CHICAGO – High-dose vitamin D supplementation is a simple, safe approach for improving on the efficacy of first-line chemotherapy for metastatic colorectal cancer, suggest findings of the SUNSHINE trial reported at the annual meeting of the American Society of Clinical Oncology.
“Vitamin D has shown anti-neoplastic properties in the laboratory, including inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, as well as anti-inflammatory and immunomodulatory effects,” said lead author Kimmie Ng, MD, director of clinical research and a Gastrointestinal Cancer Center physician at the Dana-Farber Cancer Institute in Boston.
“The vitamin D hypothesis is also supported by a large body of epidemiologic evidence, both from our group as well as from others, that have shown that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in patients with colorectal cancer,” she added.
Notably, in the CALGB/SWOG 80405 trial of first-line therapy for colorectal cancer, patients’ median 25-hydroxy vitamin D level at baseline fell below the cutoff for deficiency (ASCO 2015 meeting, Abstract 3503). Moreover, those having higher levels ultimately had better overall survival even after other factors were taken into account.
In the SUNSHINE trial, the investigators studied 139 patients with untreated metastatic colorectal cancer. Results showed that those given FOLFOX chemotherapy and the antiangiogenic agent bevacizumab (Avastin) plus high-dose vitamin D had a one-third lower risk of progression or death compared with counterparts given the same regimen plus low-dose vitamin D.
High-dose supplementation was not associated with greater toxicity. In fact, patients in that group had a much lower incidence of grade 3 or 4 diarrhea.
“After a decade of observational data linking higher vitamin D status with improved outcomes in colorectal cancer patients, SUNSHINE is the first completed randomized double-blind controlled clinical trial of vitamin D supplementation for treatment of colorectal cancer,” Dr. Ng said. “The trial met its primary endpoint. Given this data, a larger, confirmatory phase III trial is warranted.”
The investigators are performing subgroup analyses and analyzing overall survival, and will measure patients’ 25-hydroxyvitamin D levels in plasma samples collected serially throughout the study to determine whether they correlate with outcomes.
In addition, “to help understand and elucidate underlying mechanisms and biology, we have planned several correlative studies looking at tumoral and plasma biomarkers related to the vitamin D pathway, inflammation, and tumor immunity, among other pathways,” she further noted. “We will also be conducting next-generation sequencing and gene expression analyses.”
Expert perspective
“It will be interesting to know [patients’ vitamin D levels] as the majority of patients were enrolled in New England, where I think there is a little less sunshine than in other parts of the United States, so perhaps the vitamin D levels will reflect that,” said invited discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York.
Data on vitamin D pertaining to chemoprevention and to outcomes in other malignancies have been mixed, she cautioned. For example, supplementation did not reduce the risk of recurrent colorectal adenomas in one study (N Engl J Med. 2015;373:1519-30), and benefit or harm in terms of developing advanced colorectal adenomas in another study hinged on vitamin D receptor genotype (JAMA Oncol. 2017;3:628-35). Among patients with prostate cancer, addition of vitamin D to chemotherapy was actually associated with poorer overall survival (J Clin Oncol. 2011;29:2191-8).
“SUNSHINE was a positive study. It was a very well carried out phase II trial with a significant progression-free survival benefit. Correlative analyses are ongoing, and these will be critical, looking at biomarkers, perhaps helping us identify those patients who will benefit,” Dr. Cercek summarized. “I agree 100% with the investigators that a phase III study is warranted, and I look forward to it.”
Study details
Patients in SUNSHINE were randomized to receive first-line modified FOLFOX chemotherapy and bevacizumab plus either high-dose vitamin D (oral vitamin D3 8,000 IU/day for 2 weeks as a loading dose, followed by 4,000 IU/day) or low-dose vitamin D (oral vitamin D3 400 IU/day) on a double-blind basis. The latter “is an amount you would find in a multivitamin and only increases plasma levels by about 3 ng/mL, thus serving as a useful active control” Dr. Ng noted.
Receipt of chemotherapy and bevacizumab was generally similar between groups. “It is interesting to note that more patients receiving high-dose vitamin D discontinued treatment to undergo potentially curative surgery compared to those in the control arm, though this was not statistically different,” she noted.
In intent-to-treat analysis conducted at a median follow-up of 17-18 months, progression-free survival, the trial’s primary endpoint, was a median of 13.1 months in the high-dose group and 11.2 months in the low-dose group (P = .04). The difference in favor of high-dose vitamin D remained significant in multivariate analysis (hazard ratio, 0.67; P = .02).
The groups were statistically indistinguishable with respect to overall response rate, but the disease control rate was marginally better with high-dose versus low-dose vitamin D (96% vs. 84%, P = .05).
Rates of most grade 3 or 4 adverse events did not differ significantly between groups. However, diarrhea of these grades was less common in the high-dose vitamin D group (1% vs. 12%; P = .02). With respect to grade 3 or 4 events possibly related to the vitamin therapy, there was one case of hyperphosphatemia in the high-dose group and one case of kidney stones in the low-dose group.
Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.