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Circulating 25-Hydroxyvitamin D Levels and Survival in Patients With Colorectal Cancer

Kimmie Ng, Jeffrey A. Meyerhardt, Kana Wu, Diane Feskanich, Bruce W. Hollis, Edward L. Giovannucci, Charles S. Fuchs

From the Division of Medical Oncology, Dana-Farber Cancer Institute; Departments of Nutrition and Epidemiology, Harvard School of Public Health; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; and Division of Pediatrics, Medical University of South Carolina, Charleston, SC

Corresponding author: Kimmie Ng, MD, MPH, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: kng4{at}partners.org

	ABSTRACT

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Purpose Higher plasma 25-hydroxyvitamin D₃ (25(OH)D) levels are associated with a decreased incidence of colorectal cancer, but the influence of plasma 25(OH)D on the outcome of patients with established colorectal cancer is unknown.

Patients and Methods We prospectively examined the association between prediagnosis 25(OH)D levels and mortality among 304 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) who were diagnosed with colorectal cancer from 1991 to 2002. Participants diagnosed within 2 years of blood collection were excluded. Patients were observed until death, June 2005 (NHS), or January 2005 (HPFS), whichever came first. The primary end point was overall mortality. Cox proportional hazards models were used to calculate hazard ratios (HR) adjusted for other risk factors for cancer survival.

Results Higher plasma 25(OH)D levels were associated with a significant reduction in overall mortality (P for trend = .02). Compared with the lowest quartile, participants in the highest quartile had an adjusted HR of 0.52 (95% CI, 0.29 to 0.94) for overall mortality. A trend toward improved colorectal cancer–specific mortality was also seen (HR = 0.61; 95% CI, 0.31 to 1.19). The results remained unchanged after excluding patients diagnosed within 5 years of blood collection (P for trend = .04); the multivariate HR for overall mortality comparing extreme quartiles was 0.45 (95% CI, 0.19 to 1.09).

Conclusion Among patients with colorectal cancer, higher prediagnosis plasma 25(OH)D levels were associated with a significant improvement in overall survival. Further study of the vitamin D pathway and its influence on colorectal carcinogenesis and cancer progression is warranted.

	INTRODUCTION

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The vitamin D hypothesis has received strong experimental support over the past two decades, based on the almost ubiquitous expression in colon cancer cells of vitamin D receptors (VDR) ^1,2 and 1--hydroxylase,³ which convert plasma 25-hydroxyvitamin D₃ [25(OH)D] into 1,25-dihydroxycholecalciferol [1,25(OH)₂D]. Binding of VDR by 1,25(OH)₂D leads to multiple cellular effects, including induction of differentiation and apoptosis^4,5 and inhibition of proliferation,⁶ angiogenesis,^7,8 and metastatic potential.^9,10

Prospective studies have demonstrated that higher baseline plasma levels of 25(OH)D are associated with a significant reduction in the risk of colorectal cancer.^11-16 A meta-analysis of five epidemiologic studies found a 51% decrease in the risk of colorectal cancer associated with plasma 25(OH)D levels in the highest versus lowest quintiles (P < .0001).¹⁷ Furthermore, a prospective, randomized, placebo-controlled trial of vitamin D and calcium supplementation in 1,179 women demonstrated a 60% decrease in all-cancer risk (including colorectal cancer) in the intervention arm (P < .03).¹⁸

In contrast, the influence of vitamin D on survival of patients with established colorectal cancer remains uncertain. A large observational study in Norway found that people diagnosed with colorectal cancer in the summer and autumn, when 25(OH)D concentrations are highest, had significantly better survival than those diagnosed in the winter. The authors speculated that a high level of circulating 25(OH)D may improve colorectal cancer prognosis.^19,20 However, this study was limited by its use of season of diagnosis, an indirect indicator of vitamin D status, as the primary exposure.

Therefore, we prospectively examined the influence of a more direct measure of vitamin D status—prediagnosis plasma levels of 25(OH)D—on survival of patients diagnosed with colorectal cancer while participating in two large prospective cohort studies, the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS).

	PATIENTS AND METHODS

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Study Population
In 1976, the NHS cohort was established when 121,700 US female registered nurses aged 30 to 55 years answered a mailed questionnaire on risk factors for cancer and cardiovascular disease.^21,22 Every 2 years, participants receive follow-up questionnaires to update information on potential risk factors and new cancer and disease diagnoses. Dietary information was first collected in 1980 via a semiquantitative food frequency questionnaire and is updated in alternate follow-up cycles. Blood samples were provided by 32,826 participants aged 43 to 70 years from 1989 to 1990.

In 1986, the HPFS cohort was established when 51,529 male dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians aged 40 to 75 years responded to a mailed questionnaire on risk factors for cancer, cardiovascular disease, and diabetes. A follow-up questionnaire is sent to participants every 2 years requesting an update on nondietary exposures and medical history, with dietary history updated every 4 years. Blood samples were provided by 18,018 participants from 1993 to 1995.

Individuals in this analysis were participants with pathologically confirmed colorectal adenocarcinoma diagnosed after the date of blood collection until June 2000 for NHS and January 2002 for HPFS. Participants were excluded if they had reported any cancer (other than nonmelanoma skin cancer) previous to the colorectal cancer diagnosis. In addition, to minimize any bias owing to the presence of occult cancer or other undiagnosed major illness, we excluded participants who received a diagnosis of colorectal cancer within 2 years of blood collection. There were 159 women from NHS and 145 men from HPFS eligible for analysis.

This study was approved by the Human Subjects Committee at Brigham and Women's Hospital and the Harvard School of Public Health in Boston, MA. All participants provided informed consent for questionnaire and blood data to be used in research studies.

Identification of Colorectal Cancer
On each follow-up questionnaire, participants were asked whether they had a diagnosis of colorectal cancer during the previous 2 years. When a participant (or next of kin for decedents) reported a diagnosis of colorectal cancer, we asked permission to obtain hospital records and pathology reports, and blinded study physicians reviewed these records and recorded information on stage, histology, and tumor location. For nonrespondents, we searched the National Death Index to discover deaths and ascertain any diagnosis of colorectal cancer that contributed to death or was a secondary diagnosis. We estimate that 96% to 97% of cases were identified through these methods.^23,24

Measurement of Mortality
Participants in the study cohort were observed until death, June 2005 (NHS), or January 2005 (HPFS), whichever came first. Ascertainment of deaths included reporting by family or postal authorities, and names of persistent nonresponders were searched in the National Death Index.²⁵ Cause of death was assigned by blinded physicians. More than 98% of deaths have been identified by these methods.^24,26

Exposure Assessment
Blood samples from both cohorts were collected in tubes with heparin and sent by overnight courier in chilled containers. On receipt, bloods were centrifuged, aliquotted, and stored in liquid nitrogen freezers at –160°C. 25(OH)D concentrations were measured by radioimmunoassay, as described previously.²⁷ Multiple masked quality control samples were interspersed among the case samples, and all laboratory personnel were blinded. The mean coefficient of variation of the assay was approximately 10%.^14,16 To assess the intraperson stability of 25(OH)D over time, plasma levels of 25(OH)D were measured in 144 men from the HPFS who were free of cancer and who donated blood in 1993 to 1994 and again in 1997. The Pearson correlation coefficient was 0.70 for the two 25(OH)D measurements (P < .0001).²⁸

Although all samples were assayed at the same laboratory, cases from the 1992, 1994, and 1996 NHS questionnaires were assayed in 2000, those from the 1998 and 2000 questionnaires in 2003, and all HPFS samples in 2005. Plasma 25(OH)D levels were lower in the 2000 assay compared with the 2003 assay; among 12 quality control samples from the same plasma pool, mean 25(OH)D values were 19.2 ng/mL in 2000 and 22.8 ng/mL in 2003.¹⁴ Therefore, quartile cutoffs for statistical analyses were determined separately for each laboratory run. Furthermore, an indicator variable for laboratory run was included in analyses that used plasma 25(OH)D as a continuous variable.

Covariates
Prognostic factors known to influence colorectal cancer mortality were extracted from the medical record, including age at diagnosis, tumor stage, grade of differentiation, primary tumor location, and year of diagnosis. In addition, body mass index (BMI) was taken from the questionnaire closest to the time of diagnosis, and physical activity was assessed between 1 and 4 years after diagnosis (postdiagnosis physical activity was shown to be correlated with survival in a separate analysis).²⁹ Race was recorded but not ultimately included in the final model, given the low number of nonwhite participants (n = 19). Analyses were also adjusted for sex and season of blood collection.

Statistical Analyses
Cox proportional hazards models were used to calculate hazard ratios (HRs) of death or death as a result of colorectal cancer, adjusted for other risk factors for cancer survival. In the main analysis, death from any cause was the primary end point. In a secondary analysis, death from colorectal cancer was the end point, and death as a result of other causes was censored. HRs were calculated according to quartiles of 25(OH)D, with the lowest quartile as the reference group. The two-tailed P value for the linear trend test across categories was calculated using 25(OH)D as a continuous variable, consistent with prior studies.¹⁴ Tests of interaction between 25(OH)D and potential effect modifiers were assessed by entering in the model the cross product of 25(OH)D as a continuous variable, with the covariate as a continuous or binary variable. Analyses stratified by the dichotomized covariate were performed using the initial quartile cutoffs that were calculated for the entire cohort. All analyses used SAS software, version 9.1 (SAS Institute, Inc, Cary, NC).

	RESULTS

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Among the 304 eligible participants with colorectal cancer, there were 123 deaths, 96 of which were colorectal cancer–specific deaths. Non–colorectal cancer causes of death included ischemic heart disease (n = 5), paroxysmal supraventricular tachycardia (n = 2), stroke (n = 3), dementia (n = 2), and lung cancer (n = 2). One death each was attributed to pancreatic cancer, prostate cancer, osteoporosis, toxicologic abnormality, acute cystitis, tracheostomy complication, and pulmonary alveolar proteinosis. Six patients had missing causes of death, for a total of 27 non–coloretal cancer–specific deaths. The median time of follow-up of participants still alive was 78 months (range, 36 to 162 months). Plasma 25(OH)D levels were assessed at a median of 72 months before cancer diagnosis (range, 25 to 128 months). Baseline characteristics according to categories of plasma 25(OH)D are listed in Table 1. Overall, participants with higher 25(OH)D levels had a lower BMI, higher physical activity and vitamin D intake, and were more likely to have their blood collected in the summer or autumn. Notably, the time interval between blood collection and cancer diagnosis did not vary significantly by quartile (P = .93).

	DISCUSSION

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We found that participants with colorectal cancer who had prediagnosis plasma 25(OH)D levels in the highest quartile experienced a significant reduction in overall mortality. This relationship was still evident after restricting our analyses to patients who were diagnosed more than 5 years after blood collection, and the effect of higher plasma 25(OH)D was similar for cases diagnosed within 6 years of plasma collection and 6 or more years after collection. We also observed a trend toward a decreased risk of colorectal cancer–specific death with higher 25(OH)D levels, which did not reach statistical significance, reflecting the more limited statistical power with this end point. Of note, the majority of overall mortality events were due to colorectal cancer.

Previous studies have suggested an inverse relationship between vitamin D and cancer incidence and mortality. Prospective observational studies demonstrated that higher plasma levels of 25(OH)D are associated with a significant reduction in risk of colorectal cancer compared with lower plasma levels.^11-16 A randomized trial of 100,000 IU of vitamin D₃ versus placebo every 4 months was conducted among 2,686 people to evaluate the effect of vitamin D on fracture risk.³⁰ Although not the primary end point of the study, an age-adjusted relative risk of 0.62 (95% CI, 0.24 to 1.60) for colon cancer mortality was found with vitamin D compared with placebo (seven v 11 colon cancer deaths, respectively). In a placebo-controlled, randomized trial of vitamin D and calcium supplementation in 1,179 women, Lappe et al¹⁸ also observed a statistically significant decrease in the incidence of cancer with supplementation, with 21 cancers in the vitamin D plus calcium arm, 32 cancers in the calcium arm, and 38 cancers in the placebo arm.

To our knowledge, no previous study has examined the influence of plasma 25(OH)D on survival in patients diagnosed with colorectal cancer. An inverse relationship between plasma 25(OH)D and mortality has been reported in patients with early-stage non–small-cell lung cancer, where high plasma 25(OH)D levels and vitamin D intake were significantly associated with improved overall and recurrence-free survival.³¹

There are several mechanisms through which vitamin D exposure may influence survival after a diagnosis of colorectal cancer. Binding of VDR by 1,25(OH)₂D, the active metabolite of vitamin D, leads to transcriptional activation and repression of target genes, resulting in differentiation and apoptosis, and inhibition of proliferation and angiogenesis.³² Linking epidemiologic observations to a biologic mechanism for colorectal cancer pathogenesis, preclinical studies have shown that VDR and 1-hydroxylase are present in both normal and malignant colon cells.^1-3 In vitro and in vivo data have demonstrated growth inhibition and differentiation of colon carcinoma cell lines and xenografts by administration of 1,25(OH)₂D,^7,33-36 and rat models of colorectal cancer maintained on a 1,25(OH)₂D diet developed fewer metastases compared with control animals.¹⁰

We found that BMI at the time of diagnosis may modify the effect of plasma 25(OH)D on overall mortality, with participants with a higher BMI demonstrating a slightly greater reduction in the risk of death. One possible hypothesis involves the interaction between vitamin D and cytokine signaling. Several studies have shown that 1,25(OH)₂D inhibits the expression of proinflammatory cytokines such as interleukin (IL) -1, IL-2, IL-6, and IL-8.^37,38 Given that adiposity is characterized by low-grade systemic inflammation and that obese individuals exhibit increased production of inflammatory markers,^39,40 it is plausible that patients with colorectal cancer with a higher BMI benefit from both the anti-inflammatory and antineoplastic properties of vitamin D. This additional beneficial effect on the inflammatory state could underlie the slightly greater reduction in mortality that was seen in this subgroup.

The strengths of our study include its prospective design, use of a direct indicator of bodily vitamin D stores, detailed data on many potential confounders, and high follow-up rate. As participants were health professionals, the accuracy of self-reported data is likely to be high; information on many exposures have been validated previously.^41,42

Several limitations of our study deserve comment. Our analysis used a single measurement of plasma 25(OH)D drawn before colorectal cancer diagnosis as the exposure and therefore may not reflect vitamin D status at the time of or after cancer diagnosis. However, a subsample of 144 men in the HPFS who provided a second blood sample showed reasonable reproducibility for 25(OH)D levels obtained 3 to 4 years apart (r = 0.70).²⁸ Indeed, our analyses show that the relationship between vitamin D and overall mortality was not significantly affected by the time interval between blood collection and cancer diagnosis. Nonetheless, any misclassification in vitamin D status should be nondifferential and would bias the results toward unity.⁴³

We cannot completely exclude the possibility that lower levels of 25(OH)D may be reflective of other occult predictors for poor prognosis or that higher prediagnosis 25(OH)D may lead to the development of more favorable tumors. It is also possible that participants with higher 25(OH)D levels may undergo colorectal cancer screening more often than those with lower levels, leading to the detection of earlier-stage tumors. However, our findings remained unchanged after adjusting for potential risk factors for colorectal cancer mortality. Indeed, there were actually more advanced-stage, higher-grade patients in the upper quartiles of plasma 25(OH)D compared with the lower quartiles. To minimize bias in the plasma 25(OH)D level by the presence of occult cancer, we excluded diagnoses within 2 years of blood collection and continued to observe a positive impact of high 25(OH)D, even when extending this restriction to 5 years.

In this cohort, data on treatment were limited. Approximately half of the participants had stage I or II disease, for which surgery alone is often the standard of care. Additionally, although there have been changes in the chemotherapeutic treatment of colorectal cancer during the timeframe under study that could influence outcomes, we adjusted for year of diagnosis in our models. Furthermore, although there are differences in likelihood of chemotherapy receipt based on factors such as socioeconomic status, the fairly homogeneous socioeconomic and educational makeup of this cohort likely minimizes such disparities in the delivery of standard therapy.⁴⁴ Lastly, because this was an observational rather than a randomized study, we cannot definitively attribute our results to plasma 25(OH)D; definitive proof of a benefit of vitamin D on survival may require a randomized placebo-controlled trial.

In conclusion, our data suggest that higher prediagnosis plasma levels of 25(OH)D after a diagnosis of colorectal cancer may significantly improve overall survival. Additional efforts to understand the mechanisms through which the vitamin D pathway influences colorectal carcinogenesis and cancer progression are warranted. Moreover, future trials should examine the role of vitamin D supplementation in patients with colorectal cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Bruce W. Hollis, DiaSorin Corporation (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Kimmie Ng, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Charles S. Fuchs

Financial support: Edward L. Giovannucci, Charles S. Fuchs

Administrative support: Kimmie Ng, Charles S. Fuchs

Collection and assembly of data: Kimmie Ng, Jeffrey A. Meyerhardt, Kana Wu, Diane Feskanich, Bruce W. Hollis, Edward L. Giovannucci, Charles S. Fuchs

Data analysis and interpretation: Kimmie Ng, Jeffrey A. Meyerhardt, Kana Wu, Diane Feskanich, Bruce W. Hollis, Edward L. Giovannucci, Charles S. Fuchs

Manuscript writing: Kimmie Ng, Charles S. Fuchs

Final approval of manuscript: Kimmie Ng, Jeffrey A. Meyerhardt, Kana Wu, Diane Feskanich, Bruce W. Hollis, Edward L. Giovannucci, Charles S. Fuchs

	Glossary Terms

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Vitamin D receptors (VDR):

The vitamin D receptor is a member of the nuclear hormone-receptor superfamily of protein receptors. This intracellular receptor has both hormone-binding and DNA-binding domains. Upon binding by 1,25-dihydroxycholecalciferol, the active metabolite of vitamin D, the receptor complexes with the retinoic acid receptor. This heterodimer subsequently recruits several co-activator molecules and binds to a DNA response element located in the promoter region of target genes to either activate or suppress transcription.

1-hydroxylase:

1-hydroxylase is a mitochondrial enzyme within the kidney that is encoded by the gene CYP27B1 and that converts 25-hydroxyvitamin D, the main circulating form of vitamin D, to 1,25-dihydroxycholecalciferol, the active metabolite. The main inducer of 1-hydroxylase activity is parathyroid hormone. Recent studies indicate that 1-hydroxylase is also expressed at extrarenal sites, including normal colon, brain, placenta, pancreas, lymph nodes, and skin.

25-hydroxyvitamin D3:

25-hydroxyvitamin D3, the main circulating form of vitamin D, is produced in the liver when vitamin D3 (cholecalciferol) from UV irradiation and dietary intake is hydroxylated by mitochondrial and microsomal enzymes in the liver. 25-hydroxyvitamin D3 is considered the best indicator of vitamin D status, because it reflects not only skin exposure to UV light and total vitamin D intake, but also cholecalciferol production in the skin and hydroxylation of all sources of cholecalciferol in the liver.

1,25-dihydroxycholecalciferol [1,25(OH)2D]:

Also known as calcitriol, 1,25-dihydroxycholecalciferol is a steroid hormone that functions as the physiologically most active form of vitamin D. It acts in an autocrine and paracrine manner, and binds to the vitamin D receptor to regulate calcium homeostatsis and bone growth and mineralization, among other cellular processes.

Radioimmunoassay:

Radioimmunoassay is a highly sensitive laboratory technique used to measure minute amounts of substances including hormones, antigens, and drugs in the blood. First, a known amount of the substance to be measured is tagged with a radioisotope, mixed with antibodies to that substance, and added to a sample of the patient's blood. The same nonradioactive substance in the blood competes with the isotope for binding to the antibodies, thus displacing the radiolabeled substance. The amount of free radioisotope is then measured to determine the level of the original substance in the blood.

Cytokines:

Cell communication molecules that are secreted in response to external stimuli.

IL-1 (interleukin 1):

Produced by activated macrophages, endothelial cells, and B cells, IL-1 is a cytokine that induces inflammatory responses. As a proinflammatory cytokine, IL-1 has a role in immune, degradative, and growth-promoting processes. Belonging to this class of cytokines, IL-1 and IL-1 are agonists while IL-1Ra is an antagonist of the IL-1 receptor.

IL-2 (interleukin 2):

A cytokine that stimulates proliferation of activated T cells and, at high doses, is used as antitumor therapy in metastatic renal cell carcinoma.

IL-6 (interleukin 6):

IL-6 is produced predominantly by activated immune cells such as microglia and is involved in the amplification of inflammatory reactions.

IL-8 (interleukin 8):

A proinflammatory cytokine structurally related to platelet factor 4, IL-8 is released by several cell types (eg, monocytes, macrophages, T cells, endothelial cells, tumor cells) in response to an inflammatory stimulus. It activates neutrophils and is a chemokine for neutrophils and T lymphocytes. It is also an angiogenic factor.

Apoptosis:

Also called programmed cell death, it is a signaling pathway that leads to cellular suicide in an organized manner. Several factors and receptors are specific to the apoptotic pathway. The net result is that cells shrink, develop blebs on their surface, and their DNA undergoes fragmentation.

Angiogenesis:

The process involved in the generation of new blood vessels. While this is a normal process that naturally occurs and is controlled by "on" and "off" switches, blocking tumor angiogenesis (antiangiogenesis) disrupts the blood supply to tumors, thereby preventing tumor growth.

	ACKNOWLEDGMENTS

 
We thank Walter C. Willett, MD, DrPH, and Meir J. Stampfer, MD, DrPH, from the Harvard School of Public Health for their expert comments on the analysis and the manuscript.

	NOTES

 
Supported in part by Grants No. CA118553, CA87969, and CA108341 from the National Cancer Institute, National Institutes of Health.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Glossary Terms REFERENCES

 
1. Meggouh F, Lointier P, Saez S: Sex steroid and 1,25-dihydroxyvitamin D3 receptors in human colorectal adenocarcinoma and normal mucosa. Cancer Res 51:1227-1233, 1991[Abstract/Free Full Text]

2. Vandewalle B, Adenis A, Hornez L, et al: 1,25-dihydroxyvitamin D3 receptors in normal and malignant human colorectal tissues. Cancer Lett 86:67-73, 1994[CrossRef][Medline]

3. Zehnder D, Bland R, Williams MC, et al: Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86:888-894, 2001[Abstract/Free Full Text]

4. Vandewalle B, Wattez N, Lefebvre J: Effects of vitamin D3 derivatives on growth, differentiation and apoptosis in tumoral colonic HT 29 cells: Possible implication of intracellular calcium. Cancer Lett 97:99-106, 1995[CrossRef][Medline]

5. Díaz GD, Paraskeva C, Thomas MG, et al: Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: Possible implications for prevention and therapy. Cancer Res 60:2304-2312, 2000[Abstract/Free Full Text]

6. Scaglione-Sewell BA, Bissonnette M, Skarosi S, et al: A vitamin D3 analog induces a G1-phase arrest in CaCo-2 cells by inhibiting cdk2 and cdk6: Roles of cyclin E, p21Waf1, and p27Kip1. Endocrinology 141:3931-3939, 2000[Abstract/Free Full Text]

7. Iseki K, Tatsuta M, Uehara H, et al: Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer 81:730-733, 1999[CrossRef][Medline]

8. Fernandez-Garcia NI, Palmer HG, Garcia M, et al: 1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells. Oncogene 24:6533-6544, 2005[Medline]

9. Lamprecht SA, Lipkin M: Cellular mechanisms of calcium and vitamin D in the inhibition of colorectal carcinogenesis. Ann N Y Acad Sci 952:73-87, 2001[Medline]

10. Evans SR, Shchepotin EI, Young H, et al: 1,25-dihydroxyvitamin D3 synthetic analogs inhibit spontaneous metastases in a 1,2-dimethylhydrazine-induced colon carcinogenesis model. Int J Oncol 16:1249-1254, 2000[Medline]

11. Garland CF, Comstock GW, Garland FC, et al: Serum 25-hydroxyvitamin D and colon cancer: Eight-year prospective study. Lancet 2:1176-1178, 1989[Medline]

12. Braun MM, Helzlsouer KJ, Hollis BW, et al: Colon cancer and serum vitamin D metabolite levels 10-17 years prior to diagnosis. Am J Epidemiol 142:608-611, 1995[Abstract/Free Full Text]

13. Tangrea J, Helzlsouer K, Pietinen P, et al: Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control 8:615-625, 1997[CrossRef][Medline]

14. Feskanich D, Ma J, Fuchs CS, et al: Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 13:1502-1508, 2004[Abstract/Free Full Text]

15. Wactawski-Wende J, Kotchen JM, Anderson GL, et al: Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354:684-696, 2006[Abstract/Free Full Text]

16. Wu K, Feskanich D, Fuchs CS, et al: A nested case control study of plasma 25-hydroxyvitamin D concentrations and risk of colorectal cancer. J Natl Cancer Inst 99:1120-1129, 2007[Abstract/Free Full Text]

17. Gorham ED, Garland CF, Garland FC, et al: Optimal vitamin D status for colorectal cancer prevention: A quantitative meta analysis. Am J Prev Med 32:210-216, 2007[CrossRef][Medline]

18. Lappe JM, Travers-Gustafson D, Davies KM, et al: Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Am J Clin Nutr 85:1586-1591, 2007[Abstract/Free Full Text]

19. Robsahm TE, Tretli S, Dahlback A, et al: Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control 15:149-158, 2004[CrossRef][Medline]

20. Moan J, Porojnicu AC, Robsahm TE, et al: Solar radiation, vitamin D and survival rate of colon cancer in Norway. J Photochem Photobiol B 78:189-193, 2005[CrossRef][Medline]

21. Belanger CF, Hennekens CH, Rosner B, et al: The nurses' health study. Am J Nurs 78:1039-1040, 1978[Medline]

22. Colditz GA, Manson JE, Hankinson SE: The Nurses' Health Study: 20-year contribution to the understanding of health among women. J Womens Health 6:49-62, 1997[Medline]

23. Giovannucci E, Colditz GA, Stampfer MJ, et al: A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. women. J Natl Cancer Inst 86:192-199, 1994[Abstract/Free Full Text]

24. Giovannucci E, Liu Y, Rimm EB, et al: Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 98:451-459, 2006[Abstract/Free Full Text]

25. Sathiakumar N, Delzell E, Abdalla O: Using the National Death Index to obtain underlying cause of death codes. J Occup Environ Med 40:808-813, 1998[CrossRef][Medline]

26. Stampfer MJ, Willett WC, Speizer FE, et al: Test of the National Death Index. Am J Epidemiol 119:837-839, 1984[Free Full Text]

27. Hollis BW: Quantitation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D by radioimmunoassay using radioiodinated tracers. Methods Enzymol 282:174-186, 1997[Medline]

28. Platz EA, Leitzmann MF, Hollis BW, et al: Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes Control 15:255-265, 2004[CrossRef][Medline]

29. Meyerhardt JA, Giovannucci EL, Holmes MD, et al: Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527-3534, 2006[Abstract/Free Full Text]

30. Trivedi DP, Doll R, Khaw KT: Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: Randomised double blind controlled trial. BMJ 326:469, 2003[Abstract/Free Full Text]

31. Zhou W, Heist RS, Liu G, et al: Circulating 25-hydroxyvitamin D levels predict survival in early-stage non–small-cell lung cancer patients. J Clin Oncol 25:479-485, 2007[Abstract/Free Full Text]

32. Deeb KK, Trump DL, Johnson CS: Vitamin D signaling pathways in cancer: Potential for anticancer therapeutics. Nat Rev Cancer 7:684-700, 2007[CrossRef][Medline]

33. Giuliano AR, Franceschi RT, Wood RJ: Characterization of the vitamin D receptor from the Caco-2 human colon carcinoma cell line: Effect of cellular differentiation. Arch Biochem Biophys 285:261-269, 1991[CrossRef][Medline]

34. Zhao X, Feldman D: Regulation of vitamin D receptor abundance and responsiveness during differentiation of HT-29 human colon cancer cells. Endocrinology 132:1808-1814, 1993[Abstract/Free Full Text]

35. Shabahang M, Buras RR, Davoodi F, et al: Growth inhibition of HT-29 human colon cancer cells by analogues of 1,25-dihydroxyvitamin D3. Cancer Res 54:4057-4064, 1994[Abstract/Free Full Text]

36. Eisman JA, Barkla DH, Tutton PJ: Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res 47:21-25, 1987[Abstract/Free Full Text]

37. Müller K, Odum N, Bendtzen K: 1,25-dihydroxyvitamin D3 selectively reduces interleukin-2 levels and proliferation of human T cell lines in vitro. Immunol Lett 35:177-182, 1993[CrossRef][Medline]

38. Gurlek A, Pittelkow MR, Kumar R: Modulation of growth factor/cytokine synthesis and signaling by 1alpha,25-dihydroxyvitamin D(3): Implications in cell growth and differentiation. Endocr Rev 23:763-786, 2002[Abstract/Free Full Text]

39. Aldhahi W, Hamdy O: Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep 3:293-298, 2003[Medline]

40. Piché ME, Lemieux S, Weisnagel SJ, et al: Relation of high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and fibrinogen to abdominal adipose tissue, blood pressure, and cholesterol and triglyceride levels in healthy postmenopausal women. Am J Cardiol 96:92-97, 2005[CrossRef][Medline]

41. Rimm EB, Stampfer MJ, Colditz GA, et al: Validity of self-reported waist and hip circumferences in men and women. Epidemiology 1:466-473, 1990[Medline]

42. Wolf AM, Hunter DJ, Colditz GA, et al: Reproducibility and validity of a self-administered physical activity questionnaire. Int J Epidemiol 23:991-999, 1994[Abstract/Free Full Text]

43. Rothman KJ, Greenland S: Precision and validity in epidemiologic studies, in Rothman KJ, Greenland S (eds): Modern Epidemiology (ed 3). Philadelphia, PA, Lippincott Williams & Wilkins, 1998, pp 115-134

44. VanEenwyk J, Campo JS, Ossiander EM: Socioeconomic and demographic disparities in treatment for carcinomas of the colon and rectum. Cancer 95:39-46, 2002[CrossRef][Medline]

Submitted October 28, 2007; accepted January 30, 2008.

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