***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 Hypertension ( HTN ) , a recognized adverse effect of angiogenesis inhibitors , may be a potential biomarker of activity of these agents . We conducted a retrospective analysis to examine the incidence and predictors of the development of on-treatment HTN with the vascular endothelial growth factor receptor tyrosine kinase inhibitor cediranib , and the relationship of this adverse event with treatment outcomes . PATIENTS AND METHODS BR24 was a double-blind placebo-controlled  phase II trial of carboplatin/paclitaxel chemotherapy with either daily oral cediranib or placebo  in patients ( n = 296 ) with advanced non-small-cell lung cancer ( NSCLC ) . Exploratory analyses characterized relationships between HTN , baseline variables , and efficacy outcomes . RESULTS New onset or worsening of preexisting HTN ( treatment-emergent HTN ) was more frequent in patients receiving cediranib ( 68 versus 45 % , P < 0.0001 ) . Factors associated with HTN in all r and omized patients were good performance status and treatment with cediranib . In both arms , treatment-emergent HTN was associated with improved efficacy outcomes , but there was no evidence of a differential treatment effect , with nonsignificant interaction P values . CONCLUSIONS In advanced NSCLC , HTN is frequent in patients receiving chemotherapy  , with or without cediranib . The development of HTN was favorably prognostic in these patients , but not predictive of a differential outcome with cediranib 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 Previous , uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer . METHODS In this phase 3 , open-label study , we r and omly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib ( 250 mg per day ) ( 609 patients ) or carboplatin ( at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute ) plus paclitaxel ( 200 mg per square meter of body-surface area ) ( 608 patients ) . The primary end point was progression-free survival . RESULTS The 12-month rates of progression-free survival were 24.9 % with gefitinib and 6.7 % with carboplatin-paclitaxel . The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority , as compared with carboplatin-paclitaxel , with respect to progression-free survival in the intention-to-treat population ( hazard ratio for progression or death , 0.74 ; 95 % confidence interval [ CI ] , 0.65 to 0.85 ; P<0.001 ) . In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene ( EGFR ) mutation , progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel ( hazard ratio for progression or death , 0.48 ; 95 % CI , 0.36 to 0.64 ; P<0.001 ) , whereas in the subgroup of 176 patients who were negative for the mutation , progression-free survival was significantly longer among those who received carboplatin-paclitaxel ( hazard ratio for progression or death with gefitinib , 2.85 ; 95 % CI , 2.05 to 3.98 ; P<0.001 ) . The most common adverse events were rash or acne ( in 66.2 % of patients ) and diarrhea ( 46.6 % ) in the gefitinib group and neurotoxic effects ( 69.9 % ) , neutropenia ( 67.1 % ) , and alopecia ( 58.4 % ) in the carboplatin-paclitaxel group . CONCLUSIONS Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia . The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib . ( Clinical Trials.gov number , NCT00322452 . PURPOSE Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor ( VEGF ) with demonstrated efficacy in combination with carboplatin and paclitaxel ( PCB ) for the treatment of advanced non-small-cell lung cancer ( NSCLC ) . Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension , which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes . PATIENTS AND METHODS Eastern Cooperative Oncology Group ( ECOG ) 4599 r and omly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel ( PC ) versus PCB .  Hypertensive patients were compared with nonhypertensive patients with respect to overall survival ( OS ) and progression-free survival ( PFS ) using blood pressure data and adverse event data separately . High blood pressure ( HBP ) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline . Results In a multivariable Cox model adjusting for HBP as a time-varying covariate , comparing those on PCB with HBP with those on PC gave an OS hazard ratio ( HR ) of 0.60 ( 95 % CI , 0.43 to 0.81 ; P = .001 ) ; comparing those on PCB without HBP with those on PC alone , the OS HR was 0.86 ( 95 % CI , 0.74 to 1.00 ; P = .05 ) . Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 ( 95 % CI , 0.41 to 0.73 ; P < .0001 ) and comparing those on PCB without HBP to those on PC , the HR was 0.72 ( 95 % CI , 0.62 to 0.84 ; P < .0001 ) . The 6-month cumulative incidence of hypertension was 6.2 % ( 95 % CI , 3.9 % to 8.6 % ) . CONCLUSION Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes , and additional studies of the downstream effects of VEGF suppression and hypertension are needed PURPOSE To evaluate the prognostic and predictive significance of plasma levels of the epidermal growth factor receptor ( EGFR ) lig and s , transforming growth factor α ( TGF-α ) and amphiregulin , in patients with non-small-cell lung cancer ( NSCLC ) enrolled in NCIC Clinical Trials Group BR.21 comparing erlotinib with placebo . PATIENTS AND METHODS TGF-α and amphiregulin were assessed retrospectively by enzyme-linked immunosorbent assay from available prospect ively collected baseline plasma sample s in 565 of 731 BR.21 patients . Cutoff points were determined for both amphiregulin ( low , < 10 pg/mL ; high , ≥10 pg/mL ) and TGF-α ( low , ≤12 pg/mL ; high , > 12 pg/mL ) using a graphical method . Cox regression models were used to correlate biomarker data and baseline characteristics with outcomes including overall ( OS ) and progression-free survival ( PFS ) . RESULTS High TGF-α and amphiregulin were associated with poorer performance status ( P=.06 and P<.0001 , respectively ) and no prior platinum therapy ( P=.06 and P=.02 , respectively ) . High amphiregulin was also associated with anemia ( P=.001 ) , increased lactate dehydrogenase ( P=.03 ) , ever-smokers ( P=.04 ) , and non-Asian ethnicity ( P=.001 ) . Patients on the placebo arm with high amphiregulin had poorer OS than patients with low amphiregulin ( hazard ratio [HR]=1.88 ; 95 % CI , 1.34 to 2.64 ; P=.0002 ) , which remained significant in multivariate  analysis . Amphiregulin levels did not predict for benefit from erlotinib ( interaction P=.87 ) 
    Output:
    
Evidence from multiple RCTs confirmed that histologic subtype is prognostic for survival and predictive of treatment efficacy and /or toxicity in NSCLC .
No biomarkers to date reliably predict response to anti-Vascular Endothelial Growth Factor ( VEGF ) therapies .
There are inconsistent data on the role of ERCC1 , BRCA , Beta tubulin III , RRM1 , K-RAS , or TP-53 in treatment decisions .