BACKGROUND: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials. METHODS: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients. RESULTS: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome. CONCLUSIONS: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.

CDC MRC Clinical Trials Unit at UCL London UK

COG Baylor College of Medicine Houston TX USA

COG Boston Children's Hospital Boston MA USA

COG Children's Oncology Group Arcadia CA USA

COG Cincinnati Children's Hospital Medical Center Cincinnati OH USA

COG Connecticut Children's Medical Center Hartford CT USA

COG Dana Farber Cancer Institute Boston MA USA

COG Five Prime Therapeutics Inc South San Francisco CA USA

COG IWK Health Center Dalhousie University Halifax NS Canada

COG Keck School of Medicine University of Southern California Los Angeles CA USA

COG Mayo Clinic Rochester MN USA

COG Memorial Sloan Kettering Cancer Center New York NY USA

COG Nationwide Children's Hospital and the Ohio State University Columbus OH USA

COG Primary Childrens Hospital The University of Utah Salt Lake City UT USA

COG Southwestern and Children's Medical Center Dallas TX USA

COG the University of Texas M D Anderson Cancer Center Houston TX USA

COG UCSF Medical Center Mission Bay Pediatric Oncology San Francisco CA USA

COG University of British Columbia Vancouver BC Canada

COG University of Washington Seattle WA USA

COSS Helios Kliniken Berlin Buch Berlin Germany

COSS Klinik Schillerhöhe Thoraxchirurgie Gerlingen Germany

COSS Klinikum Stuttgart Olgahospital Stuttgart Germany

COSS Medizinische Universität Wien Vienna Austria

COSS Semmelweis Egyetem Budapest Budapest Hungary

COSS St Anna Kinderspital CCRI Wien Austria

COSS Universitätsklinikum Essen Essen Germany

COSS Universitätsklinikum Ulm Ulm Germany

COSS Universitätsspital Basel Basel Switzerland

COSS University Hospital MOTOL Praha Czech Republic

EISD Centre for Clinical Trials University Hospital Muenster Muenster Germany

EOI Leiden University Medical Center Leiden the Netherlands

EOI Netherlands

EOI Our Lady's Children's Hospital Dublin Ireland

EOI Royal National Orthopaedic Hospital Stanmore; Cancer Institute University College London London UK

EOI Royal Orthopaedic Hospital Birmingham UK

EOI University College Hospital London UK

EOI University Hospital Ghent Gent Belgium

EOI University Hospital Leuven Leuven Belgium

QLCC Pädiatrische Hämatologie und Onkologie Universitätsklinikum Bonn Bonn Germany

SSG Lund University Lund Sweden

SSG Oslo University Hospital and Scandinavian Sarcoma Group and Institute for Clinical Medicine University of Oslo Norway

SSG Oslo University Hospital Oslo Norway

SSG Rigshospitalet University of Copenhagen Copenhagen Denmark

TMG Path Leiden University Medical Centre Leiden Netherlands

Zobrazit více v PubMed

Berner K., Johannesen T.B., Berner A., Haugland H.K., Bjerkehagen B., Bohler P.J. Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma. Acta Oncol. 2015;54(1):25–33. PubMed PMC

Fletcher C.D. The evolving classification of soft tissue tumours - an update based on the new 2013 WHO classification. Histopathology. 2014;64(1):2–11. PubMed

Isakoff M.S., Bielack S.S., Meltzer P., Gorlick R. Osteosarcoma: current treatment and a collaborative pathway to success. J Clin Oncol. 2015;33(27):3029–3035. PubMed PMC

Mirabello L., Troisi R.J., Savage S.A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results Program. Cancer. 2009;115(7):1531–1543. PubMed PMC

Marina N., Bielack S., Whelan J., Smeland S., Krailo M., Sydes M.R. International collaboration is feasible in trials for rare conditions: the EURAMOS experience. In: Jaffe N., Bruland O.S., Bielack S., editors. 1st ed. vol. 152. 2010. pp. 339–354. (Pediatric and adolescent osteosarcoma series: cancer treatment and research). PubMed

Whelan J.S., Bielack S.S., Marina N., Smeland S., Jovic G., Hook J.M. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2015;26(2):407–414. PubMed PMC

Meyers P.A., Schwartz C.L., Krailo M., Kleinerman E.S., Betcher D., Bernstein M.L. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005;23(9):2004–2011. PubMed

Meyers P.A., Schwartz C.L., Krailo M.D., Healey J.H., Bernstein M.L., Betcher D. Children's Oncology G. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group. J Clin Oncol. 2008;26(4):633–638. PubMed

Bacci G., Ferrari S., Bertoni F., Ruggieri P., Picci P., Longhi A. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000;18(24):4016–4027. PubMed

Bielack S.S., Kempf-Bielack B., Delling G., Exner G.U., Flege S., Helmke K. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20(3):776–790. PubMed

Janeway K.A., Barkauskas D.A., Krailo M.D., Meyers P.A., Schwartz C.L., Ebb D.H. Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children's Oncology Group. Cancer. 2012;118(18):4597–4605. PubMed PMC

Petrilli A.S., de Camargo B., Filho V.O., Bruniera P., Brunetto A.L., Jesus-Garcia R. Brazilian osteosarcoma treatment group S, III, Iv. Results of the Brazilian osteosarcoma treatment group studies III and IV: prognostic factors and impact on survival. J Clin Oncol. 2006;24(7):1161–1168. PubMed

Smeland S., Muller C., Alvegard T.A., Wiklund T., Wiebe T., Bjork O. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer. 2003;39(4):488–494. PubMed

Whelan J.S., Jinks R.C., McTiernan A., Sydes M.R., Hook J.M., Trani L. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2012;23(6):1607–1616. PubMed PMC

Bielack S.S., Smeland S., Whelan J.S., Marina N., Jovic G., Hook J.M. EURAMOS-1 investigators. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon Alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 good response randomized controlled trial. J Clin Oncol. 2015;33(20):2279–2287. PubMed PMC

Marina N.M., Smeland S., Bielack S.S., Bernstein M., Jovic G., Krailo M.D. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016;17(10):1396–1408. PubMed PMC

Collins M., Wilhelm M., Conyers R., Herschtal A., Whelan J., Bielack S. Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol. 2013;31(18):2303–2312. PubMed

Bartlett J., Morris T. Multiple imputation of covariates by substantive-model compatible fully conditional specification. STATA J. 2015;15(2):437–456.

Ferrari S., Ruggieri P., Cefalo G., Tamburini A., Capanna R., Fagioli F. Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1. J Clin Oncol. 2012;30(17):2112–2118. PubMed

Fuchs N., Bielack S.S., Epler D., Bieling P., Delling G., Korholz D. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 1998;9(8):893–899. PubMed

Le Deley M.C., Guinebretiere J.M., Gentet J.C., Pacquement H., Pichon F., Marec-Berard P. SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007;43(4):752–761. PubMed

Kager L., Zoubek A., Potschger U., Kastner U., Flege S., Kempf-Bielack B. Cooperative German-Austrian-Swiss Osteosarcoma Study G. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol. 2003;21(10):2011–2018. PubMed

Bacci G., Rocca M., Salone M., Balladelli A., Ferrari S., Palmerini E. High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol. 2008;98(6):415–420. PubMed

Meyers P.A., Heller G., Healey J.H., Huvos A., Applewhite A., Sun M. Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol. 1993;11(3):449–453. PubMed

Angelini A., Mavrogenis A.F., Trovarelli G., Ferrari S., Picci P., Ruggieri P. Telangiectatic osteosarcoma: a review of 87 cases. J Cancer Res Clin Oncol. 2016;142(10):2197–2207. PubMed

Bacci G., Picci P., Ferrari S., Sangiorgi L., Zanone A., Brach del Prever A. Primary chemotherapy and delayed surgery for non-metastatic telangiectatic osteosarcoma of the extremities. Results in 28 patients. Eur J Cancer. 1994;30A(5):620–626. PubMed

Bielack S., Jurgens H., Jundt G., Kevric M., Kuhne T., Reichardt P. Osteosarcoma: the COSS experience. Cancer Treat Res. 2009;152:289–308. PubMed

Boye K., Del Prever A.B., Eriksson M., Saeter G., Tienghi A., Lindholm P. High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study. Pediatr Blood Cancer. 2014;61(5):840–845. PubMed

Bacci G., Longhi A., Versari M., Mercuri M., Briccoli A., Picci P. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer. 2006;106(5):1154–1161. PubMed

Hauben E.I., Weeden S., Pringle J., Van Marck E.A., Hogendoorn P.C. Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup. Eur J Cancer. 2002;38(9):1218–1225. PubMed

Transcription factor c-Myb: novel prognostic factor in osteosarcoma

Improved osteosarcoma survival with addition of mifamurtide to conventional chemotherapy - Observational prospective single institution analysis