Medical Policies - Surgery


Handheld Radiofrequency Spectroscopy for Intraoperative Assessment of Surgical Margins During Breast-Conserving Surgery

Number:SUR701.037

Effective Date:06-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins during breast-conserving surgery is considered experimental, investigational and/or unproven.

Description:

As part of the treatment of localized breast cancer, breast-conserving surgery is optimally achieved by attaining tumor-free margins around the surgical resection site. 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 to determine definitively whether clear margins were achieved. Intraoperative 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.

The MarginProbe device is based on the principles of radiofrequency spectroscopy that measures the dielectric properties of tissue into which it comes in contact. Cancer cells and normal breast tissues produce different signals. A handheld probe is applied to a small area of the lumpectomy specimen and analyzes whether the tissue is likely malignant or benign. The device gives a positive or negative reading for each touch. If any touch on a particular margin gives a positive reading, the margin is considered to be positive and more tissue should be re-excised if possible. The device can only be used on the main lumpectomy specimen; it cannot be used on shavings or in the lumpectomy cavity of the patient’s breast. Use of MarginProbe is intended to increase the probability that the surgeon will achieve clear margins in the initial surgery, thus avoiding the need for a second procedure to excise more breast tissue.

Regulatory Status

In January 2013, MarginProbe® (Dune Medical Devices, Caesarea, Israel) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process as an adjunctive diagnostic tool for identification of cancerous tissue at the margins (≤1 mm) of the main ex vivo lumpectomy specimen after primary excision. It is indicated for intraoperative use in conjunction with standard methods (e.g., intraoperative imaging and palpation) for patients undergoing lumpectomy for previously diagnosed breast cancer. PMA product code: OEE.

Rationale:

This medical policy was developed in November 2017 based on searches of the MEDLINE database. The development of this medical policy was informed by a 2013 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment. (1) Following is a summary of the key literature.

MarginProbe For Breast Cancer Margin Detection

Clinical Context and Test Purpose

Breast cancer outcomes can be optimized by a thorough excision of breast cancer. A standard surgical practice of surgeons is to remove more breast tissue if pathologic examination of the initial excision shows positive margins. The purpose of MarginProbe is to evaluate the resected specimen to determine if further excision is necessary during the initial lumpectomy. The targeting of additional resection should reduce re-excision rates, maintain a low cancer recurrence rates, and minimize the volume of breast tissue excised.

The following PICO were used to select literature to inform this medical policy:

Patients

The relevant populations of interest are patients with localized breast cancer who are undergoing lumpectomy.

Interventions

The intervention of interest is use of MarginProbe as an adjunct to standard assessment of margins.

Comparators

The comparator of interest is standard intraoperative assessment of margins. This can vary, however, in different settings and the incremental benefit of MarginProbe may vary according to what is considered the standard intraoperative assessment.

Outcomes

The short-term outcome of interest is the re-excision rate. However, the re-excision rate can only be considered a valid outcome if all other downstream outcomes (e.g., local recurrence rate, long-term cancer outcome) are either equivalent or in favor of MarginProbe. For example, if the use of MarginProbe results in lower re-excision rates, but local cancer recurrence rates are higher, the adequacy of the initial treatment must be questioned.

Pivotal Trial

The evidence evaluating the efficacy of MarginProbe comes from the pivotal trial that led to device approval by the U.S. Food and Drug Administration (FDA). (2-4) An earlier study evaluating its use did not use the same classification algorithm and may not represent the current performance of the device. (5) 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 permitted assessments of diagnostic test performance of MarginProbe, which will help inform judgments of its utility.

The pivotal trial (NCT00749931) compared surgical processes and short-term outcomes in patients undergoing lumpectomies for nonpalpable breast malignancies whose excised tissue was and was not assessed using MarginProbe. The control strategy did not include intraoperative histologic techniques, but did include radiographic imaging of the main resection specimen in addition to inspection and palpation of the resection specimen. The pivotal trial was a multicenter (21 sites) randomized study of 596 patients assigned equally to the 2 treatment arms. Enrolled patients met criteria described in the FDA labeling, but all also had nonpalpable lesions that required image-guided localization. Trial design was complex and included several steps in 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 specifically noted if not re-excised. It was not necessary for the re-excision to result in a clear margin. This outcome is not fully clinically relevant.

For the principal outcome, surgeries using MarginProbe had a rate of successful surgical excision of 71.8% versus 22.4% for controls, with positive margin subjects as the denominator. The large magnitude of difference was statistically significant. However, this outcome was biased against the control group and included nonclinically relevant events as outcomes, such as positive margins not resected. The volume of tissue resected, on both a relative and an absolute scale, was greater in the MarginProbe group, but the trial only presents conclusions of a noninferiority analysis without specifying the noninferiority margin.

More clinically relevant outcomes included the proportion of patients with positive margins on final pathology after surgery, which was 31% for the MarginProbe group and 42% for the control group (p=0.008). Some patients with positive margins in the MarginProbe group did not have positive margins in their main specimen on final pathology. However, due to false-positive MarginProbe readings, additional shavings were taken, and cancer tissue was found at the margin. Without these additional shavings in response to MarginProbe assessment, these patients would have been considered to have clear margins. This occurrence reflects the uncertainty of final pathology in ascertaining whether all cancer tissue had been removed. The uncertainty complicated the comparison of outcomes between groups because a measure usually considered a poor outcome (e.g., positive margin), in this case, was not due to inadequate surgery but to inadvertent discovery of residual cancer due to false-positive MarginProbe readings.

Re-excision rates using all patients enrolled in the trial 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 reoperate was based on surgeon judgment of patient and tumor characteristics and the totality of pathologic findings. The trial did not assess outcomes beyond the short-term re-excision rate; thus, it is unknown whether the lower re-excision rates resulted in at least equivalent local recurrence rates. Without knowing whether recurrence rate is at least equivalent, a lower re-excision rate could reflect inadequate initial surgery.

The trial also reported the diagnostic characteristics of MarginProbe. Of 1788 margins with final histopathology, MarginProbe readings were valid or not missing in 1750 samples. Three hundred twenty-seven margins were positive, and MarginProbe was positive in 246, for a sensitivity of 75%. Of 1423 negative margins on final pathology, MarginProbe was negative in 660, for a specificity of 46%. 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 (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% sensitive but only 9% specific. Although this test performance characteristic is less clinically relevant, the low specificity in this trial indicates that MarginProbe was positive for at least 1 margin in almost every patient in the trial, even though the prevalence of at least 1 positive margin was 52%.

Systematic Reviews

The trial also reported the diagnostic characteristics of MarginProbe. Of 1788 margins with final histopathology, MarginProbe readings were valid or not missing in 1750 samples. Three hundred twenty- seven margins were positive, and MarginProbe was positive in 246, for a sensitivity of 75%. Of 1423 negative margins on final pathology, MarginProbe was negative in 660, for a specificity of 46%. 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 (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% sensitive but only 9% specific. Although this test performance characteristic is less clinically relevant, the low specificity in this trial indicates that MarginProbe was positive for at least 1 margin in almost every patient in the trial, even though the prevalence of at least 1 positive margin was 52%.

Systematic Reviews

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. (6) This conclusion was based on the pivotal trial previously reviewed and earlier studies.

Nonrandomized Studies

In 2014, Thill et al. reported final results of a 2011 cohort study of MarginProbe in DCIS. (7,8) 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 paraffin-embedded pathologic 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 (p=0.018) with MarginProbe, and “procedure success” occurred in 24 (57%) of 42 patients. Sensitivity was 57% (95% confidence interval [CI], 48% to 66%) and specificity was 50% (95 CI, 42% to 58%). It is possible that the observed reduction in the re-excision rate was due to an increased incidence of mastectomies.

A 2015 retrospective, multicenter, before-after study found a reduction in re-excision procedures from 26% to 10% after introduction of Margin Probe. (9) Investigators reviewed case records of 4 surgeons in 3 centers who used individual (nonstandardized), routine lumpectomy methods including criteria for re-excision (186 cases before MarginProbe; 165 cases with MarginProbe). For each surgeon, re-excision rates using MarginProbe were compared to those from a historical set, comprising a consecutive series of cases shortly before each surgeon started using MarginProbe. With 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 (e.g., sensitivity, 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.

A 2016 retrospective single-center study by Blohmer et al. compared the use of MarginProbe in 150 patients to a historical control group of 172 patients. (10) 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 Coble et al. compared the use of MarginProbe in 137 patients to a historical control group of 199 patients. (11) 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).

Section Summary: MarginProbe for Breast Cancer Margin Detection

Although these nonrandomized historical control studies showed a reduction in re-excision rate when using MarginProbe compared to historical controls, they were not rigorously controlled. Moreover, re-excision rate is an intermediate outcome that is only valid if long-term patient outcomes (e.g., recurrence rate) are equivalent between MarginProbe and the alternative strategy. The available RCT comparing short-term outcomes for patients undergoing breast surgery for nonpalpable breast malignancies managed with and without MarginProbe reported moderate sensitivity and low specificity, and did not find significant differences in re-excision rates between the 2 trial arms.

Summary of Evidence

For individuals who have localized breast cancer or ductal carcinoma in situ undergoing breast- conserving surgery (lumpectomy) who receive handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins (e.g., MarginProbe), the evidence includes 1 randomized trial, several historical control studies, and 1 systematic review. Relevant outcomes are change in disease status (relapse rates) and morbid events (re-excision rates). In the randomized trial, histologic examination of surgical margins was not used in the control arm; the outcome measure (complete surgical resection) was not directly clinically relevant and was biased against the control arm; and patient follow-up was insufficient to assess local recurrence rates. The difference in re-excision rates between the 2 trial arms was not statistically significant. Diagnostic characteristics of the device showed only moderate sensitivity and poor specificity; thus, the device will miss some cancers and provide frequent false-positive results. Although several historical control studies have shown lower re-excision rates among patients in whom MarginProbe was used, the studies lacked adequate rigor to demonstrate whether the outcomes are attributable to MarginProbe. The studies did not report recurrence outcomes, which is important for assessing adequacy of resection. A randomized trial that assesses recurrence rates is required to evaluate whether the net health outcome improves with handheld radiofrequency spectroscopy compared with standard intraoperative surgical margin evaluation, including histologic techniques. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

Current National Comprehensive Cancer Network guidelines for breast cancer (v2.2017) do not include recommendations for intraoperative assessment of surgical margins using radiofrequency spectroscopy for ductal carcinoma in situ or invasive breast cancer. (12)

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might impact this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT02406599a

MarginProbe® System U.S. Post-Approval Study Protocol CP-07- 001

440

January 2019

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

19499

HCPCS Codes

None

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Handheld radiofrequency spectroscopy for intraoperative margin assessment during breast-conserving surgery. TEC Assessments. 2013; Volume 28: Tab 4.

2. Schnabel F, Boolbol SK, Gittleman M, et al. 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

3. Rivera RJ, Holmes DR, Tafra L. 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

4. U.S. Food and Drug Administration (FDA). Summary of safety and effectiveness data: MarginProbe System. 2012 December 7; Available at: <http://www.accessdata.fda.gov> (accessed June 15, 2015).

5. Allweis TM, Kaufman Z, Lelcuk S, et al. 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

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

7. Thill M, Dittmer C, Baumann K, et al. MarginProbe(R)--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

8. Thill M, Roder K, Diedrich K, et al. 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

9. Sebastian M, Akbari S, Anglin B, et al. The impact of use of an intraoperative margin assessment device on re- excision rates. Springerplus. 2015; 4:198. PMID 26020017

10. Blohmer JU, Tanko J, Kueper J, et al. 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

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

12. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology: breast cancer. Version 2.2017. Available at: https://www.nccn.org (accessed November 2, 2017).

13. Handheld Radiofrequency Spectroscopy for Intraoperative Assessment of Surgical Margins During Breast-Conserving Surgery. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (February 2017) Surgery 7.01.102.

Policy History:

DateReason
6/15/2018 Reviewed. No changes.
1/1/2018 New medical document. Handheld radiofrequency spectroscopy for intraoperative assessment of surgical margins during breast-conserving surgery is considered experimental, investigational and/or unproven.

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