Long Term Rates of Lymphedema in Hypofractionated Nodal Regional Irradiation for Women with Breast Cancer: A Phase 2 Clinical Trial – “HeNRIetta”

Purpose/Objective(s)

Moderate hypofractionation in the management of localized breast cancer is considered standard of care. Data suggests its use in the setting of regional nodal irradiation (RNI) yields equivalent oncologic and cosmetic outcomes but has not yet achieved universal acceptance into practice. The risk of lymphedema (LA) has not been the focus of study in this setting and therefore, we sought to evaluate the risk and establish the rate of moderate or marked LA for patients treated with hypofractionated RNI utilizing an established and commonly used hypofractionation treatment scheme with standardized treatment volumes for patients with node-positive breast cancer.

Materials/Methods

Women with node positive breast cancer who underwent definitive surgical resection were eligible for enrollment. Breast surgery may have been lumpectomy (Lp), mastectomy without reconstruction (M-R), or mastectomy with reconstruction (M+R). Nodal staging by sentinel lymph node (SLN) or by axillary lymph node (ALN) dissection were included. Patients could undergo neoadjuvant or adjuvant chemotherapy at the discretion of the treating medical oncologist. Breast and RNI was administered to 42.56 Gy in 16 daily fractions. The dissected axilla was excluded as a target volume in patients who underwent ALN dissection. Primary endpoint was rate of LA at 3 years following RNI for two cohorts, SLN (cohort A) and ALN (cohort B). Lymphedema was defined as ≥ 10% increase in arm circumference over baseline circumference as compared to the contralateral arm measured every 6 months for the first 3 years. Per protocol-defined to declare moderate hypofractionation non-inferior to recent historical controls cohorts A and B rate of lymphedema were estimated to be 6% and 10% respectively, a non-inferiority margin of +/- 7% was used. Secondary objectives included 5-year oncologic outcomes, grade 3 or higher toxicities, cosmesis and patient reported outcomes.

Results

Between September 2015 and July 2021, a total of 134 women were enrolled, 84 underwent SLN only and 50 completed ALN dissection. Mean age was 58.1 years for cohort A and 62.5 years for cohort B. Lp, M+R, and M-R was performed in 58.2%, 19.4, and 30% respectively. LA was observed in 11 patients (13.1%) with SLN only (P = 0.5897) and 9 patients (18%) who underwent ALN dissection (P = 0.65971). Only 2 patients developed grade 2 LA (limiting instrumental activities of daily living) and no grade 3 (limiting self-care activities of daily living) was observed. At 36 month follow up 85.5% in the lumpectomy group and 75.9% in the mastectomy with reconstruction group had excellent or good cosmesis.

Conclusion

Moderate hypofractionation did not meet the criteria defined by the protocol for non-inferiority. However, the absolute rates of LA remain low and predominantly grade 1. Cosmetic outcomes in this advanced disease group of patients are favorable. This data does not appear to support the argument that the risk of LA is a reason to avoid moderate hypofractionated regional nodal irradiation.