Efficacy and safety of ultra-hypofractionated post-operative radiation therapy for breast cancer: a systematic review and meta-analysis

To evaluate the efficacy and safety of ultra-hypofractionated post-operative radiation therapy (UHF-RT) compared with moderately hypofractionated radiotherapy (MHF-RT) in patients with breast cancer. A comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to June 30, 2025. Both randomized controlled trials (RCTs) comparing UHF-RT to MHF-RT and non-randomized observational studies (prospective or retrospective cohort studies) containing only UHF-RT were included. The primary outcomes were grade ≥ 2 acute radiation dermatitis and late radiation therapy-related toxicities. Secondary outcomes included cosmetic outcomes and survival metrics. A total of 35 studies were included, comprising 7 RCTs and 28 non-randomized cohort studies, with 4,926 patients in the RCTs and 4,548 patients in the cohort studies. Meta-analysis of RCTs revealed no significant differences between UHF-RT and MHF-RT for grade ≥ 2 acute radiation dermatitis (RR = 0.84, 95% CI 0.48–1.47), late breast edema (RR = 1.37, 95% CI 0.50–3.75), breast shrinkage (RR = 1.02, 95% CI 0.55–1.92), or telangiectasia (RR = 0.79, 95% CI 0.20–3.02). Analysis of non-randomized cohort studies revealed that the most common grade ≥ 2 acute toxicities were radiation dermatitis (10.23%, 95% CI 9.26–11.30%). Subgroup analysis revealed a dose-dependent relationship for toxicity: regimens with total doses ≥ 30 Gy showed significantly higher rates of acute radiation dermatitis (28.85% vs. 2.73%, p < 0.01) and late breast fibrosis (12.94% vs. 1.90%, p < 0.01) compared to regimens with total doses < 30 Gy. Late toxicity rates were generally low in regimens with total doses < 30 Gy, with breast fibrosis (1.90%, 95% CI 1.30–2.78%) and breast edema (1.65%, 95% CI 1.23–2.20%) being the most frequent. Cosmetic outcomes were rated as excellent or good in over 90% of patients receiving UHF-RT in most trials, although a few trials reported lower rates. Patients receiving UHF-RT or MHF-RT showed similar survival outcomes, although fewer RCTs reported these metrics. UHF-RT is a safe and effective alternative to MHF-RT for breast cancer in the short-to-mid term, with comparable acute toxicity outcomes. The reduced treatment time and improved patient convenience make UHF-RT an attractive option for clinical practice. However, further large-scale randomized controlled trials with long-term follow-up are needed to confirm these findings and to guide the optimal implementation of UHF-RT in breast cancer treatment.