Low plasma vitamin D is associated with adverse colorectal cancer survival after surgical resection, independent of systemic inflammatory response

Abstract

ObjectiveWe assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival.DesignWe sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response.ResultsSerial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1–2). CRP peaked 3–5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I–III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival (https://apps.igmm.ed.ac.uk/mortalityCalculator/) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77).ConclusionsCRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.

Effect of Vitamin D Supplementation on Survival of Digestive Tract Cancer Patients with Low Bioavailable 25-Hydroxyvitamin D Levels: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial

“…Although we did not measure these levels before surgery, results suggest that surgical stress may decrease albumin levels, probably via accelerated catabolism, and that DBP levels may increase by unknown mechanisms. In previous studies, 1 to 2 days after surgery, total 25(OH)D levels were reported to decrease to nadir levels and to start recovering 6 days after surgery [12,13]. We hypothesized that the mechanism of increase in DBP occurred through surgical stress and reduced total 25(OH)D levels, which subsequently increased DBP levels through a negative feedback loop; the increased DBP helped total 25(OH)D levels to recover.…”

“…Third, in the present trial, patients underwent blood sampling to measure serum total 25(OH)D levels at the first outpatient visit between 2 and 6 weeks after surgery, but not preoperatively. Serum levels of 25(OH)D and albumin have been reported to decrease after surgery [12,13]. Thus, baseline levels of total and bioavailable 25(OH)D could have been affected by stress induced by surgery and cannot be exactly compared with 25(OH)D levels in other studies in which blood sampling took place before surgery or before a diagnosis of cancer.…”

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

“…A consistent reduction in adverse survival outcomes irrespective of the trial inclusion criteria, supplementation dose or survival outcome measure is supportive of a true causal effect, which supports observational data linking 25OHD level and cancer outcomes. 16,17 There are a number of limitations in the currently available trial data impacting on this analysis. First, our literature search demonstrates a lack of well-designed and adequately powered randomised controlled trials investigating vitamin D supplementation and CRC outcomes.…”

“…In support of a causal effect, several studies have demonstrated an interaction between vitamin D-related genetic variation, 25hydroxyvitamin D (25OHD) level and CRC or neoplasia risk or outcome, mitigating against potential confounding effects. [14][15][16][17] In a sub-analysis of VITAL trial data, a lower rate of all cancer death was observed after 2 years of follow-up (hazard ratio (HR) = 0.75; 95% confidence interval (CI 0.59-0.96)). Furthermore, a recent meta-analysis found reduced total cancer mortality with vitamin D supplementation (HR = 0.87; 95% CI 0.79-0.96).…”

Vitamin D receptor protects against dysbiosis and tumorigenesis via the JAK/STAT pathway in intestine

“…Current research has implicated vitamin D deficiency as a critical factor in the pathology and clinical outcome of colon rectal cancer (CRC) [1, 2]. Low plasma vitamin D is associated with adverse CRC survival after surgical resection [3, 4]. Vitamin D receptor (VDR) is a nuclear receptor that mediates functions of 1,25-dihydroxyvitamin D (1,25(OH) 2 D 3 ), the biological active form of vitamin D [5].…”