***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: PURPOSE Dose-dense doxorubicin and cyclophosphamide ( AC ) followed by paclitaxel and trastuzumab ( PT ) is feasible . Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 ( HER2 ) -positive metastatic breast cancer . We conducted a pilot study of dose-dense AC followed by PT plus lapatinib ( PTL ) followed by trastuzumab plus lapatinib ( TL ) . PATIENTS AND METHODS Patients with stages I to III , HER2-positive breast cancer and left ventricular ejection fraction ( LVEF ) of > or = 50 % were enrolled . Treatment consisted of AC ( 60 mg/m(2 ) and 600 mg/m(2 ) ) for 4 cycles every 2 weeks ( with pegfilgrastim 6 mg on day 2 ) followed by paclitaxel ( 80 mg/m(2 ) ) for 12 doses weekly plus trastuzumab and lapatinib . Trastuzumab ( 4 mg/kg loading dose , then 2 mg/kg weekly during paclitaxel then 6 mg/kg every 3 weeks after paclitaxel ) and lapatinib ( 1,000 mg daily ) were given for 1 year . The primary end points were feasibility defined as > or = 80 % patients completing the PTL phase without a dose delay/reduction and a cardiac event rate of < or = 4 % . RESULTS From March 2007 to April 2008 , we enrolled 95 patients . Median age was 46 years ( range , 28 to 73 years ) . At a median follow-up of 22 months , 92 were evaluable . Of the 92 patients , 41 patients ( 45 % ) withdrew for PTL-specific toxicities . Overall , 40 ( 43 % ) of 92 patients had lapatinib dose reductions , and 27 ( 29 % ) of 92 patients had grade 3 diarrhea . Three patients ( 3 % ) had congestive heart failure ; three patients dropped out because of significant asymptomatic LVEF decline during PTL followed by TL . CONCLUSION Dose-dense AC followed by PTL and then followed by TL was not feasible because of a high rate of lapatinib dose reduction , mostly caused by unacceptable grade 3 diarrhea . Lapatinib ( 1,000 mg/d ) was not feasible combined with weekly PT We evaluated the survival benefit , safety , feasibility , and tolerability of dose-dense ( DD ) adjuvant chemotherapy with epirubicin and paclitaxel for women with node-positive primary breast cancer . R and omised patients ( n=216 ) received DD or conventional-schedule ( CS ) chemotherapy . Dose-dense regimen patients ( n=108 ) received epirubicin 90 mg m−2 plus paclitaxel 175 mg m−2 in four 14-day cycles , then cyclophosphamide 600 mg m−2 , methotrexate 40 mg m−2 , and fluorouracil 600 mg m−2 ( CMF 600/40/600 ) in three 14-day cycles , plus filgrastim 5 μg kg day−1 as growth support in every cycle . Conventional-schedule regimen patients ( n=108 ) received epirubicin 90 mg m−2 plus cyclophosphamide 600 mg m−2 in four 21-day cycles , then CMF 600/40/600 in three 21-day cycles , plus filgrastim if required . After a median follow-up of 38.4 months , 71 patients ( 33 % ) relapsed or died : DD , 33 patients ( 15 deaths ) ; CS , 38 patients ( 22 deaths ) . Dose dense showed a trend for improved disease-free survival ( DFS ) and overall survival ( OS ) . Four-year rates of DFS and OS were 64 and 85 % for DD , and 58 and 75 % for CS . All seven cycles were administered to 208 patients ( 96 % ) . Rates of cycle delay , discontinuation , dose reduction , and adverse events were similar in both groups . Dose-dense sequential chemotherapy with epirubicin/paclitaxel then CMF , supported by filgrastim , is safe and improves survival for patients with node-positive breast cancer BACKGROUND To determine whether a dose-dense regimen improves outcome in early breast cancer patients , we compared outcomes with the same fluorouracil , epirubicin , and cyclophosphamide ( FEC ) chemotherapeutic regimen administered every 3 weeks ( FEC21 ) or administered every 2 weeks ( FEC14 including support with filgrastim , a granulocyte colony-stimulating factor ) in a multicenter phase III r and omized trial . METHODS A total of 1214 patients with early-stage breast cancer were r and omly assigned to receive six cycles of FEC14 ( 604 patients ) or of FEC21 ( 610 patients ) . Study endpoints were overall survival and event-free survival . Associations were assessed by multivariable analysis with adjustment for age ; tumor size ; grade ; proliferative rate ; and menopausal , lymph node , estrogen receptor , and progesterone receptor status . All statistical tests were two-sided . RESULTS Patients in the FEC14 arm had fewer dose reductions or treatment delays or discontinuation ( 26 % ) than those in the FEC21 arm ( 33 % ) ( difference = 7 % , 95 % confidence interval [ CI ] = 2 % to 12 % ; P = .008 ) . FEC14 therapy , compared with FEC21 therapy , was associated with more asthenia ( 36 % versus 29 % , difference = 7 % , 95 % CI = 2 % to 12 % ; P = .01 ) , bone pain ( 33 % versus 4 % , difference = 29 % , 95 % CI = 25 % to 33 % ; P < .001 ) , anemia ( 38 % versus 19 % , difference = 19 % , 95 % CI = 14 % to 24 % ; P < .001 ) , and thrombocytopenia ( 8 % versus 2 % , difference = 6 % , 95 % CI = 4 % to 9 % ; P < .001 ) , but with less leukopenia ( 12 % versus 45 % , difference = 33 % , 95 % CI = 28 % to 37 % ; P < .001 ) . No acute myelogenous leukemia or myelodysplastic syndrome was observed . At a median follow-up of 10.4 years , no statistically significant difference in the hazard of death ( hazard ratio [ HR ] = 0.87 , 95 % CI = 0.67 to 1.13 ) or recurrence ( HR = 0.88 , 95 % CI = 0.71 to 1.08 ) was found between FEC14 and FEC21 groups after adjustment by multivariable analysis . Although the study was underpowered for subset analysis , we found no evidence that the effect of the treatment type was associated with any of the potential prognostic factors . CONCLUSION Our results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer . However , this therapy was not associated with improved outcome , but because of the limited statistical power of our study , we can not rule out a modest improvement in outcome associated with FEC14 therapy 513 Background : Dose-dense chemotherapy will become a new treatment option in breast cancer patients ( pts ) ( INT C9741 ) . Here we report the initial results of a second prospect i ve r and omized trial that compares dose-dense vs. conventionally scheduled sequential chemotherapy in high-risk node positive pts . METHODS A multi-center phase-III trial of the German " Arbeitsgemeinschaft fuer Gynaekologische Onkologie ( AGO ) " recruited 1284 pts from 12/98 until 4/03 . Pts below 65 years of age were eligible if they had at least 4 involved axillary lymph nodes . In the experimental arm , pts were assigned to receive three courses each of epirubicin(150 mg/m2 ) , paclitaxel ( 225 mg/m2 ) and cyclophosphamide ( 2500 mg/m2 ) at 2 weeks interval ( q2wks ) ( ETC ) with G-CSF support ( 5μg/kg/SC day 3 - 10 ) . A second r and omization ± Epoetin-alpha was performed ( 150 IU/kg/SC three times weekly ) . In the st and ard arm 4 courses of conventional dosed epirubicin/cyclophosphamide ( 90/600 mg/m2 ) followed by 4 courses of paclitaxel ( 175 mg/m2 ) ( q3wks ) were given . RESULTS  Median patient age was 50 years . Risk factors were well balanced in both arms . 59 % and 41 % of the pts had 4 - 9 and ≥10 infiltrated nodes . The median number of positive nodes was 8 . In this second interim analysis 1169 pts were fully evaluable . No unusual toxicities were seen , especially no severe cardiotoxicity . Hematological toxicity ( anemia , neutropenia and thrombopenia ) was more frequent in the ETC arm ( p<0,0001 ) and varied distinctly between drugs . The incidence was highest during treatment with cyclophosphamide and lowest during treatment with paclitaxel . 7 % of pts in the ETC arm vs. 2 % in the st and ard arm were hospitalized for febrile neutropenia ( p<0,0001 ) . There were no treatment-related deaths during therapy . 82 % of pts in the ETC arm vs. 90 % in the st and ard arm received the planned number of cycles . The number of dose reductions was relatively small , ranging from 6,5 % on the ETC arm to 2 % on the st and ard arm . At a median follow-up of 28 months 94 pts in the ETC arm vs. 127 pts in the st and ard arm had relapsed . This difference was highly significant in the two-sided log-rank test ( p=0,0009 ) with a HR of 0,64 ( 95 % CI : 0,49 - 0,83 ) . Estimated 3-year RFS is 80 % in the ETC arm vs. 70 % in the st and ard arm . 103 pts have died ( 43 events vs. 60 events ) favoring again the ETC arm ( two-sided log-rank test : p=0,030 ; HR : 0,65 ( 95 % CI : 0,44 - 0,96 ) . Estimated 3-year OAS is 90 % in the ETC arm vs. 87 % in the st and ard arm . There was a highly significant difference in anemia grade 1 - 4 as well as in the number of RBC 's transfusions between ETC ± Epoetin alpha ( p<0,0001 ) . No difference in DFS ( p=0,84 ) or OAS ( p=0,98 ) was found between ETC ± Epoetin alpha . CONCLUSIONS Evidence to date indicates that the dose-dense ETC-regimen as adjuvant therapy in high-risk breast cancer pts is well tolerated and significantly improves DFS and OAS . Confirming the results of INT C9741 , dose-dense sequential regimens may become a future st and ard option in the adjuvant treatment of node positive breast cancer pts . [ Table : see text ] PURPOSE Dose-dense and sequential administration of cytotoxic drugs are current approaches to improve outcomes in patients with early-stage breast cancer . METHODS This phase III study investigated 913 women with untreated operable breast cancer ( T2 - 3 , N0 - 2 , M0 ) r and omly assigned to receive either doxorubicin 50 mg/m2 plus docetaxel 75 mg/m2 every 14 days for four cycles with filgrastim support ( ADOC ) , or doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 21 days followed by docetaxel 100 mg/m2 every 21 days for four cycles each ( AC-DOC ) . The primary end point was the incidence of pathologic complete ( invasive and noninvasive ) response ( pCR ) in the breast and axillary nodes . Secondary end points were predictors for pCR , clinical response , rate of breast conservation , and safety . RESULTS A pCR was achieved in 94 patients ( 10.6 % ) , but the likelihood was significantly greater with AC-DOC ( 14.3 % ; n = 63 ) than with ADOC ( 7.0 % ; n = 31 ) ( odds ratio , 2.22 ; 90 % CI , 1.52 to 3.24 ; P < .001 ) . Independent predictors of attaining a pCR included the use of sequential therapy , high tumor grade , and negative hormone receptor status . The response rates detected by palpation and by imaging were significantly higher with AC-DOC ( 85.0 % and 78. 
    Output:
    
The advantages of meta- analysis include higher statistical power than a small individual study ; a meta- analysis also allows for generalizations to the studied population .