Association Between Vitamin D and Risk of Colorectal Cancer: A Systematic Review of Prospective Studies
Publication: Journal of Clinical Oncology
Abstract
Purpose
To conduct a systematic review of prospective studies assessing the association of vitamin D intake or blood levels of 25-hydroxyvitamin D [25(OH)D] with the risk of colorectal cancer using meta-analysis.
Methods
Relevant studies were identified by a search of MEDLINE and EMBASE databases before October 2010 with no restrictions. We included prospective studies that reported relative risk (RR) estimates with 95% CIs for the association between vitamin D intake or blood 25(OH)D levels and the risk of colorectal, colon, or rectal cancer. Approximately 1,000,000 participants from several countries were included in this analysis.
Results
Nine studies on vitamin D intake and nine studies on blood 25(OH)D levels were included in the meta-analysis. The pooled RRs of colorectal cancer for the highest versus lowest categories of vitamin D intake and blood 25(OH)D levels were 0.88 (95% CI, 0.80 to 0.96) and 0.67 (95% CI, 0.54 to 0.80), respectively. There was no heterogeneity among studies of vitamin D intake (P = .19) or among studies of blood 25(OH)D levels (P = .96). A 10 ng/mL increment in blood 25(OH)D level conferred an RR of 0.74 (95% CI, 0.63 to 0.89).
Conclusion
Vitamin D intake and blood 25(OH)D levels were inversely associated with the risk of colorectal cancer in this meta-analysis.
Introduction
25-hydroxyvitamin D [25(OH)D] is the precursor of the physiologically active form of vitamin D. The serum level of 25(OH)D is a result of exposure of the skin to sunlight, total vitamin D intake, and other factors such as age and skin pigmentation.1–2 Vitamin D has the ability to inhibit cell proliferation and increase apoptosis in vitro, and several tissues can locally produce the physiologically active form of vitamin D, which has anticarcinogenic properties.3–6 In addition, many cell types, including colorectal epithelial cells, contain vitamin D receptors. These cells are able to convert the circulating 25(OH)D into active 1 to 25(OH)D metabolites, which in turn bind to the cells' own vitamin D receptors to produce an autocrine effect by inducing cell differentiation and inhibiting proliferation, invasiveness, angiogenesis, and metastatic potential.7 Therefore, low vitamin D levels may increase the risk of colorectal cancer through the above potential mechanism. Currently, vitamin D deficiency is an important health problem in the industrial world8–9; in the United States, 25% to 58% of adolescents and adults are deficient in vitamin D.10
The results from prospective studies that have examined the association between vitamin D intake or 25(OH)D levels in the blood and the risk of colorectal cancer have been inconsistent. The aim of this review was to evaluate the evidence from prospective studies on vitamin D intake or blood levels of 25(OH)D and the risk of colorectal cancer by summarizing it quantitatively with a meta-analysis approach.
Methods
Search Strategy
The literature search was conducted before October 2010 in the MEDLINE and EMBASE databases without restrictions and included articles ahead of publication. The following keywords were used in searching: “vitamin D or 25(OH)D” and “colorectal cancer or colon cancer or rectal cancer.” Moreover, we searched for the keywords in headers and in abstracts and also performed a manual search of references cited in the selected articles and published reviews to search for additional relevant studies. This systematic review was planned, conducted, and reported in adherence to the standards of quality for reporting meta-analysis.11
Eligibility Criteria
Citations selected from the initial search were subsequently screened for eligibility. Studies were included in the meta-analysis if they met the following criteria: prospective design; the study of interest was the intake of vitamin D or the levels of 25(OH)D in the blood (plasma or serum); the outcome of interest was colorectal, colon, or rectal cancer; and the relative risk (RR) estimates with 95% CIs (or data to calculate these) were reported. Where data sets overlapped or were duplicated, only the most recent information was included. All identified studies were reviewed independently for eligibility by two authors. Studies not published in English were excluded after identification.
Data Extraction
Data were extracted independently by two authors and cross-checked to reach a consensus. The following variables were recorded: the first author's last name, publication year, country where the study was performed, study period, participant sex and age, sample size (cases and controls or cohort size), measure and range of exposure, variables adjusted for in the analysis, and RR estimates with corresponding 95% CIs for the highest versus lowest categories of vitamin D intake or for each category of blood 25(OH)D levels. We extracted the RRs that reflected the greatest degree of control for potential confounders for use in the primary analysis. If necessary, the primary authors were contacted to retrieve additional information. The study quality was assessed by using the nine-star Newcastle-Ottawa Scale.12
Statistical Analysis
Study-specific RR estimates were combined using a random-effects model, which considers both within-study and between-study variation.13 In the dose-response meta-analysis of blood 25(OH)D levels, we used the method proposed by previously published studies14–15 to compute the trend from the correlated log RR estimates across categories of 25(OH)D levels. For each study, the median level of 25(OH)D for each category was assigned to each corresponding RR estimate. We examined a potential nonlinear dose-response relationship between 25(OH)D levels and colorectal cancer by modeling 25(OH)D levels using restricted cubic splines with three knots at percentiles 25%, 50%, and 75% of the distribution. A P value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to 0.15–16
Statistical heterogeneity among studies was evaluated with Q and I2 statistics.17 Sensitivity analysis was performed to evaluate the stability of the results. Subgroup analysis was performed by geographic area and anatomic location (colon cancer or rectal cancer; proximal colon cancer or distal colon cancer). Each study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set on the pooled odds ratios (ORs).
An estimation of potential publication bias was executed by the funnel plot, in which the SE of log (OR) of each study was plotted against its log (OR). An asymmetrical plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger's linear regression test, a linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of the OR.18 The significance of the intercept was determined by the t test suggested by Egger (P < .05 was considered representative of statistically significant publication bias). All statistical tests were performed with the STATA software (version 10.0; Stata Corporation, College Station, Texas). P < .05 was considered statistically significant.
Results
Literature Search
A flow diagram of our literature search is shown in Figure 1. Total searches yielded 2,528 entries. After the removal of 882 duplicates, 1,646 titles and abstracts were assessed; 114 articles appeared to be potentially relevant for inclusion in the review. Ninety-seven articles were excluded for the following reasons: no original articles besides editorials, comments, reviews or meta-analysis (n = 63); vitamin D intake or serum 25(OH)D not measured (n = 18); duplicate reports from the same study population (n = 4); no data on colorectal cancer (n = 6); or associations of vitamin D intake or 25(OH)D with colorectal cancer risk not reported/not derivable from reported data (n = 6). The remaining articles, including nine on vitamin D intake19–27 and nine on blood 25(OH)D levels19,28–35 (one article reported both the vitamin D intake and blood 25(OH)D levels19), were included in the meta-analysis.
Study Characteristics
The nine studies on vitamin D intake (eight cohort studies and one nested case-control study) were published between 1993 and 2010 (Table 1) and involved a total of 6,466 patients. Of these nine studies, four were conducted in the United States, three in Europe, and two in Asia. The nine studies on blood 25(OH)D levels (seven cohort studies and two nested case-control studies) were published between 1989 and 2010 (Table 2) and comprised a total of 2,767 cases and 3,948 controls. Of those studies, six were conducted in the United States, two were conducted in Europe, and one was conducted in Asia. The studies on blood 25(OH)D levels met higher quality criteria (7 to 9 stars) than did the studies on vitamin D intake (6 to 7 stars). Most studies provided risk estimates that were adjusted for body mass index (16 studies), age (15 studies), smoking (15 studies), physical activity (14 studies), red meat consumption (12 studies), and alcohol consumption (11 studies). Fewer studies were adjusted for vegetable consumption (eight studies), fruit consumption (eight studies), family history (eight studies), calcium (eight studies), fat (seven studies), fiber (seven studies), education (five studies), and total intake of energy (four studies). Few studies adjusted for colorectal cancer screening.
| Study | Location | Study Period | Sex | Age(years) | Cancer Type and No. of Cases | No. of Participants | Measure/Range of Exposure* (μg/d) | Study Quality† | Adjustment for Covariates |
|---|---|---|---|---|---|---|---|---|---|
| Jenab et al19 | Western European countries | 1992-2002 | F/M | 30-77 | CRC (F): 628 CRC (M): 620 CC (F): 416 CC (M): 369 RC (F): 212 RC (M): 251 |
520,000 | Dietary vitamin D:< 2.10 (Q1)≥ 5.8 (Q5) | 7 | Age, BMI, physical activity, smoking, education level, total intake of energy, fruit intake, vegetable intake, red and processed meat intake, alcohol intake, fiber intake, fish intake |
| Lipworth et al20 | Italy | 1992-1996 | F/M | 20-74 | CRC: 1,953 (F, 537; M, 688) CC: 1,225 RC: 728 |
NR | Dietary vitamin D:< 1.57 (decile 1) > 5.10 (decile 10) | 7 | Age, BMI, sex, education, physical activity, family history of CRC, fruit and vegetable consumption, total energy intake, smoking and alcohol drinking habits, intensity of sunlight exposure, calcium intake, anatomic subsite |
| Ishihara et al21 | Japan | 1995-2004 | F/M | 45-74 | CRC (F): 297 CRC (M): 500 CC (M): 312 RC (M): 146 |
74,639 | Dietary vitamin D (M): < 5.60 (Q1)> 14.8 (Q5) Dietary vitamin D (F): < 5.80 (Q1)> 14.5 (Q5) |
6 | Age, BMI, alcohol intake, smoking, physical activity, CRC screening, menopausal status, supplement use, study area, energy-adjusted dietary intake of: red meat, vegetables, fruit, folate, vitamin B-6, and vitamin B-12 |
| Mizoue et al22 | Japan | 2000-2003 | F/M | 20-74 | CRC: 836 (F, 334; M, 502) CC: 476 RC: 354 |
2,599 | Dietary vitamin D:< 5.60 (Q1)> 13.3 (Q5) | 6 | Age, sex, job, parental history of CRC, smoking, alcohol intake, BMI, leisure time, physical activity, energy intake, vegetable intake, fruit intake, and red meat intake |
| Terry et al23 | Sweden | 1987-2000 | F | 40-74 | CRC: 572 CC: 371 RC: 191 |
90,303 | Dietary vitamin D:< 2.9 (Q1)> 3.7 (Q4) | 6 | Age, BMI, education level, alcohol intake, red meat intake, energy-adjusted folic acid, vitamin C intake, fat intake, fiber intake, folic acid intake, fruit and vegetable intake |
| Zheng et al24 | United States | 1986-1994 | F | 55-69 | RC: 144 | 34,702 | Dietary vitamin D:< 5.60 (T1)> 11.89 (T3) | 6 | Age, BMI, smoking, hormone replacement therapy, meat intake, fiber intake, vegetable intake, fruit intake, fat and protein intake, alcohol consumption, physical activity, education |
| Martínez et al25 | United States | 1980-1992 | F | 30-55 | CRC: 501 CC: 396 RC: 105 |
89,448 | Dietary vitamin D:< 1.90 (Q1)> 6.13 (Q5) Total vitamin D:< 2.30 (Q1)> 11.93 (Q5) |
6 | Age, BMI, history of CRC, smoking, physical activity, aspirin use, red meat intake, alcohol intake |
| Kearney et al26 | United States | 1986-1992 | M | 40-75 | CRC: 203 | 47,935 | Dietary vitamin D:< 3.35 (Q1)≥ 8.95 (Q5) Total vitamin D:< 4.03 (Q1)> 15.33 (Q5) |
6 | Age, BMI, history of colon cancer, history of previous polyps, prior screening, smoking, aspirin use, alcohol consumption, physical activity, red meat intake, saturated fat intake, fiber intake, vitamin E intake |
| Bostick et al27 | United States | 1986-1990 | F | 55-69 | CC: 212 | 35,216 | Dietary vitamin D:< 3.18 (Q1)> 9.33 (Q5) Total vitamin D:< 3.98 (Q1)> 15.45 (Q5) |
6 | Age, BMI, education, occupation, waist/hip ratio, physical activity, any type of vitamin or mineral supplement use combined, fat intake, fiber intake, vegetable intake, fruit intake, red meat intake, alcohol intake, interaction of age with the total intake of calcium or milk products, interactions of total calcium intake with height and with intakes of: total fat, phosphorus, dietary fiber, and vitamin D |
Abbreviations: BMI, body mass index; CC, colon cancer; CRC, colorectal cancer; NR, not reported; Q, quartile/quintile; RC, rectal cancer; T, tertile.
*
Dietary vitamin D includes vitamin D from foods only and total vitamin D includes vitamin D from foods and supplements. Range of exposure indicates the cut points for the highest and lowest categories of daily vitamin D intake.
†
Study quality was judged on the basis of the Newcastle-Ottawa Scale (1-9 stars).
| Study | Location | Study Period | Patient Characteristics | Measure/Range of Exposure*(ng/mL) | Study Quality† | Adjustment for Covariates | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Sex | Age (years) | No. of Participants | No. of Cases | No. of Controls | ||||||
| Jenab et al19 | Western European countries | 1992-2002 | F/M | 30-77 | 520,000 | 1,248 | 1,248 | Serum 25(OH)D:< 20.0 (T1)≥ 28.0 (T3) | 7 | Age, BMI, physical activity, smoking, education level, total intake of energy, fruit intake, vegetable intake, red and processed meats intake, alcohol intake, fiber intake, fish intake |
| Woolcott et al28 | United States | 1993-2006 | F/M | 45-75 | 215,000 | 229 | 434 | Plasma 25(OH)D: < 16.8 (Q1) ≥ 32.8 (Q5) | 8 | Age, BMI, sex, physical activity, smoking, education, alcohol intake, use of nonsteroidal anti-inflammatory drugs for > 2 years, processed red meat intake, fruit and vegetable intake, season, family history, calcium intake |
| Wu et al29 | United States | 1993-2002 | M | Case: 66.3 ± 8.2Control: 66.1 ± 8.1 | 69,354 | 179 | 356 | Plasma 25(OH)D: 18.4 (Q1) 39.4 (Q5) | 9 | Age, BMI, physical activity, calcium intake, retinol intake, season at blood draw, cancer subsite, smoking, folate intake, red and processed meats intake, alcohol intake, family history of CRC, aspirin use |
| Otani et al30 | Japan | 1990-2003 | F/M | 40-69 | 133,323 | 375 | 750 | Plasma 25(OH)D (M):< 22.9 (Q1)> 32.1 (Q4) Plasma 25(OH)D (F): < 18.7 (Q1) > 27.0 (Q4) |
9 | Age, BMI, smoking, alcohol consumption, physical exercise, vitamin supplement use, family history of CRC, total energy intake, dietary fiber intake, folate intake, calcium intake, vitamin D intake, n-3 fatty acid intake, red meat intake, fish intake |
| Wactawski-Wende et al31 | United States | 1974-1983 | F | 50-79 | 36,282 | 306 | 306 | Serum 25(OH)D:< 12.4 (Q1) ≥ 23.4 (Q4) | 8 | Age, BMI, level of education, family history of CRC, presence or absence of a history of polyps, physical activity, caloric intake, saturated fat intake, multivitamin use, intake of elemental calcium, personal intake of vitamin D, level of ultraviolet exposure, smoking status, history of hormone use, and random assignment in the Hormone Therapy and Dietary Modification trials |
| Feskanich et al34 | United States | 1989-2000 | F | 43-70 | 32,826 | 193 | 383 | Serum 25(OH)D:≤ 14.9 (Q1) > 35.3 (Q5) | 8 | BMI, physical activity, folate intake, methionine intake, retinol intake, alcohol intake, red meat intake, smoking, aspirin use, menopausal status, history of CRC |
| Tangrea et al32 | Finland | 1985-1993 | M | 50-69 | 169,751 | CRC: 146CC: 91RC: 55 | CRC: 290CC: 181RC: 109 | Serum 25(OH)D:≤ 9.8 (Q1)> 19.3 (Q4) | 8 | BMI, education, physical activity, marital status, smoking history and place of residence, fat intake, fiber intake, protein intake, calcium intake, history of adenomatous polyps, family history of CRC |
| Braun et al33 | United States | 1984-1991 | F/M | NR | 20,305 | 57 | 114 | Serum 25(OH)D:< 17.2 (Q1) > 30.1 (Q5) | 8 | Age, BMI, smoking, race, sex, medications taken, date of blood draw |
| Garland et al35 | United States | 1974-1983 | F/M | 35-75 | 25,620 | 34 | 67 | Serum 25(OH)D:< 19.0 (Q1) > 42.0 (Q4) | 6 | Age, race, sex, smoking, calcium intake, vitamin D intake |
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; BMI, body mass index; CC, colon cancer; CRC, colorectal cancer; NR, not reported; Q, quartile/quintile; RC, rectal cancer; T, tertile.
*
Median blood 25(OH)D levels in the lowest and highest categories or the cut points for the highest and lowest categories.
†
Study quality was judged on the basis of the Newcastle-Ottawa Scale (1-9 stars).
High Versus Low Vitamin D or 25(OH)D Levels
The multivariable-adjusted RRs for each study and combination of all studies for the highest versus lowest categories of vitamin D intake or blood 25(OH)D levels are shown in Figure 2. Results from the studies on vitamin D intake or blood 25(OH)D levels in relation to colorectal cancer risk were inconsistent, with both inverse and positive associations reported. The pooled RRs of colorectal cancer for the highest versus lowest categories of vitamin D intake and blood 25(OH)D level were 0.88 (95% CI, 0.80 to 0.96) and 0.67 (95% CI, 0.54 to 0.80), respectively. There was no statistically significant heterogeneity among the studies of vitamin D intake (P = .191; I2 = 26.6%) and among studies of blood 25(OH)D levels (P = .962; I2 = 0%).
Stratifying Analysis
Stratifying by geographic region, the pooled RRs of colorectal cancer for the highest versus lowest categories of vitamin D intake were 0.88 (95% CI, 0.76 to 1.00) for studies conducted in the United States, 0.88 (95% CI, 0.74 to 1.02) for studies conducted in Europe, and 0.87 (95% CI, 0.65 to 1.09) for studies conducted in Asia. The pooled RRs of colorectal cancer for the highest versus lowest categories of blood 25(OH)D levels were 0.61 (95% CI, 0.43 to 0.79) for studies conducted in the United States, 0.72 (95% CI, 0.51 to 0.93) for studies conducted in Europe, and 0.84 (95% CI, 0.35 to 1.32) for studies conducted in Asia. There was no statistically significant heterogeneity among studies of vitamin D intake (United States, P = .174 and I2 = 39.6%; Europe, P = .097 and I2 = 52.6%; Asia, P = .312 and I2 = 14.3%) and among studies of blood 25(OH)D levels (United States, P = .966 and I2 = 0%; Europe, P = .480 and I2 = 0%; Asia, P = .497 and I2 = 0%), with stratification according to geographic region (Table 3).
| Factor | Vitamin D Intake | Blood 25(OH)D Levels | ||||||
|---|---|---|---|---|---|---|---|---|
| RR | 95% CI | Heterogeneity | RR | 95% CI | Heterogeneity | |||
| P | I2 (%) | P | I2 (%) | |||||
| Colorectal cancer subsite | ||||||||
| Colon | 0.79 | 0.67 to 0.90 | .283 | 18.0 | 0.62 | 0.43 to 0.81 | .795 | 0 |
| Proximal | 0.62 | 0.42 to 0.83 | .249 | 27.2 | 0.80 | 0.31 to 1.30 | .726 | 0 |
| Distal | 0.69 | 0.49 to 0.90 | .254 | 26.4 | 0.62 | 0.22 to 1.02 | .967 | 0 |
| Rectal | 0.78 | 0.63 to 0.93 | .245 | 24.1 | 0.61 | 0.43 to 0.79 | .324 | 14.1 |
| Geographic region of study | ||||||||
| United States | 0.88 | 0.76 to 1.00 | .174 | 39.6 | 0.61 | 0.43 to 0.79 | .966 | 0 |
| Europe | 0.88 | 0.74 to 1.02 | .097 | 52.6 | 0.72 | 0.51 to 0.93 | .480 | 0 |
| Asia | 0.87 | 0.65 to 1.09 | .312 | 14.3 | 0.84 | 0.35 to 1.32 | .497 | 0 |
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; RR, relative risk.
Among the eight studies that provided results on vitamin D intake in relation to colon cancer risk, the RR was 0.79 (95% CI, 0.67 to 0.90). We also conducted analyses that were stratified according to rectum subsites, using seven studies that reported results on vitamin D intake in relation to rectal cancer risk. The RR for rectal cancer was 0.78 (95% CI, 0.63 to 0.93). The results showed that vitamin D intake results in an equal risk reduction on colon cancer and rectal cancer. Among eight studies that provided results on blood 25(OH)D levels in relation to colon cancer risk, the RR was 0.62 (95% CI, 0.43 to 0.81). The analysis was stratified according to rectum subsites with five studies that reported results on blood 25(OH)D levels in relation to rectal cancer risk. The RR for rectal cancer was 0.61 (95% CI, 0.43 to 0.79). There was no statistically significant heterogeneity among studies of vitamin D intake (colon cancer, P = .283 and I2 = 18.0%; rectal cancer, P = .245 and I2 = 24.1%) and among studies of blood 25(OH)D levels (colon cancer, P = .795 and I2 = 0%; rectal cancer, P = .324 and I2 = 14.1%) with stratification according to colon and rectum subsites (Table 3).
When we stratified the analysis according to proximal colon and distal colon subsites, the pooled RRs of proximal colon cancer (four studies) and distal colon cancer (four studies) for the highest versus lowest categories of vitamin D intake were 0.62 (95% CI, 0.42 to 0.83) and 0.69 (95% CI, 0.49 to 0.90), respectively. The results showed that there is a strong risk reduction for vitamin D intake associated with proximal colon cancer or distal colon cancer. There was no statistically significant heterogeneity among studies of vitamin D intake (proximal colon cancer, P = .249 and I2 = 27.2%; distal colon cancer, P = .254 and I2 = 26.4%) with stratification according to proximal colon and distal colon subsites. Meanwhile, the pooled RRs of proximal colon cancer (three studies) and distal colon cancer (three studies) were 0.80 (95% CI, 0.31 to 1.30) and 0.62 (95% CI, 0.22 to 1.02) for the highest versus lowest categories of blood 25(OH)D levels, respectively. The results showed that there was no significant risk reduction for blood 25(OH)D levels associated with proximal colon and distal colon cancer, which might result from smaller sample sizes, particularly for distal colon cancer. There was no statistically significant heterogeneity among studies of blood 25(OH)D levels (proximal colon cancer, P = .726 and I2 = 0%; distal colon cancer, P = .967 and I2 = 0%) with stratifying according to proximal colon and distal colon subsites (Table 3).
Dose-Response Meta-Analysis
Next, we assessed the dose-response relationship between blood 25(OH)D levels and the risk of colorectal cancer. We found obvious evidence of statistically significant departure from linearity (P < .001). A 10 ng/mL increment in blood 25(OH)D level conferred an RR of 0.74 (95% CI, 0.63 to 0.89; Fig 3).
Sensitivity Analysis and Publication Bias
The results suggest that the influence of each individual data set to the pooled RRs is not significant. The Egger's test showed no evidence of publication bias for vitamin D intake (P = .31) or blood 25(OH)D levels (P = .64).
Discussion
The current meta-analysis summarizes the results of prospective studies, including nine studies19–27 on vitamin D intake with a total of 6,466 patients and nine studies19,28–33 on blood 25(OH)D levels with a total of 2,767 cases and 3,948 controls. The results indicated that lower vitamin D intake and blood 25(OH)D levels are inversely associated with colorectal cancer risk. Analyses stratified according to anatomic site suggest that vitamin D intake causes an equal risk reduction for colon cancer and rectal cancer. When the analysis was stratified according to proximal colon and distal colon subsites, the results showed that there was a strong risk reduction associated with vitamin D intake for proximal colon cancer or distal colon cancer subsites. The analysis of blood 25(OH)D levels stratified according to proximal colon and distal colon subsites showed that there is no risk reduction associated with blood 25(OH)D levels for proximal and distal colon sites. There was no heterogeneity in subsite-specific results, which could reach statistical significance in meta-analysis.
Vitamin D deficiency is considered an important risk factor for many types of solid cancers, especially colorectal cancer. Among patients with colorectal cancer, the prevalence of vitamin D deficiency is much higher, approaching 90%, than among other patients.36 Several studies have demonstrated that vitamin D may decrease the risk of cancer through various mechanisms, including regulation of cellular proliferation and differentiation, induction of apoptosis, and inhibition of angiogenesis.37–38 The research breakthrough revealing the direct cancer risk reduction by vitamin D intake was reported by Lappe et al.39 In their randomized controlled trial study, which included 1,179 postmenopausal women, the results indicated that taking 1,100 IU of vitamin D plus 1,400 to 1,500 mg of daily calcium for four years resulted in 60% to 70% overall cancer risk reduction. The preventive role of vitamin D in patients with colorectal cancer was first confirmed by Garland et al2 on the basis of an observation of higher incidence of colorectal cancer mortality in regions with low solar radiation levels. After this finding, the association between vitamin D intake and the risk of colorectal cancer has been assessed in several case-control and prospective cohort studies, with most studies showing a statistically significant inverse association.19,22,24,26–27,40
An inverse association was observed in studies that assessed blood 25(OH)D levels in relation to the risk of colorectal cancer. In a meta-analysis of five studies,40 the results revealed a 50% lower risk of colorectal cancer associated with a serum 25(OH)D level of ≥ 33 ng/mL compared with ≤ 12 ng/mL. A recent updated review combining eight original articles published before September 2008 confirms and extends earlier results of a meta-analysis conducted by Yin et al,41 which determined the OR of colorectal cancer to be 0.57 (95% CI, 0.43 to 0.76), associated with an increase of 25(OH)D by 20 ng/mL. In a recent nested case-control study with 1,248 cases of incident colorectal cancer and 1,248 controls, those in the highest quintile of plasma 25(OH)D concentration had a 40% lower risk of coloretal cancer than did those in the lowest quintile after adjustment for potential confounders (RR, 0.72; 95% CI, 0.57 to 0.91).19
Meta-analysis is an important tool for revealing trends that might not be apparent in a single study. Pooling of independent but similar studies increases precision and therefore increases the confidence level of the findings.41 The current meta-analysis had some advantages. First, the number of total cases and controls were substantial, which significantly increased the statistical power of the analysis. Second, our quantitative assessment was based on prospective studies, which will minimize the possibility that our results resulted from recall or selection bias. Third, no publication biases were detected, which indicates that the entire pooled result may be unbiased.
Despite these advantages, some limitations of the current meta-analysis should be acknowledged. First, the controls were not uniformly defined. Although most of the patients in the control groups were selected from healthy populations, some might have had benign disease. Therefore, nondifferential misclassification bias was possible, because these studies may have included control groups with different risks of developing colorectal cancer. Second, the related data on vitamin D intake and blood 25(OH)D levels in individuals were not available from each study; only the median, midpoints, and mean of the groups were used for pooling. This may possibly lead to less accurate estimates of risk if data points on each individual were used. Meanwhile, the number of studies involved in the meta-analysis was relatively small; therefore, some of the subgroup analyses were difficult to perform. Third, the current meta-analysis is unable to solve problems with confounding factors that could be inherent in the included studies. Inadequate control of the confounders might bias the results either toward exaggeration or underestimation of risk estimates. Although most studies adjusted for other known risk factors for colorectal cancer, unknown confounders cannot be excluded as a potential explanation for the observed findings. Therefore, a more precise analysis should be conducted if individual data are available, which would allow for adjustment by other covariates, including age, smoking status, drinking status, and lifestyle. Fourth, there is a wide range of values for the cutoff points for the lowest and highest categories for both the vitamin D intake and the plasma 25(OH)D levels in several studies, which might also impact the current analysis. Therefore, a large randomized clinical trial must be performed with uniform criteria for vitamin D intake and plasma 25(OH)D in several countries. Finally, although the lack of indication of major publication bias in the formal evaluation used, potential publication bias is impossible to completely exclude because small studies with null results tend not to be published.
In summary, the results from this meta-analysis of prospective studies demonstrate that vitamin D intake and blood 25(OH)D levels are both inversely associated with risk of colorectal cancer. However, available data are still sparse, and in-depth analyses of the assessed associations in the context of additional longitudinal studies are highly desirable to enable more-precise estimates and a better understanding of the role of vitamin D in colorectal cancer carcinogenesis. The findings from these observational studies need to be confirmed in large randomized clinical trials for vitamin D supplementation.
Authors' Disclosures of Potential Conflicts of Interest
The author(s) indicated no potential conflicts of interest.
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Information & Authors
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© 2011 by American Society of Clinical Oncology.
History
Published online: August 29, 2011
Published in print: October 01, 2011
Authors
Author Contributions
Conception and design: Yanlei Ma, Feng Wang
Financial support: Yanlei Ma
Provision of study materials or patients: Peng Zhang, Feng Wang, Jianjun Yang, Zhihua Liu, Huanlong Qin
Collection and assembly of data: Yanlei Ma, Peng Zhang, Feng Wang, Zhihua Liu, Huanlong Qin
Data analysis and interpretation: Peng Zhang, Jianjun Yang,Huanlong Qin
Manuscript writing: All authors
Final approval of manuscript: All authors
Disclosures
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Funding Information
Supported by Grants No. 11QA1404800 from the Shanghai Rising-Star Program, 81001069 from the National Natural Science Foundation of China, and 2009AA02Z118 from the National 863 High Technology Foundation.
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Association Between Vitamin D and Risk of Colorectal Cancer: A Systematic Review of Prospective Studies. JCO 29, 3775-3782(2011).
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Journal of Clinical Oncology 2011 29:28, 3775-3782
Journal of Clinical Oncology 2011 29:28, 3775-3782
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