Examining the Role of Vitamin D in Colorectal Cancer Survival

Kimmie Ng, MD, MPH

Assistant Professor of Medicine

Center for Gastrointestinal Oncology

Dana-Farber Cancer Institute

Harvard Medical Center

Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer. Little is known, however, about how these factors may impact the survival of patients with established colorectal cancer, many of whom seek to understand which diet and lifestyle behaviors—beyond standard treatment with surgery, chemotherapy, or radiation—will improve their outcome.

Following on the recommendation of an American Cancer Society consensus panel highlighting the urgent need for more research on the effect of nutrition and physical activity on the prognosis of cancer survivors, the Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute has developed an innovative, crossdisciplinary, translational research program to elucidate the role of diet and lifestyle behaviors in the survival of colorectal cancer patients.

Among the factors that we have identified as being potentially protective are exercise,^1-3 avoiding a Western pattern diet,⁴ maintaining a normal body-mass index,⁵ aspirin use,^6,7 and vitamin D status. For vitamin D, in particular, abundant data from the laboratory as well as epidemiologic studies support a potential antineoplastic effect. Efforts are underway to further understand the biologic mechanisms by which vitamin D may contribute to colorectal cancer pathogenesis and the potential clinical impact of supplementation on patient management.

The hypothesis that vitamin D status is related to colorectal cancer has received strong experimental support over the past two decades, based on the almost ubiquitous expression in colon cancer cells of the vitamin D receptor (VDR)^8,9 and 1-a-hydroxylase (CYP27B1),¹⁰ which converts plasma 25-hydroxyvitamin D₃ [25(OH)D] into 1,25-dihyroxycholecalciferol [1,25(OH)2D], the active metabolite. Binding of VDR by 1,25(OH)2D leads to transcriptional control of target genes, resulting in induction of differentiation and apoptosis,^11,12 and inhibition of proliferation,¹³ angiogenesis,^14,15 and metastatic potential.^16,17

Vitamin D inhibits growth and promotes differentiation of colorectal cancer cell lines and xenografts.14,18-21 Rats maintained on a diet enriched in 1,25(OH)2D develop fewer intestinal tumors and metastases compared to control animals.^17,22 Treatment of ApcMin mice with vitamin D or a synthetic analog reduces the size of intestinal adenomas,^23-25 and epidemiologic data also suggest that vitamin D plays a role in colorectal cancer carcinogenesis. A meta-analysis of nine prospective studies showed that individuals with higher plasma levels of 25(OH)D, the best indicator of vitamin D status, have a significantly reduced risk of developing colorectal cancer.²⁶

The influence of vitamin D on survival of patients with established colorectal cancer remains uncertain, however, and we conducted several studies to try and address this knowledge gap.

Figure. Plasma 25(OH)D and Survival in 304 Colorectal Cancer Patients (NHS/HPFS)

Adjusted for age, gender, stage, grade, site, year of diagnosis, season of blood draw, BMI, and post-diagnosis physical activity. (Ng K, et al. J Clin Oncol. 2008;26[18]:2984-2991.)

Among 304 colorectal cancer patients in the Nurses’ Health Study (NHS) and the Health Professionals Follow- Up Study (HPFS) who had blood samples available, we measured 25(OH)D concentrations prior to colorectal cancer diagnosis and assessed for a correlation with survival. We found that higher plasma 25(OH)D levels were associated with a significant reduction in overall mortality (Figure).²⁷ This finding was subsequently confirmed in another study of 1017 colorectal cancer patients in the NHS and HPFS, where higher postdiagnosis vitamin D scores calculated from known clinical determinants of vitamin D status were found to be significantly associated with improved cancer-specific (adjusted hazard ratio [HR] = 0.50; 95% CI, 0.26-0.95; P trend = .02) and overall survival (HR = 0.62; 95% CI, 0.42- 0.93; P trend = .002).28 In subgroup analyses, the benefit of higher plasma 25(OH)D seemed greater in stage III and IV patients than stage I and II (adjusted HR = 0.40 vs 0.90, respectively, comparing extreme quartiles).²⁷

To further test the benefit of vitamin D in advancedstage colorectal cancer, we conducted an analysis of plasma 25(OH)D levels drawn at study registration in 515 stage IV colorectal cancer patients enrolled in a completed, National Cancer Institute-sponsored clinical trial of palliative chemotherapy (North Central Cancer Treatment Group N9741).²⁹ We found extremely low circulating concentrations of 25(OH)D in this population, with a median level of 20.0 ng/ mL. Indeed, only 10% of the cohort had levels ≥33 ng/mL, the threshold believed to be required for a protective effect of vitamin D on colorectal cancer risk.³⁰ These low levels of plasma 25(OH)D are especially concerning in light of laboratory and epidemiologic evidence that higher levels are associated with improved outcome.

Given the prevalence of vitamin D deficiency and insufficiency among metastatic colorectal cancer patients, the hypothesis-generating finding of a greater benefit of vitamin D among advanced-stage patients, and preclinical studies revealing potential synergy between vitamin and cytotoxic drugs such as platinums^31-34 and 5-FU,³⁵ we are now translating our observational findings into a clinical intervention for patients.

We are currently conducting a multicenter, randomized, blinded, placebo-controlled phase II study of FOLFOX + bevacizumab in combination with either standard-dose vitamin D₃ at 400 IU/day versus higher- dose vitamin D₃ at 4000 IU/day in previously untreated, stage IV colorectal cancer patients, with a primary endpoint of progression-free survival (ClinicalTrials.gov identifier NCT01516216). Approximately 120 patients will be enrolled on the study, and accrual is actively ongoing at multiple centers across the United States. Serial plasma and DNA samples and archival tumor tissue will be collected from all patients and banked for future correlative studies.

These correlative studies will be critical to fully understanding the role of vitamin D in colorectal cancer pathogenesis. Despite the abundant laboratory and observational data discussed above, the exact molecular and genetic mechanisms underlying vitamin D’s antineoplastic effects are unknown. Consequently, an entire project in our Dana-Farber/Harvard Cancer Center SPORE (Specialized Programs of Research Excellence) in gastrointestinal cancer is devoted to investigating the transcriptional targets of VDR in cell lines, xenograft mouse models, and human primary colon tumor samples. Moreover, multiple analyses of germline polymorphisms in vitamin D pathway genes are ongoing to determine if genetic variation significantly affects response to vitamin D supplementation as well as colorectal cancer patient outcome.

The potential to modulate the progression of colorectal cancer through nutritional and lifestyle factors is very real but insufficiently studied, and a clinical and translational approach that steps beyond purely observational studies is required to establish causality. In addition, elucidation of a biological mechanism underlying these clinical findings would enhance the acceptability of vitamin D as critical for cancer prevention and treatment.

In this era of expensive and often toxic antineoplastic drugs, vitamin D represents an attractive treatment option for patients and oncologists with respect to both safety and cost, and improving understanding of vitamin D in colorectal cancer could potentially shift the paradigm in managing this disease.

References

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