***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 We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma ( HCC ) that had progressed following first-line sorafenib . PATIENTS AND METHODS Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function ( Child-Pugh class A ) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression , unacceptable toxicity , death or patient/physician decision to discontinue . The primary end-point was safety ; secondary end-points included efficacy ( including time to progression and overall survival ) . RESULTS The median treatment duration was 19.5 weeks ( range 2 - 103 ) . At data cutoff , three patients remained on treatment . Reasons for discontinuation were adverse events ( n=20 ) , disease progression ( n=10 ) , consent withdrawal ( n=2 ) and death ( n=1 ) . Seventeen patients required dose reductions ( mostly for adverse events [ n=15 ] ) ; 35 patients had treatment interruption ( mostly for adverse events [ n=32 ] or patient error [ n=11 ] ) . The most frequent treatment-related adverse events were h and -foot skin reaction ( any grade n=19 ; grade ≥3 n=5 ) , diarrhoea ( n=19 ; n=2 ) , fatigue ( n=19 ; n=6 ) , hypothyroidism ( n=15 ; n=0 ) , anorexia ( n=13 ; n=0 ) , hypertension ( n=13 ; n=1 ) , nausea ( n=12 ; n=0 ) and voice changes ( n=10 ; n=0 ) . Disease control was achieved in 26 patients ( partial response n=1 ; stable disease n=25 ) . Median time to progression was 4.3 months . Median overall survival was 13.8 months . CONCLUSION Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib Summary Background The combination of bevacizumab ( B ) and erlotinib ( E ) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients . We aim ed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment . Methods Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited . All patients received bevacizumab(B ) at 10 mg/kg every 2 weeks with erlotinib(E ) at 150 mg daily for a maximum of 6 cycles . Response assessment s using both RECIST and modified RECIST criteria were performed after every 6 weeks . The primary endpoint was clinical benefit ( CB ) rate and a Simon two-stage design was employed . Results The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited . The median age was 47 years ( range , 28–61 ) and all patients were in ECOG performance status 1 . Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis . Among these 10 patients , none of the enrolled patients achieved response or stable disease . The median time-to-progression was 1.81 months ( 95 % confidence interval [ C.I. ] , 1.08–1.74 months ) and overall survival was 4.37 months ( 95 % C.I. , 1.08–11.66 months ) . Rash ( 70 % ) , diarrhea ( 50 % ) and malaise ( 40 % ) were the most commonly encountered toxicities . Conclusion The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population . Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population Background : A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose ( MTD ) , pharmacokinetic/pharmacodynamic relationships , and clinical activity in patients with advanced hepatocellular carcinoma ( HCC ) . Experimental Design : Asian patients ( N = 28 ) were dose escalated on pazopanib ( 200–800 mg ) once daily ( QD ) on 21-day cycles , with MTD as the primary endpoint using a modified 3 + 3 design . Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI ( DCE — MRI ) . Results : Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [ grade 3 aspartate aminotransferase (AST)/alanine aminotransferase ( ALT ) elevations and grade 3 malaise ] . The MTD in patients with HCC ( Child – Pugh class A ) was 600 mg QD . Diarrhea , skin hypopigmentation , and AST elevation were the most commonly reported adverse events at the MTD . Mean Cmax and area under the concentration-time curve ( AUC0–6 ) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range . Reductions in IAUGC and Ktrans were shown at all pazopanib doses evaluated , with the greatest reductions at 600 and 800 mg . Although larger DCE-MRI parameter decreases were associated with larger C24 and Cmax values , there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters . Overall , 19 patients ( 73 % ) had either partial response or stable disease . Conclusion : Pazopanib has a manageable safety profile in patients with advanced HCC , and 600 mg was chosen for further development of pazopanib in advanced HCCs . Moreover , pazopanib reduced tumor vessel leakage , as shown by DCE-MRI , indicating a direct effect on HCC vasculature that might be associated with its antitumor activity . Clin Cancer Res ; 17(21 ) ; 6914–23 . © 2011 AACR BACKGROUND Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma ( HCC ) . The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated . METHODS Patients who experienced disease progression while on sorafenib 400 mg twice daily were r and omized to sorafenib 600 mg twice daily ( n = 49 ) or best supportive care ( n = 52 )  . The primary end point was progression-free survival ( PFS ) . Time to progression , overall survival , and safety were also evaluated . RESULTS The study did not meet its primary end point . The difference in PFS between the sorafenib arm ( 3.91 months ) and the best supportive care arm ( 2.69 months ) did not reach statistical significance ( p = 0.086 ) . Adverse events were mainly grade 1 - 2 and similar across both groups . In the sorafenib arm , the most frequent events were diarrhea ( 80 % ) , weight loss ( 75 % ) , fatigue ( 67 % ) , h and -foot-skin reaction ( 49 % ) , abdominal pain ( 37 % ) , and stomatitis ( 26 % ) . CONCLUSIONS Escalated-dose sorafenib in patients with advanced HCC who progressed while on sorafenib , failed to provide any clinical benefit . Second-line treatment still remains an open issue to be explored in appropriate clinical trials Background : Hepatocellular carcinoma ( HCC ) is a highly vascularised and poor-prognosis tumour . NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR , which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels . Methods : Twenty-seven patients with advanced-stage disease resistant to either locoregional ( 59 % ; range , 1–3 ) , systemic treatments ( 52 % ; range , 1–3 ) or both ( 33 % ) received NGR-hTNF 0.8 μg m−2 once every 3 weeks . The primary aim of the study was progression-free survival ( PFS ) . Results : No grade 3–4 treatment-related toxicities were noted . Common toxicity included mild-to-moderate , short-lived chills ( 63 % ) . Median PFS was 2.3 months ( 95 % CI : 1.7–2.9 ) . A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient , yielding a response rate of 7 % . Six patients ( 22 % ) experienced stable disease . The disease control rate ( DCR ) was 30 % and was maintained for a median PFS time of 4.3 months . Median survival was 8.9 months ( 95 % CI : 7.5–10.2 ) . In a subset of 12 sorafenib-resistant patients , the response rate was 8 % and the median survival was 9.5 months . Conclusion : NGR-hTNF was well tolerated and showed single-agent activity in HCC . Further investigation in HCC is of interest Summary Background Sorafenib is the only systemic treatment that has shown a significant benefit in overall survival ( OS ) and in progression-free survival ( PFS ) in advanced hepatocellular carcinoma ( HCC ) patients . No st and ard of care currently exists for second-line treatment . The association of Gemcitabine-Oxaliplatine ( GEMOX ) has shown efficacy in the first-line setting . The aim of this study was to evaluate the efficacy of GEMOX after failure of at least one line of anti-angiogenic ( AA ) therapy . Patient and methods We performed a multicenter retrospective analysis of advanced HCC patients that received GEMOX chemotherapy after progression on at least one line of AA therapy .  Results We analyzed a total of 40 patients that received a median of 7 cycles of GEMOX over a 6-year period .  Grade 3/4 toxicity was observed in 25 % of patients , mainly neurotoxicity , thrombocytopenia and neutropenia in 12.5 % , 5 % and 5 % of patients respectively . Grade <3 toxicity was mainly hematological and neurotoxicity . In the sub-cohort of 35 patients evaluable for response , partial response was observed in 20 % of patients , while 46 % had stable disease . Median OS was 8.3 months , with a 6-month OS rate of 59 % . Median PFS was 3.1 months . Prognostic factors for OS in univariable analysis were the performance status and AFP levels at GEMOX start , and the BCLC score at diagnosis . None of these factors were prognostic for PFS or tumor response . Conclusion The GEMOX schedule seems to show clinical activity and an acceptable toxicity profile in advanced HCC patients who progressed after anti-angiogenic treatment . The observed median OS of over 8 months is encouraging in this population of heavily pretreated patients . These results would merit confirmation in a prospect i ve r and omized study The classifications of hepatocellular carcinoma ( HCC ) currently used are based on prognostic factors obtained from studies performed years ago when most tumors were diagnosed at advanced stages and the survival rates were substantially poor . Recent investigations have review ed the survival of early tumors properly selected to receive radical therapies and the natural outcome of nonsurgical HCC patients . These data enable a new staging system to be proposed , the Barcelona Clinic Liver Cancer ( BCLC ) staging classification , that comprises four stages that select the best c and i date s for the best therapies currently available . Early stage ( A ) includes patients with asymptomatic early tumors suitable for radical therapies -- resection , transplantation or percutaneous treatments . Intermediate stage ( B ) comprises patients with asymptomatic multinodular HCC . Advanced stage ( C ) includes patients with symptomatic tumors and /or an invasive tumoral pattern ( vascular invasion/extrahepatic spread ) . Stage B and C patients may receive palliative treatments/new agents in the setting of phase II investigations or r and omized controlled trials . End-stage disease ( D ) contain patients with extremely grim prognosis ( Okuda stage III or PST 3 - 4 ) that should merely receive symptomatic treatment Objectives : Hepatocellular carcinoma ( HCC ) is the fifth most common cancer worldwide . Sorafenib is considered the st and ard of care for patients with advanced HCC . Methods : We conducted a retrospective analysis of our cancer center ’s experience with sorafenib in patients with advanced HCC . Eligible patients were required to have measurable disease and were allowed to have been refractory ( with documented progression ) to prior systemic therapies before starting on sorafenib . Results : Twenty-six patients ( median age = 56 years ) who were treated at the Ohio State University with sorafenib  were included in this study . Thirty-eight percent had exposure to prior systemic therapy . The median time to tumor progression was 5.4 months and the median overall survival 7 months . For the patients with exposure to prior systemic therapy , the median time to tumor progression was 9.1 months and is the median overall survival 9.83 months . There were no unexpected toxicities . Conclusion : Sorafenib has interesting activity and acceptable tolerability in patients with advanced HCC , including those who failed prior therapies Second‐line treatment options in advanced hepatocellular carcinoma ( HCC ) are limited . Axitinib , a selective potent tyrosine kinase inhibitor ( TKI ) of vascular end 
    Output:
    
Reported grade 3/4 toxicities were regimen-specific and it includes hepatotoxicity , hypertension , and hematologic toxicities .