Toxicity profiles of proton and photon radiotherapy in postoperative breast cancer: a 10-year real-world cohort study

BACKGROUND: Proton therapy, with its superior dose distribution, has emerged as a promising radiotherapy (RT) technique. This study evaluates the clinical benefits of proton therapy in reducing treatment-related toxicities in breast cancer patients undergoing radiotherapy. METHODS: A retrospective analysis was performed using the Chang Gung Research Database, identifying 8189 breast cancer patients treated with adjuvant radiotherapy from 2012 to 2022. Patients received either intensity-modulated proton therapy (IMPT, n = 501) or photon-based IMRT/VMAT (n = 7688). Propensity score weighting was applied to adjust for baseline differences. The clinical outcomes photon and proton therapy were investigated, with a particular focus on radiation-induced toxicities including dermatitis, pulmonary changes, and cardiac events. In addition, N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of cardiac stress, was prospectively assessed in a subset of patients to assess subclinical cardiac injury between 2023 and 2024. RESULTS: Compared with photon therapy, proton therapy significantly reduced the incidence of radiographic pulmonary changes and subclinical cardiac biomarker elevations, while maintaining comparable loco-regional control and overall survival. Proton therapy significantly reduced the incidence of radiographic pulmonary changes (5.8% vs. 10.0%, p = 0.02; HR: 0.64, 95% CI 0.44–0.93) and grade 2 radiation dermatitis (13.4% vs. 20.9%, p < 0.001), though grade ≥ 1 skin toxicity was more common with IMPT (82% vs. 57.1%). Among left-sided patients, photon RT resulted in significantly greater NT-proBNP elevation post-treatment compared to proton therapy (mean ratio: 1.16 vs. 0.95, p = 0.0099), suggesting more subclinical cardiac stress. However, no significant difference in clinically evident cardiac events was noted between the groups during the follow-up period. CONCLUSIONS: Proton therapy is associated with reduced radiation-induced pulmonary toxicity and moderate dermatitis, while achieving comparable oncologic outcomes to photon therapy. The lower NT-proBNP elevation suggests potential cardiac sparing, although longer follow-up is needed to confirm clinically meaningful cardiac benefits. These findings highlight the potential role of proton therapy in mitigating treatment-related toxicities in breast cancer patients at elevated risk for cardiopulmonary complications.