***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 To evaluate safety and efficacy of combined transarterial chemoembolization ( TACE ) with doxorubicin-eluting beads ( DEB ) and sorafenib in patients with advanced hepatocellular carcinoma ( HCC ) . PATIENTS AND METHODS A prospect i ve single-center phase II study was undertaken involving patients with unresectable HCC . The protocol involved sorafenib 400 mg twice per day combined with DEB-TACE . Safety and response were assessed . Results DEB-TACE in combination with sorafenib was successfully administered in 35 patients : mean age , 63 years ; Child 's A , 89 % ; Barcelona Clinic Liver Cancer stage C , 64 % ; Eastern Cooperative Oncology Group performance status of 0 and 1 , 46 % and 54 % , respectively ; and mean index tumor size , 7.7 cm ( st and ard deviation , ± 4.2 cm ) . Patients underwent 128 cycles of therapy ( sorafenib plus DEB-TACE , 60 cycles ; sorafenib alone , 68 cycles ) . Median number of cycles per patient was two ( range , one to five cycles ) ; median number of days treated with sorafenib was 71 ( range , 4 to 620 days ) . The most common toxicities during cycle one were fatigue ( 94 % ) , anorexia ( 67 % ) , alterations in liver enzymes ( 64 % ) , and dermatologic adverse effects ( 48 % ) . Although most patients experienced at least one grade 3 to 4 toxicity , most toxicities were minor ( grade 1 to 2 , 83 % v grade 3 to 4 , 17 % ) . Toxicity during cycle two was decreased . Over the course of the study , there were 40 sorafenib dose interruptions and 25 sorafenib dose reductions . Sorafenib plus DEB-TACE was associated with a disease control rate of 95 % ( Response Evaluation Criteria in Solid Tumors Group)/100 % ( European Association for the Study of the Liver [ EASL ] ) , with an objective response of 58 % ( EASL ) . CONCLUSION The combination of sorafenib and DEB-TACE in patients with unresectable HCC  is well tolerated and safe , with most toxicities  related to sorafenib  . Toxicity is manageable with dose adjustment of sorafenib . Preliminary efficacy data are promising Summary Background Sorafenib is the sole molecular-targeted agent showing a survival benefit in patients with advanced hepatocellular carcinoma ( HCC ) . We evaluated the tolerability and effectiveness of a combination of S-1 with sorafenib in patients with advanced HCC . Methods S-1 was administered during days 1–14 and sorafenib was administered every day . This treatment was repeated every 21 days . In phase I , we determined the maximum tolerated dose ( MTD ) and dose-limiting toxicities ( DLTs ) . The dose of each drug was planned as follows : cohort 1 : S-1 48 mg/m2/day and sorafenib 400 mg/day , cohort 2a : S-1 48 mg/m2/day and sorafenib 800 mg/day , cohort 2b : S-1 64 mg/m2/day and sorafenib 400 mg/day , cohort 3 : S-1 64 mg/m2/day and sorafenib 800 mg/day , and cohort 4 : S-1 80 mg/m2/day and sorafenib 800 mg/day . In phase II , the patients were treated at the MTD to evaluate safety and efficacy . Results Nineteen patients were enrolled in phase I. One of the six patients in cohort 1 and one of the six patients in cohort 3 experienced DLT . None of the three patients in cohort 2a experienced DLT and three of the four patients in cohort 4 experienced DLT . Therefore , cohort 3 was considered the MTD . Subsequently , 26 patients were enrolled in phase II . The most common grade 3/4 toxicities were an increase of aspartate aminotransferase ( 38.5 % ) , thrombocytopenia ( 23.1 % ) , neutropenia ( 19.2 % ) , hyperbilirubinemia ( 15.4 % ) , an increase of alanine aminotransferase ( 15.4 % ) , hyponatremia ( 11.5 % ) , rash ( 11.5 % ) , and hypophosphatemia ( 11.5 % ) . Sudden death occurred in one patient ( 3.8 % ) . A patient ( 3.8 % ) had a partial response , 15 ( 57.7 % ) had stable disease , and 10 ( 38.5 % ) had progressive disease . The median times to progression and overall survival were 2.4 and 10.5 months , respectively . Conclusion The MTD of S-1 and sorafenib in patients with advanced HCC was 64 mg/m2/day and 800 mg/day , respectively . This dose/regimen demonstrated substantial clinical activity among patients with advanced HCC 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 In Japan , transarterial infusion chemotherapy using cisplatin ( CDDP-TAI ) is frequently used for advanced hepatocellular carcinoma ( HCC ) . Moreover , oral chemotherapy with S-1 , an oral fluoropyrimidine derivative , has also elicited promising responses in HCC patients . We determined the recommended dosage for CDDP-TAI plus S-1 combination therapy for advanced HCC . Methods Twelve Child – Pugh class A or B patients with advanced HCC who met the eligibility criteria were enrolled in this phase I trial . Patients received CDDP-TAI ( infusion , day 1 ) plus S-1 ( oral administration , days 1–21 ) every 5 weeks until disease progression . Results Cisplatin ( 65 mg/m2 ) was administered with S-1 at 50 mg · m-2 day-1 ( level 1 , 3 patients ) , 60 mg · m-2 day-1 ( level 2 , 3 patients ) , or 80 mg · m-2 day-1 ( level 3 , 6 patients ) . The total number of treatment courses was 25 ( median , 2 courses/patient ; range , 1–6 courses ) . Dose-limiting toxicity was not observed in any patient at any level ; therefore , the recommended dosage for cisplatin and S-1 in combination was level 3 . Grade 3 adverse events were elevated alanine aminotransferase levels ( 2 patients ) , elevated aspartate aminotransferase levels ( 2 patients ) , anemia ( 1 patient ) , and decreased platelet counts ( 1 patient ) . Median progression-free survival and overall survival were 73 days and 328 days , respectively . The disease control rate was 58 % ( 7/12 ) ; 17 % ( 2/12 ) of patients achieved partial response and 42 % ( 5/12 ) achieved stable disease . CDDP-TAI plus S-1  is safe for the treatment of HCC . Conclusion The recommended dosage for further evaluation of this combination therapy in phase II studies is 65 mg/m2 CDDP and 80 mg/m2 S-1.Trial registration UMIN ; number : 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 S‐1 , an oral fluoropyrimidine derivative , has been shown to be clinical ly effective against various solid tumors , and pre clinical studies have demonstrated activity against hepatocellular carcinoma . We conducted a phase I/II study in patients with advanced hepatocellular carcinoma to examine the pharmacokinetics , recommended dose , safety and efficacy of S‐1 . In phase I , the administered dose of S‐1 was approximately 64 mg/m2 per day in three patients ( level 1 ) and approximately 80 mg/m2 per day in six patients ( level 2 ) . There was no dose‐limiting toxicity at level 1 , but two patients had dose‐limiting toxicity at level 2 ( grade 3 anorexia and grade 2 rash requiring eight or more consecutive days of rest ) . The recommended dose was finally estimated to be 80 mg/m2 per day . There were no significant differences in the pharmacokinetics of S‐1 between patients with Child‐Pugh A and those with B. In phase II , five of 23 patients ( 21.7 % ) had partial responses . The median progression‐free survival and overall survival were 3.7 and 16.6 months , respectively . The most common toxicities of grade 3 or 4 were elevated serum aspartate aminotransferase levels , hypochromia and thrombocytopenia . In conclusion , S‐1 showed an acceptable toxicity profile and promising antitumor activity for hepatocellular carcinoma , warranting further evaluation in r and omized clinical trials . ( Cancer Sci 2010 ; 101 : 2606–2611 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 - 
    Output:
    
CONCLUSION This systematic review suggests that S-1 plus sorafenib showed modest clinical efficacy and tolerable toxicity profile in patients with advanced HCC .