Pancreatic cancerVitamin D levels

Oral vitamin D intake generally provides only a small portion of total vitamin D, with most vitamin D coming from casual solar UVB irradiance. Serum 25(OH)D levels are a measure of both oral intake and production from UVB irradiance.

The first nested case-control study of vitamin D intake and risk of pancreatic cancer (PC) was conducted on two Harvard cohort studies, including: 46,771 men ages 40 to 75 years as of 1986 (the Health Professionals Follow-up Study), and 75,427 women ages 38 to 65 years as of 1984 (the Nurses’ Health Study), documenting incident pancreatic cancer through the year 2000:

Diet was ascertained by semiquantitative food-frequency questionnaire. We identified 365 incident cases of pancreatic cancer over 16 years of follow-up. Compared with participants in the lowest category of total vitamin D intake (<150 IU/d), pooled multivariate relative risks for pancreatic cancer were 0.78 [95% confidence interval (95% CI), 0.59-1.01] for 150 to 299 IU/d, 0.57 (95% CI, 0.40-0.83) for 300 to 449 IU/d, 0.56 (95% CI, 0.36-0.87) for 450 to 599 IU/d, and 0.59 (95% CI, 0.40-0.88) for >/=600 IU/d (P(trend) = 0.01). These associations may be stronger in men than women. After adjusting for vitamin D intake, calcium and retinol intakes were not associated with pancreatic cancer risk1

The Harvard cohort studies also found a beneficial role of vitamin D in reducing risk of PC:

We prospectively followed 118 597 participants in the Nurses’ Health Study and Health Professionals Follow-up Study from 1986 to 2006. We calculated a 25-hydroxyvitamin D (25(OH)D) score from known predictors of vitamin D status for each individual and then examined the predicted 25(OH)D levels in relation to pancreatic cancer risk. Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models adjusted for age, sex, race, height, smoking, and diabetes. We then further adjusted for body mass index (BMI) and physical activity in a sensitivity analysis. RESULTS: During 20 years of follow-up, we identified 575 incident pancreatic cancer cases. Higher 25(OH)D score was associated with a significant reduction in pancreatic cancer risk; compared with the lowest quintile, participants in the highest quintile of 25(OH)D score had an adjusted RR of 0.65 (95% CI=0.50-0.86; P(trend)=0.001). Results were similar when we further adjusted for BMI and physical activity2.

The results in this study were more closely tied to solar UVB irradiance than oral intake since both measures of oral intake, diet and supplements, did not exhibit a significant trend at intakes above the median value for diet or for supplemental vitamin D use. The results showed a significant trend of reduced incidence with increasing serum 25(OH)D level for nonsmokers but not for smokers.

However, other studies of PC incidence with respect to prediagnostic serum 25(OH)D levels have not found a beneficial effect of vitamin D. In a cohort study of male Finnish smokers, ages 50 to 69 years at baseline, higher vitamin D concentrations were associated with a 3-fold increased risk for PC (highest versus lowest quintile, >65.5 versus <32.0 nmol/L: OR, 2.92; 95% CI, 1.56-5.48, P(trend) = 0.001) that remained after excluding cases diagnosed early during follow-up3

In a second study, one in the United States, the Prostate, Lung, Colorectal, and Ovarian Screening Trial cohort of men and women 55 to 74 years of age at baseline, between 1994 and 2006, 184 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Serum 25(OH)D: “concentrations were not associated with PC overall (highest versus lowest quintile, >82.3 versus <45.9 nmol/L: OR, 1.45; 95% CI, 0.66-3.15; P trend = 0.49). However, positive associations were observed among subjects with low estimated annual residential solar UBV exposure, but not among those with moderate to high annual exposure (P interaction = 0.015)4.”

In this study, 61% of the cases were smokers, again suggesting that the effects of vitamin D on risk of PC differ between those for smokers and nonsmokers. Smokers have lower serum calcium levels than nonsmokers5, and the Harvard cohort studies found that higher vitamin D intake was also associated with higher calcium intake1. Calcium seems to have a beneficial effect in reducing risk of a number of types of cancer6.

A series of papers on incidence of rarer cancers with respect to prediagnostic serum 25(OH)D levels was reported7 including one for PC4. The study pooled findings from ten cohort studies, seven in the United States, two from China, and one from Finland. Those in the cohorts were followed for a mean observation time of about ten years. Those who developed PC were matched with controls who did not develop PC. The 39 who developed PC who had serum 25(OH)D levels >100 nmol/L had a multivariate-adjusted odds ratio = 2.24 (95% CI, 1.22-4.12). The only cohort with a statistically significant increased risk of PC was the same cohort studied by Stolzenberg-Solomon et al4. Excluding this cohort would result in no correlation between serum 25(OH)D levels and incidence of PC.

The main problem with the observational studies that failed to find an inverse correlation between serum 25(OH)D level and incidence of pancreatic cancer proposed is that a single value loses prognostic value as time since serum draw increases. For example, case-control studies of serum 25(OH)D level and cancer incidence, for which the serum is drawn at the time of diagnosis, nearly always find an inverse correlation with breast and colorectal cancer incidence8. However, for nested case-control studies, in which members of a cohort are followed for several years after serum draw, statistically significant inverse correlations are not found after three years of follow up8. One reason for the decrease of prognostic value is that serum 25(OH)D levels can vary greatly during the year due to the seasonal variations in solar UVB doses9. Cancers such as breast cancer can grow rapidly when serum 25(OH)D (and melatonin) levels are low10.

Another study from the same Finnish cohort as in the study by by Stolzenberg-Solomon et al. reported changes in correlations between serum 25(OH)D and cancer incidence rates such as for non-Hodgkin’s lymphoma, for which: “Cases diagnosed less than 7 years from the baseline showed an inverse association (OR for highest vs. lowest tertile = 0.43; 95% CI: 0.23, 0.83; p for trend = 0.01), but not later diagnoses (OR = 1.52; 95% CI: 0.82, 2.80; p for trend = 0.17).”11. As this finding was from the same cohort as the pancreatic cancer study by Stolzenberg-Solomon et al.3, it serves to further discredit the findings of that study, which had up to a 16.7-year follow-up period.

Page last edited: 01 July 2011

References

  1. Skinner, H. G. Michaud, D. S. Giovannucci, E. Willett, W. C. Colditz, G. A. Fuchs, C. S. Vitamin D intake and the risk for pancreatic cancer in two cohort studies. Cancer Epidemiol Biomarkers Prev. 2006 Sep; 15 (9): 1688-95.
  2. Bao, Y. Ng, K. Wolpin, B. M. Michaud, D. S. Giovannucci, E. Fuchs, C. S. Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies. Br J Cancer. 2010 Apr 27; 102 (9): 1422-7.
  3. Stolzenberg-Solomon, R. Z. Vieth, R. Azad, A. Pietinen, P. Taylor, P. R. Virtamo, J. Albanes, D. A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res. 2006 Oct 15; 66 (20): 10213-9.
  4. Stolzenberg-Solomon, R. Z. Hayes, R. B. Horst, R. L. Anderson, K. E. Hollis, B. W. Silverman, D. T. Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial. Cancer Res. 2009 Feb 15; 69 (4): 1439-47.
  5. Jorde, R. Saleh, F. Figenschau, Y. Kamycheva, E. Haug, E. Sundsfjord, J. Serum parathyroid hormone (PTH) levels in smokers and non-smokers. The fifth Tromsø study. Eur J Endocrinol. 2005 Jan.; 52 (1): 39-45.
  6. Peterlik, M. Grant, W. B. Cross, H. S. Calcium, vitamin D and cancer. Anticancer Res. 2009 Sep; 29 (9): 3687-98.
  7. Helzlsouer, K. J. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010 Jul 1; 172 (1): 4-9.
  8. Grant, W. B. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermato-endocrinology. 2011; 3 (3):
  9. Hypponen, E. Power, C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007 Mar; 85 (3): 860-8.
  10. Oh, E. Y. Ansell, C. Nawaz, H. Yang, C. H. Wood, P. A. Hrushesky, W. J. Global breast cancer seasonality. Breast Cancer Res Treat. 2010 Aug; 123 (1): 233-43.
  11. Lim, U. Freedman, D. M. Hollis, B. W. Horst, R. L. Purdue, M. P. Chatterjee, N. Weinstein, S. J. Morton, L. M. Schatzkin, A. Virtamo, J. Linet, M. S. Hartge, P. Albanes, D. A prospective investigation of serum 25-hydroxyvitamin D and risk of lymphoid cancers. Int J Cancer. 2009 Feb 15; 124 (4): 979-86.