Identification and Dosimetric Analysis of Axillary Substructures Associated with Breast Cancer Related Lymphedema

Abstract

It has been hypothesized that substructures in the axillary region may be involved in the development of upper limb lymphedema in breast cancer patients. We aimed to compare dosimetric parameters of different substructures to identify risk regions and dose indicators related to the development of lymphedema. A total of 486 patients with breast cancer treated with axillary node dissection (ALND) and regional node irradiation (RNI) between 2017 and 2020 were analyzed. Ten axillary substructures were retrospectively contoured, and dose-volume histogram (DVH) parameters (maximum dose [Dmax], Dmean, Dmin, V5 Gy, V10 Gy, V15 Gy, V20 Gy, V25 Gy, V30 Gy, V35 Gy, V40 Gy, V45 Gy and V50 Gy) were evaluated. EQD2 using α/β = 3 was applied for hypofractionation. The cumulative incidence of lymphedema was 32.5% during the median follow-up of 25 month (IQR 15-35). Higher BMI (≥21.77 kg/m2, hazard ratio [HR]1.6, 95% CI 1.1-2.3, p = 0.019) and higher number of dissected lymph nodes (≥13, HR 1.8, 95% CI 1.1-3.0, p = 0.026) were baseline risk factors associated with breast cancer related lymphedema (BCRL). A cohort of 196 patients was obtained by 1:1 propensity score matching based on the above two factors (154 treated with 50 Gy/25 fractions [Fx] and 42 with 40.05 Gy/15Fx). The optimal metric was axillary-lateral thoracic vessel juncture (ALTJ) Dmean ≥36.84 Gy (HR 3.7, 95% CI 1.6-8.6, p = 0.002). Other significant risk factors are Medial of Axillary Nodes level I(ALN-I-M) Dmin <9.19 Gy (HR 2.3, 95% CI 1.4-3.7, p = 0.001) and Posterior of Axillary Nodes level II(ALN-II-P) Dmax <52.75 Gy (HR 2.0, 95% CI 1.2-3.5, p = 0.015). A nomogram incorporated the above three parameters was created to predict the risk of lymphedema with reasonable accuracy confirmed by both self-training (area under curve [AUC], 0.76; 95% CI, 0.67-0.84) and internal validation (AUC 0.66; 95% CI, 0.50-0.80). A mean dose of 36.84 Gy of ALTJ may be a suggested dose limit for patients indicated RNI after ALND, especially when patients with higher BMI and higher dissected nodes. Ideally, avoidance of ALTJ may be realized without compromising dose coverage to high-risk nodal region. Confirmation of this finding in future prospective studies is needed.