***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 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 Summary Pemetrexed has demonstrated activity in hepatocellular carcinoma ( HCC ) cell lines , and has a manageable toxicity profile in clinical trials , suggesting its potential as a treatment for HCC patients . A multicenter , Phase II community-based study was conducted to assess the response rate and toxicity profile of single-agent pemetrexed in first-line patients with advanced or metastatic HCC . Patients premedicated with folic acid , vitamin B12 , and dexamethasone were administered pemetrexed 600 mg/m2 IV on day 1 of each 21-day cycle until disease progression . This nonr and omized study employed Simon ’s 2-stage design , enrolling 21 eligible patients in the first stage , stopping accrual if ≤2 responders were observed . Responses were four stable disease , 14 progressive disease , and three not evaluable : two had early toxicities ( renal/liver failure , sepsis ) and one was noncompliant . The most common grade 3 hematological toxicities were neutropenia 6 of 21 ( 29 % ) and thrombocytopenia 3 of 21 ( 14 % ) ; with no grade 4 toxicities . Thirteen patients died on- study : 12 PD and one liver failure ; none were drug-related . The median survival was 5.2 months ( range , < 1–12.2 ) . The planned second stage was cancelled , and the trial was closed owing to lack of response . While pemetrexed was tolerated in this patient population , it was not active Background : The expression of platelet-derived growth factor , a potent mitogen , and its receptor both in tissue and serum correlate with the severity of liver cirrhosis . Over-expression of platelet-derived growth factor has been demonstrated in human hepatocellular carcinoma ( HCC ) tumors and cell lines . Imatinib , a potent inhibitor of BCR-ABL and c-kit , also inhibits the platelet-derived growth factor receptor tyrosine kinase . The trial was design ed to assess the efficacy and safety of imatinib in patients with unresectable HCC . Methods : Eligibility criteria consisted of HCC patient over the age of 18 with reasonable organ function , unresectable but measurable disease , not c and i date s for chemoinfusion , and a performance status of 0 to 2 .  Imatinib was started at 300 mg/d orally with 100 mg/wk dose escalation up to 800 mg/d if toxicity permitted . Results : Fifteen patients , median age 58 years , were enrolled and treated with imatinib . Most , or 7 , patients had hepatitis B virus as a risk factor for HCC , followed by hepatitis C virus in 3 patients . Metastatic disease ( American Joint Committee on Cancer stage IV ) was noted in 13 patients and locally advanced ( stage III ) in the remainder . The median dose-level of imatinib was 500 mg/d . Two patients had stable disease lasting more than 2 months . The remainder progressed within 2 months of initiation of imatinib . No grade 3 or 4 hematologic toxicity was observed . Two patients had grade 3 elevated liver function tests during treatment ; otherwise , there was no other grade 3 or 4 nonhematologic toxicity noted . Conclusion : Although toxicities were tolerable , imatinib as a monotherapy for the treatment of unresectable HCC has little , if any , significant efficacy BACKGROUND & AIMS Sorafenib , a multi-kinase inhibitor with anti-angiogenic activity , was recently approved for the treatment of advanced hepatocellular carcinoma ( HCC ) .  Metronomic chemotherapy using tegafur/uracil ( 4:1 molar ratio ) , an oral fluoropyrimidine , has been shown to enhance the anti-tumor effect of anti-angiogenic agents in pre clinical models . This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC . METHODS Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib ( 400 mg twice daily ) and tegafur/uracil ( 125 mg/m(2 ) based on tegafur twice daily ) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies . The primary endpoint was progression-free survival ( PFS ) . RESULTS The study enrolled 53 patients . Thirty-eight patients ( 72 % ) were hepatitis B surface antigen-positive . The median PFS was 3.7 months ( 95 % C.I. , 1.9 - 5.5 ) and the median overall survival was 7.4 months ( 95 % C.I. , 3.4 - 11.4 ) . According to RECIST criteria , 4 patients ( 8 % ) had a partial response and 26 patients ( 49 % ) had a stable disease . Major grade 3/4 toxicities included fatigue ( 15 % ) , abnormal liver function ( 13 % ) , elevated serum lipase ( 10 % ) h and -foot skin reaction ( HFSR ) ( 9 % ) , and bleeding ( 8 % ) . HFSR was the major adverse event result ing in dose reduction ( 19 % ) or treatment delay ( 21 % ) . CONCLUSIONS Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients Background The sole effective option for patients with advanced HCC is sorafenib and there is an urgent need to develop new therapeutic approaches . Immunotherapy is a promising option that deserves major investigation . In this open label , single arm clinical trial , we analyzed the effect of a low dose cyclophosphamide treatment in combination with a telomerase peptide ( GV1001 ) vaccination in patients with advanced HCC . Methods 40 patients with advanced HCC were treated with 300 mg/m2 cyclophosphamide on day -3 followed by GM-CSF + GV1001 vaccinations on days 1 , 3 , 5 , 8 , 15 , 22 , 36 followed by 4-weekly injections . Primary endpoint of this phase II trial was tumor response ; secondary endpoints evaluated were TTP , TTSP , PFS , OS , safety and immune responses . Results None of the patients had a complete or partial response to treatment , 17 patients ( 45.9 % ) demonstrated a stable disease six months after initiation of treatment . The median TTP was 57.0 days ; the median  TTSP  was estimated to be 358.0 days . Cyclophosphamide , GV1001 and GM-CSF treatment were well tolerated and most adverse events , which were of grade 1 or 2 , were generally related to the injection procedure and injection site reactions . GV1001 treatment result ed in a decrease in CD4+CD25+Foxp3 + regulatory T cells ; however , no GV1001 specific immune responses were detected after vaccination . Conclusions Low dose cyclophosphamide treatment followed by GV1001 vaccinations did not show antitumor efficacy as per tumor response and time to progression . Further studies are needed to analyze the effect of a combined chemo-immunotherapy to treat patients with HCC.Trial registration Purpose We design ed a phase II trial of the combination with oxaliplatin and doxorubicin for patients with unresectable HCC to evaluate the overall response rate ( ORR ) and the toxicity . Methods Forty patients with inoperable , systemic chemotherapy naive HCC were enrolled . Finally , 32 patients received oxaliplatin ( 130 mg/m2 ) and doxorubicin ( 60 mg/m2 ) every 3 weeks . Results Eighty-two treatment cycles were administered ( median 2 cycles , range 1–6 ) . There was no treatment-related mortality . The ORR was 15.6 % ( 95 % CI , 3.3–28.7 ) with five partial responses . The median overall survival and median overall progression free survival were 31 weeks ( 95 % CI , 22–40 weeks ) and 12 weeks ( 95 % CI , 5 - 19 weeks ) . Nausea and peripheral neuropathy were most frequent non-hematologic toxicities ( nausea , n = 15 ; peripheral neuropathy , n = 10 ) . The most frequent grade 3–4 hematologic adverse event was neutropenia ( 14 of 82 cycles ) including three cases of febrile neutropenia . Conclusions The combination of oxaliplatin and doxorubicin showed modest activity and a tolerable toxicity profile in advanced HCC patients 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 Summary Background : Arsenic trioxide induces growth inhibition and apoptosis in human hepatocellular carcinoma ( HCC ) cell lines . A phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with HCC . Methods : Inclusion criteria included advanced HCC patients to whom no st and ard palliative treatment can be offered , good organ function and liver function reserve . Patients received arsenic trioxide 0.16–0.24 mg/kg per day for 5–6 days per week for 3–4 weeks , followed by one-week rest . Tumor response was assessed every 2 cycles . Primary endpoint was the percentage of patients with 6-month disease stabilization . Results : Twenty-nine patients ( median age , 59 ) with 
    Output:
    
This analysis of both r and omized and nonr and omized studies evaluating an antiangiogenic agent in HCC showed that whereas the use of sorafenib was associated with an increased risk of bleeding in HCC , this was primarily for lower- grade events and similar in magnitude to the risk encountered in RCC