The RELAX trial is an open-label, multicenter, non-inferiority, randomized, phase 3 clinical trial.

Multiple randomized trials have demonstrated the safety of omitting complete axillary-lymph-node dissection in patients with invasive breast cancer and limited sentinel lymph node metastases. However, the necessity and optimal extent of regional nodal irradiation remains uncertain. The aim of this study is to evaluate whether level I-II axillary irradiation is non-inferior to whole regional nodal irradiation in terms of disease-free survival in clinically node-negative breast cancer patients with 1-2 sentinel lymph node macro-metastases.

PRIMARY OBJIECTIVE:

To evaluate whether level I-II axillary irradiation is non-inferior to whole regional nodal irradiation in terms of disease-free survival in clinically node-negative breast cancer patients with 1-2 sentinel lymph node macro-metastases.

SECONDARY OBJECTIVES:

I. to estimate the difference of overall survival; II. to estimate the difference of ipsilateral regional recurrence; III. to estimate the difference of ipsilateral local regional recurrence; IV. to estimate the difference of distant recurrence; V. to estimate the difference of radiation related toxicities and quality of life.

Outline: Patients are randomized in a 1:1 ratio to two treatment arms.

Arm A (Level I-II axillary irradiation): Radiation is delivered to the breast after breast conserving surgery(BCS) or chest wall after mastectomy, level I-II axillary lymph nodes. Internal mammary nodes(IMN) is optional and it is recommended to irradiate IMN when the tumor is located in the medial or central quadrant.

Arm B (Entire regional nodal irradiation): Radiation is delivered to the breast after BCS or chest wall after mastectomy, whole axillary lymph nodes (levels I-III) and supraclavicular lymph nodes. IMN is optional and it is recommended to irradiate IMN when the tumor is located in the medial or central quadrant.

Inclusion Criteria:

1. Female ≥ 18 years of age;
2. Newly diagnosed primary invasive breast cancer;
3. Clinically stage T1-3N0M0;
4. Patients received surgery as first treatment,and have undergone breast conserving-surgery or mastectomy (with or without breast reconstruction) with negative margins;
5. Have one or two macrometastases (>2 mm) at sentinel lymph node biopsy,and without further axillary lymph node dissection;
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
7. Will receive endocrine therapy for at least 5 years for estrogen receptor (ER) and/or progesterone receptor (PR) positive patients; will receive anti-HER2 (human epidermal growth factor receptor 2) therapy for 1 year for HER2 positive patients;
8. Radiation therapy must begin no later than 12 weeks after the last dose of adjuvant chemotherapy or the last breast cancer surgery if no adjuvant chemotherapy;
9. Patients have adequate organ function;
10. Acquirement of informed consent.

Exclusion Criteria:

1. Patients have received neoadjuvant systemic therapy;
2. Clinical stage T4 or IV (metastatic) breast cancer, or presence of regional metastases before surgery;
3. History of any prior ipsilateral or contralateral invasive breast cancer, history of other malignancies except for appropriately treated skin basal cell carcinoma and cervical carcinoma in situ;
4. History of previous radiotherapy towards the ipsilateral chest/lymph nodes.
5. The ipsilateral axillary lymph node dissection or other previous axillary surgery;
6. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, or psychiatric disease), inability to tolerate radiotherapy or systemic therapy if indicated;
7. Current pregnancy and/or lactation;
8. Inability or unwillingness to comply with protocol requirements.