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

Gut

Apr 2019

DOI: 10.1136/gutjnl-2018-317922

Citations:45

Influential Citations:5

Observational Studies (Human)

Enhanced Details

Methods

Serial perioperative measurements in 92 adults with colorectal cancer undergoing curative resection (mean age 67.1 years; 55% male; BMI 26.1). Prospective observational design with survival analyses in two large temporally distinct CRC cohorts (cohort 1: n=2006; cohort 2: n=2100) from the SOCCS/SOCCS3 studies; included AJCC stages I–III; metastatic disease excluded; measured plasma 25OHD and CRP; rs11568820 genotyped; follow-up through 1 July 2017; analyses adjusted for age, sex, BMI, AJCC stage (and CRP where reported); season-adjusted May-25OHD used; survival analyses via Cox models with meta-analysis across cohorts.

Results

Postoperative 25OHD falls (mean reduction ~17.3 nmol/L; nadir 1–2 days) with CRP peaking at 3–5 days; the 25OHD decline is independent of CRP. In two cohorts, higher May-adjusted 25OHD after surgery associated with lower CRC-specific mortality (HR ~0.66–0.69) and lower all-cause mortality (HR ~0.63–0.65), independent of CRP and sampling time. A genotype interaction showed strongest benefit in rs11568820 GG individuals (HR ~0.51). An online survival tool incorporating 25OHD demonstrated AUC ~0.77. Meta-analysis confirmed associations (CRC-specific HR ~0.69; all-cause HR ~0.68). Conclusion: vitamin D deficiency after CRC surgery is a modifiable risk factor linked to poorer survival; findings support a randomized trial of vitamin D supplementation after CRC surgery and suggest 25OHD status could aid prognosis.

Limitations

Observational design with potential residual confounding; differences in baseline 25OHD between cohorts; possible effects from sample handling/storage; perioperative 25OHD decline could reflect non-surgical factors; limited CRP data in some analyses; generalizability may be limited to the studied population.

Abstract

Objective We 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. Design We 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. Results Serial 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). Conclusions CRC 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. show less