Coverage Policy Manual
Policy #: 2013033
Category: Radiology
Initiated: September 2013
Last Review: February 2019
  Localization Devices for Nonpalpable Breast Lesions

Description:
Radioactive seed localization is used to identify the location of nonpalpable breast lesions, which have become more common with increasing use of breast cancer screening in asymptomatic women. This technique is used to target breast-conserving surgery or excisional biopsies, or to identify the location of the original cancer after neoadjuvant chemotherapy. A radiologist places a titanium “seed” containing radioactive I-125 with an 18-gauge needle using ultrasound, mammography, or stereotactic guidance. The surgeon then locates the seed, and the breast tissue that needs to be removed, using a gamma probe. Alternative methods to localize nonpalpable breast lesions include wire localization, the traditional approach, or radioguided occult lesion localization.
 
More nonpalpable lesions are currently detected (about 25% to 35% of breast cancers at diagnosis) due to the increased use of breast screening in asymptomatic women. These nonpalpable lesions require a localization technique to perform excisional biopsies or breast-conserving surgery (i.e., lumpectomy).
 
 Radioactive seed localization on nonpalpable breast lesions uses radio-opaque titanium seed(s) containing radioactive I-125. These seeds are inserted by a radiologist using ultrasound or stereotactic guidance to identify the location of a nonpalpable breast lesion. They may be placed several days or weeks before surgery. The surgeon then uses a gamma probe to locate the radioactive seed and remove it with surrounding tissue. One study mentioned that the radiation dose associated with the I-125 seeds (0.29 mCi) was less than for a mammogram or chest X-ray. The radioactive dose in one group of studies ranged from 3.7 to 10.7 MBq (one megabecquerel [MBq] equals 0.027 millicuries). The seed was 4.5 x .8 mm, which has been described as similar to a grain of rice. The half-life of I-125 is 60 days and I-125 is a 27-keV source of gamma radiation. It can be detected on a different signal than the 140-keV Tc-99 that may be used for sentinel lymph node biopsy. Once the radioactive seed is removed, its presence in the tumor specimen is confirmed using the gamma probe, and the lack of radioactivity in the tumor cavity is also assessed to ensure that the radioactive seed has not been left in the breast. A disadvantage of radioactive seed localization is that special procedures must be followed to safely handle and track the radioactive seed, before placement and after excision. In one public hospital (i.e., in clinical practice), a seed was lost following excision, and procedures were changed to prevent reoccurrence.
 
Radioactive seed localization may also be used to guide excision after neoadjuvant chemotherapy, which is performed primarily in women with locally advanced cancer in an effort to shrink the tumor. About 25% to 32% of these women are then able to have breast-conserving surgery rather than mastectomy. The challenge is that if there is a complete clinical and radiological response, it may be difficult to localize the original tumor bed. Pathologic confirmation of response is needed since there is residual microscopic cancer in about half of these patients. Radioactive seed localization can mark the tumor location before beginning neoadjuvant chemotherapy.
 
The traditional localization method for nonpalpable breast lesions is image-guided wire localization. This approach has limitations including the following: the wire can bend or be displaced (since the wire protrudes from the breast); there may be scheduling issues, because the wire should be placed on the same day as the surgery; and the radiologist may follow a different route to place the wire than the surgeon does to excise the lesion, which may make it more difficult to locate all of the lesion and may worsen cosmetic outcomes. The percentage of cases with positive margins following wire localization ranges from 14% to 47%.
 
An alternative developed in the late 1990s is radioguided occult lesion localization (ROLL). First, a twist marker is placed in the breast to mark the tumor. Prior to surgery, a liquid radioactive radiotracer (Tc-99) is injected next to the twist marker using image guidance. Again, the surgeon uses a gamma probe to locate the radiotracer and guide the incision. The main disadvantage of this approach is that the radiotracer has a short half-life of about 6 hours. It also does not provide a point source of radiation as radioactive seed localization does. An advantage is that Tc-99 may also be used for sentinel lymph node biopsy, so the same radiotracer is used for both purposes. On the other hand, the radioactive seed and Tc-99 for sentinel lymph node biopsy can also be used concurrently.
 
A final alternative is intraoperative ultrasound-guided resection, although it is discussed less frequently in this literature. It can only be used when the lesion can be detected using ultrasound. No studies comparing this approach to radioactive seed localization was found.
 
Radioguided seed localization was first tested in a randomized trial in 2001. Based on the number of publications and systematic reviews, there appears to have been an increased interest in this technique since about 2010.
 
Several new devices have been developed to localize non-palpable breast lesions and do not require the use of any radioactive material. These devices include infrared radar (eg, SaviScout®), magnetic seeds (eg, MAGSEED®), or radiofrequency identification tags and can be implanted days prior to surgery.
 
Regulatory Status
The BrachySciences Radioactive Seed Localization Needle with AnchorSeed™ (Biocompatibles, Inc., Oxford, CT) received 510(k) marketing approval on October 18, 2011 (K111979). This device is indicated for the localization of suspicious tissues (non-palpable lesions) for excision with the use of radioactive seeds.
 
On December 19, 2012, the Best® Localization Needle with I-125 Seed received 510(k) marketing clearance (K122704). This device is indicated for breast localization under the direct supervision of a qualified physician. It consists of an iodine-125 seed and an 18-gauge 5cm to 20cm needle.
 
These devices are not always used for radioactive seed localization. Radioactive seeds approved for another indication (i.e., off-label) may also be implanted with an 18-gauge needle. These seeds were initially approved for permanent implantation (i.e., brachytherapy) in selected localized tumors such as prostate cancer. These seeds use 125I beads (activity from 0.1 to 1.0 mCi) encapsulated in a titanium tube. An example is International Isotopes Inc. I3RAD 125I Seed which received 510(k) marketing clearance September 21, 1999 (K992963).
In August 2014, the SAVI SCOUT® (Cianna Medical, Inc.) surgical guidance system received 510(k) U.S. Food and Drug Administration (FDA) (K181007) approval for its breast tumor localization device to be placed in the target tissue up to seven days prior to surgery. In 2016 Cianna received an additional FDA clearance to place the device up to 30 days prior to surgical removal and in 2018 to expand the indication to be used in localization of soft tissue, including lymph nodes (FDA, 2014, 2016, 2018).   
 
In 2016, the Sentimag+Magseed breast cancer diagnostic system gained 510(k) U.S. Food and Drug Administration (FDA) approval to be used for breast localization procedures. On February 16, 2018, the FDA approved the Magseed marker (K173587) for long-term and soft tissue implantation (FDA, 2014, 2016).    
 
In 2017, the FDA approved LOCalizer™by Faxitron  radiofrequency identification (RFID) device tag for use in breast lesion localization.  The LOCalizer™device can be implanted up to 30 days prior to surgery (FDA, 2017).
 
Coding
There is no specific coding for radioactive seed localization of breast lesions. The CPT code for the placement of the seed is likely 19499 (unlisted procedure, breast). The seeds might be reported with A4641.
 
The code for the imaging used to localize the lesion would depend on the type of imaging used. This might be reported with 76942 (ultrasonic guidance for needle placement (e.g., biopsy, aspiration, injection, localization device), imaging supervision and interpretation).
  

Policy/
Coverage:
EFFECTIVE FEBRUARY 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
The following localization devices meet primary coverage criteria for the localization of nonpalpable breast lesions:  
 
    • Wire localization
    • Radioactive seed localization
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
The use of any other device not listed above does not meet primary coverage criteria for the localization of nonpalpable breast lesions, including but not limited to the following:
 
    • Infrared radar (eg, SaviScout®)
    • Magnetic seed device (eg, MAGSEED®)
    • Radiofrequency identification tag
 
For members with contracts without primary coverage criteria, the use of any other device not listed above is considered investigational for the localization of nonpalpable breast lesions, including but not limited to the following:
 
    • Infrared radar (eg, SaviScout®)
    • Magnetic seed device (eg, MAGSEED®)
    • Radiofrequency identification tag
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
 
EFFECTIVE PRIOR TO FEBRUARY 2019
Radioactive seed localization of nonpalpable breast lesions meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is covered for members with contracts without primary coverage criteria.
  
 

Rationale:
Two randomized controlled trials (RCTs) compared radioactive seed localization to wire localization among patients scheduled for breast-conserving surgery or excisional biopsy (Gray, 2001; Lovrics, 2011). Gray and colleagues randomized 97 women in the US with nonpalpable breast lesions to radioactive seed localization or wire localization; 51 had radioactive seed localization and 47, wire localization (Gray, 2001). The method of randomization was not reported. Fifty-six patients underwent excisional biopsies for suspicious lesions that were judged inappropriate for percutaneous biopsy techniques, while 41 patients with a confirmed diagnosis of breast cancer by core needle biopsy had breast-conserving surgery (47% of radioactive seed localization patients and 37% of wire localization patients). On imaging, 42 patients had calcification and 55, a density. Both wire localization and radioactive seed localization were performed using ultrasound or mammography guidance. Surgery was performed up to 5 days later. Radiologists and patients rated the difficulty of the procedure following localization on a Likert scale from 1 (easiest) to 10 (most difficult), while the surgeons completed the same task after excision. Margins were considered to be positive if imprint cytology of the margins demonstrated malignant cells or if final histology demonstrated malignant cells <1 mm from any margin; only malignant tumors were included.
 
Fifty-two patients had invasive carcinoma; 9 had ductal carcinoma in situ; and 36 had benign lesions. There was no statistically significant difference in the number of patients with radioactive seed localization versus wire localization within each category. The outcomes for both localization techniques were the same for migration of the localization device (i.e., seed or wire); ability to locate the lesion during surgery; time for radiographic localization and for surgical excision; subjective ease of procedure for radiologists, patients, or surgeons; and volume of tissue removed. Specimen radiographs were used with wire localization but not with radioactive seed localization. There were fewer positive margins with radioactive seed localization than with wire localization (26% vs. 57%, p=0.02).
 
The second RCT published in 2011 was conducted at three Canadian sites and had a sample size of 205 (Lovrics, 2011). The participants had nonpalpable early stage breast cancer and were undergoing breast-conserving surgery. Randomization to radioactive seed localization or wire localization was centralized, concealed, and stratified (by surgeon for 7 surgeons). The two groups were similar except that multifocal disease was more common in the radioactive seed localization patients. The mean age was 60.9 years for the radioactive seed localization arm and 59.9 years for the wire localization arm. Exclusion criteria included male patients, pregnancy or lactation, multicentric or locally advanced disease, lobular carcinoma in situ (LCIS) only, and contraindications for breast-conserving surgery. Localization was performed using mammography or ultrasound on the day of surgery. The location was confirmed using 2-view mammography. An intention-to-treat analysis was performed. The power calculation was reported: A sample size of 333 patients could detect a 15% difference in positive margins across arms with 80% power and a 5% significance level.
 
In the radioactive seed localization arm, 18 had wire localization: 6 because the seed was not available at surgery; 3 because the seed would not deploy; and 2 because the seed was displaced. For 7 patients, no explanation was provided. In 3 cases, wire was added to seed localization to bracket larger lesions. One seed migrated, and two wires did. One wire fell out during surgery.
 
All index lesions were removed. There were no differences between the two groups except the following: the mean operative time was shorter for radioactive seed localization (19.4 min for radioactive seed localization vs. 22.2 min for wire localization; p<0.001). Surgeons found excision following radioactive seed localization easier (p=0.008), while patients found it less painful (p=0.038). However, there was no statistically significant difference in patients’ anxiety level. There were no differences between groups in proportion of positive margins (10.5% for radioactive seed localization vs. 11.8% for wire localization) or reoperation rates. The results for positive margins were similar when the analysis was rerun based on the treatment patients received. Also, the percentage of positive margins was higher for ductal carcinoma in situ (DCIS) than for invasive cancer (20.4% vs. 9.2%; p=0.020). A related study analyzed factors associated with positive margins, including localization under stereotactic guidance, in situ disease, large tumor size, and multifocal disease (Reedijk, 2012).
 
In a third study, an apparently retrospective analysis compared radioguided occult lesion localization, or ROLL, using Tc-99 to radioactive seed localization placed using ultrasound guidance (Donker, 2013).  Mammography was used to confirm correct placement of the twist marker or seed. The Dutch patients then had neoadjuvant chemotherapy and breast-conserving surgery with wide local incision. Prior to surgery, patients underwent contrast-enhanced MRI; those without enhancement in the original tumor area were considered complete radiological responders and had more limited excision to confirm complete response pathologically (carcinoma in situ was not counted). With ROLL, after injection of the radiotracer, scintigraphy with a dual-head gamma camera was performed to verify correct placement of the tracer. Radiologists and surgeons reported the time for each procedure and the level of difficulty (Likert scale from 1=no difficulty to 5=very difficult); while patients were asked to report on pain and anxiety (Likert scare from 0=no pain to 6=severe pain).
 
After neoadjuvant chemotherapy, 24 patients had palpable lesions or a different localization method was performed. ROLL (n=83) or radioactive seed localization (n=71) was performed in 154 patients. No complications occurred during the localization procedure. For the patients undergoing the ROLL technique, 51% had complete radiological response and 30% had complete pathological response. For the patients with radioactive seed localization, 51% had complete radiological response and 38% had complete pathological response. Both groups were comparable in terms of the weight of the excised specimen. Thirteen patients in each group had positive pathological margins. Six patients in each group underwent further surgery, either additional local excision or mastectomy (5 ROLL patients and 3 radioactive seed localization patients). The other patients with positive margins underwent adjuvant radiotherapy with a boost to the original tumor bed. There were no major postoperative complications in either group, with a median follow-up of 51 months (range, 5-67). Fifteen of 83 ROLL patients had disease recurrence (including one DCIS local recurrence); 6 of these women died due to metastatic disease after a mean follow-up of 22 months (range, 4-45 months). Eight of 71 patients undergoing radioactive seed localization developed metastatic disease and died within 24 months of follow-up; no isolated local recurrences occurred.
 
Additional comparative articles include one by Hughes and colleagues, who compared radioactive seed localization in 383 patients to wire localization performed previously in 99 patients with nonpalpable lesions undergoing breast procedures (Gray, 2004; Hughes, 2008). The patients were from 3 sites of the same institution. Seed migration > 2 cm occurred in one patient, possibly due to a hematoma that developed after localization, and re-excision was performed during the initial surgery. Positive margins occurred in 27% of radioactive seed localization patients and in 46% of wire localization patients (p<0.001). Re-excision was undertaken in 8% of radioactive seed localization patients and in 25% of wire localization patients to achieve negative margins (p<0.001). Patients were asked to score the pain of the localization procedure and convenience of localization and surgery on a ten-point visual analog scale. The median pain scores were similar between groups (2.2 and 2.3; p=0.9). There were no major adverse effects, but 6 radioactive seed localization patients (2%) and 1 wire localization patient (1%) had wound infections.
 
Rao and colleagues reported on their experience in using radioactive seed localization in a public hospital, with a retrospective matched-pair analysis of patients undergoing wire localization during the same period (Rao, 2010). One seed was lost after excision (it was not in the specimen removed) and was assumed discarded in the surgical drapes or suctioned into the suction canister and discarded. Procedures were changed after this event to prevent recurrence. The study reported on 50 successful seed localizations in cancer patients and the matched controls. All seeds were recovered, and there was no seed migration. The re-excision rate was 42% for radioactive seed localization and 54% for wire localization. This difference was not statistically significant (p=0.46), which the authors attributed to small sample size.
 
In addition to these comparative studies, there are single arm studies of radioactive seed localization (Gobardhan, 2013; McGhan, 2011; Sung, 2013; van Riet, 2010a; van Riet, 2010b). Gobardhan and colleagues examined the use of radioactive seed localization among 85 patients undergoing neoadjuvant chemotherapy and breast-conserving surgery for invasive cancer (Gobardhan, 2013). Another 4 patients requested mastectomy on their own and 8 were scheduled for mastectomy based on tumor characteristics; they are not included in the analysis. Thirty-two of the 85 patients had multifocal tumors; 23 patients had more than one seed placed. The seeds were in place for a median of 4 months (range, 0-8). All patients received radiotherapy after breast-conserving surgery, and some received hormonal therapy or trastuzumab, as appropriate. After chemotherapy, 26 patients achieved clinically complete response, and 51, partial response. No residual tumor, i.e., pathologically complete response, occurred in 19 (36%) patients, and the resection was microscopically complete in 78 (92%) patients. Four patients had focally involved margins and had a higher radiation boost to the tumor bed; 3 patients had extensively involved margins and had mastectomies. No re-excisions were performed, nor were there any wound healing problems. At a mean follow-up of 11 months, there were no local recurrences.
 
McGhann and colleagues reported on a retrospective review of 1,000 consecutive radioactive seed localizations in 978 patients following percutaneous biopsy at a single US institution (McGhan, 2011).  Some of these cases were reported by Hughes and colleagues (Hughes, 2008). The breast surgery was performed by 3 surgeons. Based on final pathology, 55% of the lesions were invasive cancer; 22%, DCIS; 11%, atypical hyperplasia; and 13%, benign pathologic lesions. In 46% of cases, intraoperative re-excision was performed based on surgeon or pathologist opinion. Fifteen percent of cancer cases underwent a second procedure for re-excision when the final margins were < 2mm. With a mean patient follow-up of 33 months (range, 0.03 to 90.6), 9 patients experienced a local recurrence; there were no regional or distant recurrences. Of 1,148 seeds deployed, there was seed displacement during successful lesion excision for 30; vasovagal response on seed deployment for 4; failure to deploy seed properly on first attempt for 3; and for 1 each, wrong incision or seed migration preoperatively. All radioactive seeds were retrieved.
 
Van Riet and colleagues reported on radioactive seed localization among 325 consecutive women with nonpalpable, biopsy-confirmed breast cancer (van Riet, 2010a).  Women with DCIS on core biopsy were excluded. Seed localization failed in 3 women and was redone successfully on the second attempt. The seed was dislodged during surgery in 6 patients, 4 of whom underwent re-excision after specimen radiology. Complete resection was accomplished in 310 procedures, while 15 had positive margins.
 
A study of seed migration following radioactive seed localization found that in 45 patients with radioactive seeds in situ for 59.5 days on average (range, 3-136 days), the reported average seed migration was 0.9 mm (standard deviation=1.0 mm) (Alderliesten, 2011). Cox and colleagues assessed whether specimen radiographs are required during breast surgery or biopsy after radioactive seed localization (Cox, 2003). (14) These radiographs are routinely used during surgery after wire localization to ensure that the suspected lesion has been excised. The aim of the study was to demonstrate that specimen radiographs are not needed with radioactive seed localization when the seed is within 1 cm of the lesion, the surgeon removed the seed without dislodging it from the tissue, and the pathologist can grossly identify the lesion and retrieve the seed. In an analysis of 124 women (142 lesions), specimen radiographs were performed on 32 lesions. This occurred more often with microcalcifications than with masses and in women undergoing excisional biopsy than in those having breast-conserving surgery.
 
A meta-analysis of radioactive seed localization versus wire localization included both of the randomized studies discussed above (although for unstated reasons, the authors categorized (Gray, 2001) as a cohort study with a control group) and 3 other cohort studies with control groups (Ahmed, 2013). The authors note that the quality of the studies is limited, with only one RCT, and cohort studies with retrospective wire localization control groups (Gray, 2001; Lovrics, 2011, Gray, 2004, Hughes, 2008, Rao, 2010). The authors tested for heterogeneity; two outcomes had moderate but statistically insignificant heterogeneity at the 0.05 level. Fixed effect models were used in all cases. The results are as follows: Positive margins for wide local incision are significantly less likely for radioactive seed localization versus wire localization (odds ratio=0.51; 95% CI: 0.36-0.72; p=0.0001) for 5 trials. Re-operations were less likely for radioactive seed localization (odds ratio=0.47; 95% CI: 0.33-0.69; p<0.0001) for the 4 trials included. Shorter surgery is significantly more likely using radioactive seed localization versus wire localization (mean difference = –1.32 min; 95% CI: –2.32 to –0.32; p=0.01) for the 2 trials included. Based on 2 trials, there was no statistically significant difference in the volume of breast tissue excised during surgery (mean difference=1.46 cm3; 95% CI: –22.35 to 25.26; p=0.90). The results of this meta-analysis should be interpreted with caution given the quality of the included studies. Barentsz and colleagues conducted a systematic review of six of the studies mentioned in this review (Barentsz, 2013).
 
Conclusions: The highest quality study on the use of radioactive seed localization versus another localization technique is the randomized controlled trial by Lovrics and colleagues (Lovrics, 2011). The study was not blinded, given the obvious nature of the different techniques. It found no statistically significant differences between the two techniques, except for a slightly shorter time to perform radioactive seed localization, surgeons’ view that it is less difficult, and patients’ views that it reduces pain but not anxiety. The smaller randomized study by Gray and colleagues did report significantly fewer positive margins, but other metrics in the table above were not statistically significant between modalities or were not reported (Gray, 2001). The more favorable results for radioactive seed localization in other studies regarding fewer positive margins or re-excisions is inconsistently reported and may be affected by tumor characteristics. Therefore, the comparative performance of radioactive seed localization versus wire localization or radioguided occult lesion localization can be assessed reliably only in randomized trials. The limited evidence does not demonstrate a difference in performance between radioactive seed localization and either wire localization or, with more limited evidence, radioguided occult lesion localization. There currently are no studies on radioactive seed localization underway, as reported on clinicaltrials.gov.
 
Ongoing Clinical Trials
No ongoing studies on this technology were found at clinicaltrials.gov.
 
Summary
Radioactive seed localization is an alternative technique to wire localization or radioguided occult lesion localization among women with nonpalpable breast lesions. It may be used before excisional biopsy or breast-conserving surgery, with or without neoadjuvant chemotherapy. The clinical outcomes of these three localization techniques are likely to be equivalent.
 
Practice Guidelines and Position Statements
A search of guidelines.gov, acr.org, and nccn.org yielded no policies on the use of radioactive seed localization in the breast.
 
2015 Update
 
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Groups from 2 cancer centers in the U.S. reported on their experience with radioactive seed localization. Diego et al (2014) compared outcomes for 128 women who underwent radioactive seed localization and 196 women who underwent wire localization before excisional breast biopsy for nonpalpable high-risk lesions during 2 consecutive years at the University of Pittsburgh Medical Center (Diego, 2014). Outcomes for excisional biopsies performed after radioactive seed localization during 1 year (postlearning curve) were collected prospectively and compared with retrospective outcomes for excisional biopsies performed after wire localization by the same surgeons (n=4) during the previous year. In both groups, mean patient age was 54 years, and the most common high-risk lesions were atypical hyperplasia (58%) and papilloma (23%). Forty-one percent of radioactive seeds and all wires (100%) were implanted/placed the day of surgery; 44%, 2%, and 13% of radioactive seeds were implanted 1, 2, and 3 days before surgery, respectively. Mean specimen volume was less in the radioactive seed localization group compared with the wire localization group (mean [SD], 26 [22] cm vs 37 [33] cm; ANOVA, p=0.001). There was no statistical between-group difference in mean operating room time (27 minutes in both groups; analysis of variance [ANOVA], p=0.9), despite greater trainee presence in the radioactive seed localization group; proportion of patients with additional tissue removed after specimen radiograph (3% in both groups; chisquare, p=0.4); proportion of target lesions retrieved (99% in the radioactive seed localization group vs 98% in the wire localization group; chi-square, p=0.5); or the proportion of patients upstaged to carcinoma (5% in the radioactive seed localization group vs 6% in the wire localization group; chi-square, p=0.5). All implanted radioactive seeds were retrieved at surgery.
 
In a similar study, researchers from Memorial Sloan-Kettering Cancer Center compared outcomes for 431 women who underwent radioactive seed localization and 256 women who underwent wire localization before lumpectomy for invasive or intraductal cancers during 2 consecutive 6-month periods.9 Outcomes for the radioactive seed localization group were collected prospectively during the first 6 months of use, and for the wire localization group, retrospectively during the previous 6 months. Surgeons (n=10) and radiologists did not change between study time periods. Median patient age was approximately 60 years in both groups (Wilcoxon test, p=0.31), and 77% of patients in both groups had invasive cancer. The proportion of patients with features known to impact the probability of positive margins, such as tumor size, presence of an extensive intraductal component, or pure DCIS, was similar between groups. Ninety percent of radioactive seeds were implanted the day before surgery, and all wires (100%) were placed the morning of surgery. There was no statistical between-group difference in the incidence of positive
margins (tumor on ink) or close margins ( mm from ink) (total 25% in both groups; chi-square, p=0.38); reoperations to improve margins (approximately 23% in both groups; chi-square, p=0.83); specimen volume (median [range], 21 cm (Murphy, 2013), [0.2-311] in the radioactive seed localization group vs 19 cm3 [0.9-198] in the wire localization group; Wilcoxon test, p=0.074); or operative time for lumpectomy alone (Wilcoxon test, p=0.18) or lumpectomy with axillary lymph node dissection (Wilcoxon test, p=0.86). Operative time for lumpectomy plus sentinel lymph node biopsy was longer in the radioactive seed localization group compared with the wire localization group (median [range], 55 minutes [29-140] vs 48 minutes [12-110]; Wilcoxon test, p<0.001), which was attributed to use of a more complex probe capable of detecting both I-     125 and T-99.
 
Ongoing and Unpublished Clinical Trials
Online site ClinicalTrials.gov currently lists 1 active, open-label trial of radioactive seed localization (NCT01901991). Patients at a single center in Denmark who have a nonpalpable breast lesion (carcinoma in situ or invasive carcinoma) will be randomized 1:1 to wire-guided localization (with ultrasound or mammography guidance) or radioactive seed localization (with ultrasound guidance). Lesion localization will be confirmed by mammography in both treatment arms. Outcomes include reoperation rates, amount of excised tissue, and breast surgery duration. Estimated enrollment is 410 patients, and expected completion date is April 2017.
 
American College of Radiology
In 2013, ACR issued a practice guideline for imaging management of DCIS and invasive breast Carcinoma (ACR, 2013). Both wire localization (using mammographic, sonographic, or magnetic resonance imaging [MRI] guidance) and radioactive seed localization (using mammographic or sonographic guidance) as techniques for preoperative image-guided localization of nonpalpable breast lesions.
 
2017 Update
A literature search was conducted using the Medline database. No new literature was identified. The coverage statement is unchanged.
 
A 2015 Cochrane review evaluated randomized controlled trials (RCTs) comparing localization techniques to guide surgical excision of nonpalpable breast lesions (Chan, 2015). Eleven RCTs were identified; 2 compared RSL with wire localization (WL), 6 compared radio-guided occult lesion localization (ROLL) with WL, and 3 used less common techniques. The primary outcomes were successful localization of the lesion, successful excision of the lesion, positive excision margins, and need for further excision. Meta-analyses were conducted for several of these outcomes for RSL and WL. There was no significant difference in the rate of successful excision with RSL or WL (relative risk [RR], 1.00; 95% CI [confidence interval], 0.99 to 1.01; rate of positive margins, RR=0.67; 95% CI, 0.43 to 1.06). The authors concluded that the published evidence does not clearly support 1 localization method over another.
 
A 2015 meta-analysis by Pouw et al included studies evaluating RSL, with or without a comparator intervention (Pouw, 2015). Sixteen studies were identified; the number of patients in individual studies ranged from 13 to 2222. Among the included studies, 6 compared RSL with WL, 1 compared RSL with ROLL, and the remaining studies were uncontrolled. However, this systematic review only reported outcomes for the RSL cases. The primary outcomes were irradicality (ie, positive margins ) and need for re-excision. In the 16 studies, the average proportion of patients with irradicality was 10.3% (range, 3%-30.3%) and the average re-excision rate was 14.2% (range, 4%-42%).
 
In 2016, Bloomquist et al published an RCT comparing RSL (n=70) and WL (n=55) (Bllomquist, 2016). The trial included adult women with nonpalpable invasive carcinoma or DCIS who were eligible for BCS. Multifocal disease and extensive disease requiring bracketing were not exclusion criteria. The primary outcomes were patient-reported assessment of procedure-related pain and overall convenience of the procedure. Patients in the RSL group completed a questionnaire immediately after the procedure and patients in the WL group completed a questionnaire at the first postoperative visit. The difference in timing could bias outcomes (eg, patients may remember pain during the procedure differently by the time they had a postoperative visit). Pain was measured on a 1- to 5-point Likert-type scale (1=no pain and 5=severe pain). Convenience was also rated on a 1-to-5 scale (1=poor convenience and 5=excellent convenience). Median pain scores during the procedure did not differ significantly between groups. However, the convenience of RSL was rated significantly higher than WL. The median convenience score was 5 in the RSL group and 3 in the WL group (p<0.001).  
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2017. No change to policy coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through January 15, 2019.  Several new devices have been developed to localize nonpalpable breast lesions and do not require the use of any radioactive material. While the positive margin rates of the newer tools appear comparable to other methods of nonpalpable lesion localization, data is limited and does not include any randomized control trials.
 
Cox et al (2016) published the results of a prospective, single arm, multi-site, clinical evaluation of a SAVI SCOUT(®) breast localization and surgical guidance system for the Location of Nonpalpable Breast Lesions during Excision. From March to November 2015, 154 patients were consented and evaluated by 20 radiologists and 16 surgeons at 11 participating centers. Patients had SCOUT(®) reflectors placed up to 7 days before surgery, and placement was confirmed by mammography or ultrasonography. Implanted reflectors were detected by the SCOUT(®) handpiece and console. For 101 patients with a preoperative diagnosis of cancer, 86 (85.1 %) had clear margins, and 17 (16.8 %) patients required margin reexcision.
 
Patel et al (2017) published the results of a comparative study of surgical outcomes between SAVI SCOUT® reflector localization (SSL) versus wire localization (WL) for breast tumors. 42 SSL cases and 42 WL cases were retrospectively studied. WL patients were consecutively matched for clinical-pathologic features. Final surgical outcome measures were tumor specimen volume, margin status, and re-excision rates. No significant differences were present in these three outcomes and the authors concluded that SSL was an acceptable alternative to WL
 
Dauphine et al (2015) published the results of a prospective clinical study to evaluate the safety and performance of wireless localization of nonpalpable breast lesions using radiofrequency identification technology. Twenty consecutive women requiring preoperative localization of a breast lesion were recruited. Twenty patients underwent placement of a radiofrequency identification tag, 12 under ultrasound guidance and eight with stereotactic guidance. In all cases, the radiofrequency identification tag was successfully localized by the reader at the level of the skin before incision, and the intended lesion was removed along with the radiofrequency identification tag.

CPT/HCPCS:
19281Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including mammographic guidance
19282Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; each additional lesion, including mammographic guidance (List separately in addition to code for primary procedure)
19283Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including stereotactic guidance
19284Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; each additional lesion, including stereotactic guidance (List separately in addition to code for primary procedure)
19285Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including ultrasound guidance
19286Placement of breast localization device(s) (eg, clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; each additional lesion, including ultrasound guidance (List separately in addition to code for primary procedure)
19287Placement of breast localization device(s) (eg clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; first lesion, including magnetic resonance guidance
19288Placement of breast localization device(s) (eg clip, metallic pellet, wire/needle, radioactive seeds), percutaneous; each additional lesion, including magnetic resonance guidance (List separately in addition to code for primary procedure)
19499Unlisted procedure, breast
76942Ultrasonic guidance for needle placement (eg, biopsy, aspiration, injection, localization device), imaging supervision and interpretation
A4641Radiopharmaceutical, diagnostic, not otherwise classified

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