Condition category
Cancer
Date applied
14/10/2019
Date assigned
16/10/2019
Last edited
16/10/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Scientific

Primary contact

Dr Jessica Foster

ORCID ID

Contact details

Cancer Research UK Clinical Trials Unit (CRCTU)
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 9021
small@trials.bham.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

RG_18-180; CPMS 40111

Study information

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

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

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

Study design

Randomised; Interventional; Design type: Treatment, Surgery

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

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

Phase

Phase III

Drug names

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 trial start date

01/01/2019

Overall trial end date

30/06/2029

Reason abandoned (if study stopped)

Eligibility

Participant 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 type

Patient

Age group

Adult

Gender

Female

Target number of participants

Planned Sample Size: 800; UK Sample Size: 800

Participant 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

31/12/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Belfast Health & Social Care Trust
Belfast
BT8 8BH
United Kingdom

Trial participating centre

Cardiff & Vale University LHB
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

North Bristol NHS Trust
Southmead Hospital Southmead Road Westbury-On-Trym
Bristol
BS10 5NB
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Manchester University NHS Foundation Trust
Cobbett House Oxford Road
Manchester
M13 9WL
United Kingdom

Sponsor information

Organisation

University of Birmingham

Sponsor details

Cancer Research UK Clinical Trials Unit
Institute for Cancer Studies
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)1214146754
a@b.c

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 17/42/32

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

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 statement:
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request

Intention to publish date

01/07/2029

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

14/10/2019: Trial’s existence confirmed by National Institute for Health Research (NIHR)