A study for women who have small breast cancers found by screening, comparing removal of the cancer by standard surgery with a smaller procedure, which is more like a biopsy
| ISRCTN | ISRCTN12240119 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12240119 |
| IRAS number | 254892 |
| Secondary identifying numbers | RG_18-180; CPMS 40111 |
- Submission date
- 14/10/2019
- Registration date
- 16/10/2019
- Last edited
- 23/04/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English Summary
Contact information
Dr Jessica Foster
Scientific
Scientific
Cancer Research UK Clinical Trials Unit (CRCTU)
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 414 9021 |
|---|---|
| small@trials.bham.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Surgery |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | SMALL: A Phase III, randomised, multi-centre trial addressing overtreatment of small screen-detected breast cancer by comparing standard surgery versus minimally invasive vacuum-assisted excision |
| Study acronym | SMALL |
| Study hypothesis | The aim of the main trial is to determine whether the extent of surgical treatment can be reduced in the context of standard adjuvant radiotherapy and endocrine therapy |
| Ethics approval(s) | Approved 07/08/2019, HSC REC A (Office for Research Ethics Committees Northern Ireland (ORECNI), Customer Care and Performance Directorate, Unit 4, Lissue Industrial Estate West, Rathdown Walk, Moira Road, Lisburn, BT28 2RF; +44 (0)28 9536 1400; reca@hscni.net), ref: 19/NI/0126 |
| Condition | Breast Cancer |
| Intervention | STUDY DESIGN & JUSTIFICATION The SMALL trial is a prospective randomised, two-arm, multi-centre trial. The recruitment target is 800 patients. It is anticipated that 70 U.K. sites will be opened to recruitment. Patients will be randomised in a 1:2 ratio to undergo either standard surgery and sentinel lymph node biopsy or vacuum-assisted excision (VAE), and it is expected that this will take place within 31 days of randomisation. All patients will be followed up via the recruiting site for 5 years post-randomisation. Further long-term follow-up data may be collected by the data linkage services. This study aims to address the issue of possible over-treatment of small screen-detected breast cancers by assessing whether such cancers can be treated with minimally-invasive vacuum excision, in the context of a randomised clinical trial. In order to be practice changing, it will be necessary to demonstrate that not only is there an acceptable local recurrence risk associated with VAE followed by radiotherapy and endocrine therapy, but also that there is not an excess requirement for additional procedures in the VAE arm, in case of radiologically-determined incomplete excision. The total number of patients to be recruited with the 1:2 allocation ratio in favor of VAE is 800 (267 surgery, 533 VAE). The total number required for the re-excision comparison was 762, and this has been inflated by 5%. This will ensure that we have sufficient patients for the single arm investigation of local recurrence rates with VAE, and allow for possible drop-outs. No formal interim analysis is planned. The final analysis following the initial procedure will be conducted 3 months following the completion of recruitment. This will ensure that all patients have undergone their randomised procedure and been assessed for re-excision. The analysis of complications arising from surgery or VAE will also be conducted at this point. Analysis of the local recurrence free survival and all remaining secondary outcomes will be conducted 3 months after all patients have completed 3 years of annual mammography following randomisation. PATIENT PATHWAY Patients enrolling in the trial will recently have attended their local NHS Breast Screening Unit following recall for assessment of a mammographic abnormality identified on their routine screening mammograms. At this time, where possible, the local screening unit will supply potentially eligible patients with a copy of the brief introductory Patient Information Leaflet (PIL), and this will be given either with the invitation to attend for assessment or at the clinic appointment. This PIL aims to provide information to prepare patients for a possible invitation to participate in a research study at an early stage in their pathway. They will also receive information regarding the Information Study (the optional recruitment intervention) at this stage. The subsequent patient pathway will be as follows: 1. Eligible patients will attend clinic to receive the results of their biopsy 2. They will be invited to take part in the optional Information Study 3. Patients will complete and sign the optional Information Study Informed Consent Form, if applicable 4. If the patient consents to participate in the Information Study, the subsequent trial discussion may be audio-recorded 5. Patients agreeing to participate in SMALL will complete and sign the Informed Consent Form for the main trail 6. Patients will complete baseline Quality of Life questionnaires 7. Randomisation by the research team 8. Patient attends for either standard surgery or VAE according to randomised allocation 9. Patients in the VAE arm will have post-procedure mammography on the same day as their procedure 10. After treatment, patient results including histopathology and post-procedure imaging will be discussed in the local MDT 11. Patients will be seen in the clinic to discuss histopathology results, any requirement for an additional procedure and subsequent radiotherapy and endocrine therapy discussed 12. In order to obtain accurate follow-up information, patients will need to attend the hospital every year for mammograms for 5 years. Patients will be informed of the results of these as soon as possible after these have been carried out (usually within 2 weeks) 13. The Trial Office will send Quality of Life questionnaires to complete at 6 months after surgery/VAE, and subsequently annually until year 5 14. The hospital research team provide follow-up information on patients for up to 5 years 15. If there is enough tissue available, the trial will collect tissue samples from the diagnostic biopsy and from any future breast investigations or surgery, for research Interventions Surgery arm: - Standard surgical treatment as deemed appropriate by local MDT, including axillary sentinel lymph node biopsy - Adjuvant radiotherapy/endocrine therapy as per local treatment guidelines VAE arm: - Image-guided vacuum excision of breast cancer - No axillary surgery - Adjuvant radiotherapy to breast - Adjuvant endocrine therapy Sites will randomise patients into the trial using a bespoke electronic Remote Data Capture system, or via completion of a Randomisation Form followed by a telephone call the SMALL Trial Office. Patients will be randomised at a ratio of 1:2 in favour of the VAE arm using computerised minimisation technique |
| Intervention type | Other |
| Primary outcome measure | 1. Re-excision following initial procedure at 3 months following the end of the recruitment period 2. Local recurrence-free survival time for VAE at 3 months after all patients have completed 3 years of annual mammography following randomisation |
| Secondary outcome measures | 1. Complications arising from surgery or VAE at 3 months following the end of the recruitment period 2. Time to ipsilateral breast cancer recurrence at 3 months after all patients have completed 3 years of annual mammography following randomisation 3. Time to development of contralateral invasive breast cancer at 3 months after all patients have completed 3 years of annual mammography following randomisation 4. Overall survival time at 3 months after all patients have completed 3 years of annual mammography following randomisation 5. Quality-adjusted life year (QALY) at 3 months after all patients have completed 3 years of annual mammography following randomisation 6. Quality of life: will be assessed using the following tools: EORTC QLQ-C30 and BR23, EuroQoL EQ-5D, BREAST-Q (breast conserving therapy module). The Quality of Life questionnaires will be completed by patients prior to randomisation at baseline, all other questionnaires will be distributed directly to the patients’ home address by the SMALL Trial office at 6, 12, 24, 36, 48 and 60 months post-randomisation |
| Overall study start date | 01/01/2019 |
| Overall study end date | 30/06/2029 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 47 Years |
| Sex | Female |
| Target number of participants | Planned Sample Size: 800; UK Sample Size: 800 |
| Participant inclusion criteria | Current inclusion criteria as of 02/06/2021: 1. Female aged ≥47 years old with screen-detected breast cancer 2. ≤15 mm maximum tumour diameter on mammogram and ultrasound 3. No associated malignant microcalcification outwith the mass lesion (calcification within the lesion is permitted) 4. Unifocal disease 5. Grade 1 disease on diagnostic core biopsy 6. ER strongly positive (Allred score of 7 or 8, or equivalent, e.g. at least moderate positivity in >66% of tumour cell nuclei) 7. PR strongly positive (Allred score of 7 or 8, or equivalent, e.g. at least moderate positivity in >66% of tumour cell nuclei) 8. HER2 negative (0 or 1+ by immunohistochemistry, or 2+ and negative by in situ hybridisation techniques (FISH or DISH) 9. Normal axillary ultrasound axillary, or equivocal ultrasound with benign fine needle aspiration cytology (FNAC) or core biopsy (CB) 10. Willing to be randomised 11. Able to provide written informed consent 12. Willing and able to undergo standard surgical treatment 13. Willing and able to undergo radiotherapy 14. Willing and able to take standard endocrine therapy 15. No previous diagnosis of ipsilateral breast cancer or DCIS (contralateral DCIS or invasive disease permitted if surgically treated ≥ 5 years previously and disease-free _____ Previous inclusion criteria: 1. Female aged ≥ 47 years old with screen-detected breast cancer 2. ≤15mm maximum tumour diameter on mammogram and ultrasound 3. No associated indeterminate, suspicious or malignant mammographic microcalcification associated with the lesion or extending beyond it 4. Unifocal disease 5. Grade 1 disease on diagnostic core biopsy 6. ER strongly positive (Allred score of 7 or 8, or equivalent, e.g. at least moderate positivity in >66% of tumour cell nuclei) 7. PR strongly positive (Allred score of 7 or 8, or equivalent, e.g. at least moderate positivity in >66% of tumour cell nuclei) 8. HER2 negative (0 or 1+ by immunohistochemistry, or 2+ and negative by in situ hybridisation techniques (FISH or DISH) 9. Normal axillary ultrasound axillary, or equivocal ultrasound with benign fine needle aspiration cytology (FNAC) or core biopsy (CB) 10. Willing to be randomised 11. Able to provide written informed consent 12. Willing and able to undergo standard surgical treatment 13. Willing and able to undergo radiotherapy 14. Willing and able to take standard endocrine therapy 15. No previous diagnosis of ipsilateral breast cancer or DCIS (contralateral DCIS or invasive disease permitted if surgically treated ≥ 5 years previously and disease-free |
| Participant exclusion criteria | Current exclusion criteria as of 02/06/2021: 1. Associated malignant microcalcification outwith the lesion 2. Bilateral breast cancer 3. Invasive lobular cancer 4. Grade 2 or grade 3 on core biopsy assessment 5. Not strongly ER or PR positive (Allred score of <7, or equivalent, e.g. <66% positivity of tumour cell nuclei) or HER2 positive tumour 6. Unable to provide informed consent 7. Any serious and/or unstable pre-existing medical, psychiatric or other condition that would prevent compliance with the trial or consent process 8. Unfit or unwilling to undergo standard surgical treatment 9. Contra-indications to standard adjuvant therapies (radiotherapy, endocrine therapy) 10. Previous ipsilateral invasive breast cancer or DCIS 11. Other invasive malignancy unless: - Disease free for 5 years, or -Previous basal cell carcinoma, cervical carcinoma in-situ, superficial bladder tumour 12. High-risk group for developing breast cancer (as defined by NICE guidance) _____ Previous exclusion criteria: 1. Lesions with associated mammographic microcalcification outwith the lesion 2. Bilateral breast cancer 3. Invasive lobular cancer 4. Grade 2 or grade 3 on core biopsy assessment 5. ER or PR negative or HER2 positive tumour 6. Unable to provide informed consent 7. Any serious and/or unstable pre-existing medical, psychiatric or other condition that would prevent compliance with the trial or consent process 8. Unfit or unwilling to undergo standard surgical treatment 9. Contra-indications to standard adjuvant therapies (radiotherapy, endocrine therapy) 10. Previous ipsilateral invasive breast cancer or DCIS 11. Other invasive malignancy treated within the last 5 years 12. High-risk group for developing breast cancer (as defined by NICE guidance) |
| Recruitment start date | 15/11/2019 |
| Recruitment end date | 30/06/2025 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Belfast City Hospital
51 Lisburn Road
Belfast
BT8 8BH
United Kingdom
Belfast
BT8 8BH
United Kingdom
Southmead Hospital
Southmead Road
Westbury-On-Trym
Bristol
BS10 5NB
United Kingdom
Westbury-On-Trym
Bristol
BS10 5NB
United Kingdom
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Aberdeen Royal Infirmary
Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Altnagelvin Area Hospital
Glenshane Road
Londonderry
BT47 6SB
United Kingdom
Londonderry
BT47 6SB
United Kingdom
Edgware Community Hospital
Edgware Community Hospital
Burnt Oak Broadway
Edgware
HA8 0AD
United Kingdom
Burnt Oak Broadway
Edgware
HA8 0AD
United Kingdom
Poole Hospital
Longfleet Road
Poole
BH15 2JB
United Kingdom
Poole
BH15 2JB
United Kingdom
The Royal Marsden Hospital (surrey)
Downs Road
Sutton
SM2 5PT
United Kingdom
Sutton
SM2 5PT
United Kingdom
The Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
Newcastle upon Tyne
NE1 4LP
United Kingdom
Thomas Linacre Centre
Parson's Walk
Wigan
WN1 1RU
United Kingdom
Wigan
WN1 1RU
United Kingdom
Churchill Hospital
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Craigavon Area Hospital
Lurgan Rd
Craigavon
BT63 5QQ
United Kingdom
Craigavon
BT63 5QQ
United Kingdom
Doncaster Royal Infirmary
Armthorpe Road
Doncaster
DN2 5LT
United Kingdom
Doncaster
DN2 5LT
United Kingdom
Ipswich Hospital
Heath Road
Ipswich
IP4 5PD
United Kingdom
Ipswich
IP4 5PD
United Kingdom
Norfolk and Norwich University Hospital
Colney Lane
Colney
Norwich
NR4 7UY
United Kingdom
Colney
Norwich
NR4 7UY
United Kingdom
Gateshead - Queen Elizabeth Hospital
Queen Elizabeth Hospital
Sherriff Hill
Gateshead
NE9 6SX
United Kingdom
Sherriff Hill
Gateshead
NE9 6SX
United Kingdom
Liverpool University Hospitals NHS Foundation Trust
Royal Liverpool University Hospital
Prescot Street
Liverpool
L7 8XP
United Kingdom
Prescot Street
Liverpool
L7 8XP
United Kingdom
The Royal Marsden Hospital (london)
Fulham Road
London
SW3 6JJ
United Kingdom
London
SW3 6JJ
United Kingdom
Southend Hospital
Prittlewell Chase
Westcliff-on-sea
SS0 0RY
United Kingdom
Westcliff-on-sea
SS0 0RY
United Kingdom
Leeds Teaching Hospitals NHS Trust
St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
North Tees General Hospital
Hardwick Road
Stockton-on-tees
TS19 8PE
United Kingdom
Stockton-on-tees
TS19 8PE
United Kingdom
York Hospital
Wigginton Road
York
YO31 8HE
United Kingdom
York
YO31 8HE
United Kingdom
Alexandra Hospital
Woodrow Drive
Redditch
B98 7UB
United Kingdom
Redditch
B98 7UB
United Kingdom
Royal Bournemouth General Hospital
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Royal Cornwall Hospital (treliske)
Treliske
Truro
TR1 3LJ
United Kingdom
Truro
TR1 3LJ
United Kingdom
Royal Devon and Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom
Exeter
EX2 5DW
United Kingdom
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Southampton
SO16 6YD
United Kingdom
Wycombe General Hospital
Queen Alexandra Road
High Wycombe
HP11 2TT
United Kingdom
High Wycombe
HP11 2TT
United Kingdom
Wythenshawe Hospital
Southmoor Road
Wythenshawe
Manchester
M23 9LT
United Kingdom
Wythenshawe
Manchester
M23 9LT
United Kingdom
Castle Hill Hospital
Castle Road
Cottingham
HU16 5JQ
United Kingdom
Cottingham
HU16 5JQ
United Kingdom
Cheltenham General Hospital
Sandford Road
Cheltenham
GL53 7AN
United Kingdom
Cheltenham
GL53 7AN
United Kingdom
Clatterbridge Hospital
Clatterbridge Rd
Bebington
Wirral
CH63 4JY
United Kingdom
Bebington
Wirral
CH63 4JY
United Kingdom
Cumberland Infirmary - Carlisle
Cumberland Infirmary
Newtown Road
Carlisle
CA2 7HY
United Kingdom
Newtown Road
Carlisle
CA2 7HY
United Kingdom
Kingston Hospital
Galsworthy Road
Kingston upon Thames
KT2 7QB
United Kingdom
Kingston upon Thames
KT2 7QB
United Kingdom
Luton and Dunstable University Hospital
Lewsey Road
Luton
LU4 0DZ
United Kingdom
Luton
LU4 0DZ
United Kingdom
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
Birmingham
B15 2TH
United Kingdom
Bolton Royal Hospital
Minerva Road
Farnworth
Bolton
BL4 0JR
United Kingdom
Farnworth
Bolton
BL4 0JR
United Kingdom
University Hospital (coventry)
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom
Coventry
CV2 2DX
United Kingdom
Worcestershire Royal Hospital
Charles Hastings Way
Worcester
WR5 1DD
United Kingdom
Worcester
WR5 1DD
United Kingdom
Macclesfield District General Hospital
Macclesfield District Hospital
Victoria Road
Macclesfield
SK10 3BL
United Kingdom
Victoria Road
Macclesfield
SK10 3BL
United Kingdom
Gartnavel General Hospital
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
Glasgow
G12 0YN
United Kingdom
Leighton Hospital
Leighton
Crewe
CW1 4QJ
United Kingdom
Crewe
CW1 4QJ
United Kingdom
Forth Valley Royal Hospital
Stirling Road
Larbert
FK5 4WR
United Kingdom
Larbert
FK5 4WR
United Kingdom
Kings College Hospital
Mapother House
De Crespigny Park
Denmark Hill
London
SE5 8AB
United Kingdom
De Crespigny Park
Denmark Hill
London
SE5 8AB
United Kingdom
Royal United Hospital
Combe Park
Bath
BA1 3NG
United Kingdom
Bath
BA1 3NG
United Kingdom
Milton Keynes University Hospital
Standing Way
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom
University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom
London
NW1 2PG
United Kingdom
Western General Hospital
Crewe Road South
Edinburgh
Lothian
EH4 2XU
United Kingdom
Edinburgh
Lothian
EH4 2XU
United Kingdom
Sponsor information
University of Birmingham
University/education
University/education
Cancer Research UK Clinical Trials Unit
Institute for Cancer Studies
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)1214146754 |
|---|---|
| a@b.c | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 17/42/32
No information available
Results and Publications
| Intention to publish date | 01/07/2029 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The results of the trial will be submitted for publication in a peer reviewed journal in 2029. The manuscript will be prepared by the Trial Management Group (TMG) and authorship will be determined by mutual agreement. Any secondary publications and presentations prepared by Investigators must be reviewed by the TMG. Manuscripts must be submitted to the TMG in a timely fashion and in advance of being submitted for publication, to allow time for review and resolution of any outstanding issues. Authors must acknowledge that the trial was performed with the support of the University of Birmingham. Intellectual property rights will be addressed in the Clinical Study Site Agreement between Sponsor and site. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 26/07/2023 | No | No | ||
| Protocol article | 08/04/2025 | 23/04/2025 | Yes | No |
Editorial Notes
23/04/2025: Publication reference added.
15/01/2025: The following changes were made to the study record:
1. The recruitment end date was changed from 31/12/2024 to 30/06/2025.
2. IRAS number added.
3. The study participating centres were updated to remove Kidderminster General Hospital and West Cumberland Hospital and add Macclesfield District General Hospital, Gartnavel General Hospital, Leighton Hospital, Forth Valley Royal Hospital, Kings College Hospital, Royal United Hospital, Milton Keynes University Hospital, University College London Hospitals NHS Foundation Trust and Western General Hospital.
08/01/2024: Study participating centres Castle Hill Hospital, Cheltenham General Hospital, Clatterbridge Hospital, Cumberland Infirmary - Carlisle, Kingston Hospital, Luton and Dunstable University Hospital, Queen Elizabeth Hospital, Bolton Royal Hospital, University Hospital Coventry, West Cumberland Hospital and Worcestershire Royal Hospital were added.
15/12/2022: The following changes were made to the trial record:
1. The recruitment end date has been changed from 31/12/2022 to 31/12/2024.
2. The trial participating centres Alexandra Hospital, Kidderminster General Hospital, Royal Bournemouth General Hospital, Royal Cornwall Hospital, Royal Devon and Exeter Hospital, Southampton General Hospital, Wycombe General Hospital and Wythenshawe Hospital were added.
14/03/2022: The following changes were made to the trial record:
1. The trial participating centres Cardiff & Vale University LHB, Manchester University NHS Foundation Trust were removed.
2. The trial participating centres Churchill Hospital, Craigavon Area Hospital, Doncaster Royal Infirmary, Ipswich Hospital, Norfolk and Norwich University Hospital, Gateshead - Queen Elizabeth Hospital, Royal Liverpool University Hospital NHS Trust, The Royal Marsden Hospital (london), Southend Hospital, Leeds Teaching Hospitals NHS Trust, North Tees Hospital, York Hospital were added.
02/06/2021: The following changes were made to the trial record:
1. The inclusion criteria were changed.
2. The exclusion criteria were changed.
3. The trial participating centres Aberdeen Royal Infirmary, Altnagelvin Hospital, Edgware Community Hospital, Poole Hospital, The Royal Marsden Hospital, Royal Victoria Infirmary, Thomas Linacre Centre were added.
03/08/2020: Added link to plain English summary on Cancer Reseach UK website.
14/10/2019: Trial’s existence confirmed by National Institute for Health Research (NIHR)
