Quantifying Risk of Ipsilateral Arm Lymphedema Causing Functional Impairment in Breast Cancer Patients: Results From a Prospective, Multi-Centre International Study of Treatment Toxicity.

PURPOSE/OBJECTIVE(S) Breast cancer related lymphedema (BCRL) of the ipsilateral arm remains a highly morbid long-term side effect of breast cancer treatment, one which can lead to functional impairment. We sought to independently examine clinical and treatment related risk factors for the development of lymphedema-associated functional impairment. MATERIALS/METHODS The REQUITE Consortium is a multi-center cohort study of patients with breast cancer treated at 26 hospitals in 8 countries from 2014-2017 who were prospectively evaluated for treatment toxicity. All patients received lumpectomy and adjuvant radiotherapy (RT) with or without chemotherapy at the discretion of their treating physician, and were enrolled prior to beginning RT. Arm circumference measurements and patient reported outcome (PRO) toxicity assessments were obtained before RT and annually after RT for a minimum of two years. Lymphedema-associated functional impairment was determined by PRO lymphedema that constrains activity and self-care. Grade 2+ BCRL was defined as ≥10% discrepancy in ipsilateral arm circumference compared to the contralateral arm. Cumulative incidence curves were stratified by the extent of axillary surgery and RT. Multivariable Cox models adjusted for axillary surgery, radiation, body mass index, and chemotherapy. RESULTS The cohort included 1921 patients followed for a median of 27 months: 1345 received sentinel node biopsy (SLNBx) alone, 90 received SLNBx and regional lymph node RT (RLNR), 136 received axillary node dissection (ALND) alone, 200 received ALND+RLNR, and 150 received no axillary treatment. Invasive breast cancer was present in 1678 (87%) patients, while 591 (30.7%) received chemotherapy. Among the whole cohort, four times as many patients reported functional impairment than Grade 2+ BCRL (4.6% vs 1.1%). On multivariable analysis, taxane-based chemotherapy resulted in a significantly higher risk of functional impairment (hazard ratio [HR] 1.90, P = 0.01), as did ALND (HR 11.92, P = 0.02) and higher BMI (HR 1.06, P < 0.001). Although RLNR and SLNBx did not confer significantly higher risk on multivariable analysis when evaluated individually, the SLNBx+RLNR treatment group demonstrated a trend towards significantly higher risk of functional impairment compared to no axillary treatment (HR 8.21, P = 0.05). The risk of functional impairment was highest in those receiving ALND+RLNR (HR 15.52, P = 0.008) and ALND alone (HR 14.58, P = 0.01), with a 3-year cumulative incidence rate of 21% in both groups. CONCLUSION Patients treated with taxane-based chemotherapy and those receiving more extensive axillary surgery are at significantly higher risk of developing ipsilateral arm lymphedema causing functional impairment. Additional variation in this toxicity may be due to genetic predisposition, which is under investigation in REQUITE. Lymphedema-associated functional impairment occurred substantially more often than Grade 2+ BCRL, highlighting the importance of capturing PROs.