***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: Summary Background Cisplatin and fluoropyrimidine ( CF ) are st and ard first- line treatment in advanced gastric cancer , but no second-line treatment has yet been established . We present a phase II study in which we evaluated the efficacy and toxicity of the combination of Sorafenib ( S ) , and Oxaliplatin as second-line therapy . Methods Patients with progressive gastric adenocarcinoma after CF- first-line , ECOG 0–2 , and measurable disease were included . The primary objective was PFS . Treatment doses were Oxaliplatin 130 mg/m2/3 weeks and Sorafenib 800 mg/bid/d . Results We included 40 patients . CR was 2.5 % and SD was 47.2 % . Grade 3–4 toxic effects were neutropenia ( 9.8 % ) , thrombocytopenia ( 7.3 % ) , neurotoxicity ( 4.9 % ) and diarrhea ( 4.9 % ) . Median PFS was 3 months ( 95 % CI : 2.3–4.1 ) and median OS was 6.5 months ( 95 % CI : 5.2–9.6 ) . Time to progression ( TTP ) to first line therapy was a prognosis factor . Median OS was 9.7 months when time-to-progression during first-line chemotherapy was > 6 months and 5.6 m when it was < 6 months ( p = 0.04 ) . Conclusions Time-to-progression under a CF-based first-line therapy determines subgroups of GC patients with different prognosis . The combination of Oxaliplatin-Sorafenib in advanced GC patients previously treated with CF appears safe , but our results do not support the implementation of a phase III trial 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 Background : Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages . On the basis of evidence of dysregulation of the epidermal growth factor receptor , vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers , we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers . Methods : Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function .  Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily , respectively . Results : Thirty-four eligible patients were recruited . The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months . There were two unconfirmed partial responses ( 6 % , 95 % CI : 1–20 % ) , with a median progression-free survival of 2 months ( 95 % CI : 2–3 ) , and median overall survival of 6 months ( 95 % CI : 3–8 months ) . Grade 3 and 4 adverse events included hypertension , AST/ALT increase , bilirubin increase , diarrhoea , hypokalaemia , hypophosphatemia and rash . Conclusions : Despite compelling pre clinical rationale , the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers . Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease Purpose : This multicenter , phase II study evaluates the efficacy and safety of erlotinib , an epidermal growth factor receptor ( EGFR ) inhibitor , plus sorafenib , a multityrosine kinase inhibitor against vascular endothelial growth factor receptors , in patients with previously untreated advanced non – small cell lung cancer ( NSCLC ) . Experimental Design : Chemotherapy-naïve patients with stage IIIB/IV NSCLC received erlotinib ( 150 mg once a day ) and sorafenib ( 400 mg twice a day ) until disease progression or unacceptable toxicity . The primary end point was the rate of nonprogression at 6 weeks . Secondary end points included objective response rate ( ORR ) , time to progression , overall survival , and adverse events . Exploratory end points included pretreatment EGFR and KRAS mutation status , pharmacokinetics , and cytochrome P450 polymorphisms . Results : Fifty patients initiated therapy . The nonprogression rate at 6 weeks was 74 % : 12 ( 24 % ) partial response and 25 ( 50 % ) stable disease . Ultimately , the ORR was 28 % . Median time to progression was 5.0 months [ 95 % confidence interval ( 95 % CI ) , 3.2 - 6.8 months ] . Median overall survival was 10.9 months ( 95 % CI , 3.8 - 18.1 months ) . Grade 3/4 adverse events included fatigue ( 16 % ) , h and -foot skin reaction ( 16 % ) , rash ( 16 % ) , diarrhea ( 14 % ) , and hypophosphatemia ( 42 % ) . There was one treatment-related fatal pulmonary hemorrhage . Patients with wild-type EGFR had a higher ORR ( 19 % ) than previously reported for single-agent erlotinib/sorafenib . Erlotinib levels were lowered . This was associated with CYP3A4 polymorphism and was possibly due to sorafenib . Conclusion : Despite a possible drug interaction , sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile . Further evaluation of this combination as potential salvage therapy in EGFR mutation – negative patients and the possible drug interaction is warranted . Clin Cancer Res ; 16(11 ) ; 3078–87 . © 2010 AACR PURPOSE To define the safety , efficacy , and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy ( CRT ) in locally advanced pancreatic cancer . METHODS AND MATERIAL S Patients received gemcitabine 1000 mg/m(2 ) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT . Weekly gemcitabine 600 mg/m(2 ) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions . Sorafenib was dosed orally 400 mg twice daily until progression , except during CRT when it was escalated from 200 mg to 400 mg daily , and 400 mg twice daily . The maximum tolerated dose cohort was exp and ed to 15 patients . Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms ( VEGF-A and VEGF-R2 single nucleotide polymorphisms ) . RESULTS Twenty-seven patients were enrolled . No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT . The most common grade 3/4 toxicities were fatigue , hematologic , and gastrointestinal . The maximum tolerated dose was sorafenib 400 mg twice daily . The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months , respectively . The median overall survival for patients with VEGF-A -2578 AA , -1498 CC , and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months . Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans ) in responding patients . CONCLUSIONS Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer . Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival PURPOSE Despite recent advances in the management of high- grade and recurrent gliomas , survival remains poor . Antiangiogenic therapy has been shown to be efficacious in the treatment of high- grade gliomas both in pre clinical models and in clinical trials . We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting . METHODS AND MATERIAL S This was a pre clinical study and an open-label phase I dose escalation trial . Multiple glioma cell lines were analyzed for viability after treatment with radiation , temozolomide , or sorafenib or combinations of them . 
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The clinical utility of sorafenib was established early in development , with low burden on patients and re sources .
However , these early successes were followed by rapid and exhaustive testing against various malignancies and combination regimens , leading to excess patient burden .
Our evaluation of sorafenib development suggests many opportunities for reducing costs and unnecessary patient burden in cancer drug development