***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 Pasireotide ( SOM230 ) , a novel multireceptor lig and somatostatin analog ( SSA ) , binds with high affinity to four of the five somatostatin receptor subtypes ( sst1–3 , 5 ) . This study evaluated the safety , tolerability , pharmacokinetics , and pharmacodynamics profiles of pasireotide long-acting release ( LAR ) formulation in patients with advanced gastroenteropancreatic neuroendocrine tumor ( GEP NET ) refractory to other SSAs . Methods In this r and omized , multicenter , open-label , phase II study , patients with biopsy-proven primary or metastatic GEP NET refractory to available SSAs were r and omly assigned 1:1:1 to receive pasireotide LAR by deep intragluteal injection at a dose of 20 , 40 , or 60 mg once every 28 days for 3 months . Results Forty-two patients received pasireotide LAR . Adverse events were reported by 34 ( 81 % ) patients , with the most frequently reported including diarrhea , fatigue , abdominal pain , and nausea . Mean fasting glucose levels were increased compared with baseline at all points throughout the study . After the third injection of pasireotide LAR , the median trough plasma concentrations on day 84 were 4.82 , 12.0 , and 19.7 ng/mL in the 20- , 40- , and 60-mg treatment groups , respectively . Drug accumulation was limited for each dose based on the increase in trough concentrations after the first to third injections ( accumulation ratios were approximately 1 from all dose levels ) . Conclusions This study demonstrated that a new , once-monthly , intramuscular LAR formulation of pasireotide was well tolerated in patients with advanced GEP NET . Steady state levels of plasma pasireotide were achieved after three injections To evaluate the treatment of advanced islet-cell carcinoma , we r and omly assigned 84 patients to streptozocin alone or streptozocin plus fluorouracil . Each regimen was given in five-day courses . The most frequent toxic effects were nausea and vomiting , mild and reversible renal toxicity , and bone-marrow depression with the combination regimen . The combination had advantages over streptozocin alone in overall rate of response ( 63 vs. 36 per cent ) and in rates of complete response ( 33 vs. 12 per cent ) . There was no evidence of a preferential response among types of functional tumors . Objective responses were generally of long duration ( median , 17 months ) and of substantive clinical benefit . Treatment with the combination also yielded a survival advantage over treatment with streptozocin alone ( medians , 26 and 16 1/2 months ) , but this difference is not statistically significant . In spite of gastrointestinal side effects , streptozocin combined with fluorouracil appears to be a valuable treatment for advanced islet-cell carcinoma Background Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs ( SSAs ) , primarily targeting somatostatin receptor ( sstr ) subtypes 2 and 5 , in neuroendocrine tumors ( NET ) . Pasireotide , a second-generation SSA , targets multiple sstr subtypes . We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced , well-differentiated , progressive pancreatic NET . Patients and methods Patients were r and omized 1 : 1 to receive a combination of everolimus ( 10 mg/day , orally ) and pasireotide long-acting release ( 60 mg/28 days , intramuscularly ) or everolimus alone ( 10 mg/day , orally ) ; stratified by prior SSA use , and baseline serum chromogranin A and neuron-specific enolase . The primary end point was progression-free survival ( PFS ) . Secondary end points included overall survival , objective response rate , disease control rate , and safety . Biomarker response was evaluated in an exploratory analysis . Results Of 160 patients enrolled , 79 were r and omized to the combination arm and 81 to the everolimus arm . Baseline demographics and disease characteristics were similar between the treatment arms . No significant difference was observed in PFS : 16.8 months in combination arm versus 16.6 months in everolimus arm ( hazard ratio , 0.99 ; 95 % confidence interval , 0.64 - 1.54 ) . Partial responses were observed in 20.3 % versus 6.2 % of patients in combination arm versus everolimus arm ; however , overall disease control rate was similar ( 77.2 % versus 82.7 % , respectively ) . No significant improvement was observed in median overall survival . Adverse events were consistent with the known safety profile of both the drugs ; grade 3 or 4 fasting hyperglycemia was seen in 37 % versus 11 % of patients , respectively . Conclusions The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study . Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted BACKGROUND Effective systemic therapies for patients with advanced , progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce . We aim ed to assess the efficacy and safety of everolimus compared with placebo in this patient population . METHODS In the r and omised , double-blind , placebo-controlled , phase 3 RADIANT-4 trial , adult patients ( aged ≥18 years ) with advanced , progressive , well-differentiated , non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide . Eligible patients were r and omly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo , both with supportive care . Patients were stratified by tumour origin , performance status , and previous somatostatin analogue treatment . Patients , investigators , and the study sponsor were masked to treatment assignment . The primary endpoint was progression-free survival assessed by central radiology review , analysed by intention to treat . Overall survival was a key secondary endpoint . This trial is registered with Clinical Trials.gov , number NCT01524783 . FINDINGS Between April 3 , 2012 , and Aug 23 , 2013 , a total of 302 patients were enrolled , of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo . Median progression-free survival was 11·0 months ( 95 % CI 9·2 - 13·3 ) in the everolimus group and 3·9 months ( 3·6 - 7·4 ) in the placebo group . Everolimus was associated with a 52 % reduction in the estimated risk of progression or death ( hazard ratio [ HR ] 0·48 [ 95 % CI 0·35 - 0·67 ] , p<0·00001 ) . Although not statistically significant , the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death ( HR 0·64 [ 95 % CI 0·40 - 1·05 ] , one-sided p=0·037 , whereas the boundary for statistical significance was 0·0002 ) . Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis ( in 18 [ 9 % ] of 202 patients in the everolimus group vs 0 of 98 in the placebo group ) , diarrhoea ( 15 [ 7 % ] vs 2 [ 2 % ] ) , infections ( 14 [ 7 % ] vs 0 ) , anaemia ( 8 [ 4 % ] vs 1 [ 1 % ] ) , fatigue ( 7 [ 3 % ] vs 1 [ 1 % ] ) , and hyperglycaemia ( 7 [ 3 % ] vs 0 ) . INTERPRETATION Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours . The safety findings were consistent with the known side-effect profile of everolimus . Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours , including those arising from the pancreas , lung , and gastrointestinal tract . FUNDING Novartis Pharmaceuticals Corporation BACKGROUND This was a two-stage , phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours ( pNETs ) ( NCT01658436 ) . PATIENTS AND METHODS In stage 1 , 11 patients received 400 mg BEZ235 orally twice daily ( bid ) . Due to tolerability concerns , a further 20 patients received BEZ235 300 mg bid . Stage 2 would be triggered by a 16-week progression-free survival ( PFS ) rate of ≥60 % in stage 1 . RESULTS As of 30 June , 2014 , 29/31 patients had discontinued treatment . Treatment-related grade 3/4 adverse events were reported in eight ( 72.7 % ) patients at 400 mg and eight ( 40.0 % ) patients at 300 mg , including hyperglycaemia , diarrhoea , nausea , and vomiting . The estimated 16-week PFS rate was 51.6 % ( 90 % confidence interval=35.7 - 67.3 % ) . CONCLUSION BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses . Although evidence of disease stability was observed , the study did not proceed to stage 2 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 . ) Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors ( NET ) compared with placebo in the RADIANT-3 study . Here , we present the final overall survival ( OS ) data and data on the impact of biomarkers on OS from the RADIANT-3 study . Methods Patients with advanced , progressive , low- or intermediate- grade pancreatic NET were r and omly assigned to everolimus 10 mg/day ( n = 207 ) or placebo ( n = 203 ) . Crossover from placebo to open-label everolimus was allowed on disease progression . Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator 's discretion ( extension phase ) . OS analysis was performed using a stratified log-rank test in the intent-to-treat population . The baseline levels of chromogranin A , neuron-specific enolase , and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored . Results Of  
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The experimental treatments led to increased incidence and risks of GI events compared to the control treatments ( P<0.05 ) .
Diarrhea was the most common GI event .
Additionally , GI NETs led to higher risk of GI events than pancreatic NETs .