AIMS Colorectal cancer (CRC) accounts for almost 1 million deaths per year. Vitamin D supplementation improves CRC survival outcomes in randomised trials, yet it remains unclear whether early peri-operative supplementation is appropriate. The aim of this study was to test the feasibility, safety and efficacy of vitamin D in the perioperative period in patients undergoing CRC surgery. METHODS Patients in the treatment group were given 3200IU oral cholecalciferol per day perioperatively. Serial serum 25OHD was measured by liquid chromatography tandem mass spectrometry and compared to untreated CRC controls. CRP was measured a marker of the systemic inflammatory response. 25OHD/CRP levels were compared using generalized linear mixed-effects models adjusted for age, gender, BMI and AJCC tumour stage. RESULTS A total of 122 patients underwent serial perioperative sampling at up to 6 time-points, including 41 patients given high-dose perioperative vitamin D supplementation. No serious adverse events occurred and supplementation was well tolerated. Preoperative supplementation induced a 2.1 fold-increase in 25OHD (48.2nmol/; P=0.01). 25OHD was higher in patients given high-dose supplementation compared to controls at all peri-operative timepoints (P<0.001). 25OHD dropped following surgery in all groups, yet high-dose supplementation attenuated this drop (46% vs 24% drop). Crucially, rates of postoperative vitamin D insufficiency were significantly less in those on supplementation (14% vs. 56%, P=0.003), with multivariate modelling indicating a ~60nmol/l higher 25OHD compared to control patients (P=1.22E-15). Supplementation was associated with lower peri-operative CRP (P=0.035). CONCLUSIONS A short course of high dose pre-operative vitamin D supplementation is associated with higher perioperative 25OHD levels, lower rates of postoperative vitamin D insufficiency and reduced early postoperative CRP. Supplementation is safe and well tolerated in the perioperative period. Our findings provide compelling rationale for early initiation of vitamin D supplementation after a diagnosis of CRC INTRODUCTION

The authors have declared no competing interest.

NCT05506696

Grant Support This work was supported by funding for the infrastructure and staffing of the Edinburgh CRUK Cancer Research Centre; CRUK programme grant C348/A18927 (MGD). The study received a grant from Bowel Disease Research Foundation (now Bowel Research UK). PVS was supported by a MRC Clinical Research Training Fellowship (MR/M004007/1). LYO is supported by a Cancer Research UK Research Training Fellowship (C10195/A12996). This work was also funded by a grant to MGD as Project Leader with the MRC Human Genetics Unit Centre Grant (U127527202 and U127527198 from 1/4/18). JB is supported by an Edinburgh Clinical Academic Track (ECAT) linked Cancer Research UK Clinical Research Fellowship (C157/A23218). Role of the Funding Source: The funders had no role in design, undertaking, analysis or writing of the above study.

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South East Scotland Research Ethics Committee 01, Study title: REC reference: IRAS project ID: The investigation of gene-environment interactions between vitamin D and colorectal cancer susceptibility genetic variants in large bowel epithelium. 13/SS/0248 135680 APPROVED

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