Axillary Management in Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy
Axillary Management in Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy
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.
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.
Inclusion Criteria:

 -  T1-3N1M0 breast cancer at diagnosis (prior to NACT) by American Joint Committee on
 Cancer (AJCC) staging 7th edition

 -  Fine-needle aspiration (FNA) or core biopsy confirmed axillary nodal metastases at
 presentation

 -  Oestrogen receptor, progesterone receptor and HER2 status evaluated on primary tumour

 -  Received standard NACT as per local guidelines

 -  Ultrasound of the axilla at completion of NACT

 -  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).

 -  No nodal metastases post NACT (isolated tumour cells, micro or macrometastasis)

 Exclusion Criteria:

 -  Bilateral invasive breast cancer

 -  Sentinel node biopsy prior to NACT

 -  Marked node not removed except where the node/s removed show

 -  evidence of downstaging with complete pathological response e.g. fibrosis or
 scarring

 -  Previous axillary surgery on the same body side as the scheduled targeted sampling

 -  Radiation therapy for the currently diagnosed breast cancer prior to randomisation

 -  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