***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 VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis . Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist . We aim ed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib . METHODS In this r and omised , placebo-controlled , double-blind , multicentre , phase 3 trial ( REACH ) , patients were enrolled from 154 centres in 27 countries . Eligible patients were aged 18 years or older , had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy , had Child-Pugh A liver disease , an Eastern Cooperative Oncology Group performance status of 0 or 1 , had previously received sorafenib ( stopped because of progression or intolerance ) , and had adequate haematological and biochemical parameters . Patients were r and omly assigned ( 1:1 ) to receive intravenous ramucirumab ( 8 mg/kg ) or placebo every 2 weeks , plus best supportive care , until disease progression , unacceptable toxicity , or death . R and omisation was stratified by geographic region and cause of liver disease with a stratified permuted block method . Patients , medical staff , investigators , and the funder were masked to treatment assignment . The primary endpoint was overall survival in the intention-to-treat population . This study is registered with Clinical Trials.gov , number NCT01140347 . FINDINGS Between Nov 4 , 2010 , and April 18 , 2013 , 565 patients were enrolled , of whom 283 were assigned to ramucirumab and 282 were assigned to placebo . Median overall survival for the ramucirumab group was 9·2 months ( 95 % CI 8·0 - 10·6 ) versus 7·6 months ( 6·0 - 9·3 ) for the placebo group ( HR 0·87 [ 95 % CI 0·72 - 1·05 ] ; p=0·14 ) . Grade 3 or greater adverse events occurring in 5 % or more of patients in either treatment group were ascites ( 13 [ 5 % ] of 277 patients treated with ramucirumab vs 11 [ 4 % ] of 276 patients treated with placebo ) , hypertension ( 34 [ 12 % ] vs ten [ 4 % ] ) , asthenia ( 14 [ 5 % ] vs five [ 2 % ] ) , malignant neoplasm progression ( 18 [ 6 % ] vs 11 [ 4 % ] ) , increased aspartate aminotransferase concentration ( 15 [ 5 % ] vs 23 [ 8 % ] ) , thrombocytopenia ( 13 [ 5 % ] vs one [ < 1 % ] ) , hyperbilirubinaemia ( three [ 1 % ] vs 13 [ 5 % ] ) , and increased blood bilirubin ( five [ 2 % ] vs 14 [ 5 % ] ) . The most frequently reported ( ≥1 % ) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression . INTERPRETATION Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma . No new safety signals were noted in eligible patients and the safety profile is manageable . FUNDING Eli Lilly and PURPOSE This phase II study of sorafenib , an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases , assessed efficacy , toxicity , pharmacokinetics , and biomarkers in advanced hepatocellular carcinoma ( HCC ) patients . METHODS Patients with inoperable HCC , no prior systemic treatment , and Child-Pugh ( CP ) A or B , received continuous , oral sorafenib 400 mg bid in 4-week cycles . Tumor response was assessed every two cycles using modified WHO criteria . Sorafenib pharmacokinetics were measured in plasma sample s. Biomarker analysis included phosphorylated extracellular signal regulated kinase ( pERK ) in pretreatment biopsies ( immunohistochemistry ) and blood-cell RNA expression patterns in selected patients . RESULTS Of 137 patients treated ( male , 71 % ; median age , 69 years ) , 72 % had CP A , and 28 % had CP B. On the basis of independent assessment , three ( 2.2 % ) patients achieved a partial response , eight ( 5.8 % ) had a minor response , and 46 ( 33.6 % ) had stable disease for at least 16 weeks . Investigator-assessed median time to progression ( TTP ) was 4.2 months , and median overall survival was 9.2 months . Grade 3/4 drug-related toxicities included fatigue ( 9.5 % ) , diarrhea ( 8.0 % ) , and h and -foot skin reaction ( 5.1 % ) . There were no significant pharmacokinetic differences between CP A and B patients . Pretreatment tumor pERK levels correlated with TTP . A panel of 18 expressed genes was identified that distinguished " nonprogressors " from " progressors " with an estimated 100 % accuracy . CONCLUSION Although single-agent sorafenib has modest efficacy in HCC , the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents PURPOSE Open-label , phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer . PATIENTS AND METHODS Patients were stratified and r and omly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day . Primary end point was overall survival ( OS ) . RESULTS Early trial termination occurred for futility and safety reasons . A total of 1,074 patients were r and omly assigned to the study ( sunitinib arm , n = 530 ; sorafenib arm , n = 544 ) . For sunitinib and sorafenib , respectively , median OS was 7.9 versus 10.2 months ( hazard ratio [ HR ] , 1.30 ; one-sided P = .9990 ; two-sided P = .0014 ) ; median progression-free survival ( PFS ; 3.6 v 3.0 months ; HR , 1.13 ; one-sided P = .8785 ; two-sided P = .2286 ) and time to progression ( TTP ; 4.1 v 3.8 months ; HR , 1.13 ; one-sided P = .8312 ; two-sided P = .3082 ) were comparable . Median OS was similar among Asian ( 7.7 v 8.8 months ; HR , 1.21 ; one-sided P = .9829 ) and hepatitis B-infected patients ( 7.6 v 8.0 months ; HR , 1.10 ; one-sided P = .8286 ) , but was shorter with sunitinib in hepatitis C-infected patients ( 9.2 v 17.6 months ; HR , 1.52 ; one-sided P = .9835 ) . Sunitinib was associated with more frequent and severe adverse events ( AEs ) than sorafenib . Common grade 3/4 AEs were thrombocytopenia ( 29.7 % ) and neutropenia ( 25.7 % ) for sunitinib ; h and -foot syndrome ( 21.2 % ) for sorafenib . Discontinuations owing to AEs were similar ( sunitinib , 13.3 % ; sorafenib , 12.7 % ) . CONCLUSION OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib . OS was comparable in Asian and hepatitis B-infected patients . OS was superior in hepatitis C-infected patients who received sorafenib . Sunitinib-treated patients reported more frequent and severe toxicity BACKGROUND The efficacy and safety of axitinib , a potent and selective vascular endothelial growth factor receptors 1 - 3 inhibitor , combined with best supportive care ( BSC ) was evaluated in a global , r and omized , placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma ( HCC ) . PATIENTS AND METHODS Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion ( presence/absence of extrahepatic spread and /or vascular invasion ) and region ( Asian/non-Asian ) and r and omized ( 2:1 ) to axitinib/BSC ( starting dose 5 mg twice-daily ) or placebo/BSC . The primary end point was overall survival ( OS ) . RESULTS The estimated hazard ratio for OS was 0.907 [ 95 % confidence interval ( CI ) 0.646 - 1.274 ; one-sided stratified P = 0.287 ] for axitinib/BSC ( n = 134 ) versus placebo/BSC ( n = 68 ) , with the median ( 95 % CI ) of 12.7 ( 10.2 - 14.9 ) versus 9.7 ( 5.9 - 11.8 ) months , respectively . Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population . Improvements favouring axitinib/BSC ( P < 0.01 ) were observed in secondary efficacy end point analyses [ progression-free survival ( PFS ) , time to tumour progression ( TTP ) , and clinical benefit rate ( CBR ) ] , and were retained among Asian patients in the prespecified subgroup analyses . Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC . Most common all-causality adverse events with axitinib/BSC  were diarrhoea ( 54 % ) , hypertension ( 54 % ) , and decreased appetite ( 47 % ) . Baseline serum analyses identified potential new prognostic ( interleukin-6 , E-selectin , interleukin-8 , angiopoietin-2 , migration inhibitory factor , and c-MET ) or predictive ( E-selectin and stromal-derived factor-1 ) factors for survival . CONCLUSIONS Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups . However , axitinib/BSC result ed in significantly longer PFS and TTP and higher CBR , with acceptable toxicity in patients with advanced HCC . TRIAL REGISTRATION Clinical Trials.gov , NCT01210495 BACKGROUND In Japan and South Korea , transarterial chemoembolisation ( TACE ) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma ( HCC ) .  Sorafenib , a multikinase inhibitor , has been shown effective and safe in patients with advanced HCC . This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE . METHODS Patients ( n=458 ) with unresectable HCC , Child-Pugh class A cirrhosis and ≥25 % tumour necrosis/shrinkage 1 - 3 months after 1 or 2 TACE sessions were r and omised 1:1 to sorafenib 400 mg bid or placebo and treated until progression/recurrence or unacceptable toxicity . Primary end-point was time to progression/recurrence ( TTP ) . Secondary end-point was overall survival ( OS ) . FINDINGS Baseline characteristics in the two groups were similar ; > 50 % of patients started sorafenib>9 weeks after TACE . Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months , respectively ( hazard ratio ( HR ) , 0.87 ; 95 % confidence interval ( CI ) , 0.70 - 1.09 ; P=0.252 ) .  HR ( sorafenib/placebo ) for OS was 1.06 ( 95 % CI , 0.69 - 1.64 ; P=0.790 ) . Median daily dose of sorafenib was 386 mg , with 73 % of patients having dose reductions and 91 % having dose interruptions . Median administration of sorafenib and placebo was 17.1 and 20.1 weeks , respectively . No unexpected adverse events were observed . INTERPRETATION This trial , conducted prior to the reporting of registration al phase III trials , found that sorafenib did not significantly prolong TTP in patients who responded to TACE . This may have been due to delays in starting sorafenib after TACE and /or low daily sorafenib doses PURPOSE This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma ( HCC ) without prior systemic therapy . PATIENTS AND METHODS Patients were r and omly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily . Patients were stratified by region ( Outside Asia , Japan , and rest of Asia ) , Eastern Cooperative Oncology 
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Therefore , the treatment effect of MTAs on OS might be different in younger and older HCC patients undergoing first-line or second-line treatment , but not for PFS benefit