A feasibility study of perioperative vitamin D supplementation in patients undergoing colorectal cancer resection

**Background:** Observational studies have linked low vitamin D with poor outcomes in colorectal cancer (CRC), and a meta-analysis of trial data demonstrated a 30% reduction in adverse CRC outcomes with vitamin D supplementation. However, no study had assessed perioperative vitamin D supplementation in patients undergoing CRC resection. Abdominal surgery causes a dramatic drop in 25-hydroxyvitamin D (25OHD), and the optimal timing for initiating supplementation was unknown. This study aimed to test the feasibility, safety, and efficacy of high-dose perioperative vitamin D supplementation in CRC surgery patients.

**Methods:** Patients undergoing curative CRC resection were given 3200 IU/day oral cholecalciferol (vitamin D3) perioperatively (Fultium-D3). Supplementation began at the pre-operative surgical clinic visit and continued until hospital discharge (maximum 12 weeks). A total of 122 patients underwent serial perioperative sampling: 41 in the supplementation group and 81 in a combined control group (contemporaneous and historical). Serial serum 25OHD was measured by liquid chromatography tandem mass spectrometry, and CRP was measured using an Abbott Architect C series analyzer. Statistical analysis used multivariable linear mixed-effects models adjusting for gender, age, BMI, cancer site, operative approach, and AJCC stage. The study was powered to detect a 50% suppression of the day 1-2 post-operative drop in 25OHD (α=0.05 one-tailed, β=0.10, n=54 per arm), though recruitment was impacted by the COVID-19 pandemic.

**Key Results:** Supplementation was well-tolerated with no adverse or serious adverse events related to supplementation. No episodes of hypercalcemia or renal impairment were reported. Pre-operative supplementation increased 25OHD levels on the day of surgery (103.9 vs. 42.5 nmol/l, P=8.2E-12). Supplementation increased 25OHD at all post-operative timepoints (P<0.001) and attenuated the post-operative drop in 25OHD (46% vs. 24% drop at days 1-2, P=3.0E-4). The rate of vitamin D insufficiency (25OHD<50 nmol/l) was significantly lower in supplemented patients (e.g., day 3-5: 14% vs. 84%, P=1.41E-08). Multivariate modeling across all timepoints indicated approximately 59 nmol/l higher 25OHD in supplemented patients compared to controls (P=3.7E-21). Post-operative CRP was lower in supplemented patients (e.g., day 3-5: 80.5 vs. 129 mg/l, P=0.04), though on multivariate mixed-effects modeling the overall impact on perioperative CRP was non-significant (P=0.07), with post-operative CRP approximately 15 mg/l lower in supplemented patients.

**Clinical Implications:** This study provides the first evidence that high-dose perioperative vitamin D supplementation is feasible, safe, and effective in CRC surgery patients. Supplementation significantly improved perioperative vitamin D status, reduced post-operative vitamin D insufficiency, and was associated with lower early post-operative CRP levels, supporting a role for vitamin D in regulating inflammatory processes. Combined with prior evidence of a 30% reduction in adverse CRC outcomes with supplementation, these findings provide strong rationale for initiating vitamin D supplementation at the time of CRC diagnosis rather than after surgery. The authors acknowledge limitations including the non-randomized design, potential historical confounding (supplemented patients recruited in 2020 vs. controls from 2012), and lack of direct survival endpoint data. Future randomized trials should consider supplementation from the point of diagnosis with survival as a primary endpoint.