The effect of vitamin D supplementation on survival in patients with colorectal cancer: systematic review and meta-analysis of randomised controlled trials

Peter G. Vaughan-Shaw,James P. Blackmur,Farhat V. N. Din,Malcolm G. Dunlop,Evi Theodoratou,Susan M. Farrington,Lina Zgaga,Louis F. Buijs

doi:10.1038/s41416-020-01060-8

Abstract

BackgroundLow circulating vitamin D levels are associated with poor colorectal cancer (CRC) survival. We assess whether vitamin D supplementation improves CRC survival outcomes.MethodsPubMed and Web of Science were searched. Randomised controlled trial (RCTs) of vitamin D supplementation reporting CRC mortality were included. RCTs with high risk of bias were excluded from analysis. Random-effects meta-analysis models calculated estimates of survival benefit with supplementation. The review is registered on PROSPERO, registration number: CRD42020173397.ResultsSeven RCTs (n = 957 CRC cases) were identified: three trials included patients with CRC at outset, and four population trials reported survival in incident cases. Two RCTs were excluded from meta-analysis (high risk of bias; no hazard ratio (HR)). While trials varied in inclusion criteria, intervention dose and outcomes, meta-analysis found a 30% reduction in adverse CRC outcomes with supplementation (n = 815, HR = 0.70; 95% confidence interval (CI): 0.48–0.93). A beneficial effect was seen in trials of CRC patients (progression-free survival, HR = 0.65; 95% CI: 0.36–0.94), with suggestive effect in incident CRC cases from population trials (CRC-specific survival, HR = 0.76; 95% CI: 0.39–1.13). No heterogeneity or publication bias was noted.ConclusionsMeta-analysis demonstrates a clinically meaningful benefit of vitamin D supplementation on CRC survival outcomes. Further well-designed, adequately powered RCTs are needed to fully evaluate benefit of supplementation in augmenting ‘real-life’ follow-up and adjuvant chemotherapy regimens, as well as determining optimal dosing.

Highlights

Low circulating vitamin D levels are associated with poor colorectal cancer (CRC) survival
In the AMATERASU trial,33 41% (n = 173) patients had insufficient 25OHD at baseline, with 2000 IU/day supplementation associated with a non-significant improvement in survival with supplementation after median follow-up 3.5 years in stage I–III patients (25OHD ~20 ng/ml at baseline, ~60 ng/ml at follow-up; hazard ratio (HR) = 0.69; 95% confidence interval (CI): 0.39–1.24)
We found that supplementation imparts a 30% reduction in adverse survival outcomes overall, with a 24% reduction in CRC-specific death and a 33% in disease progression or death

Summary

Introduction

Low circulating vitamin D levels are associated with poor colorectal cancer (CRC) survival. CONCLUSIONS: Meta-analysis demonstrates a clinically meaningful benefit of vitamin D supplementation on CRC survival outcomes. Observational data implicating vitamin D deficiency in CRC aetiology or survival are limited by potential bias: environmental risk factors associated with CRC are associated with vitamin D status (co-causality; e.g. physical activity, obesity); heterogeneity in assay type and performance across studies; the development of CRC itself—or its treatment—may induce lower vitamin D levels (reverse causation).[5] Mendelian randomisation is an approach that can provide evidence for causality, but studies have far failed to detect a causal association between blood 25-hydroxyvitamin D level and CRC risk.[7] This may be due to weakness of the available genetic instruments, combined with powerful environmental influences, such as variation in exposure to vitamin D-making ultraviolet B (UVB) sunlight

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Results

Conclusion