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 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 BACKGROUND Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor ( TKI ) therapy in non-small-cell lung cancer ( NSCLC ) . The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus st and ard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC . METHODS We undertook an open-label , r and omised , phase 3 trial at 22 centres in China . Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received either oral erlotinib ( 150 mg/day ) until disease progression or unacceptable toxic effects , or up to four cycles of gemcitabine plus carboplatin . Patients were r and omly assigned ( 1:1 ) with a minimisation procedure and were stratified according to EGFR mutation type , histological subtype ( adenocarcinoma vs non-adenocarcinoma ) , and smoking status . The primary outcome was progression-free survival , analysed in patients with confirmed disease who received at least one dose of study treatment . The trial is registered at Clinical Trials.gov , number NCT00874419 , and has completed enrolment ; patients are still in follow-up . FINDINGS 83 patients were r and omly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin ; 82 in the erlotinib  group and 72 in the  chemotherapy group were included in analysis of the primary endpoint . Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy ( 13.1 [ 95 % CI 10.58 - 16.53 ] vs 4.6 [ 4.21 - 5.42 ] months ; hazard ratio 0.16 , 95 % CI 0.10 - 0.26 ; p<0.0001 ) . Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib ( including neutropenia in 30 [ 42 % ] of 72 patients and thrombocytopenia in 29 [ 40 % ] patients on chemotherapy vs no patients with either event on erlotinib ) ; the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations ( three [ 4 % ] of 83 patients ) and skin rash ( two [ 2 % ] patients ) . Chemotherapy was also associated with increased treatment-related serious adverse events ( ten [ 14 % ] of 72 patients [ decreased platelet count , n=8 ; decreased neutrophil count , n=1 ; hepatic dysfunction , n=1 ] vs two [ 2 % ] of 83 patients [ both hepatic dysfunction ] ) . INTERPRETATION Compared with st and ard chemotherapy , erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability . These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC . FUNDING F Hoffmann-La Roche Ltd ( China ) ; Science and Technology Commission of Shanghai Municipality 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 . FINDINGS Of the 1022 patients enrolled , 939 participated in the induction phase . Of these , 539 patients were r and omly assigned to receive continuation maintenance with pemetrexed plus best supportive care ( n=359 ) or with placebo plus best supportive care ( n=180 ) . Among the 359 patients r and omised to continuation maintenance with pemetrexed , there was a significant reduction in the risk of disease progression over the placebo group ( HR 0·62 , 95 % CI 0·49 - 0·79 ; p<0·0001 ) . The median progression-free survival , measured from r and omisation , was 4·1 months ( 95 % CI 3·2 - 4·6 ) for pemetrexed and 2·8 months ( 2·6 - 3·1 ) for placebo . Possibly treatment-related laboratory grade 3 - 4 adverse events were more common in the pemetrexed group ( 33 [ 9 % ] of 359 patients ) than in the placebo group ( one [ < 1 % ] of 180 patients ; p<0·0001 ) , as were non-laboratory grade 3 - 5 adverse events ( 32 [ 9 % ] of 359 patients in the pemetrexed group ; eight [ 4 % ] of 180 patients in the placebo group ; p=0·080 ) ; one possibly treatment-related death was reported in each group . The most common adverse events of grade 3 - 4 in the pemetrexed group were anaemia ( 16 [ 4 % ] of 359 patients ) , neutropenia ( 13 [ 4 % ] ) , and fatigue ( 15 [ 4 % ] ) . In the placebo group , these adverse events were less common : anaemia ( one 
    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 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 BACKGROUND Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor ( TKI ) therapy in non-small-cell lung cancer ( NSCLC ) . The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus st and ard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC . METHODS We undertook an open-label , r and omised , phase 3 trial at 22 centres in China . Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received either oral erlotinib ( 150 mg/day ) until disease progression or unacceptable toxic effects , or up to four cycles of gemcitabine plus carboplatin . Patients were r and omly assigned ( 1:1 ) with a minimisation procedure and were stratified according to EGFR mutation type , histological subtype ( adenocarcinoma vs non-adenocarcinoma ) , and smoking status . The primary outcome was progression-free survival , analysed in patients with confirmed disease who received at least one dose of study treatment . The trial is registered at Clinical Trials.gov , number NCT00874419 , and has completed enrolment ; patients are still in follow-up . FINDINGS 83 patients were r and omly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin ; 82 in the erlotinib  group and 72 in the  chemotherapy group were included in analysis of the primary endpoint . Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy ( 13.1 [ 95 % CI 10.58 - 16.53 ] vs 4.6 [ 4.21 - 5.42 ] months ; hazard ratio 0.16 , 95 % CI 0.10 - 0.26 ; p<0.0001 ) . Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib ( including neutropenia in 30 [ 42 % ] of 72 patients and thrombocytopenia in 29 [ 40 % ] patients on chemotherapy vs no patients with either event on erlotinib ) ; the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations ( three [ 4 % ] of 83 patients ) and skin rash ( two [ 2 % ] patients ) . Chemotherapy was also associated with increased treatment-related serious adverse events ( ten [ 14 % ] of 72 patients [ decreased platelet count , n=8 ; decreased neutrophil count , n=1 ; hepatic dysfunction , n=1 ] vs two [ 2 % ] of 83 patients [ both hepatic dysfunction ] ) . INTERPRETATION Compared with st and ard chemotherapy , erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability . These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC . FUNDING F Hoffmann-La Roche Ltd ( China ) ; Science and Technology Commission of Shanghai Municipality 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 . FINDINGS Of the 1022 patients enrolled , 939 participated in the induction phase . Of these , 539 patients were r and omly assigned to receive continuation maintenance with pemetrexed plus best supportive care ( n=359 ) or with placebo plus best supportive care ( n=180 ) . Among the 359 patients r and omised to continuation maintenance with pemetrexed , there was a significant reduction in the risk of disease progression over the placebo group ( HR 0·62 , 95 % CI 0·49 - 0·79 ; p<0·0001 ) . The median progression-free survival , measured from r and omisation , was 4·1 months ( 95 % CI 3·2 - 4·6 ) for pemetrexed and 2·8 months ( 2·6 - 3·1 ) for placebo . Possibly treatment-related laboratory grade 3 - 4 adverse events were more common in the pemetrexed group ( 33 [ 9 % ] of 359 patients ) than in the placebo group ( one [ < 1 % ] of 180 patients ; p<0·0001 ) , as were non-laboratory grade 3 - 5 adverse events ( 32 [ 9 % ] of 359 patients in the pemetrexed group ; eight [ 4 % ] of 180 patients in the placebo group ; p=0·080 ) ; one possibly treatment-related death was reported in each group . The most common adverse events of grade 3 - 4 in the pemetrexed group were anaemia ( 16 [ 4 % ] of 359 patients ) , neutropenia ( 13 [ 4 % ] ) , and fatigue ( 15 [ 4 % ] ) . In the placebo group , these adverse events were less common : anaemia ( one 
    Output:
    