Effect of High-Dose vs Standard-Dose Vitamin D₃ Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer

Abstract

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 D 3 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 D 3 (n = 69) or standard-dose vitamin D 3 (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 D 3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D 3 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 3 (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 D 3 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 D 3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D 3 (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 D 3 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 D 3 , vs standard-dose vitamin D 3 , 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.

Serum Bioavailable, Rather Than Total, 25‐hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival

“…(9) In addition, two recent RCTs suggest that patients with digestive tract cancers, especially colorectal cancer, may benefit from vitamin D supplementation. (47,48) Our findings indicate that the assessment of vitamin D status using bioavailable instead of total 25OHD levels would aid in the identification of individuals who are most likely to benefit from vitamin D supplementation.…”

Vitamin D deficiency 2.0: an update on the current status worldwide

“…Several very large randomized controlled trials have been or are being performed in recent years. They are summarized in Table 2 [53][54][55][56][57][58][59][60][61][62][63].…”

Vitamin D receptor protects against dysbiosis and tumorigenesis via the JAK/STAT pathway in intestine

“…Current research has implicated vitamin D deficiency as a critical factor in the pathology and clinical outcome of colon rectal cancer (CRC) [1, 2]. Low plasma vitamin D is associated with adverse CRC survival after surgical resection [3, 4]. Vitamin D receptor (VDR) is a nuclear receptor that mediates functions of 1,25-dihydroxyvitamin D (1,25(OH) 2 D 3 ), the biological active form of vitamin D [5].…”