***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 In metastatic colorectal cancer , phase III studies have demonstrated the superiority of fluorouracil ( FU ) with leucovorin ( LV ) in combination with irinotecan or oxaliplatin over FU + LV alone . This phase III study investigated two sequences : folinic acid , FU , and irinotecan ( FOLFIRI ) followed by folinic acid , FU , and oxaliplatin ( FOLFOX6 ; arm A ) , and FOLFOX6 followed by FOLFIRI ( arm B ) . PATIENTS AND METHODS Previously untreated patients with assessable disease were r and omly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2 ) or dl-LV 400 mg/m(2 ) followed by a FU bolus 400 mg/m(2 ) and 46-hour infusion 2,400 to 3,000 mg/m(2 ) every 46 hours every 2 weeks , either with irinotecan 180 mg/m(2 ) or with oxaliplatin 100 mg/m(2 ) as a 2-hour infusion on day 1 . At progression , irinotecan was replaced by oxaliplatin ( arm A ) , or oxaliplatin by irinotecan ( arm B ) . RESULT Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI ( P = .99 ) . Median second progression-free survival ( PFS ) was 14.2 months in arm A versus 10.9 in arm B ( P = .64 ) . In first-line therapy , FOLFIRI achieved 56 % response rate ( RR ) and 8.5 months median PFS , versus FOLFOX6 which achieved 54 % RR and 8.0 months median PFS ( P = .26 ) . Second-line FOLFIRI achieved 4 % RR and 2.5 months median PFS , versus FOLFOX6 which achieved 15 % RR and 4.2 months PFS . In first-line therapy , National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis , nausea/vomiting , and grade 2 alopecia were more frequent with FOLFIRI , and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6 . CONCLUSION Both sequences achieved a prolonged survival and similar efficacy . The toxicity profiles were different The present exploratory analysis examined the efficacy , safety , and quality -of-life effects of everolimus ( EVE ) + exemestane ( EXE ) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting . In BOLERO-2 , patients with hormone-receptor-positive ( HR+ ) , human epidermal growth factor receptor-2-negative ( HER2− ) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor ( NSAI ) were r and omly assigned ( 2:1 ) to receive EVE ( 10 mg/day ) + EXE ( 25 mg/day ) or placebo ( PBO ) + EXE . The primary endpoint was progression-free survival ( PFS ) by local assessment . Overall , 137 patients received first-line EVE + EXE ( n = 100 ) or PBO + EXE ( n = 37 ) . Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE ( hazard ratio = 0.39 ; 95 % CI 0.25–0.62 ) , while maintaining quality of life . This was confirmed by central assessment ( 15.2 vs 4.2 months ; hazard ratio = 0.32 ; 95 % CI 0.18–0.57 ) . The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting . Furthermore , the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR+ , HER2− advanced breast cancer in postmenopausal patients BACKGROUND The BOLERO-2 study previously demonstrated that adding everolimus ( EVE ) to exemestane ( EXE ) significantly improved progression-free survival ( PFS ) by more than twofold in patients with hormone-receptor-positive ( HR(+ ) ) , HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors ( NSAIs ) . The overall survival ( OS ) analysis is presented here . PATIENTS AND METHODS BOLERO-2 is a phase III , double-blind , r and omized international trial comparing EVE 10 mg/day plus EXE 25 mg/day versus placebo ( PBO ) + EXE 25 mg/day in postmenopausal women with HR(+ ) advanced breast cancer with prior exposure to NSAIs . The primary end point was PFS by local investigator assessment ; OS was a key secondary end point . RESULTS At the time of data cutoff ( 3 October 2013 ) , 410 deaths had occurred and 13 patients remained on treatment .  Median OS in patients receiving EVE + EXE was 31.0 months [ 95 % confidence interval ( CI ) 28.0 - 34.6 months ] compared with 26.6 months ( 95 % CI 22.6 - 33.1 months ) in patients receiving PBO + EXE ( hazard ratio = 0.89 ; 95 % CI 0.73 - 1.10 ; log-rank P = 0.14 ) . Post study treatments were received by 84 % of patients in the EVE + EXE arm versus 90 % of patients in the PBO + EXE arm . Types of post study therapies were balanced across arms , except for chemotherapy ( 53 % EVE + EXE versus 63 % PBO + EXE ) . No new safety concerns were identified . CONCLUSIONS In BOLERO-2 , adding EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinical ly meaningful and statistically significant improvement in the primary end point , PFS ( 4.6-months prolongation in median PFS ; P < 0.0001 ) . Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting . TRIAL REGISTRATION NUMBER NCT00863655 Background Few targeted therapies ( TTs ) are registered for sarcoma treatment despite numerous phase II studies and yet there are potential treatment options for patients after st and ard treatment escape . The French Sarcoma Group - Bone Tumor Study Group ( GSF-GETO ) created a national registry to evaluate the outcome of patients treated with off-label TTs .  Methods Every consecutive sarcoma-patient receiving an off-label TT outside a clinical trial was included . The objective was to describe this patient efficacy and safety data in routine practice . Results From October 2008 to October 2011 , 249 patients in 24 centers received 278 treatment lines with TTs .  Twenty-five histological subtypes were included : most frequent were leiomyosarcoma ( n = 48 , receiving sorafenib in 63 % , and sunitinib in 27 % ) , GIST ( n = 39 , receiving sorafenib in 79 % ) , and angiosarcoma ( n = 18 , receiving sorafenib in 78 % ) . The overall response rate to TTs was 15 % ( 95 % CI [ 10,6 - 20,2 ] ) , the disease control rate at 2 months was 59 % . The median progression-free survival was 4,1 months ( IC 95 % [ 3,2 - 4,8 ] ) . Three complete responses were observed . No toxic death occurred , grade 3 and 4 toxicities were reported in 74 ( 27 % ) and 14 patients ( 5 % ) respectively . Conclusion Off-label TTs can be used for sarcoma patients in routine practice with an acceptable toxicity profile and efficacy similar to that reported in non-r and omized clinical trials BACKGROUND Cetuximab , an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor ( EGFR ) , has activity against colorectal cancers that express EGFR . METHODS From December 2003 to August 2005 , 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine , irinotecan , and oxaliplatin or had contraindications to treatment with these drugs underwent r and omization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care  ( 287 patients ) or best supportive care alone  ( 285 patients ) . The primary end point was overall survival . RESULTS In comparison with best supportive care alone , cetuximab treatment was associated with a significant improvement in overall survival ( hazard ratio for death , 0.77 ; 95 % confidence interval [ CI ] , 0.64 to 0.92 ; P=0.005 ) and in progression-free survival ( hazard ratio for disease progression or death , 0.68 ; 95 % CI , 0.57 to 0.80 ; P<0.001 ) . These benefits were robust after adjustment in a multivariable Cox proportional-hazards model . The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone . Partial responses occurred in 23 patients ( 8.0 % ) in the cetuximab group but in none in the group assigned to supportive care alone ( P<0.001 ) ; the disease was stable in an additional 31.4 % of patients assigned to cetuximab and in 10.9 % of patients assigned to supportive care alone ( P<0.001 ) . Quality of life was better preserved in the cetuximab group , with less deterioration in physical function and global health status scores ( both P<0.05 ) . Cetuximab treatment was associated with a characteristic rash ; a rash of grade 2 or higher was strongly associated with improved survival ( hazard ratio for death , 0.33 ; 95 % CI , 0.22 to 0.50 ; P<0.001 ) . The incidence of any adverse event of grade 3 or higher was 78.5 % in the cetuximab group and 59.1 % in the group assigned to supportive care alone ( P<0.001 ) . CONCLUSIONS Cetuximab improves overall survival and progression-free survival and preserves quality -of-life measures in patients with colorectal cancer in whom other treatments have failed . ( Clinical Trials.gov number , NCT00079066 [ Clinical Trials.gov ] . ) BACKGROUND Postmenopausal women with hormone receptor-positive ( HR(+ ) ) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor ( NSAI )  are usually treated with exemestane ( EXE ) , but no single st and ard of care exists in this setting . The BOLERO-2 trial demonstrated that adding everolimus ( EVE ) to EXE improved progression-free survival ( PFS ) while maintaining quality of life when compared with EXE alone . Because many women with HR(+ ) advanced breast cancer are elderly , the tolerability profile of EVE plus EXE in this population is of interest . PATIENTS AND METHODS BOLERO-2 , a phase III r and omized trial , compared EVE ( 10 mg/d ) and placebo ( PBO ) , both plus EXE ( 25 mg/d ) , in 724 postmenopausal women with HR(+ ) advanced breast cancer recurring/progressing after treatment with NSAIs . Safety and efficacy data in elderly patients are reported at 18-month median follow-up . RESULTS Baseline disease characteristics and treatment histories among the elderly subsets ( ≥ 65 years , n = 275 ; ≥ 70 years , n = 164 ) were generally comparable with younger patients . The addition of EVE to EXE improved PFS regardless of age ( hazard ratio , 0.59 [ ≥ 65 years ] and 0.45 [ ≥ 70 years ] ) . Adverse events ( AEs ) of special interest ( all grade s ) that occurred more frequently with EVE than with PBO included stomatitis , infections , rash , pneumonitis , and hyperglycemia . Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths . CONCLUSION Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR(+ ) advanced breast cancer . Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population BACKGROUND Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway . We aim ed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to tr 
    Output:
    
In comparison with NCT alone , NCT plus bevacizumab  significantly improve ORR and R0 hepatic resection rate but not for hepatic resection rate .