In our large population-based case–control study, approximately half of all study participants had adequate total vitamin D intake according to current guidelines. Our results provided support for increased risk of pancreatic cancer with dietary vitamin D intake in men, although increased risk associated with total vitamin D (vitamin supplements and food) was limited to men with low to moderate levels of intake and was diminished in the highest category of intake. The pattern of association between calcium intake (total and dietary) and pancreatic cancer risk was similar to that observed with vitamin D and again was observed in men and not in women. In both men and women, the association with calcium was confounded by vitamin D intake. Vitamin A intake was not associated with pancreatic cancer risk in men or women. Increased risks were suggested for men and women with increased dietary retinol intake, although results could have been due to chance.
The Institute of Medicine’s (IOM) Food and Nutrition Board currently recommends Dietary Reference Intake (DRI) of total vitamin D at 400 IU/day for most adults and 600 IU/day for those >70 years of age. In our study, median total vitamin D intake was adequate for those under the age of 70 years (423 IU/day for men, 487 IU/day for women), but not for those who were >70 years of age (453 IU/day for men, 497 IU/day for women). We observed that men with total vitamin D intake above the DRI had lower risks than those in the lowest category of intake. Recommendations recently have been published advocating that the DRI be doubled [31
] or be raised to 2,000 IU/day [32
]. An expert panel of the IOM currently is reviewing the official vitamin D recommendations that last were updated in 1997. Final recommendations are expected in 2010 [33
Few population-based studies have investigated the association between vitamin D and its analogs with pancreatic cancer risk, and their results have been inconsistent, and overall, inconclusive. Similar to our findings, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) among male Finnish smokers aged 50–69 years reported a threefold significantly increased risk of pancreatic cancer among those with the highest serum concentrations of the vitamin D metabolite 25(OH)D [15
] (>65.5 vs. <32.0 nmol/l). However, in the earlier analyses, dietary-related vitamin D levels were not associated with risk [14
]. The authors importantly noted that for the majority of the Finnish study participants, vitamin D levels indicated vitamin D deficiency (median dietary and total intake 4.9 mcg (196 IU/day) for cases and controls) and therefore their results may be applicable to a vitamin D deficient population only [14
]. The largest to date pooled analysis of eight cohort studies reported a statistically significant twofold increase in the risk of pancreatic cancer associated with a high 25(OH)D serum concentration (≥100 vs. 50–75 nmol/l) [17
These results contrast with those from a pooled analysis of two cohort studies [10
] and with a recent case–control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial [16
]. Although the results from the cohort studies showed a decreased risk with increased vitamin D intake, similar to our results, the effect appeared to be restricted to men [10
]. The results from the PLCO study are inconsistent with our and other’s results. Investigators reported no association between serum 25(OH)D and pancreatic cancer in models adjusted for time of year of blood draw (to account for a seasonal UVB effect on vitamin D metabolite levels) [16
]. The discrepant results emphasize the complexity of a relationship between vitamin D and pancreatic cancer risk that includes the multiple methods that have been used by studies to determine a valid and informative measure of vitamin D status.
Vitamin D is a fat-soluble vitamin, and its concentration depends upon supplements, dietary consumption of vitamin D-rich foods and on endogenous production when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis [34
]. Studies based on reported dietary vitamin D intake have a limited ability to account for solar-associated skin production of vitamin D. This is further complicated by known differences in individual ability to synthesize vitamin D from the sun, including phenotypic characteristics of the skin, i.e., melanin, age, geographic longitude and latitude, seasonal variation, and personal sun protection. Thus, accurate measurement of vitamin D depends upon measuring concentrations of its metabolites. One metabolite, 25-hydroxyvitamin D [35
], is produced by the liver and is affected by recent vitamin D intake. In addition, the integral effects of vitamin A and retinol levels (antagonists to vitamin D), calcium intake and absorption (regulated by vitamin D and at high levels a regulator of the production of the active form of vitamin D) [18
], and genetic variation in the expression of vitamin D receptors need to be considered as they may confound or modify the association between vitamin D levels and pancreatic cancer risk. Our results combined with those of other published studies emphasize a need to identify measures of dietary and non-dietary effects on vitamin D status to gain a better understanding of whether vitamin D may alter risk of pancreatic cancer.
Intake of vitamin D supplements, retinol, and calcium level of physical activity or smoking did not confound or modify the association between dietary vitamin D intake and risk of pancreatic cancer. Further, the increased risks observed among men did not differ by high or low level of dietary retinol, or by level of physical activity, although ORs were slightly lower for higher physical activity levels (2–3 times/week). In contrast, there was no clear pattern of risks among women. The difference in risks between men and women may be due to: differential sun exposure; women’s higher percentage of body fat beyond that measured by body mass index [36
]; or differences in dietary and supplement-use patterns.
The strengths and weaknesses of case–control study design and methods used to ascertain dietary intake should be considered when interpreting the results from our study. Information bias due to differential reporting of diet by cases and controls is possible, although dietary risk factors for pancreatic cancer are not firmly established nor widely known in the community [5
]. Therefore, it is less likely that cases recalled their diet differently from controls, and our response rates for cases and controls were similar. Overall survival of our cases was not associated with vitamin D intake among men and women (trend-p
= 0.68 men, and trend-p
= 0.89 women, respectively), and the median time from diagnosis to interview was less than 2 months. Thus, although it is unlikely that our results were affected by selection bias related to the rapid and high mortality among pancreatic cancer cases, it is possible that our results pertain to ‘healthier’ pancreatic cancer patients.
Vitamin D levels also are affected by endogenous vitamin D synthesis in the skin related to relatively short exposure to ultraviolet rays from sunlight [6
]. Due to rapid progression of pancreatic cancer, most cases are unlikely to have experienced conditions or symptoms that would greatly limit their activities for an extended period of time before their pancreatic cancer diagnosis. Thus, differentially lower sun exposure among cases is unlikely, but the data regarding sun exposure were not available for these analyses. It is more likely that age-related factors would impact outdoor activity and sun-related vitamin D production and our matching by age groups would help to adjust for age-related effects.
The strengths of our study are many and include the population-based design providing for comparability of cases and controls on many measured and unmeasured confounding variables. Case–control study design allowed for greater power to test study hypotheses by including a large number of population-based incident pancreatic cancer cases identified from a cancer registry. The large sample size provided adequate power to explore statistical associations of interest and to explore confounding and effect modification. Adequacy of the FFQ instrument has been validated in multiple studies, both by re-testing study participants using the same instrument and by comparing nutrient intake from a food-frequency questionnaire with a 7-day recall diary [20
Our results suggesting that lower intake of dietary vitamin D and dietary calcium may be associated with risk of pancreatic cancer in men require confirmation in independent studies with careful assessment in the highest categories of intake where risk was diminished. Continued investigation in studies designed to assess multiple exposures, and factors that affect vitamin D levels are warranted to elucidate the non-linear associations with vitamin D and calcium intake that were observed in our study population. Few modifiable risk factors have been identified for pancreatic cancer. Data that can be used to determine an ideal level of vitamin D intake and clarify the complex role of vitamin D and calcium intake in pancreatic cancer risk may be translated to prevention and intervention strategies for this highly fatal cancer.