Vitamin-D Supplements Could Have Role in Cancer Treatment

By Megan Brooks

NEW YORK (Reuters Health) - Vitamin-D supplementation could have a role in treating some types of cancer, but the findings are not clear-cut, according to two randomized controlled trials online in JAMA today.

The phase 2 SUNSHINE trial found that supplementing standard chemotherapy with high doses of vitamin D may delay disease progression in patients with metastatic colorectal cancer.

"The big takeaway from this study is that vitamin-D supplementation may have a role in the treatment of patients with previously untreated metastatic colorectal cancer. In this era of rising healthcare costs and potentially some very toxic drugs, vitamin D represents a really important, potential advance," first author Dr. Kimmie Ng of Dana-Farber Cancer Institute, in Boston, said in a podcast.

The trial enrolled 139 patients (mean age, 56; 43 women) with advanced or metastatic colorectal cancer at 11 centers in the U.S. All patients received standard chemotherapy (mFOLFOX6 plus bevacizumab) plus either high-dose vitamin D3 (8,000 IU per day for 14 days, then 4,000 IU a day thereafter) or standard-dose vitamin D3 (400 IU daily). Median follow up was 22.9 months.

Patients taking high-dose vitamin D had a statistically nonsignificant two-month increase in median progression-free survival (PFS) compared with their peers taking standard-dose vitamin D (13 months, 49 PFS events versus 11 months, 62 PFS events; log-rank P=0.07).

In adjusted analyses, the odds of disease progression or death during follow up were 36% lower in the high-dose group (hazard ratio, 0.64; P=0.02). There were no significant between-group differences in the secondary endpoints of tumor overall response rate or overall survival.

At baseline, median plasma 25(OH)D levels were deficient in both the high-dose (16.1 ng/mL) and low-dose (18.7 ng/mL) groups. Only 9% of study patients had sufficient levels (30 ng/mL or higher) at baseline.

Over the course of the study, patients taking low-dose vitamin D 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.

In exploratory subgroup analyses, the benefit of high-dose vitamin D appeared to be less in obese patients and those with KRAS-mutated tumors, suggesting "that certain subsets of patients may need even higher doses of vitamin D for anti-tumor activity," the researchers write in their article.

Based on the "very encouraging" results of the SUNSHINE trial, a larger phase 3 trial is planned, Dr. Ng said in a news release.

The other trial, called AMATERASU, enrolled 417 patients (mean age, 66; 66% men) from Japan with stage I to III digestive-tract cancer (48% colorectal, 42% gastric, and 10% esophageal) who underwent curative surgery with complete tumor resection. They were randomly assigned to 2,000 IU/day of vitamin D3 or placebo initiated at the first postoperative visit.

During the mean follow-up of 3.5 years (maximum, 7.6 years), 20% of patients in the vitamin D arm and 26% in the placebo arm had a relapse or died. In unadjusted analyses, vitamin D did not lead to a statistically significant improvement in five-year relapse-free survival (hazard ratio, 0.76; 95% CI, 0.50 to 1.14; P=0.18) or overall survival (82% vs. 81%; HR for death, 0.95; 95% CI, 0.57 to 1.57; P=0.83).

Because patients were older in the vitamin-D group than in the placebo group, hazard ratios were adjusted by age quartile. In this analysis, the cumulative hazard of relapse or death was significantly lower in the vitamin D group compared with the placebo group (adjusted HR, 0.66; P=0.048).

In addition, vitamin D appeared effective in the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL: five-year relapse-free survival was 85% with vitamin D versus 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24 to 0.86; P=0.02).

"However, this finding must be considered exploratory and interpreted with caution in the context of the null findings for the primary outcome measures in the total population, as well as the potential for type I error due to multiple comparisons," Dr. Mitsuyoshi Urashima from Jikei University School of Medicine in Tokyo and colleagues caution in their paper.

"I failed to conclude that vitamin D supplementation is able to reduce relapse or death in patients with cancer for now, but I'm still positive and feel confident that vitamin D is effective in certain subgroups of patients," Dr. Urashima added in an email to Reuters Health. "Right now, we are doing a couple of post hoc analyses using stocked serum samples and pathological samples obtained from participants. Some results are positive and very interesting. We would like to expand data of this trial to individual patient data meta-analysis in collaboration with vitamin D researchers in the world to clarify true effects of vitamin-D supplementation among patients with cancers."

Both trials reported no increased toxicity from vitamin D supplementation, although both were underpowered to detect adverse events, Dr. Elizabeth Barry and co-authors from Geisel School of Medicine at Dartmouth in Lebanon, New Hampshire, note in an accompanying editorial.

"It may be tempting to interpret the preliminary findings regarding recurrence- and progression-free survival as specific antineoplastic effects of vitamin D3 supplementation. However, higher vitamin D levels have been associated with substantially decreased mortality and morbidity among hospitalized patients with a range of nonneoplastic diseases as well as with cancer. Thus, the findings of the 2 trials may reflect relatively broad biological effects of vitamin D," they write.

"Confirmatory trials are needed to evaluate these preliminary findings, ideally with longer follow-up to obtain better estimates of effects on survival as well as biological measurements to clarify underlying mechanisms," they conclude.

The SUNSHINE trial was supported in part by the National Cancer Institute, Consano, Pharmavite LLC, and Genetech. Pharmavite provided the vitamin D3 and placebo capsules for the trial. Dr. Ng received grants and non-financial support from Pharmavite, grants from Genentech, and grants from Consano during the conduct of the study. The AMATERASU trial had no commercial funding and the authors have declared no relevant conflicts of interest.

SOURCES: https://bit.ly/2G5gC4F, https://bit.ly/2G3YlV3 and https://bit.ly/2G0Vc8M

JAMA 2019.

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