Hypofractionated radiotherapy (HFRT) is gaining acceptance as a potential alternative to conventional fractionated radiotherapy (CFRT) for patients with breast cancer. However, evidence from randomized trials with long-term follow-up in the setting of regional nodal irradiation (RNI) remains limited.

In this phase 3, randomized, open-label, non-inferiority trial conducted at the National Cancer Center in China, 820 women with high-risk breast cancer who had undergone mastectomy and axillary dissection were randomized 1:1 to receive either CFRT (50 Gy in 25 fractions) or HFRT (43.5 Gy in 15 fractions) to the chest wall and supra-/infra-clavicular nodal region. The primary endpoint was 5-year cumulative locoregional recurrence (LRR); secondary endpoints included disease-free survival (DFS), overall survival (OS), and late toxicities.

The median follow-up was 10.3 years (IQR 7.3–12.7). Among the 810 patients analyzed (409 CFRT, 401 HFRT), the 5-year LRR was 8.7% with CFRT and 10.2% with HFRT (hazard ratio [HR] 1.28, 90% CI: 0.92–1.80; non-inferiority p = 0.0256). At 10 years, LRR remained comparable (10.7% vs. 12.9%; P=0.22), and no significant differences were found in DFS or OS at 10 years (65.4% vs. 70.0%; 73.2% vs. 77.5%). Grade ≥3 late toxicity rates were low in both groups; however, grade 1–2 pulmonary fibrosis was more common in the HFRT arm (20% vs. 12%). No brachial plexopathy was observed.

HFRT provides durable locoregional control with comparable survival outcomes and acceptable late toxicity in high-risk patients receiving postmastectomy RNI. These 10-year outcomes support postmastectomy HFRT as a clinically effective, resource-efficient alternative to CFRT.