TADPOLE

Overview

Breast cancer affects 55,000 patients each year, the majority of whom have surgery as their primary treatment. Currently, NICE recommends that axillary node clearance (ANC) is offered to all patients with node positive disease at diagnosis, even those with low volume nodal disease which is defined as having clinical node negative disease with 1-2 nodes seen on USS. One in three patients, however, will experience major life changing complications after ANC. These include lymphoedema, long-term pain, and problems with shoulder function. These complications dramatically affect patients' quality of life and as they are life-long, are costly to the NHS. 

Removal of all the lymph nodes in the armpit was traditionally believed to give patients the best chance of surviving their breast cancer, but there is no evidence to show that this is needed if the spread to the axillary lymph nodes is limited. More targeted surgery to the armpit, called a targeted axillary dissection (TAD), in which just the lymph nodes containing cancer and the first draining (sentinel) lymph nodes are removed may be just as safe and reduce the risk of patients having life-changing, long-term complications.

Objectives

Aim

The TADPOLE study aims to compare the clinical and cost-effectiveness of TAD compared with ANC in patients with low volume node positive breast cancer having primary surgery and test the hypothesis that TAD is superior to ANC in terms of reducing rates of lymphoedema without adversely affecting long-term locoregional recurrence (LRR)

Primary objective 

To determine whether, in breast cancer patients with biopsy-confirmed low volume axillary nodal disease having primary surgery, TAD is superior to ANC in terms of reducing lymphoedema at 12 months while maintaining acceptable rates of locoregional recurrence at 5 years.

Secondary objectives

1. To determine the difference between groups with respect to a range of patient-reported, clinical and oncological secondary outcomes
2. The short and long-term cost-effectiveness of TAD compared with ANC by combining trial data with data from the literature.

Study design

TADPOLE is a multicentre pragmatic phase 3 randomised controlled trial (RCT) with a 9-month internal pilot, embedded qualitative work and surgical quality assurance (QA); two parallel groups with 2:1 randomisation to TAD vs ANC and co-primary endpoints, integrated study within a trial (SWAT) to optimise recruitment of minority ethnic groups; patient follow up for 60 months and a trial-based economic evaluation with development of an economic model to estimate the long-term cost-effectiveness of TAD vs ANC.

Intervention – Targeted axillary dissection (TAD)

Comparator – Axillary node clearance (ANC)

Outcomes

Primary outcomes

TADPOLE has co-primary outcomes

1. Lymphoedema at 12 months
2. Locoregional recurrence at 5 years

Secondary outcomes

1. Surgical complications at 1 month post-last axillary surgery
2. Surgical and oncological outcomes at 1-month post-last axillary surgery
3. Patient-reported lymphoedema at 12, 24 and 60 months assessed using two questions from the LBCQ questionnaire
4. Objective assessment of lymphoedema at 12 months using measurement of arm circumference
5. Arm and shoulder morbidity using the QuickDASH (51) at 12, 24 and 60 months
6. Pain at 1 and 12 months using the Numerical Pain Rating Scale (NPRS)
7. Overall and disease-free survival at 60 months
8. Health-related quality of life using the EQ-5D-5L, FACT-B+4 and LYMPH-Q at 12,24, 60 months
9. Resource use to estimate costs at 12, 24, 60 months and modelled beyond the end of the trial

Eligibility Criteria

Inclusion criteria

1. Adults (≥18 years of age)
2. Primary T1-2 breast cancer of any grade (multifocal/multicentric disease is permitted)
3. Low volume N1 axillary nodal disease confirmed on core biopsy or fine needle aspiration cytology, defined as:
   a.    clinically normal(cN0)
   b.    radiologically detected nodal involvement
   c.    with <=2 involved nodes on USS
4. Able and willing to provide written informed consent
5.  Willing, fit and able to undergo primary surgical treatment

Exclusion criteria

1. ≥3 suspicious nodes on USS or clinically abnormal (cN1)
2. T3 or T4 disease by clinical or radiological assessment
3. Pure invasive lobular carcinoma
4. Bilateral breast cancer
5. Previous ipsilateral breast cancer or ductal carcinoma in situ
6. Received neoadjuvant systemic anticancer therapy (neoSACT)
7. Received neoadjuvant endocrine therapy (defined as >4 weeks of treatment)
8. Previous axillary surgery (sentinel node biopsy, axillary node clearance or axillary sample)
9. Other invasive cancers unless: a) Disease free for 5 years or b) Previous basal cell carcinoma, cervical carcinoma in situ; non-muscle invasive urothelial carcinoma
10. High risk group for developing breast cancer as defined by NICE guidance
11. Pregnant or breast feeding
12. Any serious and/or unstable pre-existing medical, psychiatric or other condition that would prevent compliance with the trial or consent process
13. Prisoners 

Planned sample size

861 patients

Total number of sites planned

Minimum of 40 UK Breast Units

Timeline

TADPOLE opened to recruitment in December 2025. Recruitment is planned for28 months. The trail will close 2023