Proton vs Photon IMRT Toxicity in Breast Cancer

Eligible breast cancer patients will receive either 4005 cGy (RBE) in 15 fractions once daily or 4256 cGy (RBE) in 16 fractions once daily, five times per week. The radiation dose will be delivered to the ipsilateral chest wall or whole breast, with or without regional nodal irradiation, including the ipsilateral supraclavicular, infraclavicular, and high-risk axillary lymph node regions, and optionally the internal mammary lymph node regions. The decision to administer a tumor bed boost will be made by the treating physician. The boost may be delivered either sequentially (10-12.5 Gy (RBE) in 4-5 fractions) or concurrently (48-49.5 Gy (RBE) in 15-16 fractions). The treating physician will evaluate clinical indications to determine the necessity of regional nodal irradiation and whether the internal mammary nodes should be included in the regional nodal clinical target volume (CTV). All patients will undergo intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT). The primary endpoint is a composite of toxicity events, including grade ≥2 ipsilateral arm lymphedema within one year post-radiotherapy, grade ≥2 lymphopenia within three months post-treatment, or grade ≥1 cardiac toxicity within one year post-treatment. Patients will be followed for at least one year to assess acute and late toxicities, cosmetic outcomes (patient-reported) in those undergoing breast-conserving surgery, and quality of life. Due to the greater difficulty in enrolling patients for IMPT compared to IMRT, the study employs an unbalanced 2:1 allocation ratio (IMRT : IMPT = 2:1). Based on an alpha level of 0.05, 80% power, a 2:1 allocation ratio, an assumed 11% difference in toxicity rates between conventional radiotherapy and IMPT during and within one year post-treatment, and a 6.4% anticipated loss-to-follow-up rate, the estimated total sample size is 750 patients (500 in the IMRT/VMAT group and 250 in the IMPT group).