Clinical trial NCT04109079: Axillary Management in Breast Cancer Patients with Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy
Official title: ATNEC - Axillary Management in T1-3N1M0 Breast Cancer Patients with Needle Biopsy Proven Nodal Metastases At Presentation After Neoadjuvant Chemotherapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Breast Cancer
Sentinel Lymph Node
Neoplasm, Breast
Keywords: 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
Lead sponsor: University Hospitals of Derby and Burton NHS Foundation Trust
Sponsor class: OTHER
First posted: 2019-09-30
Enrollment: 1900
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Disease free survival (DFS)
timeFrame: 5 years
measure: Patient reported lymphoedema
timeFrame: 5 years
Secondary outcomes:
measure: Arm function
timeFrame: 5 years
measure: Health related quality of life: EQ-5D-5L
timeFrame: 5 years
measure: Axillary recurrence free interval
timeFrame: 5 years
measure: Overall survival
timeFrame: 5 years
measure: Local (breast or chest wall) recurrence
timeFrame: 5 years
measure: Regional (nodal) recurrence
timeFrame: 5 years
measure: Distant metastasis
timeFrame: 5 years
measure: Contralateral breast cancer
timeFrame: 5 years
measure: Non-breast cancer
timeFrame: 5 years
Other outcomes:
Locations:
city: Galway
country: Ireland
facility: Galway University Hospitals
city: Keighley
country: United Kingdom
facility: Airedale NHS Foundation Trust
state: Bd20 6td
city: Carlisle
country: United Kingdom
facility: North Cumbria Integrated Care NHS Foundation Trust
state: Ca2 7hy
city: Camberley
country: United Kingdom
facility: Frimley Health NHS Foundation Trust
state: Gu16 7uj
city: Inverness
country: United Kingdom
facility: NHS Highland
state: Iv2 3uj
city: Great Yarmouth
country: United Kingdom
facility: James Paget University Hospitals NHS Foundation Trust
state: Nr31 6la
city: Reading
country: United Kingdom
facility: Royal Berkshire NHS Foundation Trust
state: Rg1 5an
city: Macclesfield
country: United Kingdom
facility: East Cheshire NHS Trust
state: Sk10 3bl.
city: Shrewsbury
country: United Kingdom
facility: The Shrewsbury and Telford Hospitals NHS Trust
state: Sy3 8xq
city: Aberdeen
country: United Kingdom
facility: NHS Grampian
city: Ashford
country: United Kingdom
facility: Ashford and St Peter's Hospitals NHS Foundation Trust
city: Ashton-under-Lyne
country: United Kingdom
facility: Tameside and Glossop Integrated Care NHS Foundation Trust
city: Ayr
country: United Kingdom
facility: NHS Ayrshire and Arran
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Birmingham
country: United Kingdom
facility: Sandwell and West Birmingham NHS Trust
city: Bolton
country: United Kingdom
facility: Bolton NHS Foundation Trust
city: Bradford
country: United Kingdom
facility: Bradford Teaching Hospitals NHS Foundation Trust
city: Brighton
country: United Kingdom
facility: University Hospitals Sussex NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: North Bristol NHS Trust
city: Burnley
country: United Kingdom
facility: East Lancashire Hospitals NHS Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cheltenham
country: United Kingdom
facility: Gloucestershire General Hospitals NHS Foundation Trust
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital NHS Trust
city: Crewe
country: United Kingdom
facility: Mid Cheshire NHS Foundation Trust
city: Darlington
country: United Kingdom
facility: County Durham and Darlington NHS Foundation Trust
city: Derby
country: United Kingdom
facility: University Hospitals of Derby and Burton NHS Foundation Trust
city: Doncaster
country: United Kingdom
facility: Doncaster and Bassetlaw Teaching Hospitals NHS Foundation Trust
city: Dudley
country: United Kingdom
facility: The Dudley Group NHS Foundation Trust
city: Dumfries
country: United Kingdom
facility: NHS Dumfries and Galloway
city: Dunfermline
country: United Kingdom
facility: NHS Fife
city: East Kilbride
country: United Kingdom
facility: NHS Lanarkshire
city: Edinburgh
country: United Kingdom
facility: NHS Lothian
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter NHS Foundation Trust
city: Gateshead
country: United Kingdom
facility: Gateshead Health NHS Foundation Trust
city: Harrogate
country: United Kingdom
facility: Harrogate and District NHS Foundation Trust
city: Hereford
country: United Kingdom
facility: Wye Valley NHS Trust
city: High Wycombe
country: United Kingdom
facility: Buckinghamshire Healthcare NHS Trust
city: Huddersfield
country: United Kingdom
facility: Calderdale and Huddersfield NHS Foundation Trust
city: Hull
country: United Kingdom
facility: Hull University Teaching Hospitals NHS Trust
city: Ipswich
country: United Kingdom
facility: East Suffolk and North Essex NHS Foundation Trust
city: Isleworth
country: United Kingdom
facility: Chelsea and Westminster Hospital NHS Foundation Trust
city: Lancaster
country: United Kingdom
facility: University Hospitals of Morecambe Bay NHS Foundation Trust
city: Larbert
country: United Kingdom
facility: NHS Forth Valley
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: Lincoln
country: United Kingdom
facility: United Lincolnshire Hospitals NHS Trust
city: Llanelli
country: United Kingdom
facility: Hywel Dda University Health Board
city: London
country: United Kingdom
facility: North Middlesex University Hospital NHS Trust
city: London
country: United Kingdom
facility: Whittington Health NHS Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Luton
country: United Kingdom
facility: Bedfordshire Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
city: Melrose
country: United Kingdom
facility: NHS Borders
city: Middlesbrough
country: United Kingdom
facility: South Tees Hospitals NHS Foundation Trust
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes University Hospital NHS Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle Upon Tyne Hospitals NHS Foundation Trust
city: North Shields
country: United Kingdom
facility: Northumbria Healthcare NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
city: Paisley
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust
city: Portsmouth
country: United Kingdom
facility: Portsmouth Hospitals University NHS Trust
city: Prescot
country: United Kingdom
facility: St Helens and Knowsley Teaching Hospitals NHS Trust
city: Preston
country: United Kingdom
facility: Lancashire Teaching Hospitals NHS Foundation Trust
city: Redhill
country: United Kingdom
facility: Surrey & Sussex Healthcare NHS Trust
city: Rotherham
country: United Kingdom
facility: The Rotherham NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
city: St Albans
country: United Kingdom
facility: West Hertfordshire Hospitals NHS Trust
city: Stevenage
country: United Kingdom
facility: East and North Hertfordshire NHS Foundation Trust
city: Stockton-on-Tees
country: United Kingdom
facility: North Tees and Hartlepool NHS Foundation Trust
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospitals of North Midlands NHS Trust
city: Swansea
country: United Kingdom
facility: Swansea Bay University Health Board
city: Taunton
country: United Kingdom
facility: Somerset NHS Foundation Trust
city: Thornton Heath
country: United Kingdom
facility: Croydon Health Services NHS Trust
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospitals NHS Trust
city: Wakefield
country: United Kingdom
facility: Mid Yorkshire Hospitals NHS Trust
city: Westcliff-on-Sea
country: United Kingdom
facility: Mid and South Essex NHS Foundation Trust
city: Wigan
country: United Kingdom
facility: Wrightington, Wigan and Leigh Teaching Hospitals NHS Foundation Trust
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre NHS Foundation Trust
city: Wirral
country: United Kingdom
facility: Wirral University Teaching Hospital NHS Foundation Trust
city: Wolverhampton
country: United Kingdom
facility: The Royal Wolverhampton NHS Trust
city: Worcester
country: United Kingdom
facility: Worcestershire Acute Hospitals NHS Trust
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital NHS Trust
city: York
country: United Kingdom
facility: York and Scarborough Teaching Hospitals NHS Foundation Trust
Study officials:
affiliation: Royal Derby Hospital, Derby, UK
name: Amit Goyal, MS, MD, FRCS
role: PRINCIPAL_INVESTIGATOR
References: