Effect of High-Dose vs Standard-Dose #VitaminD3 #Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic #Colorectal #Cancer – The #SUNSHINE #RCT (JAMA, abstract)

[Source: The Journal of the American Medical Association, full page: (LINK). Abstract, edited.]

Original Investigation / April 9, 2019

Effect of High-Dose vs Standard-Dose Vitamin D3Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal CancerThe SUNSHINE Randomized Clinical Trial

Kimmie Ng, MD, MPH1; Halla S. Nimeiri, MD2; Nadine J. McCleary, MD, MPH1; et alThomas A. Abrams, MD1; Matthew B. Yurgelun, MD1; James M. Cleary, MD, PhD1; Douglas A. Rubinson, MD, PhD1; Deborah Schrag, MD, MPH1; Rebecca Miksad, MD3; Andrea J. Bullock, MD, MPH3; Jill Allen, MD4; Dan Zuckerman, MD5; Emily Chan, MD, PhD6; Jennifer A. Chan, MD, MPH1; Brian M. Wolpin, MD, MPH1; Michael Constantine, MD7; Douglas J. Weckstein, MD8; Meredith A. Faggen, MD9; Christian A. Thomas, MD10; Chryssanthi Kournioti, MD11; Chen Yuan, ScD1; Christine Ganser, MSc1; Brittney Wilkinson, BS1; Christopher Mackintosh, MLA1; Hui Zheng, PhD4; Bruce W. Hollis, PhD12; Jeffrey A. Meyerhardt, MD, MPH1; Charles S. Fuchs, MD, MPH13

Author Affiliations: 1 Dana-Farber Cancer Institute, Boston, Massachusetts; 2 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois; 3 Beth Israel Deaconess Medical Center, Boston, Massachusetts; 4 Massachusetts General Hospital, Boston; 5 St Luke’s Mountain States Tumor Institute, Boise, Idaho; 6 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; 7 Dana-Farber at Milford Regional Medical Center, Milford, Massachusetts; 8 New Hampshire Oncology Hematology, Hookset; 9 Dana-Farber at South Shore Hospital, South Weymouth, Massachusetts; 10 New England Cancer Specialists, Scarborough, Maine; 11 Newton-Wellesley Hospital, Newton, Massachusetts; 12 Medical University of South Carolina, Charleston; 13 Yale Cancer Center, New Haven, Connecticut

JAMA. 2019;321(14):1370-1379. doi:10.1001/jama.2019.2402

 

Key Points

  • Question  – Does high-dose vitamin D3 supplementation prolong progression-free survival when added to standard chemotherapy in patients with advanced or metastatic colorectal cancer?
  • Findings  – In this phase 2 randomized clinical trial that included 139 patients with advanced or metastatic colorectal cancer, treatment with chemotherapy plus high-dose vitamin D3 supplementation vs chemotherapy plus standard-dose vitamin D3 resulted in a median progression-free survival of 13 months vs 11 months, respectively, that was not statistically significant, but a multivariable hazard ratio of 0.64 for progression-free survival or death that was statistically significant.
  • Meaning  – These findings regarding a potential role for high-dose vitamin D3 supplementation in the treatment of patients with advanced or metastatic colorectal cancer warrant further evaluation in a larger multicenter 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

Keywords: Cancer; Vitamin D.

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Published by

Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.