Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT.

/pdf/obtaining-adequate-surgical-margins-in-breast-conserving-187503wa0e.pdf

Obtaining adequate surgical margins in breast-conserving therapy for patients with early-stage breast cancer: current modalities and future directions.

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology.

/pdf/a-comprehensive-overview-of-radioguided-surgery-using-gamma-46u7urctug.pdf

A comprehensive overview of radioguided surgery using gamma detection probe technology

As breast cancer treatment has progressed to offering breast preservation to the majority of patients, a new challenge has arisen. That challenge is adequate margins on the partial mastectomy specimen. The literature reports positive margins in 20–70% of patients, resulting in additional surgery. While the consequences of that additional surgery probably do not affect survival from breast cancer, they do potentially have an affect on cosmesis, wound infection risk, and the confidence that the patient has with the surgeon wondering “why didn’t you get it all?”

The article “Predictors of Re-excision Among Women Undergoing Breast Conserving Surgery for Cancer” by Waljee et al.1 attempts to identify the factors that increase the risk of a positive margin. This avenue of research is important in clinical management of breast cancer, allowing surgeons to more intelligently counsel patients regarding risk of re-excision. The authors identified several factors that predict a higher rate of positive margins. Smaller breast size, surgical biopsy for diagnosis, use of adjuvant chemotherapy, and lobular histology all predicted a higher rate of positive margins. Another study published in the Annals of Surgical Oncology studied the same topic and agreed that method of biopsy and lobular histology result in higher positive margin rates.2 A large prospective study reported from the University of Louisville Breast Cancer Sentinel Lymph Node Study included 2658 patients treated with lumpectomy and evaluated factors that resulted in positive margins. They found that larger tumor size and lobular histology both resulted in higher positive margin rates, but that method of biopsy had no impact.3 While these studies agree on many risk factors for positive margins, unfortunately, these factors, with the exception of biopsy method, cannot be modified.

Few women would agree to undergo mastectomy instead of lumpectomy because of a prediction of positive margins. Because the factors predicting higher re-excision rates are not modifiable, this line of research can only result in providing additional knowledge but cannot result in changes in practice. Efforts to investigate mechanisms that reduce the rate of positive margins have much greater potential to impact treatment. A number of studies have investigated surgical interventions that may reduce the rate of positive margins. Many have investigated intraoperative pathologic assessment as a mechanism to identify positive margins at the time of surgery so that re-excision can be accomplished in the same setting. These have focused primarily on touch imprint cytology, frozen section, and gross examination. Muttalib et al. evaluated intraoperative imprint and scrape cytology to assess margins. While the authors recommend adoption of the technique, the positive margin rate reported in the study remained at 22% with use of the technique.4 Intraoperative assessment of gross margins has been reported to result in a final margin positive rate of 25%.5 Investigators at MD Anderson Cancer Center evaluated a combination of intraoperative gross margin assessment, specimen radiography, and in some cases frozen section with a final positive margin rate of 20% using these methods.6 Others have evaluated intraoperative methods of tumor localization and their impact on positive margins. Tafra et al. completed a randomized study comparing cryoassisted localization with wire localization and demonstrated no difference in positive margins.7 Radioguided occult lesion localization was compared with wire localization by Nadeem et al., who demonstrated a positive margin rate of 83% and 57%, respectively.8 Other techniques have focused on volume of excision with oncoplastic techniques allowing for larger margin excisions while maintaining the cosmetic appearance of the breast. While these techniques in intraoperative assessment and changes in surgical technique may reduce the rate of positive margins, they have not solved the problem.

Other possible mechanisms that are currently unproven but that may result in lower re-excision rates include improved preoperative imaging to better establish extent of disease and increased use of neoadjuvant chemotherapy. Studies evaluating the utility of magnetic resonance imaging (MRI) find an increased sensitivity for detection of multicentric and multifocal disease. Identifying this situation preoperatively will result in better patient selection for attempted partial mastectomy. We have also found MRI helpful in defining the extent of disease in the breast more accurately identifying the extent of resection required. Improved neoadjuvant chemotherapy regimens have resulted in patients with significantly smaller tumors and in some cases patients with a pathologic complete response. Neoadjuvant chemotherapy regimens that include Herceptin report a pathologic complete response rate of up to 60%.9 Of course this would reduce those patients with positive margins by reducing the number of patients with evidence of disease in the breast and also by reducing the tumor volume. In fact, the study by Waljee reported a lower positive margin rate with neoadjuvant chemotherapy.1

While many of these techniques may reduce the rate of positive margins, the best reports result in at least 20% of the patients returning to the operating room for re-excision. This rate remains too high despite our best efforts. New innovative surgical techniques, methods of intraoperative margin assessment, imaging for patient selection, and improved neoadjuvant chemotherapies are needed to prevent one in five patients from returning to the operating room.

/pdf/positive-margins-the-challenge-continues-for-breast-surgeons-cu0qjmzel6.pdf

Positive Margins: The Challenge Continues for Breast Surgeons

Freehand SPECT is a 3-D tomographic imaging modality based on data acquisition with a hand-held detector that is moved freely, in contrast to conventional, fixed gamma camera systems. In this pilot study, the feasibility of freehand SPECT for 3-D lymphatic mapping in breast cancer was evaluated. A total of 85 patients (age: 29–88 years) with an initial diagnosis of invasive breast cancer and no clinical evidence of nodal involvement prospectively underwent sentinel lymph node (SLN) biopsy. Preoperative lymphatic mapping (35–87 MBq 99mTc-Nanocoll) included tomographic imaging with a SPECT/CT device (Siemens Symbia T6) serving as reference. Initially, the freehand SPECT approach was assessed in a pilot study consisting of 50 patients. The quality of each freehand SPECT acquisition was assessed and ranked as good, intermediate or poor. In another series comprising a further 35 patients (validation study), a guidance system for the acquisition was implemented based on the results of the pilot study, ensuring acquisitions with good quality. For 3-D tomographic image reconstruction, ad hoc models and iterative reconstruction algorithms were used in all 85 patients. To allow for adequate comparison, SPECT/CT data and freehand SPECT data were registered within the same coordinate system. In the pilot study, freehand SPECT enabled mapping of 24 of 83 SLNs in 20 of 44 patients (3 dropouts, 3 patients without SLN either in SPECT/CT or in freehand SPECT). Using SPECT/CT as reference, the accuracy of freehand SPECT was 77.8% (7/9 nodes) in scans with good quality, while for intermediate and poor quality scans, the accuracy was reduced to 34.3 and 12.8%, respectively. In the validation study, quality feedback improved the results significantly and freehand SPECT enabled the mapping of at least one SLN in 87.5% of the patients (28/32 − 3 dropouts). Compared to the reference method, freehand SPECT showed a sensitivity of 83.3% (35/42 nodes). False-negative findings were related to insufficient scanning time, insufficient coverage of the axillary region, close proximity of the SLN to the injection site and low tracer uptake in the SLNs. In this preliminary study, we could demonstrate that 3-D localization of SLNs is feasible using freehand SPECT technology. Prerequisites for acquisition of a good scan quality, most likely allowing precise SLN mapping, have been defined. This approach has high potential to allow image-guided biopsy and further standardization of SLN dissection, thus bringing 3-D nuclear imaging into the operating room.

First demonstration of 3-D lymphatic mapping in breast cancer using freehand SPECT

Background
Breast cancer is the most common form of cancer and the second leading cause of death amongst women in Europe. Amongst five invasive cancers per 1000 women detected in screening, 2.7 were < 15 mm in diameter; and others reported that over one third of excised breast lesions were clinically occult. The challenge is to accurately locate small non-palpable lesions intraoperatively for optimal therapeutic outcome. A secondary important goal is to remove the smallest amount possible of healthy glandular tissue for optimal cosmesis. Currently the most widely adopted approach (80% in one survey) in guided breast-conserving surgery for excising non-palpable breast lesions is wire-guided localization (WGL). With the clinical setting shifting towards earlier non-palpable breast lesions being detected through screening, we investigated whether the current standard in assisting surgical excision of these lesions, WGL, yields the best therapeutic outcome for women with breast cancer.

Objectives
To assess the therapeutic outcomes of any new form of guided surgical intervention for non-palpable breast lesions against wire-guided localization, the current gold standard.

Search methods
We searched the Cochrane Breast Cancer Group's (CBCG) Specialized Register, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal from the earliest available date up to 30 March 2015. We also handsearched recent conference proceedings and sought information from experts in the field.

Selection criteria
Two review authors, BC and RJ, independently screened by title and abstract the studies we had identified through the search strategy; when this was inconclusive, they examined the full-text article for inclusion. We resolved any discrepancies regarding eligibility by discussion with a third review author, RA.

Data collection and analysis
Three review authors, BC, JW, and RJ, independently extracted data using a standardized data sheet. We performed all analyses using Review Manager (RevMan) or the R meta package, and in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. We reported results via a graphical assessment using forest plots showing the study estimates. We considered and discussed additional subgroup and sensitivity analyses.

Main results
We identified 11 randomized controlled trials (RCTs) that met the inclusion criteria of this Cochrane review and included eight trials in the meta-analyses. Six RCTs compared radioguided occult lesion localization (ROLL) versus WGL, and two RCTs compared radioactive iodine (125I) seed localization (RSL) versus WGL. Of the three remaining trials, one RCT compared cryo-assisted techniques (CAL) versus WGL, one compared intraoperative ultrasound-guided lumpectomy (IOUS) versus WGL, and one compared modified ROLL technique in combination with methylene dye (RCML) versus WGL. Of the trials we included in the meta-analysis, there were a total of 1273 participants with non-palpable breast lesions (627 participants (WGL); 443 participants (ROLL); and 203 participants (RSL)). The participant population varied considerably between included trials, which included participants with both non-palpable benign and malignant lesions, and varied in defining clear margins. The included trials did not report any long-term outcomes.

In general, the outcomes of WGL, ROLL and RSL were comparable.

ROLL demonstrated favourable results in successful localization (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.16 to 2.28; 869 participants; six trials), positive excision margins (RR 0.74, 95% CI 0.42 to 1.29; 517 participants; five trials), and re-operation rates (RR 0.51, 95% CI 0.21 to 1.23; 583 participants; four trials) versus WGL, but none were statistically significant. WGL was significantly superior to RSL in successfully localizing non-palpable lesions (RR 3.85, 95% CI 1.21 to 12.19; 402 participants; two trials). However, for successful excision, ROLL and RSL have comparable outcomes versus WGL (ROLL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 871 participants; six trials; RSL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 402 participants; two trials). These findings were similar in that RSL demonstrated favourable results over WGL in positive tumour margins (RR 0.67, 95% CI 0.43 to 1.06; 366 participants; two trials), and re-operation rates (RR 0.80, 95% CI 0.48 to 1.32; 305 participants; one trial) but neither reached statistical significance. In contrast, WGL had fewer postoperative complications to both ROLL (RR 1.18, 95% CI 0.71 to 1.98; 642 participants; four trials) and RSL (RR 1.51, 95% CI 0.75 to 3.03; 305 participants; one trial), although this was also not statistically significant.

The overall quality of evidence was good. The main risk of bias amongst included studies consisted of incomplete data sets, selective reporting, and allocation concealment. Interpretation and applicability of this meta-analysis was hindered by the mixed indication of diagnostic versus therapeutic purposes when undertaking WGL, ROLL, or RSL, leading to a high level of mixed pathology in numerous trials. Other limitations include underpowered studies, lack of data in standardized format for meta-analysis, lack of complete data amongst the trials, and absence of long-term data.

Authors' conclusions
Owing to a lack of trials in certain localization techniques, we could only draw conclusions about ROLL and RSL versus WGL. There is no clear evidence to support one guided technique for surgically excising a non-palpable breast lesion over another. Results from this Cochrane review support the continued use of WGL as a safe and tested technique that allows for flexibility in selected cases when faced with extensive microcalcification. ROLL and RSL could be offered to patients as a comparable replacement for WGL as they are equally reliable. Other techniques such as IOUS, RCML, and CAL are of academic interest, but recommendation for routine use in the clinical environment and oncological outcomes require further validation. The results of this Cochrane review also stress the need for more fully powered RCTs to evaluate the best technique according to the comprehensive criteria described, with a more consistent and standardized approach in outcome reporting.

Localization techniques for guided surgical excision of non-palpable breast lesions

Occult breast lesions: A comparison between radioguided occult lesion localisation (ROLL) vs. wire-guided lumpectomy (WGL).

INTRODUCTION: To test the feasibility and reliability of ROLL in a district general hospital (DGH) dealing with screening detected breast lesions. PATIENTS AND METHODS: [(99m) Tc]-labelled colloidal human serum albumin was injected in the core of the breast lesion under ultrasound or stereotactic guidance 2-4 h prior to surgery. At operation, the radioactivity is localised using a gamma-probe. This allows optimal placement of the skin incision and subsequent WLE of the abnormal area. RESULTS: ROLL was utilised on 36 patients (median age, 61 years; range, 43-75 years); of these, 33 B5 lesions had a therapeutic one-step procedure (lumpectomy and axillary dissection) and 3 B4 patients had the lesion excised for diagnostic purposes. Localisation lasted a median of 8 min (range, 5-15 min), ROLL-guided wide tumour excision lasted 20 min (range, 15-30 min), and median postoperative hospital stay was 2 days (range, 1-3 days). Median cancer diameter was 12 mm (range, 6-40 mm). Margins were clear in 29 patients, while 7 patients with DCIS had involved margins. Median minimal clearance was 5 mm (range, < 1-10 mm). Patients had either excellent (24/36) or good (12/36) cosmetic results. CONCLUSIONS: ROLL successfully localised all lesions; this technique can be implemented in any DGH with a Nuclear Medicine Department. The learning curve is short, cost effectiveness is proven, and cosmetic results are highly rewarding. ROLL could rapidly become the standard localisation technique in the UK.

/pdf/radioguided-occult-lesion-localisation-roll-is-available-in-x3brdcf0bf.pdf

Radioguided occult lesion localisation (ROLL) is available in the UK for impalpable breast lesions.

Recurrence after ROLL lumpectomy for invasive breast cancer.

SNOLL is up and running in UK - an early experience

Background
Occult breast lesions are being successfully targeted by means of Radioactive-guided Occult Lesion Localization (ROLL). Several reports demonstrate suitability of ROLL technique to excise non-palpable breast lesions with immediate advantages.

/pdf/long-term-outcomes-after-roll-lumpectomy-2x57wz7vnp.pdf

Long-term outcomes after ROLL lumpectomy

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