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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Ng reported receiving grants from the National Cancer Institute, Genentech, Consano, Gilead Sciences, Tarrex Biopharma, Trovagene, Celgene, and Pharmavite; and receiving personal fees from Genentech, Lilly, Tarrex Biopharma, Bayer, and Seattle Genetics. Dr Nimeiri reported being employed at AbbVie. Dr Abrams reported receiving grants from Eli Lilly and Bristol-Myers Squibb; and receiving personal fees from Bristol-Myers Squibb and Genentech. Dr Yurgelun reported receiving grants from Myriad Genetic Laboratories Inc. Dr Cleary reported receiving grants from Merck and Tesaro; receiving personal fees from Bristol-Myers Squibb; and receiving nonfinancial support from Agios, Roche, and Bristol-Myers Squibb. Dr Schrag reported receiving personal fees from JAMA; receiving grants from Pfizer, the Alliance for Clinical Trials in Oncology, the American Association for Cancer Research, the National Cancer Institute, the Patient-Centered Outcomes Research Institute, and the American Cancer Society; and receiving nonfinancial support from Epic Systems Corporation. Dr Miksad reported being employed at Flatiron Health and working with the De Luca Foundation. Dr Bullock reported receiving personal fees from Taiho Oncology, Bayer, Eisai, Exelixis, and Celgene. Dr E. Chan reported being employed at Amgen; and receiving funding from Dana-Farber Cancer Institute. Dr J. Chan reported receiving personal fees from Novartis, Ipsen, Lexicon, AAA, and Exelixis; and receiving support from Novartis, Merck, Sanofi, and Lilly. Dr Wolpin reported receiving grants from Celgene; and receiving personal fees from BioLineRx and Grail. Dr Thomas reported receiving personal fees from Genetech/Roche, Bristol-Myers Squibb, and Aztra Zeneca. Dr Zheng reported receiving grants from the National Institutes of Health. Dr Meyerhardt reported receiving personal fees from Array Pharmaceutical, Ignyta, and Cota. Dr Fuchs reported receiving personal fees from Eli Lilly, Entrinsic Health, Pfizer, Merck, Sanofi, Roche, Genentech, Merrimack Pharma, Dicerna, Bayer, Celgene, Agios, Gilead Sciences, Five Prime Therapeutics, Taiho, KEW, and CytomX Therapeutics; and receiving support from CytomX Therapeutics. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients Through the Phase 2 Randomized Trial of High-Dose vs Standard-Dose Vitamin D3 Supplementation

Figure 2.. Kaplan-Meier Estimates of Progression-Free Survival by Vitamin D3 Treatment Group (N = 139)

Patients in the high-dose vitamin D3 group had a median follow-up of 21.0 months (interquartile range, 11.2-34.4 months) compared with 24.3 months (interquartile range, 14.5-34.5 months) for patients in the standard-dose vitamin D3 group. The hazard ratio was adjusted for age, sex, race/ethnicity, body mass index, Eastern Cooperative Oncology Group performance status, and number of metastatic sites.