***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: Medical treatment and chemotherapy are seldom successful in achieving objective tumour reduction in patients with metastatic neuroendocrine tumours . Treatment with the radiolabelled somatostatin analogue [90Y-DOTA0,Tyr3]octreotide may result in partial remissions in 10–25 % of patients . The newer analogue [DOTA0,Tyr3]octreotate ( octreotate ) has a ninefold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA0,Tyr3]octreotide . Also , labelled with the beta- and gamma-emitting radionuclide 177Lu , it has proved very successful in achieving tumour regression in animal models . The effects of 177Lu-octreotate therapy were studied in 35 patients with neuroendocrine gastro-entero-pancreatic ( GEP ) tumours who underwent follow-up for 3–6 months after receiving their final dose . Patients were treated with doses of 100 , 150 or 200 mCi 177Lu-octreotate , to a final cumulative dose of 600–800 mCi , with treatment intervals of 6–9 weeks . Nausea and vomiting within the first 24 h after administration were present in 30 % and 14 % of the administrations , respectively . WHO toxicity grade 3 anaemia , leucocytopenia and thrombocytopenia occurred after 0 % , 1 % and 1 % of the administrations , respectively . Serum creatinine and creatinine clearance did not change significantly . The effects of the therapy on tumour size were evaluable in 34 patients . Three months after the final administration , complete remission was found in one patient ( 3 % ) , partial remission in 12 ( 35 % ) , stable disease in 14 ( 41 % ) and progressive disease in seven ( 21 % ) , including three patients who died during the treatment period . Tumour response was positively correlated with a high uptake on the octreoscan , limited hepatic tumour mass and a high Karnofsky Performance Score . Because of the limited efficacy of alternative therapies , many physicians currently adopt an expectant attitude when dealing with patients with metastatic GEP tumours . However , in view of the high success rate of therapy with 177Lu-octreotate and the absence of serious side-effects , we advocate its use in patients with GEP tumours without waiting for tumour progression Objective Everolimus , an inhibitor of the mammalian target of rapamycin , has recently demonstrated efficacy and safety in a Phase III , double-blind , r and omized trial ( RADIANT-3 ) in 410 patients with low- or intermediate- grade advanced pancreatic neuroendocrine tumours .  Everolimus 10 mg/day provided a 2.4-fold improvement compared with placebo in progression-free survival , representing a 65 % risk reduction for progression . The purpose of this analysis was to investigate the efficacy and safety of everolimus in the Japanese subgroup enrolled in the RADIANT-3 study . Methods Subgroup analysis of the Japanese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally ( n = 23 ) and matching placebo ( n = 17 ) . The primary endpoint was progression-free survival . Safety was evaluated on the basis of the incidence of adverse drug reactions . Results Progression-free survival was significantly prolonged with everolimus compared with placebo . The median progression-free survival was 19.45 months ( 95 % confidence interval , 8.31–not available ) with everolimus vs 2.83 months ( 95 % confidence interval , 2.46–8.34 ) with placebo , result ing in an 81 % risk reduction in progression ( hazard ratio , 0.19 ; 95 % confidence interval , 0.08–0.48 ; P < 0.001 ) . Adverse drug reactions occurred in all 23 ( 100 % ) Japanese patients receiving everolimus and in 13 ( 77 % ) patients receiving placebo ; most were grade 1/2 in severity . The most common adverse drug reactions in the everolimus group were rash ( n = 20 ; 87 % ) , stomatitis ( n = 17 ; 74 % ) , infections ( n = 15 ; 65 % ) , nail disorders ( n = 12 ; 52 % ) , epistaxis ( n = 10 ; 44 % ) and pneumonitis ( n = 10 ; 44 % ) . Conclusions These results support the use of everolimus as a valuable treatment option for Japanese patients with advanced pancreatic neuroendocrine tumours BACKGROUND Gastric carcinoid tumours type 1 ( GCA1 ) originate from hyperplastic enterochromaffin-like ( ECL ) cells secondary to hypergastrinaemia . Treatment with somatostatin analogues ( SSA ) might impede ECL-cell hyperplasia by suppressing gastrin secretion and /or by a direct anti-proliferative effect on ECL cells . We conducted a multicentre prospect i ve study to assess the effects of long-acting SSA on hypergastrinaemia and ECL-cell proliferation in patients with GCA1 . METHODS We studied 15 patients with GCA1 treated with monthly long-acting release octreotide ( LAR ) ( 20 - 30 mg ; n=14 ) or Lanreotide 90 mg ( n=1 ) for at least 6 months . Patients had serum gastrin and chromogranin A measurements performed and biopsies taken from both tumours and surrounding mucosa before , and every 6 - 12 months following treatment . Sections were immunostained for neuroendocrine markers . The cell proliferation index Ki-67 , intensity of staining before and after treatment and the degree of gastric wall invasion were also assessed . RESULTS All patients tolerated treatment well ( mean follow-up of 18 months ) . In 11 patients ( 73 % ) , a complete disappearance of the tumours at 1 year of treatment was observed on endoscopy , while in three patients ( 20 % ) , the tumours decreased significantly in number and size . Gastrin levels normalized in 25 % of patients , and were reduced by more than 80 % in the remaining 75 % . CONCLUSIONS Treatment with SSAs in GCA1 leads to a substantial tumour load reduction , with a concomitant decrease of serum gastrin levels . Our data indicate an important anti-proliferative effect of SSA on ECL cells , providing clinical benefit and obviating , at least temporarily , the need for invasive therapies for GCA1 4008 Background : In a double-blind phase 3 trial , SU improved PFS vs PBO ( 11.4 vs 5.5 months ; HR 0.418 , 95 % CI 0.263 , 0.662 ; p=0.0001 ) and was well tolerated in pts with advanced well-differentiated , unresectable NET that had progressed in ≤12 months ( NEJM , Feb 2011 ) . Initial OS showed a benefit for SU over PBO , but median OS was not reached ( NR ) . Here we report up date d results of median OS and also PFS assessed by BICR to correct for potential unblinding due to identifiable adverse events ( AE ) . METHODS Pts were r and omized 1:1 to SU 37.5 mg as a continuous daily dose or PBO , each with best supportive care . Primary endpoint was PFS ; secondary endpoint was OS . Median OS and HR were estimated using Kaplan-Meier ( K-M ) methods and Cox proportional hazards models . Baseline and on- study CT/MRI scans were evaluated by a 2-reader , 2-time point lock , followed by a sequential locked-read , batch-mode paradigm by blinded , third-party radiologists . RESULTS 171 pts were r and omized ( SU , n=86 ; PBO , n=85 ) from 6/2007 to 4/2009 . The trial ended early when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO . The study was unblinded at closure , and pts were offered open-label SU . At study end , there were 9 and 21 deaths  in SU and PBO arms , respectively ; HR of 0.409 ( 95 % CI 0.187 , 0.894 ; p=0.0204 ) favoring SU . By 6/2010 , there were 34 and 39 deaths , respectively ; median OS was 30.5 ( 95 % CI 20.6 , NR ) and 24.4 ( 95 % CI : 16.3 , NR ) months , respectively . The HR of 0.737 ( 95 % CI 0.465 , 1.168 ; p=0.1926 ) continued to favor SU ; a K-M plot showed early/persistent separation of curves . For BICR analysis , scans were collected for 170 ( 99.4 % ) pts , with 160 ( 93.6 % ) having complete scan sets/time points . Median PFS by BICR was 12.6 vs 5.8 months for SU and PBO ( HR 0.315 [ 95 % CI 0.181 , 0.546 ; p=0.000015 ] ) . CONCLUSIONS SU led to a 6.1-month improvement in median OS vs PBO , and BICR analysis confirmed the investigator-assessed PFS benefit of SU . These up date d results support the robustness of the initial findings and the clinical benefit of treatment with sunitinib 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 PURPOSE Optimal treatments for metastatic carcinoid tumor remain undefined , and the role of chemotherapy for symptomatic patients with progressive disease is uncertain . PATIENTS AND METHODS Two hundred forty-nine patients with advanced carcinoid tumors were r and omized to either doxorubicin with fluorouracil ( FU/DOX ) or streptozocin with fluorouracil ( FU/STZ ) . Patients crossed over to the dacarbazine ( DTIC ) treatment after disease progression following first-line treatment ( either FU/DOX or FU/STZ ) , and 73 patients were assigned to one of these three treatments based on their previous treatment or on abnormal baseline cardiac or renal function . RESULTS In the r and omized group , there was no difference between FU/DOX and FU/STZ in response rates ( 15.9 % v 16 % ) and progression-free survival ( 4.5 v 5.3 months ) . FU/STZ ( 24.3 months ) was superior to FU/DOX ( 15.7 months ; P = .0267 ) in median survival . The response rate of crossover DTIC treatment was 8.2 % , with a median survival of 11.9 months . Hematologic toxicities were the major treatment-related toxicities for both FU/DOX and FU/STZ , and mild to moderate renal toxicity was reported in 40 ( 34.8 % ) of 115 patients in the FU/STZ arm . CONCLUSION Response to all three treatment regimens were modest . FU/STZ improved survival compared with the doxorubicin-based regimen , suggesting that the combination should be considered to be an active regimen of therapy when chemotherapy is judged to be an option for selected patients with car 
    Output:
    
The pNETs trials consistently found that the interventions improved PFS and overall survival ( OS ) compared with BSC .
Our indirect comparison found no significant difference in PFS between everolimus and sunitinib .
After adjustment , our indirect comparison suggested a lower , but non-significant , hazard of death for sunitinib compared with everolimus .
In GI and lung NETs , everolimus significantly improved PFS compared with BSC and showed a non-significant trend towards improved OS compared with BSC .
Adverse events were more commonly reported following treatment with targeted interventions than after treatment with BSC .
Given NICE 's current stated range of £ 20,000 - 30,000 per QALY for the cost-effectiveness threshold , based on list prices , only sunitinib might be considered good value for money in Engl and and Wales .