title: 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.
abstract: OBJECTIVE
  The European Intergroup Cooperative Ewing's Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients.
  
  
  METHODS
  SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume >or=100 mL or metastases) were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). Outcome measures were event-free survival (EFS; defined as the time to first recurrence, progression, second malignancy, or death) and overall survival (OS).
  
  
  RESULTS
  A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, -35% to 5%; P = .12) and 15% reduction in dying (95% CI, -34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84).
  
  
  CONCLUSIONS
  Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.
authors.affiliation: Department of PaediatricHaematology/Oncology, University Children's Hospital Münster, Switzerland. michael.paulussen@ukbb.ch
authors.forename: Michael
authors.initials: M
authors.lastname: Paulussen
authors.forename: Alan W
authors.initials: AW
authors.lastname: Craft
authors.forename: Ian
authors.initials: I
authors.lastname: Lewis
authors.forename: Allan
authors.initials: A
authors.lastname: Hackshaw
authors.forename: Carolyn
authors.initials: C
authors.lastname: Douglas
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dunst
authors.forename: Andreas
authors.initials: A
authors.lastname: Schuck
authors.forename: Winfried
authors.initials: W
authors.lastname: Winkelmann
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.forename: Andreas
authors.initials: A
authors.lastname: Zoubek
authors.forename: Ruth
authors.initials: R
authors.lastname: Ladenstein
authors.forename: Henk
authors.initials: H
authors.lastname: van den Berg
authors.forename: Andrea
authors.initials: A
authors.lastname: Hunold
authors.forename: Anna
authors.initials: A
authors.lastname: Cassoni
authors.forename: David
authors.initials: D
authors.lastname: Spooner
authors.forename: Robert
authors.initials: R
authors.lastname: Grimer
authors.forename: Jeremy
authors.initials: J
authors.lastname: Whelan
authors.forename: Anne
authors.initials: A
authors.lastname: McTiernan
authors.forename: Herbert
authors.initials: H
authors.lastname: Jürgens
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003609:Dactinomycin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage*; D007223:Infant; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D009367:Neoplasm Staging; D011446:Prospective Studies; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D003609:Dactinomycin; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D007069:Ifosfamide