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

Breast Cancer Clinical Trial

— ATNEC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04109079
• Other study ID #: NIHR 128311
• Status: Recruiting
• Phase: N/A
• Start date: February 26, 2021
• Est. completion date: February 28, 2030

Study information

• Verified date: January 2024
• Source: University Hospitals of Derby and Burton NHS Foundation Trust
• Contact: Amit Goyal, MS, MD, FRCS
• Phone: +44 1332785538
• Email: amit.goyal[@]nhs.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1900
• Est. completion date: February 28, 2030
• Est. primary completion date: February 28, 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• cT1-3N1M0 breast cancer at diagnosis (prior to NACT) by American Joint Committee on Cancer (AJCC) staging 8th edition

• Patients with occult primary breast cancer (no identifiable invasive cancer in the breast) with FNA or core biopsy proven nodal metastases are also eligible for the study.

• 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, as required, to assess response to NACT (per local guidelines)

• Undergo a dual tracer sentinel node biopsy (SNB) after NACT with at least 3 nodes removed in total (sentinel nodes and marked node).

• If a single tracer SNB is performed, the patient is eligible only if the involved node is marked before or during NACT, and at least 3 nodes (including the marked node) are removed during sentinel node biopsy.

• If the node is not marked, or the marked node is not removed, the patient is eligible only 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 only if BOTH points a) and b) below, are met:

1. involved node was marked and removed during SNB; and

2. removed marked node shows evidence of downstaging on histology e.g. fibrosis or scarring.

• If the sentinel node(s) cannot be localised on SNB: axillary node sampling should be performed, the patient will be eligible if at least 3 nodes are removed (including the marked node).

• No evidence of nodal metastases post NACT (isolated tumour cells, micro or macro metastasis)

• Patients with complete pathological response in the axilla but residual disease in the breast post NACT are eligible for the study.

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Neoplasm, Breast
• Sentinel Lymph Node

Intervention

Procedure:
• Axillary lymph node dissection
Participants will undergo removal of at least level I and II axillary lymph nodes.

Radiation:
• Axillary radiotherapy
Axillary radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.
• Breast or chest wall radiotherapy
Breast or chest wall radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.

Locations

Country	Name	City	State
United Kingdom	NHS Grampian	Aberdeen
United Kingdom	Ashford and St Peter's Hospitals NHS Foundation Trust	Ashford
United Kingdom	Tameside and Glossop Integrated Care NHS Foundation Trust	Ashton-under-Lyne
United Kingdom	NHS Ayrshire and Arran	Ayr
United Kingdom	Belfast Health and Social Care Trust	Belfast
United Kingdom	Sandwell and West Birmingham NHS Trust	Birmingham
United Kingdom	University Hospitals Birmingham NHS Foundation Trust	Birmingham
United Kingdom	Bolton NHS Foundation Trust	Bolton
United Kingdom	Bradford Teaching Hospitals NHS Foundation Trust	Bradford
United Kingdom	University Hospitals Sussex NHS Foundation Trust	Brighton
United Kingdom	North Bristol NHS Trust	Bristol
United Kingdom	East Lancashire Hospitals NHS Trust	Burnley
United Kingdom	Frimley Health NHS Foundation Trust	Camberley	Gu16 7uj
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	North Cumbria Integrated Care NHS Foundation Trust	Carlisle	Ca2 7hy
United Kingdom	Countess of Chester Hospital NHS Trust	Chester
United Kingdom	Mid Cheshire NHS Foundation Trust	Crewe
United Kingdom	County Durham and Darlington NHS Foundation Trust	Darlington
United Kingdom	University Hospitals of Derby and Burton NHS Foundation Trust	Derby
United Kingdom	Doncaster and Bassetlaw Teaching Hospitals NHS Foundation Trust	Doncaster
United Kingdom	The Dudley Group NHS Foundation Trust	Dudley
United Kingdom	NHS Dumfries and Galloway	Dumfries
United Kingdom	NHS Fife	Dunfermline
United Kingdom	NHS Lanarkshire	East Kilbride
United Kingdom	NHS Lothian	Edinburgh
United Kingdom	Royal Devon and Exeter NHS Foundation Trust	Exeter
United Kingdom	Gateshead Health NHS Foundation Trust	Gateshead
United Kingdom	James Paget University Hospitals NHS Foundation Trust	Great Yarmouth	Nr31 6la
United Kingdom	Harrogate and District NHS Foundation Trust	Harrogate
United Kingdom	Wye Valley NHS Trust	Hereford
United Kingdom	Buckinghamshire Healthcare NHS Trust	High Wycombe
United Kingdom	Calderdale and Huddersfield NHS Foundation Trust	Huddersfield
United Kingdom	Hull University Teaching Hospitals NHS Trust	Hull
United Kingdom	NHS Highland	Inverness	Iv2 3uj
United Kingdom	East Suffolk and North Essex NHS Foundation Trust	Ipswich
United Kingdom	Chelsea and Westminster Hospital NHS Foundation Trust	Isleworth
United Kingdom	Airedale NHS Foundation Trust	Keighley	Bd20 6td
United Kingdom	University Hospitals of Morecambe Bay NHS Foundation Trust	Lancaster
United Kingdom	NHS Forth Valley	Larbert
United Kingdom	Leeds Teaching Hospitals NHS Trust	Leeds
United Kingdom	University Hospitals of Leicester NHS Trust	Leicester
United Kingdom	United Lincolnshire Hospitals NHS Trust	Lincoln
United Kingdom	Hywel Dda University Health Board	Llanelli
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	North Middlesex University Hospital NHS Trust	London
United Kingdom	Royal Free London NHS Foundation Trust	London
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	Bedfordshire Hospitals NHS Foundation Trust	Luton
United Kingdom	East Cheshire NHS Trust	Macclesfield	Sk10 3bl.
United Kingdom	Manchester University NHS Foundation Trust	Manchester
United Kingdom	NHS Borders	Melrose
United Kingdom	South Tees Hospitals NHS Foundation Trust	Middlesbrough
United Kingdom	Milton Keynes University Hospital NHS Trust	Milton Keynes
United Kingdom	Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle Upon Tyne
United Kingdom	Oxford University Hospitals NHS Foundation Trust	Oxford
United Kingdom	NHS Greater Glasgow and Clyde	Paisley
United Kingdom	University Hospitals Plymouth NHS Trust	Plymouth
United Kingdom	St Helens and Knowsley Teaching Hospitals NHS Trust	Prescot
United Kingdom	Royal Berkshire NHS Foundation Trust	Reading	Rg1 5an
United Kingdom	The Rotherham NHS Foundation Trust	Rotherham
United Kingdom	The Shrewsbury and Telford Hospitals NHS Trust	Shrewsbury	Sy3 8xq
United Kingdom	West Hertfordshire Hospitals NHS Trust	St Albans
United Kingdom	East and North Hertfordshire NHS Foundation Trust	Stevenage
United Kingdom	North Tees and Hartlepool NHS Foundation Trust	Stockton-on-Tees
United Kingdom	University Hospitals of North Midlands NHS Trust	Stoke-on-Trent
United Kingdom	Somerset NHS Foundation Trust	Taunton
United Kingdom	Croydon Health Services NHS Trust	Thornton Heath
United Kingdom	Royal Cornwall Hospitals NHS Trust	Truro
United Kingdom	Mid Yorkshire Hospitals NHS Trust	Wakefield
United Kingdom	Mid and South Essex NHS Foundation Trust	Westcliff-on-Sea
United Kingdom	Wrightington, Wigan and Leigh Teaching Hospitals NHS Foundation Trust	Wigan
United Kingdom	Clatterbridge Cancer Centre NHS Foundation Trust	Wirral
United Kingdom	Wirral University Teaching Hospital NHS Foundation Trust	Wirral
United Kingdom	The Royal Wolverhampton NHS Trust	Wolverhampton
United Kingdom	Yeovil District Hospital NHS Trust	Yeovil
United Kingdom	York and Scarborough Teaching Hospitals NHS Foundation Trust	York

Sponsors (1)

Lead Sponsor	Collaborator
University Hospitals of Derby and Burton NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	Health related quality of life: EQ-5D-5L	Health related quality of life will be assessed with EQ-5D-5L	5 years
Secondary	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
Secondary	Overall survival	Overall survival calculated as the time from randomisation until the date of death by any cause or the censor date.	5 years
Secondary	Local (breast or chest wall) recurrence	Number of participants with local (breast or chest wall) recurrence	5 years
Secondary	Regional (nodal) recurrence	Number of participants with regional (nodal) recurrence	5 years
Secondary	Distant metastasis	Number of participants with distant metastasis.	5 years
Secondary	Contralateral breast cancer	Number of participants with contralateral breast cancer.	5 years
Secondary	Non-breast cancer	Number of participants with non-breast cancer	5 years

External Links

•   ATNEC breast cancer study - Example Doctor and Patient Consultation
•   ATNEC breast cancer study - Research Nurse and Patient Consultation
•   Training video for radiologists to mark the node using black dye tattoo
•   Training video for radiologists to mark the node using clip
•   Training video for surgeons to remove the marked node during sentinel node biopsy