Vitamin D and Physical Activity in Patients With Colorectal Cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality in the U.S. Notwithstanding major improvements in the early detection and treatment of CRC, an important proportion of patients diagnosed with localized disease ultimately recur and die, underscoring the need of new therapeutic approaches. Vitamin D and physical activity (PA) have emerged as two potential interventions for both prevention and treatment of CRC. Plausible biological mechanisms have been described for the anti-neoplastic effects of vitamin D and PA, and a wealth of epidemiological evidence indicates that 25(OH)D (the main circulating form of vitamin D) and PA levels are inversely associated with CRC risk. Recent efforts have now focused on the role of vitamin D and PA as adjunct treatments after a CRC diagnosis. Observational studies evaluating pre- and post-diagnosis circulating 25(OH)D levels among patients with CRC of all stages have found that subjects with levels in the highest quantiles have improved overall and CRC-specific survival compared with those with levels in the lowest quantiles. Similarly, prospective studies of PA have found that higher levels of post-diagnosis PA are associated with lower overall and CRC-specific mortality in patients with non-metastatic CRC. Meta-analyses of the observational studies of 25(OH)D and post-diagnosis PA have confirmed significant protective associations against overall and CRC-specific mortality as well as significant dose-response relationships. No randomized, controlled trial of vitamin D or PA using survival outcomes as endpoints has been completed to date. Two randomized, placebo-controlled trials of vitamin D in patients with metastatic CRC assessing patient survival as an endpoint are underway: the first is a phase II trial comparing high-dose vitamin D3 (8000 IU day-1 for two weeks followed by 4000 IU day-1) versus standard dose (400 IU day-1), and the second is a phase I-II trial comparing customized oral doses of vitamin D3 titrated to raise serum 25(OH)D levels to 80-100 ng mL-1, versus 2000 IU day-1. For PA, the ongoing phase III Colon Health and Life-Long Exercise Change (CHALLENGE) study is the first randomized, controlled trial using survival as an endpoint among patients with stage II-III colon cancer. The results of these trials will pave the way to more conclusive phase III trials that will provide more definitive answers about the role of these interventions in the treatment of CRC. Lastly, the advent of genomic technologies will allow identifying molecular signatures in CRC associated with improved response to vitamin D and PA and will usher in a precision medicine approach to these therapies.

Circulating Vitamin D and Overall Survival in Breast Cancer Patients: A Dose-Response Meta-Analysis of Cohort Studies

“…We identified a statistically significant dose-response relationship in breast cancer between patient survival and circulating levels of 25-OH-D. A protective effect of higher vitamin D levels have also been shown in skin cancer, 48 ovarian cancer, 49 prostate cancer, 50 and colorectal cancer. 51 As shown in Table 1 and Figure 3 , the linear relationship encompasses vitamin D levels from 23.3 to 187.5 nmol/L. It should be noted that due to limited data presented in the studies the highest 3 vitamin D levels (187.5, 121.5, and 94.1 nmol/L) were all estimated and therefore the linear relationship at higher levels of vitamin D are likely to be unreliable.…”

MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin

“…Evidence shows that the vitamin D levels are inversely associated with CRC risk and positively associated with improved overall and CRC-specific survival ( Morales-oyarvide et al, 2016 ). Vitamin D and its nuclear transcriptional receptor VDR have chemo-prevention activities for CRC ( Aggarwal and Kallay, 2016 ).…”

Vitamin D inhibits the epithelial-mesenchymal transition by a negative feedback regulation of TGF-β activity

“…Several studies in vitro demonstrated the efficacy of 1,25(OH) 2 D 3 in contrasting the EMT triggered by TGF-β, due to the inhibited expression of EMT markers and the decreased migration and invasion of epithelial and ovarian cancer cells [6][7][8][9][10]. The clinical studies that have evaluated the efficacy of vitamin D supplementation have described a role merely preventive in cancer formation and progression, whereas there are no evidences for curative properties on malignant tumors [11][12][13].…”