Coverage Policy Manual
Policy #: 2013026
Category: Surgery
Initiated: August 2013
Last Review: August 2018
  Handheld Radiofrequency Spectroscopy for Intraoperative Assessment of Surgical Margins during Breast-Conserving Surgery

Description:
Breast-conserving surgery as part of the treatment of localized breast cancer is optimally achieved by attaining margins around the surgical resection that are free from tumor cells. MarginProbe® is intended to increase the probability that the surgeon will achieve clear margins in the initial operation, thus avoiding the need for a second surgery to excise more breast tissue.
 
Breast-conserving surgery as part of the treatment of localized breast cancer is optimally achieved by attaining margins around the surgical resection that are free from tumor cells. Failure to achieve clear margins will often require additional surgery to re-excise breast tissue. Currently, histologic examination of excised tissues after completion of surgery is the only method of definitively determining whether clear margins were achieved. Intra-operative methods of assessing surgical margins such as specimen imaging, frozen section pathology, and touch print cytology, are either not highly accurate, not commonly available, or require considerable time and resources.
 
MarginProbe® is a device based on the principles of dielectric spectroscopy that characterizes tissue that the device comes in contact with. Cancer cells and normal breast tissues produce different signals. A handheld probe is applied to a small area of the resected surgical specimen and analyzes the tissue as to whether it is likely malignant or benign. During the operation, the surgeon touches the MarginProbe device to each surface of the biopsy specimen. The device gives a reading of positive or negative for each touch. If any one of the touches on a particular margin gives a positive reading, the margin is considered to be positive and should be re-excised if possible. The device can only be used on the main lumpectomy specimen, and cannot be used on shavings or in the lumpectomy cavity in the patient’s breast. Use of the MarginProbe® device is intended to increase the probability that the surgeon will achieve clear margins in the initial operation, thus avoiding the need for a second surgery to excise more breast tissue.
 
Regulatory Status
In January 2013, MarginProbe® received PMA approval from the Food and Drug Administration (FDA). The Dune MarginProbe®™ System is an adjunctive diagnostic tool for identification of cancerous tissue at the margins (≤ 1mm) of the main ex-vivo lumpectomy specimen following primary excision and is indicated for intraoperative use in conjunction with standard methods (such as intraoperative imaging and palpation) for patients undergoing lumpectomy for previously diagnosed breast cancer.
  
Coding
There is no specific CPT code for this spectroscopic assessment. A possible unlisted CPT code that might be used is 19499 unlisted procedure breast.
  
 

Policy/
Coverage:
Handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins during breast-conserving surgery does not meet member benefit certificate primary coverage criteria that there be scientific evidence in improving health outcomes.
 
For members with contracts without primary coverage criteria, handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins during breast-conserving surgery is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 

Rationale:
Evidence evaluating the efficacy of MarginProbe comes from FDA documents describing the clinical trial that led to FDA approval (FDA, 2012). The trial has not yet been published in a peer-reviewed journal as of May 2013. An earlier study evaluating its use did not use the same classification algorithm and may not represent the current performance of the device (Allweis, 2008). The reviewed study reports the most relevant patient outcomes available for evaluating MarginProbe® with the largest number of patients including a large proportion of US patients. In addition to clinical outcomes, the study allows assessments of diagnostic test performance of MarginProbe®, which will help inform judgments of its utility.
 
The pivotal study compared surgical processes and short-term outcomes in patients in whom MarginProbe® was used versus patients in whom margin probe was not used. The control strategy did not include intraoperative histologic techniques, but did include radiographic imaging of the main resection specimen in addition to inspection of the resection specimen. The pivotal study was a multicenter (21 sites) randomized study of 596 patients assigned equally to the two arms of the study.
 
Patients enrolled in the study met criteria mentioned in the FDA labeling, but also all had non-palpable lesions which required image-guided localization. The study design was complex, and included several steps in the study sequence in which additional shavings of breast tissue could be taken during the operation. The declared principal outcome of the trial was called complete surgical resection, in which positive margins were either re-excised or noted if not re-excised. It was not necessary for the re-excision to result in a clear margin. Thus this outcome is not fully clinically relevant, and appears to be biased against the control arm of the study.
 
For the principal outcome of complete surgical resection, MarginProbe® showed a rate of 71.8% versus 22.4% for controls, with positive margin subjects as the denominator, which is a large magnitude of difference and statistically significant. However, this outcome is biased against the control group and includes non-clinically relevant events as outcomes, such as positive margins that were not resected. Volume of tissue resected on both a relative and absolute scale were greater in the MarginProbe® group, but the data analysis only presents conclusions of a non-inferiority analysis. The non-inferiority margin for the normalized total tissue volume was not specified.
 
More clinically relevant outcomes include the proportion of patients with positive margins on final pathology after surgery, which was 31% for the MarginProbe® group and 42% in the control group (p=0.0082). Some patients with positive margins in the MarginProbe® group arise from subjects that did not have positive margins in their main specimen. However, due to false positive MarginProbe® readings, additional shavings were undertaken in which cancer tissue was found at the margin. Without these additional shavings taken in response to MarginProbe® assessment, these patients would have been considered to have a clear margin. This occurrence reflects the uncertainty of final pathology in trying to ascertain whether all cancer tissue has been removed. It complicates the comparison of outcomes between the two groups because a measure usually considered a poor outcome like a positive margin, in this case is not due to inadequate surgery but inadvertent discovery of residual cancer due to false positive MarginProbe® readings.
 
Re-excision rates using all patients enrolled in the study as the denominator showed about a 5% absolute reduction in the MarginProbe® group (28.5% vs. 23.8%), which was not statistically significant. The decision to re-operate was based on judgment of the surgeon based on patient and tumor characteristics and the totality of pathologic findings. The study does not assess outcomes beyond the short term outcome of the re-excision rate; thus it is unknown if the lower re-excision rates resulted in at least equivalent local recurrence rates. Without knowing if the recurrence rate is at least equivalent, a lower re-excision rate could reflect inadequate initial surgery.
 
The study also reports the diagnostic characteristics of MarginProbe. Out of 1,788 margins with final histopathology, MarginProbe® readings were valid or not missing in 1,750. Three hundred twenty seven margins were positive, and MarginProbe® was positive in 246 for a sensitivity of 75.2%. Out of 1423 negative margins, MarginProbe® was negative in 660 for a specificity of 46.4%. These performance characteristics showing moderate sensitivity and poor specificity are consistent with better than random capability of the device in detecting positive margins. Given the 19% (327/1750) prevalence of positive margins, the positive predictive value of a positive MarginProbe® test for a margin is 24%. In another analysis (apparently performed or requested by FDA) in which the location of the positive margin was ignored, and the test was considered positive if any margin tested positive, MarginProbe® was 96.3% sensitive but only 8.9% specific. Although this test performance characteristic is less clinically relevant, the low specificity in this study indicates that MarginProbe® was positive for at least one margin in almost every patient in the study, even though the prevalence of at least one positive margin was 52%.
 
Conclusions: The reviewed study showed a non-statistically significant difference in the re-excision rate in the two study arms. The declared principal outcome of the study, complete surgical resection, is not directly clinically relevant and is biased against the control arm of the study. The study does not follow patients long enough to assess the local recurrence rate, which would be important to assess when evaluating the adequacy of initial excision. The diagnostic characteristics of the device show only moderate sensitivity and poor specificity; thus the device will miss some cancers and have frequent false-positive results.
 
Ongoing Clinical Trials
No ongoing studies on MarginProbe® for assessment of surgical margins during breast conservation surgery are currently listed at online site ClinicalTrials.gov.
 
Summary
Breast-conserving surgery as part of the treatment of localized breast cancer is optimally achieved by attaining margins around the surgical resection that are free from tumor cells. Handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins (i.e., MarginProbe®) is intended to increase the probability that the surgeon will achieve clear margins in the initial operation, thus avoiding the need for a second surgery to excise more breast tissue. The one clinical trial of MarginProbe® does not provide sufficient evidence that it improves the adequacy of initial surgical treatment of localized breast cancer. This device has not been assessed in comparison to other techniques of intraoperative margin assessment such as frozen section and touch-print cytology. There is a lack of evidence that the use of handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins improves net health outcomes.
 
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Evidence evaluating the efficacy of MarginProbe® comes from FDA documents describing the pivotal trial that led to FDA approval (Schnabel, 2014; Rivera, 2012). The trial has not yet been published in a peer-reviewed journal as of May 2013. An earlier study evaluating its use did not use the same classification algorithm and may not represent the current performance of the device (Allweis, 2008). The reviewed trial reported the most relevant patient outcomes available for evaluating MarginProbe® with the largest number of patients including a large proportion of U.S. patients. In addition to clinical outcomes, the trial allows assessments of diagnostic test performance of MarginProbe®, which will help inform judgments of its utility.
 
A 2014 systematic review of techniques used for intraoperative assessment of margins in breast conserving therapy for ductal carcinoma in situ (DCIS) concluded that larger studies are needed to determine whether MarginProbe® has a role to play in breast-conserving surgery (Butler-Henderson, 2014). This conclusion was based on the pivotal trial reviewed above and earlier studies.
 
In 2014, Thill et al reported final results of a cohort study of MarginProbe® in DCIS (Thill, 2014; Thill, 2011). Forty-two (76%) of 55 patients enrolled from the general screening population at 3 centers in Germany were eligible for analysis. Patients underwent preoperative wire localization followed by breast-conserving surgery, with intraoperative assessment of the excised specimen by MarginProbe®, radiograph, and paraffinembedded pathological review. MarginProbe® also was used on additional shavings. Outcome measures were re-excision rate compared with a historical control rate of 39% and “procedure success,” defined as (1) negative margins after breast-conserving surgery, and (2) early identification of an extended lesion, with conversion to mastectomy rather than re-excision. Criteria for re-excision defined a negative margin of 5 mm. The historical cohort comprised 67 patients with DCIS who underwent breast-conserving surgery by the same surgeons involved in the study during the year before enrollment began. Because information about patient selection and baseline data were not provided for either cohort, it is unknown how comparable the 2 cohorts were. Re-excision rate was 17%, a statistically significant difference from the historical control rate (Fisher exact test, p=0.018), and “procedure success” occurred in 24 (57%) of 42 patients. Sensitivity was 57% (95 CI, 48 to 66), and specificity was 50% (95 CI, 42 to 58). It is possible that the observed reduction in the reduced re-excision rate was due to an increased incidence of mastectomies. A randomized trial that assesses recurrence is required to demonstrate improvement in net health outcome with MarginProbe®.
 
A subsequent study in women with DCIS showed poor sensitivity and specificity and suggested that more mastectomies may be performed with MarginProbe®. A randomized trial that assesses recurrence is required to demonstrate whether net health outcome is improved.
 
Two clinical studies of MarginProbe® provide insufficient evidence that the device improves initial surgical treatment of localized breast cancer or ductal carcinoma in situ (DCIS). The device has not been assessed in comparison with other techniques of intraoperative margin assessment. Lacking evidence for improved net health outcomes, use of handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins during breast conservation surgery is considered investigational.
 
National Comprehensive Cancer Network (NCCN)
Current NCCN guidelines for breast cancer (version 3.2014) do not include recommendations for intraoperative assessment of surgical margins using radiofrequency spectroscopy for either DCIS or invasive breast cancer (NCCN, 2014).
 
2015 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement. One new retrospective, multicenter study was identified. Sebastian and colleagues found a reduction in re-excision procedures from 26% to 10% after introduction of Margin Probe® (Sebastian, 2015). Investigators reviewed case records of 4 surgeons in 3 centers who used individual (nonstandardized), routine lumpectomy methods including criteria for reexcision (n=186 cases before MarginProbe®; n=165 cases with MarginProbe®). For each surgeon, reexcision rates with the use of MarginProbe® were compared with those from a historical set, comprising a consecutive series of cases from a time period shortly before each surgeon started using MarginProbe®. With use of the device, there were 28 cases in which the margin on the main specimen was clear, but the corresponding shaving contained cancer. Three (1.8%) of 165 patients in the “after” group underwent mastectomy; mastectomy rate in the “before” group was not reported. Performance characteristics (eg, sensitivity and specificity) of MarginProbe® cannot be calculated from these data. Other study limitations include lack of baseline description of the control (“before”) group, potential confounding by secular trends over time, and lack of recurrence outcomes.
 
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2016 retrospective single-center study by Blohmer and colleagues compared the use of MarginProbe in 150 patients to a historical control group of 172 patients (Blohmer, 2016). The 2 groups had approximately similar proportions of patients with invasive breast cancer and DCIS. The historical control group underwent gross pathology examination and radiogram of the specimen as standard intraoperative procedures. The principal outcome of the study was re-excision rate. In patients for whom MarginProbe was used, the re-excision rate was 14.6%; in the historical control group, it was 29.7%. Nothing in the study assessed the performance of MarginProbe, the criteria for re-excision, or long-term patient outcomes. The difference in the amount of breast tissue removed between strategies was not reported.
 
A 2016 retrospective single-center study by Reid Coble compared the use of MarginProbe in 137 patients to a historical control group of 199 patients (Coble, 2016). The 2 groups had approximately similar demographic characteristics and proportions with invasive breast cancer and DCIS. The historical control group underwent standard lumpectomy followed by additional shavings taken circumferentially from all aspects of the cavity. The principal outcome of the study was re-excision rate. For procedures using MarginProbe, the re-excision rate was 6.6%; in the historical control group, the rate was 15.1%. The total volume of tissue (main specimen plus additional shavings) removed was also less in the MarginProbe cases (78 cm3 vs 116 cm3; p= 0.002).
 
2018 Update
A literature search was conducted through July 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
A systematic review by St John et al of intraoperative techniques to assess margins following breast conservation surgery identified 55 studies, 35 of which were included in meta-analysis (St John, 2017). The primary end point was diagnostic accuracy of the various techniques, which was based on pooled sensitivity, specificity, and area under the receiver operating characteristic curve. Reviewers found only one prospective study on MarginProbe, which was found to have a diagnostic accuracy of 68.2%, based in part on sensitivity (71.4%) and specificity (67.7%). Re-excision rates were a secondary outcome: of 57 patients in the MarginProbe study, 15.8% required re-excision during the initial surgery. Because there was only 1 study on the MarginProbe, it was not included in the meta-analysis. Other intraoperative techniques included in meta-analysis had pooled specificity ranging from 81% to 96%, depending on the modality, and pooled sensitivity ranging from 53% to 91%. The meta-analysis was limited by heterogeneity between studies in methodology and varying criteria for diagnosis and assessment of margins. A number of studies identified for the review could not be included in meta-analysis because of missing raw data.
 
Kupstas et al retrospectively reviewed charts of patients from a single center who were treated with MarginProbe during lumpectomy for invasive carcinoma and DCIS; 120 patients were intraoperatively assessed using standard of care, and 120 patients were intraoperatively assessed using the MarginProbe device (Kupstas, 2017). Reviewers found an improvement in the device group for the primary outcome, re-excision rate (9.2% of patients treated with MarginProbe required re-excision surgery vs 18.2% of those treated with standard of care; p=0.039). Included in this re-excision group were those who needed a second lumpectomy¾5.8% (n=7) of the device group vs 15% (n=18) of the standard care group (p=0.020). The study population differed in initial specimen volume; the device group was with significantly smaller breast volume on average (p=0.032). It also differed in the number of shavings required, as those in the device group tended to receive 1.5 more shavings than their counterparts. The final mean volume of removed tissue was comparable between the device group (53.6 mL) and the standard of care group (53.5 mL; p=0.974). Study limitations included the absence of long-term outcomes.

CPT/HCPCS:
19499Unlisted procedure, breast

References: Allweis TM, Kaufman Z, Lelcuk S et al.(2008) A prospective, randomized, controlled, multicenter study of a real-time, intraoperative probe for positive margin detection in breast conserving surgery. Am J Surg 2008; 196(4):483-9.

Allweis TM, Kaufman Z, Lelcuk S, et al.(2008) A prospective, randomized, controlled, multicenter study of a real-time, intraoperative probe for positive margin detection in breast-conserving surgery. Am J Surg. Oct 2008;196(4):483-489. PMID 18809049

Blohmer JU, Tanko J, Kueper J, et al.(2016) MarginProbe(c) reduces the rate of re-excision following breast conserving surgery for breast cancer. Arch Gynecol Obstet. Aug 2016;294(2):361-367. PMID 26796680

Blue Cross and Blue Shield Association Technology Evaluation Center (TEC).(2013) Handheld Radiofrequency Spectroscopy for Intraoperative Margin Assessment During Breast-Conserving Surgery. TEC Assessments 2013, Volume 28, Tab TBD.

Butler-Henderson K, Lee AH, Price RI, et al.(2014) Intraoperative assessment of margins in breast conserving therapy: a systematic review. Breast. Apr 2014;23(2):112-119. PMID 24468464

Coble J, Reid V(2016) Achieving clear margins. Directed shaving using MarginProbe, as compared to a full cavity shave approach. Am J Surg. Dec 30 2016. PMID 28049561

Kupstas A, Ibrar W, Hayward RD, et al.(2017) A novel modality for intraoperative margin assessment and its impact on re-excision rates in breast conserving surgery. Am J Surg. Nov 21 2017. PMID 29191356

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: breast cancer, version http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed July 2014.

Rivera RJ, Holmes DR, Tafra L.(2012) Analysis of the Impact of Intraoperative Margin Assessment with Adjunctive Use of MarginProbe versus Standard of Care on Tissue Volume Removed. Int J Surg Oncol. 2012;2012:868623. PMID 23326653

Schnabel F, Boolbol SK, Gittleman M, et al.(2014) A randomized prospective study of lumpectomy margin assessment with use of MarginProbe in patients with nonpalpable breast malignancies. Ann Surg Oncol. May 2014;21(5):1589-1595. PMID 24595800

Sebastian M, Akbari S, Anglin B, et al.(2015) The impact of use of an intraoperative margin assessment device on reexcision rates. Springerplus. 2015;4:198.

St John ER, Al-Khudairi R, Ashrafian H, et al.(2017) Diagnostic accuracy of intraoperative techniques for margin assessment in breast cancer surgery: a meta-analysis. Ann Surg. Feb 2017;265(2):300-310. PMID 27429028

Thill M, Dittmer C, Baumann K, et al.(2014) MarginProbe®--final results of the German post-market study in breast conserving surgery of ductal carcinoma in situ. Breast. Feb 2014;23(1):94-96. PMID 24291375

Thill M, Roder K, Diedrich K, et al.(2011) Intraoperative assessment of surgical margins during breast conserving surgery of ductal carcinoma in situ by use of radiofrequency spectroscopy. Breast. Dec 2011;20(6):579-580. PMID 21885281

U.S. Food and Drug Administration (FDA).(2012) Summary of safety and effectiveness data: MarginProbe® System. 2012. Accessed at http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110014b.pdf


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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