Effect of High Dose vs Standard Dose Vitamin D3 Supplementation on Progression Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial
Importance In observational studies, higher plasma 25 hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC) Objective To determine if high dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. Design, Setting, and Participants Double blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018) Interventions mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high dose vitamin D3 (n 69) or standard dose vitamin D3 (n 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures The primary end point was progression free survival (PFS) assessed by the log rank test and a supportive Cox proportional hazards model. Testing was 1 sided. Secondary end points included tumor objective response rate (ORR) overall survival (OS) and change in plasma 25(OH)D level. Results Among 139 patients (mean age, 56 years; 60 [43% women) who completed or discontinued chemotherapy and vitamin D3 (median follow up, 22.9 months) the median PFS for high dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard dose vitamin D3 (log rank P .07) multivariable hazard ratio for PFS or death was 0.64 (1 sided 95% CI, 0 to 0.90; P .02) There were no significant differences between high dose and standard dose vitamin D3 for tumor ORR (58% vs 63% respectively; difference, 5% [95% CI, 20% to 100% P .27) or OS (median, 24.3 months vs 24.3 months; log rank P .43) The median 25(OH)D level at baseline for high dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard dose vitamin D3 (difference, 2.6 ng/mL [95% CI, 6.6 to 1.4] P .30) at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6] P .001) at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5] P .001) and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4] P .001) The most common grade 3 and higher adverse events for chemotherapy plus high dose vs standard dose vitamin D3 were neutropenia (n 24 [35% vs n 21 [31% respectively) and hypertension (n 9 [13% vs n 11 [16% Conclusions and Relevance Among patients with metastatic CRC, addition of high dose vitamin D3, vs standard dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. Trial Registration ClinicalTrials.gov Identifier: NCT01516216
JAMA