EWING 2008

EWING 2008 is a randomised, prospective, multi-centre, international study of several cooperative groups, to improve treatment and outcome in patients with Ewing sarcoma. The aim of the protocoll is the improvement of the treatment and the treatment results for all patients with Ewing-sarcom. EWING 2008 is open for all patients with local or metastatic desease 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).
 

Study objectives:

Standard Risk R1: in a randomised trial, to examine whether add-on treatment with fenretinide or zoledronic acid, or zoledronic acid plus fenretinide 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 highdose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion, compared with standard chemotherapy, improves event-free survival
in patients with localised Ewing sarcoma and unfavourable 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 eventfree survival in patients with primary disseminated disease.

Induction Therapy

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 sixth 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-Risiko 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 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 busulfanmelphalan (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.

• Diagnosis: Histologically confirmed Ewing sarcoma of bone or soft tissue.
• Age and sex: Either sex, age > 48 months (Germany) and < 50 years at the date of diagnostic biopsy. Patients outside this age range may be reported to the appropriate national or group office (see Section 1.4), but will not be included in this study.
• Registration: ≤ 45 days from diagnostic biopsy/surgery.
• Start of chemotherapy: ≤ 45 days from diagnostic biopsy/surgery.
• Informed consent: According to national guidelines and GCP guidelines, signed prior to study entry.
• Performance status: Lansky or Karnofsky score > 50%, may be modified for handicapped patients
• haematologic: Hb > 8 g/dl (Transfusion allowed), Thrombocytes > 80 000/µ (Transfusion allowed), Leukocytes > 2000 /µ
• Cardiac: LVEF > 40%, SF > 28%

• More than one cycle of chemotherapy prior to registration
• Second malignancy
• Pregnancy or lactation
• Concurrent treatment within any other clinical trial, except trials with different endpoints
• that due to the nature of their endpoints must run parallel to EWING 2008, e.g. trials on antiemetics, antimycotics, antibiotics etc.
• strategies for psychosocial support,
• Any other medical, psychiatric, or social condition incompatible with the protocol treatment.