We designed the EURAMOS-1 trial to investigate whether intensified .. and a normal creatinine concentration for their age as per protocol. EURAMOS-1, an international randomised study for osteosarcoma: Results from Pre-operative chemotherapy was completed according to protocol in 94%. The EURAMOS 1 trial is a multimodal therapy of osteosacoma with precluding treatment with protocol chemotherapy (for example HIV.
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Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on euramod of changing post-operative chemotherapy based on histological response.
Patients were randomised after surgery. Longitudinal evaluation of quality of life was undertaken. Recruitment was completed protodol the largest osteosarcoma study to date in 75 months. Commencing Marchpatients were registered from centres across 17 ruramos. There were three 0. 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.
Osteosarcoma is the commonest primary bone cancer affecting young people with an overall age-standardised incidence rate of 5. Cure of osteosarcoma in a proportion of patients was consistently reported first in the s, achieved through the combination of surgical extirpation of the primary tumour with multi-drug chemotherapy. The results were further improved during the next decade, but since then, no clinically significant advances have been made in survival, although more patients access combination chemotherapy within and outside trials.
Infour clinical study groups agreed to collaborate to conduct osteosarcoma studies more rapidly. Additional objectives were to facilitate biological research in osteosarcoma, more rapidly identify new therapeutic approaches and develop a common understanding and methodologies for staging, pathology and other aspects of disease management [ 2 ].
Good histological response, assessed in the resected tumour, has been associated with improved survival [ 3 — 5 protocl. Therefore, this study addressed separate treatment questions based on histological response.
EURAMOS-1 was notable for addressing randomised questions in a rare cancer on an unprecedented scale and for launching at a time of profound change to European legislation related to trial regulation and governance [ 6 ].
We describe the study, its population and the initial treatment of registered patients. We designed a clinical trial to include patients with newly diagnosed localised or metastatic osteosarcoma see supplementary Material, available at Annals of Oncology online of the extremity or axial skeleton deemed to be suitable for complete resection of all disease sites.
Standard staging and organ function investigations were undertaken. Diagnostic biopsies were to be examined by local institutional pathologists and reviewed by each study group’s reference pathologists. Response classification was dichotomised: Registered protockl were offered randomisation when also had: Data collection including registration characteristics and reports on pre-operative chemotherapy, surgery and pathology had to be received by the randomising data centre.
Consent euramls obtained according to national regulations. Preferred schedules were h infusion for doxorubicin and either h infusion or two 4-h infusions on separate days for cisplatin. Methotrexate was given over 4 h and folinic acid rescue commenced at 24 h.
Surgery was scheduled after two cycles of MAP, i. The protocol detailed dose modifications to account for euramps for all treatments. Granulocyte growth factors were recommended but not mandated. Dexrazoxane could be used at investigators’ discretion for reduced cardiac function remaining in the normal range; this applied throughout in North America but was withdrawn by the European Medicines Agency in Response assessment was required to determine protocop for surgery and to exclude progression see supplementary Material, available at Annals of Oncology online.
Quality of life QL was assessed using self- and parent-completed questionnaires to determine short- and long-term impacts.
The initial QL assessment was at week 5, then 3 months after definitive surgery, at 18 months and 3 years after commencing therapy. The primary outcome measure was event-free survival EFSdefined as time from randomisation to the first of: EFS was chosen because prevention of first recurrence is the principal goal of adjuvant treatment of osteosarcoma, given the low rate of survival after first recurrence.
Furthermore, treatment of recurrence is heterogeneous; treatment guidance for relapse accompanied the protocol, but sites’ existing standard practice was accepted. Secondary outcome measures were overall survival OStoxicity and QL. This paper describes the full, registered patient population, including all patients who signed the informed consent documents, up to the point of surgery.
Standard descriptive statistics are used. We estimated accrual as a proportion of expected age-related osteosarcoma incidence osteosarcoma to address whether participation was equally likely within the study age range. Randomisation was offered to eligible registered patients with reported histological response. There was some variability in proportion randomised between groups: Thirty-one patients were deemed ineligible post-registration based on reference histological review of the biopsy.
Median time from start of chemotherapy to surgery was 82 days IQR 76; Median time from surgery to starting post-operative chemotherapy for randomised patients was 18 days IQR 14; The pre-operative toxicities reported were as expected.
CTCAE grade 3—4 toxicity was common: Severe renal, neurological and left ventricular dysfunctions were uncommon. Three deaths were treatment-related two from infective complications and one from toxic epidermal necrolysis secondary to methotrexate and three occurred after surgery. Excludes three deaths occurred after surgery. Of those patients, one Good Responder had worst toxicity of grade 1; one poor responder had worst toxicity of grade 3 and one person with unknown histological response had a worst toxicity of grade 4.
There were three post-operative deaths: Long-term event data were sought in all patients, regardless of randomisation.
Long-term event data from the full cohort, including second malignancy data, will be reported with further follow-up. Osteosarcoma therapy was revolutionised by the introduction of adjuvant combination chemotherapy, in the s, but has improved little since.
The cost of seeking cure is exceptionally high as patients receive particularly complex and toxic chemotherapy regimens, plus disabling surgery.
The single new treatment which has emerged, mifamurtide MTP-PEhas been the subject of considerable controversy and its availability varies internationally, due to disagreements about interpretation of the available clinical data and cost.
While many studies have been undertaken for osteosarcoma, they are often characterised by being non-randomised or, if randomised, by their long accrual periods proticol 15 — 18 ]. This was the background against which we joined together to attempt to develop new paradigms for treating this disease. The two questions chosen for this first study stratified post-operative treatment according to the histologically assessed response to pre-operative chemotherapy. It assessed maintenance therapy in patients with a better lrotocol Good Response [ 19 ] and intensification in patients with poorer prognosis Poor Response [ 920 — 22 ].
These important questions were amenable to duramos relatively simple trial design. However, the agents chosen highlight the paucity of new or investigational products appropriate to include in phase III trials.
The study was developed through a commitment to collaboration between four well-established study groups. With patients with resectable osteosarcoma randomised, it doubled the size of the previous largest RCT in this population and accrual was completed in around 6 years. Other indicators of quality and safety for a trial on this scale are reassuring. Concordance with protocol chemotherapy was excellent. Toxicities were consistent with previous experience of these agents.
The treatment-related death rate of 0. In other areas, the study has highlighted where improvement is needed. This eufamos the first publicly-funded pan-European clinical trial to be activated after European countries implemented the European Clinical Trials Directive, which created new challenges [ 23 ].
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There were limits to the accessibility of the trial for osteosarcoma patients. We were unable to open EURAMOS-1 in some countries that wished to participate either because of regulatory constraints or insufficient funding. The feasibility of delivering intensive chemotherapy for a rare cancer in multiple centres within a Good Clinical Practice framework is amply demonstrated here.
However, it is also clear that the treatment burden of MAP is exceptionally high, reflected in levels of grade 3—4 haematological and non-haematological toxicity. While the link between increased toxicity and improved survival from osteosarcoma remains to be unravelled [ 26 ], future approaches must look to reduce this burden as well as improve efficacy.
At the time of trial planning, few data were available to guide a sample size calculation to accurately estimate randomisation rates and these were markedly lower than expected, which contributed to a decision to expand registration targets from to over Information collected on reasons for non-randomisation has been relatively non-informative but anecdotally, young people expressed a reluctance to risk allocation to experimental treatments that were substantially longer than the standard MAP schedule.
Further investigation of this important area is needed [ 27 ]. Greater patient involvement at the design stage may help in the future. First results of the Good Response randomisation have been presented orally [ 28 ], with a clear demonstration that large-scale practice-changing randomised, controlled trials can be undertaken in rare cancers by extending the traditional boundaries of collaboration.
A successor study has not yet emerged despite willingness by investigators and other trials groups joining the collaboration to face the formidable regulatory and financial challenges which must be overcome. The absence of testable new innovations in this disease is a cause for major concern and even more apparent now we have established a successful test platform.
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A list of all participating centres and the responsible clinicians can be found in the supplementary Material, available at Annals of Oncology online. Acknowledgement of research support: EURAMOS-1 is an academic clinical trial funded through multiple national and international government agencies and cancer charities see http: National Center for Biotechnology InformationU. Published online Nov Whelan1 S. Bielack2 N. Marina3 S.
Smeland4, 5 G. Jovic6 J. Hook6 M. Krailo7 J. Anninga8 T. Butterfass-Bahloul9 T. Calaminus11 M. Capra12 C.