Vitamin D and Physical Activity in Patients With Colorectal Cancer: Epidemiological Evidence and Therapeutic Implications.

Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality in the United States. Notwithstanding major improvements in the early detection and treatment of CRC, an important proportion of patients who received a diagnosis of localized disease ultimately have a recurrence and die, underscoring the need of new therapeutic approaches. Vitamin D and physical activity (PA) have emerged as 2 potential interventions for both prevention and treatment of CRC. Plausible biological mechanisms have been described for the antineoplastic 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 prediagnosis and postdiagnosis 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 postdiagnosis PA are associated with lower overall and CRC-specific mortality in patients with nonmetastatic CRC. Meta-analyses of the observational studies of 25(OH)D and postdiagnosis 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/d for 2 weeks followed by 4000 IU/d) versus standard dose (400 IU/d), 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 to 100 ng/mL versus 2000 IU/d. For PA, the ongoing phase III CHALLENGE (Colon Health and Life-Long Exercise Change) 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.