Efficiency Gain and Early Toxicity Profile of Ultra—Versus Moderate-Hypofractionation: A Matched Real-World Comparison of the Two Current Standard Schedules for Adjuvant Breast Radiotherapy

Background: Ultra-hypofractionation (UHF) and moderate-hypofractionation (MHF) represent standard adjuvant radiotherapy (RT) schedules in breast cancer (BC). This study evaluates the departmental workflow impact and early physician-assessed toxicity kinetics of UHF compared to MHF in a matched real-world cohort. Methods: Patients receiving UHF (26 Gy in 5 fractions ± simultaneous boost) during the first year of institutional adoption were matched 1:1 with historical MHF patients (40.05 Gy in 15 fractions ± sequential boost). Departmental workflow metrics and treatment delays were evaluated. Physician-graded acute toxicities (CTCAE v5.0) were recorded at treatment completion (Day 0), Day 10, and Day 50 post-RT. Results: In total, 240 patients were analyzed. Transitioning to UHF coincided with enhanced efficiency, increasing adjuvant breast RT patient volume by 167% and reducing treatment delays (11% vs. 66%). UHF demonstrated lower G2 erythema at Day 0 (2% vs. 14%) and Day 10 (13% vs. 25%). Conversely, UHF exhibited higher G2 mastodynia (9% vs. 2%), oedema (10% vs. 3%) and G1 nipple–areola hyperpigmentation (NAC) (45% vs. 5%) at Day 10. Most acute toxicities were transient, becoming comparable between cohorts by Day 50. Conclusions: Implementing UHF coincided with efficiency gain without compromising overall acute safety. However, findings necessitate prospective translational validation. Personalization of radiotherapy in breast cancer remains a cornerstone of modern cancer care.