***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: From 1984 to 2001 , the Pediatric Oncology Group ( POG ) conducted 12 acute lymphoblastic leukemia ( ALL ) studies . Ten-year event-free survival ( EFS ) for patients > 12 months of age with B-precursor ALL on acute leukemia in children 14 , 15 and 16 series were 66.7±1.2 % , 68.1±1.4 % and 73.2±2.1 % , respectively . Intermediate dose methotrexate ( ID MTX ; 1 g/m2 ) improved outcomes for st and ard risk patients ( 10-year EFS 77.5±2.7 % vs 66.3±3.1 % for oral MTX ) . Neither MTX intensification ( 2.5 g/m2 ) nor addition of cytosine arabinoside/daunomycin/teniposide  improved outcomes for higher risk patients . Intermediate dose mercaptopurine ( 1 g/m2 ) failed to improve outcomes for either group . Ten-year EFS for patients with T-cell ALL , POG 8704 and 9404 were 49.1±3.1 % and 72.2±4.7 % , respectively . Intensive asparaginase  ( 10-year EFS 61.8 vs 42.7 % ) and high-dose MTX ( 5 g/m2 ) ( 10-year EFS 78.0 vs 65.8 % ) improved outcomes . There was a non-significant improvement in EFS for infants ( 10-year EFS 17.7±7.2–31.9±8.3 % ) . Prognostic indicators for B-precursor ALL were age and WBC at diagnosis , gender , central nervous system disease , DNA index and cytogenetic abnormalities . Only gender was prognostic in T-cell ALL . In infants , WBC and MLL translocation were linked to inferior outcome 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 PURPOSE To determine the cardioprotective effect of dexrazoxane ( DZR ) used in a doxorubicin-based combination therapy in advanced breast cancer . PATIENTS AND METHODS Between November 1988 and January 1991 , 534 patients with advanced breast cancer were r and omized to two multicenter , double-blind studies ( 088001 and 088006 ) . Patients received fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) with either DZR ( DZR-to-doxorubicin ratio , 10:1 ) or placebo ( PLA ) every 3 weeks and were monitored with serial multiplegated acquisition ( MUGA ) scans . RESULTS The hazards ratio ( HR ) of PLA to DZR for a cardiac event , which was predefined ejection fraction changes or congestive heart failure ( CHF ) , was 2.63 ( 95 % confidence interval [ CI ] , 1.61 to 4.27 ; P < .001 ) for 088001 and 2.00 ( 95 % CI , 1.01 to 3.96 ; P = .038 ) for 088006 . The objective response rates for 088001 were 46.8 % for DZR and 60.5 % for PLA , a difference of 14 % ( 95 % CI , -25 % to -2 % ; P = .019 ) , and for 088006 were 53.7 % for DZR and 49.3 % for PLA , a difference of 4 % ( 95 % CI , -13 % to 22 % ; P = .63 ) . Time to progression and survival were not significantly different between treatment arms in either study . Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir ( P = .009 and P = .004 , respectively ) and more pain on injection ( P = .001 ) , with no difference in the rates of fever , infection , or hemorrhage . CONCLUSION DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF . One of the two studies ( 088001 ) showed a lower response rate with DZR , but time to progression and survival were not significantly different . DZR is the first agent shown to reduce cardiotoxicity from doxorubicin Doxorubicin is an effective agent for many malignancies . To limit cardiotoxicity , doxorubicin can be given as prolonged infusion ( PIDX ) or bolus infusion following dexrazoxane ( DZX ) . The authors report their institutional experience comparing PIDX and DZX in a sarcoma cohort . Retrospective record review for newly diagnosed sarcoma patients at the University of Texas M.D. And erson Cancer Center from June 1998 to June 2006 . There were 23 Ewing 's sarcoma ( EWS ) patients treated with DZX and 40 osteosarcoma ( OS ) patients treated with PIDX  . The DZX group had higher mean cumulative anthracycline dose ( 510 mg/m2 [ SD 120 mg/m2 ] versus 414 mg/m2 [ SD 99 mg/m2 ] , P = .002 ) , however mean lowest left ventricular ejection fraction ( EF ) values were higher for DZX ( 52.5 % [ SD 5.6 % ] versus 47.2 % [ SD 10.9 % ] , P = .014 ) . Fifteen of 19 patients  with cardiac dysfunction were PIDX patients ( P = .15 ) . Five PIDX patients required cardiac medication , and 1 patient died of congestive heart failure ( CHF ) . Sixteen patients with cardiac dysfunction had improvement , demonstrated by EF ≥ 50 % at last echocardiogram . Although not statistically significant , there were 4 DZX patients with cardiac dysfunction . Prospect i ve studies are required to determine which strategy has long-term advantages and if certain patients are at increased risk for cardiac dysfunction This manuscript describes the experience from registration until r and omisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial . This includes pre-operative chemotherapy and surgery . It sets out the practical issues in collaboration and in achieving r and omisation BACKGROUND Previous r and omized controlled trials that used the two-drug chemotherapy regimen of cisplatin and doxorubicin as the conventional arm showed no evidence of benefit from an increase in the number of agents or the length of treatment . It was then proposed that survival could be improved by increasing the planned dose intensity of cisplatin and doxorubicin . METHODS Previously untreated patients with nonmetastatic , high- grade , central osteosarcoma of an extremity were r and omly assigned to Regimen-C ( conventional treatment with six 3-week cycles of cisplatin [ 100 mg/m2 by 24-hour infusion ] and doxorubicin [ 25 mg/m2/day by 4-hour infusion for 3 days ] ) or to Regimen-DI ( intensified treatment with identical total doses of cisplatin and doxorubicin , planned as six 2-week cycles supported by granulocyte colony stimulating factor ( G-CSF ) . Surgery was scheduled for week 6 in both arms . Primary and secondary outcome measures were overall and progression-free survival , respectively . Intention-to-treat analyses were performed using st and ard survival analysis methods . L and mark analyses were performed in patients with known surgical details and central ly review ed histologic response . All statistical tests were two-sided . RESULTS Between May 1993 and September 2002 , treatment was r and omly allocated to 497 eligible patients . Six cycles of chemotherapy were completed by 78 % of patients in Regimen-C and 80 % of patients in Regimen-DI . The delivered preoperative median dose intensity of cisplatin was 86 % in Regimen-C and 111 % in Regimen-DI ( as the percentage of that planned for the conventional regimen ) . Postoperative median dose intensity of cisplatin was 82 % in Regimen-C and 110 % in Regimen-DI ( the corresponding figures for doxorubicin dose intensity were similar ) . Regimen-DI was associated with lower risks of severe leucopenia and neutropenia and higher risks of thrombocytopenia and mucositis . Good histologic response ( >  
    Output:
    
On the basis of our model , current dosing regimens — doxorubicin doses > 375 mg/m2 without dexrazoxane — overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity .