The Effect of Regional Node Irradiation on the Thyroid Gland in the Breast Cancer Patients: The Clinical Significance of Optimization of Radiation Target Volume

Abstract

Although current international consensus recommends considering regional node irradiation (RNI) even in high-risk early-stage breast cancer, the risk of radiotherapy (RT)-related late toxicities including radiation-induced-hypothyroidism (RIH) has been neglected so far. Here, we investigated the long-term contribution of RNI on the risk of RIH and whether optimizing RT target volumes for supraclavicular (SCV) lymph node could minimize its risk. We identified 4,073 patients who received adjuvant RT after surgery for breast cancer between 2007 and 2016 at a single institution. Patients were divided into three groups by the volume of regional RT field: no RNI (n=2,468), low SCV-RNI (cranial border at the subclavian artery according to ESTRO guideline, n=215), and standard-RNI (cranial border at the cricoid cartilage according to RTOG atlas, n=1,390). Development of subclinical or biochemical RIH was evaluated by medical chart review. The incidences of hypothyroidism were compared among three groups, and the dosimetric analysis was performed to estimate the Dmean to the thyroid in randomly-sampled matching patients (n = 200). At a median of 60 months (range, 5.2-140.2), 89 patients (2.2%) developed RIH (1.5% subclinical, 0.7% biochemical). The time interval from RT to detection of hypothyroidism was mean 30.2±24.0 months, and the 3- and 5-year rates were 1.3% and 2.2%. Patients with RNI had a significantly higher rate of hypothyroidism than patients without RNI (3.4% vs. 1.4%, P<.001). In RNI group (n = 1,605), low SCV-RNI was significantly associated with lowered risk of hypothyroidism than standard-RNI (0.5% vs. 3.8%, P<.001). After adjusting all confounders, standard-RNI was the only independent risk factor for development of RIH (vs. low SCV, HR 1.46, 95% CI, 1.05-2.03). In the dosimetric analysis, mean radiation dose to the thyroid was significantly lowered in low SCV-RNI group than standard-RNI group (2.9±1.9 Gy vs. 9.3±8.4 Gy P<.001). Standard supraclavicular lymph node irradiation increased the risk of newly developed hypothyroidism. However, optimization of RT target volume could reduce the lifelong RIH risk, which further supports adoption of smaller volume for supraclavicular lymph node in breast cancer with limited nodal tumor burden.