***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 In the non-curative setting , the sequence in which anticancer agents are used , singly or in combination , may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects . We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer , who were regarded as not potentially curable irrespective of response . METHODS We studied patients with advanced colorectal cancer , starting treatment with non-curative intent . 2135 unpretreated patients were r and omly assigned to three treatment strategies in the ratio 1:1:1 . Strategy A ( control group ) was single-agent fluorouracil ( given with levofolinate over 48 h every 2 weeks ) until failure , then single-agent irinotecan . Strategy B was fluorouracil until failure , then combination chemotherapy . Strategy C was combination chemotherapy from the outset . Within strategies B and C , patients were r and omly assigned to receive , as the combination regimen , fluorouracil plus irinotecan ( groups B-ir and C-ir ) or fluorouracil plus oxaliplatin ( groups B-ox and C-ox ) . The primary endpoint was overall survival , analysed by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N 79877428 . RESULTS Median survival of patients allocated to control strategy A was 13.9 months . Median survival of each of the other groups was longer ( B-ir 15.0 , B-ox 15.2 , C-ir 16.7 , and C-ox 15.4 months ) . However , log-rank comparison of each group against control showed that only C-ir -- the first-line combination strategy including irinotecan -- satisfied the statistical test for superiority ( p=0.01 ) . Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less ( HR=1.06 , 90 % CI 0.97 - 1.17 ) . INTERPRETATION Our data challenge the assumption that , in this non-curative setting , maximum tolerable treatment must necessarily be used first-line . The staged approach of initial single-agent treatment up grade d to combination when required is not worse than first-line combination , and is an alternative option for discussion with patients BACKGROUND No prospect i ve trials have specifically addressed the efficacy and safety of panitumumab in elderly patients with metastatic colorectal cancer ( CRC ) . We aim ed at assessing the efficacy and safety of single agent panitumumab in " frail " elderly patients diagnosed with metastatic RAS and BRAF wild-type CRC . MATERIAL S AND METHODS Forty elderly patients ( aged ≥ 75 years ) with metastatic RAS-BRAF wild-type CRC received off-label prescriptions of single-agent panitumumab at seven Italian institutions . Treatment was administered as first line in patients with absolute contraindication to any chemotherapy or as second-line treatment after failure of a fluoropyrimidine-based treatment , in the presence of contraindication to irinotecan . The outcome measures included objective response rate ( ORR ) , as well as progression-free survival ( PFS ) , disease control rate ( DCR ) , overall survival ( OS ) , and safety . RESULTS The median PFS and OS were 6.4 months ( 95 % confidence interval [ CI ] : 4.9 - 8 months ) and 14.3 months ( 95 % CI : 10.9 - 17.7 months ) , respectively . ORR was 32.5 % , and DCR was 72.5 % . Dose reductions related to adverse events ( AEs ) were reported in 9 ( 23 % ) patients , but no permanent treatment discontinuation caused by was reported . The most frequent grade 3 AE was skin rash , with an incidence of 20 % . CONCLUSION Panitumumab is effective and well-tolerated in frail elderly patients with RAS-BRAF wild-type metastatic CRC and deemed unfit for chemotherapy . A r and omized study is needed to confirm these data . IMPLICATION S FOR PRACTICE Treatment of elderly patients with metastatic colorectal cancer represents a difficult challenge in clinical practice . A significant proportion of frail elderly patients do not receive treatment , reflecting ongoing uncertainty of clinical benefit and toxicity of chemotherapy . Unfit condition in this cohort of patients further limits antineoplastic prescription and consequently patient survival . RAS and BRAF wild-type status could help select an elderly and unfit population that could benefit from anti-epidermal growth factor receptor single agent therapy . In the present study , single-agent off-label panitumumab was effective and well-tolerated as first-line treatment in frail elderly patients deemed unfit for chemotherapy for metastatic RAS and BRAF wild-type colorectal cancer BACKGROUND In an ageing population , a greater proportion of geriatric patients will be considered for systemic chemotherapy . Colorectal cancer ( CRC ) is a common malignancy and will be a major health issue in geriatrics . We used the MAX population to investigate whether age affected the improved outcome found in CRC when bevacizumab is added to capecitabine chemotherapy . PATIENTS AND METHODS MAX , a three arm study of Capecitabine ( C ) versus CBevacizumab ( CB ) versus C BMi tomycin C ( CBM ) , found an improvement in progression-free survival ( PFS ) , with addition of B [ + /- mitomycin C ( MMC ) ] to C. This analysis assesses the effect of adding B ( + /- MMC ) to C on PFS , overall survival ( OS ) , response rate ( RR ) , toxicity and dose intensity in geriatric patients ( age ≥ 75 years ) . RESULTS Ninety-nine patients ( 21 % ) were aged 75 - 86 years . Baseline characteristics were well balanced . Eighty-eight per cent commenced C at the lower optional dose of 2000 mg/m(2)/day ; days 1 - 14 , q21 ( 61 % for < 75 years ) and 88 % were Eastern Cooperative Oncology Group 0 - 1 . Co-morbidities were as expected in this population . The addition of B significantly improved PFS in geriatric patients ( C 5.8 months versus CB 8.8 months , Hazard ratio ( HR ) 0.65 and C versus CBM 10.4 months HR 0.38 ) . The interaction test for OS , RR and PFS revealed no impact of age . Dose intensity was maintained > 90 % in all patients . There were no major differences in toxicity patterns between age cohorts . CONCLUSIONS Addition of B to C significantly improved PFS in this geriatric population , with similar benefits to those aged < 75 years . Treatment was well tolerated with no signal of increased toxicity ( including thromboembolism ) when compared with those aged < 75 years Background : Bevacizumab provides clinical benefit in multiple solid tumours , but is associated with some increase in bleeding risk . Thrombotic events necessitating therapeutic anticoagulation ( TA ) are common in cancer . This report describes the safety of concurrent bevacizumab and TA in three large placebo-controlled clinical studies . Methods : Study 1 ( metastatic colorectal cancer ( mCRC ) ) , study 2 ( mCRC ) , and study 3 ( advanced non-small cell lung cancer ) were blinded phase III studies . Eligibility criteria excluded patients on TA . Patients on protocol treatment who developed thrombotic events requiring TA were permitted to continue bevacizumab or placebo under specified conditions . Adverse events in patients who received bevacizumab and TA concurrently were assessed using the NCI – CTCAE scale . Results : While experience is limited , venous thrombotic events were the most common reason for TA initiation in the three studies . Severe bleeding event rates for patients receiving TA in the bevacizumab-treated groups were similar in frequency to the placebo groups , ranging from 0 to 8 % or 0 to 67 events per 100 patient-years . No severe pulmonary bleeding was reported in any of the TA-treated population s. Conclusions : These data suggest that bevacizumab did not increase the risk of severe bleeding in cancer patients who received TA Background : Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer ( mCRC ) . The prospect i ve BECOX study examined the efficacy and safety of bevacizumab plus XELOX , followed by bevacizumab plus capecitabine in elderly patients with mCRC . Methods : Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included . Patients received bevacizumab 7.5 mg kg−1 and oxaliplatin 130 mg m−2 on day 1 , plus capecitabine 1000 mg m−2 bid orally on days 1–14 every 21 days ; oxaliplatin was discontinued after 6 cycles . The primary end point was time to progression ( TTP ) . Results : The intent-to-treat population comprised 68 patients ( 65 % male , median age 76 years ) . Median TTP was 11.1 months ; median overall survival was 20.4 months ; overall response rate was 46 % . Grade 3 or 4 adverse events included diarrhoea ( 18 % ) and asthenia ( 16 % ) . Grade 3 or 4 adverse events of special interest for bevacizumab  included deep-vein thrombosis ( 6 % ) and pulmonary embolism ( 4 % ) . Conclusions : Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study . The adverse-event profile was similar to previous reports ; no new safety concerns were identified . Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX BACKGROUND The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined . Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer . METHODS In this open-label , r and omised , phase 3 trial , we r and omly assigned patients ( 1:1 ratio ) with advanced , measurable , non-resectable colorectal cancer and WHO performance status 0 - 2 to receive either first-line treatment with bolus ( 400 mg/m(2 ) ) and infusional ( 2400 mg/m(2 ) ) fluorouracil plus leucovorin ( 400 mg/m(2 ) ) ( simplified LV5FU2 regimen ) , second-line LV5FU2 plus oxaliplatin ( 100 mg/m(2 ) ) ( FOLFOX6 ) , and third-line LV5FU2 plus irinotecan ( 180 mg/m(2 ) ) ( FOLFIRI ) or first-line FOLFOX6 and second-line FOLFIRI . Chemotherapy was administered every 2 weeks . R and omisation was done central ly using minimisation ( minimisation factors were WHO performance status , previous adjuvant chemotherapy , number of disease sites , and centre ) . The primary endpoint was progression-free survival after two lines of treatment . Analyses were by intention-to-treat . This trial is registered at Clinical Trials.gov , NCT00126256 . FINDINGS 205 patients were r and omly assigned to the sequential group and 205 to the combination group . 161 ( 79 % ) patients in the sequential group and 161 ( 79 % ) in the combination group died during the study . Median progression-free survival after two lines was 10·5 months ( 95 % CI 9·6 - 11·5 ) in the sequential group and 10·3 months ( 9·0 - 11·9 ) in the combination group ( hazard ratio 0·95 , 95 % CI 0·77 - 1·16 ; p=0·61 ) . All six deaths caused by toxic effects of treatment occurred in the combination group . During first-line chemotherapy , significantly fewer severe ( grade 3 - 4 ) haematological adverse events ( 12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group ; p<0·0001 ) and non-haematological adverse events ( 26 events vs 186 events ; p<0·0001 ) occurred in the sequential group than in the combination group . INTERPRETATION Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced , non-resectable colorectal cancer . FUNDING Sanofi-Aventis France 
    Output:
    
Conclusion : Adding bevacizumab to first‐line fluoropyrimidine monochemotherapy significantly improved progression‐free and overall survival in unfit and elderly patients with mCRC , with a manageable safety profile and no unexpected toxicities