Title: Does intra-operative use of the MarginProbe device reduce the need for further re-excision procedures after conservation surgery for breast cancer?
Funder: Department of Health and Social Care

Abstract: Standard of care for patients diagnosed with breast cancer is surgical excision, followed by adjuvant radiotherapy[2]. Surgical excision aims to produce circumferentially clear tissue margins to prevent local recurrence. NICE guidelines indicate BCS should aim for clear margins around a tumour[2], although a recent metaanalysis has demonstrated a 1mm margin is sufficient in invasive cancers. The 2011 Association of Breast Surgeons Audit revealed further re-excision surgery rates following an initial BCS operation of 25-40% for DCIS[1,3-6] and 25% for invasive breast cancers with surrounding DCIS (9% mastectomy, 16% re-excision) because of the presence of close or involved circumferential margins. Re-excision is costly to the NHS (further hospitalisation, visits to theatre) and potentially very disturbing to the patient (extended period of worry/uncertainty, effects of further surgery). Re-excision operations are usually completed within a month of first therapeutic operation but will be completed by 9 months even if chemotherapy is required. The examination of frozen section of margins during surgery undertaken in the USA has reported lower re-excision rates of 5-6% from 30-33% in several non-randomised studies. Frozen section adds considerable operating time and cost to common procedures and with insufficient breast histopathologist resource, it is not standard practice in the UK[7,8]. An alternative approach is to use an intraoperative device to assess margins[9,10], avoiding undue delays awaiting transfer of tissues to the laboratory and time to perform frozen section assessment (20 minutes) as well as the difficulty of assessing DCIS at margins on frozen (rather than formalin-fixed) material. The MarginProbe uses nearfield radiofrequency spectroscopy[9] to measure tissue electromagnetic signal. The device generates and records a signal containing information on the electric properties of the specimen during surgery, comparing the reading with parameters defined for known tissue types, classifying the margin reading as normal or malignant[9,10], allowing intra-operative identification/resection of additional involved cancerous tissue adjacent to margins, reducing the need for multiple operations to obtain clear margins[9-12]. In a randomised controlled trial of patients undergoing wide local excision (BCS), we will compare the use of the MarginProbe device during surgery (after BCS and specimen radiology) with standard treatment (wound closure) to determine: 1 Reduction of second operations compared to standard treatment, 9 months after randomisation; 2. Quality of Life Patient Related Outcome Measures and health related utility measures (EQ5D); 3. Resource utilisation and cost of each strategy; 4. Tissue weight excised from both groups; 5. Clinical and cost-effectiveness of both management techniques; 6. Impact on patients/carers regarding patient experience of MarginProbe, including preference, satisfaction, convenience, discomfort and financial costs; 7. The cost implications of adopting MarginProbe use intraoperatively, compared with standard of care. Women with breast cancer (invasive or DCIS) undergoing BCS, will be randomised after completion of excision and specimen radiology, to either standard procedure or the use of the MarginProbe on the excised specimen to determine whether margins are involved and further re-excision is required. The frequency of clear (>1mm) margins in both groups and the need for second excision operations will be compared in each arm at nine months. We will compare Quality of Life, cosmetic outcome and health economics for both strategies. With 230 patients randomised in each group, we have a 90% power to demonstrate a 50% reduction in re-excision rate from 26% to 12.5% allowing for drop-out and confirm the cost effectiveness (or not) of the MarginProbe. If MarginProbe leads to reduction in the re-excision rate, there are significant potential cost savings for the NHS via a reduced need for second operations. Patients will benefit from improved cosmetic outcomes, decreased risk of wound infection and will be able to return to normal life quicker.

Lay abstract: Of the 48,000 breast cancers diagnosed annually in UK, almost 60% of patients undergo breast conserving surgery (BCS). Surgical removal of the cancer aims to reduce the risk of local recurrence and patient mortality. In order to minimise the amount of tissue removed, excision up to the cancer-free area (margins) is undertaken. Further surgery following BCS is required in 25% of patients with invasive cancers with surrounding DCIS and 30% of DCIS patients because of disease found at the edges of the tissue removed. Reducing the need for further operations benefits patients (by reducing the number of operations required, minimising anxiety) and the NHS (by realising economic benefits). MarginProbe, a disposable probe which measures the margins of tissue removed during BCS surgery, allows the surgeon to remove further tissue during the same surgical procedure to clear any involved margins, minimising subsequent re-operations. Four hundred and sixty patients in 6 specialist Breast Units will be randomly allocated after BCS (and specimen radiology), by telephone randomisation, to either: - MarginProbe assessment of the surgical specimen with re-excision of margins if required; - Standard BCS (clinical and radiological clear margins) whereby the wound will be closed and the surgery completed (standard UK practice). The primary aim of the study is to determine whether the MarginProbe device reduces the need for second surgical procedures by enabling the removal of involved margins during the same procedure. Main outcome: number of people requiring second surgery within 9 months of their first BCS. We will also look at the impact on quality of life, cosmetic appearance and the results of laboratory assessments of removed tissues. The health related quality of life and cosmetic appearance of the surgery (photographs of 2 views - front/side) will be compared by researchers who do not know which treatment people received.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS