Adding high-dose vitamin D3 to standard chemotherapy plus bevacizumab did not improve progression-free survival (PFS) in patients with previously untreated metastatic colorectal cancer (mCRC), according to results from the phase III SOLARIS trial led by Kimmie Ng, MD, MPH, and colleagues and published in JAMA. Median PFS was 11.8 months with high-dose vitamin D3 vs 10.3 months with standard-dose vitamin D3.
The trial was designed to confirm earlier findings from the phase II SUNSHINE study, in which high-dose vitamin D3 added to standard treatment was associated with longer PFS. Preclinical and observational studies have also suggested a potential antitumor role for vitamin D in colorectal cancer.
Study Details
SOLARIS was a double-blind, multicenter, phase III randomized clinical trial conducted at 151 academic and community cancer centers across the United States. The study enrolled 455 adults with histologically confirmed unresectable locally advanced or metastatic colorectal adenocarcinoma who had not previously received systemic therapy for advanced or metastatic disease. Patients were required to have measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Participants were randomly assigned 1:1 to receive either high-dose or standard-dose vitamin D3 in addition to investigator-selected mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks. The high-dose group received 8,000 IU of vitamin D3 daily during the first treatment cycle followed by 4,000 IU daily, whereas the standard-dose group received 400 IU daily. Treatment continued until disease progression, intolerable toxicity, or discontinuation. The primary endpoint was PFS. Secondary endpoints included objective response rate, overall survival, changes in plasma vitamin D levels, and safety.
Of the 455 randomized patients, 228 were assigned to high-dose vitamin D3 and 227 to standard-dose vitamin D3. Median age was 59 years, and 40% of patients were women. Most patients received mFOLFOX6 as the chemotherapy backbone, and vitamin D3 adherence was high in both groups.
Key Findings
After a median follow-up of 20 months, the difference in median PFS was not statistically significant: 11.8 months with high-dose vitamin D3 vs 10.3 months with standard-dose vitamin D3 (HR = 0.92; P = .25).
There was also no significant difference in objective response rate: 51% with high-dose vitamin D3 vs 44% with standard-dose vitamin D3. Median overall survival was 25.6 months vs 27.0 months, respectively.
High-dose vitamin D3 increased plasma vitamin D levels into the sufficient range. At the time of first restaging, median plasma 25-hydroxyvitamin D levels were 38.3 ng/mL in the high-dose group compared with 23.5 ng/mL in the standard-dose group, and the difference between groups persisted through treatment discontinuation.
Toxicity was broadly similar between groups. The most common grade 3 or higher adverse events included neutropenia, hypertension, leukopenia, peripheral sensory neuropathy, and diarrhea, with no clinically meaningful overall differences between the high- and standard-dose groups. Vitamin D–associated toxicities, including hypercalcemia, hyperphosphatemia, and renal calculi, were uncommon.
A prespecified subgroup analysis suggested a possible PFS benefit among patients with left-sided primary tumors. Median PFS in that subgroup was 13.8 months with high-dose vitamin D3 vs 10.2 months with standard-dose vitamin D3, with a significant treatment-by-tumor-location interaction. The investigators emphasized, however, that this finding was exploratory and requires further study.
The authors noted several possible reasons why the phase III results differed from those of SUNSHINE. Patients in SOLARIS had higher baseline vitamin D levels, and vitamin D levels also increased in the standard-dose group during treatment, potentially narrowing the difference between groups.
“On the basis of these findings, the addition of high-dose vitamin D3 to standard chemotherapy cannot be recommended for unselected patients with previously untreated mCRC,” they concluded.
Dr. Ng, of Dana-Farber Cancer Institute, Boston, is the corresponding author of the article.
DISCLOSURE: The trial was funded in whole or in part by the National Cancer Institute of the National Institutes of Health. Pharmavite LLC provided the vitamin D3 and placebo capsules. Dr. Ng and several coauthors reported relationships with pharmaceutical and health-care companies. For full disclosures of the study authors, visit jama.com.
