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

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.

Keywords: cancer prevention; colorectal cancer; colorectal surgery; vitamin D receptor gene.

Figure 1

Perioperative 25OHD and CRP in patients undergoing colorectal cancer surgery. Unadjusted 25OHD charted with CRP. Sixty-two patients undergoing colorectal cancer surgery sampled at up to six perioperative time points. Mean 25OHD and CRP for each time point category given with error bars representing SD. 25OHD, 25-hydroxyvitamin D; CRP, C-reactive protein.

Figure 2

Flow chart of study participants. Patients were sampled from the Scottish colorectal cancer study from 2000 to 2006 (cohort 1) and from 2009 to 2017 (cohort 2, recruited up to 23 February 2017). *Tx and/or Nx and/or Mx indicates pathology report and AJCC stage not available, AJCC stage 4 indicates stage at time of surgery. Cohort 2 recruited and assayed up to 23 February2017. 25OHD, 25-hydroxyvitamin D; AJCC, American Joint Committee on Cancer; CRC, C-reactive protein; LCMS, liquid chromatography–mass spectrometry.

Figure 3

Difference in May-adjusted 25OHD levels by sample time point in cohorts. Mean May-adjusted 25OHD level at 0–12 months’ time point used as reference. 25OHD values scaled against reference mean and mean difference for each time point category given with error bars representing SEM. Cohort 1 (n=2006), cohort 2 (n=2100). 25OHD, 25-hydroxyvitamin D; CRC, C-reactive protein.

Figure 4

Meta-analysis of HR of 25OHD tertile 3 versus tertile 1 with colorectal cancer (CRC)-specific and all-cause mortality. Adjusted HRs used for meta-analysis, adjusted for age, sex, American Joint Committee on Cancer (AJCC) stage, body mass index, tumour site (colon/rectum) and time between definitive treatment and sampling. 25OHD, 25-hydroxyvitamin D; CRP, C-reactive protein.

Figure 5

Meta-analysis of HR of 25OHD tertile 3 versus tertile 1 for colorectal cancer (CRC) mortality stratified by rs11568820 genotype. Adjusted HRs used for meta-analysis, adjusted for age, sex, American Joint Committee on Cancer (AJCC) stage, body mass index, tumour site (colon/rectum) and time between definitive treatment and sampling. 25OHD, 25-hydroxyvitamin D; CRP, C-reactive protein.