Vitamin D Tied to Lower Risk for Immunotherapy-Induced Colitis

Veronica Hackethal, MD

July 02, 2020

Taking vitamin D before starting immune checkpoint inhibitor (ICI) therapy may decrease the risk for treatment-related colitis, say researchers in an article published online on June 22 in the journal Cancer.

The study is the first to find a link between pretreatment vitamin D use and decreased risk for ICI colitis, they comment. They caution that the results are preliminary and require confirmation in further studies.

"Our findings of a link between vitamin D intake and reduced risk for colitis could potentially impact practice if validated in future prospective studies," senior author Osama Rahma, MD, said in a press release. Rahma is an assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts.

"Vitamin D supplementation should be tested further to determine if it could be a safe, easily accessible, and cost-effective approach towards preventing immunotherapy's gastrointestinal toxicity and extending the effectiveness of immune checkpoint inhibitor treatment in cancer patients," he added.

ICIs can dramatically improve outcomes for patients who respond to them.

They work by blocking either of two immune checkpoints, CTLA-4 or PD-1/PD-L1. This enhances the ability of the immune system to recognize and attack cancer cells. The problem is that blocking these checkpoints can unleash serious inflammatory reactions and immune-related adverse events, which can limit therapy.

The most frequent and severe of these immune-related adverse reactions is colitis, note Rahma and colleagues. Physicians can treat ICI-related colitis with high-dose steroids. In cases in which response is inadequate, TNF blockers such infliximab or monoclonal antibodies such as vedolizumab can be used.

Patients who receive CTLA-4 blocking therapy or combined ICI therapy are more likely to develop colitis than those taking PD1/PD-L1 blockers alone. Aside from that, little is known regarding risk factors for ICI colitis and how to prevent it, the authors comment.

Results from animal studies suggest that vitamin D may modulate the immune system and protect against inflammatory bowel diseases such as ulcerative colitis and Crohn disease. ICI colitis shows similarities with inflammatory bowel disease, which may account for why vitamin D may be protective against ICI colitis.

To investigate the issue, the team conducted a retrospective analysis of electronic medical record data recorded at the time of ICI initiation. The analysis included 213 patients with stage III or IV melanoma treated at Dana Farber Cancer Institute in Boston between May 2011 and October 2017. Patients were included if they received any US Food and Drug Administration–approved ICI (ipilimumab, nivolumab, pembrolizumab, or combined ipilimumab plus nivolumab) and developed immune-related adverse events during therapy.

The team classified vitamin D intake into three dosage categories: no use, ≤1000 IU per day, and >1000 IU per day. The primary outcome was development of ICI-related colitis, as confirmed with flexible sigmoidoscopy and colon biopsy.

The investigators checked results in a confirmatory cohort, a separate group of 169 patients with melanoma who received ICIs at Massachusetts General Hospital between December 2010 and July 2019.

In the Dana Farber group, 31% (66/123) reported taking vitamin D before starting ICI therapy, and 17.4% (37/123) developed ICI colitis.

The percentage of patients who took vitamin D before starting ICIs was significantly higher for patients who did not develop colitis than for those with colitis (34.1% [60/176] vs 16.2% [6/37]; P = .03).

Further analyses identified the following factors as potentially related to increased risk for colitis: age younger than 70 years, pneumococcal or influenza immunization around the time of ICI treatment, neutrophil-to-lymphocyte ratio (NLR) ≥5 (a measure of systemic inflammation), past cancer therapy, and concomitant aspirin or NSAID use.

Multivariable analyses accounting for these factors revealed three independent predictors of ICI colitis: checkpoint inhibitor class (increased risk with ipilimumab and combined therapy), baseline NLR ≥5, and pre-ICI vitamin D use.

Vitamin D use was linked to 65% decreased odds of developing ICI colitis (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.1 – 0.9; P = .01).

For the confirmatory cohort of patients from Massachusetts General, results were similar: 29% (49/169) developed ICI colitis, and vitamin D intake was tied to 54% decreased odds of colitis (OR, 0.4; 95% CI, 0.2 – 0.9; P = .03).

No statistically significant differences were found for high (>1000 IU) vs low (<1000 IU) doses of vitamin D.

Approached for comment, Jeffrey Weber, MD, PhD, told Medscape Medical News that the study was "very well done" and was conducted "by perhaps the best people in the US at evaluating immune related colitis." Weber is a professor of medicine at NYU Langone Medical Center, New York City, and recently presented a Medscape review of immune-related adverse events.

"The Harvard system is big enough to justify an inpatient hospital service dedicated to immune-related adverse events from checkpoint inhibitors. There are very few places in the US that could do a study like this. Most institutions wouldn't have enough patients," he said.

He also pointed out several limitations of the study. The retrospective design relied on accurate documentation in the medical record, which may not be as reliable as data collected in a clinical trial. Also, the study was not designed to prospectively compare vitamin D intake against placebo for protection against ICI colitis. In addition, the researchers did not measure baseline serum vitamin D levels, so the study cannot provide information about the impact of vitamin D dosage on ICI colitis.

"These are preliminary data, but I think it's good work that will provoke some serious thought," Weber said. "It provides grist for the mill for future research."

The study was funded by the Parker Institute for Cancer Immunotherapy, Massachusetts General Hospital, the American Gastroenterological Association, and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. The authors' relevant financial relationships are listed in the original article. Weber consults for and receives travel expenses and honoraria from Merck and Bristol-Myers Squibb.

Cancer. Published online June 22, 2020. Abstract

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