CombinaiR3 - First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 45
- 试验地点
- 17
- 主要终点
- Anti-tumour effect of the treatment strategy assessed by the number of patients event-free survival (EFS) at 18 months
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- Ewing tumour histologically or cytologically confirmed, harboring a specific transcript, and with extrapulmonary metastases (including nodal extension) - histology and FISH results must be consistent, specific transcript can be obtained after inclusions.
- •- Ewing tumour not previously treated.
- •- Age between 2 and 50 years.
- •- Measurable disease by cross sectional imaging (RECIST 1.1) or evaluable disease with functional metabolic, positron emission tomography scanner (PET SCAN) or other methods (e.g., cytology/histology).
- •- General status compatible with the study treatments (LANSKY score ≥ 50%, or Karnofsky ≥ 50%, or Eastern Cooperative Oncology Group (ECOG) ≤ 2).
- •- Adequate bone marrow function (not applicable in case of bone marrow disease).
- •Platelets ≥ 100 x 109 /L
- •Absolute Neutrophil Count (ANC) ≥ 1 x 109 /L
- •Hemoglobin ≥ 8g /dL.
- •- Adequate liver function :
- •Aspartate Aminotransferase (AST) and Alanine Transferase (ALT) ≤ 5 x Upper Limit Normal (ULN)
- •Total Bilirubin ≤ 2 Upper Limit Normal (ULN). If total bilirubin > 2xULN, Bilirubin Conjugated Fraction (BCF) ≤ 2 x ULN
- •- No absolute contra-indication of Busulfan-Melphalan if radiotherapy of the primary tumour is necessary with specific attention to patient with primary spinal tumor.
- •- Adequate cardiac and renal functions:
- •Creatinine < 1.5 of normal for age or clearance > 60 ml/min/1.73 m²;
- •Left Ventricular Ejection Fraction (LVEF) > 50% and/or shortening fraction > 28%.
- •- No underlying disease contra-indicating the study treatments.
- •- Patient likely compliant with the recommended study medical monitoring during and after treatments.
- •- Patients of childbearing potential must agree to use adequate contraception for the duration of study treatments and up to 12 months for women and 6 months for men following completion of therapy.
- •- Females of childbearing potential must have a negative serum β-human chorionic gonadotropin (HCG) pregnancy test within 10 days prior study inclusion, and/or urine pregnancy test within 48 hours before the first administration of the study treatment.
- •- Patients covered by a health insurance system.
- •- Patient, or patient's legal representative, informed and having signed the informed consent.
排除标准
- •- Age below 2 or greater than 50 years.
- •- Ewing tumour localized, or solely with pleural and/or lung metastases.
- •- Concomitant disease, particularly infectious disease, likely to interfere with patient's treatment.
- •- History of cancer, according to investigator's judgment.
- •- Life expectancy < 2 months.
- •- Patient already included in another clinical trial with an investigational drug.
- •- Pregnant or breastfeeding patient.
- •- Person deprived of liberty or under guardianship.
- •- Patient likely unable to comply with the study medical monitoring for geographical, social or psychological reasons.
研究组 & 干预措施
VDC - IE x2 & Surgery
Patients in Arm A receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: VDC-IE x2 (Drug)
VDC - IE x2 & Surgery
Patients in Arm A receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Consolidation BuMel (Drug)
VDC - IE x2 & Surgery
Patients in Arm A receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Maintenance (Drug)
VDC - IE x2 & Surgery
Patients in Arm A receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Local treatment by surgery (Procedure)
VDC - IE x2 & Surgery
Patients in Arm A receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine Doxorubicine Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Local treatment by radiotherapy (Radiation)
VDC - IE & TEMIRI & Surgery
Patients in Arm B receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: VDC-IE (Drug)
VDC - IE & TEMIRI & Surgery
Patients in Arm B receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: TEMIRI (Drug)
VDC - IE & TEMIRI & Surgery
Patients in Arm B receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Consolidation BuMel (Drug)
VDC - IE & TEMIRI & Surgery
Patients in Arm B receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Maintenance (Drug)
VDC - IE & TEMIRI & Surgery
Patients in Arm B receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Local treatment by surgery (Procedure)
VDC - IE & TEMIRI & Surgery
Patients in Arm B receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by surgery of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision. Radiotherapy can be added
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Local treatment by radiotherapy (Radiation)
VDC - IE x2 & Radiotherapy
Patients in Arm C receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: VDC-IE x2 (Drug)
VDC - IE x2 & Radiotherapy
Patients in Arm C receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Consolidation BuMel (Drug)
VDC - IE x2 & Radiotherapy
Patients in Arm C receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Maintenance (Drug)
VDC - IE x2 & Radiotherapy
Patients in Arm C receive
-
VDC-IE x2: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "good response" after the 4th treatment, followed by:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Local treatment by radiotherapy (Radiation)
VDC - IE & TEMIRI & Radiotherapy
Patients in Arm D receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: VDC-IE (Drug)
VDC - IE & TEMIRI & Radiotherapy
Patients in Arm D receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: TEMIRI (Drug)
VDC - IE & TEMIRI & Radiotherapy
Patients in Arm D receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Consolidation BuMel (Drug)
VDC - IE & TEMIRI & Radiotherapy
Patients in Arm D receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Maintenance (Drug)
VDC - IE & TEMIRI & Radiotherapy
Patients in Arm D receive
-
VDC-IE & TEMIRI: Intensified induction phase:
-
4 cycles of VDC (Vincristine-Doxorubicine-Cyclophosphamide) association alternative with 4 cycles of IE (Ifosfamide-Etoposide) association if "poor response" after the 4th treatment, followed by:
-
4 cycles of TEMIRI (Temozolomide-Irinotecan) association
-
Local treatment by radiotherapy of primary tumour/metastatic sites (outside pulmonary sites): indicated before of after consolidation phase (BuMel) among multidisciplinary decision.
-
Consolidation BuMel High dose chemotherapy (Busulfan-Melphalan) followed by Peripheral Blood Stem Cell Infusion
-
Maintenance phase
-
1st year : VC (Vincristine Cyclophosphamide) association
-
2nd year : Cyclophosphamide po 25 mg/m²
干预措施: Local treatment by radiotherapy (Radiation)
结局指标
主要结局
Anti-tumour effect of the treatment strategy assessed by the number of patients event-free survival (EFS) at 18 months
时间窗: 18 months after inclusion of the last patient
EFS is defined as the time from inclusion date to the first documentation of progression, distant disease, second cancer or death (or last news for patients free of event). The event free survival is estimated by Kaplan-Meier method.
次要结局
- 18F-FDG PET evaluation efficacy assessed by metabolic tumour volume (MTV)(study inclusion, after week 8 (RE1), after week18-19 (if VDC-IE) or week19-20 (if TEMIRI)=RE2, after local treatment ≤week30 (RE3), from week31 (=RE4), 3 years = EOT RE)
- Percentage of circulating tumour cells in blood and bone marrow to correlate with patient outcome (EFS). Ancillary study(at diagnosis (before treatment), at 1st evaluation time (RE1=wk8 if bone marrow involvement at diagnosis), at RE2=week19-20 (or RE3=<week30), after PBSC infusion=RE4 or RE5=< week38 (if bone marrow involvement at diagnosis), at End of Treatment)
- Comparison of transcriptomic profiles between those of primary disease and those of bone marrow metastases to determine if they are the same or not. Ancillary study(study inclusion)
- 3-years event-free survival (EFS) is assessed by the number of patients without any event at the end of treatment phase(3 years = EOT RE)
- Number of patients with treatment-related adverse events as assessed by CTCAE v4.03(week 19-20 = RE2 ; week 27-28 = Response Evaluation 3 (RE3); 3 years = EOT RE)
- 18F-FDG PET evaluation efficacy assessed by primary tumour uptake(study inclusion, after week 8 (RE1), after week18-19 (if VDC-IE) or week19-20 (if TEMIRI)=RE2, after local treatment ≤week30 (RE3), from week31 (=RE4), 3 years = EOT RE)
- Anti-tumour effect of the dose-intensified induction chemotherapy assessed by the response rate of patients(week 19-20 = Response Evaluation 2 (RE2))
- Anti-tumour effect of the dose-intensified induction chemotherapy assessed by the number of patients eligible for consolidation phase(week 19-20 = RE2)
- Overall survival (OS) is assessed by the number of patients still alive at the end of the three years of treatment(3 years = Response Evaluation End-Of-Treatment (EOT RE))
- Number of patients with treatment-related toxicities on laboratory data as assessed by CTCAE v4.03 of the different phases of treatment(week 19-20 = RE2 ; week 27-28 = RE3; 3 years = EOT RE)