Systematic vitamin D supplementation improves outcomes among cancer patients on immune checkpoint inhibitors

The findings, published in the peer-reviewed journal Cancer Immunology, Immunotherapy, support adequate repletion as a possible prophylaxis for thyroid immune-related adverse events (irAEs).

In cancer patients, hypovitaminosis D is extremely frequent with a recognized negative prognostic impact. Calcitriol, or 1,25-dihydroxy-vitamin D3, is a multifunctional steroid hormone with many extraskeletal effects, possibly regulating signalling pathways related to the development and progression of cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation.

Considering the evidence in support of the multifaceted immunological role of vitamin D, Alessio Cortellini, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy, and colleagues hypothesized that systematic vitamin D repletion could impact clinical outcomes in cancer patients receiving immune checkpoint inhibitors.

They planned a prospective observational study (PROVIDENCE) to evaluate serum vitamin D levels in advanced cancer patients receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on toxicity and survival outcomes.

In an exploratory analysis, the researchers compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centres who did not receive systematic vitamin D repletion.

A total of 164 patients were recruited in the study. Cohort 1 comprised 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, and at three months of re-assessment, adequate repletion with cholecalciferol was obtained in 70.1%. Cohort 2 comprised 63 patients evaluated for vitamin D at a median time of 3.7 months since immunotherapy initiation, no patients had adequate levels (> 30 ng/ml). At the three-month re-assessment, systematic supplementation led to adequate levels in 77.8% of patients in cohort 2.

The authors reported the following findings:

· Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS), time to treatment failure (TTF), and higher disease control rate (DCR).

· The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55) and treatment discontinuation (HR 0.61) for patients from PROVIDENCE cohort 1 in comparison to the control cohort.

· In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events was higher in the PROVIDENCE cohort 1 compared to the control cohort.

· Patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16).

"To the best of our knowledge, the study is the first to prospectively describe baseline vitamin D levels in a cohort of patients with advanced cancer treated with ICIs," the authors wrote, "providing practice informative evidence about the prevalence of hypovitaminosis D and the possible positive impact of systematic supplementation in this setting."

The team, however, states the need for properly powered comparative studies to confirm the findings along with comprehensive research to fully elucidate the underlying mechanism involved.

Reference:

Bersanelli, M., Cortellini, A., Leonetti, A. et al. Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study. Cancer Immunol Immunother (2023). https://doi.org/10.1007/s00262-023-03522-3