The healthcare community has increasingly recognized the important role of vitamin D in numerous medical conditions, from preventing rickets in the young to inhibiting dementia in the elderly.1,2 Recently, 2 trials investigated its effect on cancer. The SUNSHINE Randomized Clinical Trial compared the effect of high-dose vs standard-dose vitamin D3 supplementation on progression-free survival (PFS) among patients with advanced or metastatic colorectal cancer3; the AMATERASU Randomized Clinical Trial investigated the effect of vitamin D supplementation on relapse-free survival (RFS) among patients with digestive tract cancers.4
Is High-Dose Better?
A number of studies have demonstrated the beneficial effects of plasma 25-hydroxyvitamin D (25[OH]D), which is the most reliable indicator of vitamin D status, for patients with cancer. For example, high levels of vitamin D were associated with a decreased risk of developing colorectal cancer, and a better chance of survival among patients who already had the disease.3 The SUNSHINE Randomized Clinical Trial, a double-blind, multicenter, phase 2 randomized clinical trial conducted in several cancer centers throughout the United States, sought to further explore these effects. The trial was designed specifically to evaluate the efficacy of high-dose vitamin D3 compared with standard-dose vitamin D3 when given in combination with conventional chemotherapy. The researchers sought to find out whether raising plasma 25(OH)D levels in patients with metastatic colorectal cancer who were receiving chemotherapy was feasible.
Chemotherapy A total of 139 patients were enrolled in the trial. All patients were treated with oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-fluorouracil (5-FU) 400 mg/m2 bolus then 2400 mg/m2 IV continuous infusion over 46 to 48 hours (mFOLFOX6) plus bevacizumab 5 mg/kg IV every 14-day cycle. At the investigator’s discretion, bevacizumab could be omitted during the first cycle and started with the second.3
Vitamin D Patients were randomized to receive high-dose vitamin D3 (69 patients) or standard-dose vitamin D3 (70 patients). The high-dose group received a loading dose of 8000 IU/day for cycle 1, followed by 4000 IU/day for subsequent cycles. The standard-dose group received 400 IU/day of vitamin D3 during all cycles.3 Median plasma 25(OH)D levels were deficient in both groups at baseline. In fact, only 9% of all participants had sufficient levels (30 ng/mL or higher) at baseline. At the trial’s end, only the patients in the high-dose vitamin D group had sufficient levels of vitamin D3 (34.8 ng/mL), whereas vitamin D levels were still deficient, with a median 25(OH)D level of 18.7 ng/mL in the standard-dose group.
Progression-free survival is a surrogate for overall survival in trials of metastatic colorectal cancer.5 In this trial, it was the primary end point, defined as from when patients first received chemotherapy and vitamin D3 until their first occurrence of disease progression or death.
Results Median PFS rates were not statistically different between the 2 groups. However, high-dose vitamin D3 had a greater effect on PFS among those patients who had a lower body mass index, more metastases, and KRAS wild-type tumors. The most common reported adverse events included neutropenia (24 patients [35%] in the high-dose group vs 21 patients [31%] in the standard-dose group), hypertension (9 patients vs 11 patients, respectively), and diarrhea (1 patient vs 8 patients, respectively). Two patients died during the trial; however, the deaths were unrelated to vitamin D3.
Tumor objective response rate and overall survival were not statistically different between the 2 groups, concluded the researchers. However, high-dose vitamin D3 supplementation increased median plasma 25(OH)D levels into the sufficient range, whereas levels remained unchanged with standard-dose vitamin D3 supplements.