***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 Neratinib , an irreversible tyrosine-kinase inhibitor of HER1 , HER2 , and HER4 , has clinical activity in patients with HER2-positive metastatic breast cancer . We aim ed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer . METHODS We did this multicentre , r and omised , double-blind , placebo-controlled , phase 3 trial at 495 centres in Europe , Asia , Australia , New Zeal and , and North and South America . Eligible women ( aged ≥18 years , or ≥20 years in Japan ) had stage 1 - 3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before r and omisation . Inclusion criteria were amended on Feb 25 , 2010 , to include patients with stage 2 - 3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously . Patients were r and omly assigned ( 1:1 ) to receive oral neratinib 240 mg per day or matching placebo . The r and omisation sequence was generated with permuted blocks stratified by hormone receptor status ( hormone receptor-positive [ oestrogen or progesterone receptor-positive or both ] vs hormone receptor-negative [ oestrogen and progesterone receptor-negative ] ) , nodal status ( 0 , 1 - 3 , or ≥4 ) , and trastuzumab adjuvant regimen ( sequentially vs concurrently with chemotherapy ) , then implemented central ly via an interactive voice and web-response system . Patients , investigators , and trial sponsors were masked to treatment allocation . The primary outcome was invasive disease-free survival , as defined in the original protocol , at 2 years after r and omisation . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00878709 . FINDINGS Between July 9 , 2009 , and Oct 24 , 2011 , we r and omly assigned 2840 women to receive neratinib ( n=1420 ) or placebo ( n=1420 ) . Median follow-up time was 24 months ( IQR 20 - 25 ) in the neratinib group and 24 months ( 22 - 25 ) in the placebo group . At 2 year follow-up , 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group ( stratified hazard ratio 0·67 , 95 % CI 0·50 - 0·91 ; p=0·0091 ) . The 2-year invasive disease-free survival rate was 93·9 % ( 95 % CI 92·4 - 95·2 ) in the neratinib group and 91·6 % ( 90·0 - 93·0 ) in the placebo group . The most common grade 3 - 4 adverse events in patients in the neratinib group were diarrhoea ( grade 3 , n=561 [ 40 % ] and grade 4 , n=1 [ < 1 % ] vs grade 3 , n=23 [ 2 % ] in the placebo group ) , vomiting ( grade 3 , n=47 [ 3 % ] vs n=5 [ < 1 % ] ) , and nausea ( grade 3 , n=26 [ 2 % ] vs n=2 [ < 1 % ] ) . QT prolongation occurred in 49 ( 3 % ) patients given neratinib and 93 ( 7 % ) patients given placebo , and decreases in left ventricular ejection fraction ( ≥ grade 2 ) in 19 ( 1 % ) and 15 ( 1 % ) patients , respectively . We recorded serious adverse events in 103 ( 7 % ) patients in the neratinib group and 85 ( 6 % ) patients in the placebo group . Seven ( < 1 % ) deaths ( four patients in the neratinib group and three patients in the placebo group ) unrelated to disease progression occurred after study drug discontinuation . The causes of death in the neratinib group were unknown ( n=2 ) , a second primary brain tumour ( n=1 ) , and acute myeloid leukaemia ( n=1 ) , and in the placebo group were a brain haemorrhage ( n=1 ) , myocardial infa rct ion ( n=1 ) , and gastric cancer ( n=1 ) . None of the deaths were attributed to study treatment in either group . INTERPRETATION Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer . Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained . FUNDING Wyeth , Pfizer , Puma Biotechnology Dual epidermal growth factor receptor ( EGFR ) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2-positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models . Ki-67 labeling index ( LI ) has prognostic and predictive value and can be used to screen drugs ' therapeutic and preventive potential in a clinical model of short-term presurgical therapy of breast cancer . We conducted a r and omized , placebo-controlled trial of lapatinib ( 1500 mg/d ) administered orally for three weeks between biopsy and surgery in 60 women with HER-2–positive breast cancer to assess lapatinib biomarker ( including the primary endpoint , Ki-67 LI ) and clinical activity in invasive breast cancer , adjacent ductal intraepithelial neoplasia ( DIN , which comprises ductal carcinoma in situ and atypical ductal hyperplasia ) , and distant ductal hyperplasia without atypia ( DH ) . Ki-67 LI increased progressively in association with disease stage , increasing in the placebo arm , for example , by medians of 3 % in DH to 20 % in DIN to 30 % in invasive cancer . Ki-67 LI in cancer tissue decreased by a mean ( ±SD ) of 9.3 % ( ±34.2 ) in the lapatinib arm and increased by 15.1 % ( ±30.9 ) in the placebo arm ( P = 0.008 ) . Compared with placebo , lapatinib reduced Ki-67 significantly more in ER-negative tumors ( by 34.8 % ; P = 0.01 ) but not significantly more in ER-positive tumors ( by 12.3 % ; P = 0.2 ) and reduced Ki-67 more ( nonsignificantly ) in cytosol PTEN-overexpressing tumors ( P = 0.057 ) . The prevalence of DIN in post-treatment surgical specimens of both arms was similar ( 70%–76 % ) , with a median Ki-67 of 15 % ( range , 5%–35 % ) on lapatinib versus 20 % ( 5%–60 % ) on placebo ( P = 0.067 ) . The prevalence of DH also was similar in both arms ( > 90 % ) , with a median Ki-67 of 1 % ( 1%–7 % ) on lapatinib versus 3 % ( 1%–5 % ) on placebo ( P = 0.006 ) . Other results of lapatinib versus placebo , respectively , were as follows : Median tumor diameter at surgery of 18 mm ( 11 mm–57 mm ) versus 24 mm ( 10 mm–37 mm ; P = 0.009 ) ; partial response of 13.6 % versus 3.7 % , stable disease of 59.1 % versus 40.7 % , and progression of 27.3 % versus 55.6 % ( P-trend = 0.035 ) . In conclusion , short-term lapatinib decreased cell proliferation in DIN , DH , and invasive HER-2–positive ( especially ER-negative ) breast cancer , thus providing the rationale for further clinical development of lapatinib for breast cancer prevention in high-risk patients , including those with HER-2–positive DIN . Cancer Prev Res ; 4(8 ) ; 1181–9 . © 2011 AACR On May 5 , 2003 , gefitinib ( Iressa ; ZD1839 ) 250-mg tablets ( AstraZeneca Inc. ) received accelerated approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies . Information provided in this summary includes chemistry manufacturing and controls , clinical pharmacology , and clinical trial efficacy and safety results . Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine , N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy ] . It has the molecular formula C22H24ClFN4O3 . Gefitinib is often referred to as a “ specific ” or “ selective ” inhibitor of epidermal growth factor receptor . Studies demonstrate , however , that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal . Maximum plasma concentrations result ing from clinical ly relevant doses are 0.5–1 μm or more , well within the IC50 values of several tyrosine kinases . No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to  gefitinib . Gefitinib is 60 % available after oral administration and is widely distributed throughout the body . Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme . Over a 10-day period , approximately 86 % of an orally administered radioactive dose is recovered in the feces , with < 4 % of the dose in the urine . After daily oral administration , steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses . Gefitinib  effectiveness was demonstrated in a r and omized , double-blind , Phase II , multicenter trial comparing two oral doses of gefitinib ( 250 versus 500 mg/day ) . A total of 216 patients were enrolled . The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis . A partial tumor response occurred in 14 % ( 9 of 66 ) of patients receiving 250 mg/day gefitinib and in 8 % ( 6 of 76 ) of patients receiving 500 mg/day gefitinib . The overall objective response rate ( RR ) for both doses combined was 10.6 % ( 15 of 142 patients ; 95 % confidence interval , 6.0–16.8 % ) . Responses were more frequent in females and in nonsmokers . The median duration of response was 7.0 months ( range , 4.6–18.6 + months ) . Other su bmi tted data included the results of two large trials conducted in chemotherapy-naive , stage III and IV non-small cell lung cancer patients . Patients were r and omized to receive gefitinib ( 250 or 500 mg daily ) or placebo  , in combination with either gemcitabine plus cisplatin ( n = 1093 ) or carboplatin plus paclitaxel ( n = 1037 ) . Results from this study showed no benefit ( RR , time to progression , or survival ) from adding gefitinib to chemotherapy . Consequently , gefinitib is only recommended for use as monotherapy . Common adverse events associated with gefitinib treatment included diarrhea , rash , acne , dry skin , nausea , and vomiting . Interstitial lung disease has been observed in patients receiving gefitinib . Worldwide , the incidence of interstitial lung disease was about 1 % ( 2 % in the Japanese post-marketing experience and about 0.3 % in a United States exp and ed access program ) . Approximately one-third of the cases have been fatal . Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point , RR . No controlled gefitinib trials , to date , demonstrate a clinical benefit , such as improvement in disease-related symptoms or increased survival . Accelerated approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit Background : Lapatinib is a dual inhibitor of epidermal growth factor receptor ( EGFR ) and human EGFR-2 ( HER-2 ) tyrosine kinases . This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . Methods : In total , 107 therapy-naive patients with locally advanced SCCHN were r and omised ( 2 : 1 ) to receive lapatinib or placebo for 2–6 weeks before chemoradiation therapy ( CRT ) . Endpoints included apoptosis and proliferation rates , clinical response , and toxicity . Results : Versus placebo , lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxyn 
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On subgroup analysis , the RR of high- grade fatigue varies significantly according to drug type , cancer type , treatment line , and treatment duration .
The available data suggested that the use of EGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients