Phase III Randomized Study Substituting CTX for IFF in VAIA (Alternating VCR/DOX/IFF and VCR/DACT/IFF) for Standard-Risk Ewing's Sarcoma, of Adding VP-16 to VAIA (EVAIA) for High-Risk Patients, and of Hyperfractionated vs Conventional Definitive and Postoperative Radiotherapy. Note: The information about this trial has not been updated by the sponsor/principal investigator/lead organization. cannot verify the accuracy of the information.

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Alternate Title

Combination Chemotherapy Plus Surgery and Radiation Therapy in Treating Patients With Ewing's Sarcoma. Note: The information about this trial has not been updated by the sponsor/principal investigator/lead organization. cannot verify the accuracy of the information.

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosed35 and underGER-GPOH-EICESS-92
MRC-EICESS-92, EU-92030, NCT00002516, EU-205116, UKCCSG-ET1993-02


I.  Determine whether morbidity can be reduced while preserving survival by 
substituting cyclophosphamide for ifosfamide in adjuvant combination 
chemotherapy in standard-risk patients with Ewing's sarcoma or peripheral 
neuroectodermal tumor (PNET).

II.  Determine whether survival is improved without unacceptable toxicity for 
high-risk patients with Ewing's sarcoma or PNET by the addition of etoposide 
to the VAIA regimen (vincristine/doxorubicin/ifosfamide/dactinomycin).

III.  Evaluate the impact of surgery and conventional vs. hyperfractionated 
radiotherapy (definitive and adjuvant) on local control, overall survival, and 
morbidity in these patients.

IV.  Relate treatment outcome with patient characteristics, histologic subtype 
at diagnosis, and histologic response to neoadjuvant treatment.

V.  Evaluate prospectively ifosfamide-induced nephrotoxicity and 
doxorubicin-induced cardiotoxicity.

Entry Criteria

Disease Characteristics:

Biopsy-proven Ewing's sarcoma, atypical Ewing's sarcoma, and
peripheral neuroectodermal tumors

No soft tissue Ewing's sarcoma or other small cell sarcomas of
soft tissue
  Such patients should be treated on the appropriate national
  Soft Tissue Sarcoma Protocol

Treatment must begin within 3 weeks after diagnostic biopsy

Registration must occur within 6 weeks after initiation of

Prior/Concurrent Therapy:

No prior therapy, including primary definitive local therapy

Patient Characteristics:

  Not over 35

Expected Enrollment

It is anticipated that 600 patients (200 standard-risk and 400 high-risk) will 
be accrued over 4 years.


Randomized study.  Patients are initially stratified as STANDARD RISK (tumor 
volume at diagnosis < 100 ml) and HIGH RISK (tumor volume at diagnosis at 
least 100 ml or, if < 100 ml, metastasis present).  All patients receive 14 
courses of chemotherapy, administered q 3 weeks throughout protocol treatment. 
 Standard-risk patients receive 4 courses of NEOADJUVANT CHEMOTHERAPY on 
Regimen A, while high-risk patients are randomized on Arms I and II for 4 
courses of neoadjuvant chemotherapy.  LOCAL THERAPY is usually initiated on 
week 12, after 4 courses of neoadjuvant chemotherapy, and consists of either 
total removal of the tumor-bearing compartment, intracompartmental surgery 
(with or without adjuvant radiotherapy), or definitive radiotherapy alone; the 
choice is dictated by the site, tumor size, and patient age, among other 
variables.  Postoperatively, all patients receive 10 courses of ADJUVANT 
CHEMOTHERAPY (plus adjuvant radiotherapy when given); standard-risk patients 
are randomized on Arms III and IV, while high-risk patients receive the same 
regimen to which they were assigned at initial randomization.  When given, 
adjuvant radiotherapy begins on week 19 and is administered concurrently with 
As a variant of this general plan, patients with < 50% regression of the 
soft tissue component of their tumors at restaging after 2 courses of 
neoadjuvant chemotherapy (slow response) may receive preoperative irradiation, 
beginning on week 7, concomitantly with the third and fourth courses of 
The following acronyms are used: 
  CTX       Cyclophosphamide, NSC-26271 
  DACT      Dactinomycin, NSC-3053 
  DOX       Doxorubicin, NSC-123127 
  IFF       Ifosfamide, NSC-109724 
  Mesna     Mercaptoethane sulfonate, NSC-113891 
  VCR       Vincristine, NSC-67574 
  VP-16     Etoposide, NSC-141540 
Regimen A (Standard risk):  Alternating 3-Drug Combination Chemotherapy 
Regimens.  VAIA:  VCR/DOX/IFF alternating with VCR/DACT/IFF. 
Arm I (High risk):  Alternating 3-Drug Combination Chemotherapy Regimens.  
VAIA:  VCR/DOX/IFF alternating with VCR/DACT/IFF. 
Arm II (High-risk):  Alternating 4-Drug Combination Chemotherapy Regimens.  
EVAIA:  VP-16/VCR/DOX/IFF alternating with VP-16/VCR/DACT/IFF. 
Surgery:  Resection of entire tumor-bearing compartment, including bone and 
soft tissue, when possible, is the treatment of choice.  The range of possible 
surgical procedures includes:  radical resection (e.g., amputation), wide 
resection (en bloc removal of the entire tumor-bearing compartment), marginal 
surgery (en bloc removal, but resection line runs through pseudocapsule and 
microscopic residual disease is likely), intralesional resection (tumor 
incised with contamination of surgical field), and no resection. 
Radiotherapy:  There are 3 settings in which radiotherapy is delivered in 
these patients:  as definitive treatment when definitive surgery is not 
feasible, as postoperative adjuvant treatment, and preoperatively in patients 
with a slow response to neoadjuvant chemotherapy.  Patients who are to receive 
definitive and postoperative adjuvant treatment are randomized between 
conventional fractionation and hyperfractionated accelerated split-course 
delivery; individuals receiving preoperative irradiation are not randomized 
for radiotherapy schedule but are assigned nonrandomly to receive the 
hyperfractionated accelerated split-course scheme (conventional fractionation 
requires that DOX and DACT be eliminated from concomitant chemotherapy, 
whereas these agents can be continued during the hyperfractionated schedule).  
Individual institutions may elect not to randomize for the radiotherapy 
fractionation scheme, i.e., to treat all patients on one schedule or the 
other; in such institutions, all patients must follow the same scheme, decided 
upon prior to treatment of the first patient.  Use of photons with energies of 
4-6 MV (including Co60) is recommended for extremity lesions, and 6-15 MV 
energies are recommended for trunk lesions; electrons may be considered for 
small superficial boosts, but are not adequate as a sole modality. 
Arm III (Standard risk):  Alternating 3-Drug Combination Chemotherapy 
Regimens.  VACA:  VCR/DOX/CTX alternating with VCR/DACT/CTX. 
Arm IV (Standard risk):  Alternating 3-Drug Combination Chemotherapy Regimens. 
 VAIA:  VCR/DOX/IFF alternating with VCR/DACT/IFF. 
High-risk patients continue with 10 additional courses of VAIA or EVAIA 
according to original randomization. 
Adjuvant Radiotherapy, when administered, begins on week 19, and is given 
concomitantly with chemotherapy. 

Published Results

Sari N, Toğral G, Cetindağ MF, et al.: Treatment results of the Ewing sarcoma of bone and prognostic factors. Pediatr Blood Cancer 54 (1): 19-24, 2010.[PUBMED Abstract]

Paulussen M, Craft AW, Lewis I, et al.: Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26 (27): 4385-93, 2008.[PUBMED Abstract]

Whelan J, McTiernan A, Weston C, et al.: Consequences of different approaches to local treatment of Ewing's sarcoma within an international randomised controlled trial: analysis of EICESS-92. [Abstract] J Clin Oncol 24 (Suppl 18): A-9533, 528s, 2006.

Paulussen M, Craft AW, Lewis I, et al.: Ewing tumor of bone - updated report of the European Intergroup Cooperative Ewing's Sarcoma Study EICESS 92. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1568, 2002.

Related Publications

Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995.[PUBMED Abstract]

Nowak-Göttl U, Schaudin E, Hoffmann C, et al.: Intraoperative clotting factor dilution and activated hemostasis in children with Ewing's sarcoma or osteosarcoma: a prospective longitudinal study. Haematologica 80 (4): 311-7, 1995 Jul-Aug.[PUBMED Abstract]

Zoubek A, Dockhorn-Dworniczak B, Delattre O, et al.: Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 14 (4): 1245-51, 1996.[PUBMED Abstract]

Boos J, Krümpelmann S, Schulze-Westhoff P, et al.: Steady-state levels and bone marrow toxicity of etoposide in children and infants: does etoposide require age-dependent dose calculation? J Clin Oncol 13 (12): 2954-60, 1995.[PUBMED Abstract]

Dunst J, Jabar S, Paulussen M, et al.: [Local therapy of Ewing sarcoma: radiotherapy aspects] Klin Padiatr 206 (4): 277-81, 1994 Jul-Aug.[PUBMED Abstract]

Hoffmann C, Jabar S, Ahrens S, et al.: [Prognosis in Ewing sarcoma patients with initial pathological fractures of the primary tumor site] Klin Padiatr 207 (4): 151-7, 1995 Jul-Aug.[PUBMED Abstract]

Nowak-Göttl U, Kehrel B, Budde U, et al.: Acquired von Willebrand disease in malignant peripheral neuroectodermal tumor (PNET). Med Pediatr Oncol 25 (2): 117-8, 1995.[PUBMED Abstract]

Ozaki T, Lindner N, Hoffmann C, et al.: Ewing's sarcoma of the ribs. A report from the cooperative Ewing's sarcoma study. Eur J Cancer 31A (13-14): 2284-8, 1995.[PUBMED Abstract]

Dockhorn-Dworniczak B, Schäfer KL, Dantcheva R, et al.: Diagnostic value of the molecular genetic detection of the t(11;22) translocation in Ewing's tumours. Virchows Arch 425 (2): 107-12, 1994.[PUBMED Abstract]

Jürgens HF: Ewing's sarcoma and peripheral primitive neuroectodermal tumor. Curr Opin Oncol 6 (4): 391-6, 1994.[PUBMED Abstract]

Shi LR, Eichelbauer D, Borchard F, et al.: Specificity and function of monoclonal antibodies directed against Ewing sarcoma cells. Cancer Immunol Immunother 38 (3): 208-13, 1994.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster

Heribert Juergens, MD, Protocol chair
Ph: 49-251-834-7742

Medical Research Council's Working Party on Leukemia in Adults and Children

Alan Craft, MD, Protocol chair
Ph: 44-191-202-3010

Registry Information

Trial Start Date1992-07-01
Registered in ClinicalTrials.govNCT00002516
Date Submitted to PDQ1992-07-01
Information Last Verified2010-01-08

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.