***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: Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor . Recent advances in conventional chemotherapy and the development of novel ‘ molecular ’ treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies . This r and omised study in pancreatic cancer compares marimastat ( orally administered matrix metalloproteinase inhibitor ) in combination with gemcitabine to gemcitabine alone .  Two hundred and thirty-nine patients with unresectable pancreatic cancer were r and omised to receive gemcitabine ( 1000 mg m−2 ) in combination with either marimastat or placebo . The primary end-point was survival . Objective tumour response and duration of response , time to treatment failure and disease progression , quality of life and safety were also assessed . There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo ( P=0.95 log-rank test ) . Median survival times were 165.5 and 164 days and 1-year survival was 18 % and 17 % respectively . There were no significant differences in overall response rates ( 11 and 16 % respectively ) , progression-free survival ( P=0.68 log-rank test ) or time to treatment failure ( P=0.70 log-rank test ) between the treatment arms . The gemcitabine and marimastat combination was well tolerated with only 2.5 % of patients withdrawn due to presumed marimastat toxicity . Grade 3 or 4 musculoskeletal toxicities were reported in only 4 % of the marimastat treated patients , although 59 % of marimastat treated patients reported some musculoskeletal events . The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer . The combination of marimastat with gemcitabine was well tolerated . Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified Gemcitabine is a key drug for the treatment of pancreatic cancer ; however , with its limitation in clinical benefits , the development of another potent therapeutic is necessary . Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis , and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide ( elpamotide ) . Based on the promising results of this phase I trial , a multicenter , r and omized , placebo‐controlled , double‐blind phase II/III clinical trial has been carried out for pancreatic cancer . The eligibility criteria included locally advanced or metastatic pancreatic cancer . Patients were assigned to either the Active group ( elpamotide + gemcitabine ) or Placebo group ( placebo + gemcitabine ) in a 2:1 ratio by the dynamic allocation method . The primary endpoint was overall survival . The Harrington – Fleming test was applied to the statistical analysis in this study to evaluate the time‐lagged effect of immunotherapy appropriately . A total of 153 patients ( Active group , n = 100 ; Placebo group , n = 53 ) were included in the analysis . No statistically significant differences were found between the two groups in the prolongation of overall survival ( Harrington – Fleming P‐value , 0.918 ; log – rank P‐value , 0.897 ; hazard ratio , 0.87 , 95 % confidence interval [ CI ] , 0.486–1.557 ) . Median survival time was 8.36 months ( 95 % CI , 7.46–10.18 ) for the Active group and 8.54 months ( 95 % CI , 7.33–10.84 ) for the Placebo group . The toxicity observed in both groups was manageable . Combination therapy of elpamotide with gemcitabine was well tolerated . Despite the lack of benefit in overall survival , subgroup analysis suggested that the patients who experienced severe injection site reaction , such as ulceration and erosion , might have better survival BACKGROUND To investigate whether addition of cetuximab to st and ard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer , specifically whether the rate of disease-free survival ( DFS ) at 18 months ( primary end point ) exceeds the previously reported 35 % of gemcitabine alone . PATIENTS AND METHODS Prospect i ve , open-label , multicenter , nonr and omized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008 .  Gemcitabine and cetuximab were administered for 24 weeks . Secondary end points included overall survival ( OS ) and toxic effect . RESULTS Seventy-three patients received cetuximab .  Median DFS was 10.0 [ 95 % confidence interval ( CI ) 8.9 - 13.6 ] months and the DFS rate at month 18 of 27.1 % ( 16.7%-37.6 % ) was inferior to 35 % . Median OS was 22.4 ( 18.2 - 27.9 ) months . Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 ( median 14.7 versus 8.3 months , P = 0.073 ) and wild-type versus mutated K-Ras ( median 11.5 versus 9.3 months , P = 0.57 ) . Grade 3/4 toxic effects included neutropenia ( 11.0 % ) , thrombopenia ( 7 % ) , skin toxic effect ( 7 % ) and allergic reactions ( 7 % ) . CONCLUSION Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients . Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed PURPOSE To evaluate , in a phase 2 study , the safety and efficacy of induction gemcitabine , oxaliplatin , and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer ( BRPC or LAPC , respectively ) . METHODS AND MATERIAL S Patients received gemcitabine and oxaliplatin chemotherapy repeated every 14 days for 6 cycles , combined with weekly cetuximab . Patients were then restaged ; " downstaged " patients with resectable disease underwent attempted resection . Remaining patients were treated with chemoradiation consisting of intensity modulated radiation therapy ( 54 Gy ) and concurrent capecitabine ;  patients with borderline resectable disease or better at restaging underwent attempted resection . RESULTS A total of 39 patients were enrolled , of whom 37 were evaluable . Protocol treatment was generally well tolerated . Median follow-up for all patients was 11.9 months . Overall , 29.7 % of patients underwent R0 surgical resection ( 69.2 % of patients with BRPC ; 8.3 % of patients with LAPC ) . Overall 6-month progression-free survival ( PFS ) was 62 % , and median PFS was 10.4 months . Median overall survival ( OS ) was 11.8 months . In patients with LAPC , median OS was 9.3 months ; in patients with BRPC , median OS was 24.1 months . In the group of patients who underwent R0 resection ( all of which were R0 resections ) , median survival had not yet been reached at the time of analysis . CONCLUSIONS This regimen was well tolerated in patients with BRPC or LAPC , and almost one-third of patients underwent R0 resection . Although OS for the entire cohort was comparable to that in historical controls , PFS and OS in patients with BRPC and /or who underwent R0 resection was markedly improved Purpose Considering promising results in phase II studies , a r and omized phase III trial was design ed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease ( ED ) small-cell lung cancer ( SCLC ) . Patients and Methods Treatment-naive patients with ED-SCLC were r and omly assigned to receive either cisplatin plus etoposide ( arm A ) or the same regimen with bevacizumab ( arm B ) for a maximum of six courses . In the absence of progression , patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses . The primary end point was overall survival ( OS ) . Results Two hundred four patients were r and omly assigned and considered in intent-to-treat analyses ( 103 patients in arm A and 101 patients in arm B ) . At a median follow-up of 34.9 months in arm A and arm B , median OS times were 8.9 and 9.8 months , and 1-year survival rates were 25 % and 37 % ( hazard ratio , 0.78 ; 95 % CI , 0.58 to 1.06 ; P = .113 ) , respectively . A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen ( hazard ratio , 0.60 ; 95 % CI , 0.40 to 0.91 ; P = .011 ) . Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B , respectively ( P = .030 ) . Regarding hematologic toxicity , no statistically significant differences were observed ; for nonhematologic toxicity , only hypertension was more frequent in arm B ( grade 3 or 4 , 1.0 % v 6.3 % in arms A v B , respectively ; P = .057 ) . Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival , which , however , did not translate into a statistically significant increase in OS . Further research with novel antiangiogenic agents , particularly in the maintenance setting , is warranted Background : We aim ed to identify molecular epidermal growth factor receptor ( EGFR ) tissue biomarkers in pancreatic cancer ( PC ) patients treated with the anti-EGFR agent erlotinib within the phase 3 r and omised AIO-PK0104 study . Methods : AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC ; primary study end point was the time-to-treatment failure after first- and second-line therapy ( TTF2 ) . Translational analyses were performed for KRAS exon 2 mutations , EGFR expression , PTEN expression , the EGFR intron 1 and exon 13 R497 K polymorphism ( PM ) . Biomarker data were correlated with TTF , overall survival ( OS ) and skin rash . Results : Archival tumour tissue was available from 208 ( 74 % ) of the r and omised patients . The KRAS mutations were found in 70 % ( 121 out of 173 ) of patients and exclusively occurred in codon 12 . The EGFR overexpression was detected in 89 out of 181 patients ( 49 % ) by immunohistochemistry ( IHC ) , and 77 out of 166 patients ( 46 % ) had an EGFR gene amplification by fluorescence in-situ hybridisation ( FISH ) ; 30 out of 171 patients ( 18 % ) had a loss of PTEN expression , which was associated with an inferior TTF1 ( first-line therapy ; HR 0.61 , P=0.02 ) and TTF2 ( HR 0.66 , P=0.04 ) . The KRAS wild-type status was associated with improved OS ( HR 1.68 , P=0.005 ) ; no significant OS correlation was found for EGFR – IHC ( HR 0.96 ) , EGFR – FISH ( HR 1.22 ) , PTEN – IHC ( HR 0.77 ) , intron 1 ( HR 0.91 ) or exon 13 R497 K PM ( HR 0.83 ) . None of the six biomarkers correlated with the occurrence of skin rash . Conclusion : The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study ; it remains to be defined whether this association is prognostic or predictive BACKGROUND Axitinib is a potent , selective inhibitor of vascular endothelial growth factor ( VEGF ) receptors 1 , 2 , and 3 . A r and omised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients . On the basis of these results , we aim ed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial . METHODS In this double-blind , placebo-controlled , phase 3 study , eligible patients had metastatic or locally advanced pancreatic adenocarcinoma , no uncontrolled hypertension or venous thrombosis , and Eastern Cooperative Oncology Group performance status 0 or 1 . Patients , stratified by disease extent ( metastatic vs locally advanced ) , were r and omly assigned ( 1:1 ) to receive gemcitabine 1000 mg/m(2 ) intravenously 
    Output:
    
In terms of safety  , gemcitabine plus anti-angiogenesis therapy did not increase the rate of grade 3 - 4 common adverse effects except for hypertension .
Conclusions : Although gemcitabine plus anti-angiogenesis therapy might prolong the progression-free survival in locally advanced or metastatic pancreatic cancer , these successful results did not translate into a significant improvement in the overall survival or change in the clinical guidelines