***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: BACKGROUND A r and omized phase III trial in high-risk breast cancer patients was conducted , to further explore the impact of dose-density in the adjuvant treatment for breast cancer . The safety analysis is presented . PATIENTS AND METHODS From October 2000 until June 2005 , 1121 node-positive patients were r and omized to sequential dose-dense epirubicin 110 mg/m(2 ) and paclitaxel ( Taxol , Bristol Myers-Squibb , Princeton , New Jersey , USA ) 250 mg/m(2 ) ( group A ) , or concurrent epirubicin 83 mg/m(2 ) and paclitaxel 187 mg/m(2 ) ( group B ) , both followed by three cycles of ' intensified ' combination chemotherapy with cyclophosphamide , methotrexate and fluorouracil ( CMF ) . Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments . RESULTS Median dose intensity of epirubicin and paclitaxel was double in group A , as design ed , with significantly less cycles administered at full dose ( P < 0.001 ) . Median cumulative dose of all drugs and total treatment duration , however , were identical between groups . Severe taxane-related toxic effects were more frequent in group A , while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects , including febrile neutropenia . The rates of secondary malignancies were low . CONCLUSION Both regimens as used in the present study are well tolerated and safe . The rates of severe taxane-related toxic effects and thrombocytopenia , although low overall , are significantly increased with the dose-dense sequential regimen PURPOSE This study was design ed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a st and ard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival . PATIENTS AND METHODS After surgical treatment , 3,121 women with operable breast cancer and involved lymph nodes were r and omly assigned to receive a combination of cyclophosphamide ( C ) , 600 mg/m(2 ) , with one of three doses of doxorubicin ( A ) , 60 , 75 , or 90 mg/m(2 ) , for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2 ) . Tamoxifen was given to 94 % of patients with hormone receptor-positive tumors . RESULTS There was no evidence of a  doxorubicin dose effect . At 5 years , disease-free survival was 69 % , 66 % , and 67 % for patients r and omly assigned to 60 , 75 , and 90 mg/m(2 ) , respectively . The hazard reductions from adding paclitaxel to CA were 17 % for recurrence ( adjusted Wald chi(2 ) P = .0023 ; unadjusted Wilcoxon P = .0011 ) and 18 % for death ( adjusted P = .0064 ; unadjusted P = .0098 ) . At 5 years , the disease-free survival ( + /- SE ) was 65 % ( + /- 1 ) and 70 % ( + /- 1 ) , and overall survival was 77 % ( + /- 1 ) and 80 % ( + /- 1 ) after CA alone or CA plus paclitaxel , respectively . The effects of adding paclitaxel were not significantly different in subsets defined by the protocol , but in an unplanned subset analysis , the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 ( 95 % confidence interval , 0.59 to 0.86 ) for those with estrogen receptor-negative tumors and only 0.91 ( 95 % confidence interval , 0.78 to 1.07 ) for patients with estrogen receptor-positive tumors , almost all of whom received adjuvant tamoxifen . The additional toxicity from adding four cycles of paclitaxel was generally modest . CONCLUSION The addition of four cycles of paclitaxel after the completion of a st and ard course of CA improves the disease-free and overall survival of patients with early breast cancer BACKGROUND AND OBJECTIVES : Doxorubicin , effective against many malignancies , is limited by cardiotoxicity . Continuous-infusion doxorubicin , compared with bolus-infusion , reduces early cardiotoxicity in adults . Its effectiveness in reducing late cardiotoxicity in children remains uncertain . We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia ( ALL ) . METHODS : The Dana-Farber Cancer Institute ALL Consortium Protocol 91 - 01 enrolled pediatric patients between 1991 and 1995 . Newly diagnosed high-risk patients were r and omly assigned to receive a total of 360 mg/m2 of doxorubicin in 30 mg/m2 doses every 3 weeks , by either continuous ( over 48 hours ) or bolus-infusion ( within 15 minutes ) . Echocardiograms at baseline , during , and after doxorubicin therapy were blindly remeasured central ly . Primary outcomes were late left ventricular ( LV ) structure and function . RESULTS : A total of 102 children were r and omized to each treatment group . We analyzed 484 serial echocardiograms from 92 patients ( n = 49 continuous ; n = 43 bolus ) with ≥1 echocardiogram ≥3 years after assignment . Both groups had similar demographics and normal baseline LV characteristics . Cardiac follow-up after r and omization ( median , 8 years ) showed changes from baseline within the r and omized groups ( depressed systolic function , systolic dilation , reduced wall thickness , and reduced mass ) at 3 , 6 , and 8 years ; there were no statistically significant differences between r and omized groups . Ten-year ALL event-free survival rates did not differ between the 2 groups ( continuous-infusion , 83 % versus bolus-infusion , 78 % ; P = .24 ) . CONCLUSIONS : In survivors of childhood high-risk ALL  , continuous-infusion doxorubicin , compared with bolus-infusion , provided no long-term cardioprotection or improvement in ALL event-free survival , hence provided no benefit over bolus-infusion A phase II study utilizing VP-16 and adriamycin in a r and omized fashion tested the concept of synchronization of the drugs in treatment of metastatic breast cancer . Although there was a trend in median survival following the synchronized schedule , there was no significant difference in survival or progression-free intervals . The concept of synchronization was not established The Dana-Farber Cancer Institute ( DFCI ) acute lymphoblastic leukemia ( ALL ) Consortium Protocol 91 - 01 was design ed to improve the outcome of children with newly diagnosed ALL while minimizing toxicity . Compared with prior protocol s , post-remission therapy was intensified by substituting dexamethasone for prednisone and prolonging the asparaginase intensification from 20 to 30 weeks .  Between 1991 and 1995 , 377 patients ( age , 0 - 18 years ) were enrolled ; 137 patients were considered st and ard risk ( SR ) , and 240 patients were high risk ( HR ) . Following a 5.0-year median follow-up , the estimated 5-year event-free survival ( EFS ) + /- SE for all patients was 83 % + /- 2 % , which is superior to prior DFCI ALL Consortium protocol s conducted between 1981 and 1991 ( P = .03 ) . There was no significant difference in 5-year EFS based upon risk group ( 87 % + /- 3 % for SR and 81 % + /- 3 % for HR , P = .24 ) . Age at diagnosis was a statistically significant prognostic factor ( P = .03 ) , with inferior outcomes observed in infants and children 9 years or older . Patients who tolerated 25 or fewer weeks of asparaginase had a significantly worse outcome than those who received at least 26 weeks of asparaginase ( P < .01 , both univariate and multivariate ) . Older children ( at least 9 years of age ) were significantly more likely to have tolerated 25 or fewer weeks of asparaginase ( P < .01 ) . Treatment on Protocol 91 - 01 significantly improved the outcome of children with ALL , perhaps due to the prolonged asparaginase intensification and /or the use of dexamethasone . The inferior outcome of older children may be due , in part , to increased intolerance of intensive therapy A prospect i ve r and omized trial was conducted to compare the cardiotoxic and therapeutic effects of doxorubicin ( 60 mg/m2 every 3 to 4 weeks ) administered by bolus or 72‐hour continuous infusion as adjuvant chemotherapy in 82 eligible patients after resection of high‐ grade soft tissue sarcoma of the extremity or superficial trunk .  Cardiac toxicity , defined as a 10 % or greater decrease in left ventricular ejection fraction as assessed by radionuclide cineangiography , was evaluated in 69 patients .  Cardiotoxicity was seen in 61 % of patients in the bolus treatment arm with the median doxorubicin dose of 420 mg/m2 . Among patients who received continuous infusion , 42 % had cardiotoxicity with a median dose of 540 mg/m2 . The rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was significantly higher in the bolus treatment arm ( P = 0.0017 ) . Two patients in each group had clinical congestive heart failure , with one cardiac death occurring in each . There was a trend toward a lower rate of metastasis ( P = 0.19 ) and a significantly lower rate of death of disease ( P = 0.036 ) for patients treated with the bolus dose . Cox model analysis identified three unfavorable characteristics for the rate of developing a distant metastasis : blood transfusion within 24 hours of operation ( P < 0.00001 ) , tumor deep to the fascia and 5 cm or more in size ( P = 0.0043 ) , and a histologic subtype other than liposarcoma ( P = 0.0002 ) . The unfavorable effect of continuous infusion was not selected in the model ( P = 0.16 ) . Adjuvant chemotherapy for patients with soft tissue sarcoma is investigational . Furthermore , the impact of perioperative blood transfusion merits further study PURPOSE Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional  adjuvant therapy .  We compared intense dose-dense ( IDD ) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer . PATIENTS AND METHODS In this r and omized , phase III trial , a total of 1,284 eligible patients with four or more involved axillary lymph nodes were r and omly assigned to receive IDD sequential epirubicin , paclitaxel , and cyclophosphamide ( IDD-ETC ) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks . The primary end point was event-free survival ( EFS ) . RESULTS At a median follow-up of 62 months , 5-year event-free survival rates were 62 % in the conventional arm and 70 % in the IDD-ETC arm , representing a 28 % reduction of the relative risk of relapse ( P < .001 ) . This benefit was independent of menopausal , hormone receptor , or human epidermal growth factor receptor 2 status . The 5-year overall survival rates were 77 % versus 82 % , representing a 24 % reduction of the relative risk of death ( P = .0285 ) . IDD therapy was associated with significantly more nonhematologic and hematologic toxicities , but no treatment-related death occurred . Four occurrences of acute myeloid leukemia or myelodysplastic syndrome ( MDS ) were observed in the IDD-ETC arm . No severe congestive heart failure was reported . CONCLUSION IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes Forty-eight patients with advanced breast carcinoma who had not received prior chemotherapy ( minimum follow up 21 months ) were r and omised to receive either adriamycin 70 mg m-2 i.v . 3-weekly for 8 cycles ( Regimen A ) or adriamycin 35 mg m-2 i.v . 3-weekly for 16 courses ( Regimen B ) . Objective responses were seen in 14/24 ( 58 % ) patients with regimen A ( 4 complete ) and 6/24 ( 25 % ) with regimen B ( 1 complete ) ( P less than 0.02 ) . The median duration of response was 14 months with regimen A and 6.5 months with regimen B. The median duration of survival was 20 months and 8 months respectively ( P less than 0.01 ) . The toxicity was similar with each reg 
    Output:
    
An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure , and it seems to reduce the risk of sub clinical cardiac damage .