No Axillary sUrgical Treatment In Clinically Lymph Node Negative Patients After UltraSonography

Study Overview
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Brief Summary
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NAUTILUS study is a prospective, multicenter, RCT. Clinically T1,T2, node negative BCS candidates with no evidence of metastases in AUS are 1:1 randomized into no SLNB group and SLNB group. NAUTILUS study aim to establish the minimally invasive treatment of breast cancer by reexamining the necessity of sentinel lymph node biopsy among patients with invasive breast cancer who have tumors under 5cm, are clinically node-negative, and are having breast conserving surgery performed.

Detailed Description
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[Background] Skipping ALND, the follow-up treatment in SN-positive patients, has non-inferior oncological outcomes compared to SLNB-only group, given that there is no severe SN metastases. Axillary ultrasound can effectively exclude high nodal burden, showing 95% NPV in a systematic review. SLNB has morbidity including lymphedema, limited range of motion, pain, and other post-surgical complications, eventually leading to reduced quality of life. Considering improvement of imaging modalities and adjuvant care, survival outcome of SLNB must be re-evaluated. Especially research reflective of the regional specificities of Korea and Asia-Pacific is needed. [Study design] Prospective, Multicenter, RCT. [Statistical considerations] According to Z0011 trial, 5yr DFS in eligible patients is expected to be 86%, which is between previous data of 88.6% in cT1,2 and SN-negative patients4, and 83.9% in cT1,2 and 1-2 SN-positive patients. Non-inferiority margin is set at 5%. With 5% significance level and 80% power, 780 patients are needed in each group. Assuming a 10% drop out rate, 1734 patients need to be recruited. [Screening and Randomization] Participants undergo screening tests that assess eligibility according to inclusion/exclusion criteria. In order to identify axillary lymph node metastases, axillary ultrasound is first performed by radiologists. Patients showing normal features are enrolled, while for conditionally normal patients, with only 1 suspicion of low nodal burden, axillary lymph node biopsy should be performed. Suspicious patients are excluded under following conditions: patients with 1 or more suspicion of high nodal burden, 2 or more suspicion of low nodal burden, or T2 invasive lobular carcinoma patients with 1 or more low nodal burden. The severity of nodal burden is defined through the criteria. Patients who underwent radiological axillary staging are randomly assigned (1:1) to the study arm and the control arm before surgical care. Stratification is done based on trial centers and tumor sizes. [Post-surgical care] All patients are planned to receive ipsilateral whole breast radiation. Patients randomized to non-SLNB arm are recommended to follow high tangential radiotherapy protocol, in which upper margin of radiation field includes axillary level I and II or lies within 2CM from humeral head. Additional treatment may be performed if deemed necessary by the researcher [Objectives] Primary objective - 5yr invasive Disease Free Survival Secondary objectives 5yr Overall Survival 5yr Distant Metastasis Free Survival Axillary recurrence rate Patient reported AE QoL

Official Title
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No Axillary sUrgical Treatment In Clinically Lymph Node Negative Patients After UltraSonography[NAUTILUS]: A Prospective, Multicenter, Phase III Clinical Trial

Conditions
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Breast Cancer, Sentinel Lymph Node

Intervention / Treatment
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* Procedure: No SLNB
* Procedure: SLNB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ≥ 19 years Invasive unilateral breast carcinoma with histological confirmation History of invasive breast cancer Histologically or radiologically no suspicion of distant metastases Performance status corresponding to ECOG grade 0-2 Tumor size clinically and radiologically ≤ 5cm, independent of hormone receptor and HER2 status Clinically and sonographically negative axillary lymph nodes before biopsy; core needle biopsy or fine needle aspiration of suspicious lymph node required BCS candidate with postoperative whole-breast irradiation and adequate systemic therapy No psychological and geographical restriction in follow-up Written informed consent Exclusion Criteria: History of any cancer in the previous 5 years Bilateral breast cancer Invasive breast cancer treated with neoadjuvant therapy Tumor size clinically and radiologically > 5cm Mastectomy candidate Pregnancy and breastfeeding Male breast cancer Unable to understand and fill out questionnaires

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: No SLNB group<br>The study arm - BCS without SLNB | Procedure: No SLNB<br>* BCS only. Ommission of SLNB by axilla ultrasonography among selective breast cancer patients<br>|
| Other: SLNB group<br>The Control Arm - BCS with SLNB(+/-ALND) | Procedure: SLNB<br>* BCS with SLNB(+/-ALND)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| invasive Disease Free Survival (iDFS) | Evaluate invasive disease free survivals | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Evaluate overall survival | 5 years | 
| Distant Metastasis Free Survival (DMFS) | Evaluate distant metastasis free survival | 5 years | 
| Axillary recurrence rate | Evaluate ipsilateral axillary recurrence rate | 5 years | 
| Locoregional Recurrence Rate (LRR) | Evaluate locoregional recurrence rate | 5 years | 
| Patient reported Adverse Events (AEs) | Evaluate Patient reported Adverse Events | 1 year | 
| QoL | Evaluate Quality of Life of patient by EORTC QLQ-C30 questionnaire | 1 year |