Prevention of paclitaxel-induced neurotoxicity with lithium: Results from a multicenter, randomized, double-blind, placebo-controlled phase 2 trial (PREPARE).

12129 Background: Chemotherapy-induced neurotoxicity is a frequent adverse effect of paclitaxel (PTX). It reduces quality of life and often necessitates treatment modifications. The objective of this clinical trial was to determine the safety and efficacy of lithium (Li + ) co-treatment on chemotherapy-induced neurotoxicity in breast cancer patients treated with PTX. Methods: Multicenter, randomized, double-blind, placebo-controlled phase-2 trial (parallel-group design) conducted in eight primary care centers in Germany between August 2022 and July 2024. Eligible breast cancer patients aged 18-70 years, with no pre-existing polyneuropathy and to be treated with PTX were randomized 1:1 to either oral Li + or placebo with sham dose adjustments. The intervention started 10-14 days prior to the first and lasted until three days after the last PTX infusion. Results: A total of 94 patients were enrolled, 86 patients were randomized and 78 were analyzed according to the intention-to-treat principle. Targeted Li + trough serum concentrations of 0.5 to 0.8mmol/l were reliably reached prior to PTX therapy. The total neuropathy score reduced (TNSr) was 0.5 points higher in the placebo group than in the Li + group (95% CI 1.6 to -0.6, not significant), while serum neurofilament light chain levels showed no difference. Structural MRI showed slightly higher total intracranial volume in the Li⁺ group, but no difference in hippocampal volume. Cognitive testing using the CANTAB indicated a strong trend towards better performance in hippocampus-dependent tasks, including delayed matching to sample and spatial working memory for the Li + group. The patient reported outcome measures (PROM) completion rates were high (baseline 99%, endpoint 95%). Patients receiving Li⁺ consistently reported higher quality of life and less pain scores on the EORTC QLQ-C30 during and after therapy, with between-group differences of 11 AU (95% CI 18 to 4) for global health status and -14 AU (95% CI −27 to -0.2) for pain, exceeding established minimal clinically important differences. The latter finding was supported by a lower reported intake of pain medication in the Li + group of 54% vs 70% in the placebo group. Eleven serious adverse events were reported in the trial, six in the placebo group and five in the Li + group. Patients in the Li + group experienced fewer adverse events compared to patients in the placebo group with a relative risk reduction of 26% for any CTCAE grade and 45% for grade ≥ 3. Conclusions: Among breast cancer patients receiving PTX chemotherapy co-treatment with Li + was not superior to placebo for the development of polyneuropathy as measured by TNSr. However, there were better patient-reported outcomes including quality of life and pain, as well as lower rates of adverse events. These observations warrant confirmation in a larger phase-3 interventional trial. Clinical trial information: DRKS00027165.