The PRINCE-BC trial: precision regional irradiation of nodal stations for clinical evaluation of high-risk pN0 breast cancer – a phase III, open-label, randomized controlled trial

Abstract

Introduction

Breast cancer is the most prevalent malignancy among women, posing a significant threat to female health. Radiation therapy serves as a critical component of comprehensive breast cancer treatment, yet its clinical benefit varies substantially across patients with differing recurrence risks. In the era of precision radiation therapy, optimizing the "escalation" or "de-escalation" of radiation therapy regimens based on individualized recurrence risk assessment to maximize net therapeutic benefit for early-stage breast cancer patients has emerged as a key research focus. Previous precision radiation therapy studies for postoperative early-stage pN0 breast cancer primarily centered on treatment de-escalation for low-risk cohorts, while clinical investigations on radiation therapy escalation for high-risk pN0 patients remain scarce.

Materials and methods

This was a prospective, open-labelled, randomized controlled trial aimed to investigate whether the addition of regional node irradiation (RNI) to whole breast irradiation (WBI)/chest wall irradiation (CWI) could improve disease-free survival in clinical high-risk pN0 breast cancer in comparison to WBI/CWI alone. Clinical high-risk was defined as breast cancer patients presented with two or more high-risk factors [tumor size (>2cm), tumor site (medial and central quadrants), ki-67 level (>14%), and Lympho-vascular Invasion Positive (LVI+)]. A total of 1355 participants would be recruited and randomized in a 1:1 ratio into RNI group and non-RNI group. All patients would receive standardized postoperative irradiation dose for WBI/CWI with or without RNI, both hypo-fractionated regimen of 2.67 Gy for 16 fractions or conventional regimen of 2 Gy for 25 fractions were allowed. For patient treated with breast-conserving surgery, sequential tumor bed boost irradiation could be delivered at the treating physician's discretion, based on individual risk factors such as close margins, high grade, or young age. (conventional regimen 10Gy/5Fx; hypo-fraction regimen: 10.68 Gy/4 Fx or 10Gy/4Fx)

Discussion

This is the first large randomized controlled trial to precisely guide decisions regarding regional nodal irradiation (RNI) for clinically high-risk pN0 breast cancer patients. In the era of precision and individualized radiotherapy, our research would provide high level evidence-based recommendations for patients with early-stage high-risk pN0 breast cancer.

Trial registration

ClinicalTrials.gov Identifier NCT05976412 (https://clinicaltrials.gov/search?term=NCT05976412). Date of registration: July 28, 2023. Status: Recruiting.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-026-15971-x.

Background

Breast cancer is the malignancy with the highest incidence and mortality rate among women globally [1]. In China, according to the 2022 National Cancer Center report, breast cancer ranks first in incidence and fourth in mortality among female malignant tumors, posing a serious threat to women’s health in China [2]. Radiation therapy, as one of the crucial treatment modalities for breast cancer, plays a vital role, which has been confirmed by large-scale clinical studies. In 2005, a major meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) [3] (involving 42,000 breast cancer patients) provided the first evidence that radiation therapy following breast-conserving surgery or radiation therapy to the chest wall ± regional nodes following mastectomy not only reduced local recurrence but also translated into a survival benefit. This large-scale clinical study was the first to affirm the positive impact of radiation therapy on survival in breast cancer. Subsequently, the EBCTCG updated the long-term follow-up results for patients receiving radiation therapy after breast-conserving surgery in 2011 [4] and after modified radical mastectomy in 2014 [5] These updates demonstrated that postoperative radiation therapy reduced the risk of local recurrence and improved survival in patients with early-stage breast cancer. However, the EBCTCG group also acknowledged that the degree of benefit derived from radiation therapy varied significantly among breast cancer patients with different recurrence risks.

Early-stage breast cancer has now entered a phase of chronic disease management, with over 90% of cases being curable. However, the long-term toxicities resulting from breast cancer treatment, including poor recovery of upper limb function and persistent lymphedema, as well as non-breast cancer causes of death such as cardiovascular diseases, have become increasingly prominent. These issues significantly impact the quality of life for long-term survivors of early-stage breast cancer. Therefore, in the era of precision radiation therapy, a key research focus is how to maximize the net benefit of radiation therapy for early-stage breast cancer patients. This involves adopting a patient-centered approach, utilizing individualized recurrence risk assessment to tailor “escalation” or “de-escalation” radiation therapy strategies. Current research on precision radiation therapy for early-stage pN0 breast cancer post-surgery primarily focuses on “de-escalation” therapy for early-stage, low-risk pN0 disease, specifically radiation therapy omission. The CALGB 9343 trial was the first prospective phase III randomized controlled study exploring radiation therapy omission after surgery in low-risk pN0 breast cancer. Its 10-year follow-up results showed that for early-stage low-risk pN0 patients (defined as age ≥ 70 years, pathological stage I [tumor ≤ 2 cm], estrogen receptor [ER] positive, negative margins), the 10-year local recurrence rates were 2% vs. 9% (P < 0.05) for those receiving postoperative radiation therapy versus those without radiation therapy. However, there was no statistically significant difference in distant metastasis rates or overall survival [6]. In 2023, updated 10-year follow-up data from the Scottish Cancer Trials Breast Group’s (SCTBG) PRIME II trial showed that the 10-year overall survival rates were nearly identical between the radiation therapy omission group and the postoperative radiation therapy group (80.8% vs. 80.7%) among early-stage low-risk breast cancer patients receiving postoperative endocrine therapy (defined as age ≥ 65 years, maximum tumor diameter ≤ 3 cm, hormone receptor-positive, axillary node-negative, negative margins [≥ 1 mm]) [7]. Based on the results of these two large phase III clinical trials, both the US National Comprehensive Cancer Network (NCCN) guidelines and the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Diagnosis and Treatment Guidelines now recommend considering de-escalation therapy (radiation therapy omission) for pN0 breast cancer patients meeting these low-risk criteria, provided patients are fully informed about recurrence and survival risks.

However, for “escalation” therapy in early-stage high-risk pN0 breast cancer patients, high-level evidence-based medical evidence is still lacking. Two large phase III randomized controlled trials, EORTC 22,922/10,925 [8] and MA20 [9] included a proportion of node-negative (pN0) patients defined as “high-risk”. In EORTC 22,922/10,925, high-risk pN0 was defined as tumors located in the medial or central quadrant, while in MA.20, it was defined as tumor size > 5 cm or tumor ≥ 2 cm with at least one adverse prognostic factor: histological grade III, hormone receptor negativity, or extensive lympho-vascular invasion. Although the definitions of high-risk pN0 differed between these studies, subgroup analyses from both trials suggested that high-risk pN0 patients receiving escalated radiation therapy (chest wall/whole breast irradiation plus comprehensive regional nodal irradiation [including internal mammary nodes]) compared to those receiving whole breast/chest wall irradiation alone, experienced an approximately 11% improvement in 10-year disease-free survival (DFS), a difference approaching statistical significance. Based on these subgroup analysis results, both the CSCO and NCCN guidelines recommend considering escalated radiation therapy (chest wall/whole breast combined with RNI) for postoperative high-risk pN0 breast cancer patients. However, the recommended evidence level is only 2B (based on single cohort studies or low-quality RCTs). In our previous study, we established a risk stratification system (tumor size, tumor location, lympho-vascular invasion (LVI) status and Ki-67 index) for identifying clinically high risk pN0 BC patients, who might benefit from RNI therapy [10]. Based on this clinical model, we perform this randomized controlled trial to clearly determine the survival benefit of RNI among clinically high-risk pN0 breast cancer patients.

Materials and methods

Hypothesis

Objectives

The primary endpoint of this prospective, open-label randomized controlled trial aimed to investigate whether the combination of RNI with chest wall/whole breast irradiation could significantly improve disease-free survival among high risk pN0 BC patients in comparison to chest wall/whole breast irradiation alone.

Methods

Trial design

This was a prospective, open-labelled, randomized controlled trial. We recruited histo-pathologically confirmed pN0 breast cancer patients after surgery and agreed to receive postoperative radiation therapy from Ruijin Hospital, Shanghai Jiaotong university school of medicine. Eligible patients will be randomly assigned in a 1:1 ratio to receive either RNI or non-RNI groups. for non-RNI group, irradiation is delivered to ipsilateral chest wall or whole breast alone. And for RNI group, irradiation is delivered to ipsilateral chest wall or whole breast with regional lymphatic regions (supra/infraclavicular nodes and/or IMN). The trial flow chart was shown in Fig. 1.

Fig. 1.

Study design

Randomization

Participants with informed consent would be checked for eligibility before randomization. Eligible patients would be randomized into the RNI group and non-RNI group in a ratio of 1:1. Randomization was conducted with computer-generated random number by using SPSS software version 21.0 (IBM Corporation, Armonk, NY, USA), stratified by type of primary surgery (BCS or mastectomy).

Primary endpoint

The primary endpoint was disease-free survival, which was defined as the time from surgery to the time of a first recurrence in the ipsilateral breast or in nodal or distant sites, a contralateral breast cancer, or death from breast cancer, which was in consistent with definition of DFS in MA-20 trial [11].

Secondary endpoints

1. 5-year Local reginal recurrence rate, which was defined as the proportion of local or regional recurrence from randomization to 5 years after radiation therapy;

2. 5-year-distant metastases rate: which was defined as the proportion of distant metastases occurring 5 years after radiation therapy;

3. 5-year overall survival rate, which was defined as the proportion of death occurring 5 years after radiation therapy.

Inclusion criteria

1. Voluntarily participated and signed an informed consent form;

2. Age > 18 years old, female;

3. Received radical surgery for breast cancer, including breast conservation surgery or mastectomy, combined with sentinel lymph node biopsy or axillary lymph node dissection;

4. Invasive breast cancer, postoperative axillary lymph node negative, with pathological stage T1-3N0M0 (Stage IA, IIA, IIB), and presenting with ≥ 2 of the following validated high-risk factors: tumor size > 2 cm, tumor location in medial or central quadrants, Ki-67 level > 14%, and presence of lymphovascular invasion. These criteria define “clinically high-risk” pN0 disease as established in our prior risk model [10]; For patients undergoing mastectomy, the presence of these factors indicates the need for chest wall irradiation as part of comprehensive locoregional therapy, consistent with evidence from the EORTC 22,922/10,925 trial [12], which demonstrated significant reductions in breast cancer mortality and recurrence with regional nodal irradiation in high-risk node-negative patients, particularly those with medial/central tumor.

5. KPS ≥ 80, estimated survival time > 5 years;

6. Complete healing of Surgical incision, no incision infection;

7. Reproductive period women should undergo contraception for at least one month before study, and promise to use contraception throughout the entire study period and continue until the specified time after the end of the study.

Exclusion criteria

1. Pregnant or lactating women; Received preoperative therapy;

2. With serious non neoplastic medical complications that affect the implementation of radiation therapy;

3. History of malignant tumor in the past 5 years (excluding previous lobular Carcinoma in situ, skin Basal-cell carcinoma, skin Carcinoma in situ, cervical Carcinoma in situ and lung Carcinoma in situ);

4. Simultaneous contralateral breast cancer;

5. Previous history of neck, chest, or ipsilateral axillary radiation therapy;

6. Active collagen vascular disease;

7. Distant metastasis confirmed by pathology or imaging.

Quality assurance

To ensure consistent interpretation of Ki-67 and lymphovascular invasion (LVI) status, all pathological specimens from enrolled patients undergo central review by dedicated breast pathologists prior to randomization. Ki-67 scoring follows the recommendations of the International Ki-67 in Breast Cancer Working Group [13], with a cutoff of ≥ 14% selected based on the St. Gallen consensus criteria for luminal B subtype classification and validated in our previously published risk model. LVI assessment is based on standardized hematoxylin and eosin staining, with equivocal cases resolved by immunohistochemistry. This central review process minimizes inter-observer variability and ensures that all patients meet the predefined high-risk criteria prior to trial entry.

Comprehensive radiation therapy quality assurance (QA) is also foreseen to ensure consistent and high-quality treatment delivery across all participants. The QA program includes the following components: (1) Pre-treatment contouring and plan review: For each participating radiation oncologist, the first 10 enrolled patients will undergo centralized review of target volume delineation and treatment plans to ensure compliance with the RUIJIN contouring guidelines and protocol-specified dose constraints. (2) Periodic dosimetric audits: Institutional treatment plans will be randomly sampled for independent dosimetric verification, including evaluation of target volume coverage and organs-at-risk doses. (3) Real-time treatment verification: Daily cone-beam CT or orthogonal kilovoltage imaging will be performed to verify setup accuracy prior to each fraction, with corrective action taken for deviations exceeding 5 mm. (4) Prospective credentialing: All participating radiation oncologists and institutions must complete a credentialing process, including contouring of a benchmark case and submission of a test plan, before enrolling patients. These measures are designed to ensure that all patients receive protocol-compliant radiation therapy, minimizing inter-institutional variability and maximizing the reliability of trial outcomes.

Treatment

General consideration

Radiation therapy (RT) should commence within 12 weeks following definitive surgery or within 8 weeks after the final dose of planned postoperative chemotherapy. The RNI target volumes encompassed the supraclavicular, infraclavicular, and internal mammary nodal (IMN) regions, with axillary inclusion if clinically indicated. Planned postoperative endocrine therapy and anti-HER2 therapy should be continued during RT.

RNI group

All patients with high-risk pN0 breast cancer following breast-conserving surgery or mastectomy will receive radiation therapy to the whole breast/chest wall plus regional nodal irradiation (RNI). Consistent with NCCN guidelines, when regional nodal irradiation is indicated, it is recommended to encompass all surgically untreated axillary levels—including levels I, II, III, and IV/supraclavicular—in addition to the internal mammary nodes (IMNs). However, we acknowledge that the optimal extent of regional nodal irradiation in pN0 breast cancer remains an area of ongoing debate and clinical uncertainty, as high-level evidence specific to this population is still lacking. Therefore, while comprehensive coverage of all undissected nodal stations is recommended as the preferred approach, the final extent of regional nodal coverage is left to the treating physician’s discretion, taking into account individual patient anatomy, the extent of axillary surgery (sentinel lymph node biopsy alone vs. axillary lymph node dissection), and the patient’s specific risk profile based on our validated high-risk criteria (≥ 2 factors: tumor size > 2 cm, medial/central location, Ki-67 > 14%, LVI+).

This discretionary approach reflects real-world clinical practice, where decisions regarding comprehensive nodal irradiation are tailored to each patient, and acknowledges the clinical equipoise that justifies our trial. For left-sided patients requiring internal mammary node irradiation, deep inspiration breath-hold (DIBH) is strongly recommended, and strict cardiac dose constraints (mean heart dose < 4 Gy, V25 < 5%) are mandated to ensure safety.

Non-RNI group

All patients with high-risk pN0 breast cancer following breast-conserving surgery or mastectomy will receive radiation therapy to the whole breast/chest wall alone.

Radiation therapy

Localization, simulation, and immobilization

Radiation will be delivered with 6-MV photons, 5 days per week. The patient is positioned supine with both upper limbs elevated and abducted, immobilized using a breast board. A non-contrast CT scan is performed with the scanning range extending from the cranial base superiorly to 4 cm below the inframammary fold inferiorly, using a slice thickness of 3–5 mm.

Radiation therapy regimen

Both hypo-fractionated regimen (40 Gy/15 fractions, 2.67 Gy per fraction) and conventional regimen (50 Gy/25 fractions, 2 Gy per fraction) were permitted. For patient treated with breast-conserving surgery, sequential tumor bed boost irradiation might be delivered at the treating physician’s discretion, based on individual risk factors such as close margins, high grade, or young age. (conventional regimen 10 Gy/5Fx; hypo-fraction regimen: 10.68 Gy/4 Fx or 10 Gy/4Fx). The dosimetric Constraints for Target Volumes was listed in Table 1. And the DVH constraints for OARs were detailed reported in our previous hypo-fraction vs. conventional postoperative radiation therapy trial protocol [14]. Both 3D-conformal radiation therapy (3D-CRT) and volumetric modulated arc therapy (VMAT) were permitted, provided that the pre-specified target volume coverage and organ-at-risk constraints were met. We also noted that deep inspiration breath-hold (DIBH) was strongly recommended for left-sided patients requiring IMN irradiation.

Table 1.

Dosimetric constraints for target volumes

Target volume	Constraints	Hypo-fractionated (40 Gy/15Fx)		Conventional (50 Gy/25Fx)
Chest wall/whole breast PTV	Objective	D95%	> 40 Gy	D95%	> 50 Gy
	Acceptable deviation	D90%	> 40 Gy	D90%	> 50 Gy
	Objective	V43Gy	< 5%	V55Gy	< 5%
	Acceptable deviation	V45Gy	< 5%	V56Gy	< 5%
	Objective	V38Gy	> 99%	V48Gy	> 99%
	Acceptable deviation	V36Gy	> 99%	V45Gy	> 99%
PTV Conformity Index (CI)	Objective	≥ 0.95, ≤2
	Acceptable deviation	≥ 0.85, ≤ 2.5
Tumor Bed PTV (Post-lumpectomy)	Objective	D95%	> 50 Gy	D95%	> 60 Gy
	Acceptable deviation	D90%	> 50 Gy	D90%	> 60 Gy
	Objective	V55Gy	< 5%	V66Gy	< 5%
	Acceptable deviation	V58Gy	< 5%	V69Gy	< 5%
	Objective	V48Gy	> 99%	V57Gy	> 99%
	Acceptable deviation	V45Gy	> 99%	V54Gy	> 99%
Tumor Bed CI	Objective	≥ 0.95, ≤ 2.5
	Acceptable deviation	≥ 0.9, ≤3

For composite targets (CW/Whole Breast + RNI): Dose evaluation excludes sequential tumor bed boost. Conformity Index (CI) = Volume covered by 95% prescription dose / PTV volume

Target volumes definition

The clinical target volume (CTV) and organs at risk (OAR) would be contoured on all CT slices when these structures are visible. The CTV was countered based on RUIJIN criterial, which was developed by our hospital for use in daily practice. The RUIJIN guidelines was established on the basis of RTOG, ESTRO guidelines and relevant literatures about breast cancer contouring (Table 2). The detailed RUIJIN contouring guidelines was described in our previous study, which effectively cover most regional nodes in postoperative breast cancer patients [15].

Table 2.

Delineation borders of the regional node CTVs in RTOG and RUIJIN guidelines

ALN-I	RTOG guideline	RUIJIN guideline
Cranial	Axillary vessels cross lateral edge of pectoralis minor muscle	below the humeral head
Caudal	Pectoralis major muscle insert into ribs	At the point where the pectoralis major inserts on the ribs (around 4th to 5th rib)
Anterior	Plane defined by: anterior surface of pectoralis major muscle and latissimus dorsi muscle	At posterior pectoralis major & minor muscles
Posterior	Anterior surface of subscapularis muscle	An imaginary line anterior to the surface of latissimus dorsi muscle, subscapularis muscle and teres major muscle
Lateral	Medial border of latissimus dorsi muscle	Cranially up to an imaginary line between the major pectoral and deltoid muscles, and further caudal up to a line between the major pectoral and latissimus dorsi muscles
Medial	Lateral border of pectoralis minor muscle	Lateral border of pectoralis minor muscle
ALN-II	RTOG guideline	RUIJIN guideline
Cranial	Axillary vessels cross medial edge of pectoralis minor muscle	Insertion point of pectoralis minor
Caudal	Axillary vessels cross lateral edge of pectoralis minor muscle	The caudal border of the pectoralis minor muscle
Anterior	Anterior surface pectoralis minor muscle	Pectoralis minor muscle
Posterior	Ribs and intercostal muscles	Anterior border of ribs and serratus anterior
Lateral	Lateral border of pectoralis minor muscle	Lateral edge of pectoralis minor muscle
Medial	Medial border of pectoralis minor muscle	Medial edge of pectoralis minor muscle
ALN-III	RTOG guideline	RUIJIN guideline
Cranial	Pectoralis minor muscle insert on cricoid	Pectoralis minor muscle insert on coracoid
Caudal	Axillary vessels cross medial edge of pectoralis minor muscle	Axillary vessels cross medial edge of pectoralis minor muscle
Anterior	Posterior surface pectoralis major muscle	Posterior surface of pectoralis major muscle
Posterior	Ribs and intercostal muscles	Anterior border of ribs or posterior border of subclavian or axillary vessels
Lateral	Medial border of pectoralis minor muscle	Medial border of pectoralis minor muscle
Medial	Thoracic inlet	Lateral border or clavicle, ribs, junction of brachioceph-axillary veins
RN	RTOG guideline	RUIJIN guideline
Cranial	Included in ALN-II/chest wall CTVs	Insertion point of pectoralis minor
Caudal		The caudal border of the pectoralis minor muscle
Anterior		Pectoralis major muscle
Posterior		Pectoralis minor muscle
Lateral		Lateral edge of pectoralis minor muscle
Medial		Medial edge of pectoralis minor muscle
SC-M	RTOG guideline	RUIJIN guideline
Cranial	Caudal to the cricoid cartilage	Caudal to the cricoid cartilage
Caudal	Junction of brachioceph-axillary veins/caudal edge clavicle head	Junction of brachioceph-axillary veins/caudal edge clavicle head
Anterior	Sternocleidomastoid muscle	Posterior edge of sternocleidomastoid muscle
Posterior	Anterior aspect of the scalene muscle	Posterior surface of internal carotid artery or anterior surface of scalene muscles
Lateral	Cranial: lateral edge of sternocleidomastoid muscle Caudal: junction 1st rib-clavicle	Medial border of clavicle head or 5 mm below the skin surface
Medial	Excludes thyroid and trachea	Medial border of internal carotid vessels
SC-L	RTOG guideline	RUIJIN guideline
Cranial	Not contoured	Caudal to the cricoid cartilage
Caudal		Junction of brachioceph-axillary veins/caudal edge clavicle head
Anterior		Posterior surface of internal carotid artery or anterior surface of scalene muscles
Posterior		At the trapezius
Lateral		Medial border of clavicle head or 5 mm below the skin surface
Medial		At the longus coli
IMN	RTOG guideline	RUIJIN guideline
Cranial	Superior aspect of the medial 1st rib	Junction of brachioceph-axillary veins
Caudal	Cranial aspect of the 4th rib	Cranial side of the 4rd rib (in selected cases 5th rib)
Anterior	Encompass the internal mammary/ thoracic vessels	Ventral limit of the vascular area
Posterior	Encompass the internal mammary/ thoracic vessels	Pleura
Lateral	Encompass the internal mammary/ thoracic vessels	7 mm from the internal mammary vein
Medial	Encompass the internal mammary/ thoracic vessels	7 mm from the internal mammary vein

Abbreviations: RTOG Radiation Therapy Oncology Group, ALN-I Axillary lymph node level I, ALN-II Axillary lymph node level II, ALN-III Axillary lymph node level III, RN Rotter’s nodes, SC-M Medial supraclavicular, SC-L Lateral supraclavicular, IMN Internal mammary nodes

In the RNI group, target volumes include the whole breast/chest wall, the supra/infraclavicular nodal region, and the internal mammary nodes (IMNs). Regarding the extent of axillary coverage, the inclusion of specific nodal levels—including whether to cover levels I-II (in patients with sentinel lymph node biopsy alone) and whether to include levels III-IV (the supraclavicular region)—is at the treating physician’s discretion, guided by an integrated assessment of individual patient factors. These factors include: (1) surgical staging (which defines which axillary levels remain undissected); (2) pathological risk profile based on our validated high-risk criteria (tumor size > 2 cm, medial/central location, Ki-67 > 14%, LVI+); (3) genomic information when available; (4) anatomical considerations and projected doses to organs at risk (lung, brachial plexus, heart); and (5) estimated risk-benefit ratio for the individual patient. This discretionary approach reflects the clinical equipoise regarding optimal target volume definition in high-risk pN0 breast cancer and allows for risk-adapted, individualized treatment planning.

Normal tissue delineation

1. Heart: Superior border: Inferior to the pulmonary trunk bifurcation; Inferior border: Cardiac apex; Includes: Pericardium; Excludes: Pulmonary trunk, ascending aorta, and superior vena cava.

2. Bilateral Lungs: Delineated on lung window settings; Contoured separately for left and right lungs; Includes: Small vessels extending from the hilum into the lung parenchyma; Excludes: Hilar structures, trachea, bronchi, and other mediastinal structures. Note: Automated lung contouring tools in the planning system may be used for efficiency.

3. Spinal Cord: Delineated based on bony boundaries of the spinal canal; Superior border: Cranial base; Inferior border: Inferior edge of the second lumbar vertebra (L2).

4. Humeral Heads: Delineated on bone window settings; Includes: Entire humeral head.

Radiation therapy interruption

In patients who experienced grade 4 hematological or grade 3 or higher nonhematological toxicity, radiation therapy will be delayed until the toxicity recover to grade ≤ 2. At most, a 2-week delay will be permitted. Patients with an interruption for more than 2 weeks would be excluded from the trial.

Sample size calculation

This Phase III randomized controlled clinical trial compared an experimental group (receiving whole breast/chest wall irradiation plus regional nodal irradiation, RNI) against a control group (omitting RNI). The primary endpoint was the 5-year disease-free survival (DFS) rate. Based on retrospective data from our institution, the 5-year DFS for postoperative clinically high-risk pN0 breast cancer patients receiving whole breast irradiation alone was 86% [10]. We hypothesized that adding RNI would improve the 5-year DFS rate in this population from 86% to 91%. With a two-sided α = 0.05 and 80% power, and accounting for a 10% dropout rate, the required sample size was calculated using PASS 11.0 software. The trial would enroll 1,355 patients (678 in the RNI group, 677 in the control group) under 1:1 randomization. The study timeline comprised 3 years enrollment period and 5 years follow-up period. And the total study duration were 8 years.

Follow-up

Follow-up would be conducted at routine intervals after completion of radiation therapy: every 6 months within the first 2 years, and annually thereafter. Follow-up assessments include:

1. Physical Examination Schedule:

   • Baseline: Before radiation therapy initiation
   • During radiation therapy: Weekly
   • Post-radiation therapy: At 4 weeks
   • Years 1–2 post-RT: Every 6 months
   • 2 years post-RT: Annually
2. Breast/Regional Lymph Node Ultrasound & Abdominal Ultrasound Schedule:

   • Baseline: Before radiation therapy initiation
   • Post-radiation therapy: At 4 weeks
   • Years 1–2 post-RT: Every 6 months
   • 2 years post-RT: Annually

3. Mammography and Chest CT Schedule: Annually starting 12 months after radiation therapy completion.

4. Pathological Examination: To be performed at the clinician’s discretion based on physical examination and imaging findings.

Any recurrence was cytologically or histologically confirmed whenever possible. According to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0) and the Radiation Therapy Oncology Group (RTOG) scale, acute and late radiation related toxicity during each follow-up visits would be recorded and graded.

Statistical analyses

Statistical analyses would follow the intent-to-treat (ITT) principle, including all enrolled patients irrespective of eligibility deviations. Categorical variables would be compared using χ² or Fisher’s exact tests and reported as counts/percentages. Normally distributed continuous variables would be analyzed with t-tests and summarized as mean ± SD or median (IQR). The primary endpoint (5-year DFS) would be compared between RNI and non-RNI groups. Survival outcomes (RFS/OS) would be estimated with 95% CIs, visualized by Kaplan-Meier curves, and compared via log-rank tests. Statistical significance was defined as p < 0.05 for all analyses.

Current trial status

The trial had been approved by the Ethics Committee of Ruijin hospital, Shanghai Jiao Tong University School of Medicine RJ 2023–148) on July 28 2023 and registered on ClinicalTrials.gov (NCT05976412) before recruitment. The currently used trial protocol version was Version 1.0 (July 2023). The recruitment of the trial was initiated on 28 July 2023. Currently, the trial remained at the recruiting stage. A total of 303 patients had been enrolled until 10 July 2025. The first patient was enrolled on the 30 July 2023 and the expect enrollment duration was 3 years. As the primary endpoint was 5-year disease-free survival, the final data of collection for the primary outcome measure was expected to be May 2031.

Patient and public involvement

Neither patients nor the public were involved in the design, conduct, reporting or dissemination plans of this trial.

Dissemination plan

We planned to publish the primary and secondary results of the present study in scientific peer- reviewed journals, and at radiation oncology conferences. If there were any important protocol modifications, we would immediately communicate with relevant parties.

Discussion

Guideline recommendations regarding regional nodal irradiation (RNI) for high-risk pN0 breast cancer lack unanimous consensus among breast radiation oncology specialists, and the debate over whether these patients require RNI remains unresolved. This uncertainty stems primarily from two factors. First, treatment toxicity remains a significant concern. Regional nodal irradiation, particularly including the internal mammary chain, inevitably increases cardiac radiation exposure. Radiation-induced heart disease is dose-dependent and irreversible, with each 1 Gy increase in mean heart dose associated with a 7.4% increase in major coronary events—a risk that persists for at least 20 years [16]. Furthermore, data from our center and previous studies had confirmed that regional nodal irradiation significantly increases the risk of upper limb lymphedema and functional impairment [11]. Second, there is ongoing controversy regarding the definition of high-risk pN0 patients, with considerable variability in criteria across different studies. To our knowledge, this study is the first prospective randomized controlled trial specifically targeting early-stage high-risk pN0 breast cancer patients. While the clinical benefit of RNI for pN1/2 disease has been established by multiple phase III trials [8, 9, 17, 18] and EBCTCG meta-analyses, high-level evidence supporting RNI for high-risk pN0 patients remains unavailable. This trial will provide rigorous clinical evidence to guide precision radiation therapy decision-making in this population.

Prior to initiating this randomized controlled trial, we conducted a retrospective analysis of 622 early-stage pN0 breast cancer patients who underwent breast-conserving surgery followed by whole-breast radiation therapy at Ruijin Hospital (2009–2016). Using Cox regression modeling, we screened 11 potential prognostic factors and identified four independent predictors of disease-free survival (DFS): tumor size, tumor location, lymphovascular invasion (LVI) status, and Ki-67 index [10]. As the number of adverse prognostic factors increased, DFS progressively declined. Patients with 0–1 risk factors demonstrated significantly superior outcomes compared to those with ≥ 2 factors, with the lowest DFS observed in patients harboring all four factors. Based on these findings, we established a clinicopathological risk model defining clinically low-risk pN0 (0–1 risk factor) and clinically high-risk pN0 (≥ 2 risk factors). The 5-year DFS was 97% in the low-risk group versus 86% in the high-risk group (p < 0.0001). External validation using the SEER database (N = 24,029 radiation-treated pN0 patients) confirmed the model’s prognostic value: 7-year overall survival was 90% for 0 risk factors, 88% for 1 risk factor, and 82% for ≥ 2 risk factors (p < 0.0001). This validated clinical prediction model provides a critical foundation for the current study.

The indication for chest wall irradiation (CWI) after mastectomy in early-stage breast cancer patients requires careful consideration. In our trial, CWI is indicated exclusively for patients meeting our validated definition of “clinically high-risk” pN0 breast cancer (≥ 2 risk factors: tumor size > 2 cm, central/medial location, Ki-67 > 14%, LVI+) [10]. While we acknowledge that T4 tumors would automatically qualify for CWI, our inclusion criteria deliberately focus on patients with T1-3N0 disease who harbor sufficient risk to potentially benefit from comprehensive locoregional irradiation. This rationale is strongly supported by the 15-year results of the EORTC 22,922/10,925 trial, which included a substantial proportion of patients treated with mastectomy (23.9%) and a large cohort of node-negative patients (44.4%) [8]. Subgroup analysis by nodal status demonstrated that the benefit of regional nodal irradiation was consistent across all nodal subgroups, with no evidence of heterogeneity (heterogeneity p = 0.86). The hazard ratio for overall survival with regional irradiation in pN0 patients was 0.88 (95% CI 0.72–1.08)—more favorable than that observed in pN1 patients (HR 0.94). These findings indicate that node-negative patients with high-risk features derive at least as much benefit from comprehensive regional nodal irradiation as node-positive patients. Notably, this benefit was achieved despite the inclusion of mastectomy patients and the use of primarily 2D and early 3D radiation techniques. In our trial, the use of modern intensity-modulated radiation therapy (IMRT) with deep inspiration breath-hold (DIBH) for left-sided patients and stricter cardiac dose constraints is expected to further improve the therapeutic ratio. Thus, the EORTC 22,922 trial provides direct evidence supporting the premise that clinically high-risk pN0 patients—particularly those with medial/central tumor location—can achieve meaningful improvements in oncologic outcomes from escalated radiation therapy, including chest wall irradiation when indicated.

The role of internal mammary node (IMN) irradiation in node-positive or high-risk breast cancer remains debated, with two key controversies: cardiac safety in left-sided patients, and the necessity of routine IMNI in all right-sided patients despite minimal cardiac dose increase. The DBCG-IMN2 study, a large prospective cohort study, reported a significant overall survival benefit with IMNI in node-positive patients treated with modern systemic therapy and 3D-conformal radiation therapy (3D-CRT) (15-year OS: 65.0% vs. 60.8%; HR 0.85, p = 0.0016), with consistent benefit across all subgroups and low cardiac mortality (0.2% in right-sided patients receiving IMNI vs. 0.7% in left-sided patients without IMNI) [19]. However, this was not a randomized trial, and the use of 3D-CRT in free-breathing may not reflect contemporary techniques with stricter dose constraints. Moreover, whether all right-sided patients require IMNI remains unresolved; population-level benefit does not guarantee individual benefit, and potential toxicities including lung injury and second malignancies must be considered [20, 21].

Our own prospective randomized trial demonstrated the cardiac safety of left-sided IMNI with modern IMRT and dose constraints (MHD ≤ 6 Gy, V30 ≤ 20%, V10 ≤ 50%), showing 0% clinical cardiac events at 1 year [22]. In the current protocol, we apply even stricter constraints (MHD < 4 Gy, V25 < 5%) and mandate IMRT with DIBH for left-sided patients. IMNI is delivered only to clinically high-risk pN0 patients defined by our validated risk model [10], ensuring selective application to those most likely to benefit—a principle that applies equally to right-sided patients, where the absence of cardiac constraint does not justify routine IMNI. We believe that routine omission of IMNI in left-sided patients is not justified, given the consistent survival benefit observed in landmark trials, the consensus reflected in international guidelines, and the demonstrated cardiac safety with modern techniques. Similarly, for right-sided patients, IMNI should be guided by individualized risk assessment rather than routine application. In exceptional cases where dose constraints cannot be met, omission may be considered after multidisciplinary discussion.

The current trial has several potential limitations. First of all, the definition of high risk is based on risk clinicopathological factors, but lack of genomic recurrence score, which would provide additional information for early-stage BC patients. Secondly, this is a single institute, open-label, randomized controlled trial, which needed to be externally validated by other institutions treated with the same radiation therapy regimen.

In conclusion, this research project aims to utilize our validated risk model for individualized stratification of recurrence risk in postoperative early-stage pN0 breast cancer patients, thereby precisely guiding decisions regarding regional nodal irradiation. For clinically high-risk pN0 patients, the study will assess whether adding RNI can further reduce locoregional recurrence and improve survival outcomes. In the era of precision and individualized radiation oncology, this prospective randomized controlled trial will provide an optimized postoperative radiation therapy strategy for patients with early-stage high-risk pN0 breast cancer and generate high-level evidence-based recommendations for this population.

Abbreviations

CW

Chest wall

WB

Whole breast

RNI

Regional nodal irradiation

BC

Breast cancer

EBCTCG

Early Breast Cancer Trialists' Collaborative Group

RT

Radiotherapy

NCCN

National Comprehensive Cancer Network

LVI

Lympho-vascular Invasion

ER

Estrogen-receptor

PR

Progesterone-receptor

SCTBG

Scottish Cancer Trials Breast Group's

DFS

Disease-free survival

OS

Overall survival

IMN

Internal mammary nodal

CTV

Clinical target volume

OAR

Organs at risk

RTOG

The Radiation Therapy Oncology Group

ITT

Intent-to-treat

CTCAE 3.0

Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 3.0)

RCT

Randomized controlled trial

Authors’ contributions

Principal investigator: J.C., G.C and W.X.Q. Drafting of the protocol manuscript: W.X.Q. and G.C. Conceptualization: J.C. G.C. and W.X.Q.; Project administration: C.X., R.C., S.L. and S.Z. data analysis, acquisition, and interpretation: D.O., S.Z., S.L., W.X.Q., G.C., J.C.; manuscript preparation: W.X.Q., C.X., G.C., J.C., Final approval of manuscript: all authors. Wei-Xiang Qi / W.X. Q. are responsible for the overall content as guarantor.

Funding

This study was supported by Clinical Research Plan of SHDC (SHDC2020CR4070), Clinical Research Special Project of Shanghai Municipal Health Commission Health Industry (202340226), Shanghai Science and Technology Innovation Action Plan Medical Innovation Research Project (23Y11904700) and Shanghai Key Laboratory of Proton therapy (23dz2261000). The funding source has no role in study design, data collection, analysis, interpretation, the writing of the manuscript, or the decision to submit the current study.

Data availability

Data sharing is not applicable to this article as the current study is still openfor inclusion of patients.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Ruijin hospital, Shanghai Jiao Tong University School of Medicine (RJ2023–148). Informed consent to participate was obtained from all of the participants in the study. The study is registered in ClinicalTrials.gov (NCT05976412). Written informed consent will be obtained from all participants included in the study prior to randomization.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.