Topical tacrolimus for the amelioration of breast cancer-related lymphedema (TACLE Trial): a study protocol for a randomized, double-blind, placebo-controlled phase II/III trial.

Background: Breast cancer-related lymphedema is a chronic condition affecting 15-30% of breast cancer patients, resulting from treatment-related inflammation and fibrosis primarily mediated by CD4 + T-cells. Tacrolimus, an immunomodulator, has shown efficacy in reducing lymphedema in both animal models and an initial clinical trial. This study aims to validate these findings in a larger cohort, hypothesizing that tacrolimus will reduce lymphedema volume, fibrosis, and fluid retention while improving quality of life.

Methods: This multicenter, double-blinded, randomized placebo-controlled trial will enroll 80 women with breast cancer-related lymphedema stages I and II. Participants will be randomized 1:1 to receive either 0.1% tacrolimus ointment or a placebo ointment for 12 months. Primary outcome will be the change in lymphedema volume measured at baseline, 6 months, and 12 months. Secondary outcomes include quality of life assessed via SF- 36, DASH, and LYMPH-Q Upper Extremity questionnaires; lymphedema index via bioimpedance spectroscopy; lymphatic function and flow via indocyanine green lymphangiography; and skin fibrosis measurement. Assessments will take place at baseline, 3, 6, 9, and 12 months.

Discussion: This trial will provide robust data on the efficacy of topical tacrolimus in reducing BCRL volume and improving patient quality of life. Positive results could establish tacrolimus as a standard treatment for BCRL, potentially enhancing clinical outcomes for affected patients. The findings will also contribute to understanding the role of immunomodulation in lymphedema management.

Trial registration: This trial is registered with the EU Clinical Trials Information System (CTIS) under EU CT Number: 2023-503644 - 13-00 (approved 16.05.2024) and ClinicalTrials.gov under identifier NCT06306274 (registered 12.03.2024).