Pharmacology Consult

The role of vitamin D in cancer prevention and treatment

The Institute of Medicine recently published a new report on the dietary reference intakes for vitamin D, which were increased modestly. Many expected that the reference intake for vitamin D would increase substantially, given recent information suggesting that vitamin D deficiency may be implicated in several conditions, such as cancer, heart disease and diabetes. The following column discusses the role of vitamin D in cancer prevention and treatment after addressing how vitamin D deficiency is defined.

Vitamin D homeostasis and deficiency

In most people, the major source of vitamin D is the formation of cholecalciferol (vitamin D3) in the skin in response to ultraviolet B light exposure. Diet alone, with the exception of supplemented foods and cold water fish, is a poor source of vitamin D. Vitamin D is important for regulating calcium absorption and skeletal health. A deficiency of vitamin D has previously been associated with adverse skeletal outcomes, including osteoporosis and falls.

Cholecalciferol is converted to 25-hydroxyvitamin D (25-OH-D) by the liver and then to the active compound 1,25-hydroxyvitamin D (1,25-OH-D), or calcitriol, by the tissues that will use it. Vitamin D measurements are most frequently drawn as serum levels of 25-OH-D due to its long half-life of 2 to 3 weeks; 1,25-OH-D only has a half-life of 3 to 4 hours in the blood. Currently, a 25-OH-D serum level of less than 20 ng/mL (50 nmol/L) would be considered deficient. It is estimated that at least one-third of adolescents and adults in the United States are vitamin D deficient, with a 25-OH-D level of less than 20 ng/dL.

Debbie Blamble, PharmD
Debbie Blamble

The goal serum level of 25-OH-D for skeletal health is 30 ng/dL. At a level of 30 ng/dL, calcium is maximally absorbed from the gastrointestinal tract and parathyroid hormone levels plateau in most people. Excess levels of vitamin D (more than 150 ng/mL) have been associated with renal stones and hypercalcemia and should be avoided. There is much debate on the optimal level of vitamin D — between 30 ng/mL and 150 ng/mL — needed to improve outcomes other than skeletal events.

Vitamin D supplements are widely available with or without a prescription. For patients with a 25-OH-D level of less than 20 ng/dL, a vitamin D3 (cholecalciferol) supplement should be initiated at a dose of at least 2,000 IU orally daily. Ergocalciferol (vitamin D2) could also be used at the same dose and schedule. Patients with more severe vitamin D deficiency (level <12 ng/dL and/or symptomatic) should be started at higher daily doses. In clinical practice, a weekly dose of 50,000 IU is commonly used. Repeat the serum level after 6 weeks in high-risk patients and after 3 to 4 months to ensure that the supplementation is adequate. The vitamin D3 dose can be lowered to a maintenance dose once the desired level is achieved.

Vitamin D and cancer risk

Vitamin D receptors are found on a number of normal tissues. Vitamin D promotes the differentiation and inhibits the proliferation of cells. In animal models, vitamin D has reduced the growth of certain tumors. Proposed antitumor mechanisms include promotion of cell cycle progression, pro-apoptotic and antiangiogenic effects and immunomodulation. Despite preclinical evidence, vitamin D supplementation trials to date that have looked at cancer or cancer-related mortality as secondary outcomes have not demonstrated a benefit of vitamin D supplementation in the overall population.

However, several observational or case-control studies have shown a correlation between 25-OH-D levels and cancer risk. Individually, the study results are not always consistent, so many have been combined in meta-analyses. A meta-analysis of eight studies (seven case-control and one cohort) demonstrated that an increase of 20 ng/dL in the 25-OH-D level decreased the incidence of colorectal cancer by 43% (OR=0.57; 95% CI, 0.43-0.76). A meta-analysis of seven observational studies found a 45% decrease in breast cancer in those patients with the highest quantile of circulating 25-OH-D (RR=0.55; 95% CI, 0.38-0.8) compared with the lowest quantile. A separate meta-analysis confirmed the inverse association between 25-OH-D levels and colorectal cancer risk but failed to find an association with breast cancer risk. This meta-analysis also evaluated and failed to find an association between vitamin D levels and prostate cancer risk.

One randomized, placebo-controlled trial (a Women’s Health Initiative study) evaluated the effect of calcium and vitamin D supplementation on the risk for colorectal and breast cancers. After an average of 7 years of treatment, there was no difference in the incidence of colorectal or breast cancer in the women receiving the supplements vs. those receiving placebo. They also confirmed the inverse association between 25-OH-D levels and colorectal cancer risk, but failed to find an association between 25-OH-D levels and breast cancer risk. Potential explanations for the lack of effect on cancer prevention include the dose of supplementation use (vitamin D dose = 400 IU) and the concomitant administration of calcium. Also, the long time during which colorectal cancer, as well as some breast cancers, develops, relative to the study length, may have affected the results.

Recently, the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) published its results. The VDPP consisted of 10 prospective, international cohort studies with stored blood samples; blood samples were assayed in a central laboratory. The VDPP was a case-control study that looked at the association between serum or plasma 25-OH-D concentrations and the development of seven types of rarer cancers: endometrial, esophageal, gastric, kidney, non-Hodgkin’s lymphoma, ovarian and pancreatic cancers. The results of the VDPP did not demonstrate a benefit of higher concentrations of vitamin D nor an increased cancer risk from lower concentrations of vitamin D. Of concern, the risk for pancreatic cancer was increased in those patients with a 25-OH-D concentration of more than 40 ng/mL (adjusted OR=2.12; 95% CI, 1.23–3.64). This adverse or so called U-shaped effect of high vitamin D levels has also been noted in case-control studies of prostate and esophageal cancer as well.

IOM Vitamin D Dietary Reference Intakes by Life Stage (Amount/Day)

Association with cancer prognosis

Vitamin D has also been associated with cancer prognosis. Low vitamin D levels have been associated with progression or poorer prognosis in numerous cancer types, including melanoma, chronic lymphocytic leukemia, NHL and cancers of the colon/rectum, breast and lung. Recently, a report from the National Health and Nutritional Examination Survey III showed a decrease in colorectal mortality but a trend toward increased mortality due to other cancers in men with the highest levels of 25-OH-D (≥40 ng/dL). Interestingly, high levels of 25-OH-D were associated with lower cancer mortality in certain women in the cohort (those living in higher latitudes). These results suggest that there may be heterogeneity in the association of vitamin D and cancer between males and females that should be considered when designing intervention studies.

Vitamin D has been administered as a part of cancer treatment, most notably in patients with prostate cancer. Clinical significant responses have been uncommon. The optimal means of administration is still under investigation. A current search of the www.clinicaltrials.gov website found 381 matches when searching for “vitamin D and cancer.” Although some were observational or prevention studies, several treatment trials were listed for many tumor types, including ones discussed here.

Several issues make it difficult to draw firm conclusions about the relationship of vitamin D and cancer: first, the difficulty of attributing outcomes to the effect of a single nutrient vs. other nutrients or non-nutrient factors. For example, vitamin D is closely tied to calcium physiologically and they are frequently administered together in intervention studies. Second, the development of most cancers is a multifactorial process, making it difficult to assign causality to a single potential risk factor. Third, randomized controlled trial data are lacking and results from observational studies are often mixed or inconclusive. Fourth, the use of serum 25-OH-D levels as a biomarker has not been validated and measurement methodologies have been variable. Finally, the relationship between levels of 25-OH-D and cancer risk or mortality is not consistent across tumor types or between males and females. Despite these limitations, the vitamin D data are interesting enough to warrant more rigorous scientific investigations.

Debbie Blamble, PharmD, BCOP, is an Oncology Clinical Pharmacy Specialist at The University of Texas MD Anderson Cancer Center. She may be reached at dblamble@mdanderson.org. She reports no relevant financial disclosures.

The Institute of Medicine recently published a new report on the dietary reference intakes for vitamin D, which were increased modestly. Many expected that the reference intake for vitamin D would increase substantially, given recent information suggesting that vitamin D deficiency may be implicated in several conditions, such as cancer, heart disease and diabetes. The following column discusses the role of vitamin D in cancer prevention and treatment after addressing how vitamin D deficiency is defined.

Vitamin D homeostasis and deficiency

In most people, the major source of vitamin D is the formation of cholecalciferol (vitamin D3) in the skin in response to ultraviolet B light exposure. Diet alone, with the exception of supplemented foods and cold water fish, is a poor source of vitamin D. Vitamin D is important for regulating calcium absorption and skeletal health. A deficiency of vitamin D has previously been associated with adverse skeletal outcomes, including osteoporosis and falls.

Cholecalciferol is converted to 25-hydroxyvitamin D (25-OH-D) by the liver and then to the active compound 1,25-hydroxyvitamin D (1,25-OH-D), or calcitriol, by the tissues that will use it. Vitamin D measurements are most frequently drawn as serum levels of 25-OH-D due to its long half-life of 2 to 3 weeks; 1,25-OH-D only has a half-life of 3 to 4 hours in the blood. Currently, a 25-OH-D serum level of less than 20 ng/mL (50 nmol/L) would be considered deficient. It is estimated that at least one-third of adolescents and adults in the United States are vitamin D deficient, with a 25-OH-D level of less than 20 ng/dL.

Debbie Blamble, PharmD
Debbie Blamble

The goal serum level of 25-OH-D for skeletal health is 30 ng/dL. At a level of 30 ng/dL, calcium is maximally absorbed from the gastrointestinal tract and parathyroid hormone levels plateau in most people. Excess levels of vitamin D (more than 150 ng/mL) have been associated with renal stones and hypercalcemia and should be avoided. There is much debate on the optimal level of vitamin D — between 30 ng/mL and 150 ng/mL — needed to improve outcomes other than skeletal events.

Vitamin D supplements are widely available with or without a prescription. For patients with a 25-OH-D level of less than 20 ng/dL, a vitamin D3 (cholecalciferol) supplement should be initiated at a dose of at least 2,000 IU orally daily. Ergocalciferol (vitamin D2) could also be used at the same dose and schedule. Patients with more severe vitamin D deficiency (level <12 ng/dL and/or symptomatic) should be started at higher daily doses. In clinical practice, a weekly dose of 50,000 IU is commonly used. Repeat the serum level after 6 weeks in high-risk patients and after 3 to 4 months to ensure that the supplementation is adequate. The vitamin D3 dose can be lowered to a maintenance dose once the desired level is achieved.

Vitamin D and cancer risk

Vitamin D receptors are found on a number of normal tissues. Vitamin D promotes the differentiation and inhibits the proliferation of cells. In animal models, vitamin D has reduced the growth of certain tumors. Proposed antitumor mechanisms include promotion of cell cycle progression, pro-apoptotic and antiangiogenic effects and immunomodulation. Despite preclinical evidence, vitamin D supplementation trials to date that have looked at cancer or cancer-related mortality as secondary outcomes have not demonstrated a benefit of vitamin D supplementation in the overall population.

However, several observational or case-control studies have shown a correlation between 25-OH-D levels and cancer risk. Individually, the study results are not always consistent, so many have been combined in meta-analyses. A meta-analysis of eight studies (seven case-control and one cohort) demonstrated that an increase of 20 ng/dL in the 25-OH-D level decreased the incidence of colorectal cancer by 43% (OR=0.57; 95% CI, 0.43-0.76). A meta-analysis of seven observational studies found a 45% decrease in breast cancer in those patients with the highest quantile of circulating 25-OH-D (RR=0.55; 95% CI, 0.38-0.8) compared with the lowest quantile. A separate meta-analysis confirmed the inverse association between 25-OH-D levels and colorectal cancer risk but failed to find an association with breast cancer risk. This meta-analysis also evaluated and failed to find an association between vitamin D levels and prostate cancer risk.

One randomized, placebo-controlled trial (a Women’s Health Initiative study) evaluated the effect of calcium and vitamin D supplementation on the risk for colorectal and breast cancers. After an average of 7 years of treatment, there was no difference in the incidence of colorectal or breast cancer in the women receiving the supplements vs. those receiving placebo. They also confirmed the inverse association between 25-OH-D levels and colorectal cancer risk, but failed to find an association between 25-OH-D levels and breast cancer risk. Potential explanations for the lack of effect on cancer prevention include the dose of supplementation use (vitamin D dose = 400 IU) and the concomitant administration of calcium. Also, the long time during which colorectal cancer, as well as some breast cancers, develops, relative to the study length, may have affected the results.

Recently, the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) published its results. The VDPP consisted of 10 prospective, international cohort studies with stored blood samples; blood samples were assayed in a central laboratory. The VDPP was a case-control study that looked at the association between serum or plasma 25-OH-D concentrations and the development of seven types of rarer cancers: endometrial, esophageal, gastric, kidney, non-Hodgkin’s lymphoma, ovarian and pancreatic cancers. The results of the VDPP did not demonstrate a benefit of higher concentrations of vitamin D nor an increased cancer risk from lower concentrations of vitamin D. Of concern, the risk for pancreatic cancer was increased in those patients with a 25-OH-D concentration of more than 40 ng/mL (adjusted OR=2.12; 95% CI, 1.23–3.64). This adverse or so called U-shaped effect of high vitamin D levels has also been noted in case-control studies of prostate and esophageal cancer as well.

IOM Vitamin D Dietary Reference Intakes by Life Stage (Amount/Day)

Association with cancer prognosis

Vitamin D has also been associated with cancer prognosis. Low vitamin D levels have been associated with progression or poorer prognosis in numerous cancer types, including melanoma, chronic lymphocytic leukemia, NHL and cancers of the colon/rectum, breast and lung. Recently, a report from the National Health and Nutritional Examination Survey III showed a decrease in colorectal mortality but a trend toward increased mortality due to other cancers in men with the highest levels of 25-OH-D (≥40 ng/dL). Interestingly, high levels of 25-OH-D were associated with lower cancer mortality in certain women in the cohort (those living in higher latitudes). These results suggest that there may be heterogeneity in the association of vitamin D and cancer between males and females that should be considered when designing intervention studies.

Vitamin D has been administered as a part of cancer treatment, most notably in patients with prostate cancer. Clinical significant responses have been uncommon. The optimal means of administration is still under investigation. A current search of the www.clinicaltrials.gov website found 381 matches when searching for “vitamin D and cancer.” Although some were observational or prevention studies, several treatment trials were listed for many tumor types, including ones discussed here.

Several issues make it difficult to draw firm conclusions about the relationship of vitamin D and cancer: first, the difficulty of attributing outcomes to the effect of a single nutrient vs. other nutrients or non-nutrient factors. For example, vitamin D is closely tied to calcium physiologically and they are frequently administered together in intervention studies. Second, the development of most cancers is a multifactorial process, making it difficult to assign causality to a single potential risk factor. Third, randomized controlled trial data are lacking and results from observational studies are often mixed or inconclusive. Fourth, the use of serum 25-OH-D levels as a biomarker has not been validated and measurement methodologies have been variable. Finally, the relationship between levels of 25-OH-D and cancer risk or mortality is not consistent across tumor types or between males and females. Despite these limitations, the vitamin D data are interesting enough to warrant more rigorous scientific investigations.

Debbie Blamble, PharmD, BCOP, is an Oncology Clinical Pharmacy Specialist at The University of Texas MD Anderson Cancer Center. She may be reached at dblamble@mdanderson.org. She reports no relevant financial disclosures.