Targeted Axillary Dissection versus axillary node clearance in patients with POsitive axillary Lymph nodes in Early breast cancer: A multicentre, pragmatic, phase III randomised controlled trial

RESEARCH QUESTION In breast cancer patients with low volume axillary nodal disease having primary surgery, compared with axillary node clearance (ANC), does targeted axillary dissection (TAD) reduce lymphoedema at 12 months following surgery without increasing locoregional recurrence (LRR) at 5 years and is it cost-effective? BACKGROUND Breast cancer affects 55,000 patients each year and ~20% will have node positive disease at diagnosis. In the UK, NICE currently recommends ANC for all patients with node positive breast cancer having primary surgery, irrespective of the number of nodes involved. This highly morbid procedure leads to life-long, life-changing complications in 1 in 3 patients including lymphoedema and chronic pain which dramatically affect their quality of life. ANC aims to reduce LRR and improve breast cancer survival but there is no evidence to support these benefits for patients with limited nodal involvement: so-called ‘low volume’ disease. This is defined as clinically node negative (cN0) radiologically-detected nodal disease with 1-2 abnormal nodes on axillary ultrasound. TADPOLE aims to determine if TAD, combining removal of the involved lymph node(s) with a sentinel node biopsy, is a safe alternative to ANC which reduces the risk of life-changing complications without compromising oncological safety in breast cancer patients with low volume nodal disease having primary surgery. AIMS & OBJECTIVES 1. To establish that TAD is superior to ANC in terms of reducing lymphoedema at 12 months without leading to unacceptable rates of LRR at 5 years 2. To estimate the difference between groups with respect to a range of patient-reported, clinical and oncological secondary outcomes 3. To estimate cost-effectiveness of TAD vs ANC DESIGN Multicentre pragmatic phase 3 randomised controlled trial with an internal pilot, embedded qualitative work and surgical quality assurance; parallel groups with 2:1 randomisation (TAD:ANC), integrated study within a trial (SWAT) to optimise recruitment of minority groups and a cost-effectiveness analysis. SETTING: 40 UK breast units POPULATION: Patients with low volume axillary nodal disease having primary surgery INTERVENTION: TAD COMPARATOR: ANC OUTCOMES Co-primary: i) Lymphoedema at 12 months; ii) LRR at 5 years Secondary: Complications; arm/shoulder morbidity; pain; overall and disease-free survival; quality of life and cost-effectiveness. SAMPLE SIZE A total of 861 patients (574 TAD:287 ANC) will be required assuming 20% lymphoedema in the ANC arm and 10% in the TAD arm, based on a 2:1 randomisation, 90% power and 5% significance, allowing for 5% dropout/5% crossover. This number will also be sufficient to exclude an undesirable LRR of 5% in the TAD cohort at 5 years with one sided 2.5% alpha and 90% power. TIMELINES 101-month project starting Sept 2024: 6 months(m) set up; 28m recruitment (9m internal pilot); 60m follow up on all participants; 7m analysis and report. Target recruitment 1 patient/site/m at 40 sites. IMPACT/DISSEMINATION TADPOLE will address the top UK breast surgery research priority identified in the recent James Lind Alliance PSP. If TAD causes less lymphoedema and is oncologically safe, TADPOLE will change practice, improving outcomes for thousands of patients with node positive breast cancer each year. We will present results at conferences, publish in peer-reviewed journals and work with our patient advisory group to share results more widely.