***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 The purpose of this study was to determine whether the addition of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ( Iressa , ZD1839 ; AstraZeneca , Wilmington , DE ) to st and ard first-line gemcitabine and cisplatin provides clinical benefit over gemcitabine and cisplatin alone in patients with advanced or metastatic non-small-cell lung cancer ( NSCLC ) .  Gefitinib has demonstrated encouraging efficacy in advanced NSCLC in phase II trials in pretreated patients , and a phase I trial of gefitinib in combination with gemcitabine and cisplatin showed favorable tolerability . PATIENTS AND METHODS This was a phase III r and omized , double-blind , placebo-controlled , multicenter trial in chemotherapy-naive patients with unresectable stage III or IV NSCLC . All patients received up to six cycles of chemotherapy ( cisplatin 80 mg/m(2 ) on day 1 and gemcitabine 1,250 mg/m(2 ) on days 1 and 8 of the 3-week cycle ) plus either gefitinib 500 mg/d , gefitinib 250 mg/d , or placebo . Daily gefitinib or placebo was continued until disease progression . End points included overall survival ( primary ) , time to progression , response rates , and safety evaluation . RESULTS A total of 1,093 patients were enrolled . There was no difference in efficacy end points between the treatment groups : for the gefitinib 500 mg/d , gefitinib 250 mg/d , and placebo groups , respectively , median survival times were 9.9 , 9.9 , and 10.9 months ( global ordered log-rank [ GOLrank ] P = .4560 ) , median times to progression were 5.5 , 5.8 , and 6.0 months ( GOLrank ; P = .7633 ) , and response rates were 49.7 % , 50.3 % , and 44.8 % . No significant unexpected adverse events were seen . CONCLUSION Gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efficacy over gemcitabine and cisplatin alone . The reasons for this remain obscure and require further pre clinical testing Purpose : A phase I clinical trial and molecular correlative studies were conducted to evaluate pre clinical evidence for combinatorial activity of the proteasome inhibitor bortezomib , the epidermal growth factor receptor ( EGFR ) inhibitor cetuximab , and radiation therapy . Experimental Design : Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck ( SCCHN ) were studied . Escalating doses of bortezomib ( 0.7 , 1.0 , and 1.3 mg/m2 ) were given intravenously twice weekly on days 1 , 4 , 8 , and 11 , every 21 days , with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy , delivered in 2 Gy fractions to 70 to 74 Gy . Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1 . Results : Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year ( progression-free survival = 4.8 months ; 95 % CI , 2.6–6.9 ) . Three patients each received bortezomib 0.7 or 1.0 mg/m2 , without dose-limiting toxicities ; one patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease ( PD ) . Expected grade 3 toxicities included radiation mucositis ( n = 4 ) , dermatitis ( n = 4 ) , and rash ( n = 1 ) . SCCHN-related cytokines increased in serial serum specimens of patients developing PD ( P = 0.029 ) . Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity , degradation of EGFR , and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1 . Conclusions : Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression , evidence for EGFR stabilization , increased prosurvival signaling , and SCCHN cytokine expression , warranting avoidance of this combination . Clin Cancer Res ; 17(17 ) ; 5755–64 . © 2011 AACR Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor ( EGFR ) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib , but little is known about how its efficacy and safety profile compares with that of st and ard chemotherapy . METHODS We r and omly assigned 230 patients with metastatic , non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel .  The primary end point was progression-free survival ; secondary end points included overall survival , response rate , and toxic effects . RESULTS In the planned interim analysis of data for the first 200 patients , progression-free survival was significantly longer in the gefitinib group than in the st and ard-chemotherapy group ( hazard ratio for death or disease progression with gefitinib , 0.36 ; P<0.001 ) , result ing in early termination of the study . The gefitinib group had a significantly longer median progression-free survival ( 10.8 months , vs. 5.4 months in the chemotherapy group ; hazard ratio , 0.30 ; 95 % confidence interval , 0.22 to 0.41 ; P<0.001 ) , as well as a higher response rate ( 73.7 % vs. 30.7 % , P<0.001 ) . The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group ( P=0.31 ) . The most common adverse events in the gefitinib group were rash ( 71.1 % ) and elevated aminotransferase levels ( 55.3 % ) , and in the chemotherapy group , neutropenia ( 77.0 % ) , anemia ( 64.6 % ) , appetite loss ( 56.6 % ) , and sensory neuropathy ( 54.9 % ) . One patient receiving gefitinib  died from interstitial lung disease . CONCLUSIONS First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival , with acceptable toxicity , as compared with st and ard chemotherapy . ( UMIN-CTR number , C000000376 . Background : Tegafur/uracil ( UFT ) is suitable for metronomic chemotherapy because of its underlying antiangiogenesis mechanism . This study aim ed to assess the efficacy of adding daily oral UFT to gefitinib treatment in patients with pulmonary adenocarcinoma who had failed previous chemotherapy . Methods : Taiwanese patients who had adenocarcinoma of the lung and failed previous chemotherapy were r and omized into gefitinib 250 mg daily alone ( G ) or plus daily oral UFT ( GU ) .  From November 2005 to August 2009 , 115 patients were enrolled . Results : There were 58 patients in the G arm and 57 in the GU arm . One-year progression-free survival ( PFS ) was 18 % in the G arm and 36.7 % in the GU arm ( p = 0.03 ) . Fifty-four patients had tissue sample s available for tumor epidermal growth factor receptor ( EGFR ) sequence analysis : 16 classical mutations and 8 wild types in the G arm , and 20 classical mutations and 10 wild-types in the GU arm . The addition of UFT significantly improved PFS in patients with EGFR mutations ( 14.4 versus 7.6 months , p = 0.0061 ) . Forty-three patients underwent tumor tissue microvessel density measurement , and a trend favoring the addition of UFT to gefitinib treatment was found in those with low microvessel density ( median PFS : 11.8 versus 2.8 months , p = 0.0536 ) . The median survival time was 18.3 months in the G arm and 23.6 months in the GU arm ( p = 0.381 ) . Conclusion : Gefitinib plus UFT treatment had better PFS than gefitinib alone treatment . Gefitinib is effective in patients with EGFR mutations , and the addition of UFT treatment produced better PFS in these patients with mutations PURPOSE Pre clinical studies indicate that gefitinib ( Iressa , ZD1839 ; AstraZeneca , Wilmington , DE ) , an orally active epidermal growth factor receptor tyrosine kinase inhibitor , may enhance antitumor efficacy of cytotoxics , and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial . Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent , with less toxicity than docetaxel , in phase II trials in refractory , advanced non-small-cell lung cancer ( NSCLC ) . This phase III , r and omized , placebo-controlled , double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC . PATIENTS AND METHODS Patients received paclitaxel 225 mg/m(2 ) and carboplatin area under concentration/time curve of 6 mg/min/mL ( day 1 every 3 weeks ) plus gefitinib 500 mg/d , gefitinib 250 mg/d , or placebo . After a maximum of six cycles , daily gefitinib or placebo continued until disease progression . End points included overall survival , time to progression ( TTP ) , response rate ( RR ) , and safety evaluation . Results A total of 1,037 patients were recruited . Baseline demographic characteristics were well balanced . There was no difference in overall survival ( median , 8.7 , 9.8 , and 9.9 months for gefitinib 500 mg/d , 250 mg/d , and placebo , respectively ; P = .64 ) , TTP , or RR between arms . Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients , with no new significant/unexpected safety findings from combination with chemotherapy . Subset analysis of patients with adenocarcinoma who received > or = 90 days ' chemotherapy demonstrated statistically significant prolonged survival , suggesting a gefitinib maintenance effect . CONCLUSION Gefitinib showed no added benefit in survival , TTP , or RR compared with st and ard chemotherapy alone . This large , placebo-controlled trial confirmed the favorable gefitinib  safety profile observed in phase I and II monotherapy trials BACKGROUND Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor ( EGFR ) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib . However , whether gefitinib is better than st and ard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain . METHODS We did an open label , phase 3 study ( WJTOG3405 ) with recruitment between March 31 , 2006 , and June 22 , 2009 , at 36 centres in Japan . 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations ( either the exon 19 deletion or L858R point mutation ) were r and omly assigned , using a minimisation technique , to receive either gefitinib ( 250 mg/day orally ; n=88 ) or cisplatin ( 80 mg/m(2 ) , intravenously ) plus docetaxel ( 60 mg/m(2 ) , intravenously ; n=89 ) , administered every 21 days for three to six cycles . The primary endpoint was progression-free survival . Survival analysis was done with the modified intention-to-treat population . This study is registered with UMIN ( University Hospital Medical Information Network in Japan ) , number 000000539 . FINDINGS Five patients were excluded ( two patients were found to have thyroid and colon cancer after r and omisation , one patient had an exon 18 mutation , one patient had insufficient consent , and one patient showed acute allergic reaction to docetaxel ) . Thus , 172 patients ( 86 in each group ) were included in the survival analyses . The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup , with a median progression-free survival time of 9.2 months ( 95 % CI 8.0 -  
    Output:
    
The synchronous combination of chemotherapy and TKIs is not superior to chemotherapy or EGFR TKIs alone for the first-line treatment of NSCLC