Clinical trials in osteosarcoma and soft tissue sarcoma

Lead Research Organisation: MRC Clinical Trials Unit

Abstract

This programme is trying to find improved ways to approach the treatment with sarcoma, in particular bone cancer (osteosarcoma).||The mainstay of treatment is surgery to remove the tumour. Outcomes for patients improved greatly when chemotherapy (drug treatment) before and after surgery became part of standard care in the 1970s. Through a collaborative research group (the European Osteosarcoma Intergroup), the MRC Clinical Trials Unit, has run four trials of chemotherapy. In the first three studies (BO02, BO03, BO06), the standard regimen was the same and involved two drugs: cisplatin and doxorubicin (adriamycin). The trials showed that the ways in which we have tried to improve chemotherapy with increased dose, increased numbers of drugs and drugs given more intensely were not reliably shown to be better than the standard treatment. In the current study, EURAMOS-1, the standard treatment is a three-drug approach that has been standard in North America.||For patients who respond well at first to chemotherapy, the research arm of EURAMOS-1 is maintenance therapy (2 years of monthly treatment with interferon, a biological drug) For patients who do not respond so well, the research arm of is more intensive treatment with more drugs. More than 1000 patients across Europe and in North America have joined the trial since Summer 2005, making it the largest single study in osteosarcoma. Around 2000 consenting patients will be recruited. Other groups are interested to use these data for further analyses and this is being discussed.

Technical Summary

Although rare in absolute terms, osteosarcoma is the most common form of primary bone cancer with an incidence of 150-250 new cases per annum in the UK. Osteosarcoma can occur at any age, but is most commonly found in teenagers and young adults, and is slightly more common in males. Any bone in the body can be affected but the commonest sites are the arms or legs, particularly around the knee joint. Prior to the introduction of adjuvant chemotherapy, 5-year survival for patients with operable osteosarcoma, treated using amputation alone, was less than 20%. The introduction in the mid-1970s of adjuvant and neo-adjuvant chemotherapy using intensive multi-agent schedules has led to 5-year survival in excess of 50%. As neo-adjuvant chemotherapy has increased in usage, limb salvage has become the mainstay of surgical management.||In order to conduct meaningful clinical trials in this rare disease, international collaboration is essential. The MRC performs trials with other leading research groups under the auspices of the European Osteosarcoma Intergroup and the EURAMOS collaboration. In two previous randomised trials, BO02 and BO03, it has been shown that lengthy, multi-agent chemotherapy regimens offer no survival benefit when compared with a shorter two-drug regimen consisting of cisplatin and doxorubicin. The trial MRC BO06 (EORTC 80931) trial, published in January 2007, investigated whether survival could be improved by increasing the intensity of the now standard two-drug regimen using granulocyte colony stimulating factor (G-CSF), a haemopoietic growth factor; no good evidence of an advantage was found for the more intensive arm.||In October 2005, the EURAMOS-1 trial opened to recruitment in the UK, where EURAMOS is the EUropean and AMerican Osteosarcoma Study group. EURAMOS is a collaboration between the European Osteosarcoma Intergroup and similar research bodies in central Europe, Scandinavia and North America. Together these groups can recruit more patients and so more quickly address the most important questions. In EURAMOS-1, all patients receive the same pre-operative chemotherapy followed by surgery as per usual practice. After surgery, patients who have had a poorer response to pre-operative chemotherapy are randomised to continue with the same treatment or to receive more intensive treatment; patients who have had a better response to pre-operative chemotherapy continue on the pre-operative chemotherapy regimen but are randomised to receive or not receive long-term maintenance therapy. Recruitment to the trial in terms of registrations has been very good. The trial is supported by the European Science Foundations EUROCORES-ECT programme, funded in the UK by MRC and Cancer Research UK and sponsored in Europe by MRC with delegated responsibilities set out in the EURAMOS Framework Agreement. MRC CTU is the Data Centre for the European Osteosarcoma Intergroup and the Coordinating Data Centre for the trial, overall. The planned associated biology studies are now being initiated.||The MRC CTU Cancer Group also conducts associated research in osteosarcoma using the wealth of clinical information collected for previous trials. Long-term follow-up data from BO02 and BO03 were presented in 2000 that suggest that relapses in patients free of disease for five years occur in less than 5% of patients and a paper in 2006 looked at baseline data for late-relapsing patients across a number of osteosarcoma trials. The relationship between received dose intensity and outcome for two-drug therapy was described in a paper published in 2000; dose intensity was found to have no influence on survival or progression-free survival. Long-term cohort data on BO02, BO03 and BO06 have been analysed together and papers are in the late stages of development.

Publications

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Collins M (2013) Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Hauben EI (2006) Clinico-histologic parameters of osteosarcoma patients with late relapse. in European journal of cancer (Oxford, England : 1990)

 
Guideline Title UK guidelines for the management of bone sarcomas
Description British Sarcoma Group: UK guidelines for the management of bone sarcomas (in BMC Clinical Sarcoma Research)
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact Not known
URL https://clinicalsarcomaresearch.biomedcentral.com/articles/10.1186/s13569-016-0047-1
 
Description CRUK / CTAAC funding for EURAMOS-1 --> U122861384 (one of many co-funders for many destinations --> approx UK total shown)
Amount £500,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2005 
End 06/2014
 
Description European Science Foundation funding for EURAMOS-1 --> U122861384 (one of many co-funders for many destinations --> approx UK total shown)
Amount £500,000 (GBP)
Funding ID CRUK/06/019 [A3804] - Cancer Research UK seems to consider this as one with the original grant. We did not expect this. 
Organisation European Science Foundation (ESF) 
Sector Charity/Non Profit
Country France
Start 01/2005 
End 12/2019
 
Description MRC trial funding grant for EURAMOS-1 --> U122861384 (one of many co-funders for many destinations --> approx UK total shown)
Amount £500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2005 
End 06/2015
 
Title BO02, BO03, BO06 
Description The databases from the three MRC CTU-coordinated trials in osteosarcoma were standardised and combined to allow long-term, cross-trial follow-up 
Type Of Material Biological samples 
Year Produced 2010 
Provided To Others? Yes  
Impact Results have been shared at conferences. Three papers have recently been published (some on-line only, still). A data release to an international collaboration (led from Australia) looking at prognostic factors in osteosarcoma was presented at ASCO 2012 and a paper accepted by JCO in Nov-2012 
 
Title EURAMOS-1 Common Data Set (collated) 
Description Collated data from our participating groups in EURAMOS-1 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact None yet; pending maturity 
 
Title EURAMOS-1 clinical trial database (EOI data) 
Description Database prospectively collecting information on patients who have joined this international clinical trial 
Type Of Material Biological samples 
Provided To Others? No  
Impact ASCO presentation 2013 Papers 2014 to 2015 -- see publications 
 
Description Australian-led group for age cohorts 
Organisation Australasian Sarcoma Study Group
Country Australia 
Sector Academic/University 
PI Contribution Provision of data from BO02, BO03 and BO06 trials. Input to design and interpretation of data
Collaborator Contribution Led research; we provided data and comments in design and interpretation
Impact Conference presentations made late in 2010. A manuscript is in preparation and will be submitted for publication in late 2011/early 2012.
Start Year 2009
 
Description EURAMOS Strategy Group 
Organisation Australasian Sarcoma Study Group
Country Australia 
Sector Academic/University 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation Cooperative Osteosarcoma Study Group
Country European Union (EU) 
Sector Academic/University 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation European Organisation for Research and Treatment of Cancer (EORTC)
Department Soft Tissue and Bone Sarcoma Sub Group
Country Belgium 
Sector Academic/University 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation ISG Italian Sarcoma Group
Country Italy 
Sector Charity/Non Profit 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation Japanese Clinical Oncology Group
Country Japan 
Sector Academic/University 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation National Cancer Institute (NCI)
Department Children's Oncology Group (COG)
Country United States 
Sector Academic/University 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation SFCE/GSF-GETO
Country France 
Sector Charity/Non Profit 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation Sarcoma Alliance for Research through Collaboration (SARC)
Country United States 
Sector Charity/Non Profit 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation Scandinavian Sarcoma Group (SSG)
Country Sweden 
Sector Charity/Non Profit 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description EURAMOS Strategy Group 
Organisation Spanish Group for Research on Sarcomas (GEIS)
Country Spain 
Sector Charity/Non Profit 
PI Contribution Collaboration of global osteosarcoma clinical research groups to develop a co-ordinated strategy for research in this rare cancer. Contribution from the MRC CTU has been to organise two consensus conferences aimed at developing future trial concepts (Future Clinical Trials for Adjuvant Treatment of Osteosarcoma - Prioritising the Questions, London 2010) and defining standard trial procedures (2nd International Meeting on Future Clinical Trials for the Adjuvant Treatment of Osteosarcoma: Creating a Strategic Consensus, London 2012). The most recent meeting was Oct-2014 in Berlin which MRC CTU attended and minuted.
Collaborator Contribution Intellectual input into regular group meetings and consensus conferences.
Impact Two detailed meeting reports on the 2010 and 2012 have been produced for the European Science Foundation and two consensus papers for publication are in development. Further combined guidelines and prioritisation papers are in development (Nov-2012)
Start Year 2010
 
Description European Osteosarcoma Intergroup 
Organisation European and American Osteosarcoma Study Group (EURAMOS)
Department European Osteosarcoma Group (EOI)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Design, central coordination and analysis of trial data
Collaborator Contribution Design and conduct of clinical trials This organisation involves a number of countries. Many of these countries provide money to a central pot. This pot provides money to support the running of the trial, including to MRC CTU. Work with the EOI led to the EURAMOS collaboration (see grant G0400248)
Impact Recent publications: 22036088, 16426841, 17227995, 21216138 and 22015453. Previous publications and trials (not listed). Development of EURAMOS collaboration (part of same program but listed under G0400248)
 
Title BO06 
Description The trial looked to see whether chemotherapy could be given more intensively by using growth factor support. The hypothesis was that instensification would improve outcomes for patients with osteosarcoma. Patients were randomised to: :: 6 cycles of MAP chemotherapy every 3 weeks :: 6 cyclles of MAP every 2 weeks with growth factor support 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2007
Development Status Closed
Clinical Trial? Yes
Impact No improvement in outcomes was demonstrated. Histological response to surgery was demonstrated to be prognostic but not predictive. This led to alternatives being researched in EURAMOS. 
URL http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=107
 
Description BO06 results to public 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Results of the BO06 trial were summarised in a patient newsletter

Information for patients
Year(s) Of Engagement Activity 2007
 
Description Presentation of the EURAMOS-1 Poor Responders randomisation first results 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact First results of this important comparison were presented at international conferences. More presentations will follow in China, UK and Germany, at least, given by the lead investigators. A paper is in development.

MAP chemotherapy will the international standard of care.
Year(s) Of Engagement Activity 2014
URL https://www.ctos.org/PDFs/CTOS%202014%20AM%20FP%20complete%20rfs%20electronic.pdf