human
***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 PURPOSE The phase III , r and omized , placebo-controlled Sequential Tarceva in Unresectable NSCLC ( SATURN ; BO18192 ) study found that erlotinib maintenance therapy extended progression-free survival ( PFS ) and overall survival in patients with advanced non-small-cell lung cancer ( NSCLC ) who had nonprogressive disease following first-line platinum-doublet chemotherapy .  This study included prospect i ve analysis of the prognostic and predictive value of several biomarkers . PATIENTS AND METHODS M and atory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor ( EGFR ) protein expression by using immunohistochemistry ( IHC ) , EGFR gene copy number by using fluorescent in situ hybridization ( FISH ) , and EGFR and KRAS mutations by using DNA sequencing . An EGFR CA simple sequence repeat in intron 1 ( CA-SSR1 ) polymorphism was evaluated in blood . RESULTS All 889 r and omly assigned patients provided tumor sample s.  EGFR IHC , EGFR FISH , KRAS mutation , and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy . A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation-positive subgroup ( hazard ratio [ HR ] , 0.10 ; P < .001 ) . Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup ( HR , 0.78 ; P = .0185 ) . KRAS mutation status was a significant negative prognostic factor for PFS . CONCLUSION This large prospect i ve biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy . No other biomarkers were predictive for outcomes with erlotinib , although the study was not powered for clinical outcomes in biomarker subgroups other than EGFR IHC-positive [ corrected ] . KRAS mutations were prognostic for reduced PFS . The study demonstrated the feasibility of prospect i ve tissue collection for biomarker analyses in NSCLC PURPOSE Gemcitabine plus carboplatin ( GC ) is active as front-line treatment for advanced non-small-cell lung cancer ( NSCLC ) . For patients without progression , timing of second-line chemotherapy for optimum clinical benefit remains uncertain . This phase III , r and omized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression . PATIENTS AND METHODS The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC .  Gemcitabine ( 1,000 mg/m(2 ) ) was administered on days 1 and 8 followed by carboplatin ( area under the curve = 5 ) on day 1 . After four 21-day cycles , patients who did not have progression were r and omly assigned either to an immediate docetaxel group ( docetaxel 75 mg/m(2 ) on day 1 every 21 days , with maximum of six cycles ) or to a delayed docetaxel group . The primary end point was overall survival ( OS ) measured from r and om assignment . Additional analyses included tumor response , toxicity , progression-free survival ( PFS ) , and quality of life ( QOL ) . RESULTS Enrollment totaled 566 patients ; 398 patients completed GC ; 309 patients were r and omly assigned equally to the two docetaxel treatment groups . Toxicity profiles were generally comparable for the docetaxel groups . Median PFS for immediate docetaxel ( 5.7 months ) was significantly greater ( P = .0001 ) than for delayed docetaxel ( 2.7 months ) . Median OS for immediate docetaxel ( 12.3 months ) was greater than for delayed docetaxel ( 9.7 months ) , but the difference was not statistically significant ( P = .0853 ) . QOL results were not statistically different ( P = .76 ) between docetaxel groups . CONCLUSION We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC , without increasing toxicity or decreasing QOL PURPOSE PointBreak ( A Study of Pemetrexed , Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer ) compared the efficacy and safety of pemetrexed ( Pem ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by pemetrexed plus bevacizumab ( PemCBev ) with paclitaxel ( Pac ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by bevacizumab ( PacCBev ) in patients with advanced nonsquamous non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were r and omly assigned to receive pemetrexed 500 mg/m(2 ) or paclitaxel 200 mg/m(2 ) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles . Eligible patients received maintenance until disease progression : pemetrexed plus bevacizumab ( for the PemCBev group ) or bevacizumab ( for the PacCBev group ) . The primary end point of this superiority study was overall survival ( OS ) . RESULTS Patients were r and omly assigned to PemCBev ( n = 472 ) or PacCBev ( n = 467 ) . For PemCBev versus PacCBev , OS hazard ratio ( HR ) was 1.00 ( median OS , 12.6 v 13.4 months ; P = .949 ) ; progression-free survival ( PFS ) HR was 0.83 ( median PFS , 6.0 v 5.6 months ; P = .012 ) ; overall response rate was 34.1 % versus 33.0 % ; and disease control rate was 65.9 % versus 69.8 % . Significantly more study drug-related grade 3 or 4 anemia ( 14.5 % v 2.7 % ) , thrombocytopenia ( 23.3 % v 5.6 % ) , and fatigue ( 10.9 % v 5.0 % ) occurred with PemCBev ; significantly more grade 3 or 4 neutropenia ( 40.6 % v 25.8 % ) , febrile neutropenia ( 4.1 % v 1.4 % ) , sensory neuropathy ( 4.1 % v 0 % ) , and alopecia ( grade 1 or 2 ; 36.8 % v 6.6 % ) occurred with PacCBev . CONCLUSION OS did not improve with the PemCBev regimen compared with the PacCBev regimen , although PFS was significantly improved with PemCBev . Toxicity profiles differed ; both regimens demonstrated tolerability Background : Prospect i ve studies have implied that maintenance therapy for non-small cell lung cancer ( NSCLC ) has its effect by giving active drugs earlier to patients who otherwise die without receiving second-line therapy . The purpose of this study was to select patients with NSCLC who could most benefit from maintenance therapy  , by evaluating which patients would be less likely to receive second-line therapy . Methods : Clinicopathologic data of patients with advanced NSCLC who received four cycles of first-line chemotherapy followed by time-off therapy and eventual disease progression or death were review ed retrospectively . Patients were grouped into ones with first-line therapy only or ones with more than first-line therapy . Clinical characteristics between the two groups were compared . Results : A total of 271 patients were eligible for analysis , and 39 patients ( 14.4 % ) received only first-line therapy . Patients significantly more likely to receive only first-line therapy had performance status of two or three after first-line therapy , large volume of initial target lesions ( sum of long diameters ≥70 mm ) , or smaller decrease in target lesions ( decrease < 20 % ) after first-line therapy . Median overall survival of the 143 patients ( 52.8 % ) with at least one of these characteristics ( 16.3 months ) was significantly shorter than that of patients without any of these characteristics ( 23.5 months , p = 0.007 ) . Conclusion : Maintenance therapy may be of greater benefit to patients with NSCLC who have clinical characteristics including poor performance status after first-line therapy , large initial target lesions , or smaller decrease in target lesions after first-line therapy BACKGROUND Patients with advanced non-squamous non-small-cell lung cancer ( NSCLC ) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing , non-pemetrexed doublet . The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin . METHODS In this double-blind , multicentre , phase 3 , r and omised placebo-controlled trial , patients with advanced non-squamous NSCLC aged 18 years or older , with no previous systemic chemotherapy for lung cancer , with at least one measurable lesion , and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 participated . Before r and omisation , patients entered an induction phase which consisted of four cycles of induction pemetrexed ( 500 mg/m(2 ) ) plus cisplatin ( 75 mg/m(2 ) ) on day 1 of a 21-day cycle . Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage ( IIIB or IV ) , ECOG performance status ( 0 or 1 ) , and induction response ( complete or partial response , or stable disease ) , and r and omly assigned ( 2:1 ratio ) to receive maintenance therapy with either pemetrexed ( 500 mg/m(2 ) every 21 days ) plus best supportive care or placebo plus best supportive care until disease progression . R and omisation was done with the Pocock and Simon minimisation method . Patients and investigators were masked to treatment assignment . The primary endpoint was progression-free survival in the intention-to-treat population . This study is registered with Clinical Trials.gov , NCT00789373 . F 
    Output:
    
agent
***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 PURPOSE The phase III , r and omized , placebo-controlled Sequential Tarceva in Unresectable NSCLC ( SATURN ; BO18192 ) study found that erlotinib maintenance therapy extended progression-free survival ( PFS ) and overall survival in patients with advanced non-small-cell lung cancer ( NSCLC ) who had nonprogressive disease following first-line platinum-doublet chemotherapy .  This study included prospect i ve analysis of the prognostic and predictive value of several biomarkers . PATIENTS AND METHODS M and atory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor ( EGFR ) protein expression by using immunohistochemistry ( IHC ) , EGFR gene copy number by using fluorescent in situ hybridization ( FISH ) , and EGFR and KRAS mutations by using DNA sequencing . An EGFR CA simple sequence repeat in intron 1 ( CA-SSR1 ) polymorphism was evaluated in blood . RESULTS All 889 r and omly assigned patients provided tumor sample s.  EGFR IHC , EGFR FISH , KRAS mutation , and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy . A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation-positive subgroup ( hazard ratio [ HR ] , 0.10 ; P < .001 ) . Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup ( HR , 0.78 ; P = .0185 ) . KRAS mutation status was a significant negative prognostic factor for PFS . CONCLUSION This large prospect i ve biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy . No other biomarkers were predictive for outcomes with erlotinib , although the study was not powered for clinical outcomes in biomarker subgroups other than EGFR IHC-positive [ corrected ] . KRAS mutations were prognostic for reduced PFS . The study demonstrated the feasibility of prospect i ve tissue collection for biomarker analyses in NSCLC PURPOSE Gemcitabine plus carboplatin ( GC ) is active as front-line treatment for advanced non-small-cell lung cancer ( NSCLC ) . For patients without progression , timing of second-line chemotherapy for optimum clinical benefit remains uncertain . This phase III , r and omized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression . PATIENTS AND METHODS The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC .  Gemcitabine ( 1,000 mg/m(2 ) ) was administered on days 1 and 8 followed by carboplatin ( area under the curve = 5 ) on day 1 . After four 21-day cycles , patients who did not have progression were r and omly assigned either to an immediate docetaxel group ( docetaxel 75 mg/m(2 ) on day 1 every 21 days , with maximum of six cycles ) or to a delayed docetaxel group . The primary end point was overall survival ( OS ) measured from r and om assignment . Additional analyses included tumor response , toxicity , progression-free survival ( PFS ) , and quality of life ( QOL ) . RESULTS Enrollment totaled 566 patients ; 398 patients completed GC ; 309 patients were r and omly assigned equally to the two docetaxel treatment groups . Toxicity profiles were generally comparable for the docetaxel groups . Median PFS for immediate docetaxel ( 5.7 months ) was significantly greater ( P = .0001 ) than for delayed docetaxel ( 2.7 months ) . Median OS for immediate docetaxel ( 12.3 months ) was greater than for delayed docetaxel ( 9.7 months ) , but the difference was not statistically significant ( P = .0853 ) . QOL results were not statistically different ( P = .76 ) between docetaxel groups . CONCLUSION We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC , without increasing toxicity or decreasing QOL PURPOSE PointBreak ( A Study of Pemetrexed , Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer ) compared the efficacy and safety of pemetrexed ( Pem ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by pemetrexed plus bevacizumab ( PemCBev ) with paclitaxel ( Pac ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by bevacizumab ( PacCBev ) in patients with advanced nonsquamous non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were r and omly assigned to receive pemetrexed 500 mg/m(2 ) or paclitaxel 200 mg/m(2 ) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles . Eligible patients received maintenance until disease progression : pemetrexed plus bevacizumab ( for the PemCBev group ) or bevacizumab ( for the PacCBev group ) . The primary end point of this superiority study was overall survival ( OS ) . RESULTS Patients were r and omly assigned to PemCBev ( n = 472 ) or PacCBev ( n = 467 ) . For PemCBev versus PacCBev , OS hazard ratio ( HR ) was 1.00 ( median OS , 12.6 v 13.4 months ; P = .949 ) ; progression-free survival ( PFS ) HR was 0.83 ( median PFS , 6.0 v 5.6 months ; P = .012 ) ; overall response rate was 34.1 % versus 33.0 % ; and disease control rate was 65.9 % versus 69.8 % . Significantly more study drug-related grade 3 or 4 anemia ( 14.5 % v 2.7 % ) , thrombocytopenia ( 23.3 % v 5.6 % ) , and fatigue ( 10.9 % v 5.0 % ) occurred with PemCBev ; significantly more grade 3 or 4 neutropenia ( 40.6 % v 25.8 % ) , febrile neutropenia ( 4.1 % v 1.4 % ) , sensory neuropathy ( 4.1 % v 0 % ) , and alopecia ( grade 1 or 2 ; 36.8 % v 6.6 % ) occurred with PacCBev . CONCLUSION OS did not improve with the PemCBev regimen compared with the PacCBev regimen , although PFS was significantly improved with PemCBev . Toxicity profiles differed ; both regimens demonstrated tolerability Background : Prospect i ve studies have implied that maintenance therapy for non-small cell lung cancer ( NSCLC ) has its effect by giving active drugs earlier to patients who otherwise die without receiving second-line therapy . The purpose of this study was to select patients with NSCLC who could most benefit from maintenance therapy  , by evaluating which patients would be less likely to receive second-line therapy . Methods : Clinicopathologic data of patients with advanced NSCLC who received four cycles of first-line chemotherapy followed by time-off therapy and eventual disease progression or death were review ed retrospectively . Patients were grouped into ones with first-line therapy only or ones with more than first-line therapy . Clinical characteristics between the two groups were compared . Results : A total of 271 patients were eligible for analysis , and 39 patients ( 14.4 % ) received only first-line therapy . Patients significantly more likely to receive only first-line therapy had performance status of two or three after first-line therapy , large volume of initial target lesions ( sum of long diameters ≥70 mm ) , or smaller decrease in target lesions ( decrease < 20 % ) after first-line therapy . Median overall survival of the 143 patients ( 52.8 % ) with at least one of these characteristics ( 16.3 months ) was significantly shorter than that of patients without any of these characteristics ( 23.5 months , p = 0.007 ) . Conclusion : Maintenance therapy may be of greater benefit to patients with NSCLC who have clinical characteristics including poor performance status after first-line therapy , large initial target lesions , or smaller decrease in target lesions after first-line therapy BACKGROUND Patients with advanced non-squamous non-small-cell lung cancer ( NSCLC ) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing , non-pemetrexed doublet . The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin . METHODS In this double-blind , multicentre , phase 3 , r and omised placebo-controlled trial , patients with advanced non-squamous NSCLC aged 18 years or older , with no previous systemic chemotherapy for lung cancer , with at least one measurable lesion , and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 participated . Before r and omisation , patients entered an induction phase which consisted of four cycles of induction pemetrexed ( 500 mg/m(2 ) ) plus cisplatin ( 75 mg/m(2 ) ) on day 1 of a 21-day cycle . Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage ( IIIB or IV ) , ECOG performance status ( 0 or 1 ) , and induction response ( complete or partial response , or stable disease ) , and r and omly assigned ( 2:1 ratio ) to receive maintenance therapy with either pemetrexed ( 500 mg/m(2 ) every 21 days ) plus best supportive care or placebo plus best supportive care until disease progression . R and omisation was done with the Pocock and Simon minimisation method . Patients and investigators were masked to treatment assignment . The primary endpoint was progression-free survival in the intention-to-treat population . This study is registered with Clinical Trials.gov , NCT00789373 . F 
    Output:
    