High-dose vitamin D supplementation has shown some benefit in patients with metastatic colorectal cancer in the first randomized clinical trial (known as SUNSHINE), but another trial in patients with gastrointestinal cancers (known as AMATERASU) found no significant effect. The American study (SUNSHINE) and the Japanese study (AMATERASU) were both published online April 9 in JAMA. These are preliminary findings, cautions Elizabeth L. Barry, PhD, Department of Epidemiology at Dartmouth College's Geisel School of Medicine in Lebanon, New Hampshire, and colleagues, in an accompanying editorial. "Confirmatory trials are needed," the editorialists write, "ideally with longer follow-up to obtain better estimates of effects on survival, as well as biological measurements to clarify underlying mechanisms." SUNSHINE Trial in Metastatic CRC The SUNSHINE phase 2 trial, led by Kimmie Ng, MD, Dana-Farber Cancer Institute in Boston, Massachusetts, was conducted in 139 patients with metastatic colorectal cancer receiving standard chemotherapy. Half of the patients were randomly assigned to additionally receive a standard dose of vitamin D (400 International Units [IU] per day) and the other half to receive a very high dose of vitamin D (8000 IU/day for 2 weeks and 4000 IU/day thereafter). "This is the first completed randomized trial of vitamin D for treatment of metastatic colon cancer," Ng told Medscape Medical News. Researchers found that patients who got high-dose vitamin D were 36% less likely to die or have disease progression during 22.9 months of follow-up. The hazard ratio [HR] for progression-free survival [PFS] or death was 0.64 (1-sided 95% confidence interval [CI], 0 to 0.90; P = .02). Patients in that group also had a median delay of 13 months until disease worsened compared with the 11-month median delay. There were too few patients to determine whether those in the high vitamin D group had improved overall survival, the researchers comment. A phase 3 trial will help answer such questions, Ng said. That trial will begin later this year and will include 400 patients enrolled from hundreds of sites across the United States. "If that study is also positive, we think vitamin D should be part of standard treatment of patients with metastatic colon cancer," she said. The effect of vitamin D was not as pronounced in people who were obese and in people who had KRAS-mutated tumors; the reasons for that may become clearer with the larger phase 3 study, she added. Additionally, analysis of blood levels found that almost all patients in the trial were vitamin D deficient at the time they enrolled and before they started chemotherapy, Ng said. "That’s obviously a concern if we think that adequate levels of vitamin D may be important in helping the cancer," she said. The team also found that the low dose of vitamin D did not raise blood levels at all. "The average level remained deficient at around 18 ng/mL throughout the trial for those taking the low dose. In contrast, with those taking the high dose, we very quickly raised their levels into the sufficient range" — above 30 ng/mL —after about 2 months, and patients maintained sufficient levels at that dose, Ng said. "For the first time, we have a clue as to what dose is necessary to raise vitamin D levels into the optimal range," she said. AMATERASU Trial in GI Cancers The randomized, double-blind, placebo-controlled AMATERASU trial was conducted in 417 patients with stage 1 to stage 3 luminal gastrointestinal cancer (48% colorectal, 42% gastric, and 10% esophageal) who had undergone complete tumor resection. The trial was conducted at a single-university hospital in Japan, led by Mitsuyoshi Urashima, MD, with the Division of Molecular Epidemiology at Jikei University School of Medicine in Tokyo. Participants were randomly assigned either to receive placebo or oral vitamin D supplements of 2000 IU/day from their first postoperative visit through the end of the trial. The 5-year, relapse-free survival rate for those on vitamin D was 77% vs 69% with placebo, a difference that was not statistically significant (HR for relapse or death, 0.76; 95% CI, 0.50 - 1.14; P = .18). However, in the editorial, Barry and colleagues note that this study had an "imbalance in age" for the treatment group. A post hoc, age-adjusted analysis showed that the vitamin D added a statistically significant benefit in relapse-free survival (HR, 0.66; 95% CI, 0.43 - 0.99). There was no sign that vitamin D improved overall survival (HR, 0.95; 95% CI, 0.57 - 1.57). Barry and colleagues note that although the studies were underpowered to analyze adverse events, neither trial showed side effects of the vitamin D doses. Ng said that the lack of side effects adds to the importance of the SUNSHINE results. "Taking something that is readily available and inexpensive — it’s very safe — and to show that something with all those favorable attributes may be beneficial for treating patients, is a very important finding," she said. The SUNSHINE study received support from the National Institutes of Health, the National Cancer Institute, the Gloria Spivak Faculty Advancement Award, Friends of Dana-Farber Cancer Institute Award, the Project P Fund, Consano, Pharmavite LLC and Genentech. Pharmavite provided the vitamin D3and placebo capsules. Ng reports grants or nonfinancial support from the National Cancer Institute, Pharmavite, Genentech, and Consano during the conduct of the study; grants, nonfinancial support or personal fees from Pharmavite, Genentech, Lilly, Gilead Sciences, Tarrex Biopharma, Bayer, Seattle Genetics, Celgen, and Trovagene outside the submitted work. The AMATERASU trial received support from the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities; and funding from the International University of Health and Welfare Hospital, and Jikei University School of Medicine. The study authors have disclosed no relevant financial relationships. The editorialists have disclosed no relevant financial relationships. JAMA. Published online April 9, 2019. SUNSHINE abstract, AMATERASU abstract, Editorial Source
