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: PURPOSE The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer . This international , double-blind , phase III study compared everolimus efficacy and safety with that of best supportive care ( BSC ) in previously treated advanced gastric cancer . PATIENTS AND METHODS Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were r and omly assigned to everolimus 10 mg/d ( assignment schedule : 2:1 ) or matching placebo , both given with BSC . R and omization was stratified by previous chemotherapy lines ( one v two ) and region ( Asia v rest of the world [ ROW ] ) . Treatment continued until disease progression or intolerable toxicity . Primary end point was overall survival ( OS ) . Secondary end points included progression-free survival ( PFS ) , overall response rate , and safety . RESULTS Six hundred fifty-six patients ( median age , 62.0 years ; 73.6 % male ) were enrolled .  Median OS was 5.4 months with everolimus and 4.3 months with placebo ( hazard ratio , 0.90 ; 95 % CI , 0.75 to 1.08 ; P = .124 ) . Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms , respectively ( hazard ratio , 0.66 ; 95 % CI , 0.56 to 0.78 ) . Common grade 3/4 adverse events included anemia , decreased appetite , and fatigue . The safety profile was similar in patients enrolled in Asia versus ROW . CONCLUSION Compared with BSC , everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy . The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers BACKGROUND Trastuzumab , a monoclonal antibody against human epidermal growth factor receptor 2 ( HER2 ; also known as ERBB2 ) , was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer . METHODS ToGA ( Trastuzumab for Gastric Cancer ) was an open-label , international , phase 3 , r and omised controlled trial undertaken in 122 centres in 24 countries . Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation . Participants were r and omly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab . Allocation was by block r and omisation stratified by Eastern Cooperative Oncology Group performance status , chemotherapy regimen , extent of disease , primary cancer site , and measurability of disease , implemented with a central interactive voice recognition system . The primary endpoint was overall survival in all r and omised patients who received study medication at least once . This trial is registered with Clinical Trials.gov , number NCT01041404 . FINDINGS 594 patients were r and omly assigned to study treatment ( trastuzumab plus chemotherapy , n=298 ; chemotherapy alone , n=296 ) , of whom 584 were included in the primary analysis ( n=294 ; n=290 ) . Median follow-up was 18.6 months ( IQR 11 - 25 ) in the trastuzumab plus chemotherapy group and 17.1 months ( 9 - 25 ) in the chemotherapy alone group . Median overall survival was 13.8 months ( 95 % CI 12 - 16 ) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months ( 10 - 13 ) in those assigned to chemotherapy alone ( hazard ratio 0.74 ; 95 % CI 0.60 - 0.91 ; p=0.0046 ) . The most common adverse events in both groups were nausea  ( trastuzumab plus chemotherapy , 197 [ 67 % ] vs chemotherapy alone , 184 [ 63 % ] ) , vomiting ( 147 [ 50 % ] vs 134 [ 46 % ] ) , and neutropenia ( 157 [ 53 % ] vs 165 [ 57 % ] ) . Rates of overall grade 3 or 4 adverse events ( 201 [ 68 % ] vs 198 [ 68 % ] ) and cardiac adverse events ( 17 [ 6 % ] vs 18 [ 6 % ] ) did not differ between groups . INTERPRETATION Trastuzumab in combination with chemotherapy can be considered as a new st and ard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer . FUNDING F Hoffmann-La Roche BACKGROUND Second-line chemotherapy for patients with oesophagogastric adenocarcinoma refractory to platinum and fluoropyrimidines has not shown benefits in health-related quality of life ( HRQoL ) . We assessed whether the addition of docetaxel to active symptom control alone can improve survival and HRQoL for patients . METHODS For this open-labelled , multicentre trial , we recruited patients aged 18 years or older from 30 UK centres . Patients were eligible if they had an advanced , histologically confirmed adenocarcinoma of the oesophagus , oesophagogastric junction , or stomach that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination . Patients could have an Eastern Cooperative Oncology Group performance status of 0 - 2 . We r and omly assigned patients using a central , computerised minimisation procedure to receive docetaxel plus active symptom control , or active symptom control alone ( 1:1 ; stratified by disease status , disease site , duration of response to previous chemotherapy , and performance status ) . Docetaxel was given at a dose of 75 mg/m(2 ) by intravenous infusion every 3 weeks for up to six cycles . The primary endpoint was overall survival , analysed by intention to treat . This is the report of the planned final analysis . This study is an International St and ardised R and omised Controlled Trial , number IS RCT N13366390 . FINDINGS Between April 21 , 2008 , and April 26 , 2012 , we recruited 168 patients , allocating 84 to each treatment group . After a median follow-up of 12 months [ IQR 10 - 21 ] ) and 161 ( 96 % ) deaths ( 80 in the docetaxel group , 81 in the active symptom control group ) , median overall survival in the docetaxel group was 5.2 months ( 95 % CI 4.1 - 5.9 ) versus 3.6 months ( 3.3 - 4.4 ) in the active symptom control group ( hazard ratio 0.67 , 95 % CI 0.49 - 0.92 ; p=0.01 ) . Docetaxel was associated with higher incidence of grade 3 - 4 neutropenia ( 12 [ 15 % ] patients vs no patients ) , infection ( 15 [ 19 % ] patients vs two [ 3 % ] patients ) , and febrile neutropenia ( six [ 7 % ] patients vs no patients ) . Patients receiving docetaxel reported less pain ( p=0.0008 ) and less nausea and vomiting ( p=0.02 ) and constipation ( p=0.02 ) . Global HRQoL was similar between the groups ( p=0.53 ) . Disease specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia ( p=0.02 ) and abdominal pain ( p=0.01 ) . INTERPRETATION Our findings suggest that docetaxel can be recommended as an appropriate second-line treatment for patients with oesophagogastric adenocarcinoma that is refractory to treatment with platinum and fluoropyrimidine . FUNDING Cancer Research UK BACKGROUND The value of second-line therapy for metastatic gastric cancer is unclear . So far there are no r and omised phase III data comparing second-line chemotherapy to best supportive care ( BSC ) . In this prospect i ve , multicenter , open label , r and omised phase III study we compared irinotecan to BSC to evaluate the impact on survival of second-line chemotherapy . METHODS Eligible patients ( pts ) had metastatic or locally advanced gastro-oesophageal junction or gastric adenocarcinoma , objective tumour progression during or within 6months after first-line chemotherapy and ECOG performance status 0 - 2 . Stratification for time of progression after first-line therapy , ECOG PS and pretreatment secured even distribution of important prognostic factors . TREATMENT Arm A : Irinotecan 250mg/m(2)q3w ( first cycle ) to be increased to 350mg/m(2 ) , depending on toxicity . Arm B : BSC . FINDINGS Between 10/2002 and 12/2006 40 pts were r and omised . The study was closed prematurely due to poor accrual . Responsefor arm A ( 19 pts evaluable ) : No objective responses , SD 53 % , PD 47 % . Improvement of tumour related symptoms : Arm A 50 % of pts , arm B 7 % . Overall Survival : ( all events in 40 pts have occurred ) : The hazard ratio for death was reduced to 0.48 ( 95%CI 0.25 - 0.92 ) in the irinotecan-arm ( p=0.012 ) . Median survival arm A : 4.0months ( 95 % CI 3.6 - 7.5 ) , arm B : 2.4months ( 95 % CI 1.7 - 4.9 ) . INTERPRETATION Irinotecan as second-line chemotherapy significantly prolongs overall survival compared to BSC in the studied pts . Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer . FUNDING The study was supported by a research grant from Aventis and Pfizer BACKGROUND Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated . In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer ( SPIRITS ) trial , we aim ed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin  than with  S-1 alone . METHODS In this phase III trial , chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26 , 2002 , and Nov 30 , 2004 , at 38 centres in Japan , and r and omly assigned to S-1 plus cisplatin or S-1 alone .  In patients assigned to S-1 plus cisplatin , S-1 ( 40 - 60 mg depending on patient 's body surface area ) was given orally , twice daily for 3 consecutive weeks , and 60 mg/m(2 ) cisplatin was given intravenously on day 8 , followed by a 2-week rest period , within a 5-week cycle . Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks , followed by a 2-week rest period , within a 6-week cycle . The primary endpoint was overall survival . Secondary endpoints were progression-free survival , proportions of responders , and safety . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00150670 . FINDINGS 305 patients were enrolled ; seven patients were ineligible or withdrew consent , therefore , 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone .  Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin ( 13.0 months [ IQR 7.6 - 21.9 ] ) than in those assigned to S-1 alone ( 11.0 months [ 5.6 - 19.8 ] ; hazard ratio for death , 0.77 ; 95 % CI 0.61 - 0.98 ; p=0.04 ) . Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone ( median progression-free survival 6.0 months [ 3.3 - 12.9 ] vs 4.0 months [ 2.1 - 6.8 ] ; p<0.0001 ) . Additionally , of 87 patients assigned S-1 plus cisplatin who had target tumours , one patient had a complete response and 46 patients had partial responses , ie , a total of 54 % ( range 43 - 65 ) . Of 106 patients assigned S-1 alone who had target tumours , one patient had a complete response and 32 had partial responses , ie , a total of 31 % ( 23 - 41 ) . We recorded more grade 3 or 
    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: PURPOSE The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer . This international , double-blind , phase III study compared everolimus efficacy and safety with that of best supportive care ( BSC ) in previously treated advanced gastric cancer . PATIENTS AND METHODS Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were r and omly assigned to everolimus 10 mg/d ( assignment schedule : 2:1 ) or matching placebo , both given with BSC . R and omization was stratified by previous chemotherapy lines ( one v two ) and region ( Asia v rest of the world [ ROW ] ) . Treatment continued until disease progression or intolerable toxicity . Primary end point was overall survival ( OS ) . Secondary end points included progression-free survival ( PFS ) , overall response rate , and safety . RESULTS Six hundred fifty-six patients ( median age , 62.0 years ; 73.6 % male ) were enrolled .  Median OS was 5.4 months with everolimus and 4.3 months with placebo ( hazard ratio , 0.90 ; 95 % CI , 0.75 to 1.08 ; P = .124 ) . Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms , respectively ( hazard ratio , 0.66 ; 95 % CI , 0.56 to 0.78 ) . Common grade 3/4 adverse events included anemia , decreased appetite , and fatigue . The safety profile was similar in patients enrolled in Asia versus ROW . CONCLUSION Compared with BSC , everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy . The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers BACKGROUND Trastuzumab , a monoclonal antibody against human epidermal growth factor receptor 2 ( HER2 ; also known as ERBB2 ) , was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer . METHODS ToGA ( Trastuzumab for Gastric Cancer ) was an open-label , international , phase 3 , r and omised controlled trial undertaken in 122 centres in 24 countries . Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation . Participants were r and omly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab . Allocation was by block r and omisation stratified by Eastern Cooperative Oncology Group performance status , chemotherapy regimen , extent of disease , primary cancer site , and measurability of disease , implemented with a central interactive voice recognition system . The primary endpoint was overall survival in all r and omised patients who received study medication at least once . This trial is registered with Clinical Trials.gov , number NCT01041404 . FINDINGS 594 patients were r and omly assigned to study treatment ( trastuzumab plus chemotherapy , n=298 ; chemotherapy alone , n=296 ) , of whom 584 were included in the primary analysis ( n=294 ; n=290 ) . Median follow-up was 18.6 months ( IQR 11 - 25 ) in the trastuzumab plus chemotherapy group and 17.1 months ( 9 - 25 ) in the chemotherapy alone group . Median overall survival was 13.8 months ( 95 % CI 12 - 16 ) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months ( 10 - 13 ) in those assigned to chemotherapy alone ( hazard ratio 0.74 ; 95 % CI 0.60 - 0.91 ; p=0.0046 ) . The most common adverse events in both groups were nausea  ( trastuzumab plus chemotherapy , 197 [ 67 % ] vs chemotherapy alone , 184 [ 63 % ] ) , vomiting ( 147 [ 50 % ] vs 134 [ 46 % ] ) , and neutropenia ( 157 [ 53 % ] vs 165 [ 57 % ] ) . Rates of overall grade 3 or 4 adverse events ( 201 [ 68 % ] vs 198 [ 68 % ] ) and cardiac adverse events ( 17 [ 6 % ] vs 18 [ 6 % ] ) did not differ between groups . INTERPRETATION Trastuzumab in combination with chemotherapy can be considered as a new st and ard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer . FUNDING F Hoffmann-La Roche BACKGROUND Second-line chemotherapy for patients with oesophagogastric adenocarcinoma refractory to platinum and fluoropyrimidines has not shown benefits in health-related quality of life ( HRQoL ) . We assessed whether the addition of docetaxel to active symptom control alone can improve survival and HRQoL for patients . METHODS For this open-labelled , multicentre trial , we recruited patients aged 18 years or older from 30 UK centres . Patients were eligible if they had an advanced , histologically confirmed adenocarcinoma of the oesophagus , oesophagogastric junction , or stomach that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination . Patients could have an Eastern Cooperative Oncology Group performance status of 0 - 2 . We r and omly assigned patients using a central , computerised minimisation procedure to receive docetaxel plus active symptom control , or active symptom control alone ( 1:1 ; stratified by disease status , disease site , duration of response to previous chemotherapy , and performance status ) . Docetaxel was given at a dose of 75 mg/m(2 ) by intravenous infusion every 3 weeks for up to six cycles . The primary endpoint was overall survival , analysed by intention to treat . This is the report of the planned final analysis . This study is an International St and ardised R and omised Controlled Trial , number IS RCT N13366390 . FINDINGS Between April 21 , 2008 , and April 26 , 2012 , we recruited 168 patients , allocating 84 to each treatment group . After a median follow-up of 12 months [ IQR 10 - 21 ] ) and 161 ( 96 % ) deaths ( 80 in the docetaxel group , 81 in the active symptom control group ) , median overall survival in the docetaxel group was 5.2 months ( 95 % CI 4.1 - 5.9 ) versus 3.6 months ( 3.3 - 4.4 ) in the active symptom control group ( hazard ratio 0.67 , 95 % CI 0.49 - 0.92 ; p=0.01 ) . Docetaxel was associated with higher incidence of grade 3 - 4 neutropenia ( 12 [ 15 % ] patients vs no patients ) , infection ( 15 [ 19 % ] patients vs two [ 3 % ] patients ) , and febrile neutropenia ( six [ 7 % ] patients vs no patients ) . Patients receiving docetaxel reported less pain ( p=0.0008 ) and less nausea and vomiting ( p=0.02 ) and constipation ( p=0.02 ) . Global HRQoL was similar between the groups ( p=0.53 ) . Disease specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia ( p=0.02 ) and abdominal pain ( p=0.01 ) . INTERPRETATION Our findings suggest that docetaxel can be recommended as an appropriate second-line treatment for patients with oesophagogastric adenocarcinoma that is refractory to treatment with platinum and fluoropyrimidine . FUNDING Cancer Research UK BACKGROUND The value of second-line therapy for metastatic gastric cancer is unclear . So far there are no r and omised phase III data comparing second-line chemotherapy to best supportive care ( BSC ) . In this prospect i ve , multicenter , open label , r and omised phase III study we compared irinotecan to BSC to evaluate the impact on survival of second-line chemotherapy . METHODS Eligible patients ( pts ) had metastatic or locally advanced gastro-oesophageal junction or gastric adenocarcinoma , objective tumour progression during or within 6months after first-line chemotherapy and ECOG performance status 0 - 2 . Stratification for time of progression after first-line therapy , ECOG PS and pretreatment secured even distribution of important prognostic factors . TREATMENT Arm A : Irinotecan 250mg/m(2)q3w ( first cycle ) to be increased to 350mg/m(2 ) , depending on toxicity . Arm B : BSC . FINDINGS Between 10/2002 and 12/2006 40 pts were r and omised . The study was closed prematurely due to poor accrual . Responsefor arm A ( 19 pts evaluable ) : No objective responses , SD 53 % , PD 47 % . Improvement of tumour related symptoms : Arm A 50 % of pts , arm B 7 % . Overall Survival : ( all events in 40 pts have occurred ) : The hazard ratio for death was reduced to 0.48 ( 95%CI 0.25 - 0.92 ) in the irinotecan-arm ( p=0.012 ) . Median survival arm A : 4.0months ( 95 % CI 3.6 - 7.5 ) , arm B : 2.4months ( 95 % CI 1.7 - 4.9 ) . INTERPRETATION Irinotecan as second-line chemotherapy significantly prolongs overall survival compared to BSC in the studied pts . Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer . FUNDING The study was supported by a research grant from Aventis and Pfizer BACKGROUND Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated . In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer ( SPIRITS ) trial , we aim ed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin  than with  S-1 alone . METHODS In this phase III trial , chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26 , 2002 , and Nov 30 , 2004 , at 38 centres in Japan , and r and omly assigned to S-1 plus cisplatin or S-1 alone .  In patients assigned to S-1 plus cisplatin , S-1 ( 40 - 60 mg depending on patient 's body surface area ) was given orally , twice daily for 3 consecutive weeks , and 60 mg/m(2 ) cisplatin was given intravenously on day 8 , followed by a 2-week rest period , within a 5-week cycle . Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks , followed by a 2-week rest period , within a 6-week cycle . The primary endpoint was overall survival . Secondary endpoints were progression-free survival , proportions of responders , and safety . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00150670 . FINDINGS 305 patients were enrolled ; seven patients were ineligible or withdrew consent , therefore , 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone .  Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin ( 13.0 months [ IQR 7.6 - 21.9 ] ) than in those assigned to S-1 alone ( 11.0 months [ 5.6 - 19.8 ] ; hazard ratio for death , 0.77 ; 95 % CI 0.61 - 0.98 ; p=0.04 ) . Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone ( median progression-free survival 6.0 months [ 3.3 - 12.9 ] vs 4.0 months [ 2.1 - 6.8 ] ; p<0.0001 ) . Additionally , of 87 patients assigned S-1 plus cisplatin who had target tumours , one patient had a complete response and 46 patients had partial responses , ie , a total of 54 % ( range 43 - 65 ) . Of 106 patients assigned S-1 alone who had target tumours , one patient had a complete response and 32 had partial responses , ie , a total of 31 % ( 23 - 41 ) . We recorded more grade 3 or 
    Output:
    