Introduction: Patients with early breast cancer (EBC) can be treated with accelerated partial breast irradiation (APBI). The objective of this study was to determine if a three-fraction APBI schedule is feasible for these patients. Methods: This single-institutional, phase 2 study included patients with age ≥45 years, tumor size <3.5 cm, negative nodes, negative surgical margins, and unicentric tumors. Patients were treated with 3D-CRT technique with a dose of 22.5 Gy in 3 fractions on 3 consecutive days. The primary end point of the study was cosmesis as assessed by physicians at 3 years. Secondary end points were cosmesis as assessed by patients, dosimetry, acute and late toxicities, disease-free and overall survival. Results: From October 2019 to October 2022, 49 patients were treated. Mean age of the patients was 55 years (range 40–75). At 3 years, physician- and patient-reported cosmetic results were excellent/good/fair in 33 (67%)/14 (29%)/2 (4%) of patients and in 29 (59%)/16 (33%)/4 (8%) of patients, respectively. Acute dermatitis grades 1 and 2 were observed in 14 (29%) and 3 (6%) of patients, respectively. At 6 months, breast edema, skin induration, subcutaneous fibrosis, pain, and pigmentation were observed in 3 (6%), 6 (12%), 3 (6%), 2 (4%), and 8 (16%) of patients, respectively. At 3 years, 1 (2%) patient had mild pain; no breast edema, skin induration, subcutaneous fibrosis, or pigmentation was observed. At a median follow-up of 39 months (range 24–60), there were no local/regional recurrences. One patient developed distant metastases in the bones, liver, and lungs at 46 months. All patients were alive at last follow-up. Conclusion: In patients with EBC, three-fraction APBI is feasible. Physician- and patient-reported cosmesis was excellent/good in 96% and 92% of patients, respectively. Late effects were only grade 1.

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