Radiofrequency localization of nonpalpable breast cancer in a multicentre prospective cohort study: feasibility, clinical acceptability, and safety

All adult breast cancer patients with nonpalpable, histologically proven, ductal carcinoma in situ or invasive breast cancer, scheduled for breast conserving surgery between April 2019 and May 2021 in Medisch Spectrum Twente (Enschede, the Netherlands) or Diakonessenhuis Utrecht (Utrecht, the Netherlands), were considered eligible for participation. A total of 100 patients were included in this feasibility study. Participants were recruited at the surgical outpatient clinic. The following exclusion criteria were applied: lesion located deeper than 7 cm assessed in supine position, pregnancy or lactating status, and multicentric breast cancer. Additional exclusion criterion was applied with respect to the standard of care for localization at each study site:

The LOCalizer™ RFID tag (10.6 × 2 mm) (Fig. 1A) was inserted during an image guided procedure up to 30 days prior to surgery by an experienced breast radiologist or radiology resident under supervision (intended use > 30 days) [14]. The image guided procedure involved ultrasound (Fig. 1B) or stereotactic imaging. The RFID tag was inserted percutaneously through a small skin incision with a preloaded 12-gauge sterile needle-applicator after injection of local anaesthesia (lidocaine 2%). Each tag has a unique identification number and can be localised transcutaneous by a handheld reader making it easy to distinguish two different tags. The reader (illustrated in Fig. 1A) has a loop probe with a detection range of up to 7 cm, and an attachable single-use sterile pencil probe (8 mm tip diameter) with a detection range up to 3.5 cm for highly accurate localization. The audible and visual feedback provide the surgeon with real-time guidance during the excision procedure. During the course of this study, the manufacturer made a modification to the applicator needle allowing a comparison between the versions.

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The quality of RFID placement was assessed by post-placement mammography and classified as successful if inserted at 0–5 mm omnidirectional distance to the tumours or the pre-NAC placed biopsy marker. In case of unsuccessful placement an additional marker was used, i.e. WL or radioactive seed in cases when an additional marker was needed at a distance shorter than 2 cm (to prevent possible signal interference [14]), or an RFID tag. For cases with a complete radiological response after NAC, the RFID tag was inserted next to the biopsy marker placed in the tumour before the start of NAC. The complete decision three is illustrated in Fig. 2. The pain score after local anaesthesia was recorded by the Visual Analogue Scale (VAS) [15]. Directly after the procedure the radiologist completed a questionnaire assessing the procedure and system usability [13, 16]. The total duration of the procedure was recorded (from start of local anaesthesia to the deposition of the marker). Directly after the tag placement, a two-view mammography, i.e. craniocaudal (CC) and mediolateral oblique (MLO) was acquired to assess the position of the RFID tag (Fig. 1C). The shortest distance from RFID tag to lesion (or biopsy clip marker) was recorded.

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All surgical procedures were performed by experienced breast cancer surgeons or surgery residents under direct supervision. The RFID tag was intraoperatively localised using the handheld portable reader device (Fig. 1A). Transcutaneous measurements were performed with the loop probe (Fig. 1D), measurements after incision were performed with a single-use sterile pencil probe (Fig. 1E). In addition to measurements with the portable reader device lumpectomy specimen radiography was performed to confirm successful retrieval of the RFID tag (Fig. 1F). Directly after the procedure the surgeon completed a questionnaire on the ease of the procedure and system usability [13] [16]. Duration of the procedure from primary incision until specimen retrieval was recorded. Postoperative complications were recorded up to 30 days postoperatively.

Lumpectomy specimens were examined by experienced breast pathologists to record the following parameters: presence and location of the RFID tag, resection margins, specimen dimensions, and tumour dimensions. The respective volumes were calculated using the three radii (1/2 of the diameter assessed by pathology protocol), and the ellipsoid equation \(V=\frac{4}{3}\pi {r}_{1}{r}_{2}{r}_{3}.\) According to the Dutch breast cancer guidelines[17], surgical margins were classified as radical (no tumour in ink), focally irradical (tumour in 1 limited area ≤ 4 mm) and more than focal irradical [17]. Re-excision or mastectomy was recommended for patients with more than focal irradical margins, whilst in patients with focal irradical margins a radiation-boost will suffice.

All data was collected using Castor Electronic Data Capture. The radical (re)excision rate is expressed as a quotient between the total number of excisions and the total number of radical (re)excisions. Descriptive statistics were used to summarise the data by mean, median, interquartile range (IQR), and 95% confidence intervals (CI). Data was analysed using IBM SPSS statistics (IBM Corp., Armonk, NY, USA, version 28).

Fourteen experienced breast radiologists performed 100 RFID procedures (7.1 procedures on average, range 1–25). A 92% success rate was achieved, summarised in Table 2. All radiologists were experienced with RSL, the radiologists from MST also with WL. In 8 procedures (all with ultrasound guidance), the placement failed due to dislocation during retraction of the needle-applicator. Dislocation of the tag occurred in BIRADS density categories A, B, and C. In two patients the distance between tag and lesion (15 mm and 18 mm) were accepted after consultation with the surgeon. Two patients received a second RFID tag, and four patients underwent WL. The median duration of the procedure was five minutes (IQR 3–10 min). The mean VAS pain score of the patient was 1.4 (range 0–6). Median time between tag placement and surgery was 7 days (IQR 4–12 days). 99 RFID tags were placed under ultrasound guidance. One patient received a stereotactic placement due to the dense breast tissue encountered during the initial biopsy procedure. Twelve patients underwent surgery after completing NAC.

Experience of the radiologists with respect to the RFID placement is illustrated in Fig. 3 Radiologists were positive about the RFID tag visibility on ultrasound and easy handling of the needle-applicator. However, they experienced difficulty penetrating through dense glandular tissue and solid tumour tissue which led to repeated punctures and manoeuvring of the needle-applicator through the tissue. In relation to this, they assessed the size of the RFID tag and accompanying 12-gauge needle-applicator as large, necessitating local anaesthesia and increasing the risk of bleeding/hematoma. For these reasons, radiologists in one study centre (Diakonessenhuis Utrecht) preferred the radioactive seed procedure over RFID localization leading to premature termination of the study at this site. In response, the needle-applicator was modified to allow for a smooth penetration of dense breast tissue and solid tumours. The modified needle-applicator, implemented after the first 50 procedures, led to an improved user satisfaction (Fig. 3) in the remaining site (MST). In addition, there was an improvement of the successful placement rate from 90% (45 out of 50) to 98% (49 out of 50). However, a substantial learning curve for the radiologists was observed (Fig. 3). Specifically, the radiologists with few or infrequent procedures had a preference towards RSL, whilst radiologists had no preference between RSL/WL and RFID seed after 10 RFID procedures and following frequent placements (monthly). In two patients, two RFID tags were placed to delineate an area of interest. In one patient with multifocal invasive carcinoma an area of 3.2 cm was delineated. In the other case two tags delineated an area of 4 cm DCIS grade 3. In one patient 1 RFID tag was placed between two areas of DCIS grade 3, which were marked with a biopsy clip marker. (Fig. 4).

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As summarised in Table 2, eight surgeons performed RFID guided BCS in 96 patients (12 procedures on average, range 2–48). Out of the 100 patients included in the surgical evaluation, four individuals experienced dislocation of the RFID tag. In all cases, the dislocation of the RFID tag was detected immediately after its placement and confirmed by the post-placement mammography. Consequently, these patients were excluded from the surgical evaluation exclusively. As per site protocol, these patients received as an alternative method for lesion localization. Transcutaneous identification of the RFID tag with the loop probe was successful in all 96 participants that entered surgical localisation. Median duration of the surgical procedure was 17 min (IQR 12–20 min). All RFID tags were successfully retrieved. User experience with respect to surgery is illustrated in Fig. 5. Surgeons reported that after five to seven procedures, they felt sufficiently familiar with the RFID tag reflecting a signal from two poles (one at each end) instead of a small point source of radioactivity from a radioactive seed.

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Clear resection margins were obtained in 89 out of 96 patients (92.7%, 95% CI [86.2, 96.7]). Four patients (4.2%) had focally involved resection margins, i.e. 3 patients with DCIS and 1 patient with focal irradical invasive carcinoma (NST).

In three additional patients (3.1%), the resection margins were irradical and these patients required re-excision surgery. Despite a complete radiological response to NAC (per MRI), one patient with infiltrating lobular carcinoma (ILC) had an extensive irradical resection. One patient had irradical resection of invasive carcinoma, i.e. the tumour size was underestimated on preoperative imaging (mammography and ultrasound). The third re-excision was in a patient with extensive florid lobular carcinoma in situ (LCIS) which size was underestimated on preoperative imaging (Mammography and Ultrasound, MRI was not performed). In two additional patients, laceration was observed at multiple sites in the lumpectomy tissue reaching into the tumour, complicating evaluation of the surgical margins (supplementary information).

Two patients had a postoperative wound infection within 30 days after surgery amongst which one patient after an oncoplastic lumpectomy. Dislocation of the marker during insertion occurred in eight patients (7.7%). After tag insertion, nine patients experienced some bleeding or hematoma after the placement.

At histopathological assessment of the lumpectomy specimens, tissue damage was found in 14 patients (16%). These specimens showed evidence of mild inflammatory and foreign body reaction with fibrosis. In addition, areas of hematomas and large cavities/ruptured tissues were seen in the area where the RFID tag was positioned (supplementary information). The majority of these cases (85%) occurred before implementation of the modified needle-applicator.