***TASK*** the task is to summarize an input biomedical literature in six sentences 
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    Input: Summary Background We design ed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy ( ≥10 % viable tumour ) improved event-free survival in patients with high- grade osteosarcoma . Methods EURAMOS-1 was an open-label , international , phase 3 r and omised , controlled trial . Consenting patients with newly diagnosed , resectable , high- grade osteosarcoma aged 40 years or younger were eligible for r and omisation . Patients were r and omly assigned ( 1:1 ) to receive either postoperative cisplatin , doxorubicin , and methotrexate ( MAP ) or MAP plus ifosfamide and etoposide ( MAPIE ) using concealed permuted blocks with three stratification factors : trial group ; location of tumour ( proximal femur or proximal humerus vs other limb vs axial skeleton ) ; and presence of metastases ( no vs yes or possible ) . The MAP regimen consisted of cisplatin 120 mg/m2 , doxorubicin 37·5 mg/m2 per day on days 1 and 2 ( on weeks 1 and 6 ) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen , with the addition of high-dose ifosfamide ( 14 g/m2 ) at 2·8 g/m2 per day with equidose mesna uroprotection , followed by etoposide 100 mg/m2 per day over 1 h on days 1–5 . The primary outcome measure was event-free survival measured in the intention-to-treat population . This trial is registered with Clinical Trials.gov , number NCT00134030 . Findings Between April 14 , 2005 , and June 30 , 2011 , 2260 patients were registered from 325 sites in 17 countries . 618 patients with poor response were r and omly assigned ; 310 to receive MAP and 308 to receive MAPIE . Median follow-up was 62·1 months ( IQR 46·6–76·6 ) ; 62·3 months ( IQR 46·9–77·1 ) for the MAP group and 61·1 months ( IQR 46·5–75·3 ) for the MAPIE group . 307 event-free survival events were reported ( 153 in the MAP group vs 154 in the MAPIE group ) . 193 deaths were reported ( 101 in the MAP group vs 92 in the MAPIE group ) . Event-free survival did not differ between treatment groups ( hazard ratio [ HR ] 0·98 [ 95 % CI 0·78–1·23 ] ) ; hazards were non-proportional ( p=0·0003 ) . The most common grade 3–4 adverse events were neutropenia ( 268 [ 89 % ] patients in MAP vs 268 [ 90 % ] in MAPIE ) , thrombocytopenia ( 231 [ 78 % in MAP vs 248 [ 83 % ] in MAPIE ) , and febrile neutropenia without documented infection ( 149 [ 50 % ] in MAP vs 217 [ 73 % ] in MAPIE ) . MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP ( 35 [ 12 % ] of 301 in the MAP group vs 71 [ 24 % ] of 298 in the MAPIE group ) . Two patients died during postoperative therapy , one from infection ( although their absolute neutrophil count was normal ) , which was definitely related to their MAP treatment ( specifically doxorubicin and cisplatin ) , and one from left ventricular systolic dysfunction , which was probably related to MAPIE treatment ( specifically doxorubicin ) . One suspected unexpected serious adverse reaction was reported in the MAP group : bone marrow infa rct ion due to methotrexate . Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival . The results define st and ard of care for this population . New strategies are required to improve outcomes in this setting . Funding UK Medical Research Council , National Cancer Institute , European Science Foundation , St Anna Kinderkrebsforschung , Fonds National de la Recherche Scientifique , Fonds voor Wetenschappelijk Onderzoek-Vla and eren , Parents Organization , Danish Medical Research Council , Academy of Finl and , Deutsche Forschungsgemeinschaft , Deutsche Krebshilfe , Federal Ministry of Education and Research , Semmelweis Foundation , ZonMw ( Council for Medical Research ) , Research Council of Norway , Sc and inavian Sarcoma Group , Swiss Paediatric Oncology Group , Cancer Research UK , National Institute for Health Research , University College London Hospitals , and Biomedical Research Centre The case histories of all patients with osteosarcoma of the trunk entered into the consecutive studies COSS 80 through COSS 86 of the Cooperative German/Austrian Osteosarcoma Study Group ( COSS ) were analyzed in order to evaluate their clinical characteristics and the impact of modern neoadjuvant therapy on prognosis . They were compared to those of all patients with extremity osteosarcoma treated according to the same protocol s. While tumors of the trunk comprised only 32 ( 4.8 % ) of 665 primary classical osteosarcomas , secondary osteosarcomas were much more likely to be located in bones of the axial skeleton ( 6 of 18 , 33 % ) . Patients with primary osteosarcoma of the axial skeleton were older ( mean : 20.8 vs. 15.2 years , P < 0.01 ) and were more likely to present with metastases at diagnosis ( 34 % vs 12 % , P < 0.001 ) than those with primary extremity osteosarcoma . In contrast to extremity tumors , local surgical treatment failure was very common in osteosarcomas of the trunk . Complete tumor removal was achieved in less than half of all evaluable cases . The prognosis of eight patients with localized primary axial osteosarcoma and effective surgical local control was not inferior to that of 483 equally evaluable patients with extremity tumors . In conclusion , while secondary systemic spread of axial osteosarcoma may be avoided in patients treated with multiagent chemotherapy , successful treatment is often barred by primary metastatic disease and inability to control the local tumor site PURPOSE To determine whether the addition of ifosfamide and /or muramyl tripeptide ( MTP ) encapsulated in liposomes to cisplatin , doxorubicin , and high-dose methotrexate ( HDMTX ) could improve the probability for event-free survival ( EFS ) in newly diagnosed patients with osteosarcoma ( OS ) . PATIENTS AND METHODS Six hundred seventy-seven patients with OS without clinical ly detectable metastatic disease were treated with one of four prospect ively r and omized treatments . All patients received identical cumulative doses of cisplatin , doxorubicin , and HDMTX and underwent definitive surgical resection of the primary tumor . Patients were r and omly assigned to receive or not to receive ifosfamide and /or MTP in a 2 double dagger 2 factorial design . The primary end point for analysis was EFS . RESULTS Patients treated with the st and ard arm of therapy had a 3-year EFS of 71 % . We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP . The addition of MTP to st and ard chemotherapy achieved a 3-year EFS rate of 68 % . The addition of ifosfamide to st and ard chemotherapy achieved a 3-year EFS rate of 61 % . The addition of both ifosfamide and MTP result ed in a 3-year EFS rate of 78 % . CONCLUSION The addition of ifosfamide in this dose schedule to st and ard chemotherapy did not enhance EFS . The addition of MTP to chemotherapy might improve EFS , but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP We conducted a r and omized controlled trial to determine whether intensive multi-agent adjuvant chemotherapy improves the chances of relapse-free survival in patients with nonmetastatic high- grade osteosarcoma of the extremity , as compared with concurrent controls . After undergoing definitive surgery , 36 patients were r and omly assigned to adjuvant chemotherapy  or to observation without adjuvant treatment . At two years the actuarial relapse-free survival was 17 percent in the control group , similar to that found in studies before 1970 , and 66 percent in the adjuvant-chemotherapy group ( P less than 0.001 ) . Similar results were observed among 77 additional patients who declined to undergo r and omization but who elected  observation or  chemotherapy . We conclude that the natural history of osteosarcoma of the extremity has remained stable over the past two decades , that adjuvant chemotherapy increases the chances of relapse-free survival of patients with high- grade osteosarcoma , and that it should be given to all such patients PURPOSE To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas , extending well beyond those of the typical young patient with seemingly localized extremity disease . PATIENTS AND METHODS A total of 1,702 consecutive newly diagnosed patients with high- grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic , tumor-related , and treatment-related variables , response , and survival . The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions . RESULTS Axial tumor site , male sex , and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis . Actuarial 10-year overall and event-free survival rates were 59.8 % and 48.9 % . Among the variables assessable at diagnosis , patient age ( actuarial 10-year survival > or = 40 , 41.6 % ; < 40 , 60.2 % ; P = .012 ) , tumor site ( axial , 29.2 % ; limb , 61.7 % ; P < .0001 ) , and primary metastases ( yes , 26.7 % ; no , 64.4 % ; P < .0001 ) , and for extremity osteosarcomas , also size ( > or = one third , 52.5 % ; < one third , 66.7 % ; P < .0001 ) and location within the limb ( proximal , 49.3 % ; other , 63.9 % ; P < .0001 ) , had significant influence on outcome . Two additional important prognostic factors were treatment related : response to chemotherapy ( poor , 47.2 % ; good , 73.4 % ; P < .0001 ) and the extent of surgery ( incomplete , 14.6 % ; macroscopically complete , 64.8 % ; P < .0001 ) . All factors except age maintained their significance in multivariate testing , with surgical remission and histologic response emerging as the key prognostic factors . CONCLUSION Tumor site and size , primary metastases , response to chemotherapy , and surgical remission are of independent prognostic value in osteosarcoma Background High- grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults . The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aim ing to improve outcomes of this rare disease by facilitating r and omised controlled trials . Methods Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high- grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible . A three-drug combination with methotrexate , doxorubicin and cisplatin was defined as st and ard chemotherapy , and between April 2005 and June 2011 , 2260 patients were registered . We report survival outcomes and prognostic factors in the full cohort of registered patients . Results For all registered patients at a median follow-up of 54 months ( interquartile range : 38–73 ) from biopsy , 3-year and 5-year event-free survival were 59 % ( 95 % confidence interval [ CI ] : 57–61 % ) and 54 % ( 95 % CI : 52–56 % ) , respectively . Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases ( hazard ratio [ HR ] = 2.34 , 95 % CI : 1.95–2.81 ) , non-pulmonary metastases ( HR = 1.94 , 95 % CI : 1.38–2.73 ) or an axial skeleton tumour site ( HR = 1.53 , 95 % CI : 1.10–2.13 ) . The histological subtypes telangiectatic ( HR 
    Output:
    
Age , tumor location , tumor size/volume , and histologic response carried independent prognostic value in the majority of the studies .