Nick Mulcahy

June 07, 2017

CHICAGO – In recent years, observational data have shown that higher plasma levels of vitamin D are associated with improved survival in colorectal cancer patients.

Now, for the first time, a randomized trial has shown that disease progression is slowed with high-dose supplements.

The results, from a phase 2 clinical trial known as SUNSHINE, indicate that a high dose of vitamin D supplementation significantly improved progression-free survival (PFS) by about 2 months compared to a low dose.

The trial was conducted in patients with previously untreated metastatic colorectal cancer. All participants received standard treatment with the mFOLFOX6 chemotherapy regimen (ie, folinic acid [leucovorin], fluorouracil, and oxaliplatin) plus bevacizumab.

This is the first-ever completed randomized trial of the use of vitamin D as a colorectal cancer therapy, said lead author Kimmie Ng, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, who presented the study here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.

"Patients seemed to do better on the high-dose vitamin D. I am really excited by the data," she told Medscape Medical News.

"A phase 3 trial is warranted," she added.

Another expert expressed similar enthusiasm about the trial. "The findings from this study are incredibly exciting," said Song Yao, PhD, a molecular epidemiologist at Roswell Park Cancer Institute in Buffalo, New York, who was asked for comment.

The findings from this study are incredibly exciting. Dr Song Yao

He pointed out that at the 2015 ASCO Gastrointestinal Cancers Symposium, the same team showed that in an observational study, patients with higher levels of vitamin D survived longer than those with lower levels. "This new study provides the much-needed evidence-based randomized trial design," he commented.

Another clinician already assesses vitamin D levels in colorectal cancer patients.

"I check vitamin D levels and replete vitamin D when necessary for my patients, but we need more data to know if this should be practice changing," said Allyson Ocean, MD, a gastrointestinal oncologist at Weill Cornell Medicine and New York–Presbyterian Hospital in New York City.

She also told Medscape Medical News that the results are "quite intriguing" and that a phase 3 trial is needed.

Dr Ng reported that in the high-dose group (n = 69), the median PFS, which was the primary endpoint, was 13.1 months, compared with 11.2 months for the low-dose group (n = 70). That translated into a 31% reduced relative risk for disease progression in the high-dose group (unadjusted hazard ratio, 0.69; P = .04).

Patients in the high-dose group received a loading dose of 8000 IU/day of vitamin D3 orally for 2 weeks followed by 4000 IU/day. Those in the low-dose group received a standard vitamin D3 dose of 400 IU/day.

Median follow-up was 16.9 months in the high-dose group and 17.9 in the low-dose group.

Each group received similar numbers of chemotherapy cycles, and both groups were highly compliant with vitamin D supplementation. The primary tumor locations (right, left, and transverse) were also similar for both groups.

The disease control rate in the high-dose group was 96% vs 84% in the low-dose group (P = .05).

The high dose did not increase toxicity. There was also significantly less serious (grade 3 and 4) diarrhea in the high-dose group (12% vs 1%; P = .02).

The results were even more impressive because there was an imbalance between the two study groups that favored the low-dose group: 60% of the low-dose group had the best possible performance status vs only 42% of the high-dose group.

In other words, the high-dose group fared better despite being less physically fit than the comparator group.

Notably, more patients in the high-dose vitamin D arm were able to undergo surgery after their chemotherapy (11 vs 6). However, the difference was not statistically significant (P = .19), Dr Ng acknowledged. "It's an intriguing finding," she said.

The trial and its results have not gone unnoticed. "There's a lot of interest from providers and patients," said Dr Ng.

Among the 139 patients who enrolled and ultimately participated in the trial, most were from New England; a minority were from Nashville, Tennessee (at Vanderbilt University).

Geography may have played a role in the results, suggested Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York City, who acted as discussant of the study. In New England, she said, "there is a little less sunshine than other parts of America."

This raised a question about already existing levels of vitamin D in the study participants. (Vitamin D3 is made by human skin when exposed to sunlight.) "It's unknown if patients were deficient by US standards," she said.

It's unknown if patients were deficient by US standards. Dr Andrea Cercek

Dr Cercek also said that results from other studies of vitamin D supplementation in cancer patients are mixed. One study indicated no reduction in the risk for adenomas, and another had a negative finding ― reduced survival in patients with prostate cancer who received vitamin D supplements.

Reservations aside, she wanted to see more research: "I agree 100% with the investigators that a phase 3 study is warranted."

The study was supported by funding from the National Cancer Institute, Dana-Farber, Consano, Pharmavite, and Genentech. Multiple study authors, including Dr Ng, have financial ties to industry, including Genentech. Dr Yao has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Abstract 3506. Presented June 5.

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