***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: 632 Background : Following the BCIRG 001 , PACS 01 and HERA trials , this r and omised , multicentre , open-label , Phase III trial was design ed to demonstrate the benefit of concomitant docetaxel and epirubicin versus anthracyclines , and evaluate the use of sequential trastuzumab . METHODS Patients ( pts ) with localised , resectable , unilateral breast cancer who met the following criteria were eligible : age < 65 years , ≥1 positive node , M0 , adequate heart and organ functions . Pts were r and omised to receive either 6 cycles of 5-fluorouracil-epirubicin-cyclophosphamide ( FEC100 : F and C , 500 mg/m2 , E 100 mg/m2 ) ( Arm A ) or epirubicin-docetaxel ( ET75 : E 75 mg/m2 , T 75 mg/m2 ) ( Arm B ) . Primary prophylaxis with G-CSF was not planned . Radiotherapy was m and atory after conservative surgery and tamoxifen was required in pts with hormone receptor-positive tumours . Pts with HER2-positive disease were then further r and omised to observation only or to 1 year of trastuzumab monotherapy ( 6 mg/kg iv every 3 weeks ) . In HER2-positive pts receiving trastuzumab , left ventricular ejection fraction ( LVEF ) was determined at Cycles 2 , 4 , 8 , 13 , 18 and after 2 years . Otherwise , LVEF was determined at baseline and at 1 year post-surgery . RESULTS Of the 3010 pts recruited ( 2622 evaluable for safety to date ) , 1518 received FEC100 and 1492 received ET75 after the first r and omisation . Haematologic toxicity was the most frequent toxicity in both arms . Grade 3 - 4 toxicities were similar for Arms A and B , except febrile neutropenia ( 10.3 % and 31.4 % , respectively ) and nausea/vomiting ( 13.2 % and 7.5 % , respectively ) . Grade 2 clinical cardiac toxicity ( decreased LVEF ) was observed in 4 pts in Arm A and 5 in Arm B , with median LVEF scores of 63 % in both arms at the end of chemotherapy . HER2-positive pts ( n=500 ) were then r and omised to either receive trastuzumab ( n=259 ) or observation only ( n=241 ) . CONCLUSIONS These preliminary safety data indicate that FEC100 and ET75 were both well tolerated , with acceptable cardiac safety values . The trial is ongoing and further analysis regarding the use of trastuzumab in this setting will be presented . [ Table : see text ] PURPOSE We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant ( HERA ) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy . PATIENTS AND METHODS The HERA trial is a three-group , r and omized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 ( HER2 ) -positive early breast cancer . Eligible patients had normal left ventricular ejection fraction ( LVEF ; > or= 55 % ) after completion of (neo)adjuvant chemotherapy with or without radiotherapy .  Cardiac function was monitored throughout the trial . This analysis considers patients r and omly assigned to 1 year of trastuzumab treatment or observation . RESULTS There were 1,698 patients r and omly assigned to observation and 1,703 r and omly assigned to 1 year of trastuzumab treatment ; 94.1 % of patients had been treated with anthracyclines . The incidence of discontinuation of trastuzumab because of cardiac disorders was low ( 5.1 % ) . At a median follow-up of 3.6 years , the incidence of cardiac end points remained low , though it was higher in the trastuzumab group than in the observation group ( severe CHF , 0.8 % v 0.0 % ; confirmed significant LVEF decreases , 3.6 % v 0.6 % ) In the trastuzumab group , 59 of 73 patients with a cardiac end point reached acute recovery ; of these 59 patients , 52 were considered by the cardiac advisory board ( CAB ) to have a favorable outcome from the cardiac end point . CONCLUSION The incidence of cardiac end points remains low even after longer-term follow-up . The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year , but it remains relatively constant thereafter BACKGROUND We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer . METHODS The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks ( group 1 ) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel ( group 2 ) . The North Central Cancer Treatment Group trial N9831 compared three regimens : doxorubicin and cyclophosphamide followed by weekly paclitaxel ( group A ) , the same regimen followed by 52 weeks of trastuzumab after paclitaxel ( group B ) , and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel ( group C ) . The studies were amended to include a joint analysis comparing groups 1 and A ( the control group ) with groups 2 and C ( the trastuzumab group ) . Group B was excluded because trastuzumab was not given concurrently with paclitaxel . RESULTS By March 15 , 2005 , 394 events ( recurrent , second primary cancer , or death before recurrence ) had been reported , triggering the first scheduled interim analysis . Of these , 133 were in the trastuzumab group and 261 in the control group ( hazard ratio , 0.48 ; P<0.0001 ) . This result crossed the early stopping boundary . The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years . Trastuzumab therapy was associated with a 33 percent reduction in the risk of death ( P=0.015 ) . The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831 . CONCLUSIONS Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer . ( Clinical Trials.gov numbers , NCT00004067 and NCT00005970 . PURPOSE To evaluate the efficacy and safety of docetaxel , cisplatin , and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2 ( HER2 ) -positive , locally advanced breast cancer ( LABC ) . PATIENTS AND METHODS Forty-eight patients with immunohistochemistry-confirmed HER2-positive LABC or inflammatory breast cancer received 12 weeks of  docetaxel , cisplatin , and trastuzumab with filgrastim , followed by surgery , adjuvant doxorubicin and cyclophosphamide , and locoregional radiotherapy with or without tamoxifen . The primary end point was pathologic complete response ( pCR ) in breast . RESULTS Baseline mean tumor size was 9.2 cm ( range , 4 to 32 cm ) . pCR occurred in breast in 11 patients ( 23 % ; 95 % CI , 12 % to 37 % ) and breast and axilla in eight patients ( 17 % ; 95 % CI , 8 % to 30 % ) . pCR rates in breast ( HER2 positive , seven of 30 patients , 23 % v HER2 negative , four of 18 patients , 22 % ; P > .05 ) and breast and axilla ( four of 30 patients , 13 % v four of 18 patients , 22 % , respectively ; P > .05 ) were similar regardless of HER2 status by fluorescence in situ hybridization ( FISH ) . At a median follow-up time of 43 months , 4-year progression-free survival ( PFS ) rate was 81 % ( 95 % CI , 64 % to 90 % ) ; overall survival ( OS ) rate was 86 % ( 95 % CI , 71 % to 94 % ) . In patients with pCR in breast and axilla , PFS and OS rates were 100 % ( 95 % CI , inestimable ) . In patients without pCR , PFS rate was 76 % ( 95 % CI , 57 % to 88 % ; P = .15 , log-rank test ) , and OS rate was 83 % ( 95 % CI , 66 % to 92 % ; P = .21 ) . Survival rates were similar regardless of FISH status . There were only two grade 4 adverse events . CONCLUSION Twelve weeks of docetaxel , cisplatin , and trastuzumab is clinical ly active and leads to excellent survival in patients with large , HER2-positive tumors BACKGROUND Trastuzumab ( T ) combined with chemotherapy has been recently shown to improve outcome in HER2-positive breast cancer ( BC ) . The aim of this study was to evaluate the toxic effects of concurrent radiation therapy ( RT ) and T administration in the adjuvant setting . PATIENTS AND METHODS Data of 146 patients with stages II-III HER2-positive BC were recorded . Median age was 46 years . In all , 32 ( 23 % ) and 114 ( 77 % ) patients received a weekly and a 3-week T schedule , respectively . A median dose of 50 Gy was delivered after surgery . Internal mammary chain ( IMC ) was irradiated in 103 ( 71 % ) patients . RESULTS Grade > 2 dermatitis and esophagitis were noted in 51 % and 12 % , respectively . According to the Common Toxicity Criteria v3.0 scale and HERA ( HERceptin Adjuvant ) trial criteria , respectively , 10 % and 6 % of the patients had a grade > /=2 of left ventricular ejection fraction ( LVEF ) decrease after RT . Multivariate analyses revealed two independent prognostic factors : weekly T administration ( for LVEF decrease ) and menopausal status ( for dermatitis ) . Higher level of T cumulative dose ( > 1600 mg ) was only borderline of statistical significance for acute esophagitis toxicity . CONCLUSION We showed that weekly concurrent T and RT are feasible in daily clinical practice with , however , a decrease of LVEF . Cardiac volume sparing and patient selection s for IMC irradiation are highly recommended . Longer follow-up is warranted to evaluate late toxic effects Despite important progress in underst and ing the molecular factors underlying the development of cancer and the improvement in response rates with new drugs , long-term survival is still disappointing for most common solid tumours . This might be because very little of the modest gain for patients is the result of the new compounds discovered and marketed recently . An assessment of the regulatory agencies ' performance may suggest improvements . The present analysis summarizes and evaluates the type of studies and end points used by the EMEA to approve new anticancer drugs , and discusses the application of current regulations . This report is based on the information available on the EMEA web site . We identified current regulatory requirements for anticancer drugs promulgated by the agency and retrieved them in the relevant directory ; information about empirical evidence supporting the approval of drugs for solid cancers through the central ised procedure were retrieved from the European Public Assessment Report ( EPAR ) . We surveyed documents for drug applications and later extensions from January 1995 , when EMEA was set up , to December 2004 . We identified 14 anticancer drugs for 27 different indications ( 14 new applications and 13 extensions ) . Overall , 48 clinical studies were used as the basis for approval ; r and omised comparative ( clinical ) trial ( RCT ) and Response Rate were the study design and end points most frequently adopted ( respectively , 25 out of 48 and 30 out of 48 ) . In 13 cases , the EPAR explicitly reported differences between arms in terms of survival : the range was 0–3.7 months , and the mean and median differences were 1.5 and 1.2 months . The majority of studies ( 13 out of 27 , 48 % ) involved the evaluation of complete and /or partial tumour responses , with regard to the end points supporting the 27 indications . Despite the recommendations of the current EMEA guidance documents , new anticancer agents are still often approved on the basis of small single arm trials that do not allow any assessment of an ‘ acceptable and extensively documented toxicity profile ’ and of end points such as response rate , time to progression or progression-free survival which at best can be considered indicators of anticancer activity and are not ‘ justified surrogate markers for clinical benefit ’ . Anticipating an earlier than ideal point along the drug approval path and the use of not fully vali date d surrogate end points in nonr and om 
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The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies , but found fewer cardiac toxicities .
Trastuzumab significantly improves OS and DFS in HER2-positive women with early and locally advanced breast cancer , although it also significantly increases the risk of CHF and LVEF decline .
Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy .