Axillary Management in Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy

Study Overview
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Brief Summary
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The aim of this study is to assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years.

Detailed Description
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Background: The presence of cancer in the axillary lymph nodes on needle biopsy in patients with early stage breast cancer before neoadjuvant chemotherapy (NACT) has been the determinant of the need for axillary treatment (in the form of axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) after completion of NACT. Treatment to the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, pain, numbness, and other sensory problems. As more effective chemotherapy is now available that results in complete eradication of cancer in the axilla in around 40 to 70% of patients, extensive axillary treatment might no longer be necessary in patients with no evidence of residual nodal disease. Aim: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years. Methods: Study design: A pragmatic, phase 3, open, randomised, multicentre trial and embedded economic evaluation in which participants will be randomised in a 1:1 ratio. Study population: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: All participants will receive human epidermal growth factor receptor 2 (HER2)-targeted treatment, endocrine therapy and radiotherapy to breast or chest wall, if indicated according to local guidelines. Patients in the intervention group will not receive further axillary treatment (ALND or ART), whereas those receiving standard care will receive axillary treatment (ALND or ART) as per local guidelines. Follow-up is annually for at least 5 years. Outcomes: The co-primary outcomes are disease free survival(DFS) and self-reported lymphoedema defined as 'yes' to the two questions participants will be asked - 'arm heaviness during the past year' and 'arm swelling now' from the Lymphoedema and Breast Cancer Questionnaire at 5 years. Secondary outcomes: arm function assessed by the QuickDASH (disabilities of the arm, shoulder and hand) questionnaire; health related quality of life assessed using euroqol EQ-5D-5L; axillary recurrence free interval (ARFI); local recurrence; regional (nodal) recurrence; distant metastasis; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years (QALYs) and cost-effectiveness. Sample size: A sample size of 1900 patients would have the ability to demonstrate a 3.5% non-inferiority margin with a 5% 1-sided significance level and 85% power, allowing for 7% non-collection of primary outcome data assuming a 90% 5-year disease free survival rate in the control arm. It would also be able to detect at least a 5% difference in proportion of patients with lymphoedema with 90% power, a 5% 2-sided significance level and allowing for 25% non-collection of primary outcome data over 5 years. Analysis plan: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Time to event outcomes, including disease free survival and axillary recurrence free interval, will be assessed using Kaplan-Meier curves and compared using Cox proportional hazards models. The proportion of patients experiencing lymphoedema at 5 years will be compared across trial arms using a chi-squared test and a logistic regression model used to adjust for stratification variables. Arm morbidity and health related quality of life will be scored using the appropriate manuals and assessed using a longitudinal mixed model regression analysis if model assumptions valid or a standardised area-under-the-curve analysis. For economic evaluation, incremental cost per QALY gained at 5 years will be estimated. Timelines for delivery: Total project duration is 120 months based on 6 months for set up; 60 months recruitment period (including an 18 months internal pilot phase); and 54 months for follow up, analysis, writing up and dissemination.

Official Title
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ATNEC - Axillary Management in T1-3N1M0 Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases at Presentation After Neoadjuvant Chemotherapy

Conditions
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Breast Cancer, Sentinel Lymph Node, Neoplasm, Breast

Intervention / Treatment
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* Procedure: Axillary lymph node dissection
* Radiation: Axillary radiotherapy
* Radiation: Breast or chest wall radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: cT1-3N1M0 breast cancer at diagnosis (prior to NACT) by American Joint Committee on Cancer (AJCC) staging 8th edition Fine-needle aspiration (FNA) or core biopsy confirmed axillary nodal metastases at presentation Oestrogen receptor and HER2 status evaluated on primary tumour Received standard NACT as per local guidelines (Patients undergoing neoadjuvant endocrine therapy as part of another clinical trial are eligible) Imaging of the axilla to assess response to NACT (as per local guidelines) Undergo dual tracer sentinel node biopsy (SNB) after NACT and at least 3 nodes removed in total (sentinel nodes and marked node). If single tracer is used, the patient will be eligible if the involved node is marked before or during NACT, and the marked node and at least 3 nodes (including the marked node) are removed during sentinel node biopsy. If axillary node sampling is performed following failed localisation of sentinel nodes, patient will be eligible if at least 3 nodes removed (including the marked node). If node is not marked, or marked node is not removed, the patient will be eligible if the histology report shows evidence of down-staging with complete pathological response e.g. fibrosis or scarring in at least one node and at least 3 nodes removed. If fewer than 3 nodes are found on histology, the patient is eligible if: a) involved node was marked and removed during SNB; and b) removed marked node shows evidence of downstaging on histology e.g. fibrosis or scarring. No evidence of nodal metastases post NACT (isolated tumour cells, micro or macro metastasis) Exclusion Criteria: Bilateral synchronous invasive breast cancer Sentinel node biopsy prior to NACT Previous axillary surgery on the same body side as the scheduled targeted sampling Any previous cancer within 5 years or concomitant malignancy except basal or squamous cell carcinoma of the skin in situ carcinoma of the cervix in situ melanoma contra- or ipsilateral in situ breast cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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 axillary treatment<br>Patients in this arm will not receive axillary treatment (axillary lymph node dissection or axillary radiotherapy). Supraclavicular fossa radiotherapy is not allowed when randomised to this arm. | Radiation: Breast or chest wall radiotherapy<br>* Breast or chest wall radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.<br>|
| Active Comparator: Axillary treatment<br>Patients in this arm will receive axillary treatment. Axillary treatment can be axillary lymph node dissection or axillary radiotherapy. | Procedure: Axillary lymph node dissection<br>* Participants will undergo removal of at least level I and II axillary lymph nodes.<br>Radiation: Axillary radiotherapy<br>* Axillary radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.<br>Radiation: Breast or chest wall radiotherapy<br>* Breast or chest wall radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) | DFS calculated as the time from randomisation until the date of first event of either a loco-regional invasive breast cancer relapse, distant relapse, ipsilateral or contralateral new invasive primary breast cancer or death by any cause or the censor date. | 5 years | 
| Patient reported lymphoedema | Lymphoedema is self-reported based on two items from the validated Lymphoedema and Breast Cancer Questionnaire (arm swelling now and arm heaviness in the past year). Lymphoedema is defined as 'yes' to both questions. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm function | Arm function will be assessed using shortened version of the Disability of the Arm, Shoulder and Hand (DASH), the 11-item QuickDASH questionnaire. Physical disability is defined as a change from baseline in the QuickDASH score of at least 14 points. | 5 years | 
| Health related quality of life: EQ-5D-5L | Health related quality of life will be assessed with EQ-5D-5L | 5 years | 
| Axillary recurrence free interval | Axillary recurrence free interval, calculated from the date of randomisation to the date of axillary recurrence or the censor date. | 5 years | 
| Overall survival | Overall survival calculated as the time from randomisation until the date of death by any cause or the censor date. | 5 years | 
| Local (breast or chest wall) recurrence | Number of participants with local (breast or chest wall) recurrence | 5 years | 
| Regional (nodal) recurrence | Number of participants with regional (nodal) recurrence | 5 years | 
| Distant metastasis | Number of participants with distant metastasis. | 5 years | 
| Contralateral breast cancer | Number of participants with contralateral breast cancer. | 5 years | 
| Non-breast cancer | Number of participants with non-breast cancer | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoadjuvant chemotherapy, sentinel node biopsy, breast cancer, tattooing node, marking node, clip node, axillary ultrasound, node positive, axillary lymph node dissection, axillary radiotherapy, axillary treatment