POSNOC - POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: A randomised controlled trial of axillary treatment in women with early stage breast cancer who have metastases in one or two sentinel nodes

Design: Pragmatic randomised, multicentre, non-inferiority trial. Setting: Hospital breast units, outpatient and inpatient. Target population: Women with operable, core biopsy proven, early stage invasive breast cancer, who have had either breast conserving surgery or mastectomy, and are sentinel node positive(i.e. they have metastasis in the sentinel node). In hospitals where sentinel node histology is checked intra-operatively, at the same time as the breast surgery, women will consent pre-operatively and then randomised intra-operatively if their sentinel nodes are found to be positive. Inclusion criteria Women will be eligible for inclusion only if ALL of the following criteria apply: • 18 years or older • Unifocal or multi-focal invasive tumour with lesion not greater than 5 cm in its largest dimension, measured pathologically or for women who are randomised intra-operatively largest tumour diameter on mammogram or ultrasound • No axillary nodal metastasis on clinical and ultrasound examination • At sentinel node biopsy have 1 or 2 sentinel nodes with macrometastases (tumour deposit >2.0 mm in largest dimension or defined as macrometastasis on molecular assay) • Fit for axillary treatment and adjuvant therapy • Have given written informed consent Exclusion criteria Women will be excluded if they have : • bilateral breast cancer • more than 2 sentinel node macrometastases or extranodal invasion • neoadjuvant therapy for breast cancer • previous axillary surgery on the same body side as the scheduled sentinel node biopsy • not fit or eligible to receive adjuvant systemic therapy • previous or concomitant malignancy except o adequately treated basal or squamous cell carcinoma of the skin or o adequately treated in situ carcinoma of the cervix or o adequately treated in situ melanoma o contra- or ipsilateral in situ breast cancer Health technologies being assessed: This trial compares adjuvant therapy alone with adjuvant therapy plus axillary treatment(axillary lymph node clearance or axillary radiotherapy). Adjuvant therapy will be based on current guidelines, and will include chemotherapy and/or hormone therapy for all women, and radiotherapy to breast or chest wall if indicated. Human epidermal growth factor receptor 2 (HER2) targeted treatment may be administered when indicated. Axillary and supraclavicular fossa radiotherapy is not allowed when randomised to adjuvant therapy alone. Study assessments: Baseline data will be collected from the participant's medical notes and questionnaires. Follow-up Assessments Follow-up will be at 6, 12, 24, 36, 48 and 60 months post-randomisation. The 36 and 60 months follow-up will be a clinic visit (doctor or nurse led), however follow-up at other time points may be conducted by a research nurse over the telephone, according to local practice. Assessments: 1. Follow-up eCRFs will be completed in the clinic or over the telephone to record information on primary and secondary outcomes at 6, 12, 24, 36, 48 and 60 months, 2. Lymphoedema and Breast Cancer Questionnaire (two questions) and QuickDASH questionnaire will be completed in the clinic or over the telephone at 6, 12, 24 and 36 months, 3. Postal questionnaires with up to two reminders, FACT B+4, Spielberger State/Trait Anxiety Inventory and EQ-5D at 3, 6, 12, 24 and 36 months. Primary Outcome The primary outcome is axillary recurrence at 5 years. Secondary Outcomes Secondary outcomes assessed at 3, 6, 12, 24 and 36 months are: • Arm morbidity • Quality of life • Anxiety • Economic outcomes Secondary outcomes assessed at 6, 12, 24, 36, 48 and 60 months are: • Local (breast or chest wall) recurrence • Regional (nodal) recurrence • Distant metastasis • Time to axillary recurrence • Axillary recurrence free survival • Disease free survival • Overall survival • Contralateral breast cancer • Non-breast malignancy Sample size: It is estimated that the axillary recurrence rate in the adjuvant therapy plus axillary treatment group at 5 years is 2%. With an absolute non-inferiority margin of 2%, to show that the axillary recurrence rate in the adjuvant therapy alone group at 5 years is not more than 4%, with a one-tailed test for non-inferiority, 1800 patients need to be randomised(with 80% power). Allowing for 5% lost to follow up over the 5 years, gives a sample size of 1900 women. Project timetables including recruitment rate: Total project duration is 10 years Set up (6 months): site training and initiation, awareness raising, developing Case Report Forms and database. Feasibility of recruitment (12 months): feasibility assessed based on total recruitment, number of active sites, compliance with the allocated treatment and losses to follow up Recruitment(33 months): 50 sites recruiting, target recruitment 58 to 63 per month Follow up(60 months): clinic visits or nurse led follow up and postal questionnaires Analysis, writing up and dissemination(9 months). Radiotherapy quality assurance: The sites will be required to adhere to the specific radiotherapy planning and delivery guidelines when treating participants in the study. The NCRI Radiotherapy Trials QA (RTTQA) group will be responsible for implementing and coordinating the Radiotherapy Quality Assurance programme.