Award Title: SMALL: Open surgery versus minimally invasive vacuum-assisted excision for small screen-detected breast cancer – a phase III randomised multi-centre trial
Funder: Department of Health and Social Care

Abstract: Aim_x000D_
This research aims to look at a new treatment for women who have a small breast cancer diagnosed by Breast Screening and compare it with surgery, which has always been used to treat these cancers._x000D_
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Background_x000D_
In the NHS Breast Screening Programme, there has been concern about the diagnosis of cancers which would never have been seen if a woman had not had a screening mammogram. This is known as overdiagnosis, and it’s estimated for every breast cancer death prevented by breast screening, about three cancers will be overdiagnosed. These cancers have always been treated with an operation. However, in this research, we plan to look at a new way of removing these small, early-stage breast cancers, using a method called vacuum-assisted excision. This uses a large needle connected to a vacuum device to remove tissue from the breast, and is done under local anaesthetic, under the control of an ultrasound scan. Afterwards, mammograms are done to make sure that the small cancer is completely removed._x000D_
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Design and Methods_x000D_
In this research, women with small, early stage breast cancers will be have their cancer removed either with a standard surgical operation (removal of the tumour along with a lymph node from the armpit) under general anaesthetic, or else using the new vacuum-assisted needle method to remove the breast tumour only._x000D_
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After standard surgery, up to 1 in 5 women will need to have a follow-up operation, because when the cancer is removed from the breast and examined in the lab, cancer cells are still present at the edge of the piece of tissue that was removed. If we are using the new method to remove cancers, we need to make sure that a larger number of women won’t need a follow-up operation afterwards if the mammogram shows that the cancer is not fully removed. We would accept that a few more women might need a follow-up operation after the new treatment, because many more would benefit from avoiding having standard surgery in the first place. In the research, we will compare the rate of women who need a follow-up operation in both groups to make sure that it is not much higher in women having the vacuum group._x000D_
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We also know that after breast cancer treatment there is a very low risk of the cancer coming back in the breast - this happens in about 1 in 100 women. We know when this happens it can be treated with another operation. We will be following women up to make sure that this doesn’t happen more often in women who have the new treatment._x000D_
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If this research shows that the new method of removing breast cancers is as safe and as good as an operation, this would have many benefits for patients and their families. They would not need to have their cancer treated with an operation, so they wouldn’t need to have a general anaesthetic and run the risk of having the side effects of surgery. Also, fewer trips to hospital would be needed. There would also be benefits for the NHS as it would mean that fewer people would need to come to hospital for an operation, so there would be more operating theatre time available for other surgery._x000D_
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Dissemination of Results_x000D_
Women who take part in this research will be offered the opportunity to be sent a copy of the results. We will also share the results with groups of patients who have an interest in this area, and with the NHS staff who look after women with breast cancer, so that they are aware of the results of the research and can use it to help them offer the best possible treatment.

Lay Abstract: 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._x000D_
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STUDY DESIGN_x000D_
•	Randomised controlled trial with embedded single arm cohort_x000D_
•	Patients randomised in a 2:1 ratio in favour of vacuum-assisted excision (VAE)_x000D_
•	Single arm analysis of VAE patients to assess local recurrence (LR) rates_x000D_
•	LR rate in VAE cohort not to exceed undesirable threshold (3% at 5 years)_x000D_
•	LR rate in standard surgical arm to be utilised to aid interpretation of VAE cohort_x000D_
•	Internal Pilot Phase to assess feasibility of intervention and recruitment_x000D_
•	QuinteT Recruitment Intervention utilised to optimise recruitment_x000D_
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STUDY SETTING_x000D_
•	Patients identified/approached within the NHS Breast Screening Programme (NHSBSP) _x000D_
•	Recruitment and treatment in secondary care specialist Breast Units_x000D_
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TARGET POPULATION_x000D_
•	Women >50 years_x000D_
•	Screen-detected breast cancer <15mm in size, ER/PR positive, HER2 negative_x000D_
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HEALTH TECHNOLOGIES BEING ASSESSED_x000D_
VAE_x000D_
•	Widely used in NHSBSP for excision of benign lesions, and acceptable to patients_x000D_
•	Repurposing for excision of small breast cancers avoiding open surgery_x000D_
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VAE Arm_x000D_
•	VAE of tumour under local anaesthesia_x000D_
•	Post-procedure imaging to determine completeness of excision_x000D_
•	Open surgical procedure if incompletely excised_x000D_
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Standard Surgery Arm_x000D_
•	Surgical excision under general anaesthetic_x000D_
•	Further surgery as required to achieve complete resection_x000D_
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Both Arms_x000D_
•	Adjuvant hormonal and radiotherapy as per local protocol_x000D_
•	5 years mammographic surveillance  _x000D_
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MEASUREMENT OF COSTS AND OUTCOMES_x000D_
Co-primary Outcomes_x000D_
•	Re-excision rate (non-inferiority)_x000D_
•	LR rate in VAE cohort_x000D_
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Secondary Outcomes_x000D_
•	Patient reported outcomes_x000D_
•	Complications_x000D_
•	Health economic evaluation_x000D_
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SAMPLE SIZE_x000D_
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.  _x000D_
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PROJECT TIMETABLE_x000D_
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._x000D_
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EXPERTISE OF THE SMALL TEAM_x000D_
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.

Research Activity Codes: 6.4 SURGERY
Health Categories: CANCER AND NEOPLASMS