pancreatic cancer is a common gastrointestinal cancer , and the incidence and mortality has been increasing in recent years . in the usa , it has been the fourth leading cause of death . in 2009 ,
approximately 42 000 new patients were diagnosed , and 35 000 americans died of pancreatic cancer . .
early diagnosis is difficult because of the lack of clinical symptoms in the early stages , and the 5-year survival rate ranges from 4% to 6% or less .
although the incidence and mortality of pancreatic cancer are remarkably high , few treatment options are effective .
the primary option is to reduce pancreatic cancer risk by taking preventive measures . in humans ,
free radicals , which result from polyunsaturated fatty acids reacting with oxygen in the lipid membranes , might be essential for the occurrence of tumors .
vitamin e is an effective antioxidant that prevents the occurrence of some tumors by protecting cells and dna from free radical damage .
whether vitamin e , as an antioxidant , could reduce the incidence of pancreatic cancer has been under consideration . in 2000 , heisler et al .
reported the results from an in vitro study showing that vitamin e could inhibit pancreatic cancer cell line growth .
another animal study showed that vitamin e increased the activity of superoxide dismutase ( sod ) and decreased the level of thiobarbituric- acid - reactive substances ( tbars ) , which might be a mechanism of decreasing liver metastasis in pancreatic cancer .
many epidemiological studies have assessed the relationship between vitamin e and the risk of pancreatic cancer . in the 1990s
, 1 of 2 case - control studies showed that vitamin e intake was linked to a decreased risk of pancreatic cancer ; however , the other study showed a null association .
subsequent epidemiological studies , including case - control and cohort studies , have suggested an inconsistent association between vitamin e intake and the risk of pancreatic cancer [ 1017 ] .
the sample size of each original study was smaller and original study was conducted in a single population , which might be the primary reason for the unsatisfactory results .
we conducted a meta - analysis of the relevant studies by combining the results from the published observational studies to assess the relationship between vitamin e intake and the risk of pancreatic cancer .
additionally , we examined the influences of various study characteristics on the overall risk estimate .
we intended to provide the best available evidence as to whether vitamin e intake has a preventive effect on pancreatic cancer .
the web of science , pubmed , and embase databases were used to identify the observational studies that reported the association between vitamin e intake and the risk of pancreatic cancer through december 31 , 2014 with the following terms :  vitamin e intake 
,  dietary vitamin e  and  vitamin e  in combination with  pancreatic cancer  and  pancreatic carcinoma  .
the reference lists of the identified studies were searched for potential studies . if necessary , we contacted the authors of the original studies for the required data . the studies that met the following criteria could be included : 1 .
the study had been published as a full text in the english language ; 3 .
the study reported the association between the vitamin e intake and the risk of pancreatic cancer ; 4 .
the study reported the rr and the corresponding 95% ci for the highest vs. the lowest level of vitamin e intake ; 5 .
if there were duplicate publications on the same study population , we included the most recent one .
an article was excluded based on to the following criteria : if it were a review , case report , or animal experiment ; if it were not published as a full text ; or if it reported an exposure factor or endpoint that was not relevant to our study .
the following information was collected from the included studies : the last name of the first author , publication year , population , number of cases and controls or total sample size , rr and the corresponding 95% ci from the most fully adjusted model for the highest vs. the lowest vitamin e intake , and the factors of adjustment for potential confounders .
all the procedures were conducted by 2 independent authors , and any disagreements were resolved by discussion .
the key components of designs ( e.g. , selection of study populations , ascertainment of exposure and outcome , duration of follow - up ) were used to estimate the quality of primary studies rather than reporting the aggregate scores .
the pooled relative risk ( rr ) and the corresponding 95% ci were used to assess the association between vitamin e intake and the risk of pancreatic cancer .
a fixed - effects model when low evidence of homogeneity was found or random - effects model when strong evidence of homogeneity was found was used to calculate the combined rr .
subgroup analysis was performed to identify the source of heterogeneity , if possible , and the effect of the potential factors on the overall risk estimate .
in addition , we conducted a sensitivity analysis to investigate the influence of a single study on the overall risk estimate by omitting 1 study at a time .
begg s and egger s tests were used to detect the evidence of a publication bias . in our study , if the p - value were less than 0.05 , it was considered statistically significant .
the web of science , pubmed , and embase databases were used to identify the observational studies that reported the association between vitamin e intake and the risk of pancreatic cancer through december 31 , 2014 with the following terms :  vitamin e intake 
,  dietary vitamin e  and  vitamin e  in combination with  pancreatic cancer  and  pancreatic carcinoma  .
the reference lists of the identified studies were searched for potential studies . if necessary , we contacted the authors of the original studies for the required data . the studies that met the following criteria could be included : 1 .
the study had been published as a full text in the english language ; 3 .
the study reported the association between the vitamin e intake and the risk of pancreatic cancer ; 4 .
the study reported the rr and the corresponding 95% ci for the highest vs. the lowest level of vitamin e intake ; 5 .
if there were duplicate publications on the same study population , we included the most recent one .
an article was excluded based on to the following criteria : if it were a review , case report , or animal experiment ; if it were not published as a full text ; or if it reported an exposure factor or endpoint that was not relevant to our study .
the following information was collected from the included studies : the last name of the first author , publication year , population , number of cases and controls or total sample size , rr and the corresponding 95% ci from the most fully adjusted model for the highest vs. the lowest vitamin e intake , and the factors of adjustment for potential confounders .
all the procedures were conducted by 2 independent authors , and any disagreements were resolved by discussion .
the key components of designs ( e.g. , selection of study populations , ascertainment of exposure and outcome , duration of follow - up ) were used to estimate the quality of primary studies rather than reporting the aggregate scores .
the pooled relative risk ( rr ) and the corresponding 95% ci were used to assess the association between vitamin e intake and the risk of pancreatic cancer .
a fixed - effects model when low evidence of homogeneity was found or random - effects model when strong evidence of homogeneity was found was used to calculate the combined rr .
subgroup analysis was performed to identify the source of heterogeneity , if possible , and the effect of the potential factors on the overall risk estimate .
in addition , we conducted a sensitivity analysis to investigate the influence of a single study on the overall risk estimate by omitting 1 study at a time .
begg s and egger s tests were used to detect the evidence of a publication bias . in our study , if the p - value were less than 0.05 , it was considered statistically significant .
according to the inclusion criteria , 10 observational studies involving 2976 patients and 254 393 participants or controls were included [ 817 ] .
the studies were published from 1991 to 2014 . in the 10 studies , 6 were case - control studies [ 810,12,13,17 ] , and 4 were cohort studies [ 11,1416 ] .
four studies were conducted in usa populations , 2 in asian populations   ( japanese   and chinese ) , and 4 in european populations [ 11,1315 ] ( finnish , italian , dutch , and british ) .
all the studies were adjusted for a wide range of potential confounders , such as age , sex , smoking , and energy intake . in total , 11 data items from the 10 included studies were used to assess the association between vitamin e intake and the risk of pancreatic cancer . of these
, 4 results showed that vitamin e intake was linked to a reduced risk of pancreatic cancer .
overall , our study found that there was a statistically significant inverse relationship between vitamin e intake and the risk of pancreatic cancer ; the summary rr and corresponding 95% ci of pancreatic cancer for the highest vs. the lowest level of vitamin e intake was 0.81 ( 0.73 , 0.89 ) .
there was minimal statistically significant evidence of heterogeneity across these studies ( i=19.8% , p=0.255 ) .
figures 3 and 4 show the results of the subgroup analyses for the influence of the study design and population on the overall risk estimate , respectively .
the results showed that there was an inverse association between the vitamin e intake and pancreatic cancer risk both in the case - control and cohort studies , in which the pooled rr ( 95% ci ) were 0.65 ( 0.54 , 0.77 ) and 0.88 ( 0.79 , 0.99 ) , respectively .
we found no evidence of heterogeneity among the case - control and cohort studies ( i=0.0% , pcase - control=0.760 and pcohort=0.868 ) .
the inverse association between vitamin e intake and pancreatic cancer was found among people in the usa , asians , and europeans , for which the combined rrs ( 95% cis ) were 0.67 ( 0.55 , 0.82 ) , 0.72 ( 0.52 , 0.99 ) , and 0.87 ( 0.77 , 0.98 ) , respectively .
there was minimal evidence across the 3-subgroup analyses ( iusa=0.0% , pusa=0.413 , iasian=0.0% , pasian=0.454 , and ieuropean=0.0% , peuropean=0.410 ) . by removing 1 study at a time
, we conducted a sensitivity analysis to assess the influence of each included study on the pooled rr .
the combined rrs were similar to each another , and none significantly modified the pooled rr .
after removing the study with the highest weight , the pooled rr was not significantly modified .
although the funnel plot shows all the included studies symmetrically distributed in the triangle area , begg s and egger s regression tests showed that there was a low probability of publication bias in our study ( p=0.049 ) .
according to the inclusion criteria , 10 observational studies involving 2976 patients and 254 393 participants or controls were included [ 817 ] .
the studies were published from 1991 to 2014 . in the 10 studies , 6 were case - control studies [ 810,12,13,17 ] , and 4 were cohort studies [ 11,1416 ] .
four studies were conducted in usa populations , 2 in asian populations   ( japanese   and chinese ) , and 4 in european populations [ 11,1315 ] ( finnish , italian , dutch , and british ) .
all the studies were adjusted for a wide range of potential confounders , such as age , sex , smoking , and energy intake .
in total , 11 data items from the 10 included studies were used to assess the association between vitamin e intake and the risk of pancreatic cancer . of these , 4 results showed that vitamin e intake was linked to a reduced risk of pancreatic cancer .
overall , our study found that there was a statistically significant inverse relationship between vitamin e intake and the risk of pancreatic cancer ; the summary rr and corresponding 95% ci of pancreatic cancer for the highest vs. the lowest level of vitamin e intake was 0.81 ( 0.73 , 0.89 ) .
there was minimal statistically significant evidence of heterogeneity across these studies ( i=19.8% , p=0.255 ) .
figures 3 and 4 show the results of the subgroup analyses for the influence of the study design and population on the overall risk estimate , respectively .
the results showed that there was an inverse association between the vitamin e intake and pancreatic cancer risk both in the case - control and cohort studies , in which the pooled rr ( 95% ci ) were 0.65 ( 0.54 , 0.77 ) and 0.88 ( 0.79 , 0.99 ) , respectively .
we found no evidence of heterogeneity among the case - control and cohort studies ( i=0.0% , pcase - control=0.760 and pcohort=0.868 ) .
the inverse association between vitamin e intake and pancreatic cancer was found among people in the usa , asians , and europeans , for which the combined rrs ( 95% cis ) were 0.67 ( 0.55 , 0.82 ) , 0.72 ( 0.52 , 0.99 ) , and 0.87 ( 0.77 , 0.98 ) , respectively .
there was minimal evidence across the 3-subgroup analyses ( iusa=0.0% , pusa=0.413 , iasian=0.0% , pasian=0.454 , and ieuropean=0.0% , peuropean=0.410 ) . by removing 1 study at a time
, we conducted a sensitivity analysis to assess the influence of each included study on the pooled rr .
the combined rrs were similar to each another , and none significantly modified the pooled rr .
after removing the study with the highest weight , the pooled rr was not significantly modified .
although the funnel plot shows all the included studies symmetrically distributed in the triangle area , begg s and egger s regression tests showed that there was a low probability of publication bias in our study ( p=0.049 ) .
our meta - analysis suggested a significant inverse relationship between vitamin e intake and the risk of pancreatic cancer  a high level of vitamin e was significantly linked to a decreased risk of pancreatic cancer .
although the included studies were conducted in different populations and varied in study design , little evidence of heterogeneity was found across the studies .
all the studies were published in english and had a high quality of assessment and the results from each original study were adjusted for a wide range of potential confounders , eliminating the most obvious confounding factors .
in the subgroup analyses , the summary risk estimate of 6 case - control studies and 4 cohort studies showed an inverse association between vitamin e intake and a risk of pancreatic cancer .
it is well known that a higher level of statistical evidence is detected in cohort studies than in case - control studies , thus , our results were credible , but more cohort studies are needed .
additionally , our subgroup analyses showed that this inverse association was not modified by different populations , including asians , europeans , and people in the usa .
the subgroup analyses added additional evidence for the association between vitamin e intake and risk of pancreatic cancer .
although there is evidence of an association of vitamin e intake with a decreased risk of many cancers [ 1820 ] , the mechanisms are not well understood .
the primary mechanism of vitamin e might be as an antioxidant , preventing dna damage by scavenging lipid peroxyl radicals and terminating the lipid peroxidation chain reaction   while increasing the activity of superoxide dismutase ( sod ) and decreasing the level of thiobarbituric - acid - reactive substances ( tbars ) .
other potential mechanisms are based on the possibility that vitamin e might decease the activity of the protein kinase c ( pkc ) pathway , enhance the immune response of the body , suppress cancer cell growth by down - regulation of the phosphoinositide 3-kinase pathway , and increase the expression of anti - oncogene p27 .
early - stage diagnosis is difficult , and the mortality associated with pancreatic cancer is remarkably high ; there are few effective treatment options to overcome this fatal cancer .
our study , which included 10 observational studies with 2976 patients and 254 393 participants or controls , significantly improved the statistical power and found a more reliable association between vitamin e intake and a pancreatic cancer risk .
we provided evidence that vitamin e intake is related to a decreased risk of pancreatic cancer , and that vitamin e intake might effectively prevent pancreatic cancer .
first , 10 studies with relatively larger sample sizes were included in our studies ; however , many of the studies were case - control studies , and recall bias and selection bias were inevitable .
although 4 cohort studies were included , the following factors limited the statistical evidence : a smaller number of sample cases and a lack of groups of patients of different ages .
second , most of the included studies did not respectively report the risk among males and/or females , and hormonal factors might lead to the male - to - female differential in the incidence of pancreatic cancer . in general , a high level of estrogen exposure via estrogen - only therapy could significantly reduce the risk of pancreatic cancer .
third , vitamin e is a mixture of 8 structurally related and naturally occurring components , including tocopherols (  ,  ,  ,  ) and tocotrienols (  ,  ,  ,  ) .
however , only 1 component is naturally contained in food , and determining the diverse biological activities between the dietary intake and supplementation is challenging . in the included studies ,
1 study reported the rrs associated with the intake of various vitamin e isoforms and the risk of pancreatic cancer .
most studies did not report the source of vitamin e. fourth , the pooled risk estimate was predominantly based on usa and european populations ; 2 asian populations and no other populations were included in the studies , and additional studies that include other populations are needed .
this study showed a significant inverse relationship between vitamin e intake and the risk of pancreatic cancer .
 backgroundsome epidemiological studies have suggested that vitamin e intake reduces the risk of pancreatic cancer ; however , this conclusion has not been supported by all the published studies . 
 we conducted a meta - analysis to assess the relationship between vitamin e intake and the risk of pancreatic cancer by combining the results from published articles.material/methodswe searched the published studies that reported the relationship between vitamin e intake and pancreatic cancer risk using the pubmed , web of science , and embase databases through december 31st , 2014 . 
 based on a fixed - effects or random - effects model , the rr and 95% ci were used to assess the combined risk.resultsin total , 10 observational studies ( 6 case - control studies and 4 cohort studies ) were included . 
 the overall rr ( 95% ci ) of pancreatic cancer for the highest vs. the lowest level of vitamin e intake was 0.81 ( 0.73 , 0.89 ) . 
 we found little evidence of heterogeneity ( i2=19.8% , p=0.255 ) . in the subgroup analyses 
 , we found an inverse association between vitamin e intake and pancreatic cancer risk both in the case - control and cohort studies . 
 additionally , this inverse association was not modified by different populations.conclusionsin our meta - analysis , there was an inverse association between vitamin e intake and the risk of pancreatic cancer . 
 a high level of vitamin e might be a protective factor for populations at risk for pancreatic cancer . 
Background
Material and Methods
Study search and selection
Data extraction and quality assessment
Statistical analysis
Results
Study selection and characteristics
Meta-analysis
Discussion
Conclusions