Results of a small clinical trial suggest that supplementing chemotherapy with high doses of vitamin D may benefit patients with metastatic colorectal cancer by delaying progression of the disease. These findings were published by Ng et al in JAMA. Initial trial findings were reported at the 2017 ASCO Annual Meeting (Abstract 3506).
Prompted by the “very encouraging” results of the SUNSHINE trial, the potential benefits of vitamin D supplementation in metastatic colorectal cancer will be evaluated in a larger clinical trial planned to open at several hundred sites across the United States later this year, said corresponding author of the SUNSHINE study Kimmie Ng, MD, MPH, Director of Clinical Research in Dana-Farber's Gastrointestinal Cancer Center.
“The results of our trial suggest an improved outcome for patients who received vitamin D supplementation, and we look forward to launching a larger trial to confirm these exciting and provocative findings,” said Charles Fuchs, MD, MPH, formerly of Dana-Farber as senior author of the study and now Director of Yale Cancer Center.
Vitamin D, which is necessary for bone health, is made in the body through a chemical reaction dependent on sun exposure and is contained in some foods. In laboratory studies, vitamin D has demonstrated anticancer properties such as triggering programmed cell death, inhibiting cancer cell growth, and reducing metastatic potential. Prospective observational studies have linked higher blood levels of vitamin D with a lower risk of colorectal cancer and improved survival of patients with the disease, but those studies could not prove that vitamin D was the cause.
The randomized, prospective phase II SUNSHINE trial recruited 139 patients at 11 academic and community centers across the United States to test whether vitamin D supplementation can improve outcomes in patients with previously untreated metastatic colorectal cancer. All patients received standard chemotherapy (mFOLFOX6 plus bevacizumab).
Patients were randomly assigned to one of two treatment groups. Patients in the high-dose vitamin D group initially took 8,000 international units (IU) a day for 14 days, then 4,000 IU a day thereafter. The low or standard-dose vitamin D group took 400 IU daily during all cycles. All patients were asked not to take any other vitamin D or calcium supplements during the trial period.
In the high-dose group, median progression-free survival was 13 vs 11 months in the standard-dose group. In addition, patients in the high-dose vitamin D group were 36% less likely to have disease progression or death during the follow-up period of 22.9 months. There were no significant differences between the high-dose and standard-dose group in terms of tumor overall response rate or overall survival.
The researchers also sampled patients’ blood to measure changes in the levels of 25-hydroxyvitamin D [25(OH)D], which is a standard test to determine a person’s vitamin D status. This test showed that only 9% of the patients in the clinical trial had sufficient vitamin D at the beginning of treatment. Over the course of the study, patients receiving low-dose had no substantial change in their vitamin D levels, while those in the high-dose group soon reached the vitamin D-sufficient range and maintained it.
Analysis of the results showed that the benefit of high-dose vitamin D appeared to be less in patients who were obese, and those whose tumors contained a mutated KRAS gene, suggesting “that certain subsets of patients may need even higher doses of vitamin D for antitumor activity,” the researchers said. They cautioned, however, that high doses of vitamin D shouldn’t be taken except within the context of a clinical trial.
The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D were neutropenia (35% vs 31%, respectively) and hypertension (13% vs 16%).
The study and its findings are “extremely important,” Dr. Ng said, because “it identifies a cost-effective, safe, and easily accessible agent as a potential new treatment for metastatic colorectal cancer. This could therefore potentially have a large and wide-reaching impact globally, regardless of a patient’s socioeconomic status or a country’s resources.”
Disclosure: The research was supported by National Cancer Institute grants P50CA127003, R01CA205406, and R01CA118553; a Gloria Spivak Faculty Advancement Award; a Friends of Dana-Farber Cancer Institute Award; the Project P Fund; Consano, Pharmavite LLC, and Genentech. For full disclosures of the study authors, visit jamanetwork.com.
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