Effect of High-Dose vs Standard-Dose Vitamin D<sub>3</sub> Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer
Authors: Kimmie Ng, Halla S. Nimeiri, Nadine J. McCleary, Thomas A. Abrams, Matthew B. Yurgelun, James M. Cleary, Douglas A. Rubinson, Deborah Schrag, Rebecca Miksad, Andrea J. Bullock, Jill Allen, Dan Zuckerman, Emily Chan, Jennifer A. Chan, Brian M. Wolpin, Michael Constantine, Douglas J. Weckstein, Meredith A. Faggen, Christian A. Thomas, Chryssanthi Kournioti, Chen Yuan, Christine Ganser, Brittney Wilkinson, Christopher Mackintosh, Hui Zheng, Bruce W. Hollis, Jeffrey A. Meyerhardt, Charles S. Fuchs
Journal: JAMA (2019)

<h3>Importance</h3> In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). <h3>Objective</h3> To determine if high-dose vitamin D<sub>3</sub>added to standard chemotherapy improves outcomes in patients with metastatic CRC. <h3>Design, Setting, and Participants</h3> 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). <h3>Interventions</h3> mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D<sub>3</sub>(n = 69) or standard-dose vitamin D<sub>3</sub>(n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D<sub>3</sub>(median follow-up, 22.9 months), the median PFS for high-dose vitamin D<sub>3</sub>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 D<sub>3</sub>(log-rank<i>P</i> = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90;<i>P</i> = .02). There were no significant differences between high-dose and standard-dose vitamin D<sub>3</sub>for tumor ORR (58% vs 63%, respectively; difference, −5% [95% CI, −20% to 100%],<i>P</i> = .27) or OS (median, 24.3 months vs 24.3 months; log-rank<i>P</i> = .43). The median 25(OH)D level at baseline for high-dose vitamin D<sub>3</sub>was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D<sub>3</sub>(difference, −2.6 ng/mL [95% CI, −6.6 to 1.4],<i>P</i> = .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],<i>P</i> &lt; .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],<i>P</i> &lt; .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],<i>P</i> &lt; .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D<sub>3</sub>were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). <h3>Conclusions and Relevance</h3> Among patients with metastatic CRC, addition of high-dose vitamin D<sub>3</sub>, vs standard-dose vitamin D<sub>3</sub>, 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01516216