For patients with breast cancer, regional nodal irradiation (RNI) can significantly reduce the risks of recurrence and mortality. Moderate hypofractionated regimens (40 to 42.5 Gy in 15 to 16 fractions over 3 weeks) is the established standard of care for RNI. Nevertheless, for the majority of patients, a three - week treatment duration is still regarded as lengthy. Although the ultra-hypofractionated regimen (26 Gy in 5 fractions over 1 week) has been proven non-inferior to the moderate hypofractionated regimen for whole breast irradiation, unambiguous evidence supporting its use in comprehensive RNI remains lacking, especially in high risk patients requiring internal mammary node irradiation (IMNI). This prospective, non-inferiority trial is designed to address this evidence gap by evaluating whether a one-week, ultra-hypofractionated regimen (26 Gy in 5 fractions) is non-inferior to the three-week regimen (40 Gy in 15 fractions) for comprehensive RNI, including IMNI.
Provide a signed and dated informed consent form (ICF) before the initiation of any trial-specific procedures.
Age ≥ 18 years.
Histologically confirmed invasive breast cancer.
Have received breast-conserving surgery or mastectomy with axillary staging, including sentinel lymph node biopsy, targeted axillary dissection and/or axillary lymph node dissection.
Nodal stage is classified as N3b or N3c, as defined by the AJCC Cancer Staging Manual, 8th Edition.
Has undergone or is planning immediate breast reconstruction with a permanent implant or tissue expander.
Evidence of distant metastatic disease.
Diagnosis of synchronous bilateral invasive breast cancer or a history of prior invasive cancer in either breast.
Parallel
Ultra-hypofractionated Regional Nodal Irradiation
Radiation26 Gy in 5 fractions over 1 week (5.2 Gy per fraction, once daily). Treatment targets include ipsilateral supraclavicular, infraclavicular, internal mammary regions, chest wall or whole breast, and any portion of the undissected axilla at risk. Sequential tumor bed boost of 10.4 Gy in 2 fractions (5.2 Gy per fraction) for patients after breast-conserving surgery.
Moderate Hypofractionated Regional Nodal Irradiation
Radiation40.05 Gy in 15 fractions over 3 weeks (2.67 Gy per fraction, once daily). Treatment targets include ipsilateral supraclavicular, infraclavicular, internal mammary regions, chest wall or whole breast, and any portion of the undissected axilla at risk. Simultaneous Integrated Boost of 48 Gy in 15 fractions (3.2 Gy per fraction) for patients after breast-conserving surgery.
Invasive Breast Cancer Recurrence-Free Survival (IBC-RFS)
IBC-RFS, defined as time from randomization until any first invasive ipsilateral breast, chest wall, regional, or distant recurrence, or death from breast cancer. Data for patients who are alive and free of an event at the time of final analysis or are lost to follow-up will be censored at the date of last contact.
Acute Radiation-Induced Toxicity
Incidence of any grade 1 or higher acute radiation-induced toxicity occurring from the start of radiotherapy through 90 days after completion of radiotherapy, graded per CTCAE v5.0, RTOG Acute Radiation Morbidity Scoring Criteria and LENT/SOMA Scoring Scale.
Late Radiation-Induced Toxicity
Incidence of any grade 1 or higher radiation-induced toxicity event occurring \>90 days after radiotherapy completion, graded using CTCAE v5.0, RTOG/EORTC Late Radiation Morbidity Scoring Schema, and LENT/SOMA Scoring Scale
Overall Survival (OS)
Time from randomization to death from any cause.
Locoregional Recurrence-Free Survival (LRRFS)
Time from randomization to the first ipsilateral breast, chest wall, or regional nodal recurrence.
Second Primary Cancers
Cumulative incidence of any new, pathologically confirmed invasive non-breast cancer other than squamous or basal cell carcinoma of the skin following randomization.
Health-Related Quality of Life (HRQoL)
Assessed using the breast cancer specific EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) questionnaires. This is a 30-item questionnaire assessing functional scales (physical, role, emotional, cognitive, social functioning) and symptom scales. Scores range from 0 to 100. For functional scales, higher scores indicate better quality of life; for symptom scales, higher scores indicate worse symptoms.
Patients reported outcomes (PROs)
Assessed using the PRO-CTCAE (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events). This is a patient-reported outcome measurement system developed by the National Cancer Institute to evaluate symptomatic adverse events in cancer clinical trials. Each symptom is rated on a 5-point scale ranging from 0 to 4, where higher scores indicate worse symptoms (0=None, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe).
Breast Cosmetic Outcome
Assessed via patient self-assessment and physician photographic review using the Harvard/NSABP/RTOG Breast Cosmesis Grading Scale. This scale rates cosmetic outcome on a 4-point scale: Excellent, Good, Fair, or Poor, where higher grades indicate worse cosmetic outcomes.
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