Clinical trials in osteosarcoma and soft tissue sarcoma

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.

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.