CombinaiR3 - First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years

Brief Summary

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.

Primary Outcomes

Secondary Outcomes

• 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)