Ultra-Hypofractionated vs Moderate Hypofractionated Radiotherapy for Regional Lymph Nodes in High Risk Breast Cancer (HARVEST-PRO)

A Multicenter, Randomized, Controlled Phase III Clinical Trial Comparing Ultra-Hypofractionated Versus Moderate Hypofractionated Radiotherapy for Regional Lymph Nodes in Post-operative Breast Cancer

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Radiation: Ultra-hypofractionated Regional Nodal Irradiation; Radiation: Moderate Hypofractionated Regional Nodal Irradiation

Detailed Description

The study intervention is RNI delivered using modern techniques, including Intensity-Modulated Radiation Therapy (IMRT), Volumetric Modulated Arc Therapy (VMAT) or Intensity-Modulated Proton Therapy (IMPT). Technical parameters for treatment delivery, such as target delineation and OARs dose constraints, will be standardized across both arms. The investigational component is the randomized comparison of the ultra-hypofractionated regimen (26 Gy in 5 fractions over one week) and the moderate hypofractionated regimen (40 Gy in 15 fractions over three weeks).

• Study Type: Interventional
• Enrollment (Estimated): 1950
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lu Cao, PhD, MD; Phone Number: +86 147824551281; Email: cl11879@rjh.com.cn
• Study Contact Backup: Name: Jia-Yi Chen, PhD, MD; Email: cjy11756@rjh.com.cn

Study Locations

• China
  • Shanghai, China
    • Ruijin Hospital, Shanghai Jiaotong University School of Medicine
    • Contact: Jia-Yi Chen, PhD, MD; Phone Number: +86 021-64370045; Email: chenjiayi0188@aliyun.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provide a signed and dated informed consent form (ICF) before the initiation of any trial-specific procedures.
2. Age ≥ 18 years.
3. Histologically confirmed invasive breast cancer.
4. Have received breast-conserving surgery or mastectomy with axillary staging, including sentinel lymph node biopsy, targeted axillary dissection and/or axillary lymph node dissection.
5. Tumor stage is classified as T1, T2, or T3, as defined by the AJCC Cancer Staging Manual, 8th Edition.

6. Meeting at least one of the following conditions:

   1. Pathological nodal status of pN2 or pN3a;
   2. Pathological nodal status of pN1 with one or more of the following high-risk factors:

   (I), Age < 40 years. (II), Tumor location in the central or inner quadrant. (III), Estrogen Receptor (ER) negative. (IV), Presence of lymphovascular invasion (LVI). (V), Histological grade III. (VI), Patients presenting with clinical stage cN2-3a before neoadjuvant treatment.

7. Pathologically negative surgical margins, defined as "no ink on tumor."
8. Karnofsky Performance Status (KPS) score ≥ 80.
9. Documented biomarker status for Estrogen Receptor (ER), Progesterone Receptor (PR), HER2, and Ki-67.
10. Sufficient wound healing from surgery, with no signs of active infection at the intended radiation site.

Exclusion Criteria:

1. Nodal stage is classified as N3b or N3c, as defined by the AJCC Cancer Staging Manual, 8th Edition.
2. Has undergone or is planning immediate breast reconstruction with a permanent implant or tissue expander.
3. Evidence of distant metastatic disease.
4. Diagnosis of synchronous bilateral invasive breast cancer or a history of prior invasive cancer in either breast.
5. History of prior radiation therapy to the chest, axillary, or supraclavicular regions.
6. Known active collagen vascular diseases, particularly systemic lupus erythematosus or scleroderma, which are contraindications to radiotherapy.
7. Presence of any severe, uncontrolled co-morbidity or medical condition that, in the investigator's judgment, would render the participant unsuitable for the study, compromise protocol compliance, or confound the interpretation of study results.
8. History of any other malignancy within the 5 years before enrollment, with the exception of adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix.
9. Participants who are pregnant or lactating at the time of study enrollment. (Note: In accordance with the standards of each participating institution, women of childbearing age are required to undergo pregnancy testing within 2 weeks prior to randomization.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ultra-hypofractionated regimen; Participants will receive ultra-hypofractionated radiotherapy to regional lymph nodes and chest wall/whole breast. For patients after breast-conserving surgery, a sequential boost to the tumor bed will be administered. Systemic therapy (chemotherapy, endocrine therapy, or targeted therapy) will be given according to standard clinical practice.	Radiation: Ultra-hypofractionated Regional Nodal Irradiation; 26 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.; Other Names: 5-fraction Regional Nodal Irradiation; Ultra-hypofractionated RNI
Active Comparator: Moderate hypofractionated regimen; Participants will receive moderate hypofractionated radiotherapy to regional lymph nodes and chest wall/whole breast. For patients after breast-conserving surgery, a simultaneous integrated boost to the tumor bed will be administered. Systemic therapy (chemotherapy, endocrine therapy, or targeted therapy) will be given according to standard clinical practice.	Radiation: Moderate Hypofractionated Regional Nodal Irradiation; 40.05 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.; Other Names: Moderate hypofractionated RNI; 15-fraction Regional Nodal Irradiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From start of radiotherapy through 90 days after completion of radiotherapy
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	From 90 days after completion of radiotherapy to 10 years
Overall Survival (OS)	Time from randomization to death from any cause.	10 years
Locoregional Recurrence-Free Survival (LRRFS)	Time from randomization to the first ipsilateral breast, chest wall, or regional nodal recurrence.	10 years
Distant Metastasis-Free Survival (DMFS)	Time from randomization to the first evidence of distant metastasis.	10 years
Disease-Free Survival (DFS)	Time from randomization to first occurrence of ipsilateral breast cancer recurrence (invasive or DCIS), locoregional recurrence (chest wall or regional lymph nodes), distant metastasis, contralateral invasive breast cancer, or death from any cause.	10 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	10 years
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.	3, 6, 12, 24, 60 months
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).	3, 6, 12, 18, 24, 36,48, 60 months
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.	12, 24, 60 months
Health-Related Quality of Life (HRQoL)	Assessed using the breast cancer specific EORTC QLQ-BR23 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Breast Cancer Module 23) questionnaire. This is a 23-item breast cancer-specific module assessing functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and symptom scales (systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss). Scores range from 0 to 100. For functional scales, higher scores indicate better functioning; for symptom scales, higher scores indicate worse symptoms.	3, 6, 12, 24, 60 months
Health-Related Quality of Life (HRQoL)	Assessed using the generic questionnaire EQ-5D (EuroQol Five-Dimension Questionnaire). This is a generic health status questionnaire comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a visual analogue scale (EQ-VAS). The EQ-5D index score ranges from -0.59 to 1.00 (with country-specific value sets), and the EQ-VAS ranges from 0 to 100. Higher scores indicate better health-related quality of life.	3, 6, 12, 24, 60 months

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Investigators: Principal Investigator: Jia-Yi Chen, PhD, MD, Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Principal Investigator: Lu Cao, PhD, MD, Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): March 30, 2026
• Primary Completion (Estimated): March 30, 2034
• Study Completion (Estimated): March 30, 2039

Study Registration Dates

• First Submitted: April 1, 2026
• First Submitted That Met QC Criteria: April 9, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Adjuvant Radiotherapy; regional nodal irradiation; hypofractionated radiation therapy; internal mammary node irradiation; ultrahypofractionated radiation therapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: RJIBC-ULTRA RNI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the publication, after deidentification (text, tables, figures, and appendices), will be shared.
• IPD Sharing Time Frame: Beginning 12 months after publication and available for 5 years.

IPD Sharing Access Criteria

Proposals should be directed to cjy11756@rjh.com.cn.

To gain access, requestors must:

1. Provide a methodologically sound research proposal
2. Obtain approval from their institutional ethics committee
3. Sign a data access and use agreement
4. Agree to use data only for the stated research purpose

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No