First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years
Condition: Ewing Sarcoma Family of Tumors
MeSH terms: Sarcoma, Ewing
Study type: Interventional
Phase: Phase 2

Summary: 
      Ewing's sarcoma and related tumours (ESFT) are rare tumours, with a peak incidence in the
      second decade of life. They start most often from bone, and are characterized by a specific
      translocation involving the so-called EWS gene. In one patient out of three, the staging
      procedures detect metastatic tumours at the diagnosis, most commonly in lungs, bones, and
      bone marrow.

      ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local
      treatment, and consolidation chemotherapy.

      The primary metastatic dissemination is the most important prognostic factor, as the survival
      rate is around 70-75% for localized tumours, in contrast with less than 50% for patients with
      primary metastatic disease.

      Among primary metastatic patients, bone involvement and / or bone marrow strike markedly the
      prognosis of these patients. While the long-term survival of patients with isolated pleural
      pulmonary metastases is approximately 50%, whereas it is only from 0 to 25% in patients with
      bone marrow involvement.

      In 1999, the Intergroup EURO EWING built a new study protocol for patients with Ewing
      tumours. For the patients with primary extrapulmonary metastatic Ewing tumours (R3 patients),
      the protocol proposed a heavy induction chemotherapy, in order to propose a consolidation
      with high dose chemotherapy to a higher rate of patients. The high-dose Busulfan Melphalan
      chemotherapy (BuMel) was based on Busulfan (600 mg/m²) and Melphalan (140 mg/m²), with
      autologous peripheral blood stem cell (PBSC) support.

      Of note, for the full population of patients with metastatic disease, the 3-year EFS rate was
      27% (SD 3%), and the OS rate was 34% (SD 4%), with a median follow-up of 3.9 years after
      diagnosis, and a median survival time of 1.6 years.
    

Detailed description: 
      Ewing's sarcoma and related tumours (ESFT) are rare tumours, with a peak incidence in the
      second decade of life. They start most often from bone, and are characterized by a specific
      translocation involving the so-called EWS gene. The gene rearrangement results in the
      production of a transcription factor, in the majority EWS-FLI1 transcription.

      In one patient out of three, the staging procedures detect metastatic tumours at the
      diagnosis; metastases involve most commonly lungs, bones, and bone marrow.

      Therefore, in addition to local imaging, the initial extension assessment of any Ewing tumour
      includes at least a chest CT scan, and a bone marrow extensive evaluation, comprising bone
      marrow punctures into several different sectors, bone marrow biopsies, and a bone imaging
      evaluation. The FDG-PET scan is more sensible than bone scan and conventional imaging as MRI
      in detection of bone metastases. It is more and more widely used in the bone metastasis
      search in Ewing tumours and seems useful to complement the search of extra-osseous metastases
      (outside the lungs), including that of bone marrow metastases. The full-body MRI is still
      under evaluation for the disease extension evaluation.

      ESFT treatment strategy is multidisciplinary, combining primary chemotherapy, a local
      treatment, and consolidation chemotherapy. The local treatment may combine surgery and / or
      radiotherapy, according to the tumour site and size, and to the tumour response. ESFT
      chemotherapy is based on alkylating agents (ifosfamide and / or cyclophosphamide), etoposide,
      anthracyclines, vincristine, and actinomycin.

      The primary metastatic dissemination is the most important prognostic factor, as the survival
      rate is around 70-75% for localized tumours, in contrast with less than 50% for patients with
      primary metastatic disease. Among primary metastatic patients, bone involvement and / or bone
      marrow strike markedly the prognosis of these patients. While the long-term survival of
      patients with isolated pleural pulmonary metastases is approximately 50%, whereas it is only
      from 0 to 25% in patients with bone marrow involvement.

      In 1999, the Intergroup EURO EWING built a new study protocol for patients with Ewing
      tumours, localized or metastatic and below 50 years of age. For the patients with primary
      extrapulmonary metastatic Ewing tumours (R3 patients), the protocol proposed a heavy
      induction chemotherapy, in order to propose a consolidation with high dose chemotherapy to a
      higher rate of patients. The high-dose BuMel chemotherapy was based on Busulfan (600 mg/m²)
      and Melphalan (140 mg/m²), with autologous peripheral blood stem cell (PBSC) support.

      The study enrolled 281 patients with primary dissemination and skeletal metastases, with or
      without bone marrow involvement and with or without additional pulmonary metastases or
      metastases to other sites. In contrast to the distribution in the entire group of patients
      with Ewing tumours, the primary site in this subgroup was extremity in only 31% patients,
      pelvis/abdomen in 45%, and axial/other in 24% patients. The overall survival at 3 years was
      28% (SD 4%) in the group with primary tumour in the abdomen or pelvis, versus 39% (SD 6%) for
      each of the two other groups. Of note, for the full population of patients with metastatic
      disease, the 3-year EFS rate was 27% (SD 3%), and the OS rate was 34% (SD 4%), with a median
      follow-up of 3.9 years after diagnosis, and a median survival time of 1.6 years.
    

Intervention name(s): VDC-IE x2; VDC-IE; TEMIRI; Consolidation BuMel; Maintenance; Local treatment by surgery; Local treatment by radiotherapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Procedure; Radiation
Intervention description(s): Week 1, 5, 9 and week 13:
Vincristine, IV, D1, 1.5mg/m²
Doxorubicine, IV, D1-D2, 37.5mg/m²
Cyclophosphamide, IV, D1, 1.2g/m²
Week 3, 7, 11 and week 15:
Ifosfamide, IV, D15 to D19, 1.8g/m²/d
Etoposide, IV, D15 to D19, 100mg/m²/d; Week 1 and week 5:
Vincristine, IV, D1, 1.5mg/m²
Doxorubicine, IV, D1-D2, 37.5mg/m²
Cyclophosphamide, IV, D1, 1.2g/m²
Week 3, and week 7:
Ifosfamide, IV, D15 to D19, 1.8g/m²/d
Etoposide, IV, D15 to D19, 100mg/m²/d; Week 9, 12, 15 and week 18:
Temozolomide, PO, D1 to D5, 150mg/m²/d
Irinotecan, IV, D1 to D5, 50mg/m²/d; After induction phase and local treatment (surgery and/or radiotherapy) and before PBSC:
Busulfan, IV, D-5 to D-2, dosa according to the weight
Melphalan, IV, D-1, 140 mg/m²
Peripheral Blood Stem Cell infusion:
- PBSC infusion, D0, at least 3.10^6 CD34/kg; * 1st year : VC
Vinblastine, IV, 3mg/m², once a week (except during radiotherapy: 1mg/m², 3 times a week)
Cyclophosphamide, PO, 25mg/m² continuously; Surgical excision of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy. Radiotherapy can be added; Radiotherapy of whole site of the primary tumour and metastatic sites (outside pulmonary sites) can take place before or after the high dose consolidation chemotherapy
Other intervention name(s): Intensified Induction VDC-IE x2; Intensified Induction VDC-IE; Intensified Induction TEMIRI; High dose Consolidation chemotherapy; 2 years maintenance; Surgery of primary tumour/metastatic sites; Radiotherapy of primary tumour/metastatic sites
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment