EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment

J S Whelan, S S Bielack, N Marina, S Smeland, G Jovic, J M Hook, M Krailo, J Anninga, T Butterfass-Bahloul, T Böhling, G Calaminus, M Capra, C Deffenbaugh, C Dhooge, M Eriksson, A M Flanagan, H Gelderblom, A Goorin, R Gorlick, G Gosheger, R J Grimer, K S Hall, K Helmke, P C W Hogendoorn, G Jundt, L Kager, T Kuehne, C C Lau, G D Letson, J Meyer, P A Meyers, C Morris, H Mottl, H Nadel, R Nagarajan, R L Randall, P Schomberg, R Schwarz, L A Teot, M R Sydes, M Bernstein, EURAMOS collaborators, J S Whelan, S S Bielack, N Marina, S Smeland, G Jovic, J M Hook, M Krailo, J Anninga, T Butterfass-Bahloul, T Böhling, G Calaminus, M Capra, C Deffenbaugh, C Dhooge, M Eriksson, A M Flanagan, H Gelderblom, A Goorin, R Gorlick, G Gosheger, R J Grimer, K S Hall, K Helmke, P C W Hogendoorn, G Jundt, L Kager, T Kuehne, C C Lau, G D Letson, J Meyer, P A Meyers, C Morris, H Mottl, H Nadel, R Nagarajan, R L Randall, P Schomberg, R Schwarz, L A Teot, M R Sydes, M Bernstein, EURAMOS collaborators

Abstract

Background: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response.

Patients and methods: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken.

Results: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen.

Conclusions: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

Keywords: international collaboration; osteosarcoma; randomised controlled trial; trial conduct.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
EURAMOS-1 study design.
Figure 2.
Figure 2.
EURAMOS-1 treatment schedule.
Figure 3.
Figure 3.
EURAMOS-1 CONSORT diagram.

References

    1. Whelan J, McTiernan A, Cooper N, et al. Incidence and survival of malignant bone sarcomas in England 1979–2007. Int J Cancer. 2011;131:E508–E517.
    1. Marina N, Bielack S, Whelan J, et al. International collaboration is feasible in trials for rare conditions: the EURAMOS experience. Cancer Treat Res. 2009;152:339–353.
    1. Rosen G, Murphy ML, Huvos AG, et al. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer. 1976;37:1–11.
    1. Bacci G, Picci P, Ruggieri P, et al. Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities. Cancer. 1990;65:2539–2553.
    1. Whelan JS, Jinks RC, McTiernan A, et al. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol. 2012;23:1607–1616.
    1. Marina N, Bielack S, Whelan J, et al. International collaboration is feasible in trials for rare conditions: the EURAMOS experience. In: Jaffe N, Bruland OS, Bielack S, editors. Pediatric and Adolescent Osteosarcoma Series: Cancer Treatment and Research. Vol. 152. 2010. pp. 339–354.
    1. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of interferon alfa-2a treatment of hemangiomas of infancy. J Pediatr. 1998;132:527–530.
    1. Meyers PA, Schwartz CL, Krailo M, et al. 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;23:2004–2011.
    1. Goorin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a Pediatric Oncology Group trial. J Clin Oncol. 2002;20:426–433.
    1. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–376.
    1. Varni JW, Burwinkle TM, Katz ER, et al. The PedsQL in pediatric cancer: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer. 2002;94:2090–2106.
    1. Calaminus G, Weinspach S, Teske C, Gobel U. Quality of life in children and adolescents with cancer. First results of an evaluation of 49 patients with the PEDQOL questionnaire. Klin Padiatr. 2000;212:211–215.
    1. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS . (28 Nov 2014, date last accessed)
    1. George SL, Desu MM. Planning the size and duration of a clinical trial studying the time to some critical event. J Chronic Dis. 1974;27:15–24.
    1. Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol. 2005;23:8845–8852.
    1. Le Deley MC, Guinebretiere JM, Gentet JC, et al. 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;43:752–761.
    1. Lewis IJ, Nooij MA, Whelan J, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007;99:112–128.
    1. Smeland S, Muller C, Alvegard TA, et al. 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;39:488–494.
    1. Whelan J, Patterson D, Perisoglou M, et al. The role of interferons in the treatment of osteosarcoma. Pediatr Blood Cancer. 2010;54:350–354.
    1. Schwartz CL, Wexler LH, Devidas M, et al. P9754 therapeutic intensification in non-metastatic osteosarcoma: a COG trial. J Clin Oncol. 2004;22 Meeting Abstracts abstr 8514.
    1. Gentet JC, Brunat-Mentigny M, Demaille MC, et al. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. Eur J Cancer. 1997;33:232–237.
    1. Rosen G, Forscher C, Lowenbraun S, et al. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer. 1994;73:2506–2511.
    1. Bielack SS. Osteosarcoma: time to move on? Eur J Cancer. 2010;46:1942–1945.
    1. Fern L, Davies S, Eden T, et al. Rates of inclusion of teenagers and young adults in England into National Cancer Research Network clinical trials: report from the National Cancer Research Institute (NCRI) Teenage and Young Adult Clinical Studies Development Group. Br J Cancer. 2008;99:1967–1974.
    1. Fern LA, Lewandowski JA, Coxon KM, et al. Available, accessible, aware, appropriate, and acceptable: a strategy to improve participation of teenagers and young adults in cancer trials. Lancet Oncol. 2014;15:e341–e350.
    1. McTiernan A, Jinks RC, Sydes MR, et al. Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: a report from the European Osteosarcoma Intergroup. Eur J Cancer. 2012;48:703–712.
    1. Pearce S, Lavender V, Brownsdon A, et al. Perceptions of participants and professionals in bone sarcoma clinical trials: implications for study design and conduct. Eur J Cancer. 2013;49(suppl 2):A3819.
    1. Bielack S, Smeland S, Whelan J, et al. MAP plus maintenance pegylated interferon α-2b (MAPIfn) 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” randomization. J Clin Oncol. 2013;31(suppl):LBA10504.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera