An Introduction to Cancer Introduction

 Pictured is a patent being tested for cancer. Evidence shows vitamin D reduces the risk of many types of cancer.

There is strong evidence that vitamin D reduces the risk of many types of cancer.

The evidence derives from numerous ecological, cross-sectional, prospective, case-control studies, meta-analyses (combination) of such studies, and laboratory investigations of mechanisms.

The evidence is strongest for colorectal and breast cancer. Additional cancers for which good evidence exists include bladder, endometrial, esophageal, gallbladder, gastric, lung, ovarian, pancreatic, prostate, renal, and vulvar cancer, Hodgkin’s and non-Hodgkin’s lymphoma (NHL), leukemia, and melanoma.

Based on case-control studies for breast and colorectal cancer, it appears that serum 25-hydroxyvitamin D [25(OH)D] levels of about 100 nmol/L (40 ng/mL) reduce the risk of all-cancer incidence by about 25% compared to a value of 30 nmol/L (12 ng/mL).

There is also one randomized controlled trial (RCT) that found a 77% reduction in all-cancer incidence between the ends of the first and fourth years for 1100 IU/day of vitamin D and 1450 mg/day of calcium.

Survival rates after diagnosis are higher for those with higher serum 25(OH)D levels at time of diagnosis as found for breast, colorectal, lung and prostate cancer, melanoma, and NHL.

The UVB-vitamin D-cancer hypothesis was originally proposed by the brothers Cedric Garland and Frank Garland1 after seeing early maps from the Atlas of Cancer Mortality in the United States2 and noticing that colon cancer mortality rates in the southwest were much lower than in the northeast. They noted that solar radiation doses were much higher in the southwest than in the northeast, and based the hypothesis on the fact that the most important physiological effect of solar radiation is production of vitamin D. After three decades of additional research, there is strong support for the hypothesis.

Since evidence for the UVB-vitamin D-cancer hypothesis comes largely from epidemiological studies, it is important to understand the types of studies involved and some of their strengths and weaknesses. [Robert P. Heaney, personal communication]

  • An ecological study is a subtype of an epidemiological study in which the sampling unit is a population defined geographically, with all of the risk-modifying factors averaged at the population level. Ecological studies integrate the effect of risk-modifying factors over entire lifetimes. Since much of the risk of cancer occurs early in life, the ecological study is very useful for studying cancer risk-modifying factors.
  • Cross-sectional studies are representative samples of an entire population, with individuals randomly selected from different locations.
  • There are two types of prospective studies, both called cohort. In each case one cohort is exposed to the putative independent variable, and the other is not. Both are followed forward in time and incidence rates computed for each at some subsequent point in time. Nested case-control studies are based on cohort studies with cases drawn from cohort studies and matched with similar people without the disease (controls).
  • By contrast, a case-control study starts not with exposure, but with outcomes, and ascertains exposure in the groups with and without the outcome concerned. Its principal weakness lies in hidden factors that influence selection/entry into the two contrast groups. Serum 25(OH)D values are determined around the time of cancer diagnosis for cases and time of enrollment for controls.
  • RCTs, are considered the strongest in terms of evidence, but are often the weakest in terms of generalizability. Moreover, if they are not conducted well (e.g., more than minimal losses of sampling units, too little vitamin D, poor compliance, other sources of vitamin D), they are inferentially weaker than cohort studies. The timeframe is limited to the years of the study.

The UVB-vitamin D-cancer hypothesis was proposed in 19801 and has been investigated since then using a variety of approaches including ecological, cross-sectional, observational, clinical and laboratory studies as well as RCTs, of which only one had sufficient vitamin D to generate an effect3.

Several reviews find that the UVB-vitamin D-cancer hypothesis is well supported45678910. However, some reviews have suggested that the hypothesis has not been fully verified1112. For example, the International Agency for Research on Cancer concluded that the evidence was convincing only for colorectal cancer11. However, a careful review of the IARC report indicates that the evidence from many studies was dismissed for trivial reasons, likely due to the bias of the committee8

A useful framework for evaluating causality in a biological system was outlined by A. Bradford Hill13. The important criteria for vitamin D and cancer prevention are strength of association, consistent observation in different populations, temporality, biological gradient (dose-response relation), plausibility (mechanisms), experiment (RCTs), and analogy. Later, accounting for confounding factors and controlling for bias were added14. The evidence for cancer was evaluated in a study by Grant8. It was reported that results for breast and colorectal cancer satisfy the criteria best, but there is also good evidence that other cancers do as well, including bladder, esophageal, gallbladder, gastric, ovarian, rectal, renal and uterine corpus cancer, as well as Hodgkin’s and NHL. Since then, the evidence has generally strengthened.

Page last edited: 21 May 2011

References

  1. Garland, C. F. Garland, F. C. Do sunlight and vitamin D reduce the likelihood of colon cancer?. Int J Epidemiol. 1980 Sep; 9 (3): 227-31.
  2. Devesa, S. S. Grauman, D. J. Blot, W. J. Pennello, G. A. Hoover, R. N. Fraumeni, J. F. Jr. Atlas of Cancer Mortality in the United States, 1950-1994. NIH Publication No. 99-4564. 1999 November 8, 2008;
  3. Lappe, J. M. Travers-Gustafson, D. Davies, K. M. Recker, R. R. Heaney, R. P. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun; 85 (6): 1586-91.
  4. Garland, C. F. Garland, F. C. Gorham, E. D. Lipkin, M. Newmark, H. Mohr, S. B. Holick, M. F. The role of vitamin D in cancer prevention. Am J Public Health. 2006 Feb; 96 (2): 252-61.
  5. Garland, C. F. Gorham, E. D. Mohr, S. B. Garland, F. C. Vitamin D for cancer prevention: global perspective. Ann Epidemiol. 2009 Jul; 19 (7): 468-83.
  6. Giovannucci, E. Epidemiology of vitamin D and colorectal cancer: casual or causal link?. J Steroid Biochem Mol Biol. 2010 Jul; 121 (1-2): 349-54.
  7. Grant, W. B. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer?: An examination using Hill’s criteria for causality. Dermatoendocrinol. 2009 Jan; 1 (1): 17-24.
  8. Grant, W. B. A critical review of Vitamin D and cancer: A report of the IARC Working Group on vitamin D. Dermato-endocrinology. 2009; 1 (1): 25-33.
  9. Grant, W. B. Mohr, S. B. Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Ann Epidemiol. 2009 Jul; 19 (7): 446-54.
  10. Mohr, S. B. A brief history of vitamin d and cancer prevention. Ann Epidemiol. 2009 Feb; 19 (2): 79-83.
  11. IARC Vitamin D and Cancer. IARC Working Group Reports. 2008; 5465 pp.
  12. Rhee, H. V. Coebergh, J. W. Vries, E. D. Sunlight, vitamin D and the prevention of cancer: a systematic review of epidemiological studies. Eur J Cancer Prev. 2009 Aug 26;
  13. Hill, A. B. The Environment and Disease: Association or Causation?. Proc R Soc Med. 1965 May; 58295-300.
  14. Weed, D. L. Gorelic, L. S. The practice of causal inference in cancer epidemiology. Cancer Epidemiol Biomarkers Prev. 1996 Apr; 5 (4): 303-11.