August 2009, Volume 13, Number 4
Journal Club Article
Optimizing Vitamin D Status to Reduce Colorectal Cancer Risk: An Evidentiary Review
Guiyun Zhou, MSN, CRNP, AOCNSฎ, Jill Stoltzfus, PhD, and Beth Ann Swan, PhD, CRNP, FAAN
Journal Club Discussion Questions
This article has been identified as appropriate for a journal club. When you read this article, think about how you would change your current practice regarding screening and managing vitamin D deficiency in your patients. See the Evidence-Based Practice column in the February 2009 Clinical Journal of Oncology Nursing (Vol. 13, No. 1, pp. 109112) on how to implement and participate in journal clubs. Photocopying of this article for discussion purposes is permitted.
1. What is the clinical practice question the authors are trying to answer?
2. Is the purpose of the article described clearly?
3. Is the literature review comprehensive and are major concepts identified and defined?
4. Are the clinical recommendations supported by evidence? What are they?
5. Do you currently screen patients for vitamin D deficiency? How do the clinical recommendations compare to your current practice?
6. What practice change recommendations will you make based on the evidence presented in this article? Who should get screened for vitamin D deficiency? When, where, and how often should they be screened? How should someone be managed if deficient?
7. What patient education materials are available on this topic?
Vitamin D deficiency is common in the general public and in patients with cancer. Optimizing vitamin D intake is increasingly recognized in cancer risk reduction, particularly in decreasing colorectal cancer risk. Therefore, summarizing the current evidence to promote best practices related to vitamin D intake and colorectal cancer risk reduction is important. The objectives of this article are to examine the current evidence regarding the impact of vitamin D on colorectal cancer risk reduction and provide practice recommendations for clinicians. Relevant research articles from 20022008 were retrieved from multiple electronic databases. Reference lists of relevant articles also were searched manually. Twenty-five research reports were selected for this article: 4 randomized, controlled trials; 11 cohort or case-control studies measuring serum 25-OH-D levels; and 10 cohort studies reporting vitamin D intake. This review generated three themes: raising 25-OH-D levels to a vitamin D sufficient state (32100 ng/ml) achieved colorectal cancer risk reduction, increasing the intake of vitamin D reduced colorectal cancer risk, and increasing vitamin D intake to 1,000 IU daily is safe and likely sufficient to raise serum 25-OH-D levels above 32 ng/ml to achieve colorectal cancer risk reduction. Several practice recommendations are suggested.
At a Glance
ท Vitamin D deficiency or insufficiency (less than 32 ng/ml or 80 nmol/L) is common in the general population and in patients with cancer.
ท Current evidence suggests that optimizing serum 25-OH-D levels to the normal range of 32100 ng/ml is associated with colorectal cancer risk reduction.
ท Daily vitamin D intake of 1,000 IU is safe and likely sufficient to reduce colorectal cancer risk.
Cancer is one of the most dreaded diagnoses from a physiological, psychological, social, and spiritual standpoint. According to the American Cancer Society ([ACS], 2008), cancer is the second leading cause of death in the Untied States; about 1.5 million Americans were diagnosed with some form of cancer in 2008 and more than 500,000 died. In addition, the estimated overall cost of cancer care reached $219 billion in 2007 (ACS). Therefore, cancer prevention and risk reduction clearly are in the national interest. Healthcare providers in particular have a major responsibility in leading the fight against cancer by actively screening for cancer, treating cancer-predisposing conditions in a timely manner, and educating the public about cancer prevention (including directly modifiable risk factors). Vitamin D deficiency is considered one such risk factor for many types of solid organ cancers, such as colorectal cancer, breast cancer, and ovarian cancer (Garland et al., 2006).
Vitamin D deficiency is an epidemic health problem in the industrial world; an estimated 1 billion people have vitamin D deficiency (Cherniack, Levis, & Troen, 2008; Holick, 2007). In the United States, 25%58% of adolescents and adults are deficient in vitamin D (Looker, Dawson-Hughes, Calvo, Gunter, & Sahyoun, 2002). Among patients with cancer, the prevalence of vitamin D deficiency is much higher, approaching 90% (Everett, 2008; Hershman et al., 2006; Li et al., 2007; Maddipatla et al., 2007).
Since the late 1990s, studying vitamin Ds effect on cancer has been of increasing interest. Ecological studies have shown that heightened sun exposure decreases internal solid organ cancers (Boscoe & Schymura, 2006; Grant, 2007; Tuohimaa et al., 2007). Researchers also have observed that higher intake of vitamin D from diet, supplements, or both is associated with a lower risk of colorectal and breast cancers (Garland et al., 2006; Lin et al., 2007; Robien, Cutler, & Lazovich, 2007). A meta-analysis of 18 randomized, controlled trials (RCTs) demonstrated that vitamin D supplementation is associated with decreased total mortality rates from life-threatening conditions such as cancer, cardiovascular disease, and diabetes mellitus (Autier & Gandini, 2007). Many studies have similarly demonstrated an inverse relationship between serum 25-OH-D levels and the risk of colorectal, breast, and prostate cancers (Garland et al., 2006). In addition, lower serum 25-OH-D levels are associated with higher overall mortality, colorectal cancerspecific mortality, and more advance-staged disease in breast cancer and colorectal cancer (Fakih & Sunga, 2006; Goodwin, Ennis, Pritchard, Koo, & Hood, 2008; Melamed, Michos, Post, & Astor, 2008; Ng et al., 2008; Palmieri, MacGregor, Girgis, & Vigushin, 2006; Sieg, Sieg, Dreyhaup, & Schmidt-Gayk, 2006).
The major research breakthrough demonstrating the direct cancer risk reduction by vitamin D intake was reported by Lappe, Travers-Gustafson, Davies, Recker, and Heaney (2007). Their RCT studied 1,179 postmenopausal women and found that taking 1,100 IU of vitamin D plus 1,4001,500 mg of daily calcium for four years resulted in a 60%77% overall cancer risk reduction. Following this report, the Canadian Cancer Society (2007) updated their vitamin D recommendation to 1,000 IU daily for typical adults during fall and winter months and year-round for adults at high risk for vitamin D deficiency. Subsequently, the Family Physicians Inquiries Network in the United States published a pivotal report in response to this research finding, suggesting that double-dose vitamin D lowers cancer risk in women older than age 55 (Schumann & Ewigman, 2007).
It has been shown that vitamin D increases the apoptosis in the colorectal epithelium, thereby reducing the risk of developing colorectal neoplasia (Holt et al., 2002, 2006). Indeed, many cell types, including colorectal epithelial cells, contain vitamin D receptors (VDRs) and express 1-a-hydroxylase. These cells are, therefore, able to convert the circulating 25-OH-D into active 1-25-OH-D metabolite, which, in turn, binds to the cells own VDRs to produce an autocrine effect by inducing cell differentiation and inhibiting proliferation, invasiveness, angiogenesis, and metastatic potentials (Giovannucci, 2006). Among a large number of published research articles on the relationship between vitamin D and various cancers, vitamin Ds effects on colorectal cancer risk reduction has been most widely studied and reported. Therefore, this evidentiary article will primarily focus on the vitamin D effect in colorectal cancer risk reduction with the goals of transforming scientific knowledge into clinical practice. The objectives are to examine the effect of vitamin D on colorectal cancer prevention and risk reduction and provide practical recommendations for clinicians to evaluate and treat vitamin D deficiency in patients, as well as optimize vitamin D status accordingly.
To retrieve the best evidence on vitamin D in colorectal cancer prevention and risk reduction, electronic searches were conducted in a variety of databases from 20022008 because, generally speaking, evidence from the most recent five-year period is considered most relevant to research. An Ovid search was carried out through Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINEฎ, and CINAHLฎ by using keywords vitamin D, 25 hydroxyvitamin D, or cholecalciferol; colorectal neoplasm; clinical trial; cohort studies; case-controlled studies; and epidemiologic studies. The PubMed database was searched using vitamin D, colorectal neoplasm, and clinical trial; vitamin D, colorectal neoplasm, and cohort studies; vitamin D, colorectal neoplasm, and case-controlled studies; and vitamin D, colorectal neoplasm, and epidemiologic studies. In addition, manual searches were conducted on reference lists of relevant articles.
No systematic reviews or meta-analyses based on randomized trials were found. Thirty-five potential research reports were identified, including RCTs, cohort studies, case-control studies, and epidemiologic studies. The study interests regarding vitamin D and colorectal neoplasm consist of vitamin D intake from diet and supplements, sun exposure, serum 25-OH-D levels, vitamin D receptor polymorphism, and clinical trials with vitamin D plus calcium intervention.
Twenty-five articles were selected for this evidentiary review (see Table 1). The selection criteria were based on strengths of evidence grade: RCTs with vitamin D as the intervention (n = 4); cohort or case-control studies using serum 25-OH-D level measurement as the indicator variable reflecting vitamin D status to assess association with colorectal neoplasm (including colorectal adenomas and colorectal cancers) (n = 11); and cohort or case-control studies measuring vitamin D intake from diet, supplements, or both to examine the association with colorectal neoplasm (n = 10). Studies on adenomas or colorectal polyps also were selected because adenomas occur prior to cancer development, making adenomas the true indicator of colorectal cancer risk. Ecologic studies were not included, as these studies provide only suggestive associations between regions or seasons and sun exposure as the vitamin D proxy. Several studies based on VDRs as the main vitamin D variables also were not included because VDRs are not well understood and are probably less practical from a clinical perspective.
Analysis and Synthesis
The Rating System for Levels of Evidence (Melnyk & Fineout-Overholt, 2005) was used to grade the research studies selected for this evidentiary review. There are seven levels of evidence in this rating system, with level I representing evidence from a systematic review or meta-analysis through level VII representing evidence from expert opinion and/or consensus groups (Melnyk & Fineout-Overholt). Most studies in this review were rated as level II (one well-designed RCT) or level IV (well-designed case control and cohort studies). For discussion purposes, the studies are grouped into three categories based on the major variable of study interest: RCTs with vitamin D as an intervention, cohort or case-control studies measuring 25-OH-D levels as the primary variable, and cohort or case-control studies measuring vitamin D intake from diet and supplements.
Vitamin D as a Research Intervention in Randomized, Controlled Trials
Lappe et al. (2007) conducted a four-year, population-based, placebo-controlled, three-arm RCT with 1,179 postmenopausal women to examine the efficacy of calcium alone versus calcium plus vitamin D on cancer incidence of all types. Results revealed that the group taking 1,100 IU of vitamin D plus 1,4001,500 mg of calcium daily had a 60% overall cancer risk reduction compared to the placebo group (risk ratio [RR] = 0.4, 95% confidence interval [CI] 0.20.82, p = 0.01). Excluding cancer cases in the first year yielded an even more dramatic reduction in risk of 77% (RR = 0.23, 95% CI 0.090.6, p < 0.005). Vitamin D plus calcium treatment accounted 5.5% of the overall variance (R2 = 0.055), with the number needed to treat to prevent one case of cancer equaling 20 patients. No difference existed in toxicity profile among the three groups. The major limitations of this RCT are the short study duration of four years, relatively few cases of cancer diagnosis (a total of 50 cancer cases, 13 during the first year and 37 during the subsequent three years), and the fact that cancer incidence was the secondary outcome.
In contrast, the double-blind, placebo-controlled Womens Health Initiative (WHI) study with 36,282 postmenopausal women found that taking 1,000 mg of calcium plus 400 IU of vitamin D daily for seven years revealed no protective effect against colorectal cancer incidence as the secondary outcome (RR = 1.08, 95% CI 0.861.34, p = 0.51) (Wactawski-Wende et al., 2006). However, the nested study of 25-OH-D level measurement at baseline did show that higher 25-OH-D levels were associated with less colorectal cancer risk (odds ratio [OR] = 2.53 for the lowest quartile of less than 31 nmol/L compared with the highest quartile of 58 nmol/L or higher, p = 0.02).
The WHI study has been subjected to several criticisms as a result of vitamin D supplementation showing no protective effects against colorectal cancer risk. First, the vitamin D dose (400 IU per day) used in the study potentially was too low to raise 25-OH-D levels into a meaningful range for a colorectal cancer risk reduction because 400 IU per day did not correct the vitamin D deficient status (Holick & Giovannucci, 2006). Instead, it only raised the mean 25-OH-D level from baseline 42 nmol/L (16.8 ng/ml) to 47 nmol/L (18.8 ng/ml), whereas the suggested 25-OH-D level needed to decrease colorectal cancer risk is above 80 nmol/L (32 ng/ml) (Gorham et al., 2007). Second, a poor adherence rate of less than 50% existed among WHI study participants. Third, the concurrent use of overlapping estrogen therapy in the WHI study likely modified the effects of the calcium plus vitamin D regimen (Ding, Mehta, Fawzi, & Giovannucci, 2008). Ding et al. (2008) re-analyzed the primary data from the WHI study to focus on women concurrently taking supplemental estrogen. The hazard ratio (HR) of colorectal cancer for women concurrently taking calcium-vitamin D and estrogen was 1.5 (95% CI 0.962.33), which suggested increased risk. The HR of colorectal cancer for women taking calcium and vitamin D but concurrently assigned to the non-estrogen arm was 0.71 (95% CI 0.461.09), which indicated a possible protective benefit. The interaction between concurrent estrogen usage and calcium plus vitamin D supplementation was statistically significant (p = 0.02).
Two small RCTs examined the effects of calcium plus vitamin D on the epithelial cell proliferation from colorectal mucosa and polyps (Holt et al., 2002, 2006). Findings demonstrated that 400 IU of vitamin D plus 1,500 mg of calcium daily for six months decreased epithelial cell proliferation of the colorectal mucosa and colorectal polyp mucosa. Additionally, vitamin D plus calcium appeared to inhibit polyp formation. The anti-carcinogenic effect of vitamin D was supported by an in vitro study, as human colon cancer cells treated with vitamin D showed up-regulation of VDR and 25-hydroxyvitamin D-1-a-hydroxylase expression (Murillo, Matusiak, Benya, & Mehta, 2007). Previous case-control studies also have demonstrated that vitamin D increases colorectal epithelium apoptosis (Diaz, Paraskeva, Thomas, Binderup, & Hague, 2000; Miller et al., 2005).
An effective dosage of vitamin D to raise 25-OH-D levels above 80 nmol/L (32 ng/ml) is critical in achieving cancer risk reduction. Previous investigators have demonstrated a dose-response relationship between cancer risk and 25-OH-D levels. Quantitative pooled analyses from cohort studies reveal that correction of vitamin D deficiency to an optimal level of 33 ng/ml or higher (82.5 nmol/L) is associated with a 50% reduction in colorectal cancer risk (Gorham et al., 2007), while a level of 52 ng/ml or higher (130 nmol/L) is associated with a 50% beast cancer risk reduction (Garland et al., 2007). In the study by Lappe et al. (2007), vitamin D intake of 1,100 IU per day raised 25-OH-D levels from a baseline of 71.8 nmol/L to 96 nmol/L. However, in the WHI study, vitamin D intake of 400 IU per day was too low to raise 25-OH-D levels above 80 nmol/L to achieve any meaningful cancer risk reduction. Given these mixed results, a RCT in a large sample using an effective vitamin D dose to keep 25-OH-D level within the range of 32100 ng/ml (measured twice a year in both winter and summer) over 10 years is needed to provide the strongest evidence of vitamin Ds long-term effects in cancer risk reduction.
Dose Response Between 25-OH-D Level and Colorectal Cancer Risk
Eleven studies based on cohort and case-control research designs examined the relationship between serum 25-OH-D levels and colorectal cancer risk. Seven of the studies showed various degrees of risk reduction for colorectal cancer and four for colorectal adenoma at higher serum 25-OH-D levels. The major limitations of the studies were that they were unable to demonstrate causal effects between vitamin D and colorectal cancer risk and that the 25-OH-D levels were mostly one-time measurements, which may not accurately represent vitamin D status because 25-OH-D levels fluctuate with seasonal changes.
Seven studies evaluated the effects of serum 25-OH-D levels on colorectal cancer risk. A predictive model based on a cohort study indicated that every 25 nmol/L increase in 25-OH-D levels produces a 37% colorectal cancer reduction (RR = 0.63, 95% CI 0.480.83) (Giovannucci et al., 2006). Wu et al. (2007) conducted a nested control study from the cohort of the Health Professional Follow-Up Study (HPFS), pooled the data with the Nurse Health Study (NHS) for analysis, and found a significant inverse relationship for colon cancer risk between the highest and the lowest quintile of 25-OH-D levels in the HPFS cohort (fifth quintile = 39.4 ng/ml and first quintile = 18.4 ng/ml, OR = 0.46, 95% CI 0.240.89, p = 0.005). The pooled analysis with the NHS showed significantly decreased risks for total colorectal and colon cancer comparing the highest to the lowest quintile of 25-OH-D levels (total colorectal cancer OR = 0.66, 95% CI 0.421.05, p = 0.01; colon cancer OR = 0.54, 95% CI 0.340.86, p = 0.002). The third study of the NHS cohort alone (Feskanich et al., 2004) revealed that 25-OH-D levels were inversely associated with colorectal cancer risk (fifth quintile versus first quintile OR = 0.53, 95% CI 0.271.04, p = 0.02). For women older than 60 years of age, the OR for colorectal cancer risk from the highest quintile of 25-OH-D levels was 0.35 (95% CI 0.140.87, p = 0.006), but no dose-response relationship was found between colorectal cancer risk and level of 1-25-OH-D (the hormonal form of vitamin D). Similarly, a case-control study by Sieg et al. (2006) supported that higher 25-OH-D levels were associated with significantly lowered colorectal cancer risk.
Otani, Iwasaki, Sasazuki, Inoue, and Tsugane (2007) conducted a population-based, nested-control study of 25-OH-D levels and colorectal cancer risk in Japan and found the lowest quartile of 25-OH-D level was associated with an elevated risk of rectal cancer in men (lowest quartile of less than 23 ng/ml versus highest quartile of more than 32.1 ng/ml, OR = 4.6, 95% CI 120) and women (lowest quartile of less than 18.7 ng/ml versus highest quartile of more than 27 ng/ml, OR = 2.7, 95% CI 0.947.6). However, Freedman, Looker, Chang, and Graubard (2007) examined the effect of 25-OH-D levels on cancer mortality from the cohort of the Third National Health and Nutrition Examination Survey and found no relationship between 25-OH-D levels and total cancer mortality. However, 25-OH-D levels of 80 nmol/L (32 ng/ml) or higher were associated with a 72% reduction in colorectal cancer mortality (95% CI 3289) compared with 25-OH-D levels of less than 50 nmol/L (p = 0.02). Ng et al. (2008) analyzed the influence of prediagnosis serum 25-OH-D levels on colorectal cancerspecific mortality from the cohort of the HPFS and the NHS and reported that 25-OH-D levels significantly reduced the overall mortality (lowest quartile of less than 18.8 ng/ml versus highest quartile of more than 29ng/ml, HR = 0.52, 95% CI 0.290.94, p for trend = 0.02). A statistically nonsignificant trend existed toward improved colorectal cancer-specific mortality (HR = 0.61, 95% CI 0.311.19, p for trend = 0.23)
Four other studies examined serum 25-OH-D levels and colorectal adenoma risk. Jacobs et al. (2006) examined the sample cohort originating from the Ursodeoxycholicacid Trial for adenoma prevention and found a moderate, non-significant inverse association between 25-OH-D levels and adenoma recurrence. Interestingly, Miller et al. (2005) revealed that higher 25-OH-D levels were associated with higher rectal epithelium apoptosis for patients with or without adenomas. Peters et al. (2004) conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Comparing the highest quintile (greater than 36.6 ng/ml) with the lowest quintile (19.2 ng/ml or lower) of 25-OH-D levels, the risk for advanced adenoma was decreased by 73% in women (OR = 0.27, 95% CI 0.110.69, p = 0.0002), but the risk was not decreased in men (OR = 1.1, 95% CI 0.62.05, p = 0.85). Again, serum 1-25-OH-D was not associated with advanced adenoma risk. Grau et al. (2003) assessed the cohort from the Calcium Polyp Prevention Trial and found a joint effect of 25-OH-D levels and calcium on adenoma recurrence. Only subjects with a 25-OH-D level above the median of 29.1 ng/ml and taking 1,500 mg of calcium daily demonstrated a statistically significant reduction for adenoma recurrence (RR = 0.71, 95% CI 0.570.89, p = 0.01).
In summary, serum 25-OH-D levels, which represent vitamin D status, have consistently revealed an inverse relationship with colorectal cancer and colorectal adenoma risks. The lower the level, the higher the risk. The levels of 25-OH-D in Grau et al. (2003), Jacobs et al. (2006), Miller et al. (2005), and Peters et al. (2004) demonstrated a significant colorectal cancer or adenoma risk reduction in the range of 2739.4 ng/ml, with a median of 33 ng/ml. Such a level is well within the normal range of 32100 ng/ml for 25-OH-D levels.
Vitamin D Intake and Colorectal Cancer Risk
Ten studies measured the effect of vitamin D intake from diet and supplementation on colorectal cancer risk using cohort or case-control designs. Although level IV evidence is assigned for these studies, the measurement of vitamin D intake may not truly reflect vitamin D status because many factors affect such status, including age, obesity, physical activity, skin color, sunshine exposure, and smoking history (Holick, 2007). Moreover, the amount of vitamin D intake cannot be determined accurately because food survey questionnaires were used to estimate the amount of vitamin D intake for individuals.
Seven of the 10 studies revealed favorable findings regarding higher vitamin D intake and colorectal tumor risk reduction. For example, one population-based case-control study in Scotland found that vitamin D intake from diet and supplementation significantly reduced colorectal cancer risk (Theodoratou et al., 2008). Another case-control study conducted in Japan reported that the combination of high vitamin D, calcium intake, and high sun exposures resulted in the greatest colorectal cancer risk reduction compared to each factor alone (Mizoue et al., 2008). Similarly, two additional studies demonstrated that high levels of vitamin D intake, increased consumption of low fat dairy products, or high levels of sunshine exposure decreased colorectal cancer risk (McCullough et al., 2003; Slattery et al., 2004). Interestingly, Park et al. (2007) examined vitamin D intake and colorectal cancer risk from a multiethnic cohort sample in California and Hawaii and found an inverse association between total vitamin D intake and colorectal cancer risk in men (RR = 0.72, 95% CI 0.511, p = 0.03) but not in women (RR = 0.89, 95% CI 0.631.27, p = 0.8). However, women who had high vitamin D intake from foods showed a significantly lowered risk (RR = 0.78, 95% CI 0.930.96), which was even more evident in women who did not take supplements (RR = 0.69, 95% CI 0.520.93, p = 0.03). Two studies assessed the effect of vitamin D intake on colorectal adenomas. One examined the NHS cohort and found that total vitamin D intake was weakly associated with reduced risk of combined distal colorectal adenomas (RR = 0.79, 95% CI 0.630.99, p = 0.07), and more strongly associated with distal colon adenoma risk reduction (RR = 0.67, 95% CI 0.520.87, p = 0.004) (Oh, Willett, Wu, Fuchs, & Giovannucci, 2007). Another study investigated vitamin D intake on polyp recurrence from the cohort of the Polyps Prevention Trial and determined that total vitamin D intake was inversely (although weakly) associated with adenoma recurrence, comparing the fifth to the first intake quintiles (OR = 0.84; 95% CI 0.621.13, p = 0.03; for vitamin D supplementation, OR = 0.82, 95% CI 0.680.99) (Hartman et al., 2005). Overall, vitamin D appeared to be more effective in preventing multiple recurrences of polyps (OR = 0.73, 95% CI 0.530.99) (Hartman et al.).
Conversely, three studies did not find an inverse relationship between vitamin D intake and colorectal cancer risk. The first study examined the relationship between vitamin D intake and the risk of colorectal adenoma and colorectal cancer among a large group of French women (N = 74,524) with no association found between colorectal tumor and vitamin D intake after almost seven years of follow-up (Kesse, Boutron-Ruault, Norat, Riboli, & Clavel-Chapelon, 2005). However, this sample had a low consumption of vitamin D, with the 90th percentile of 4.34 mcg per day (less than 400 IU per day). A second study conducted in the United States reported similar findings when analyzing vitamin D intake in the large WHI female cohort (N = 36,976) (Lin et al., 2005). The median vitamin D intake of 271 IU per day also was low in this sample (Lin et al., 2005). Likewise, Martinez, Marshall, Sampliner, Wilkinson, and Alberts (2002) assessed the effect of vitamin D intake from dietary and supplemental sources on colorectal adenoma recurrence among 1,304 men and women who had polyps removed within three months of study entry. They were unable to detect any significant impact of vitamin D intake on polyp recurrence after an average follow-up time of three years; however, the vitamin D dose for cutoff in this analysis also was low, about 400 IU per day. Therefore, low doses of vitamin D intake likely contributed to the non-significant results in colorectal cancer risk reduction in all three studies.
In summary, the studies of vitamin D intake and colorectal tumor risk reveal inconsistent results. Vitamin D intake may only represent a portion of the overall vitamin D resource availability and is, therefore, unable to reflect true vitamin D status. In addition, vitamin D intake was estimated from food questionnaires, which were subject to measurement errors and recall biases. Moreover, different studies adopted different food questionnaires. Despite these limitations, higher vitamin D intake generally decreased colorectal tumor risk.
Safety, Cost, and Benefits
Vitamin D intoxication (hypercalcemia and hyperphosphatemia) occurs when 25-OH-D levels reach 150 ng/ml (375 nmol/L) (Holick, 2007). However, as described earlier, 1,100 IU per day of vitamin D revealed no difference in toxicity profile compared with placebo (Lappe et al., 2007). In Hathcock, Shao, Vieth, and Heaney (2007), subjects taking 10,000 IU per day of vitamin D for up to five months did not demonstrate toxic effects. In light of these findings, many experts are urging the Food and Nutrition Board of the Institute of Medicine to update the original vitamin D recommendation from 1997 because it no longer is supported by the evidence. The U.S. Food and Drug Administration (FDA) recommendations for vitamin D are 200 IU per day for ages 1950, 400 IU per day for age 5170, and 600 IU per day for ages 71 and older.
Studies suggest that vitamin D intake should be around 1,000 IU per day to provide benefits for bone health and cancer risk reduction (Lappe et al., 2007; Vieth et al., 2007). Considering that more than 50% of Americans and about 80% of cancer survivors use dietary supplements without medical advice (Miller et al., 2008; Velicer & Ulrich, 2008), an evidence-based vitamin D recommendation will help guide the general public regarding safety and quality-of-life outcomes. Grant, Garland, and Gorham (2007) estimated that 1,000 IU per day of vitamin D would result in a 7%9% absolute cancer reduction in the United States and a 14%20% cancer reduction in Western Europe. In short, the overall health benefits of vitamin D greatly outweigh the potential risks (Grant & Garland, 2008). In fact, to date, no health risk associated with daily vitamin D intake of 1,0002,000 IU has been reported.
Regarding the financial savings associated with increased vitamin D intake, the cost-to-benefit ratio can be calculated based on Lappe et al. (2007), which noted that treating 20 people prevents one cancer case over four years. The per-person cost of 1,000 IU per day of vitamin D is about $20 per year, or $80 for four years per person, which translates into $1,600 for 20 people over four years. In 2008, the overall cost for one cancer case was about $152,520, calculated from the estimated 1,437,180 cancer cases with a cost of $219.2 billion based on ACS (2008). Dividing the cost for one cancer case in 2008 ($152,520) by four years equals $38,130, meaning that for every $1,600 spent on vitamin D, a potential cost-saving of $38,130 in cancer treatment exists. This yields an excellent cost-benefit ratio of 1:24 just from cancer alone.
Healthcare providers play important roles in disease prevention, health promotion, and education. Because vitamin D deficiency is a widespread public health issue linked to cancer and other health risks, healthcare providers should not ignore this easily correctable condition. The FDA recommendations for vitamin D were set by the Institute of Medicine in 1997, but results from the WHI suggest that these recommendations are ineffective in preventing vitamin D deficiency as well as decreasing the risk for osteoporotic fractures and colorectal cancer development (Jackson et al., 2006; Wactawski-Wende et al., 2006). Higher vitamin D dosages of 7001,100 IU per day used in previously cited RCTs resulted in 25-OH-D levels in the 80100 nmol/L range with subsequent reductions in fracture and cancer risks (Bischoff-Ferrari et al., 2005; Lappe et al., 2007). Previous studies also have clearly revealed that vitamin D status (25-OH-D level) and vitamin D intake are inversely associated with cancer risks, particularly for colorectal cancer (Garland et al., 2006). Therefore, optimizing vitamin D intake provides win-win benefits of correcting vitamin D deficiency, promoting bone health, and reducing colorectal cancer risks. Based on currently available evidence, Table 2 outlines treatment recommendations for vitamin D deficiency.
Implications and Conclusion
Although government healthcare agencies have not adopted any vitamin D recommendations for cancer risk reduction, current evidence is substantial and compelling and supports the role of vitamin D in reducing colorectal cancer risk. Nationally and internationally, many experts are urging healthcare agencies and international food and nutritional boards to recommend an effective allowance for vitamin D intake (Veith et al., 2007). Ideally, more definitive evidence of vitamin D on any cancer risk reduction should be obtained through large, population-based, longitudinal RCTs with adequate doses of vitamin D as interventions. However, such trials are expensive, and sales of vitamin D, a rather low-cost supplement, cannot generate enough profits to offset the trial cost. However, the Vitamin D/Calcium Polyp Prevention Study (20042017), a double-blinded, four-arm RCT with 2,200 subjects, currently is underway to evaluate the effects of placebo, calcium (1,200 mg per day), vitamin D (1,000 IU per day), and calcium plus vitamin D (1,200 mg plus 1,000 IU per day) on colorectal neoplasia risk reduction, but the result will not be available until after the studys completion. (For more information on the trial, visit http://clinicaltrials.gov/ct2/show/NCT00153816.) In the meantime, vitamin D debates will continue regarding optimal vitamin D intakes, optimal vitamin D status, emerging roles of vitamin D, and so forth, adding the complexity of future vitamin D researches (Beres, 2008).
Considering that more than 50% of Americans and 80% of cancer survivors are taking dietary supplements without clinical advice (Miller et al., 2008; Velicer & Ulrich, 2008), and acknowledging the overall safety profile of vitamin D and its wide range of health benefits, recommending that patients take 1,000 IU of vitamin D daily is reasonable and practical and clinicians should make every effort to promote and maintain optimal vitamin D status in their patients. Above all, given that patient care is a multi-faceted process, clinicians must consider the current research evidence, their patients condition and preferences, and their own experiences and judicious clinical judgment in addressing the need for vitamin D supplementation.
The authors take full responsibility for the content of the article. The authors did not receive honoraria for this work. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or editorial staff.
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Guiyun Zhou, MSN, CRNP, AOCNSฎ, is a nurse practitioner at Vita Hematology/Oncology in Bethlehem, PA, and a doctoral student at the Jefferson School of Nursing at Thomas Jefferson University in Philadelphia, PA; Jill Stoltzfus, PhD, is the director of the research institute at St. Lukes Hospital and Health System in Bethlehem; and Beth Ann Swan, PhD, CRNP, FAAN, is an associate dean in the Jefferson School of Nursing at Thomas Jefferson University. (Submitted November 2008. Accepted for publication January 14, 2009.)