Arch Gynecol Obstet DOI 10.1007/s00404-016-4011-3
GYNECOLOGIC ONCOLOGY
MarginProbeÓ reduces the rate of re-excision following breast conserving surgery for breast cancer Jens-Uwe Blohmer1,2 • Julia Tanko2 • Janina Kueper1 • Jessica Groß1,2 Ragna Vo¨lker1,2 • Anna Machleidt1,2
•
Received: 15 October 2015 / Accepted: 5 January 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Abstract Purpose A positive margin status after breast conserving surgery (BCS) is one of the strongest predictors for local recurrence of intraductal (DCIS) and invasive carcinoma. As much as 20–50 % of patients with BCS need to undergo a second operation to receive free margins. In this study we tested the clinical performance of MarginProbeÓ (Dune Medical Devices, Paoli, PA, USA), a device for the intraoperative evaluation of surgical margins. Methods A prospective clinical study was performed: The device was utilized in BCS of 150 patients treated at a single facility from November 2012 to June 2013. The reexcision rate was compared to the re-excision rate of a historical group of 172 patients treated with BCS at the same hospital without the application of the device. We analyzed whether the results of MarginProbeÓ are affected by the morphology, grading, size of the tumor, breast density, age, BMI or the use of marker-wires. Results The application of MarginProbeÓ resulted in an overall decreased re-excision rate of 14.6 %. In the subgroup of DCIS the re-excision rate was reduced from 61.7 to 23.1 %. In the subgroup of invasive lobular carcinomas the re-excision rate decreased from 37.0 to 19.0 %. MarginProbeÓ results were not affected by grading, tumor size, breast density, age, BMI or marker-wire application. Conclusion MarginProbeÓ detects positive margins in invasive carcinoma, DCIS as well as in invasive lobular & Anna Machleidt [email protected] 1
Breast Center, Charite´-Universita¨tsmedizin Berlin, Charite´platz 1, 10117 Berlin, Germany
2
Department of Gynecology and Breast Center, SanktGertrauden Hospital, Paretzer Str. 12, 10713 Berlin, Germany
carcinoma. The device decreases the re-excision rate after BCS significantly. It does not interfere with any of the factors we examined. Keywords Re-excision rate breast cancer Free-margins breast cancer Breast conserving therapy MarginProbeÓ
Introduction The aim of breast conserving surgery (BCS) of invasive and pre-invasive breast cancers is to achieve clear margins to avoid re-excision and achieve good esthetic results. Excised lumps are examined intraoperatively to ensure an R0-resection. Various methods which have shown limited clinical success expressed by a reduced re-excision rate and resection volume compared with the standard of care include gross macroscopic examinations, touch-prep cytology, frozen sectioning, and intraoperative ultrasound [1–5]. MarginProbeÓ has been introduced as a novel device for the detection of tumor-positive surgical margins. A cell’s malignancy is indicated by various changes in the cell’s metabolism and morphology. The cellular membrane is depolarized, the nuclear:cytoplasmic ratio is increased and neoangiogenesis is induced. Inter- and intracellular communication and contact inhibition are lost. All of these phenomena have been the subject of research for decades and have been found to be measurable by high-frequency spectroscopy [6–9]. MarginProbeÓ uses the altered ‘electromagnetic signature’ of malignant tissue to differentiate it from healthy tissue. Previous studies showed a reduction of the re-excision rate utilizing MarginProbeÓ [11–14]. Thill et al. included patients with DCIS in three clinics. The MarginProbeÓ results were compared with historical data of breast
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conserving therapy for DCIS. The reduction of the re-excision rate was 56 % (p = 0.01) of MarginProbeÓ group compared with historical group [14]. Rivera et al. analyzed a group of 664 women with non-palpable invasive cancer and/or DCIS undergoing BCS. Intraoperatively women were randomized to standard of care (SOC) lumpectomy or utilization of MarginProbeÓ. Using the device resulted in a 57 % reduction in re-excision compared to the control group [MarginProbeÓ: 42/298 (14.1 %), control: 98/298 (29.9 %), p \ 0.0001] [11]. The primary study endpoint was the reduction of reexcision rate (ROR) using MarginProbeÓ additional to standard operation procedure (SOP) compared with standard operation procedure alone (gross pathology examination, radiogram of specimen; intraoperative ultrasound was not performed during the study period). The secondary study endpoint was to evaluate possible predictive factors for reduced ROR: tumor type, invasive cancer or DCIS, grading, tumor size, age of patient, breast density, body mass index (BMI), palpable or no-palpable lesion, and wire-localization of malignant breast lesion.
Materials and methods This prospective study was approved by our institution’s ethical committee. Patient selection and data review From November 22th in 2012 to June 11th in 2013 all patients undergoing BCS at the Sankt Gertrauden Hospital in Berlin with invasive breast cancer (with and without concomitant DCIS) and pure DCIS were intraoperatively examined with MarginProbeÓ in addition to the standard operation procedure (SOP). This patient cohort was compared to a group of patients treated from December 2011 to March 2012 in the same clinic without the use of MarginProbeÓ only using the SOP. Data were collected on patients age, breast density, body mass index (BMI), the histologic tumor type, grading and tumor size. The surgical procedure and surgical details (re-excision, volume of removed breast tissue) were noted. Both cohorts also include patients with BCS after neoadjuvant chemotherapy (2 in the MarginProbe groupÓ, 8 in the control group), patients with pathologic complete remission were excluded. The MarginProbeÓ device and utilization The MarginProbeÓ System is comprised of two distinct components: a hand-held probe and a console. The console includes a display, audio components and operation
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Fig. 1 Intraoperative MarginProbeÓ
examination
of
tumor
margins
using
buttons. The probe is a detachable, sterile, single-use, single-patient component. It is connected to the console by cables and a vacuum tube via a single connector. The system utilizes radiofrequency spectroscopy to characterize human tissue in real-time, measuring differences in dielectric properties between normal and malignant breast tissue. MarginProbeÓ has a measuring depth of 1 mm and a diameter of 7 mm. Five to eight measurements are made for each of the six sides of the excised tissue. Measurements last one and a half seconds, which extend the operating time by a mean of 7–8 min (Fig. 1). The signals received from the excised breast tissue are analyzed and compared to values in the database. The classification as malignant (?) or normal breast tissue (-) is consequently signaled both visually as a bar diagram in the display as well as acoustically. The evaluation in realtime is meant to allow the surgeon an immediate extension of the excision upon finding tumor-positive margins in the excised lump. A tumor-free surgical margin of 1 mm for invasive carcinomas with and without concomitant DCIS and 2 mm for DCIS alone were implemented per the recommended contemporary German clinical practice guidelines [2].
Statistical analysis Statistical analysis was conducted using Fisher’s exact test for categorical and discrete variables or the FisherFreeman-Halton test. Significant variables were defined as having a p value \ 0.05. Continuous variables were expressed as mean ± standard deviation. The effect of the breast cancer’s morphology, grading, or size of the tumor as well as the breast density, age, BMI or the use of marker-wires on the results of Margin ProbeÓ was evaluated.
Arch Gynecol Obstet
Results
Table 1 Tumor and patients characteristics of the MarginProbeÓ group and the historic group MarginProbeÒ group
Patient characteristics The experimental group included 150 patients with 137 invasive breast cancer and 13 pure DCIS. Eight surgeons in total performed the surgeries. 46 % of the patients in the MarginProbeÓ group had an invasive ductal carcinoma, 25 % had an invasive ductal carcinoma with concomitant DCIS. We found 9 % of patients with DCIS only and 14 % with an invasive lobular carcinoma. 22.3 % of the tumors were well differentiated, 60.1 % moderate and 17.6 % were poorly differentiated. The mean age of the patients was 60.88 years, with a range between 24 and 96 years. The mean BMI was 25.1. The historic control group included 172 patients with 154 invasive breast cancer and 18 DCIS treated identically by eight surgeons with the difference of no utilization of the MarginProbeÓ device following the lumpectomy. 43 % of the patients had an invasive ductal carcinoma, 23 % had an invasive ductal carcinoma with concomitant DCIS. 11 % was diagnosed with a DCIS and 16 % with an invasive lobular carcinoma. 19.8 % of the tumors were poorly differentiated, 61.6 % moderate and 18.6 % poorly differentiated. The youngest patient in the control group was 29 years old, the oldest patient was 86 years old. The mean age was 60.3 years. The mean BMI was 25.2. The characteristics of the tumors and patients were not found to differ significantly between the groups (Table 1). Operative details and outcome The utilization of MarginProbeÓ led to a significant reduction of the re-excision rate (ROR) for all patients (p = 0.001). The re-excision rate was reduced by an absolute 15.1 % and a relative 51 % (41/172 patients: 29.7 % vs. 22/150 patients: 14.6 %) (Fig. 2; Table 2). The re-excision rate following the utilization of MarginProbeÓ was 14.6 % (n = 23) compared to a re-excision rate of 29.7 % in the control group (n = 58). The re-excision rate was significant reduced in the group utilizing MarginProbeÓ compared with the control group in patients diagnosed with invasive ductal cancer (14.7 vs. 1.5 %; p = 0.005) (Table 2). Furthermore, the re-excision rate was reduced in the group utilizing MarginProbeÓ compared with the control group in patients diagnosed with pure DCIS (61.1 vs. 23.1 %; p = 0.067) (Fig. 3; Table 2). In the group of patients diagnosed with lobular invasive carcinoma there was a remarkable, but no significant difference in ROR according to the number of performed surgeries (44.4 vs. 23.8 %; p = 0.224; Fig. 4; Table 2). As
Control group
p value
Number of patients
150
172
Invasive cancer
137
154
0.705
Invasive ductal Invasive ductal ? DCIS
68 38
75 40
0.857
Invasive lobular
21
27
DCIS
13
18
0.705 0.852
Grading G1
33
34
G2
89
106
G3
26
32
Tumor size \0.5 cm
7
8
0.5–1 cm
28
31
1–2 cm 2–5 cm
65 42
68 52
[5 cm
8
7
20–29
1
1
30–39
6
5
40–49
25
22
50–59
37
55
60–69
39
51
70–79
34
28
80–89
6
10
[90
2
0
3
4
18.5–24.9
82
89
25.0–29.9 [30
36 25
52 26
0.962
Age 0.377
BMI \18.5
0.706
some patients had to underwent more than one surgery to achieve free margins, the difference in ROR according to the patients in this group was 37.0 vs. 19.0 % (p = 0.213; Fig. 4; Table 2). In the group of invasive ductal carcinoma with concomitant DCIS there was no reduction of ROR found by utilization of MarginProbeÓ (36.9 vs. 37.5 %; p = 0.999, Table 2). Analysis of predictive factors of re-excision following BCS with MarginProbeÓ The effect of a variety of tumor- and patient details on the re-excision rate following BCS with MarginProbeÓ were analyzed (Table 3). The patient’s age, BMI, clinical
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Arch Gynecol Obstet 40.00%
50.00% 33.70%
35.00%
44.40%
45.00% 29.70%
30.00%
40.00%
37.00%
35.00%
25.00% 20.00% 15.30%
14.60%
15.00%
Without use of MarginProbe© With use of MarginProbe©
10.00%
30.00% Without use of MarginProbe©
23.80%
25.00%
19.00%
20.00%
With use of MarginProbe©
15.00% 10.00%
5.00%
5.00%
0.00%
0.00% Re-excision procedures
Patients with re-excision procedure
Re-excision procedures
Fig. 2 Re-excision rates per procedure and patient for all patients with invasive breast cancer (with and without accompanying DCIS) and DCIS alone Table 2 Re-excision rate of the MarginProbeÓ group and the historic group ROR %: MarginProbeÒ All patients
14.6
ROR %: control group 29.7
1.5 36.9
14.7 37.5
Table 3 Re-excision rates grouped by demographic and tumor characteristics Characteristics Grading (all)
0.001 0.005 0.999
Invasive lobular
19.0
37.0
0.213
DCIS
23.1
61.1
0.067
\0.5
14.3
50.0
n.s.
0.5–1
10.7
12.9
n.s.
1–2
12.3
19.1
n.s.
2–5
21.4
45.6
0.012
12.5
57.1
n.s.
p value
14.6
0.212
12.0
G2
18.0
G3 Breast density (all)
66.70% 61.10%
3.8 14.6
ACR 1 (A)
9.1
ACR 2 (B) ACR 3 (C)
14.3 19.0
Age (all) (years) \50 60–69
20.5
70–79
8.8
80–89
16.7 0
BMI (all)
14.6
\18.5
0
18.5–24.9
14.6
50.00%
25.0–29.9
13.9
[30
16.0
40.00% 30.00%
23.10%
23.10%
20.00%
With use of MarginProbe©
Localization (all palpable and non-palpable) With wire
0.856
8.0 21.6
60.00%
Without use of MarginProbe©
0.679
5.9 14.6
50–59
[90 80.00% 70.00%
ROR %
G1
ACR 4 (D)
Tumor size (cm)
[5
Fig. 4 Re-excision rates of patients with invasive lobular cancer for MarginProbeÓ group and the historic group
p value
Invasive cancer Invasive ductal Invasive ductal ? DCIS
Patients with re-excision procedure
14.6 15.3
0.999
0.179
10.00% 0.00% Re-excision procedures
Patients with re-excision procedure
Fig. 3 Re-excision rates of patients with DCIS for MarginProbeÓ group and the historic group
presentation and breast density as well as the grade of the carcinoma and the utilization of marker-wires were found to have no significant impact on the re-excision rate following primary BCS. A tumor size between 2 and 5 cm
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was found to correlate with a significant reduction of the re-excision rate in the patient cohort which received BCS with MarginProbeÓ (Table 2). There was no analysis performed relating to the intraoperative use of scissors versus electric dissection. A mean 47.3 ml of breast tissue was removed during the primary BCS. The 47.3 ml of overall resection volume consist of 41.3 ml from the main tumor tissue and 6.0 ml of intraoperative re-excision to achieve free margins. The
Arch Gynecol Obstet Table 4 Mean excised volume of breast tissue
Removed breast tissue total
47.3 cm3
Main tumor tissue
41.3 cm3
Intraoperative re-excision volume based on MarginProbeÓ result
1.8 cm3
Intraoperative re-excision volume based on pathologists gross sectioning
4.2 cm3
Table 5 Impact of surgeon on the re-excision rate, the rate of subsequent mastectomies and their different reactions on MarginProbeÓ results Surgeon
Number of operations
1
36
2
35
3
22
4 5
Reexcision rate (%)
Rate of mastectomy (%)
Right reaction on MarginProbeÓ result total (%)
Right reaction on MarginProbeÓ result when result was ? (malignant) (%)
Mean resection volume (without re-excision) (g)
5.6
16.7
92
89
47.9
22.9
2.9
88.6
85
48.2
18.2
4.5
91
86
42.3
33
9.1
6.1
61
24
65.5
14
35.7
0
36
18
22.1
Right reaction on MarginProbeÓ result means: surgeon chose re-excision intraoperatively because the device indicated positive margin
re-excision volume of 6.0 ml comprises 4.2 ml tissue volume which has been excised because of macroscopic margin evaluation from the pathologist (gross sectioning) and another 1.8 ml tissue volume in consequence of MarginProbeÓ result (Table 4). An analysis of the resection volumes as shown in Table 4 was done in the MarginProbeÓ group only. A possible influence of the surgeon and the surgeons decision is shown in Table 5: a high rate of mastectomy causes a low rate of re-excision. In addition, a high volume of removed breast tissue during BCS causes a low rate of re-excision. Both, mastectomy and high volume resection, result in frequent contralateral breast adapting surgery, reconstruction and psychological disorders, which is not the aim of breast conserving therapy. In our study patients benefit from the surgeons reaction on Margin Probe result.
Discussion Comparing a group of patients who received BCS with and without MarginProbeÓ we found a significant reduction in the re-excision rate of patients with invasive ductal cancer and a remarkable, but not significant reduction of ROR for DCIS and invasive lobular cancer [10]. In multiple studies utilizing this device a reduction of re-excision rates was seen [11, 12]. In a prospective randomized study for non-palpable invasive breast cancer and DCIS differences in re-excision rates between the MarginProbeÓ group and the SOC group were evaluated [11]. 664 patients from 21 clinics were included. The reexcision rate was reduced by 57 % (MarginProbeÓ: 14.1 %; control group: 29.9 %; p \ 0.0001). There was a mild increased resection volume in the MarginProbeÓ
group [11, 12]. Pappo et al. [13] demonstrated that the sensitivity of the device is 100 % in tumors larger than 5 mm, but may sink as low as 56 % in smaller tumors. The specificity has been found to be 87 %. The homo- or heterogeneity of the tissue being analyzed appears to have a significant impact on the specificity [13]. An additional multicenter study analyzed patients with DCIS alone treated with BCS. Similarly as our study, the group of patients receiving BCS with MarginProbeÓ was compared to a historic group of patients whose surgical margins were not intraoperatively analyzed with the device. The reduction of the re-excision rate was 56 % (p = 0.01) in the MarginProbeÓ group compared with the historic group of patients. In our study MarginProbeÓ was found to decrease the re-excision rate from approximately 30 % to under 15 %. This corresponds to a relative reduction of re-excisions of 50 %, a rate which is confirmed by prior studies evaluating the device [12, 13]. However, increased tissue volume was noted to have been removed in groups of patients receiving BCS with MarginProbeÓ [12]. Current studies and metaanalysis were unable to show advantages for local recurrence rates (LRR) of invasive carcinoma and concomitant DCIS comparing different width of free tumor margins (e.g., no ink on tumor, 1, 2, 5 mm). Increasing margins have not shown statistically trends for lower local recurrence rates [15]. Studies show that with the use of adjuvant systemic therapy the LRR diminished despite of less radical operative therapy. This finding also counts for high-risk patients with node positive disease. There is no benefit on wider tumor-free margins in patients with triple negative carcinoma than in hormone receptor positive patients [16, 17]. The recommended tumor-free margin during our study period for BCS with or
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without concomitant DCIS was 1 mm and for DCIS alone 2 mm [1, 2, 20]. To achieve an R0-resection with tumor-free surgical margins, excellent preoperative planning and advanced surgical technique are necessary. Touch-prep cytology, frozen sectioning, intraoperative ultrasound and gross intraoperative palpation are among the methods utilized to recognize tumor-positive surgical margins [1–3]. Pre- and postoperative MRI-Imaging has been shown to be ineffective in reducing re-excision rates at all [21]. No advanced technique designed to evaluate surgical margins during BCS have resulted in a 100 % success rate in determining tumor-positive tissue, though all have shown an advantage when compared to intraoperative palpation [1–5, 12–14]. The rate of re-excisions and secondary mastectomies following BCS to achieve tumor-free margins has been described to range from 30 to 40 % in Europe and North America [4, 12, 16]. The pre-operative evaluation of the size of the tumor plays a vital role in planning the surgery. Whilst sonography has been shown to underestimate the size of the tumor, MRI’s have been found to overestimate it. Especially with patients diagnosed with invasive lobular carcinomas, mammograms and manual palpation have proven to be the most reliable methods in evaluating tumor size [18]. One dilemma with surgical margins of breast cancers are that a lack of tumor cells cannot be confirmed until the surgical specimen has been examined by a pathologist. Methods of intraoperative surgical margin evaluation seek to minimize re-excision rates by allowing for a timely and cost-effective search for tumor cell-positive tissue. A relatively new method of intraoperative surgical margin evaluation, intraoperative ultrasound has shown promising results. Krekel et al. [4] compared intraoperative ultrasound evaluation to manual palpation and found that the reexcision rate was significantly lower at 11 % in the patient cohort assigned to intraoperative ultrasound when compared to the patient cohort which received manual palpation. They also found a significant reduction of the overall volume of tissue excised. Another option to decrease re-excision rates are oncoplastic techniques. Losken et al. [19] found that though a R1-resection was significantly less likely to occur, the overall volume of tissue resected was four times as large when compared to the standard of care. The re-excision rate was found to be lower, but the rate of secondary mastectomies was found to be higher. Patients were more satisfied with the esthetic results if they had been operated on with oncoplastic techniques. Some of the limitations of our study evaluating the MarginProbeÓ system to achieve tumor-free margins and low ROR are the retrospective collection of the data of the historic patient cohort as well as the lack of a matched
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cohort of patients. At the time this study was underway, a clear surgical margin of 1 or 2 mm for invasive carcinoma with or without DCIS and DCIS alone, respectively, was considered the gold standard in Germany. To achieve these margins of 1–2 mm more re-excisions have been made during the study period than it would be done today, as surgeons now accept the recommendation of ‘no ink on tumor cells’. The relative reduction of the rate of re-excisions, however, should remain the same independent of the demand for ‘no ink on tumor cells’ or a 1–2 mm clear surgical margin. It may be notable that the rate of re-excision in our control group with DCIS is relatively high with 61 %. In literature rates of re-excision in DCIS are described between 40 and 64 % [22, 23]. One of our patients received 2 re-excisions in this group, 3 patients receives secondary mastectomies. Therefore, a comparatively high number of extensive DCIS may be an explanation for the percentage in the upper range. MarginProbeÓ appears to be a safe and useful manner to evaluate surgical margins in patients receiving BCS for DCIS or invasive carcinoma, resulting in significantly decreased re-excision rates. As there is no reduction of ROR in the group of ductal invasive cancer with concomitant DCIS, further studies are needed to evaluate this aspect. Studies also should detect whether the use of the MarginProbeÓ is a clinical viable und cost-effective method for the determination of tumor-free margins in BCS. Future studies should compare various methods of intraoperative surgical margin evaluation in a prospective, randomized manner, to allow for a more definitive understanding of the advantages and disadvantages of each technique. Acknowledgments Unrestricted grant from Dunne Medical Corp. for scientific work. Prof. Blohmer got honoraria for presentations from Dunne Medical Corp. Compliance with ethical standards Conflict of interest The author declares that there is no actual or potential conflict of interest in relation to this article exists apart from what is mentioned under acknowledgements. Ethical standards This prospective study was approved by our institution’s ethical committee. Authors had full control of all primary data and agree to allow the Journal to review the data if requested.
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GYNECOLOGIC ONCOLOGY
MarginProbeÓ reduces the rate of re-excision following breast conserving surgery for breast cancer Jens-Uwe Blohmer1,2 • Julia Tanko2 • Janina Kueper1 • Jessica Groß1,2 Ragna Vo¨lker1,2 • Anna Machleidt1,2
•
Received: 15 October 2015 / Accepted: 5 January 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Abstract Purpose A positive margin status after breast conserving surgery (BCS) is one of the strongest predictors for local recurrence of intraductal (DCIS) and invasive carcinoma. As much as 20–50 % of patients with BCS need to undergo a second operation to receive free margins. In this study we tested the clinical performance of MarginProbeÓ (Dune Medical Devices, Paoli, PA, USA), a device for the intraoperative evaluation of surgical margins. Methods A prospective clinical study was performed: The device was utilized in BCS of 150 patients treated at a single facility from November 2012 to June 2013. The reexcision rate was compared to the re-excision rate of a historical group of 172 patients treated with BCS at the same hospital without the application of the device. We analyzed whether the results of MarginProbeÓ are affected by the morphology, grading, size of the tumor, breast density, age, BMI or the use of marker-wires. Results The application of MarginProbeÓ resulted in an overall decreased re-excision rate of 14.6 %. In the subgroup of DCIS the re-excision rate was reduced from 61.7 to 23.1 %. In the subgroup of invasive lobular carcinomas the re-excision rate decreased from 37.0 to 19.0 %. MarginProbeÓ results were not affected by grading, tumor size, breast density, age, BMI or marker-wire application. Conclusion MarginProbeÓ detects positive margins in invasive carcinoma, DCIS as well as in invasive lobular & Anna Machleidt [email protected] 1
Breast Center, Charite´-Universita¨tsmedizin Berlin, Charite´platz 1, 10117 Berlin, Germany
2
Department of Gynecology and Breast Center, SanktGertrauden Hospital, Paretzer Str. 12, 10713 Berlin, Germany
carcinoma. The device decreases the re-excision rate after BCS significantly. It does not interfere with any of the factors we examined. Keywords Re-excision rate breast cancer Free-margins breast cancer Breast conserving therapy MarginProbeÓ
Introduction The aim of breast conserving surgery (BCS) of invasive and pre-invasive breast cancers is to achieve clear margins to avoid re-excision and achieve good esthetic results. Excised lumps are examined intraoperatively to ensure an R0-resection. Various methods which have shown limited clinical success expressed by a reduced re-excision rate and resection volume compared with the standard of care include gross macroscopic examinations, touch-prep cytology, frozen sectioning, and intraoperative ultrasound [1–5]. MarginProbeÓ has been introduced as a novel device for the detection of tumor-positive surgical margins. A cell’s malignancy is indicated by various changes in the cell’s metabolism and morphology. The cellular membrane is depolarized, the nuclear:cytoplasmic ratio is increased and neoangiogenesis is induced. Inter- and intracellular communication and contact inhibition are lost. All of these phenomena have been the subject of research for decades and have been found to be measurable by high-frequency spectroscopy [6–9]. MarginProbeÓ uses the altered ‘electromagnetic signature’ of malignant tissue to differentiate it from healthy tissue. Previous studies showed a reduction of the re-excision rate utilizing MarginProbeÓ [11–14]. Thill et al. included patients with DCIS in three clinics. The MarginProbeÓ results were compared with historical data of breast
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conserving therapy for DCIS. The reduction of the re-excision rate was 56 % (p = 0.01) of MarginProbeÓ group compared with historical group [14]. Rivera et al. analyzed a group of 664 women with non-palpable invasive cancer and/or DCIS undergoing BCS. Intraoperatively women were randomized to standard of care (SOC) lumpectomy or utilization of MarginProbeÓ. Using the device resulted in a 57 % reduction in re-excision compared to the control group [MarginProbeÓ: 42/298 (14.1 %), control: 98/298 (29.9 %), p \ 0.0001] [11]. The primary study endpoint was the reduction of reexcision rate (ROR) using MarginProbeÓ additional to standard operation procedure (SOP) compared with standard operation procedure alone (gross pathology examination, radiogram of specimen; intraoperative ultrasound was not performed during the study period). The secondary study endpoint was to evaluate possible predictive factors for reduced ROR: tumor type, invasive cancer or DCIS, grading, tumor size, age of patient, breast density, body mass index (BMI), palpable or no-palpable lesion, and wire-localization of malignant breast lesion.
Materials and methods This prospective study was approved by our institution’s ethical committee. Patient selection and data review From November 22th in 2012 to June 11th in 2013 all patients undergoing BCS at the Sankt Gertrauden Hospital in Berlin with invasive breast cancer (with and without concomitant DCIS) and pure DCIS were intraoperatively examined with MarginProbeÓ in addition to the standard operation procedure (SOP). This patient cohort was compared to a group of patients treated from December 2011 to March 2012 in the same clinic without the use of MarginProbeÓ only using the SOP. Data were collected on patients age, breast density, body mass index (BMI), the histologic tumor type, grading and tumor size. The surgical procedure and surgical details (re-excision, volume of removed breast tissue) were noted. Both cohorts also include patients with BCS after neoadjuvant chemotherapy (2 in the MarginProbe groupÓ, 8 in the control group), patients with pathologic complete remission were excluded. The MarginProbeÓ device and utilization The MarginProbeÓ System is comprised of two distinct components: a hand-held probe and a console. The console includes a display, audio components and operation
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Fig. 1 Intraoperative MarginProbeÓ
examination
of
tumor
margins
using
buttons. The probe is a detachable, sterile, single-use, single-patient component. It is connected to the console by cables and a vacuum tube via a single connector. The system utilizes radiofrequency spectroscopy to characterize human tissue in real-time, measuring differences in dielectric properties between normal and malignant breast tissue. MarginProbeÓ has a measuring depth of 1 mm and a diameter of 7 mm. Five to eight measurements are made for each of the six sides of the excised tissue. Measurements last one and a half seconds, which extend the operating time by a mean of 7–8 min (Fig. 1). The signals received from the excised breast tissue are analyzed and compared to values in the database. The classification as malignant (?) or normal breast tissue (-) is consequently signaled both visually as a bar diagram in the display as well as acoustically. The evaluation in realtime is meant to allow the surgeon an immediate extension of the excision upon finding tumor-positive margins in the excised lump. A tumor-free surgical margin of 1 mm for invasive carcinomas with and without concomitant DCIS and 2 mm for DCIS alone were implemented per the recommended contemporary German clinical practice guidelines [2].
Statistical analysis Statistical analysis was conducted using Fisher’s exact test for categorical and discrete variables or the FisherFreeman-Halton test. Significant variables were defined as having a p value \ 0.05. Continuous variables were expressed as mean ± standard deviation. The effect of the breast cancer’s morphology, grading, or size of the tumor as well as the breast density, age, BMI or the use of marker-wires on the results of Margin ProbeÓ was evaluated.
Arch Gynecol Obstet
Results
Table 1 Tumor and patients characteristics of the MarginProbeÓ group and the historic group MarginProbeÒ group
Patient characteristics The experimental group included 150 patients with 137 invasive breast cancer and 13 pure DCIS. Eight surgeons in total performed the surgeries. 46 % of the patients in the MarginProbeÓ group had an invasive ductal carcinoma, 25 % had an invasive ductal carcinoma with concomitant DCIS. We found 9 % of patients with DCIS only and 14 % with an invasive lobular carcinoma. 22.3 % of the tumors were well differentiated, 60.1 % moderate and 17.6 % were poorly differentiated. The mean age of the patients was 60.88 years, with a range between 24 and 96 years. The mean BMI was 25.1. The historic control group included 172 patients with 154 invasive breast cancer and 18 DCIS treated identically by eight surgeons with the difference of no utilization of the MarginProbeÓ device following the lumpectomy. 43 % of the patients had an invasive ductal carcinoma, 23 % had an invasive ductal carcinoma with concomitant DCIS. 11 % was diagnosed with a DCIS and 16 % with an invasive lobular carcinoma. 19.8 % of the tumors were poorly differentiated, 61.6 % moderate and 18.6 % poorly differentiated. The youngest patient in the control group was 29 years old, the oldest patient was 86 years old. The mean age was 60.3 years. The mean BMI was 25.2. The characteristics of the tumors and patients were not found to differ significantly between the groups (Table 1). Operative details and outcome The utilization of MarginProbeÓ led to a significant reduction of the re-excision rate (ROR) for all patients (p = 0.001). The re-excision rate was reduced by an absolute 15.1 % and a relative 51 % (41/172 patients: 29.7 % vs. 22/150 patients: 14.6 %) (Fig. 2; Table 2). The re-excision rate following the utilization of MarginProbeÓ was 14.6 % (n = 23) compared to a re-excision rate of 29.7 % in the control group (n = 58). The re-excision rate was significant reduced in the group utilizing MarginProbeÓ compared with the control group in patients diagnosed with invasive ductal cancer (14.7 vs. 1.5 %; p = 0.005) (Table 2). Furthermore, the re-excision rate was reduced in the group utilizing MarginProbeÓ compared with the control group in patients diagnosed with pure DCIS (61.1 vs. 23.1 %; p = 0.067) (Fig. 3; Table 2). In the group of patients diagnosed with lobular invasive carcinoma there was a remarkable, but no significant difference in ROR according to the number of performed surgeries (44.4 vs. 23.8 %; p = 0.224; Fig. 4; Table 2). As
Control group
p value
Number of patients
150
172
Invasive cancer
137
154
0.705
Invasive ductal Invasive ductal ? DCIS
68 38
75 40
0.857
Invasive lobular
21
27
DCIS
13
18
0.705 0.852
Grading G1
33
34
G2
89
106
G3
26
32
Tumor size \0.5 cm
7
8
0.5–1 cm
28
31
1–2 cm 2–5 cm
65 42
68 52
[5 cm
8
7
20–29
1
1
30–39
6
5
40–49
25
22
50–59
37
55
60–69
39
51
70–79
34
28
80–89
6
10
[90
2
0
3
4
18.5–24.9
82
89
25.0–29.9 [30
36 25
52 26
0.962
Age 0.377
BMI \18.5
0.706
some patients had to underwent more than one surgery to achieve free margins, the difference in ROR according to the patients in this group was 37.0 vs. 19.0 % (p = 0.213; Fig. 4; Table 2). In the group of invasive ductal carcinoma with concomitant DCIS there was no reduction of ROR found by utilization of MarginProbeÓ (36.9 vs. 37.5 %; p = 0.999, Table 2). Analysis of predictive factors of re-excision following BCS with MarginProbeÓ The effect of a variety of tumor- and patient details on the re-excision rate following BCS with MarginProbeÓ were analyzed (Table 3). The patient’s age, BMI, clinical
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Arch Gynecol Obstet 40.00%
50.00% 33.70%
35.00%
44.40%
45.00% 29.70%
30.00%
40.00%
37.00%
35.00%
25.00% 20.00% 15.30%
14.60%
15.00%
Without use of MarginProbe© With use of MarginProbe©
10.00%
30.00% Without use of MarginProbe©
23.80%
25.00%
19.00%
20.00%
With use of MarginProbe©
15.00% 10.00%
5.00%
5.00%
0.00%
0.00% Re-excision procedures
Patients with re-excision procedure
Re-excision procedures
Fig. 2 Re-excision rates per procedure and patient for all patients with invasive breast cancer (with and without accompanying DCIS) and DCIS alone Table 2 Re-excision rate of the MarginProbeÓ group and the historic group ROR %: MarginProbeÒ All patients
14.6
ROR %: control group 29.7
1.5 36.9
14.7 37.5
Table 3 Re-excision rates grouped by demographic and tumor characteristics Characteristics Grading (all)
0.001 0.005 0.999
Invasive lobular
19.0
37.0
0.213
DCIS
23.1
61.1
0.067
\0.5
14.3
50.0
n.s.
0.5–1
10.7
12.9
n.s.
1–2
12.3
19.1
n.s.
2–5
21.4
45.6
0.012
12.5
57.1
n.s.
p value
14.6
0.212
12.0
G2
18.0
G3 Breast density (all)
66.70% 61.10%
3.8 14.6
ACR 1 (A)
9.1
ACR 2 (B) ACR 3 (C)
14.3 19.0
Age (all) (years) \50 60–69
20.5
70–79
8.8
80–89
16.7 0
BMI (all)
14.6
\18.5
0
18.5–24.9
14.6
50.00%
25.0–29.9
13.9
[30
16.0
40.00% 30.00%
23.10%
23.10%
20.00%
With use of MarginProbe©
Localization (all palpable and non-palpable) With wire
0.856
8.0 21.6
60.00%
Without use of MarginProbe©
0.679
5.9 14.6
50–59
[90 80.00% 70.00%
ROR %
G1
ACR 4 (D)
Tumor size (cm)
[5
Fig. 4 Re-excision rates of patients with invasive lobular cancer for MarginProbeÓ group and the historic group
p value
Invasive cancer Invasive ductal Invasive ductal ? DCIS
Patients with re-excision procedure
14.6 15.3
0.999
0.179
10.00% 0.00% Re-excision procedures
Patients with re-excision procedure
Fig. 3 Re-excision rates of patients with DCIS for MarginProbeÓ group and the historic group
presentation and breast density as well as the grade of the carcinoma and the utilization of marker-wires were found to have no significant impact on the re-excision rate following primary BCS. A tumor size between 2 and 5 cm
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was found to correlate with a significant reduction of the re-excision rate in the patient cohort which received BCS with MarginProbeÓ (Table 2). There was no analysis performed relating to the intraoperative use of scissors versus electric dissection. A mean 47.3 ml of breast tissue was removed during the primary BCS. The 47.3 ml of overall resection volume consist of 41.3 ml from the main tumor tissue and 6.0 ml of intraoperative re-excision to achieve free margins. The
Arch Gynecol Obstet Table 4 Mean excised volume of breast tissue
Removed breast tissue total
47.3 cm3
Main tumor tissue
41.3 cm3
Intraoperative re-excision volume based on MarginProbeÓ result
1.8 cm3
Intraoperative re-excision volume based on pathologists gross sectioning
4.2 cm3
Table 5 Impact of surgeon on the re-excision rate, the rate of subsequent mastectomies and their different reactions on MarginProbeÓ results Surgeon
Number of operations
1
36
2
35
3
22
4 5
Reexcision rate (%)
Rate of mastectomy (%)
Right reaction on MarginProbeÓ result total (%)
Right reaction on MarginProbeÓ result when result was ? (malignant) (%)
Mean resection volume (without re-excision) (g)
5.6
16.7
92
89
47.9
22.9
2.9
88.6
85
48.2
18.2
4.5
91
86
42.3
33
9.1
6.1
61
24
65.5
14
35.7
0
36
18
22.1
Right reaction on MarginProbeÓ result means: surgeon chose re-excision intraoperatively because the device indicated positive margin
re-excision volume of 6.0 ml comprises 4.2 ml tissue volume which has been excised because of macroscopic margin evaluation from the pathologist (gross sectioning) and another 1.8 ml tissue volume in consequence of MarginProbeÓ result (Table 4). An analysis of the resection volumes as shown in Table 4 was done in the MarginProbeÓ group only. A possible influence of the surgeon and the surgeons decision is shown in Table 5: a high rate of mastectomy causes a low rate of re-excision. In addition, a high volume of removed breast tissue during BCS causes a low rate of re-excision. Both, mastectomy and high volume resection, result in frequent contralateral breast adapting surgery, reconstruction and psychological disorders, which is not the aim of breast conserving therapy. In our study patients benefit from the surgeons reaction on Margin Probe result.
Discussion Comparing a group of patients who received BCS with and without MarginProbeÓ we found a significant reduction in the re-excision rate of patients with invasive ductal cancer and a remarkable, but not significant reduction of ROR for DCIS and invasive lobular cancer [10]. In multiple studies utilizing this device a reduction of re-excision rates was seen [11, 12]. In a prospective randomized study for non-palpable invasive breast cancer and DCIS differences in re-excision rates between the MarginProbeÓ group and the SOC group were evaluated [11]. 664 patients from 21 clinics were included. The reexcision rate was reduced by 57 % (MarginProbeÓ: 14.1 %; control group: 29.9 %; p \ 0.0001). There was a mild increased resection volume in the MarginProbeÓ
group [11, 12]. Pappo et al. [13] demonstrated that the sensitivity of the device is 100 % in tumors larger than 5 mm, but may sink as low as 56 % in smaller tumors. The specificity has been found to be 87 %. The homo- or heterogeneity of the tissue being analyzed appears to have a significant impact on the specificity [13]. An additional multicenter study analyzed patients with DCIS alone treated with BCS. Similarly as our study, the group of patients receiving BCS with MarginProbeÓ was compared to a historic group of patients whose surgical margins were not intraoperatively analyzed with the device. The reduction of the re-excision rate was 56 % (p = 0.01) in the MarginProbeÓ group compared with the historic group of patients. In our study MarginProbeÓ was found to decrease the re-excision rate from approximately 30 % to under 15 %. This corresponds to a relative reduction of re-excisions of 50 %, a rate which is confirmed by prior studies evaluating the device [12, 13]. However, increased tissue volume was noted to have been removed in groups of patients receiving BCS with MarginProbeÓ [12]. Current studies and metaanalysis were unable to show advantages for local recurrence rates (LRR) of invasive carcinoma and concomitant DCIS comparing different width of free tumor margins (e.g., no ink on tumor, 1, 2, 5 mm). Increasing margins have not shown statistically trends for lower local recurrence rates [15]. Studies show that with the use of adjuvant systemic therapy the LRR diminished despite of less radical operative therapy. This finding also counts for high-risk patients with node positive disease. There is no benefit on wider tumor-free margins in patients with triple negative carcinoma than in hormone receptor positive patients [16, 17]. The recommended tumor-free margin during our study period for BCS with or
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without concomitant DCIS was 1 mm and for DCIS alone 2 mm [1, 2, 20]. To achieve an R0-resection with tumor-free surgical margins, excellent preoperative planning and advanced surgical technique are necessary. Touch-prep cytology, frozen sectioning, intraoperative ultrasound and gross intraoperative palpation are among the methods utilized to recognize tumor-positive surgical margins [1–3]. Pre- and postoperative MRI-Imaging has been shown to be ineffective in reducing re-excision rates at all [21]. No advanced technique designed to evaluate surgical margins during BCS have resulted in a 100 % success rate in determining tumor-positive tissue, though all have shown an advantage when compared to intraoperative palpation [1–5, 12–14]. The rate of re-excisions and secondary mastectomies following BCS to achieve tumor-free margins has been described to range from 30 to 40 % in Europe and North America [4, 12, 16]. The pre-operative evaluation of the size of the tumor plays a vital role in planning the surgery. Whilst sonography has been shown to underestimate the size of the tumor, MRI’s have been found to overestimate it. Especially with patients diagnosed with invasive lobular carcinomas, mammograms and manual palpation have proven to be the most reliable methods in evaluating tumor size [18]. One dilemma with surgical margins of breast cancers are that a lack of tumor cells cannot be confirmed until the surgical specimen has been examined by a pathologist. Methods of intraoperative surgical margin evaluation seek to minimize re-excision rates by allowing for a timely and cost-effective search for tumor cell-positive tissue. A relatively new method of intraoperative surgical margin evaluation, intraoperative ultrasound has shown promising results. Krekel et al. [4] compared intraoperative ultrasound evaluation to manual palpation and found that the reexcision rate was significantly lower at 11 % in the patient cohort assigned to intraoperative ultrasound when compared to the patient cohort which received manual palpation. They also found a significant reduction of the overall volume of tissue excised. Another option to decrease re-excision rates are oncoplastic techniques. Losken et al. [19] found that though a R1-resection was significantly less likely to occur, the overall volume of tissue resected was four times as large when compared to the standard of care. The re-excision rate was found to be lower, but the rate of secondary mastectomies was found to be higher. Patients were more satisfied with the esthetic results if they had been operated on with oncoplastic techniques. Some of the limitations of our study evaluating the MarginProbeÓ system to achieve tumor-free margins and low ROR are the retrospective collection of the data of the historic patient cohort as well as the lack of a matched
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cohort of patients. At the time this study was underway, a clear surgical margin of 1 or 2 mm for invasive carcinoma with or without DCIS and DCIS alone, respectively, was considered the gold standard in Germany. To achieve these margins of 1–2 mm more re-excisions have been made during the study period than it would be done today, as surgeons now accept the recommendation of ‘no ink on tumor cells’. The relative reduction of the rate of re-excisions, however, should remain the same independent of the demand for ‘no ink on tumor cells’ or a 1–2 mm clear surgical margin. It may be notable that the rate of re-excision in our control group with DCIS is relatively high with 61 %. In literature rates of re-excision in DCIS are described between 40 and 64 % [22, 23]. One of our patients received 2 re-excisions in this group, 3 patients receives secondary mastectomies. Therefore, a comparatively high number of extensive DCIS may be an explanation for the percentage in the upper range. MarginProbeÓ appears to be a safe and useful manner to evaluate surgical margins in patients receiving BCS for DCIS or invasive carcinoma, resulting in significantly decreased re-excision rates. As there is no reduction of ROR in the group of ductal invasive cancer with concomitant DCIS, further studies are needed to evaluate this aspect. Studies also should detect whether the use of the MarginProbeÓ is a clinical viable und cost-effective method for the determination of tumor-free margins in BCS. Future studies should compare various methods of intraoperative surgical margin evaluation in a prospective, randomized manner, to allow for a more definitive understanding of the advantages and disadvantages of each technique. Acknowledgments Unrestricted grant from Dunne Medical Corp. for scientific work. Prof. Blohmer got honoraria for presentations from Dunne Medical Corp. Compliance with ethical standards Conflict of interest The author declares that there is no actual or potential conflict of interest in relation to this article exists apart from what is mentioned under acknowledgements. Ethical standards This prospective study was approved by our institution’s ethical committee. Authors had full control of all primary data and agree to allow the Journal to review the data if requested.
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