***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 Several studies have shown the efficacy , tolerability , and ease of administration of pemetrexed-an antifolate antineoplastic agent-in  patients with advanced non-small-cell lung cancer . We assessed pemetrexed as maintenance therapy in patients with this disease . METHODS This r and omised double-blind study was undertaken in 83 centres in 20 countries . 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy  were r and omly assigned ( 2:1 ratio ) to receive pemetrexed ( 500 mg/m(2 ) , day 1 ) plus best supportive care ( n=441 ) or placebo plus best supportive care ( n=222 ) in 21-day cycles until disease progression . Treatment was r and omised with the Simon and Pocock minimisation method . Patients and investigators were masked to treatment . All patients received vitamin B(12 ) , folic acid , and dexamethasone . The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT00102804 . FINDINGS All r and omly assigned participants were analysed . Pemetrexed significantly improved progression-free survival ( 4.3 months [ 95 % CI 4.1 - 4.7 ] vs 2.6 months [ 1.7 - 2.8 ] ; hazard ratio [ HR ] 0.50 , 95 % CI 0.42 - 0.61 , p<0.0001 ) and overall survival ( 13.4 months [ 11.9 - 15.9 ] vs 10.6 months [ 8.7 - 12.0 ] ; HR 0.79 , 0.65 - 0.95 , p=0.012 ) compared with placebo . Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group ( 21 [ 5 % ] vs three [ 1 % ] ) . Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo ( 70 [ 16 % ] vs nine [ 4 % ] ; p<0.0001 ) , specifically fatigue ( 22 [ 5 % ] vs one [ 1 % ] , p=0.001 ) and neutropenia ( 13 [ 3 % ] vs 0 , p=0.006 ) . No  pemetrexed-related deaths occurred . Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy ( 227 [ 51 % ] vs 149 [ 67 % ] ; p=0.0001 ) . INTERPRETATION Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer . FUNDING Eli Lilly BACKGROUND We conducted a r and omized , placebo-controlled , double-blind trial to determine whether the epidermal growth factor receptor inhibitor erlotinib prolongs survival in non-small-cell lung cancer after the failure of first-line or second-line chemotherapy . METHODS Patients with stage IIIB or IV non-small-cell lung cancer , with performance status from 0 to 3 , were eligible if they had received one or two prior chemotherapy regimens .  The patients were stratified according to center , performance status , response to prior chemotherapy , number of prior regimens , and prior platinum-based therapy and were r and omly assigned in a 2:1 ratio to receive oral erlotinib , at a dose of 150 mg daily , or placebo . RESULTS The median age of the 731 patients who underwent r and omization was 61.4 years ; 49 percent had received two prior chemotherapy regimens , and 93 percent had received platinum-based chemotherapy .  The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group ( P<0.001 ) ; the median duration of the response was 7.9 months and 3.7 months , respectively . Progression-free survival was 2.2 months and 1.8 months , respectively ( hazard ratio , 0.61 , adjusted for stratification categories ; P<0.001 ) . Overall survival was 6.7 months and 4.7 months , respectively ( hazard ratio , 0.70 ; P<0.001 ) , in favor of erlotinib . Five percent of patients discontinued erlotinib because of toxic effects . CONCLUSIONS Erlotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy Background Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance . BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel . We have retrospectively examined the effect of RRM1 , RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer ( NSCLC ) patients . Methodology and Principal Findings Tumor sample s were collected from 102 chemotherapy-naïve advanced NSCLC patients treated with gemcitabine plus docetaxel as part of a r and omized trial . RRM1 , RRM2 and BRCA1 mRNA levels were assessed by quantitative PCR and correlated with response , time to progression and survival . As BRCA1 levels increased , the probability of response increased ( Odds Ratio [ OR ] , 1.09 : p = 0.01 ) and the risk of progression decreased ( hazard ratio [ HR ] , 0.99 ; p = 0.36 ) . As RRM1 and RRM2 levels increased , the probability of response decreased ( RRM1 : OR , 0.97 ; p = 0.82 ; RRM2 : OR , 0.94 ; p<0.0001 ) and the risk of progression increased ( RRM1 : HR , 1.02 ; p = 0.001 ; RRM2 : HR , 1.005 ; p = 0.01 ) . An interaction observed between BRCA1 and RRM1 allowed patients to be classified in three risk groups according to combinations of gene expression levels , with times to progression of 10.13 , 4.17 and 2.30 months ( p = 0.001 ) . Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin-based second-line therapy . Conclusions The mRNA expression of BRCA1 , RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy and warrants further investigation in prospect i ve studies Purpose : No chemotherapy regimen , including the widely used combination of gemcitabine/cisplatin , confers significantly improved survival over any other in metastatic non-small cell lung cancer ( NSCLC ) ; however , the selection of patients according to key genetic characteristics can help to tailor chemotherapy . Ribonucleotide reductase subunit M1 ( RRM1 ) is involved in DNA synthesis and repair and in gemcitabine metabolism , and the excision repair cross-complementing group 1 ( ERCC1 ) gene has been related to cisplatin activity . Experimental Design : Patients were part of a large r and omized trial carried out from September 1998 to July 2000 , comparing  gemcitabine/cisplatin versus gemcitabine/cisplatin/vinorelbine versus gemcitabine/vinorelbine followed by vinorelbine/ifosfamide . We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded sample s obtained from bronchoscopy by real-time quantitative reverse transcription-PCR . Results were correlated with survival using the Kaplan-Meier method . Results : A total of 100 patients were assessed . There was a strong correlation between RRM1 and ERCC1 mRNA expression levels ( Spearman r = 0.410 ; P < 0.001 ) . In the gemcitabine/cisplatin arm , patients with low RRM1 mRNA expression levels had significantly longer median survival than those with high levels [ 13.7 versus 3.6 months ; 95 % confidence interval ( CI ) , 9.6–17.8 months ; P = 0.009 ] . Median survival was also significantly longer among patients with low mRNA expression levels of both RRM1 and ERCC1 ( not reached ) , than among those with high levels of both genes ( 6.8 months ; 95 % CI , 2.6–11.1 months ; P = 0.016 ) . Conclusions : RRM1 mRNA expression is a crucial predictive marker of survival in  gemcitabine/cisplatin-treated patients . Genetic testing of RRM1 mRNA expression levels can and should be used to personalize chemotherapy PURPOSE V and etanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor ( VEGFR ) and epidermal growth factor receptor ( EGFR ) signaling . In this two-part phase II study , the efficacy and safety of v and etanib was compared with that of gefitinib , an inhibitor of EGFR signaling . PATIENTS AND METHODS Patients ( N = 168 ) with locally advanced or metastatic ( stage IIIB/IV ) non-small-cell lung cancer ( NSCLC ) , after failure of first-line with or without second-line platinum-based chemotherapy  , received once-daily v and etanib 300 mg ( n = 83 ) or gefitinib 250 mg ( n = 85 ) until disease progression or evidence of toxicity ( part A ) . After a 4-week washout period , eligible patients had the option to switch to the alternative treatment ( part B ) . Progression-free survival ( PFS ) was the primary efficacy assessment in part A , which was design ed to have a higher than 75 % power to detect a 33 % prolongation of PFS at a one-sided significance level of .2 . RESULTS In part A , v and etanib  prolonged PFS compared with gefitinib ( hazard ratio = 0.69 ; 95 % CI , 0.50 to 0.96 ; one-sided P = .013 ) . Patients receiving v and etanib experienced adverse events that were manageable and generally consistent with inhibition of EGFR and VEGFR signaling , including diarrhea , rash , and hypertension . There were no unexpected safety findings with gefitinib . Overall survival , a secondary assessment , was not significantly different between patients initially r and omly assigned to either v and etanib or gefitinib . CONCLUSION The primary efficacy objective was achieved , with v and etanib demonstrating a significant prolongation of PFS versus gefitinib . V and etanib 300 mg/d is currently being evaluated as a monotherapy in two r and omized phase III studies in advanced NSCLC PURPOSE To confirm the promising phase II results of docetaxel monotherapy , this phase III trial was conducted of chemotherapy for patients with advanced non-small-cell lung cancer ( NSCLC ) who had previously failed platinum-containing chemotherapy . PATIENTS AND METHODS A total of 373 patients were r and omized to receive either docetaxel 100 mg/m(2 ) ( D100 ) or 75 mg/m(2 ) ( D75 ) versus a control regimen of vinorelbine or ifosfamide ( V/I ) . The three treatment groups were well-balanced for key patient characteristics . RESULTS Overall response rates were 10.8 % with D100 and 6.7 % with D75 , each significantly higher than the 0.8 % response with V/I ( P = .001 and P = .036 , respectively ) . Patients who received docetaxel had a longer time to progression ( P = .046 , by log-rank test ) and a greater progression-free survival at 26 weeks ( P = .005 , by chi(2 ) test ) . Although overall survival was not significantly different between the three groups , the 1-year survival was significantly greater with D75 than with the control treatment ( 32 % v 19 % ; P = .025 , by chi(2 ) test ) . Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel , nor did it impact survival . There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2 . Toxicity was greatest with D100 , but the D75 arm was well-tolerated . CONCLUSION This first r and omized trial in this setting demonstrates that D75 every 3 weeks can offer clinical ly meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy PURPOSE To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy .  Secondary end points included assessment of response ( docetaxel arm only ) , toxicity , and quality of life . PATIENTS AND METHODS Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and 
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There is some evidence that histology is prognostic for survival .
There is evidence from multiple r and omized clinical trials to recommend the following : histologic subtype is predictive of treatment efficacy and for some agents toxicity .
Clinical data on K-RAS mutations are inconsistent , therefore testing is not recommended .
There is insufficient evidence to recommend other biomarker testing .
No biomarkers to date reliably predict improved efficacy for anti-VEGF therapy .