Description
Radioactive seed localization is used to detect nonpalpable breast lesions, which have become more common with increasing use of breast cancer screening in asymptomatic women. This technique is used before breast-conserving surgery or excisional biopsies, or to identify the location of an original cancer after neoadjuvant chemotherapy. A radiologist places a titanium "seed" containing radioactive iodine 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 radio-guided occult lesion localization.

For individuals who have a nonpalpable breast lesion who are undergoing a procedure that requires lesion localization who receive radioactive seed localization, the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are other test performance measures, resource utilization, and treatment-related morbidity. There are 3 RCTs comparing radioactive seed localization and wire localization, and overall they have found similar outcomes (e.g., rate of successful excision, rate of positive margins) with both techniques. Systematic reviews have also found that outcomes with both localization methods are similar. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Background  
NONPALPABLE LESIONS
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 (BCS; i.e., lumpectomy).

Localization Methods
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 (because the wire protrudes from the breast); there may be scheduling issues given 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 complicate locating all of the lesion (in addition to potentially causing cosmetic concerns). The percentage of cases with positive margins after wire localization is 14% to 47%.

Radioactive seed localization of nonpalpable breast lesions uses radio-opaque titanium seed(s) containing radioactive iodine 125 (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 I-125 seeds (0.29 mCi) was less than that for a mammogram or chest radiograph. The range of radioactive doses in 1 group of studies was 3.7 to 10.7 MBq (1 MBq = 0.027 mCi).^1,2 Seeds were 4.5x0.8 mm, which have 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.³ I-125 can be detected on a different signal than the 140-keV technetium 99 (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. 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.

Radioactive seed localization also may 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. A proportion of these women (25% – 32%) are then able to have BCS rather than mastectomy. The challenge is that if there is a complete clinical and radiologic response, it may be difficult to localize the original tumor bed. Pathologic confirmation of response is needed because there is residual microscopic cancer in about half of these patients. Radioactive seed localization can mark the tumor location before beginning neoadjuvant chemotherapy.

An alternative to wire localization or radioactive seed localization, developed in the late 1990s, is radio-guided occult lesion localization. First, a twist marker is placed in the breast to identify the tumor. Before surgery, a liquid radioactive radiotracer (Tc-99) is injected next to the twist marker using image guidance. 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 (6 hours). It also does not provide a point source of radiation. An advantage is that Tc-99 may be used for sentinel lymph node biopsy, so the same radiotracer is used for both purposes. Alternatively, a radioactive seed and Tc-99 for sentinel lymph node biopsy can be used concurrently. Another alternative is intraoperative ultrasound-guided resection, although the procedure is discussed less frequently in this literature. It can only be done when the lesion is detectable by ultrasound.

Regulatory Status 
In October 2011, the BrachySciences Radioactive Seed Localization Needle with AnchorSeed™ (Biocompatibles Inc., Oxford, CT) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process (K111979). This device is indicated for the localization of suspicious tissues (nonpalpable lesions) for excision with the use of radioactive seeds.

In December 2012, the Best^® Localization Needle with I-125 Seed was cleared for marketing by FDA through the 510(k) process (K122704). This device is indicated for breast localization under the direct supervision of a qualified physician. It comprises an iodine-125 seed and an 18-gauge 5- to 20-cm needle.

These devices are not always used for radioactive seed localization. Radioactive seeds approved for another indication (ie, off-label) also may be implanted with an 18-gauge needle. These seeds were initially approved for permanent implantation (i.e., brachytherapy) in select localized tumors such as prostate cancer. These seeds use I-125 beads (activity from 0.1 to 1.0 mCi) encapsulated in a titanium tube. An example is the International Isotopes I3RAD I-125 Seed, which, in September 1999, was cleared for marketing by FDA through the 510(k) process (K992963). FDA product code: KXK.

Policy
Radioactive seed localization of nonpalpable breast lesions may be considered MEDICALLY NECESSARY for the purposes of locating lesions to guide excisional biopsy or breast-conserving surgery, because the clinical outcomes are likely to be equivalent to wire localization (see Policy Guidelines and Benefit Application sections).

Policy Guidelines
Based on the currently available evidence, radioactive seed localization of nonpalpable breast lesions is likely to produce equivalent outcomes compared with wire localization. Therefore, the "least costly alternative" provision of the medically necessary definition may apply (see Benefit Application section).

When breast localization device(s) such as radioactive seeds are placed without biopsy, the procedure would be reported with codes 19281 – 19288, depending on the type of imaging guidance used and whether the lesion is an initial or subsequent lesion. If the breast localization device(s) is placed at the time of image-guided biopsy, it would be reported with codes 19081 – 19086, depending on the type of imaging guidance used and whether the lesion is an initial or subsequent lesion. The seeds might be reported with the tissue marker HCPCS code A4648.

Benefit Application
BlueCard/National Account Issues 
State or federal mandates (e.g., FEP) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Radioactive seed localization of nonpalpable breast lesions is likely to produce equivalent outcomes compared with wire localization, but may be more costly. Some plans may use a definition of "medical necessity" that states that a medically necessary service must not be more costly than an alternative service or sequence of services that is at least as likely to produce equivalent health outcomes. In these cases, when it is determined that a strategy using radioactive seed localization is more costly than one using wire localization (as determined by plan pricing, provider charges, and/or other mechanisms), then radioactive seed localization may be considered not medically necessary for localization of nonpalpable breast lesions.

For contracts that do not use this definition of medical necessity, benefit or contract language describing the "least costly alternative" may also be applicable for this choice of treatment.

In addition, other contract provisions including contract language concerning use of out-of-network providers and services may be applied. That is, if the alternative therapy (e.g., wire localization) is available in-network but radioactive seed localization is not, radioactive seed localization would not be considered an in-network benefit.

Rationale
This evidence review was created in September 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through Aug. 8, 2021.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Radioactive Seed Localization
Clinical Context and Test Purpose
The purpose of implanting localized radioactive seeds in patients who have a nonpalpable breast lesion and are undergoing a procedure that requires lesion localization is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does implantation of localized radioactive seeds improve the net health outcomes of individuals with a nonpalpable breast lesion that requires lesion localization prior to surgical excision?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest are individuals with a nonpalpable breast lesion that requires lesion localization prior to surgery.

Interventions
The therapy being considered is implantation of localized radioactive seeds.

Comparators
The following therapies are currently being used to make decisions about identifying nonpalpable breast lesions: wire localization and radio-guided occult lesion localization.

Outcomes
The general outcomes of interest are the accuracy of breast lesion localization, surgical margins, and reoperation rates.

Short-term follow-up is necessary to ensure positive surgical margins.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Several systematic reviews have compared radioactive seed localization (RSL) with other localization methods. A Cochrane review by Chan et al. (2015) evaluated RCTs comparing localization techniques to guide surgical excision of nonpalpable breast lesions.⁴ Eleven RCTs were identified; 2 compared RSL with wire localization (WL), 6 compared radio-guided occult lesion localization with WL, and 3 used less common techniques. The primary outcomes were the successful localization of the lesion, successful excision of the lesion, positive excision margins, and the need for further excision. Meta-analyses were conducted for several of these outcomes for RSL and WL. There were no significant differences in the rates of successful excision with RSL or WL (relative risk, 1.00; 95% CI [confidence interval], 0.99 to 1.01) or rates of positive margins (relative risk, 0.67; 95% CI, 0.43 to 1.06). Reviewers concluded that the published evidence did not clearly support 1 localization method over another.

A meta-analysis by Pouw et al. (2015) included studies evaluating RSL, with or without a comparator intervention.⁵ Sixteen studies were identified; the number of patients in individual studies ranged from 13 to 2,222. Among the included studies, 6 compared RSL with WL, 1 compared RSL with radio-guided occult lesion localization, and the remaining studies were uncontrolled. However, this systematic review only reported outcomes for RSL cases. The primary outcomes were irradicality (i.e., positive margins) and 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%).

Ahmed et al. (2013) published a systematic review and meta-analysis of RCTs and nonrandomized controlled studies of RSL and WL.⁶ Positive margins for wide local incision were significantly less likely for RSL versus WL (odds ratio, 0.51; 95% CI, 0.36 to 0.72; p < .001) for 5 studies. Reoperations were less likely for RSL (odds ratio, 0.47; 95% CI, 0.33 to 0.69; p < .001) for the 4 trials included. Shorter surgery was significantly more likely using RSL than WL (mean difference, -1.32 minutes; 95% CI, -2.32 to -0.32 minutes; p = .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 cm3; p = .90).

Randomized Controlled Trials
RCTs published subsequent to the systematic reviews are described below and summarized in Tables 1 (characteristics) and 2 (results).

Chagpar et al. (2021) published a secondary analysis of two RCTs that included 515 women with stage 0 to 3 breast cancer undergoing localization of nopalpable tumors prior to breast conserving surgery.⁷ Localization method was determined by the treating surgeon. No difference was found between RSL and WL in either the positive margin rate (p = .34) or in re-excision rate (p = .96). The analysis also found no difference in postoperative incidence of seroma or hematoma in RSL (0%) and WL (0.9%; p = .63).

Langhans et al. (2017) published an RCT comparing RSL (n=207) with WL (n = 206).⁸ Patients with nonpalpable invasive breast cancer or ductal carcinoma in situ (DCIS) visible on ultrasound were included. The primary outcome was margin status after breast-conserving surgery (BCS); secondary outcomes were the duration of the surgical procedure, the weight of the surgical specimen, and the patient's pain perception. Resection margins were positive in 11.8% of cases in the RSL group compared with 13.3% of the WGL group (p = .65). There was no difference in margin status based on per-protocol analysis (p = .62). There was no significant difference in the duration of surgical procedure (p = .12), the weight of the surgical specimen (p = .54), or the patients' pain perception (p = .28).

Bloomquist et al. (2016) published an RCT comparing RSL (n = 70) with WL (n = 55).⁹ 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 the 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 have biased outcomes (e.g., patients may remember pain during the procedure differently by the time they had a postoperative visit). The pain was measured on a 1- (no pain) to 5- (severe pain) point Likert-type scale. Convenience was also rated from 1 (poor convenience) to 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 < .001).

Surgical outcomes were also reported. There was no significant difference in the rate of positive margins (RSL = 19.4% vs WL = 15.3%; p = .053). There were also no significant differences in the volume of extracted tissue: the mean volume was 77.0 cm2 in the RSL group and 67.4 cm2 in the WL group (p = .67). All targeted lesions were successfully excised, and there were no lost seeds or transected wires.

Table 1. Summary of Key Randomized Controlled Trial Characteristics for RSL and WL

RSL radioactive seed localization; WL: wire localization.

Table 2. Summary of Randomized Controlled Trial Results for RSL and WL

NR: not reported; NS: not significant; RSL: radioactive seed localization; WL: wire localization.

Summary of Evidence
For individuals who have a nonpalpable breast lesion who are undergoing a procedure that requires lesion localization who receive RSL, the evidence includes systematic reviews and RCTs Relevant outcomes are other test performance measures, resource utilization, and treatment-related morbidity. Randomized controlled trials comparing RSL with wire localization (WL) have reported similar outcomes (e.g., rates of successful excision, the rate of positive margins) with both techniques. Systematic reviews have also found that outcomes with both localization methods are similar. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Radiology
The American College of Radiology practice parameter (2020) for performing stereotactic breast interventional procedures indicates that stereotactic-guided localization, including radioactive seed localization, may be used as an alternative to standard localization using mammography for identification of lesions prior to surgical procedures.¹⁰

Canadian Agency for Drugs and Technology in Health
A 2019 rapid evidence review conducted by the Canadian Agency for Drugs and Technology in Health (CADTH) identified no evidence-based guidelines on radioactive seed localization for nonpalpable breast lesions.¹¹

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT: national clinical trial.

References  

1. Gray RJ, Salud C, Nguyen K, et al. Randomized prospective evaluation of a novel technique for biopsy or lumpectomy of nonpalpable breast lesions: radioactive seed versus wire localization. Ann Surg Oncol. Oct 2001; 8(9): 711-5. PMID 11597011
2. Hughes JH, Mason MC, Gray RJ, et al. A multi-site validation trial of radioactive seed localization as an alternative to wire localization. Breast J. Mar-Apr 2008; 14(2): 153-7. PMID 18248562
3. Ahmed M, Douek M. ROLL versus RSL: toss of a coin?. Breast Cancer Res Treat. Jul 2013; 140(2): 213-7. PMID 23793603
4. Chan BK, Wiseberg-Firtell JA, Jois RH, et al. Localization techniques for guided surgical excision of non-palpable breast lesions. Cochrane Database Syst Rev. Dec 31 2015; (12): CD009206. PMID 26718728
5. Pouw B, de Wit-van der Veen LJ, Stokkel MP, et al. Heading toward radioactive seed localization in non-palpable breast cancer surgery? A meta-analysis. J Surg Oncol. Feb 2015; 111(2): 185-91. PMID 25195916
6. Ahmed M, Douek M. Radioactive seed localisation (RSL) in the treatment of non-palpable breast cancers: systematic review and meta-analysis. Breast. Aug 2013; 22(4): 383-8. PMID 23673078
7. Chagpar AB, Garcia-Cantu C, Howard-McNatt MM, et al. Does Localization Technique Matter for Non-palpable Breast Cancers?. Am Surg. Apr 15 2021: 31348211011135. PMID 33856948
8. Langhans L, Tvedskov TF, Klausen TL, et al. Radioactive Seed Localization or Wire-guided Localization of Nonpalpable Invasive and In Situ Breast Cancer: A Randomized, Multicenter, Open-label Trial. Ann Surg. Jul 2017; 266(1): 29-35. PMID 28257326
9. Bloomquist EV, Ajkay N, Patil S, et al. A Randomized Prospective Comparison of Patient-Assessed Satisfaction and Clinical Outcomes with Radioactive Seed Localization versus Wire Localization. Breast J. Mar-Apr 2016; 22(2): 151-7. PMID 26696461
10. ACR Practice Parameter for the performance of stereotactic-guided breast interventional procedures. Accessed August 8, 2021.
11. Preoperative seed placement for breast cancer surgery: clinical effectiveness, cost-effectiveness, and guidelines. Ottawa: CADTH; 2019 Apr. (CADTH rapid response report: summary of abstracts). Accessed August 8, 2021.

Coding Section 

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.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines. 

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