International collaboration is feasible in trials for rare conditions: the EURAMOS experience.
The introduction of multi-agent chemotherapy dramatically improved the outcome for patients with osteosarcoma. However, we appear to have reached a plateau in outcome with a long-term event-free survival of 60-70%. Therefore, detection of further improvements will likely require larger numbers of patients. This goal is best achieved via randomized clinical trials (RCTs) requiring large-scale cooperation and collaboration. With this background, four multinational groups agreed on the merits of collaboration: Children's Oncology Group (COG), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI) and Scandinavian Sarcoma Group (SSG); they designed a study to determine whether altering postoperative therapy based on histological response improved the outcome. The study design includes a backbone of 10 weeks of preoperative therapy using MAP (methotrexate, Adriamycin and cisplatin). Following surgery, patients are stratified according to histological response. Patients classified as "good responders" (>or=90% necrosis) are randomized to continue MAP or to receive MAP followed by maintenance pegylated interferon, while "poor responders" (<90% necrosis) are randomized to either continue MAP or to receive MAPIE (MAP+ifosfamide, etoposide). The design includes the registration of 1,400 patients over 4 years as well as the evaluation of quality of life using two different instruments. The group has established an efficient infrastructure to ensure successful implementation of the trial. This has included the EURAMOS Intergroup Safety Desk, which has established an international system for SAE, SAR and SUSAR reporting to the relevant competent authorities and ethics committees for each participating country. The group has also developed trial site monitoring and data center audits with funding from the European Science Foundation (ESF). The ESF has also funded three training courses to familiarize institutional staff with the requirements of multinational GCP trials. We have established a successful collaboration, and as of February 2008, 901 patients have been enrolled (COG 448; COSS 226; EOI 181; SSG 46) from 249 institutions in 16 different countries. As expected, 80% of the patients are <18 years of age, and accrual into the Quality of Life sub-study is proceeding as planned with 90% of the subjects agreeing to participate. International awareness is increasing and procedures for applicant countries wishing to join the collaboration have been implemented. Details about EURAMOS can be found at www.euramos.org. International trials in rare diseases are practicable with appropriate funding, planning and support. Although the implementation of such trials is difficult and time consuming, it is a worthwhile effort to rapidly complete RCTs and identify interventions that will improve the outcome of all osteosarcoma patients.EURAMOS-1 is the fastest accruing osteosarcoma trial and is already the largest osteosarcoma study conducted.
Marina
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Stanford University Medical Center, 1000 Welch Road, Suite 300, Palo Alto, CA 94304-1812, USA. Neyssa.marina@stanford.edu
Bielack
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Whelan
J
J
Smeland
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S
Krailo
M
M
Sydes
M R
MR
Butterfass-Bahloul
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T
Calaminus
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Bernstein
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M
D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003299:Cooperative Behavior; D006801:Humans; D007391:International Cooperation; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic