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 Three-year disease-free survival ( DFS ) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin ( LV5FU2 ) with the addition of oxaliplatin ( FOLFOX4 ) . Final results of the study , including 6-year overall survival ( OS ) and 5-year up date d DFS , are reported . PATIENTS AND METHODS A total of 2,246 patients were r and omly assigned to receive LV5FU2 or FOLFOX4 for 6 months . The primary end point was DFS . Secondary end points were OS and safety . Results Five-year DFS rates were 73.3 % and 67.4 % in the FOLFOX4 and LV5FU2 groups , respectively ( hazard ratio [ HR ] = 0.80 ; 95 % CI , 0.68 to 0.93 ; P = .003 ) . Six-year OS rates were 78.5 % and 76.0 % in the FOLFOX4 and LV5FU2 groups , respectively ( HR = 0.84 ; 95 % CI , 0.71 to 1.00 ; P = .046 ) ; corresponding 6-year OS rates for patients with stage III disease were 72.9 % and 68.7 % , respectively ( HR = 0.80 ; 95 % CI , 0.65 to 0.97 ; P = .023 ) . No difference in OS was seen in the stage II population . The incidence of second noncolorectal cancers was 5.5 % and 6.1 % in the FOLFOX4 and LV5FU2 groups , respectively . Among patients receiving oxaliplatin , the frequency of grade 3 peripheral sensory neuropathy was 1.3 % 12 months after treatment and 0.7 % at 48 months . CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease Summary Background Preoperative ( neoadjuvant ) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal , gastric , and rectal cancers , perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery . The FOxTROT trial aims to investigate the feasibility , safety , and efficacy of preoperative chemotherapy for colon cancer . Methods In the pilot stage of this r and omised controlled trial , 150 patients with radiologically staged locally advanced ( T3 with ≥5 mm invasion beyond the muscularis propria or T4 ) tumours from 35 UK centres were r and omly assigned ( 2:1 ) to preoperative ( three cycles of OxMdG [ oxaliplatin 85 mg/m2 , l-folinic acid 175 mg , fluorouracil 400 mg/m2 bolus , then 2400 mg/m2 by 46 h infusion ] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG ) or st and ard postoperative chemotherapy ( 12 cycles of OxMdG ) . Patients with KRAS wild-type tumours were r and omly assigned ( 1:1 ) to receive panitumumab ( 6 mg/kg ; every 2 weeks with the first 6 weeks of chemotherapy ) or not . Treatment allocation was through a central r and omisation service using a minimised r and omisation procedure including age , radiological T and N stage , site of tumour , and presence of defunctioning colostomy as stratification variables . Primary outcome measures of the pilot phase were feasibility , safety , and tolerance of preoperative therapy , and accuracy of radiological staging . Analysis was by intention to treat . This trial is registered , number IS RCT N 87163246 . Findings 96 % ( 95 of 99 ) of patients started and 89 % ( 85 of 95 ) completed  preoperative chemotherapy  with grade 3–4 gastrointestinal toxicity in 7 % ( seven of 94 ) of patients . All 99 tumours in the preoperative group were resected , with no significant differences in postoperative morbidity between the preoperative and control groups : 14 % ( 14 of 99 ) versus 12 % ( six of 51 ) had complications prolonging hospital stay ( p=0·81 ) . 98 % ( 50 of 51 ) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91 % ( 90 of 99 ) of patients following preoperative chemotherapy ( p=0·10 ) . Preoperative therapy result ed in significant downstaging of TNM5 compared with the postoperative group ( p=0·04 ) , including two pathological complete responses , apical node involvement ( 1 % [ one of 98 ] vs 20 % [ ten of 50 ] , p<0·0001 ) , resection margin involvement ( 4 % [ four of 99 ] vs 20 % [ ten of 50 ] , p=0·002 ) , and blinded central ly scored tumour regression grading : 31 % ( 29 of 94 ) vs 2 % ( one of 46 ) moderate or greater regression ( p=0·0001 ) . Interpretation Preoperative chemotherapy for radiologically staged , locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity . Proceeding to the phase 3 trial , to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome , is appropriate . Funding Cancer Research UK The laparoscopic approach to st and ard resections in colorectal cancer has proven that it may provide equal rates of R0 resections and adequate retrieval of lymph nodes as open procedures if performed by experienced h and s. There might be difficulties in more advanced tumors or those with lymphatic spread beyond typical drainage areas and more extensive operations might be required . An atypical pattern of lymphatic spread often is associated with other adverse factors such as multifocality of primary cancers and adverse tumorbiological factors such as grade . Such patient subgroups may be defined beforeh and and include particularly patients with underlying ulcerative colitis . Repetitively , extended lymph node dissection approaches have been advocated , however neither in r and omised trails nor in meta‐ analysis has a more favourable outcome of patients undergoing such extended lymphatic dissections been demonstrated . Sticking to the rules of classical dissection of lymphatic drainage basins with removal of adequate lymph node numbers is one corner stone for successful treatment of colorectal cancer . The other one refers to a detailed description of the procedure performed in order to make the surgical procedure trackable Background : Enhancer of zeste homologue 2 ( EZH2 ) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation . Methods : We studied EZH2 expression in 409 patients with colorectal cancer stages II and III . The patients were included in a r and omised study , and treated with surgery alone or surgery followed by adjuvant chemotherapy . Results : EZH2 expression was significantly related to increased tumour cell proliferation , as assessed by Ki-67 expression . In colon cancer , strong EZH2 expression ( P=0.041 ) and high proliferation ( ⩾40 % ; P=0.001 ) were both associated with better relapse-free survival ( RFS ) . In contrast , no such associations were found among rectal cancers . High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy ( P=0.001 ) , but not among those who were treated by surgery alone ( P=0.087 ) . In colon cancers stage III , a significant association between RFS and r and omisation group was found in patients with high proliferation ( P=0.046 ) , but not in patients with low proliferation ( P=0.26 ) . Multivariate analyses of colon cancers showed that stage III ( hazard ratio ( HR ) 4.00 ) and high histological grade ( HR 1.80 ) were independent predictors of reduced RFS , whereas high proliferation indicated improved RFS ( HR 0.55 ) . Conclusion : Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer , but not so in rectal cancer Twelve hundred ninety-six patients with resected colon cancer that either was locally invasive ( Stage B2 ) or had regional nodal involvement ( Stage C ) were r and omly assigned to observation or to treatment for one year with levamisole combined with fluorouracil .  Patients with Stage C disease could also be r and omly assigned to treatment with levamisole alone . The median follow-up time at this writing is 3 years ( range , 2 to 5 1/2 ) . Among the patients with Stage C disease , therapy with levamisole plus fluorouracil reduced the risk of cancer recurrence by 41 percent ( P less than 0.0001 ) . The overall death rate was reduced by 33 percent ( P approximately 0.006 ) . Treatment with levamisole alone had no detectable effect . The results in the patients with Stage B2 disease were equivocal and too preliminary to allow firm conclusions . Toxic effects of levamisole alone were infrequent , usually consisting of mild nausea with occasional dermatitis or leukopenia , and those of levamisole plus fluorouracil were essentially the same as those of fluorouracil alone -- i.e . , nausea , vomiting , stomatitis , diarrhea , dermatitis , and leukopenia . These reactions were usually not severe and did not greatly impede patients ' compliance with their regimen . We conclude that adjuvant therapy with levamisole and fluorouracil should be st and ard treatment for Stage C colon carcinoma . Since most patients in our study were treated by community oncologists , this approach should be readily adaptable to conventional medical practice PURPOSE The National Surgical Adjuvant Breast and Bowel Project ( NSABP ) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin ( FULV ) improved disease-free survival ( DFS ) in patients with stage II or III colon cancer . This analysis is the first publication of overall survival ( OS ) for the NSABP C-07 study . We up date d DFS and examined both end points in clinical ly relevant patient subsets . PATIENTS AND METHODS Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective . We investigated toxicity as a driver of divergent outcomes in these subsets . RESULTS In all , 2,409 eligible patients with follow-up were r and omly assigned to either FULV ( FU 500 mg/m(2 ) by intravenous [ IV ] bolus weekly for 6 weeks ; leucovorin 500 mg/m(2 ) IV weekly for 6 weeks of each 8-week cycle for three cycles ) or FLOX ( FULV plus oxaliplatin 85 mg/m(2 ) IV on days 1 , 15 , and 29 of each cycle ) . With 8 years median follow-up , OS was similar between treatment groups ( hazard ratio [ HR ] , 0.88 ; 95 % CI , 0.75 to 1.02 ; P = .08 ) . FLOX remained superior for DFS ( HR , 0.82 ; 95 % CI , 0.72 to 0.93 ; P = .002 ) . The effect of oxaliplatin on OS did not differ by stage of disease ( interaction P = .38 for OS ; interaction P = 0.37 for DFS ) but did vary by age for OS ( younger than age 70 v 70 + interaction P = .039 ) . There was a similar trend for DFS ( interaction P = .073 ) . Oxaliplatin significantly improved OS in patients younger than age 70 ( HR , 0.80 ; 95 % CI , 0.68 to 0.95 ; P = .013 ) , but no positive effect was evident in older patients . CONCLUSION Overall , the addition of oxaliplatin to FULV has not been proven to extend OS in this trial , but the DFS effect remained strong . Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70 BACKGROUND Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer . Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma . METHODS Patients from 330 centres in 34 countries were enrolled into this phase 3 , open-label r and omised trial . Patients with curatively resected stage III or high-risk stage II colon carcinoma were r and omly assigned ( 1:1:1 ) to receive FOLFOX4 ( oxaliplatin 85 mg/m(2 ) , leucovorin 200 mg/m(2 ) , and fluorouracil 400 mg/m(2 ) bolus plus 600 mg/m(2 ) 22-h continuous infusion on day 1 ; leucovorin 200 mg/m(2 ) plus fluorouracil 400 mg/m(2 ) bolus plus 600 mg/m(2 ) 22-h continuous infusion on day 
    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 Three-year disease-free survival ( DFS ) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin ( LV5FU2 ) with the addition of oxaliplatin ( FOLFOX4 ) . Final results of the study , including 6-year overall survival ( OS ) and 5-year up date d DFS , are reported . PATIENTS AND METHODS A total of 2,246 patients were r and omly assigned to receive LV5FU2 or FOLFOX4 for 6 months . The primary end point was DFS . Secondary end points were OS and safety . Results Five-year DFS rates were 73.3 % and 67.4 % in the FOLFOX4 and LV5FU2 groups , respectively ( hazard ratio [ HR ] = 0.80 ; 95 % CI , 0.68 to 0.93 ; P = .003 ) . Six-year OS rates were 78.5 % and 76.0 % in the FOLFOX4 and LV5FU2 groups , respectively ( HR = 0.84 ; 95 % CI , 0.71 to 1.00 ; P = .046 ) ; corresponding 6-year OS rates for patients with stage III disease were 72.9 % and 68.7 % , respectively ( HR = 0.80 ; 95 % CI , 0.65 to 0.97 ; P = .023 ) . No difference in OS was seen in the stage II population . The incidence of second noncolorectal cancers was 5.5 % and 6.1 % in the FOLFOX4 and LV5FU2 groups , respectively . Among patients receiving oxaliplatin , the frequency of grade 3 peripheral sensory neuropathy was 1.3 % 12 months after treatment and 0.7 % at 48 months . CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease Summary Background Preoperative ( neoadjuvant ) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal , gastric , and rectal cancers , perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery . The FOxTROT trial aims to investigate the feasibility , safety , and efficacy of preoperative chemotherapy for colon cancer . Methods In the pilot stage of this r and omised controlled trial , 150 patients with radiologically staged locally advanced ( T3 with ≥5 mm invasion beyond the muscularis propria or T4 ) tumours from 35 UK centres were r and omly assigned ( 2:1 ) to preoperative ( three cycles of OxMdG [ oxaliplatin 85 mg/m2 , l-folinic acid 175 mg , fluorouracil 400 mg/m2 bolus , then 2400 mg/m2 by 46 h infusion ] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG ) or st and ard postoperative chemotherapy ( 12 cycles of OxMdG ) . Patients with KRAS wild-type tumours were r and omly assigned ( 1:1 ) to receive panitumumab ( 6 mg/kg ; every 2 weeks with the first 6 weeks of chemotherapy ) or not . Treatment allocation was through a central r and omisation service using a minimised r and omisation procedure including age , radiological T and N stage , site of tumour , and presence of defunctioning colostomy as stratification variables . Primary outcome measures of the pilot phase were feasibility , safety , and tolerance of preoperative therapy , and accuracy of radiological staging . Analysis was by intention to treat . This trial is registered , number IS RCT N 87163246 . Findings 96 % ( 95 of 99 ) of patients started and 89 % ( 85 of 95 ) completed  preoperative chemotherapy  with grade 3–4 gastrointestinal toxicity in 7 % ( seven of 94 ) of patients . All 99 tumours in the preoperative group were resected , with no significant differences in postoperative morbidity between the preoperative and control groups : 14 % ( 14 of 99 ) versus 12 % ( six of 51 ) had complications prolonging hospital stay ( p=0·81 ) . 98 % ( 50 of 51 ) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91 % ( 90 of 99 ) of patients following preoperative chemotherapy ( p=0·10 ) . Preoperative therapy result ed in significant downstaging of TNM5 compared with the postoperative group ( p=0·04 ) , including two pathological complete responses , apical node involvement ( 1 % [ one of 98 ] vs 20 % [ ten of 50 ] , p<0·0001 ) , resection margin involvement ( 4 % [ four of 99 ] vs 20 % [ ten of 50 ] , p=0·002 ) , and blinded central ly scored tumour regression grading : 31 % ( 29 of 94 ) vs 2 % ( one of 46 ) moderate or greater regression ( p=0·0001 ) . Interpretation Preoperative chemotherapy for radiologically staged , locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity . Proceeding to the phase 3 trial , to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome , is appropriate . Funding Cancer Research UK The laparoscopic approach to st and ard resections in colorectal cancer has proven that it may provide equal rates of R0 resections and adequate retrieval of lymph nodes as open procedures if performed by experienced h and s. There might be difficulties in more advanced tumors or those with lymphatic spread beyond typical drainage areas and more extensive operations might be required . An atypical pattern of lymphatic spread often is associated with other adverse factors such as multifocality of primary cancers and adverse tumorbiological factors such as grade . Such patient subgroups may be defined beforeh and and include particularly patients with underlying ulcerative colitis . Repetitively , extended lymph node dissection approaches have been advocated , however neither in r and omised trails nor in meta‐ analysis has a more favourable outcome of patients undergoing such extended lymphatic dissections been demonstrated . Sticking to the rules of classical dissection of lymphatic drainage basins with removal of adequate lymph node numbers is one corner stone for successful treatment of colorectal cancer . The other one refers to a detailed description of the procedure performed in order to make the surgical procedure trackable Background : Enhancer of zeste homologue 2 ( EZH2 ) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation . Methods : We studied EZH2 expression in 409 patients with colorectal cancer stages II and III . The patients were included in a r and omised study , and treated with surgery alone or surgery followed by adjuvant chemotherapy . Results : EZH2 expression was significantly related to increased tumour cell proliferation , as assessed by Ki-67 expression . In colon cancer , strong EZH2 expression ( P=0.041 ) and high proliferation ( ⩾40 % ; P=0.001 ) were both associated with better relapse-free survival ( RFS ) . In contrast , no such associations were found among rectal cancers . High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy ( P=0.001 ) , but not among those who were treated by surgery alone ( P=0.087 ) . In colon cancers stage III , a significant association between RFS and r and omisation group was found in patients with high proliferation ( P=0.046 ) , but not in patients with low proliferation ( P=0.26 ) . Multivariate analyses of colon cancers showed that stage III ( hazard ratio ( HR ) 4.00 ) and high histological grade ( HR 1.80 ) were independent predictors of reduced RFS , whereas high proliferation indicated improved RFS ( HR 0.55 ) . Conclusion : Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer , but not so in rectal cancer Twelve hundred ninety-six patients with resected colon cancer that either was locally invasive ( Stage B2 ) or had regional nodal involvement ( Stage C ) were r and omly assigned to observation or to treatment for one year with levamisole combined with fluorouracil .  Patients with Stage C disease could also be r and omly assigned to treatment with levamisole alone . The median follow-up time at this writing is 3 years ( range , 2 to 5 1/2 ) . Among the patients with Stage C disease , therapy with levamisole plus fluorouracil reduced the risk of cancer recurrence by 41 percent ( P less than 0.0001 ) . The overall death rate was reduced by 33 percent ( P approximately 0.006 ) . Treatment with levamisole alone had no detectable effect . The results in the patients with Stage B2 disease were equivocal and too preliminary to allow firm conclusions . Toxic effects of levamisole alone were infrequent , usually consisting of mild nausea with occasional dermatitis or leukopenia , and those of levamisole plus fluorouracil were essentially the same as those of fluorouracil alone -- i.e . , nausea , vomiting , stomatitis , diarrhea , dermatitis , and leukopenia . These reactions were usually not severe and did not greatly impede patients ' compliance with their regimen . We conclude that adjuvant therapy with levamisole and fluorouracil should be st and ard treatment for Stage C colon carcinoma . Since most patients in our study were treated by community oncologists , this approach should be readily adaptable to conventional medical practice PURPOSE The National Surgical Adjuvant Breast and Bowel Project ( NSABP ) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin ( FULV ) improved disease-free survival ( DFS ) in patients with stage II or III colon cancer . This analysis is the first publication of overall survival ( OS ) for the NSABP C-07 study . We up date d DFS and examined both end points in clinical ly relevant patient subsets . PATIENTS AND METHODS Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective . We investigated toxicity as a driver of divergent outcomes in these subsets . RESULTS In all , 2,409 eligible patients with follow-up were r and omly assigned to either FULV ( FU 500 mg/m(2 ) by intravenous [ IV ] bolus weekly for 6 weeks ; leucovorin 500 mg/m(2 ) IV weekly for 6 weeks of each 8-week cycle for three cycles ) or FLOX ( FULV plus oxaliplatin 85 mg/m(2 ) IV on days 1 , 15 , and 29 of each cycle ) . With 8 years median follow-up , OS was similar between treatment groups ( hazard ratio [ HR ] , 0.88 ; 95 % CI , 0.75 to 1.02 ; P = .08 ) . FLOX remained superior for DFS ( HR , 0.82 ; 95 % CI , 0.72 to 0.93 ; P = .002 ) . The effect of oxaliplatin on OS did not differ by stage of disease ( interaction P = .38 for OS ; interaction P = 0.37 for DFS ) but did vary by age for OS ( younger than age 70 v 70 + interaction P = .039 ) . There was a similar trend for DFS ( interaction P = .073 ) . Oxaliplatin significantly improved OS in patients younger than age 70 ( HR , 0.80 ; 95 % CI , 0.68 to 0.95 ; P = .013 ) , but no positive effect was evident in older patients . CONCLUSION Overall , the addition of oxaliplatin to FULV has not been proven to extend OS in this trial , but the DFS effect remained strong . Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70 BACKGROUND Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer . Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma . METHODS Patients from 330 centres in 34 countries were enrolled into this phase 3 , open-label r and omised trial . Patients with curatively resected stage III or high-risk stage II colon carcinoma were r and omly assigned ( 1:1:1 ) to receive FOLFOX4 ( oxaliplatin 85 mg/m(2 ) , leucovorin 200 mg/m(2 ) , and fluorouracil 400 mg/m(2 ) bolus plus 600 mg/m(2 ) 22-h continuous infusion on day 1 ; leucovorin 200 mg/m(2 ) plus fluorouracil 400 mg/m(2 ) bolus plus 600 mg/m(2 ) 22-h continuous infusion on day 
    Output:
    