Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221

Abstract

Background: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor.

Methods: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet.

Results: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05).

Conclusions: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.

Keywords: chemotherapy-induced peripheral neuropathy; paclitaxel; predictive biomarker; racial disparity; vitamin D.

Figure 1.. Incidence of sensory peripheral neuropathy by vitamin D sufficiency.

Incidence of grade 3–4 sensory chemotherapy-induced peripheral neuropathy (CIPN) in patients who were vitamin D sufficient and insufficient prior to treatment. Patients with vitamin D insufficiency had a higher incidence of CIPN (20.7% vs. 14.2%, odds ratio (OR)= 1.57 [1.14, 2.15], P=0.005). Error bars represent sampling error.

Figure 2.. Association between vitamin D insufficiency and grade 3–4 sensory CIPN incidence in covariate subgroups.

Odds ratios (OR) and 95% confidence intervals (CI) were from simple logistic regression. The size of the box represents the exponent of the subgroup size.

Figure 3.. Vitamin D deficiency induces mechanical hypersensitivity and worsens paclitaxel-induced mechanical hypersensitivity in mice.

(A) Time course showing the development of mechanical hypersensitivity in mice consuming vitamin D deficient diet (VDD) compared to mice on regular diet (RD) before treated with paclitaxel. Significance from RD group indicated as: *P<0.05. (B) Time course showing the impact of paclitaxel (PAC) or vehicle (VEH) on mechanical hypersensitivity in mice following 8 weeks of RD or VDD. Significance of VDD-PAC compared with RD-VEH indicated as: **P< 0.01; ***P< 0.001; ****P< 0.0001 and compared with RD-PAC indicated as: #P< 0.05.