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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.
JAMA. 2019 04 09; 321(14):1370-1379.JAMA

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.

Authors+Show Affiliations

Dana-Farber Cancer Institute, Boston, Massachusetts.Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Beth Israel Deaconess Medical Center, Boston, Massachusetts.Beth Israel Deaconess Medical Center, Boston, Massachusetts.Massachusetts General Hospital, Boston.St Luke's Mountain States Tumor Institute, Boise, Idaho.Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber at Milford Regional Medical Center, Milford, Massachusetts.New Hampshire Oncology Hematology, Hookset.Dana-Farber at South Shore Hospital, South Weymouth, Massachusetts.New England Cancer Specialists, Scarborough, Maine.Newton-Wellesley Hospital, Newton, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.Massachusetts General Hospital, Boston.Medical University of South Carolina, Charleston.Dana-Farber Cancer Institute, Boston, Massachusetts.Yale Cancer Center, New Haven, Connecticut.

Pub Type(s)

Clinical Trial, Phase II
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30964527

Citation

Ng, Kimmie, et al. "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." JAMA, vol. 321, no. 14, 2019, pp. 1370-1379.
Ng K, Nimeiri HS, McCleary NJ, et al. 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. JAMA. 2019;321(14):1370-1379.
Ng, K., Nimeiri, H. S., McCleary, N. J., Abrams, T. A., Yurgelun, M. B., Cleary, J. M., Rubinson, D. A., Schrag, D., Miksad, R., Bullock, A. J., Allen, J., Zuckerman, D., Chan, E., Chan, J. A., Wolpin, B. M., Constantine, M., Weckstein, D. J., Faggen, M. A., Thomas, C. A., ... Fuchs, C. S. (2019). 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. JAMA, 321(14), 1370-1379. https://doi.org/10.1001/jama.2019.2402
Ng K, et al. 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. JAMA. 2019 04 9;321(14):1370-1379. PubMed PMID: 30964527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Ng,Kimmie, AU - Nimeiri,Halla S, AU - McCleary,Nadine J, AU - Abrams,Thomas A, AU - Yurgelun,Matthew B, AU - Cleary,James M, AU - Rubinson,Douglas A, AU - Schrag,Deborah, AU - Miksad,Rebecca, AU - Bullock,Andrea J, AU - Allen,Jill, AU - Zuckerman,Dan, AU - Chan,Emily, AU - Chan,Jennifer A, AU - Wolpin,Brian M, AU - Constantine,Michael, AU - Weckstein,Douglas J, AU - Faggen,Meredith A, AU - Thomas,Christian A, AU - Kournioti,Chryssanthi, AU - Yuan,Chen, AU - Ganser,Christine, AU - Wilkinson,Brittney, AU - Mackintosh,Christopher, AU - Zheng,Hui, AU - Hollis,Bruce W, AU - Meyerhardt,Jeffrey A, AU - Fuchs,Charles S, PY - 2019/4/10/entrez PY - 2019/4/10/pubmed PY - 2019/4/23/medline SP - 1370 EP - 1379 JF - JAMA JO - JAMA VL - 321 IS - 14 N2 - 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/30964527/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_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2019.2402 DB - PRIME DP - Unbound Medicine ER -