***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 Sorafenib improves overall survival and time to progression of advanced hepatocellular ( aHCC ) patients such as demonstrated in 2 phase III trials . However , aHCC patients ’ outcome is still poor despite these results . In order to improve the efficacy of systemic treatment for aHCC , we evaluated the combination of sorafenib plus 5-fluorouacil infusion in a phase II trial . Methods Patients with aHCC not eligible for loco-regional therapies , Child-Pugh A-B , ECOG-PS 0 - 1 , and without history of anti-cancer systemic treatment were enrolled . Treatment schedule was : sorafenib 400 mg/bid continuously and continuum infusion of 5-fluorouracil 200 mg/sqm/daily day 1–14 every 3 weeks . Results Thirty-nine patients were enrolled : ECOG-PS 0 - 1 : 29 - 10 , Child-Pugh A-B : 36 - 3 . Grade 3/4 ( % ) toxicities included : diarrhea 5.1/0 , mucositis 20.5/2.6 , h and foot skin reaction 20.5/0 , skin rash 10.5/0 , hypertension 10.3/0 , hyperbilirubinemia 5.1/2.6 , glutamic-oxaloacetic transaminase increase 10.3/0 , glutamic-pyruvic transaminase increase 7.7/0 , cardiac toxicity ( one heart failure , two atrial fibrillation cases ) 7.7/0 , and bleeding ( melena ) in 2.6/0 . One partial response was observed . Stable disease was obtained in 46.2 % of patients with a median duration of 16.2 months . Median time to progression was 8 months ( CI 95 % = 5.7–10.4 ) , and median overall survival was 13.7 months ( CI 95 % = 9.5–17.9 ) . Conclusions The results show an encouraging disease control rate , time to progression , and overall survival . The combination of sorafenib and 5-fluorouracil was feasible , and the side effects were manageable for patients carefully selected for liver function and performance status 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 Purpose Advanced hepatocellular carcinoma ( HCC ) not eligible for local therapies has limited chances of cure . Sorafenib is a multikinase inhibitor with proven activity in advanced HCC . Octreotide is used in this setting with conflicting results . Treatment with sorafenib and long-acting octreotide was tested in advanced HCC to evaluate safety and activity . Methods Fifty patients with advanced HCC , Child-Pugh A or B , received sorafenib at a dosage of 800 mg/day for 28 days with a following week of rest and long-acting octreotide at a dose of 40 mg , administered every 28 days . Results All patients were assessable for safety and efficacy . Sixteen patients out of 50 ( 34 % ) were naïve from other therapies , while all the others were previously treated with local and /or systemic treatments . We achieved 5 partial responses ( 10 % ) , 33 stable diseases ( 66 % ) and 12 progressions of disease ( 24 % ) . Median time to progression was 7.0 months ( 95 % CI , 3.0–10.9 months ) , and median overall survival was 12 months ( 95 % CI , 6.3–17.4 months ) . Treatment was well tolerated . Diarrhoea ( 6 % ) and hypertension ( 4 % ) were the most frequent grade 3 toxicities . Conclusions Our data suggest that the combination between sorafenib and long-acting octreotide is active and well tolerated in patients with advanced HCC and could represent another efficacious chance for the management of this population Summary Purpose Sorafenib is a multi-kinase inhibitor , which was approved as first-line treatment for patients with advanced hepatocellular carcinoma ( HCC ) . We conducted a phase 1 study of sorafenib plus S-1 in patients with advanced HCC . Experimental design We design ed to escalate S-1 at 4 different dose levels with fixed dose of sorafenib . Four dose levels were as follows : level 1 , D1 - 14 S-1 50 mg/m2/day + D1 - 21 sorafenib 400 mg bid ; level 2 , D1 - 14 S-1 60 mg/m2/day + D1 - 21 sorafenib 400 mg bid ; level 3 , , D1 - 14 S-1 70 mg/m2/day + D1 - 21 sorafenib 400 mg bid ; level 4 , D1 - 14 S-1 80 mg/m2/day + D1 - 21 sorafenib 400 mg bid . The treatment was repeated every 3 weeks . Results From August 2009 to July 2010 , 20 patients with advanced HCC were enrolled . The median age was 48 years ( range , 29–74 ) . Eighteen ( 90 % ) patients had hepatitis B viral infection and 19 ( 95 % ) patients were rated as Child-Pugh class A.  The dose-limiting toxicities were grade 4 infection and thrombocytopenia . After a median follow-up duration of 8.6 months ( range , 3.7–14.2 months ) , median PFS was 3.9 months ( 95 % CI , 0.8–7.0 months ) and median OS was 10.4 months ( 95 % CI , 0–22.4 months ) . In pharmacokinetic analysis , there was no statistically significant drug interaction between sorafenib and S-1 . Conclusions The combination of sorafenib and S-1  showed tolerable toxicity profile and modest clinical efficacy in patients with advanced HCC . The recommended dose of sorafenib and S-1 was 400 mg twice daily and 40 mg/m2 twice daily , respectively There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma ( HCC ) after liver transplantation . This open , multicenter , retrospective , uncontrolled cohort study was design ed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin ( mTOR ) inhibitor and sorafenib in this setting . In 31 patients who suffered from HCC recurrence after liver transplantation , the immunosuppressive therapy was changed to mTOR inhibitors , and systemic treatment with sorafenib was initiated . This combination was maintained until symptomatic tumor progression , death , hepatic decompensation , or unacceptable toxicity occurred . Primary treatment efficacy was determined by overall survival and progression-free survival , and secondary efficacy was determined by the overall response rate . Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed . The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8 % ( 1/26 ) , and there was sustained stabilization of the disease in 13 additional cases ( 50.0 % ) . The median overall survival was 19.3 months [ 95 % confidence interval ( CI ) = 13.4 - 25.1 months ] , and the median time to progression was 6.77 months ( 95 % CI = 2.3 - 11.1 months ) . Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported , and they were possibly related to mTOR inhibitors . The most common severe adverse event probably related to sorafenib was diarrhea ( 12.9 % ) . In conclusion , the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy . The toxicity and efficacy need to be further evaluated in r and omized controlled studies for this combination to be considered a valid option The only approved systemic therapy for patients with advanced hepatocellular carcinoma ( HCC ) till now is sorafenib . A preliminary study suggested that capecitabine , an oral fluoropyrimidine , may be effective in advanced HCC . We have tested this hypothesis in this phase 2 study . In this single-center , phase 2 , open-label trial , we r and omly assigned 52 patients with advanced HCC who had not received previous systemic treatment to receive either sorafenib ( at a dose of 400 mg twice daily ) or capecitabine ( 1,000 mg/m2 twice daily ) ( day 1–day 14 ) . Primary outcome was progression-free survival . Secondary outcomes included the overall survival and safety . Median overall survival was 7.05 months in the sorafenib group and 5.07 months in the capecitabine group ( hazard ratio in the capecitabine group 2.36 ; 95 % confidence interval 1.174–4.74 ; P < 0.016 ) . The median progression-free survival was 6 months in the sorafenib group and 4 months in the capecitabine group ( P < 0.005 ) . Three patients in the sorafenib group ( 11.5 % ) and one patient in the capecitabine group ( 3 % ) had a partial response ; one patient ( 3 % ) had a complete response in the sorafenib group . H and –foot skin reaction was more frequent in the sorafenib group , hyperbilirubinemia was more common in the capecitabine group , and diarrhea was equivalent between both groups . In patients with advanced HCC , capecitabine is inferior to sorafenib in terms of median progression-free survival and overall survival , and it should not be used alone for the treatment of advanced HCC , but rather , combination therapy with sorafenib should be considered CONTEXT In a r and omized phase 3 trial , 400 mg of sorafenib twice daily prolonged overall survival of patients with advanced hepatocellular carcinoma ( HCC ) and Child-Pugh A disease . In a phase 1 study , sorafenib combined with doxorubicin , 60 mg/m(2 ) , was well tolerated by patients with refractory solid tumors . The combination of sorafenib and doxorubicin in patients with advanced HCC has not been evaluated in a phase 2 or 3 trial . OBJECTIVE To evaluate the efficacy and safety of doxorubicin plus sorafenib compared with doxorubicin alone in patients with advanced HCC and Child-Pugh A disease . DESIGN , SETTING , AND PATIENTS In a double-blind phase 2 multinational study , conducted from April 2005 to October 2006 , 96 patients ( 76 % male ; median age , 65 years [ range , 38 - 82 years ] ) with advanced HCC , Eastern Cooperative Oncology Group performance status 0 to 2 , Child-Pugh A status , and no prior systemic therapy were r and omly assigned to receive 60 mg/m(2 ) of doxorubicin intravenously every 21 days plus either 400 mg of sorafenib or placebo orally twice a day . The date of the last patient 's follow-up was April 2008 . MAIN OUTCOME MEASURE Time to progression as determined by independent review . RESULTS Following complete accrual , an unplanned early analysis for efficacy was performed by the independent data monitoring committee , so the trial was halted . The 2 patients remaining in the placebo group at that time were offered sorafenib 
    Output:
    
Frequently reported Grade 3/4 toxicities were increased AST/ALT , fatigue , hypertension , h and foot skin reaction and diarrhea .
The current evidence from the available clinical trials suggests that sorafenib-based combination with some anticancer agents ( especially mTOR inhibitors ) could be a more effective and tolerable treatment for advanced HCC in the future .