EURAMOS-1: an international collaboration for osteosarcoma
1University College Hospital, London, UK,2Olgahospital, Klinikum Stuttgart, Stuttgart, Germany,3Stanford University School of Medicine, Palo Alto, CA, USA,4Oslo University Hospital, The Norwegian Radium Hospital, Scandinavian Sarcoma Group, Oslo, Norway,5Center for Clinical Trials, University of Münster,, Münster, Germany,6University Hospital of Münster, Münster, Germany,7Skane University Hospital and Lund University, Lund, Sweden,8Leiden University Medical Center, Leiden, The Netherlands,9The Children’s Hospital, Bronx, NY, USA,10MRC Clinical Trials Unit at UCL, London, UK,11St Anna Children’s Hospital, Vienna, Austria,12Childrens Oncology Group, Arcadia, CA, USA,13University Children’s Hospital Basel, Basel, Switzerland,14Huntsman Cancer Inst, Salt Lake City, UT, USA,15Children’s Hospital Boston, Boston, MA, USA,16IWK Health Centre, Halifax, NS, Canada
Osteosarcoma treatment involves surgery of the primary tumor and metastases plus pre- and postoperative chemotherapy; high-dose methotrexate, adriamycin (doxorubicin), and cisplatin (MAP) is an international standard. Histologic response to pre-operative chemotherapy is prognostic for survival. The European and American Osteosarcoma Study trial, EURAMOS-1, assessed alternatives. We reflect on the findings and the challenges.
Patients were registered before MAP chemotherapy and were assessed for response at surgery. "Poor responders" were randomized postoperatively to continue MAP (to week 29) or to augment MAP with high-dose ifosfamide and etoposide (to week 40; MAPIE). "Good responders" were randomised to continue MAP then have 18 months maintenance pegylated Interferon-?-2b or not. The primary outcome measure was event-free survival.
2,260 patients from 17 countries joined EURAMOS-1. 716/1,041 "good responders" were randomised. There was no evidence of improved EFS with interferon (HR=0.83, 95%CI 0.61-1.12), complicated by one quarter not starting their allocated interferon. 618/1,059 "poor responders" were randomised. There was no evidence MAPIE improved EFS (HR=0.99, 95%CI 0.79 to 1.24) but was associated with more severe acute toxicities, poorer treatment compliance and increased secondary acute leukaemias. In the full cohort, 3-yr and 5-yr estimates of EFS from biopsy were 60% (95%CI 57 to 62) and 54% (95%CI 52 to 57) and survivals at 3-yr and 5-yr from biopsy were 79 (95%CI 78 to 81) and 71% (95%CI 69 to 73).
Data from the trial do not support a change away from MAP in post-operative treatment for patients with a good response nor those with a poor response. The EURAMOS investigators surmounted considerable practical challenges in undertaking this trial. The consortium will initiate further front-line trials in an expanded collaboration when agents suitable for testing are identified. Current efforts focus on finding genomic and immunologic targets.