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

Overview

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.

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.