Lymphedema following regional nodal irradiation (RNI) is a severe complication that could be minimized without significantly compromising nodal coverage if the anatomic region(s) associated with lymphedema was better defined. This study sought to correlate dose-volume relationships within sub-regions of the axilla with lymphedema outcomes in order to generate treatment planning guidelines for reducing lymphedema risk.

Women with stage II-III breast cancer who underwent breast surgery with axillary assessment and RNI were identified. Nodal targets were prospectively contoured per RTOG guidelines for field design. The axilla was divided into 8 distinct sub-regions that were retrospectively contoured. Lymphedema outcomes were assessed by arm circumferences. Multivariate cox proportional hazards regression assessed patient, surgical and dosimetric predictors of lymphedema outcomes.

Treatment planning CTs for 265 women treated between 2013 and 2017 were identified. Median post-radiotherapy follow-up was 3 years (Interquartile range [IQR], 1.9-3.6). Dose to the Axillary-Lateral Thoracic vessel Juncture (ALTJ, superior to level I) was most associated with lymphedema risk (maximally selected rank statistic=6.3, p<0.001). The optimal metric was ALTJ minimum dose (D) <38.6Gy (3-year lymphedema rate 5.7% vs. 37.4%, p<0.001), although multiple parameters relating to sparing of the ALTJ were highly correlated. Multivariate analysis confirmed ALTJ D <38.6Gy (HR 0.13, p<0.001), body mass index (HR 1.06/unit, p=0.002) and number of lymph nodes removed (HR 1.08/node, p<0.001) as significant predictors. Women with ALTJ D <38.6Gy maintained median V in the supraclavicular, 99% (IQR, 94-100%); level III, 100% (IQR, 97-100%); level II, 98% (IQR, 86-100%); and level I, 91% (IQR, 75-98%) nodal basins respectively.

Anatomic studies suggest the ALTJ region is typically traversed by arm lymphatics, and appears to be an "organ-at-risk" (OAR) in breast radiotherapy. Ideally, avoidance of the ALTJ may be feasible while simultaneously encompassing breast-draining nodal basins. Confirmation of this finding in future prospective studies is warranted.