***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: Background . Osteosarcoma is a highly malignant bone tumour . After the second relapse , the 12-month postrelapse disease-free survival ( PRDFS ) rate decreases below 20 % . Oral Etoposide is often used in clinical practice after surgery as an “ adjuvant ” outside any protocol and with only limited evidence of improved survival .  Viscum album fermentatum Pini ( Viscum ) is an extract of mistletoe plants grown on pine trees for subcutaneous ( sc ) injection with immunomodulatory activity . Methods . Encouraged by preliminary findings , we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were r and omly assigned to Viscum sc or Oral Etoposide . Our goal was to compare 12-month PRDFS rates with an equivalent historical control group . Results . Twenty patients have been enrolled , with a median age of 34 years ( range 11–65 ) and a median follow-up time of 38.5 months ( 3–73 ) . The median PRDSF is currently 4 months ( 1–47 ) in the Etoposide and 39 months ( 2–73 ) in the Viscum group . Patients getting Viscum reported a higher quality of life due to lower toxicity . Conclusion . Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients . A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients Two hundred and thirty five patients with osteosarcoma , aged less than 40 years , and treated by amputation or radiotherapy , were entered in a r and omised trial of two forms of adjuvant chemotherapy . A two drug regimen , namely vincristine 2 mg m-2 ( maximum 2 mg ) followed by methotrexate 200 mgm-2 , given every three weeks , was compared with a three drug regimen , comprising the same vincristine-methotrexate treatment , alternating every three weeks with doxorubicin 60 mg m-2 . Both regimens were continued for 54 weeks . Forty-one patients were excluded , most because of inadequate histology , leaving 194 patients for analysis . One hundred and seventy of these had immediate amputation , 14 were treated by a policy of radiotherapy , with surgery delayed for 9 months , provided no distant metastases had appeared , and 10 by a policy of radiotherapy only . Patients have been followed-up for between 26 and 94 months after entry to the trial . The 2- and 5-year survival rates were 48 % and 27 % . No significant difference in survival was observed between the two regimens , but toxicity was less with the two drug regimen BACKGROUND Based on pre clinical data for the antitumour effect of zoledronate in osteosarcoma , we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma . METHODS In this r and omised , multicentre , open-label , phase 3 trial ( OS2006 ) , patients aged between 5 years and 50 years with newly diagnosed high- grade osteosarcoma were r and omly assigned to receive st and ard chemotherapy with or without ten zoledronate intravenous infusions ( four preoperative and six postoperative ) . Adults older than 25 years received 4 mg zoledronate per infusion , patients aged 18 - 25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions , and younger patients received 0·05 mg/kg per infusion . Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years , and doxorubicin , ifosfamide , and cisplatin in adults older than 25 years ; patients aged 18 - 25 years were treated with either regime at the discretion of the treating centre . Balanced r and omisation between the two groups was done central ly with online r and omisation software , based on a minimisation algorithm taking into account centre , age , combined with chemotherapy regimen , and risk group ( resectable primary and no metastasis vs other ) . Patients and investigators were not masked to treatment assignment , but the endpoint adjudication committee members who review ed suspected early progressions were masked to group allocation . The primary endpoint was event-free survival , estimated from the r and omisation to the time of first failure ( local or distant relapse , progression , death ) or to the last follow-up visit for the patients in first complete remission , analysed on a modified intention-to-treat population , which excluded patients found not to have a malignant tumour after central review . Three interim analyses were planned . This trial is registered with Clinical Trials.gov , number NCT00470223 . FINDINGS Between April 23 , 2007 , and March 11 , 2014 , 318 patients , median age 15·5 years ( range 5·8 - 50·9 ) , were enrolled from 40 French centres ; of whom 158 were assigned to the control group ( chemotherapy alone ) and 160 to the zoledronate group , including 55 ( 17 % ) patients with definite metastases . The trial was stopped for futility after the second interim analysis . With a median follow-up of 3·9 years ( IQR 2·7 - 5·1 ) , 125 events occurred ( 55 in the control group and 70 in the with zoledronate group ) . Event-free survival at 3 years for all 315 r and omly assigned patients was 60·3 % ( 95 % CI 64·5 - 65·9 ) ; 3-year event-free survival was 63·4 % ( 55·2 - 70·9 ) for the control group and 57·1 % ( 48·8 - 65·0 ) for the zoledronate  group . The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group ( hazard ratio [ HR ] 1·36 [ 95 % CI 0·95 - 1·96 ] ; p=0·094 ) . No major increase in severe toxic effects of grade 3 or higher associated with zoledronate , barring expected hypocalcaemia ( 45 [ 29 % ] of 153 participants in the zoledronate group vs ten [ 6 % ] of 155 participants in the control group ; p<0·0001 ) and hypophosphataemia ( 61 [ 40 % ] of 151 in the zoledronate group vs 26 [ 17 % ] of 156 in the control group ; p<0·0001 ) . No significant difference in orthopaedic complications was noted between the two groups ( 27 in the control group and 29 in the zoledronate group ) . Two treatment-related deaths were reported ( one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion ) . INTERPRETATION From the results observed in this study , we do not recommend zoledronate in osteosarcoma patients . Further biological studies are required to underst and the discordance between the results of OS2006 trial and pre clinical data . FUNDING French National Cancer Institute ( INCa ) , Novartis , Chugai , Ligue Nationale contre le Cancer , Fédération Enfants et Santé , Société Française des Cancers et Leucémies de l'Enfant 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 Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival ( MFS ) in osteosarcoma , a r and omized study was undertaken with the aim of ( 1 ) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin ( DOX ) and cisplatin ( CPDD ) by administering these drugs postoperatively only after poor response with a milder preoperative regimen , and ( 2 ) improving the prognosis of patients responding poorly to the initial treatment by use of a  salvage chemotherapy  postoperatively . The available patients were divided into two groups . Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate ( HDMTX ) and the triple drug combination of bleomycin , cyclophosphamide , and dactinomycin ( BCD ) and were switched to DOX/CPDD postoperatively in case of poor response . DOX 
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Conclusions We concluded that multi-drug regimens have a better effect on prolonging the PFS and OS of osteosarcoma patients , and the T12 protocol has a better effect on prolonging the PFS of osteosarcoma patients , particularly in combination with ifosfamide or vincristine .
The OS analysis showed that the T12 protocol plus vincristine or the T12 protocol with the removal of cisplatinum might be a better regimen for improving the OS of patients .