***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 Pertuzumab ( P ) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer . We assessed the tolerability , with particular focus on cardiac safety , of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer . PATIENTS AND METHODS In this multicenter , open-label phase II study , patients with operable , locally advanced , or inflammatory breast cancer were r and omized 1 : 1 : 1 to receive six neoadjuvant cycles q3w ( Arm A : 5-fluorouracil , epirubicin , cyclophosphamide [ FEC ] + H + P ×3 → docetaxel [ T ] + H + P ×3 ; Arm B : FEC ×3 → T + H + P ×3 ; Arm C : T + carboplatin + H [TCH]+P ×6 ) . pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS Two hundred twenty-five patients were r and omized . During neoadjuvant treatment , two patients ( 2.7 % ; Arm B ) experienced symptomatic left ventricular systolic dysfunction ( LVSD ) and 11 patients ( Arm A : 4 [ 5.6 % ] ; Arm B : 4 [ 5.3 % ] ; Arm C : 3 [ 3.9 % ] ) had declines in left ventricular ejection fraction of ≥10 % points from baseline to < 50 % . Diarrhea was the most common adverse event . pCR ( ypT0/is ) was reported for 61.6 % ( Arm A ) , 57.3 % ( Arm B ) , and 66.2 % ( Arm C ) of patients . CONCLUSION The combination of P with H and st and ard chemotherapy result ed in low rates of symptomatic LVSD BACKGROUND Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30 - 65 % of patients . We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy . METHODS This r and omised trial was done at 36 centres in the USA and Puerto Rico . Women with operable HER2-positive invasive breast cancer were r and omly assigned ( 1:1 ) with a biased coin minimisation algorithm , stratified for age , tumour size , and hormone receptor status . Neither patients nor investigators ( except for a cardiac safety review panel ) were masked to treatment assignment . Patients r and omly assigned to sequential treatment received fluorouracil 500 mg/m(2 ) , epirubicin 75 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ( FEC-75 ) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2 ) and trastuzumab 2 mg/kg ( after a 4 mg/kg loading dose ) once per week for 12 weeks , while those r and omly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 ( on day 1 of each 21-day cycle ) and once-weekly trastuzumab , in the same doses as the sequential group . Surgery , including evaluation of the axilla , was done within 6 weeks of completion of neoadjuvant treatment . The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT00513292 . FINDINGS From Sept 15 , 2007 , to Dec 15 , 2011 , 282 women were enrolled ( 140 in the sequential group , 142 in the concurrent group ) . Two patients in the sequential group withdrew consent before starting treatment . 78 of 138 ( 56·5 % , 95 % CI 47·8 - 64·9 ) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 ( 54·2 % , 95 % CI 45·7 - 62·6 ) who received concurrent treatment ( difference 2·3 % , 95 % CI -9·3 to 13·9 ) . No treatment-related deaths occurred . The most common severe toxic effects were neutropenia ( 35 [ 25·3 % ] of 138 patients in the sequential group vs 45 [ 31·7 % ] of 142 patients in the concurrent group ) and fatigue ( six [ 4·3 % ] vs 12 [ 8·5 % ] ) . Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one ( 0·8 % ) of 130 patients who received sequential treatment and four ( 2·9 % ) of 137 patients who received concurrent treatment ; by week 24 , it had dropped below this limit in nine ( 7·1 % ) of 126 patients and in six ( 4·6 % ) of 130 patients , respectively . INTERPRETATION Concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted . FUNDING US National Cancer Institute PURPOSE This study sought to estimate cardiac dysfunction ( CD ) risk for patients receiving trastuzumab ;  to characterize observed CD by severity , treatment , and clinical outcome ; to assess effects of baseline clinical risk factors on CD ; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD . PATIENTS AND METHODS A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed . Predefined criteria were used for the diagnosis , and the New York Heart Association functional classification system was used to document CD severity . Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset . RESULTS Patients treated with trastuzumab  were found to be at an increased risk for CD . The incidence was greatest in patients receiving concomitant  trastuzumab and anthracycline plus cyclophosphamide ( 27 % ) . The risk was substantially lower in patients receiving paclitaxel and trastuzumab ( 13 % ) or trastuzumab alone ( 3 % to 7 % ) ; however , most of these patients had received prior anthracycline therapy . CD was noted in 8 % of patients receiving anthracycline plus cyclophosphamide and 1 % receiving paclitaxel alone . Most trastuzumab-treated patients developing CD were symptomatic ( 75 % ) , and most improved with st and ard treatment for congestive heart failure ( 79 % ) . CONCLUSION Trastuzumab is associated with an increased risk of CD , which is greatest in patients receiving concurrent anthracyclines . In most patients with metastatic breast cancer , the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab Background A r and omized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER-2 . Patients and methods Among 124 patients r and omized , 123 are assessable for toxicity and 118 for response . Patients received weekly paclitaxel single agent ( 80 mg/m2 ) or combined with trastuzumab ( 4 mg/kg loading dose , then weekly 2 mg/kg ) . HER-2 overexpression was determined by immunohistochemistry ( IHC ) . Patients with 2+/3 + IHC scores were eligible . IHC was compared with HER-2 serum extracellular domain ( ECD ) . Results Patient characteristics were similar in the two arms . Both treatments were feasible and well tolerated with no grade 4 hematologic toxicity . No patient developed cardiac toxicity . The combined treatment was statistically significant superior for overall response rate ( ORR ) ( 75 % vs. 56.9 % ; P = 0.037 ) , particularly in the subset of IHC 3 + patients ( 84.5 % vs. 47.5 % ; P = 0.00050 ) . A statistically significant better median time to progression was seen in the subgroup with IHC 3 + ( 369 vs. 272 days ; P = 0.030 ) and visceral disease ( 301 vs. 183 days ; P = 0.0080 ) treated with combination . Multivariable analysis of predictive factors showed that only IHC score retained statistically significant value for ORR ( P = 0.0035 ) . Conclusion Weekly paclitaxel plus trastuzumab is highly active and safe and it is superior to paclitaxel alone in patients with IHC score of 3 + 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 omised trials looks like a dangerous shortcut that might jeopardise consumers ' health , leading to unsafe and ineffective drugs being marketed and prescribed . The present Note for Guidance for new anticancer agents needs revising . Drugs must be rapidly released for patients who need them but not be at the expense of adequate knowledge about the real benefit of the drugs PURPOSE Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer . In the German Breast Group 26/Breast International Group 03 - 05 trial , we investigated if trastuzumab treatment should be continued beyond progression . METHODS Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were r and omly assigned to receive capecitabine ( 2,500 mg/m(2 ) body-surface area on days 1 through 14 [ 1,250 mg/m(2 ) semi-daily ] ) alone or with continuation of trastuzumab ( 6 mg/kg body weight ) in 3-week cycles . The primary end point was time to progression . RESULTS We r and omly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab .  Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up . Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 ( 95 % CI , 0.48 to 0.97 ; two-sided log-rank P = .0338 ) . Overall survival rates were 20.4 months ( 95 % CI , 17.8 to 24.7 ) in the capecitabine group and 25.5 months ( 95 % CI , 19.0 to 30.7 ) in the capecitabine-plus-trastuzumab group ( P = .257 ) . Overall response rates were 27.0 % with capecitabine and 48.1 % with capecitabine plus trastuzumab ( odds ratio , 2.50 ; P = .0115 ) . Continuation of trastuzumab beyond progression was not associated with increased toxicity . CONCLUSION Continuation of trastuzumab plus capecit 
    Output:
    
For haematological toxicities , such as neutropenic fever and anaemia , there was no clear evidence that risks differed between groups , while trastuzumab seemed to raise the risk of neutropenia .
The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens .
The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens , and patients treated as first-line or subsequent lines .
Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer , but it also increased the risk of cardiac toxicities , such as congestive heart failure and LVEF decline .