Multicenter phase 3 trial of hypo- versus standard fractionated locoregional radiotherapy for high-risk breast cancer

Adjuvant radiotherapy (RT) for node-positive breast cancer (BC) using 50 Gy in 25 fractions has been Danish Breast Cancer Group (DBCG) standard. Hypofractionated RT 40Gy/15fx has been increasingly used. The multicenter noninferiority phase 3 DBCG Skagen 1 trial compared both schedules among patients with high-risk BC. The primary endpoint was arm lymphedema; assuming a 3-year incidence of 10% with 50Gy/25fx, noninferiority was predefined as maximum 5% excess incidence with 40Gy/15fx. Between 2015 and 2021, 2963 patients consented. The intention-to-treat cohort comprised 2908 patients: 1444 had 50Gy/25fx and 1464 had 40Gy/15fx. At a median follow-up of 4.1 years (IQR 3.0-5.0), the 3-year rates of lymphedema were 9.4% in the 50Gy/25fx group and 8.0 Gy in the 40Gy/15fx group (OR 0.84; p=0.27), confirming noninferiority of 40Gy/15fx. The median follow-up for cancer outcomes was 5.25 years (IQR 4.26-6.96). Within 8 years, the HR for locoregional recurrence was 0.96 (95% CI 0.62-6.96), the HR for distant recurrence was 1.10 (0.89-1.37), the HR for BC mortality was 1.25 (0.93-1.66), and the HR for all-cause mortality was 1.08 (0.85-1.36). The authors conclude that the hypofractionated locoregional RT for high-risk BC did not result in more lymphedema compared with the standard schedule, without compromising oncological outcomes.