- Email: [email protected]
A device for real-time, intraoperative margin assessment in breast-conservation surgery
The American Journal of Surgery 194 (2007) 467– 473
Presentation
A device for real-time, intraoperative margin assessment in breast-conservation surgery Tami Karni, M.D.a,e,*, Itzhak Pappo, M.D.a,e, Judith Sandbank, M.D.b,e, Oleg Lavon, M.D.b,e, Varda Kent, M.D.a,e, Rona Spector, M.D.c,e, Sara Morgenstern, M.D.d,e, Shlomo Lelcuk, M.D.c,e a Breast Care Institute, Assaf Harofeh Medical Center, Zrifin Beer Yaakov, 70300, Israel Department of Pathology, Assaf Harofeh Medical Center, Zrifin, Beer Yaakov, 70300, Israel c Department of Surgery, Rabin Medical Centers, Beilinson Campus, Petah Tikva, 49100, Israel d Department of Pathology, Rabin Medical Centers, Beilinson Campus, Petah Tikva, 49100, Israel e Sackler School of Medicine, Tel Aviv University, PO Box 39040, Tel Aviv, 69978, Israel b
Manuscript received April 26, 2007; revised manuscript June 26, 2007 Presented at the 8th Annual Meeting of the American Society of Breast Surgeons, Phoenix, AZ, May 2– 6, 2007
Abstract Background: This trial was designed to study performance of a novel handheld probe (Dune Medical Devices, Caesarea, Israel) in intraoperative detection of positive margins and its potential benefit toward minimizing the positive margin rate. Methods: The probe was intraoperatively applied to 57 lumpectomy specimens. Surgeons were blinded to device output, and surgical decisions were not affected by probe data. Probe readings were compared with histological analysis per margin and per patient. Results: Nineteen of 22 (86%) pathology-positive patients were intraoperatively detected with device use. Per-margin sensitivity was .71, and specificity was .68, maintained within a range of positive margin definitions (0 –.4 cm). Conclusions: The device is an effective tool for intraoperative detection of positive margins with the potential for significant positive margin rate reduction. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Breast cancer; Breast-conservation surgery; Intraoperative margin assessment; Surgical margins; Lumpectomy
Breast carcinoma is the most frequently diagnosed malignancy in women. Because of the increased use of screening mammography, the stage at diagnosis decreased over the past years. Today, as a result, approximately 60% of initial diagnoses are localized disease, 30% are locoregional disease, and the remainder are distant metastatic disease [1]. Since the 1990 Consensus Conference, the National Institutes of Health has recommended conservation surgery as an acceptable procedure for stage I and II breast cancer. Thus, the combination of breast-conservation surgery and radiotherapy has become a standard of treatment for most breast tumors. Since then, a number of randomized trials
* Corresponding author. Tel.: ⫹972-8-977-8195; fax: ⫹972-8-9778192. E-mail address: [email protected]
document that mastectomy or breast-conserving therapy (BCT) with lumpectomy and whole-breast irradiation are medically equivalent primary treatment options in the majority of women with stage I and stage II breast cancers [2–5]. The choice of BCT is based on the ability to achieve a pathological negative margin of resection. According to the National Comprehensive Cancer Network 2007 guidelines [6], cases in which there is a positive margin should undergo further surgery. Guided by the orientation of the initial resection specimen, the involved margin can be re-excised to achieve negative margins. Patients undergoing breast-conservation surgery carry a lifelong risk of local recurrence, with positive margin being the strongest predictor. Several controlled retrospective studies have shown significantly increased recurrence rates if no re-excision was performed for focally positive or close
0002-9610/07/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.06.013
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T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473
margins. In an exhaustive review of these works, Singletary [7] reports that microscopic residual disease at margins seems to be responsible for a local recurrence rate of up to 25% 3 to 5 years after breast-conservation surgery and radiotherapy as compared with a maximum of 5% for negative-margin patients. Margin status is also an important factor for planning adjuvant radiation therapy. Most radiation oncologists take into account the patient’s margin status for initiation and protocol planning of radiation therapy. This was further emphasized with the introduction of partial-breast irradiation solutions such as balloon catheter brachytherapy, interstitial brachytherapy, and intraoperative radiation therapy. Optimally, clear margins should be obtained within the first surgical procedure. Nevertheless, with currently available techniques, repeated surgical procedures are often required for conversion of patients to negative-margin status. Reported re-excision rates fall within a wide range, partly because of the lack of consensus with regard to the required clear margin width [8]. Recent patient re-excision rates reported are 21% [9] and 50% [10]. Because excision of unnecessarily large-tissue volumes negatively impacts cosmetic results, a reliable method is necessary for optimized assessment of the excision intraoperatively. Such a tool will help balance the risk of local recurrence, multiple re-excisions and associated psychological issues, cost, and acceptable cosmesis. The availability of intraoperative margin assessment data could enable more corrective intraoperative measures such as additional tissue removal (reshaving), which are currently performed in a limited manner to prevent additional surgical procedures. This, combined with postoperative pathologic data, may improve patient management. An intraoperative margin-assessment device (Dune Medical Devices, Caesarea, Israel) is designed for use by breast surgeons. The device is based on radiofrequency spectroscopy, measuring and quantifying the variable electromagnetic response of malignant and normal cell types under a range of frequencies. This process enables a comparison of the reflected signal to a preacquired library of signals and a classification as “positive” or “negative.” The device includes a console and a sterile disposable probe and is sensitive to malignant tissue at the resected specimen surface up to a depth of .1 cm. This device was previously studied under various protocols [11,12]. These earlier protocols evolved from an initial feasibility study performed in the pathology laboratory on fresh breast cancer–surgery specimens [12] to a study that included an application of the device in the operating room, which was followed by comparison of device readings to histological analysis on individual measurement points and their affiliated margins [11]. The former showed the ability of the technology to accurately detect both invasive and in situ carcinoma, the latter showed the successful application of the technology in an actual tool used in the operating room. This study was designed to further assess the potential of the device under its future intended workflow for intraoperative detection of positive margins and the subsequent potential reduction of postoperative positive margins.
Materials and Methods Study design and patient selection The study was performed at 2 sites under institutional review board approval. Every patient signed an informed consent. All medical staff members were blinded to device output, and patient management was not affected by device readings. The study was designed to calculate device performance by comparing readings on multiple margin points with routine histological margin assessments on the same margins. Comparison of device readings to histology was performed at both the margin and the patient levels as detailed in the data analysis section. Women included were over 18 years of age with diagnosed breast carcinoma. They were eligible for breast-conservation surgery, had not received systemic neoadjuvant therapy, and had no prior surgery or implants in the breast. Device description and intraoperative use The device was used for intraoperative margin assessment. The device components include a console and handheld disposable probe that are interconnected by cables. Measurement is performed by applying the probe tip to a tissue segment (Fig. 1). During every measurement cycle, radiofrequency signals are transmitted by the probe into the tissue, reflected back from the tissue to the probe, and collected by the console. The reflected signals are algorithmically analyzed to yield a “positive” or “negative” classification for the tissue area in contact with the probe’s tip. Each individual measurement takes 1.5 seconds to complete, allowing for multiple sampling on the specimen surface. The probe has a footprint of 1.4 cm in diameter, an effective measurement area diameter of .7 cm, and a detection depth of ⬃.1 cm (Fig. 2). The console is a rackmounted, portable unit. Measurements were logged into the console and analyzed in retrospect in order to blind operating room staff to the device output. In the operating room, the device was intraoperatively applied to the margin surface of freshly excised and sutureoriented lumpectomy specimens. Multiple samples were taken for each of the 6 specimen margins (lateral, medial, inferior, superior, superficial, and deep). Relating the precise area (1 of the 6 margins) sampled by the device uniquely to the margin orientation noted in the pathology report was crucial for an accurate comparison with histological results. Thus, a method was designed to uniquely define the surface margin orientation intraoperatively and to maintain this marking on the single histology slide level. Frames (nonradiopaque, polycarbonate, in variable sizes) and elastic bands were used to mark the margin outlines on the excised specimens (Fig. 3). Once all 6 margins were sampled within the frames, the specimen was sent to pathology for coded color inking based on the frames that were still in place (Fig. 4). Following the coded color inking, the frames were removed from the fresh specimens, and routine processing and margin assessment were performed. Removal of the frames before fixation prevented any permanent compression of the specimen. Pathologists reported margin status for every specimen aspect (1 of the 6 margins) using the ink color as a guide. Intraoperative mounting of the frames on the spec-
T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473
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imen, sampling with the probe within the frame-defined margin, and subsequent color-inking accordingly ensures accurate comparison of data down to the single slide level. Data analysis Data analysis was based on comparison of device readings per margin, as compiled from all points affiliated with that margin, to histologically determined margin status. Device output from all points per margin was compiled to give a positive/negative result per margin based on a percentage threshold. A margin was labeled as positive according to the device if the positive point rate in that margin was higher than 22%. Otherwise, the margin was labeled as negative. A margin was considered positive by histology if any invasive ductal, invasive Fig. 2. Effective detection volume of the probe is .7 cm in diameter and .1 cm deep.
lobular or ductal in situ cancer cells were detected at a distance of D ⱕ .1 cm from any inked margin. Further analysis was included when the value of D was altered to allow for assessment of device performance under different patient-management paradigms. Data were further analyzed at the patient level. Results from all individual margins for a patient were compiled to yield the patient-level classification. For a patient with a positive specimen to be considered as “successfully detected,” it was required that all pathological positive margins on the specimen will be detected or that 3 or more margins will be detected as positive.
Fig. 1. Margin assessment probe as applied to lumpectomy specimen.
Fig. 3. Frames mounted on specimen before device application to mark the margin contours.
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T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473 Table 1 Stratification of per-margin data by specimen margin status: performance results for patients with positive specimens Device
Histology Positive Negative Total
Fig. 4. Color inking of margins guided by frame contours.
Results From February 2005 through December 2005, 68 patients were enrolled in the study. Of these, 11 patients did not fit the inclusion/exclusion criteria for the study and therefore were excluded, 5 were not diagnosed with carcinoma, 3 received neoadjuvant therapy, 1 had prior surgery in the ipsilateral breast, 2 were not color inked according to protocol). The average number of points that were sampled per margin is 11.5 ⫾ 8. This is equivalent to actual average measurement of 4.4 cm2 on every margin and a total of 26.5 cm2 on an entire specimen of average dimensions. The average time of device use in the intraoperative setting was 7:37 minutes (2:10 –18:14 minutes). Three hundred fourteen margins were evaluated from 57 patients, with overall 3,601 measurement points.
Positive
Negative
30 57 87
12 67 79
42 124 166
Per-patient performance In 31 of 57 patients, the initially excised specimens were positive by permanent histology when the margin distance criterion D was set at ⱕ.1 cm. In 9 of these patients, using palpation, specimen radiography, and/or intraoperative pathologist involvement, the positive margins were intraoperatively detected by the surgeon and converted to final negative margins by reshaving, leaving 22 patients with final postoperative positive margin status. In 19 of these patients, all positive margins were detected by the device intraoperatively. Per-patient outcome as observed without device use and intraoperative device detection of positive patients is displayed in Figure 5. Of the 26 patients with negative specimens, 8 had no excess (negative) margins detected as positive by the device, 11 patients had 1 excess margin detected, 3 had 2 excess margins detected, and in 4 patients an entire specimen was detected in excess. For these latter 4 patients, however, pathological data showed that in 3 of them the tumor was found less than .3 cm from the inked surface. Per-margin performance Margin level performance was obtained by comparing the device per-margin outcome to that of pathology when D was set at ⱕ.1 cm. When looking at the entire patient group (314 margins), sensitivity was calculated to be .71 (95% confidence interval [CI], .55–.84) and specificity .68 (95% CI, .61–.73). Specificity was stratified by the specimens’ margin status. Specimens with positive margin status had a per-margin specificity of .54 (95% CI, .445–.63) (Table 1). Specificity in negative specimens is .79 (95% CI, .71–.85) (Table 2). Device performance under variable definitions of positive margins To simulate device performance under various definitions of positive margins, the value of D, which constiTable 2 Stratification of per-margin data by specimen margin status: performance results for patients with negative specimens Device
Fig. 5. Patient outcome as observed without device use and intraoperative detection by device of positive patients.
Histology Positive Negative Total
Positive
Negative
0 31 31
0 117 117
0 148 148
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Table 3 Per-margin and per-patient results with variable positive margin definitions
Number of histology positive specimens (before reshavings) Number of histology final positive patients (after surgeon’s reshavings) Number of histology positive margins Average number of positive margins per positive specimen Per-margin device performance Sensitivity Specificity Per-patient device detection Positive patient rate without device use Device positive patient detection rate Rate of patients undetected by device
D ⫽ 0 cm
D ⱕ .1 cm
D ⱕ .2 cm
D ⱕ .3 cm
D ⱕ .4 cm
18
31
36
40
44
13 21
22 42
27 55
32 69
36 77
1.2 (21/18)
1.3 (42/31)
1.5 (55/36)
1.7 (69/40)
1.8 (77/44)
.67 (14/21) .65 (189/293)
.71 (30/42) .68 (184/272)
.67 (37/55) .69 (178/259)
.67 (46/69) .71 (173/245)
.64 (49/77) .71 (168/237)
.23 (13/57) .92 (12/13) .02 (1/57)
.39 (22/57) .86 (19/22) .05 (3/57)
.47 (27/57) .81 (22/27) .09 (5/57)
.56 (32/57) .69 (22/32) .18 (10/57)
.63 (36/57) .58 (21/36) .26 (15/57)
tutes the depth of a positive margin, was lowered from .1 cm to 0 cm and raised to .2, .3, and .4 cm. Both margin level analysis and patient level analysis were repeated with these alternative D values. Results are displayed in Table 3. The results show that the more conservative the margin definition, the higher the number of histologically positive patients and the greater the number of positive margins per patient. Accordingly, the detection rate of the device decreases and so does the surgeon’s ability to perform intraoperative margin correction without the device. Consequently, the improvement in positive patient detection rate enabled by the device is maintained throughout the analyzed range of margin widths (Fig. 6A). Surprisingly, for margin level results, device performance (sensitivity and specificity) remain essentially the same for the entire range of positive margin definitions (0 cm through .4 cm) (Fig. 6B). Comments This study evaluated the use of a new device, which is used by breast surgeons in an intraoperative setting for real-time assessment of lumpectomy margin status. The availability of intraoperative margin assessment data, even if not as accurate as histology, could enable guided corrective intraoperative measures such as additional tissue removal (reshaving) at the exact moment when a small additional excision can change the patient outcome. Multiple measurements were taken on each margin of the lumpectomy specimen. The device is simple to use in the operating room, and the time required for use is reasonable and well accepted by surgeons. Surgeons were blinded to device readings in real time. Breast surgeons usually orient lumpectomy specimens and reshave additional tissue by margins and, likewise, interface with pathologists in the same manner. Oriented relumpectomy procedures are generally performed based on detailed pathology data regarding the location and orientation of the involved margin. Recognizing this current practice, the device and protocol were designed to support margin-oriented surgical work. Data from this study show
Fig. 6. Performance trends when observed under variable positive margin definitions: (A) per patient and (B) per margin.
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device per-margin sensitivity and specificity and the device’s ability to detect all positive margins of histological positive patients. In line with current breast surgical practice, it is reasonable to assume that had device data been intraoperatively available, surgeons would have chosen to re-excise margins detected as positive by the device, thus converting them to negative. This conversion to negative margin would have been potentially enabled in 86% of positive patients (19/22). Where negative patients are concerned, 4 of 26 (15%) would have had the entire cavity reshaved; however, 3 of these had close margins of .2 or .3 cm. This is noteworthy because surgeons usually define their acceptable clean margin width, or the need to bring the patient back to the operating room for a re-excision, in the context of postoperative patient management. Intraoperatively, real-time margin information is delivered in a setting in which reshaving of additional tissue is simple and not associated with risks, complications, or adverse psychological effects for the patients, which are typically associated with a separate surgical procedure. Keeping this distinction in mind, it is logical to assume that surgeons would intraoperatively choose to reshave additional tissue for close (versus positive) margins. Per-margin specificity was calculated to be 68%. Falsepositive data points were indicated when the device gave a positive reading, but the pathology reported a margin distance greater than 0.1 cm. The device involves probe application and actual measurements of a larger portion of specimen surface than does the histological assessment. It does so with more sampling than typical of pathology. Consequently, we see a possibility that the lower sampling rate in histological analysis may have missed some positive margins that the device has detected. Therefore, actual device specificity may be higher than observed. When assessing device performance, only positive patients are affected by sensitivity, whereas specificity affects negative patients to a far greater extent. In negative patients, it is important for the device to maintain adequate specificity so as not to suggest removal of excess tissue that may adversely affect cosmesis. On the other hand, in marginpositive patients, the lumpectomy procedure will not have a successful outcome if additional tissue is not excised, and the patient will most likely require additional surgery. Thus, for these patients, additional tissue removal is needed for success, and excess tissue removal (as reflected in specificity) has less significance. This reasoning triggered the stratification of per-margin specificity by patient histological margin status. It was observed that the per-margin specificity in negative patients is much higher (79%) than that calculated in positive patients (54%). This sheds a new light on device performance values because the specificity is highest where it is most needed. Without a standard definition of what constitutes a positive margin, different surgeons use different criteria. Therefore, per-margin and per-patient study data were reanalyzed by broadening the primary definition of this study in both directions. Surprisingly, per-margin sensitivity and specificity values for the entire analyzed range of positive margin definition (0 –.4 cm) remain very similar. Why is this the case? The effective reading depth of the device is about .1 cm so it is unlikely that the device detects deeper occurrences of tumor with the same sensitivity. This leads us to suggest that when
pathology sampling detected a close margin (eg, .3 cm), another, narrower margin is present nearby (eg, .1 cm) that the device detected and pathology may have not. Reviewing the correlation between local recurrence and clear margin width, Singletary [7] concludes that, surprisingly, there is no such correlation. Although Singletary offers additional explanations, her observation may also imply that any close margin may actually be closer than sampled. Also noteworthy was the observation that the similarity in per-margin performance among variable positive-margin definitions does not translate to a similarity in patient detection. Device-detection ability decreases with the increase in margin depth and so does the surgeon’s detection without device. In this context, it is appropriate to remember that in this study for a patient to be “successfully detected” all positive margins in that patient have to be detected by the device. With the increase in the defined positive-margin depth, more margins per patient on average are found to be positive. The chance to detect all margins is thus the permargin sensitivity raised to the power of the average number of positive margins. Because the base is smaller than one, the higher the exponent is, the lower the result. It is this effect that brings about the continuous decrease in positive patient detection, whereas the basic margin sensitivity remains the same as the margin definition increases. If we consider the potential effect of device-detection ability on positive patient rate (Fig. 6A) as a measure of effectiveness, the effectiveness is maintained through changes in positive margin definition, and thus the device is expected to be of equal effectiveness under different margin criteria. Results from this study show that the probe might give breast surgeons the ability to effectively tackle a significant barrier in today’s management of breast-conservation surgery patients, namely, the ability to seek and rapidly detect unsatisfactory resection margins. These data support additional investigation of this device to further examine its convenience and possible integration in the surgical management of breast-conservation surgery patients. Future clinical investigations performed by using the device should include a study in which the device is implemented in lumpectomy procedures and its output data are used to guide surgical decisions. Acknowledgment This study was supported by Dune Medical Devices. References [1] Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2007. CA Cancer J Clin 2007;57:43– 66. [2] Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233– 41. [3] Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227–32. [4] Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995;332:907–11. [5] Arriagada R, Le MG, Rochard F, Contesso G. Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 1996;14:1558 – 64.
T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473 [6] National Comprehensive Cancer Network, Inc. The NCCN Breast Cancer Clinical Practice Guidelines in Oncology (Version 1. 2007, 2006). Available at: http://www.nccn.org. Accessed July 30, 2007. [7] Singletary SE. Surgical margins in patients with early-stage breast cancer with breast conservation surgery. Am J Surg 2002;184:383–93. [8] Taghian A, Mohiuddin M, Jagsi R, et al. Current perceptions regarding surgical margin status after breast-conserving therapy: results of a survey. Ann Surg 2005;241:629 –39. [9] Tafra L, Fine R, Whitworth P, et al. Prospective randomized study comparing cryo-assisted and needle-wire localization of ultrasound visible breast tumors. Am J Surg 2006;192:462–70.
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[10] Menes TS, Tartter PA, Bleiweiss I, et al. The consequence of multiple re-excisions to obtain clear lumpectomy margins in breast cancer patients. Ann Surg Oncol 2005;12:1–5. [11] Tafra L, Karni T, Cheng Z, et al. Handheld intraoperative margin assessment device for partial mastectomy specimens. Paper presented at: 7th Annual Meeting of the American Society of Breast Surgeons; April 5–9, 2006; Baltimore, MD. [12] Karni T, Pappo I, Sandbank J, et al. Intra-operative tissue characterization probe as a potential tool for surgical margin assessment. Paper presented at: 28th Annual San Antonio Breast Cancer Symposium; December 8 –11, 2005; San Antonio, TX.
Presentation
A device for real-time, intraoperative margin assessment in breast-conservation surgery Tami Karni, M.D.a,e,*, Itzhak Pappo, M.D.a,e, Judith Sandbank, M.D.b,e, Oleg Lavon, M.D.b,e, Varda Kent, M.D.a,e, Rona Spector, M.D.c,e, Sara Morgenstern, M.D.d,e, Shlomo Lelcuk, M.D.c,e a Breast Care Institute, Assaf Harofeh Medical Center, Zrifin Beer Yaakov, 70300, Israel Department of Pathology, Assaf Harofeh Medical Center, Zrifin, Beer Yaakov, 70300, Israel c Department of Surgery, Rabin Medical Centers, Beilinson Campus, Petah Tikva, 49100, Israel d Department of Pathology, Rabin Medical Centers, Beilinson Campus, Petah Tikva, 49100, Israel e Sackler School of Medicine, Tel Aviv University, PO Box 39040, Tel Aviv, 69978, Israel b
Manuscript received April 26, 2007; revised manuscript June 26, 2007 Presented at the 8th Annual Meeting of the American Society of Breast Surgeons, Phoenix, AZ, May 2– 6, 2007
Abstract Background: This trial was designed to study performance of a novel handheld probe (Dune Medical Devices, Caesarea, Israel) in intraoperative detection of positive margins and its potential benefit toward minimizing the positive margin rate. Methods: The probe was intraoperatively applied to 57 lumpectomy specimens. Surgeons were blinded to device output, and surgical decisions were not affected by probe data. Probe readings were compared with histological analysis per margin and per patient. Results: Nineteen of 22 (86%) pathology-positive patients were intraoperatively detected with device use. Per-margin sensitivity was .71, and specificity was .68, maintained within a range of positive margin definitions (0 –.4 cm). Conclusions: The device is an effective tool for intraoperative detection of positive margins with the potential for significant positive margin rate reduction. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Breast cancer; Breast-conservation surgery; Intraoperative margin assessment; Surgical margins; Lumpectomy
Breast carcinoma is the most frequently diagnosed malignancy in women. Because of the increased use of screening mammography, the stage at diagnosis decreased over the past years. Today, as a result, approximately 60% of initial diagnoses are localized disease, 30% are locoregional disease, and the remainder are distant metastatic disease [1]. Since the 1990 Consensus Conference, the National Institutes of Health has recommended conservation surgery as an acceptable procedure for stage I and II breast cancer. Thus, the combination of breast-conservation surgery and radiotherapy has become a standard of treatment for most breast tumors. Since then, a number of randomized trials
* Corresponding author. Tel.: ⫹972-8-977-8195; fax: ⫹972-8-9778192. E-mail address: [email protected]
document that mastectomy or breast-conserving therapy (BCT) with lumpectomy and whole-breast irradiation are medically equivalent primary treatment options in the majority of women with stage I and stage II breast cancers [2–5]. The choice of BCT is based on the ability to achieve a pathological negative margin of resection. According to the National Comprehensive Cancer Network 2007 guidelines [6], cases in which there is a positive margin should undergo further surgery. Guided by the orientation of the initial resection specimen, the involved margin can be re-excised to achieve negative margins. Patients undergoing breast-conservation surgery carry a lifelong risk of local recurrence, with positive margin being the strongest predictor. Several controlled retrospective studies have shown significantly increased recurrence rates if no re-excision was performed for focally positive or close
0002-9610/07/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.06.013
468
T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473
margins. In an exhaustive review of these works, Singletary [7] reports that microscopic residual disease at margins seems to be responsible for a local recurrence rate of up to 25% 3 to 5 years after breast-conservation surgery and radiotherapy as compared with a maximum of 5% for negative-margin patients. Margin status is also an important factor for planning adjuvant radiation therapy. Most radiation oncologists take into account the patient’s margin status for initiation and protocol planning of radiation therapy. This was further emphasized with the introduction of partial-breast irradiation solutions such as balloon catheter brachytherapy, interstitial brachytherapy, and intraoperative radiation therapy. Optimally, clear margins should be obtained within the first surgical procedure. Nevertheless, with currently available techniques, repeated surgical procedures are often required for conversion of patients to negative-margin status. Reported re-excision rates fall within a wide range, partly because of the lack of consensus with regard to the required clear margin width [8]. Recent patient re-excision rates reported are 21% [9] and 50% [10]. Because excision of unnecessarily large-tissue volumes negatively impacts cosmetic results, a reliable method is necessary for optimized assessment of the excision intraoperatively. Such a tool will help balance the risk of local recurrence, multiple re-excisions and associated psychological issues, cost, and acceptable cosmesis. The availability of intraoperative margin assessment data could enable more corrective intraoperative measures such as additional tissue removal (reshaving), which are currently performed in a limited manner to prevent additional surgical procedures. This, combined with postoperative pathologic data, may improve patient management. An intraoperative margin-assessment device (Dune Medical Devices, Caesarea, Israel) is designed for use by breast surgeons. The device is based on radiofrequency spectroscopy, measuring and quantifying the variable electromagnetic response of malignant and normal cell types under a range of frequencies. This process enables a comparison of the reflected signal to a preacquired library of signals and a classification as “positive” or “negative.” The device includes a console and a sterile disposable probe and is sensitive to malignant tissue at the resected specimen surface up to a depth of .1 cm. This device was previously studied under various protocols [11,12]. These earlier protocols evolved from an initial feasibility study performed in the pathology laboratory on fresh breast cancer–surgery specimens [12] to a study that included an application of the device in the operating room, which was followed by comparison of device readings to histological analysis on individual measurement points and their affiliated margins [11]. The former showed the ability of the technology to accurately detect both invasive and in situ carcinoma, the latter showed the successful application of the technology in an actual tool used in the operating room. This study was designed to further assess the potential of the device under its future intended workflow for intraoperative detection of positive margins and the subsequent potential reduction of postoperative positive margins.
Materials and Methods Study design and patient selection The study was performed at 2 sites under institutional review board approval. Every patient signed an informed consent. All medical staff members were blinded to device output, and patient management was not affected by device readings. The study was designed to calculate device performance by comparing readings on multiple margin points with routine histological margin assessments on the same margins. Comparison of device readings to histology was performed at both the margin and the patient levels as detailed in the data analysis section. Women included were over 18 years of age with diagnosed breast carcinoma. They were eligible for breast-conservation surgery, had not received systemic neoadjuvant therapy, and had no prior surgery or implants in the breast. Device description and intraoperative use The device was used for intraoperative margin assessment. The device components include a console and handheld disposable probe that are interconnected by cables. Measurement is performed by applying the probe tip to a tissue segment (Fig. 1). During every measurement cycle, radiofrequency signals are transmitted by the probe into the tissue, reflected back from the tissue to the probe, and collected by the console. The reflected signals are algorithmically analyzed to yield a “positive” or “negative” classification for the tissue area in contact with the probe’s tip. Each individual measurement takes 1.5 seconds to complete, allowing for multiple sampling on the specimen surface. The probe has a footprint of 1.4 cm in diameter, an effective measurement area diameter of .7 cm, and a detection depth of ⬃.1 cm (Fig. 2). The console is a rackmounted, portable unit. Measurements were logged into the console and analyzed in retrospect in order to blind operating room staff to the device output. In the operating room, the device was intraoperatively applied to the margin surface of freshly excised and sutureoriented lumpectomy specimens. Multiple samples were taken for each of the 6 specimen margins (lateral, medial, inferior, superior, superficial, and deep). Relating the precise area (1 of the 6 margins) sampled by the device uniquely to the margin orientation noted in the pathology report was crucial for an accurate comparison with histological results. Thus, a method was designed to uniquely define the surface margin orientation intraoperatively and to maintain this marking on the single histology slide level. Frames (nonradiopaque, polycarbonate, in variable sizes) and elastic bands were used to mark the margin outlines on the excised specimens (Fig. 3). Once all 6 margins were sampled within the frames, the specimen was sent to pathology for coded color inking based on the frames that were still in place (Fig. 4). Following the coded color inking, the frames were removed from the fresh specimens, and routine processing and margin assessment were performed. Removal of the frames before fixation prevented any permanent compression of the specimen. Pathologists reported margin status for every specimen aspect (1 of the 6 margins) using the ink color as a guide. Intraoperative mounting of the frames on the spec-
T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473
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imen, sampling with the probe within the frame-defined margin, and subsequent color-inking accordingly ensures accurate comparison of data down to the single slide level. Data analysis Data analysis was based on comparison of device readings per margin, as compiled from all points affiliated with that margin, to histologically determined margin status. Device output from all points per margin was compiled to give a positive/negative result per margin based on a percentage threshold. A margin was labeled as positive according to the device if the positive point rate in that margin was higher than 22%. Otherwise, the margin was labeled as negative. A margin was considered positive by histology if any invasive ductal, invasive Fig. 2. Effective detection volume of the probe is .7 cm in diameter and .1 cm deep.
lobular or ductal in situ cancer cells were detected at a distance of D ⱕ .1 cm from any inked margin. Further analysis was included when the value of D was altered to allow for assessment of device performance under different patient-management paradigms. Data were further analyzed at the patient level. Results from all individual margins for a patient were compiled to yield the patient-level classification. For a patient with a positive specimen to be considered as “successfully detected,” it was required that all pathological positive margins on the specimen will be detected or that 3 or more margins will be detected as positive.
Fig. 1. Margin assessment probe as applied to lumpectomy specimen.
Fig. 3. Frames mounted on specimen before device application to mark the margin contours.
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T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473 Table 1 Stratification of per-margin data by specimen margin status: performance results for patients with positive specimens Device
Histology Positive Negative Total
Fig. 4. Color inking of margins guided by frame contours.
Results From February 2005 through December 2005, 68 patients were enrolled in the study. Of these, 11 patients did not fit the inclusion/exclusion criteria for the study and therefore were excluded, 5 were not diagnosed with carcinoma, 3 received neoadjuvant therapy, 1 had prior surgery in the ipsilateral breast, 2 were not color inked according to protocol). The average number of points that were sampled per margin is 11.5 ⫾ 8. This is equivalent to actual average measurement of 4.4 cm2 on every margin and a total of 26.5 cm2 on an entire specimen of average dimensions. The average time of device use in the intraoperative setting was 7:37 minutes (2:10 –18:14 minutes). Three hundred fourteen margins were evaluated from 57 patients, with overall 3,601 measurement points.
Positive
Negative
30 57 87
12 67 79
42 124 166
Per-patient performance In 31 of 57 patients, the initially excised specimens were positive by permanent histology when the margin distance criterion D was set at ⱕ.1 cm. In 9 of these patients, using palpation, specimen radiography, and/or intraoperative pathologist involvement, the positive margins were intraoperatively detected by the surgeon and converted to final negative margins by reshaving, leaving 22 patients with final postoperative positive margin status. In 19 of these patients, all positive margins were detected by the device intraoperatively. Per-patient outcome as observed without device use and intraoperative device detection of positive patients is displayed in Figure 5. Of the 26 patients with negative specimens, 8 had no excess (negative) margins detected as positive by the device, 11 patients had 1 excess margin detected, 3 had 2 excess margins detected, and in 4 patients an entire specimen was detected in excess. For these latter 4 patients, however, pathological data showed that in 3 of them the tumor was found less than .3 cm from the inked surface. Per-margin performance Margin level performance was obtained by comparing the device per-margin outcome to that of pathology when D was set at ⱕ.1 cm. When looking at the entire patient group (314 margins), sensitivity was calculated to be .71 (95% confidence interval [CI], .55–.84) and specificity .68 (95% CI, .61–.73). Specificity was stratified by the specimens’ margin status. Specimens with positive margin status had a per-margin specificity of .54 (95% CI, .445–.63) (Table 1). Specificity in negative specimens is .79 (95% CI, .71–.85) (Table 2). Device performance under variable definitions of positive margins To simulate device performance under various definitions of positive margins, the value of D, which constiTable 2 Stratification of per-margin data by specimen margin status: performance results for patients with negative specimens Device
Fig. 5. Patient outcome as observed without device use and intraoperative detection by device of positive patients.
Histology Positive Negative Total
Positive
Negative
0 31 31
0 117 117
0 148 148
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Table 3 Per-margin and per-patient results with variable positive margin definitions
Number of histology positive specimens (before reshavings) Number of histology final positive patients (after surgeon’s reshavings) Number of histology positive margins Average number of positive margins per positive specimen Per-margin device performance Sensitivity Specificity Per-patient device detection Positive patient rate without device use Device positive patient detection rate Rate of patients undetected by device
D ⫽ 0 cm
D ⱕ .1 cm
D ⱕ .2 cm
D ⱕ .3 cm
D ⱕ .4 cm
18
31
36
40
44
13 21
22 42
27 55
32 69
36 77
1.2 (21/18)
1.3 (42/31)
1.5 (55/36)
1.7 (69/40)
1.8 (77/44)
.67 (14/21) .65 (189/293)
.71 (30/42) .68 (184/272)
.67 (37/55) .69 (178/259)
.67 (46/69) .71 (173/245)
.64 (49/77) .71 (168/237)
.23 (13/57) .92 (12/13) .02 (1/57)
.39 (22/57) .86 (19/22) .05 (3/57)
.47 (27/57) .81 (22/27) .09 (5/57)
.56 (32/57) .69 (22/32) .18 (10/57)
.63 (36/57) .58 (21/36) .26 (15/57)
tutes the depth of a positive margin, was lowered from .1 cm to 0 cm and raised to .2, .3, and .4 cm. Both margin level analysis and patient level analysis were repeated with these alternative D values. Results are displayed in Table 3. The results show that the more conservative the margin definition, the higher the number of histologically positive patients and the greater the number of positive margins per patient. Accordingly, the detection rate of the device decreases and so does the surgeon’s ability to perform intraoperative margin correction without the device. Consequently, the improvement in positive patient detection rate enabled by the device is maintained throughout the analyzed range of margin widths (Fig. 6A). Surprisingly, for margin level results, device performance (sensitivity and specificity) remain essentially the same for the entire range of positive margin definitions (0 cm through .4 cm) (Fig. 6B). Comments This study evaluated the use of a new device, which is used by breast surgeons in an intraoperative setting for real-time assessment of lumpectomy margin status. The availability of intraoperative margin assessment data, even if not as accurate as histology, could enable guided corrective intraoperative measures such as additional tissue removal (reshaving) at the exact moment when a small additional excision can change the patient outcome. Multiple measurements were taken on each margin of the lumpectomy specimen. The device is simple to use in the operating room, and the time required for use is reasonable and well accepted by surgeons. Surgeons were blinded to device readings in real time. Breast surgeons usually orient lumpectomy specimens and reshave additional tissue by margins and, likewise, interface with pathologists in the same manner. Oriented relumpectomy procedures are generally performed based on detailed pathology data regarding the location and orientation of the involved margin. Recognizing this current practice, the device and protocol were designed to support margin-oriented surgical work. Data from this study show
Fig. 6. Performance trends when observed under variable positive margin definitions: (A) per patient and (B) per margin.
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device per-margin sensitivity and specificity and the device’s ability to detect all positive margins of histological positive patients. In line with current breast surgical practice, it is reasonable to assume that had device data been intraoperatively available, surgeons would have chosen to re-excise margins detected as positive by the device, thus converting them to negative. This conversion to negative margin would have been potentially enabled in 86% of positive patients (19/22). Where negative patients are concerned, 4 of 26 (15%) would have had the entire cavity reshaved; however, 3 of these had close margins of .2 or .3 cm. This is noteworthy because surgeons usually define their acceptable clean margin width, or the need to bring the patient back to the operating room for a re-excision, in the context of postoperative patient management. Intraoperatively, real-time margin information is delivered in a setting in which reshaving of additional tissue is simple and not associated with risks, complications, or adverse psychological effects for the patients, which are typically associated with a separate surgical procedure. Keeping this distinction in mind, it is logical to assume that surgeons would intraoperatively choose to reshave additional tissue for close (versus positive) margins. Per-margin specificity was calculated to be 68%. Falsepositive data points were indicated when the device gave a positive reading, but the pathology reported a margin distance greater than 0.1 cm. The device involves probe application and actual measurements of a larger portion of specimen surface than does the histological assessment. It does so with more sampling than typical of pathology. Consequently, we see a possibility that the lower sampling rate in histological analysis may have missed some positive margins that the device has detected. Therefore, actual device specificity may be higher than observed. When assessing device performance, only positive patients are affected by sensitivity, whereas specificity affects negative patients to a far greater extent. In negative patients, it is important for the device to maintain adequate specificity so as not to suggest removal of excess tissue that may adversely affect cosmesis. On the other hand, in marginpositive patients, the lumpectomy procedure will not have a successful outcome if additional tissue is not excised, and the patient will most likely require additional surgery. Thus, for these patients, additional tissue removal is needed for success, and excess tissue removal (as reflected in specificity) has less significance. This reasoning triggered the stratification of per-margin specificity by patient histological margin status. It was observed that the per-margin specificity in negative patients is much higher (79%) than that calculated in positive patients (54%). This sheds a new light on device performance values because the specificity is highest where it is most needed. Without a standard definition of what constitutes a positive margin, different surgeons use different criteria. Therefore, per-margin and per-patient study data were reanalyzed by broadening the primary definition of this study in both directions. Surprisingly, per-margin sensitivity and specificity values for the entire analyzed range of positive margin definition (0 –.4 cm) remain very similar. Why is this the case? The effective reading depth of the device is about .1 cm so it is unlikely that the device detects deeper occurrences of tumor with the same sensitivity. This leads us to suggest that when
pathology sampling detected a close margin (eg, .3 cm), another, narrower margin is present nearby (eg, .1 cm) that the device detected and pathology may have not. Reviewing the correlation between local recurrence and clear margin width, Singletary [7] concludes that, surprisingly, there is no such correlation. Although Singletary offers additional explanations, her observation may also imply that any close margin may actually be closer than sampled. Also noteworthy was the observation that the similarity in per-margin performance among variable positive-margin definitions does not translate to a similarity in patient detection. Device-detection ability decreases with the increase in margin depth and so does the surgeon’s detection without device. In this context, it is appropriate to remember that in this study for a patient to be “successfully detected” all positive margins in that patient have to be detected by the device. With the increase in the defined positive-margin depth, more margins per patient on average are found to be positive. The chance to detect all margins is thus the permargin sensitivity raised to the power of the average number of positive margins. Because the base is smaller than one, the higher the exponent is, the lower the result. It is this effect that brings about the continuous decrease in positive patient detection, whereas the basic margin sensitivity remains the same as the margin definition increases. If we consider the potential effect of device-detection ability on positive patient rate (Fig. 6A) as a measure of effectiveness, the effectiveness is maintained through changes in positive margin definition, and thus the device is expected to be of equal effectiveness under different margin criteria. Results from this study show that the probe might give breast surgeons the ability to effectively tackle a significant barrier in today’s management of breast-conservation surgery patients, namely, the ability to seek and rapidly detect unsatisfactory resection margins. These data support additional investigation of this device to further examine its convenience and possible integration in the surgical management of breast-conservation surgery patients. Future clinical investigations performed by using the device should include a study in which the device is implemented in lumpectomy procedures and its output data are used to guide surgical decisions. Acknowledgment This study was supported by Dune Medical Devices. References [1] Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2007. CA Cancer J Clin 2007;57:43– 66. [2] Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233– 41. [3] Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227–32. [4] Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995;332:907–11. [5] Arriagada R, Le MG, Rochard F, Contesso G. Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 1996;14:1558 – 64.
T. Karni et al. / The American Journal of Surgery 194 (2007) 467– 473 [6] National Comprehensive Cancer Network, Inc. The NCCN Breast Cancer Clinical Practice Guidelines in Oncology (Version 1. 2007, 2006). Available at: http://www.nccn.org. Accessed July 30, 2007. [7] Singletary SE. Surgical margins in patients with early-stage breast cancer with breast conservation surgery. Am J Surg 2002;184:383–93. [8] Taghian A, Mohiuddin M, Jagsi R, et al. Current perceptions regarding surgical margin status after breast-conserving therapy: results of a survey. Ann Surg 2005;241:629 –39. [9] Tafra L, Fine R, Whitworth P, et al. Prospective randomized study comparing cryo-assisted and needle-wire localization of ultrasound visible breast tumors. Am J Surg 2006;192:462–70.
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[10] Menes TS, Tartter PA, Bleiweiss I, et al. The consequence of multiple re-excisions to obtain clear lumpectomy margins in breast cancer patients. Ann Surg Oncol 2005;12:1–5. [11] Tafra L, Karni T, Cheng Z, et al. Handheld intraoperative margin assessment device for partial mastectomy specimens. Paper presented at: 7th Annual Meeting of the American Society of Breast Surgeons; April 5–9, 2006; Baltimore, MD. [12] Karni T, Pappo I, Sandbank J, et al. Intra-operative tissue characterization probe as a potential tool for surgical margin assessment. Paper presented at: 28th Annual San Antonio Breast Cancer Symposium; December 8 –11, 2005; San Antonio, TX.