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

Not Applicable

Recruiting

• Conditions: Breast Cancer; Sentinel Lymph Node; Neoplasm, Breast

• Registration Number: NCT04109079
• Lead Sponsor: University Hospitals of Derby and Burton NHS Foundation Trust

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.

Study Timeline

• Study First Submitted: 2019-09-27
• Study First Submitted QC: 2019-09-27
• Study First Posted: 2019-09-30
• Study Start: 2021-02-26
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-22
• Last Update Posted: 2024-10-24
• Primary Completion: 2030-02-28
• Study Completion: 2030-02-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1900

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Overall survival	5 years	Overall survival calculated as the time from randomisation until the date of death by any cause or the censor date.
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.
Distant metastasis	5 years	Number of participants with distant metastasis.
Non-breast cancer	5 years	Number of participants with non-breast cancer
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.
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
Contralateral breast cancer	5 years	Number of participants with contralateral breast cancer.

Trial Locations

Locations (88)

Galway University Hospitals; 🇮🇪 Galway, Ireland

Gloucestershire General Hospitals NHS Foundation Trust; 🇬🇧 Cheltenham, United Kingdom

Whittington Health NHS Trust; 🇬🇧 London, United Kingdom

Northumbria Healthcare NHS Foundation Trust; 🇬🇧 North Shields, United Kingdom

Portsmouth Hospitals University NHS Trust; 🇬🇧 Portsmouth, United Kingdom

Lancashire Teaching Hospitals NHS Foundation Trust; 🇬🇧 Preston, United Kingdom

Surrey & Sussex Healthcare NHS Trust; 🇬🇧 Redhill, United Kingdom

Sheffield Teaching Hospitals NHS Foundation Trust; 🇬🇧 Sheffield, United Kingdom

Swansea Bay University Health Board; 🇬🇧 Swansea, United Kingdom

Worcestershire Acute Hospitals NHS Trust; 🇬🇧 Worcester, United Kingdom

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