (A). [Abstract] Proceedings of the American Society of Clinical Oncology 13: A1443, 1994.

Related Publications

Askin FB, Perlman EJ: Neuroblastoma and peripheral neuroectodermal tumors. Am J Clin Pathol 109 (4 Suppl 1): S23-30, 1998.[PUBMED Abstract]

de Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 16 (4): 1248-55, 1998.[PUBMED Abstract]

Maale GE, Katz JA, Timmons CC, et al.: Persistent tumor in resected specimens after pretreatment with chemotherapy and radiation for Ewing's sarcoma: an indication for surgical therapy. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1423, 416, 1994.

Trial Contact Information

Trial Lead Organizations

Pediatric Oncology Group

Holcombe Grier, MD, Protocol chair
Ph: 617-632-3971; 866-790-4500
Email: holcombe_grier@dfci.harvard.edu

Children's Cancer Group

James Miser, MD, Protocol chair
Ph: 626-256-8696; 800-826-4673
Email: jmiser@coh.org

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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