Study in Localized and Disseminated Ewing Sarcoma
Condition: Ewing's Sarcoma
MeSH terms: Sarcoma; Sarcoma, Ewing
Study type: Interventional
Phase: Phase 3

Summary: 
      Ewing Sarcoma

      Primary objectives:

      Standard Risk R1: in a randomised trial, to examine whether add-on treatment with zoledronic
      acid in addition to induction and maintenance chemotherapy improves event-free survival in
      patients with localised Ewing sarcoma and good histological response or with initial tumour
      volume <200 mL compared to no add-on treatment.

      *High Risk R2: in a randomised trial, to examine whether high-dose chemotherapy using
      busulfan-melphalan with autologous stem cell reinfusion, compared with standard chemotherapy,
      improves event-free survival in patients with localised Ewing sarcoma and poor histological
      response or tumour volume ≥200 mL (R2loc). In patients with pulmonary metastases high dose
      busulfan-melphalan chemotherapy with autologous stem cell reinfusion is randomised versus
      standard chemotherapy plus whole lung irradiation (R2pulm).

      Very High Risk R3: in a randomised trial, to examine whether the addition of high dose
      chemotherapy using treosulfan-melphalan followed by autologous stem cell reinfusion to eight
      cycles of standard adjuvant chemotherapy, compared to eight cycles of standard adjuvant
      chemotherapy alone, improves event-free survival in patients with primary disseminated
      disease.

      *R2 accrual discontinued on December 1st 2015.
    

Detailed description: 
      EWING 2008 is a joint protocol of European and North American Ewing sarcoma study groups. The
      protocol is aimed at optimising treatment and treatment results of patients with Ewing
      sarcomas. The EWING 2008 protocol is open to all patients diagnosed with Ewing sarcomas,
      localised or metastatic, who are considered eligible for neoadjuvant chemotherapy. All
      patients registered will receive induction chemotherapy consisting of six cycles of
      vincristine, ifosfamide, doxorubicin and etoposide (VIDE). The decision regarding local
      therapy must be made following the fifth cycle of induction treatment, with a preference for
      surgical intervention with or without additional radiotherapy. Preoperative radiotherapy may
      be considered to improve the operability of otherwise inoperable lesions. In patients with
      localised disease or with pulmonary metastases, local treatment should be performed following
      the 6th cycle of VIDE chemotherapy, and should be a complete tumour resection, whenever
      feasible. Post-operative radiotherapy is determined by the completeness of surgery and the
      histological response to chemotherapy.

      Standard Risk R1 Good responders (R1) (< 10% viable tumour cells) with localised disease are
      allocated to the standard risk arm and will receive a further eight cycles of chemotherapy
      composed of vincristine, actinomycin D, and cyclophosphamide (VAC) (females) or ifosfamide
      instead of cyclophosphamide (VAI) (males). They will be randomised to receive add-on
      treatment with either fenretinide, zoledronic acid, fenretinide plus zoledronic acid, or no
      add-on treatment.

      High Risk R2 *Poor responders (R2) with localised disease will continue to be randomised as
      in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose
      treatment with busulfan-melphalan (R2loc).

      Patients with primary pulmonary metastases are also allocated to continue to be randomised as
      in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose
      treatment with busulfan-melphalan (R2pulm).

      Very High Risk R3 Patients with disseminated disease, i.e. dissemination to bone and/or other
      sites and possibly additional pulmonary dissemination (R3), receive six cycles of VIDE
      induction chemotherapy. Patients are then randomised to either continue with eight cycles of
      vincristine, actinomycin D and cyclophosphamide (VAC) chemotherapy or high dose
      treosulfan-melphalan (TreoMel) chemotherapy followed by autologous stem cell reinfusion
      followed thereafter by eight cycles of VAC chemotherapy. Local therapy in R3 patients is
      following VIDE induction, whenever feasible prior to high dose therapy (HDT). When long
      periods of immobilisation following surgery are anticipated, e.g pelvic reconstruction,
      surgery following HDT may be advisable. Depending on clinical response to induction
      chemotherapy radiotherapy prior to HDT and surgery may be an option to be considered in such
      patients. Any delay between VIDE and HDT for reasons of e.g. local treatment must be bridged
      with VAC cycles. The total number of VAC cycles is not to exceed eight cycles.

      *R2 accrual discontinued on December 1st 2015.
    

Intervention name(s): Zoledronic acid; Busulfan; Treosulfan
Intervention type(s): Drug; Drug; Drug
Intervention description(s): intravenously at 28 day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy for a total period of nine months.
Patients < 18 years will receive 0.05 mg/kg BW by IV infusion 30 min-1 h.
Patients >= 18 years will receive a bodyweight-dependent dose:
Patients >40kg receive 4 mg by IV infusion 30 min-1h Patients 20-40 kg receive 2 mg by IV infusion 30 min-1h; intravenously, day -6 to d -3 adults: 0.8 mg/kg body weight (BW) children and adolescents: <9 kg= 1mg/kg BW 9 - <16 kg= 1.2 mg/kg BW 16 - 23 kg= 1.1 mg/kg BW >23 - 34 kg= 0.95 mg/kg BW >34 kg = 0.8 mg/kg BW; 12 g/m² d-5 to d-3
Other intervention name(s): Zometa; Bisphosphonate; Busilvex
Intervention MeSH terms: Zoledronic Acid; Diphosphonates; Busulfan; Treosulfan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Ewing Sarcoma; localized; disseminated; metastases; bone; soft tissue