SMALL: Open surgery versus minimally invasive vacuum-assisted excision for small screen-detected breast cancer – a phase III randomised multi-centre trial

SMALL is a phase III multi-center randomised trial to assess whether vacuum-assisted excision of biologically-favourable screen-detected breast cancer is as effective as standard surgical excision with sentinel lymph node biopsy in terms of requiring a second surgical procedure, and in achieving acceptable local recurrence rates. STUDY DESIGN • Randomised controlled trial with embedded single arm cohort • Patients randomised in a 2:1 ratio in favour of vacuum-assisted excision (VAE) • Single arm analysis of VAE patients to assess local recurrence (LR) rates • LR rate in VAE cohort not to exceed undesirable threshold (3% at 5 years) • LR rate in standard surgical arm to be utilised to aid interpretation of VAE cohort • Internal Pilot Phase to assess feasibility of intervention and recruitment • QuinteT Recruitment Intervention utilised to optimise recruitment STUDY SETTING • Patients identified/approached within the NHS Breast Screening Programme (NHSBSP) • Recruitment and treatment in secondary care specialist Breast Units TARGET POPULATION • Women >50 years • Screen-detected breast cancer <15mm in size, ER/PR positive, HER2 negative HEALTH TECHNOLOGIES BEING ASSESSED VAE • Widely used in NHSBSP for excision of benign lesions, and acceptable to patients • Repurposing for excision of small breast cancers avoiding open surgery VAE Arm • VAE of tumour under local anaesthesia • Post-procedure imaging to determine completeness of excision • Open surgical procedure if incompletely excised Standard Surgery Arm • Surgical excision under general anaesthetic • Further surgery as required to achieve complete resection Both Arms • Adjuvant hormonal and radiotherapy as per local protocol • 5 years mammographic surveillance MEASUREMENT OF COSTS AND OUTCOMES Co-primary Outcomes • Re-excision rate (non-inferiority) • LR rate in VAE cohort Secondary Outcomes • Patient reported outcomes • Complications • Health economic evaluation SAMPLE SIZE 801 patients will be recruited, allowing for a 5% drop out. In the randomised comparison of re-excision rates, the probability of success in both arms is 80%: one-sided 2.5% alpha, 90% power to detect a maximum difference of 10%. 762 patients are required. To exclude an undesirable local recurrence rate of 97% in the VAE cohort at 5 years with one-sided 2.5% alpha and 90% power requires 511 VAE patients to be followed for 3 years. PROJECT TIMETABLE The study duration is 9 years. Recruitment will last 4 years with 18 month internal pilot. At the pilot’s conclusion, 141 patients will be recruited and maximum recruitment achieved, by which time we aim to recruit 22 patients/month from 70 centres. Analysis of the first primary outcome will be carried out once all patients are recruited. Follow-up continues for 5 years and analysis of LR rate in the VAE arm will occur when all patients have 3 years follow up. EXPERTISE OF THE SMALL TEAM A multidisciplinary team with a proven track record in breast cancer research will ensure delivery of this practice-changing trial. The clinical and PPI team brings wide experience in treatment de-escalation studies. Methodological and statistical expertise comes from the CR UK Clinical Trials Unit at Birmingham University, as do Health Economic and Trial Management skills. PPI representatives are key members of the trial development group and vital to ensuring it's successful delivery. Finally, the QuinteT Recruitment Intervention team bring extensive experience of addressing and overcoming recruitment difficulties in challenging trials.