High-intensity focused ultrasound in the treatment of breast fibroadenomata (HIFU-F trial).

BACKGROUND: High-intensity focussed ultrasound (HIFU) is a non-invasive ablative technique utilising the application of high frequency ultrasound (US) pressure waves to cause tissue necrosis. This emerging technology is currently limited by prolonged treatment times. The aim of the HIFU-F trial was to perform circumferential HIFU treatment as a means of shortening treatment times. METHODS: A prospective trial was set up to treat 50 consecutive patients ≥18 years of age. Eligible patients possessed symptomatic fibroadenomata, visible on US. Patients ≥25 years of age required histological confirmation of the diagnosis. Primary outcome measures were reduction in treatment time, reduction in volume on US after 12 months and complication rates. RESULTS: HIFU treatment was performed in 51 patients (53 treatments) with a mean age of 29.8 years (SD 7.2 years) and a diameter of 2.6 cm (SD 1.4 cm). Circumferential ablation reduced treatment times by an estimated 19.9 min (SD 25.1 min), which is a 29.4% (SD 15.2%) reduction compared with whole lesion ablation. Volume reduction of 43.2% (SD 35.4%; p < 0.005, paired t-test) was observed on US at 12 months post-treatment. Local complications completely resolved at 1 month apart from skin hyper-pigmentation, which persisted in nine cases at three months, six cases at 6 months and six at 12 months. CONCLUSION: Circumferential HIFU treatment for breast fibroadenomata is feasible to reduce both lesion size and treatment time. HIFU is a non-invasive alternative technique for the treatment of breast fibroadenomata. ISRCTN registration: 76622747.

International validation of the European Organisation for Research and Treatment of Cancer QLQ-BRECON23 quality-of-life questionnaire for women undergoing breast reconstruction.

BACKGROUND: The aim was to carry out phase 4 international field-testing of the European Organisation for Research and Treatment of Cancer (EORTC) breast reconstruction (BRECON) module. The primary objective was finalization of its scale structure. Secondary objectives were evaluation of its reliability, validity, responsiveness, acceptability and interpretability in patients with breast cancer undergoing mastectomy and reconstruction. METHODS: The EORTC module development guidelines were followed. Patients were recruited from 28 centres in seven countries. A prospective cohort completed the QLQ-BRECON15 before mastectomy and the QLQ-BRECON24 at 4-8 months after reconstruction. The cross-sectional cohort completed the QLQ-BRECON24 at 1-5 years after reconstruction, and repeated this 2-8 weeks later (test-retest reliability). All participants completed debriefing questionnaires. RESULTS: A total of 438 patients were recruited, 234 in the prospective cohort and 204 in the cross-sectional cohort. A total of 414 reconstructions were immediate, with a comparable number of implants (176) and donor-site flaps (166). Control groups comprised patients who underwent two-stage implant procedures (72, 75 per cent) or delayed reconstruction (24, 25 per cent). Psychometric scale validity was supported by moderate to high item-own scale and item-total correlations (over 0·5). Questionnaire validity was confirmed by good scale-to-sample targeting, and computable scale scores exceeding 50 per cent, except nipple cosmesis (over 40 per cent). In known-group comparisons, QLQ-BRECON24 scales and items differentiated between patient groups defined by clinical criteria, such as type and timing of reconstruction, postmastectomy radiotherapy and surgical complications, with moderate effect sizes. Prospectively, sexuality and surgical side-effects scales showed significant responsiveness over time (P < 0·001). Scale reliability was supported by high Cronbach's α coefficients (over 0·7) and test-retest (intraclass correlation more than 0·8). One item (finding a well fitting bra) was excluded based on high floor/ceiling effects, poor test-retest and weak correlations in factor analysis (below 0·3), thus generating the QLQ-BRECON23 questionnaire. CONCLUSION: The QLQ-BRECON23 is an internationally validated tool to be used alongside the EORTC QLQ-C30 (cancer) and QLQ-BR23 (breast cancer) questionnaires for evaluating quality of life and satisfaction after breast reconstruction.

Meta-analysis of tumour burden in pre-operative axillary ultrasound positive and negative breast cancer patients.

BACKGROUND: Management of the axilla in breast cancer is becoming increasingly conservative. Patients identified with a low axillary nodal burden (two or fewer involved nodes) at sentinel node biopsy (SNB) can avoid completion axillary node clearance (cANC). 'Fast track' to ANC in patients with involved nodes on pre-operative ultrasound may be over-treating a subgroup of these patients with low nodal burden, which would have precluded their need for ANC. This systematic review assesses the proportion of patients with involved nodes on pre-operative axillary ultrasound, which would fit low axillary burden criteria. METHODS: Meta-analysis of studies comparing axillary burden of breast cancer patients identified as pre-operative ultrasound negative versus positive was performed. The primary outcome measure was the number of patients with two or fewer involved nodes (macrometastases only). Pooled odds ratio (OR), 95% confidence intervals (CIs), means and probabilities of identifying two or fewer involved nodes versus greater than two were calculated. RESULTS: Six studies reported the axillary burden in 4271 patients who were either directed straight to ANC or cANC after SNB. There was a significantly greater axillary burden in the ultrasound positive versus negative groups (OR 5.95, 95% CI 5.80-6.11) with mean nodal retrieval values of 2.9 [standard error (SE) 0.2] and 1.6 (SE 0.2) nodes, respectively. Cumulative probabilities identified 78.9% of ultrasound negative and 43.2% of ultrasound positive patients possessed low axillary burden. CONCLUSIONS: Pre-operative ultrasound positive patients have significantly higher axillary burden. However, nearly half do fit the criteria of low axillary burden and could be considered for omission of ANC.

Is there a role for sentinel node biopsy in the pre-operative ultrasound positive axilla?

Axillary management in breast cancer is becoming increasingly conservative. This approach is based on the identification of low axillary burden on sentinel node biopsy (SNB). The modern practice of routine pre-operative axillary ultrasound has meant that patients are 'fast tracked' to axillary node clearance (ANC) in the presence of a histologically confirmed positive axilla. This practice reduces the number of patients undergoing SNB compared to the original trials, which evaluated the role of SNB, and those assessing safety of omission of ANC in low axillary burden. The risk of depriving patients with low axillary burden the opportunity to avoid ANC as a consequence of pre-operative ultrasound is discussed.

Meta-analysis of sentinel lymph node biopsy in breast cancer using the magnetic technique.

BACKGROUND: The standard for sentinel lymph node biopsy (SLNB), the dual technique (radiolabelled tracer and blue dye), has several drawbacks. A novel magnetic technique without these drawbacks has been evaluated in a number of clinical trials. It uses a magnetic tracer and a handheld magnetometer to identify and excise sentinel lymph nodes. A systematic review and meta-analysis was performed to assess the performance and utility of the magnetic in comparison to the standard technique. METHODS: MEDLINE, PubMed, Embase and the Cochrane online literature databases were used to identify all original articles evaluating the magnetic technique for SLNB published up to April 2016. Studies were included if they were prospectively conducted clinical trials comparing the magnetic with the standard technique for SLNB in patients with breast cancer. RESULTS: Seven studies were included. The magnetic technique was non-inferior to the standard technique (z = 3·87, P < 0·001), at a 2 per cent non-inferiority margin. The mean identification rates for the standard and magnetic techniques were 96·8 (range 94·2-99·0) and 97·1 (94·4-98·0) per cent respectively (risk difference (RD) 0·00, 95 per cent c.i. -0·01 to 0·01; P = 0·690). The total lymph node retrieval was significantly higher with the magnetic compared with the standard technique: 2113 (1·9 per patient) versus 2000 (1·8 per patient) (RD 0·05, 0·03 to 0·06; P = 0·003). False-negative rates were 10·9 (range 6-22) per cent for the standard technique and 8·4 (2-22) per cent for the magnetic technique (RD 0·03, 0·00 to 0·06; P = 0·551). The mean discordance rate was 3·9 (range 1·7-6·9) per cent. CONCLUSION: The magnetic technique for SLNB is non-inferior to the standard technique, with a high identification rate but with a significantly higher lymph node retrieval rate.

High intensity focused ultrasound in the treatment of breast fibroadenomata: results of the HIFU-F trial.

OBJECTIVES: Breast fibroadenomata (FAD) are the most common breast lumps in women. High intensity focused ultrasound (HIFU) is a non-invasive ablative technique that can be used to treat FAD but is associated with prolonged treatment times. In the HIFU-F trial, we evaluated the change in volume over time with circumferential HIFU treatment of FAD and compared this to no treatment. METHODS: Patients ≥18 years, diagnosed with symptomatic, palpable FAD, visible on ultrasound (US) were recruited. Twenty patients were treated using US-guided HIFU under local anaesthesia. Another 20 participants underwent an US 6 months after diagnosis. Outcome measures included: reduction in treatment time compared to whole lesion ablation; feasibility to achieve a 50% reduction in volume after 6 months; decrease in volume compared to a control group and reduction in symptoms. RESULTS: Circumferential ablation reduced the mean treatment time by 37.5% (SD 20.1%) compared to whole lesion ablation. US demonstrated a significant mean reduction in FAD volume of 43.5% (SD 38.8%; p = 0.016, paired t-test) in the HIFU group compared to 4.6% (SD 46.0%; p = 0.530) in the control group after 6 months. This mean reduction in FAD volume between the two groups was significant in favour of the HIFU group (p = 0.002, grouped t-test). Pre-treatment pain completely resolved in 6 out of 8 patients 6 months post-treatment. CONCLUSION: Circumferential HIFU ablation of FAD is feasible, with a significant reduction in pain and volume compared to control participants. It provides a simple, non-invasive, outpatient-based alternative to surgical excision for FAD.

Systematic review of axillary reverse mapping in breast cancer.

BACKGROUND: Axillary reverse mapping (ARM) assesses the lymphatic drainage of the arm simultaneously with that of the breast, enabling preservation of arm lymphatics during axillary surgery for breast cancer. This article systematically reviews the evidence on the lymphoedema rate and oncological safety of the ARM technique. METHODS: PubMed, Embase and the Cochrane Library were searched systematically for studies that addressed the use of ARM during axillary surgery in breast cancer. Studies were eligible if they performed ARM during sentinel node biopsy (SNB) or axillary node clearance (ANC) for breast cancer in prospective studies of more than 50 patients, with assessment of lymphoedema and oncological outcomes during a minimum follow-up of 6 months. RESULTS: Eight studies reported data on ARM in 1142 patients undergoing axillary surgery for breast cancer. Lymphoedema rates ranged from 0 to 6 per cent during ARM-assisted SNB, and from 5.9 to 24 per cent during ARM lymphatic preservation at ANC. Crossover nodes between the arm and breast lymphatics were identified in 0-10 per cent of patients, and metastases were present in 0-20 per cent of these patients. ARM nodes were not preserved in between 11 and 18 per cent of patients with ARM nodes identified, and metastases were detected in 0-19 per cent of these patients. CONCLUSION: ARM can achieve low rates of lymphoedema, but the risk of metastasis in crossover and clinically suspicious ARM nodes, or those in close proximity to an involved sentinel node, warrants their excision.

Systematic review of high-intensity focused ultrasound ablation in the treatment of breast cancer.

BACKGROUND: A systematic review was undertaken to assess the clinical efficacy of non-invasive high-intensity focused ultrasound (HIFU) ablation in the treatment of breast cancer. METHODS: MEDLINE/PubMed library databases were used to identify all studies published up to December 2013 that evaluated the role of HIFU ablation in the treatment of breast cancer. Studies were eligible if they were performed on patients with breast cancer and objectively recorded at least one clinical outcome measure of response (imaging, histopathological or cosmetic) to HIFU treatment. RESULTS: Nine studies fulfilled the inclusion criteria. The absence of tumour or residual tumour after treatment was reported for 95·8 per cent of patients (160 of 167). No residual tumour was found in 46·2 per cent (55 of 119; range 17-100 per cent), less than 10 per cent residual tumour in 29·4 per cent (35 of 119; range 0-53 per cent), and between 10 and 90 per cent residual tumour in 22·7 per cent (27 of 119; range 0-60 per cent). The most common complication associated with HIFU ablation was pain (40·1 per cent) and less frequently oedema (16·8 per cent), skin burn (4·2 per cent) and pectoralis major injury (3·6 per cent). MRI showed an absence of contrast enhancement after treatment in 82 per cent of patients (31 of 38; range 50-100 per cent), indicative of coagulative necrosis. Correlation of contrast enhancement on pretreatment and post-treatment MRI successfully predicted the presence of residual disease. CONCLUSION: HIFU treatment can induce coagulative necrosis in breast cancers. Complete ablation has not been reported consistently on histopathology and no imaging modality has been able confidently to predict the percentage of complete ablation. Consistent tumour and margin necrosis with reliable follow-up imaging are required before HIFU ablation can be evaluated within large, prospective clinical trials.

Magnetic sentinel node and occult lesion localization in breast cancer (MagSNOLL Trial).

BACKGROUND: Non-palpable breast cancers require localization-guided surgery and axillary staging using sentinel lymph node biopsy (SLNB). This study investigated the novel technique of magnetic-guided lesion localization and concurrent SLNB, which avoids the need for wire-guided localization and radioisotopes. METHODS: An ultrasound-guided intratumoral injection of magnetic tracer (0·5 ml) was performed in a protocol-driven predefined minimum of ten patients with palpable breast cancer to assess the ability of the magnetic tracer safely to localize the tumour at the site of injection and concurrently drain to the lymphatics. Once successful lesion localization had been confirmed (peak magnetometer count retained at the centre of the tumour), the technique was undertaken in a further 20 patients with non-palpable breast cancers awaiting wide local excision and SLNB. All patients underwent SLNB with both the magnetic and standard dual (radioisotope and Patent Blue V dye) techniques. RESULTS: Thirty-two patients were recruited, of whom 12 (1 with bilateral disease) presented with palpable and 20 with non-palpable breast cancer. Peak magnetometer counts were retained at the tumour centre in all palpable (13) and non-palpable (20) breast cancers. Re-excisions for involved margins were necessary in two patients with non-palpable breast cancers. The sentinel lymph node identification rates were 28 of 33 procedures for the magnetic technique alone, 32 of 33 for the magnetic technique combined with blue dye, and 32 of 33 for the standard dual technique. CONCLUSION: Magnetic lesion localization is feasible, with intratumoral magnetic tracer injection combined with a periareolar injection of blue dye for subsequent SNLB.

Intraoperative radiotherapy in early breast cancer.

BACKGROUND: Intraoperative radiotherapy (IORT) constitutes a paradigm shift from the conventional 3-5 weeks of whole-breast external beam radiotherapy (EBRT). IORT enables delivery of radiation at the time of excision of the breast tumour, targeting the area at highest risk of recurrence, while minimizing excessive radiation exposure to healthy breast tissue. The rationale for IORT is based on the observation that over 90 per cent of local recurrences after breast-conserving surgery occur at or near the original operation site. METHODS: This article reviews trials of IORT delivered with different techniques and devices. RESULTS: IORT is a very attractive option for delivering radiotherapy, reducing the traditional fractionated treatment to a single fraction administered at the time of surgery. IORT has been shown to be associated with reduced toxicity and has several potential benefits over EBRT. Only two randomized clinical trials have been published to date. The TARGIT-A and ELIOT trials have demonstrated that IORT is associated with a low rate of local recurrence, although higher than that after EBRT (TARGIT-A: 3·3 versus 1·3 per cent respectively, P = 0·042; ELIOT: 4·4 versus 0·4 per cent, P < 0·001). However, the local recurrence rate for IORT fell within the predefined 2·5 per cent non-inferiority margin in TARGIT-A, and the 7·5 per cent equivalence margin in ELIOT. CONCLUSION: Longer follow-up data from existing trials, optimization of patient criteria and cost-effectiveness analyses are needed. Based on the current evidence, IORT can be offered as an alternative to EBRT to selected patients within agreed protocols, and outcomes should be monitored within national registries.

Meta-analysis of superficial versus deep injection of radioactive tracer and blue dye for lymphatic mapping and detection of sentinel lymph nodes in breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in early breast cancer. Currently, no consensus exists on the optimal site of injection of the radioactive tracer or blue dye. METHODS: A systematic review and meta-analysis of studies comparing superficial and deep injections of radioactive tracer or blue dye for lymphatic mapping and SLNB was performed. The axillary and extra-axillary sentinel lymph node (SLN) identification rates obtained by lymphoscintigraphy and intraoperative SLNB were evaluated. Pooled odds ratios (ORs) and 95 per cent c.i. were estimated using fixed-effect analyses, or random-effects analyses if there was statistically significant heterogeneity (P < 0·050). RESULTS: Thirteen studies were included in the meta-analysis. There was no significant difference between superficial and deep injections of radioactive tracer for axillary SLN identification on lymphoscintigraphy (OR 1·59, 95 per cent c.i. 0·79 to 3·17), during surgery (OR 1·27, 0·60 to 2·68) and for SLN identification using blue dye (OR 1·40, 0·83 to 2·35). The rate of extra-axillary SLN identification was significantly greater when deep rather than superficial injection was used (OR 3·00, 1·92 to 4·67). The discordance rate between superficial and deep injections ranged from 4 to 73 per cent for axillary and from 0 to 61 per cent for internal mammary node mapping. CONCLUSION: Both superficial and deep injections of radioactive tracer and blue dye are effective for axillary SLN identification. Clinical consequences of discordance rates between the two injection techniques are unclear. Deep injections are associated with significantly greater extra-axillary SLN identification; however, this may not have a significant impact on clinical management.

Why should breast surgeons use ultrasound?

Portable ultrasound is now used in a variety of clinical settings by specialties outside of radiology. Despite increased accessibility to ultrasound, the overall performance of ultrasound by breast surgeons is consistently low. We discuss the reasons why this is unacceptable for future patient care and answer the question, 'Why should breast surgeons use ultrasound?' We reviewed the literature for evidence assessing the outcomes of breast surgeon-performed ultrasound both intra-operatively and in the outpatient department. Intra-operative ultrasound performed by surgeons reduces re-excision rates in breast-conserving surgery. Outpatient-based ultrasound performed by surgeons frees up the resources of radiology departments, allowing them to focus upon patients requiring more complex diagnostic and interventional procedures. For surgeons to competently perform intra-operative and outpatient-based ultrasound, a period of formal ultrasound training is necessary to acquire knowledge of ultrasound skills and techniques. This should be followed by a period of mentorship and supervised training with an experienced breast radiologist. Breast surgeon-performed ultrasound is beneficial to the multi-disciplinary care of breast cancer patients. To further improve multidisciplinary care, breast surgeons and radiologists should work more collaboratively to optimise imaging applications both in the operating theatre and outpatient department. Current advances in therapeutic percutaneous techniques are of interest to both surgeons and radiologists. In future, a hybrid specialisation should be considered to incorporate accreditation in both specialties for breast interventional procedures.

What is the future of magnetic nanoparticles in the axillary management of breast cancer?

Magnetic nanoparticles (MNPs) possess unique properties, which make them highly attractive for medical applications. The use of MNPs in surgery has mainly been focused on their role in the identification of metastatic lymph node involvement. There have been developments within this field, including ongoing and newly conducted clinical trials. The current published evidence for the use of MNPs in assessing metastatic lymph node spread using sentinel lymph node biopsy and non-invasive imaging modalities is reviewed and future applications considered.

When is a completion axillary lymph node dissection necessary in the presence of a positive sentinel lymph node?

BACKGROUND: The management of the axilla in the presence of positive sentinel lymph node (SLN) remains controversial. Many centres forgo completion axillary lymph node dissection (cALND) in the presence of micrometastatic disease. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trialists argue for extending this to macrometastasis. The aim of this study was to correlate tumour burden in SLNs with that in the residual lymph node basin to determine the likelihood of residual disease in patients with micro- and macrometastasis in the SLN. METHODS: Patients who underwent cALND following a positive SLN were analysed for histopathological features of the primary tumour and burden of axillary disease. RESULTS: Of 155 patients, 115 (74%) had macrometastases and 40 (26%) micrometastases in the SLNs. Residual axillary disease was detected in 55/155 (35%) patients with macrometastases and 4/40 (10%) with micrometastases. Generally, with increasing size of metastasis in the SLN there was an increasing risk of further disease in residual lymph nodes. Logistic regression analysis showed increased odds ratios for further disease for all groups when compared with the <2mm (micrometastasis) SLN group. CONCLUSION: Patients may be advised to forgo cALND where the SLN contains isolated tumour cells or micrometastasis. Recommendations for proceeding to cALND can be based on the size of metastasis in the SLN, which relates to the risk of further disease in the residual axillary lymph nodes and subsequent regional recurrence.