ATNEC: Axillary Management in Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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N/A |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: No axillary treatment 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
Breast or chest wall radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.
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Active Comparator: Axillary treatment Patients in this arm will receive axillary treatment. Axillary treatment can be axillary lymph node dissection or axillary radiotherapy. |
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.
Radiation: Breast or chest wall radiotherapy
Breast or chest wall radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.
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Outcome Measures
Primary Outcome Measures
- Disease free survival (DFS) [5 years]
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.
- Patient reported lymphoedema [5 years]
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.
Secondary Outcome Measures
- Arm function [5 years]
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.
- Health related quality of life: EQ-5D-5L [5 years]
Health related quality of life will be assessed with EQ-5D-5L
- Axillary recurrence free interval [5 years]
Axillary recurrence free interval, calculated from the date of randomisation to the date of axillary recurrence or the censor date.
- Overall survival [5 years]
Overall survival calculated as the time from randomisation until the date of death by any cause or the censor date.
- Local (breast or chest wall) recurrence [5 years]
Number of participants with local (breast or chest wall) recurrence
- Regional (nodal) recurrence [5 years]
Number of participants with regional (nodal) recurrence
- Distant metastasis [5 years]
Number of participants with distant metastasis.
- Contralateral breast cancer [5 years]
Number of participants with contralateral breast cancer.
- Non-breast cancer [5 years]
Number of participants with non-breast cancer
Eligibility Criteria
Criteria
Inclusion Criteria:
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T1-3N1M0 breast cancer at diagnosis (prior to NACT) by American Joint Committee on Cancer (AJCC) staging 7th edition
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Fine-needle aspiration (FNA) or core biopsy confirmed axillary nodal metastases at presentation
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Oestrogen receptor, progesterone receptor and HER2 status evaluated on primary tumour
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Received standard NACT as per local guidelines
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Ultrasound of the axilla at completion of NACT
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Undergo dual tracer sentinel node biopsy after NACT and at least 3 nodes removed (sentinel nodes and marked node). 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).
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No nodal metastases post NACT (isolated tumour cells, micro or macrometastasis)
Exclusion Criteria:
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Bilateral invasive breast cancer
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Sentinel node biopsy prior to NACT
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Marked node not removed except where the node/s removed show
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evidence of downstaging with complete pathological response e.g. fibrosis or scarring
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Previous axillary surgery on the same body side as the scheduled targeted sampling
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Radiation therapy for the currently diagnosed breast cancer prior to randomisation
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Previous cancer within 5 years or concomitant malignancy except
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basal or squamous cell carcinoma of the skin
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in situ carcinoma of the cervix
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in situ melanoma
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contra- or ipsilateral in situ breast cancer
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Airedale NHS Foundation Trust | Keighley | Bd20 6td | United Kingdom | |
2 | North Cumbria Integrated Care NHS Foundation Trust | Carlisle | Ca2 7hy | United Kingdom | |
3 | Frimley Health NHS Foundation Trust | Camberley | Gu16 7uj | United Kingdom | |
4 | NHS Highland | Inverness | Iv2 3uj | United Kingdom | |
5 | James Paget University Hospitals NHS Foundation Trust | Great Yarmouth | Nr31 6la | United Kingdom | |
6 | Royal Berkshire NHS Foundation Trust | Reading | Rg1 5an | United Kingdom | |
7 | East Cheshire NHS Trust | Macclesfield | Sk10 3bl. | United Kingdom | |
8 | The Shrewsbury and Telford Hospitals NHS Trust | Shrewsbury | Sy3 8xq | United Kingdom | |
9 | NHS Grampian | Aberdeen | United Kingdom | AB25 2ZN | |
10 | Sandwell and West Birmingham NHS Trust | Birmingham | United Kingdom | B18 7QH | |
11 | Bolton NHS Foundation Trust | Bolton | United Kingdom | BL4 0JR | |
12 | Bradford Teaching Hospitals NHS Foundation Trust | Bradford | United Kingdom | BD5 0NA | |
13 | Cambridge University Hospitals NHS Foundation Trust | Cambridge | United Kingdom | CB2 0QQ | |
14 | Countess of Chester Hospital NHS Trust | Chester | United Kingdom | CH2 1HJ | |
15 | Mid Cheshire NHS Foundation Trust | Crewe | United Kingdom | CW1 4QJ | |
16 | County Durham and Darlington NHS Foundation Trust | Darlington | United Kingdom | DL3 6HX | |
17 | University Hospitals of Derby and Burton NHS Foundation Trust | Derby | United Kingdom | DE22 3NE | |
18 | NHS Dumfries and Galloway | Dumfries | United Kingdom | DG2 8RX | |
19 | NHS Fife | Dunfermline | United Kingdom | KY12 0SU | |
20 | NHS Lanarkshire | East Kilbride | United Kingdom | G75 8RG | |
21 | NHS Lothian | Edinburgh | United Kingdom | EH4 2XU | |
22 | Royal Devon and Exeter NHS Foundation Trust | Exeter | United Kingdom | EX2 5DW | |
23 | Gateshead Health NHS Foundation Trust | Gateshead | United Kingdom | NE9 6SX | |
24 | Wye Valley NHS Trust | Hereford | United Kingdom | HR1 2ER | |
25 | Calderdale and Huddersfield NHS Foundation Trust | Huddersfield | United Kingdom | HD3 3EA | |
26 | Hull University Teaching Hospitals NHS Trust | Hull | United Kingdom | HU16 5JQ | |
27 | NHS Forth Valley | Larbert | United Kingdom | FK5 4WR | |
28 | Leeds Teaching Hospitals NHS Trust | Leeds | United Kingdom | LS9 7TF | |
29 | University Hospitals of Leicester NHS Trust | Leicester | United Kingdom | LE3 9QP | |
30 | Hywel Dda University Health Board | Llanelli | United Kingdom | SA14 8QF | |
31 | North Middlesex University Hospital NHS Trust | London | United Kingdom | N18 1QX | |
32 | University College London Hospitals NHS Foundation Trust | London | United Kingdom | NW1 2BU | |
33 | Royal Free London NHS Foundation Trust | London | United Kingdom | NW3 2QG | |
34 | King's College Hospital NHS Foundation Trust | London | United Kingdom | SE5 9RS | |
35 | The Royal Marsden NHS Foundation Trust | London | United Kingdom | SM2 5PT | |
36 | Imperial College Healthcare NHS Trust | London | United Kingdom | W6 8RF | |
37 | Bedfordshire Hospitals NHS Foundation Trust | Luton | United Kingdom | LU4 0DZ | |
38 | Manchester University NHS Foundation Trust | Manchester | United Kingdom | M8 5RB | |
39 | NHS Borders | Melrose | United Kingdom | TD6 9BS | |
40 | South Tees Hospitals NHS Foundation Trust | Middlesbrough | United Kingdom | TS4 3BW | |
41 | Milton Keynes University Hospital NHS Trust | Milton Keynes | United Kingdom | MK6 5LD | |
42 | Newcastle Upon Tyne Hospitals NHS Foundation Trust | Newcastle Upon Tyne | United Kingdom | NE1 4LP | |
43 | Oxford University Hospitals NHS Foundation Trust | Oxford | United Kingdom | OX3 7LE | |
44 | St Helens and Knowsley Teaching Hospitals NHS Trust | Prescot | United Kingdom | L35 5DR | |
45 | The Rotherham NHS Foundation Trust | Rotherham | United Kingdom | S60 2UD | |
46 | West Hertfordshire Hospitals NHS Trust | St Albans | United Kingdom | AL3 5PN | |
47 | North Tees and Hartlepool NHS Foundation Trust | Stockton-on-Tees | United Kingdom | TS19 8PE | |
48 | University Hospitals of North Midlands NHS Trust | Stoke-on-Trent | United Kingdom | ST4 6QG | |
49 | Somerset NHS Foundation Trust | Taunton | United Kingdom | TA1 5DA | |
50 | Royal Cornwall Hospitals NHS Trust | Truro | United Kingdom | TR1 3LJ | |
51 | Mid Yorkshire Hospitals NHS Trust | Wakefield | United Kingdom | WF1 4DG | |
52 | Mid and South Essex NHS Foundation Trust | Westcliff-on-Sea | United Kingdom | SS0 0RY | |
53 | Wrightington, Wigan and Leigh Teaching Hospitals NHS Foundation Trust | Wigan | United Kingdom | WN1 2NN | |
54 | Clatterbridge Cancer Centre NHS Foundation Trust | Wirral | United Kingdom | CH63 4JY | |
55 | Wirral University Teaching Hospital NHS Foundation Trust | Wirral | United Kingdom | CH63 4JY | |
56 | Yeovil District Hospital NHS Trust | Yeovil | United Kingdom | BA21 4AT |
Sponsors and Collaborators
- University Hospitals of Derby and Burton NHS Foundation Trust
Investigators
- Principal Investigator: Amit Goyal, MS, MD, FRCS, Royal Derby Hospital, Derby, UK
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Training video for surgeons to remove the marked node during sentinel node biopsy
- Training video for radiologists to mark the node using black dye tattoo
- Training video for radiologists to mark the node using clip
- ATNEC breast cancer study - Research Nurse and Patient Consultation
Publications
None provided.- NIHR 128311