***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 Effective systemic therapy for advanced carcinoid is lacking . The combination of bevacizumab ( BEV ) and pegylated ( PEG ) interferon alpha-2b was evaluated among patients with metastatic or unresectable carcinoid tumors . PATIENTS AND METHODS Forty-four patients on stable doses of octreotide  were r and omly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b . At disease progression ( PD ) or at the end of 18 weeks ( whichever occurred earlier ) , patients received bevacizumab plus PEG interferon until progression . Functional computer tomography ( CT ) scans were performed to measure effect on tumor blood flow . RESULTS In the bevacizumab arm , four patients ( 18 % ) achieved confirmed partial response ( PR ) , 17 patients ( 77 % ) had stable disease ( SD ) , and one patient ( 5 % ) had PD . In the PEG interferon arm , 15 patients ( 68 % ) had SD and six patients ( 27 % ) had PD . Progression-free survival ( PFS ) rates after 18 weeks of monotherapy were 95 % in bevacizumab versus 68 % on the PEG interferon arm . The overall median PFS for all 44 patients is 63 weeks . Compared with paired baseline measurements on functional CT scans , we observed a 49 % ( P < .01 ) and 28 % ( P < .01 ) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab . No significant changes in tumor blood flow were observed following PEG interferon . PEG interferon alpha-2b treatment was associated with decrease in plasma basic fibroblast growth factor ( bFGF ; P = .04 ) and increase in plasma interleukin-18 ( IL-18 ; P < .01 ) . No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed . CONCLUSION Bevacizumab therapy result ed in objective responses , reduction of tumor blood flow , and longer PFS in patients with carcinoid than PEG interferon treatment Background Well-differentiated neuroendocrine carcinomas are highly vascularized and may be sensitive to drugs administered on a metronomic schedule that has shown antiangiogenic properties . A phase II study was design ed to test the activity of protracted 5-fluorouracil ( 5FU ) infusion plus long-acting release ( LAR ) octreotide in patients with neuroendocrine carcinoma . Methods Twenty-nine patients with metastatic or locally advanced well-differentiated neuroendocrine carcinoma were treated with protracted 5FU intravenous infusion ( 200 mg/m2 daily ) plus LAR octreotide ( 20 mg monthly ) . Patients were followed for toxicity , objective response , symptomatic and biochemical response , time to progression and survival . Results Assessment by Response Evaluation Criteria in Solid Tumors ( RECIST ) criteria showed partial response in 7 ( 24.1 % ) , stable disease in 20 ( 69.0 % ) , and disease progression in 2 patients . Response did not significantly differ when patients were stratified by primary tumor site and proliferative activity . A biochemical ( chromogranin A ) response was observed in 12/25 assessable patients ( 48.0 % ) ; symptom relief was obtained in 9/15 symptomatic patients ( 60.0 % ) . There was non significant decrease in circulating vascular epithelial growth factor ( VEGF ) over time . Median time to progression was 22.6 months ( range , 2.7 - 68.5 ) ; median overall survival was not reached yet . Toxicity was mild and manageable . Conclusion Continuous/metronomic 5FU infusion plus LAR octreotide is well tolerated and shows activity in patients with well-differentiated neuroendocrine carcinoma . The potential synergism between metronomic chemotherapy and antiangiogenic drugs provides a rationale for exploring this association in the future . Trial registration Purpose Sorafenib and everolimus are both active against neuroendocrine tumors ( NET ) . Because of potential synergy between VEGF pathway and mTOR inhibitors , we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET . Methods Patients were treated with everolimus 10 mg daily in combination with sorafenib ( dose level 1 : 200 mg twice daily ; dose level 2 : 200 mg per morning , 400 mg per evening ) using st and ard phase I dose escalation design . Dose-limiting toxicity ( DLT ) was defined within the first cycle ( 28 days ) of therapy . Treatment was continued until tumor progression , unacceptable toxicity , or withdrawal of consent . Twelve additional patients were treated at the maximum tolerated dose ( MTD ) level to further characterize safety and a preliminary assessment of activity . Results One patient in Cohort 1 experienced DLT ( grade 3 skin rash ) ; the cohort was exp and ed to 6 patients with no further DLTs . All 3 patients in Cohort 2 experienced DLT , consisting of thrombocytopenia , h and –foot skin reaction , and rash/allergic reaction .  Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD . Independently review ed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage . By RECIST , we observed partial response in 1 patient , stable disease in 13 patients , and progressive disease in 3 patients . ConclusionS orafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET . While the combination is active , toxicity concerns may preclude more widespread use BACKGROUND The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in pre clinical models and phase 1 and 2 trials . METHODS We conducted a multinational , r and omized , double-blind , placebo-controlled phase 3 trial of sunitinib in patients with advanced , well-differentiated pancreatic neuroendocrine tumors . All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline . A total of 171 patients were r and omly assigned ( in a 1:1 ratio ) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo . The primary end point was progression-free survival ; secondary end points included the objective response rate , overall survival , and safety . RESULTS The study was discontinued early , after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib . Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group ( hazard ratio for progression or death , 0.42 ; 95 % confidence interval [ CI ] , 0.26 to 0.66 ; P<0.001 ) . A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied . The objective response rate was 9.3 % in the sunitinib group versus 0 % in the placebo group . At the data cutoff point , 9 deaths were reported in the sunitinib group ( 10 % ) versus 21 deaths in the placebo group ( 25 % ) ( hazard ratio for death , 0.41 ; 95 % CI , 0.19 to 0.89 ; P=0.02 ) . The most frequent adverse events in the sunitinib group were diarrhea , nausea , vomiting , asthenia , and fatigue . CONCLUSIONS Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival , overall survival , and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors . ( Funded by Pfizer ; Clinical Trials.gov number , NCT00428597 . ) 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 BACKGROUND Sorafenib and bevacizumab as single agents have shown efficacy and acceptable toxicity in NETs phase II trials . Sorafenib and bevacizumab combination has shown manageable toxicity in phase I trials in solid tumours . The purpose of this study was to evaluate the safety and efficacy of the combination of sorafenib and bevacizumab in patients with advanced neuroendocrine tumours . METHODS Open-label , uncontrolled , multicenter , phase II clinical trial . ELIGIBILITY CRITERIA age ≥18 years , histologically confirmed measurable advanced NETs ; 1 prior chemotherapy allowed ; ECOG-PS 0 - 2 . Patients were treated during 6 months and followed up for an additional 6 months . TREATMENT sorafenib 200 mg bid ( days 1 - 5 of each week ) and bevacizumab 5mg/kg once every 2 weeks ( day 1 , week 1 ) . Tumour response was performed according to RECIST ( v1.0 ) every 2 months during the treatment period . Adverse events were grade d according to CTCAE ( v3.0 ) . FINDINGS 44 Patients enrolled , 59.1 % men , median age 60 years ( range 32 - 76 ) . 70.5 % carcinoid tumours , 29.5 % pancreatic tumour . Baseline target lesions mainly in the liver ( 86.4 % ) . Global PFSR was 90.9 % ( 91.7 % carcinoid tumours and 88.9 % pancreatic tumours ) . Median PFS was 12.4 months , median TTP was 14.5 months , ORR was 9.4 % and DCR was 95.1 % . Most common grade 3 - 4 toxicities : asthenia ( 11.4 % ) and h and -foot skin reaction ( 15.9 % ) . INTERPRETATION Sorafenib and bevacizumab combination showed clinical benefit but unfavourable safety results compared with drugs in monotherapy . Further development of this combination is not warranted and a sequential approach is recommended instead PURPOSE Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor ( VEGF ) receptor and bevacizumab , a monoclonal antibody targeting VEGF , have antitumor activity in neuroendocrine tumors ( NETs ) . Temozolomide , an oral analog of dacarbazine , also has activity against NETs when administered alone or in combination with other agents . We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs . PATIENTS AND METHODS Thirty-four patients ( 56 % with carcinoid , 44 % with pancreatic NETs ) were treated with temozolomide 150 mg/m(2 ) orally per day on days 1 through 7 and days 15 through 21 , together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle . All patients received prophylaxis against Pneumocystis carinii and varicella zoster . Patients were followed for toxicity , biochemical and radiologic response , and survival . RESULTS The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 to 
    Output:
    
Conclusions The current evidence from the available clinical trials suggests that bevacizumab in combination with some other anticancer agents ( especially mTOR inhibitors and interferons ) could be a more effective and tolerable treatment for advanced GEP-NENs in the future .