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 D₃added 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 D₃was 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-rankP = .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 D₃for 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-rankP = .43). The median 25(OH)D level at baseline for high-dose vitamin D₃was 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 D₃were 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

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