Longitudinal assessment of anchored transponder migration following lung stereotactic body radiation therapy

Abstract Purpose To assess the long‐term stability of the anchored radiofrequency transponders and compare displacement rates with other commercially available lung fiducial markers. We also sought to describe late toxicity attributable to fiducial implantation or migration. Materials and methods The transponder cohort was comprised of 17 patients at our institution who enrolled in a multisite prospective clinical trial and underwent bronchoscopic implantation of three anchored transponders into small (2–2.5 mm) airways. We generated a comparison cohort of 34 patients by selecting patients from our institutional lung SBRT database and matching 2:1 based on the lobe containing tumor and proximity to the bronchial tree. Assessment of migration was performed by rigidly registering the most recent follow‐up CT scan to the simulation scan, and assessing whether the relative geometry of the fiducial markers had changed by more than 5 mm. Toxicity outcomes of interest were hemoptysis and pneumothorax. Results The median follow‐up of patients in the transponder cohort was 25.3 months and the median follow‐up in the comparison cohort was 21.7 months. When assessing the most recent CT, all fiducial markers were within 5 mm of their position at CT simulation in 11 (65%) patients in the transponder group as compared to 23 (68%) in the comparison group (P = 0.28). One case of hemoptysis was identified in the transponder cohort, and bronchoscopy confirmed bleeding from recurrent tumor; no cases of hemoptysis were noted in the comparison cohort. No case of pneumothorax was noted in either group. Conclusion No significant difference in the rates of fiducial marker retention and migration were noted when comparing patients who had anchored transponders placed into small airways and a 2:1 matched cohort of patients who had other commercially available lung fiducial markers placed. In both groups, no late or chronic toxicity appeared to be related to the implanted fiducial markers.


| INTRODUCTION
Stereotactic body radiation therapy (SBRT) has revolutionized the treatment of early stage non-small cell lung cancer (NSCLC) for medically inoperable patients, and those who decline surgical resection. Since SBRT requires delivery of ablative radiation doses with steep dose gradients, accounting for target motion is critical. Early lung SBRT techniques required large internal target volume (ITV) expansions in order to account for target motion throughout the respiratory cycle. 1 As SBRT utilization has evolved, a number of techniques have been developed to reduce the amount of normal lung tissue within the treatment volume. Respiratory gating is commonly utilized to restrict treatment delivery to only a portion of the respiratory cycle, typically near end-expiration, and therefore reducing the necessary ITV margin. 2 A potential concern with respiratory gating is that many gating systems rely on the position of an external marker, which has the potential to be a poor surrogate for target motion. [3][4][5] To mitigate the concern that movement of the gating marker and tumor may be discordant, real time radiographic tracking of implanted fiducial markers can be combined with respiratory gating.
The use of triggered planar imaging to assess fiducial marker position improves the accuracy of treatment delivery, 6 but this technique has a number of limitations. For instance, the tumor is periodically assessed rather than continuously monitored, treatment delivery remains tied to the respiratory cycle rather than tumor position, and fiducial deviation is assessed visually and therefore subject to human error. In order to overcome these limitations, the Calypso ® System (Varian Medical Systems, Palo Alto, CA, USA) has been suggested as a potential solution. 7 The Calypso System consists of electromagnetic transponders paired with a detector array. The Calypso System has been validated for providing real-time tumor tracking within a variety of solid tissues. 8 In order to extend this technology to lung tumor localization, a 5-legged nitinol stabilization system has been developed to anchor the transponders within the lung tissue. The anchored transponders are placed within small airways, on the order of 2 mm diameter, via navigational bronchoscopy. The short-term stability and accuracy of anchored transponders was recently the subject of a prospective clinical trial, but no long-term stability and safety data have yet been reported. The purpose of this study was to assess the long-term stability of anchored transponders. We also sought to describe late toxicity attributable to fiducial implantation or migration. Finally, we compared migration rates with other commercially available lung fiducial markers as a surrogate for the possibility of unexpected future clinical manifestations.

2.A | Patient cohorts
The transponder cohort consisted of all patients at our institution who underwent placement of anchored transponders into small airways as part of a prospective clinical trial (NCT01396551); no patients who underwent transponder placement were excluded. A

2.C | Assessment of fiducial movement
The simulation CT scan was considered as the reference image for baseline fiducial location. On the 4-dimensional simulation CT data set, the implanted markers were manually segmented on the earliest phase of the respiratory cycle for which treatment was planned (corresponding to when the treatment gate opens) using Varian Eclipse software and a uniform 5 mm spherical expansion structure around each marker was generated (depicted in red in Figs. 1-3). The most recent CT scan, up to 2.5 yr post-SBRT, was then imported for registration to the simulation CT scan. Scans beyond 2.5 yr in the comparison cohort were not considered since no patient within the transponder cohort had been followed longer than that period of time. The follow-up CT scan was then rigidly registered to the simulation scan (Fig. 1). Registration methods consisted of a rigid 3-point registration to the fiducial markers with manual adjustments allowed.
Unreasonable distortion of patient anatomy (eg, 90 degree rotation) was not allowed. Fiducial displacement was said to have occurred if the follow-up CT could not be registered in such a way that all markers were within the 5 mm sphere around the initial position.
The 5 mm threshold to define displacement was based on the investigators' judgment regarding the magnitude of fiducial position changes that were not likely due to respiratory motion or CT acquisition technique.
For cases where marker displacement was noted, the follow-up CT scan was further assessed to determine whether the displaced marker(s) was located within an area of fibrosis or normal appearing lung parenchyma. In each case, whether marker displacement was most likely due to evolving postradiation fibrosis (Fig. 2) or to migration ( Fig. 3) was recorded.

2.D | Analysis and regulatory review
All statistical analyses were performed using SPSS Statistics 24 (IBM Corporation, Armonk, New York, USA). Differences in frequencies between the two patient cohorts were assessed using the χ 2 test.
An unconditional test of frequencies was chosen because of the large number of potential pairings between patients in the transponder and comparison cohorts. 10 This study was reviewed and approved by the Institutional Review Board at the University of Alabama at Birmingham. This research was funded by Varian Medical Systems. The funding agent had no role in the study design, data collection, analysis, or results interpretation.

3.A | Baseline characteristics
A description of baseline patient and treatment characteristics is given in Table 1   Of the six patients with marker displacement within the transponder group, five instances appeared to be related to radiation fibrosis around one or more transponders. Of the 11 patients with fiducial displacement within the comparison group, four instances of fiducial displacement appeared to be related to progressive radiation fibrosis.

3.C | Toxicity
No patient within either group developed a pneumothorax at any time point. One patient in the transponder group experienced gross hemoptysis approximately 1 yr from fiducial implantation, but bronchoscopic evaluation confirmed the bleeding was due to local tumor recurrence.
No patient in the comparison group experienced gross hemoptysis.

| DISCUSSION
The Calypso System utilizing electromagnetic transponders has multiple characteristics that offer potential advantages over current respiratory motion management techniques for lung SBRT. In contrast with traditional fiducial markers combined with respiratory gating, electromagnetic transponders provide nearly constant target localization, with their position updated approximately 25 times per F I G . 3. Only one instance of transponder displacement apart from post-SBRT fibrotic change was noted. Three anchored transponders were placed within the right middle lobe. Representative angled axial (left pane) and angled coronal (right pane) slices are shown on the follow-up CT scan, which was performed 19 months after SBRT was completed. The follow-up CT was registered to the CT simulation scan and the red circle represents a 5 mm expansion around the initial position of the anchored transponder. One transponder was noted to have been displaced superiorly and laterally (yellow arrow). No symptoms were attributed to fiducial displacement at clinical follow-up. One patient with two transponders placed in LUL and one in LLL was treated as LUL for purposes of case matching.
second. 11 Decreased target position uncertainty should allow for a reduction in ITV and PTV margins and therefore reduce the amount of nontumor tissue within the treatment volume. When combined with the Dynamic Edge Gating system, the Calypso System obviates the need for an external surrogate gating marker since a beam-hold is imposed if the transponders move beyond a prespecified margin.
Gating treatment delivery based on target position rather than the respiratory cycle may also improve the overall efficiency of treatment, particularly for patients with irregular respirations, by reducing unnecessary beam-holds.
Anchored transponders are placed via bronchoscopy and utilize a 5-legged nitinol stabilization system to aid retention. 12 Preliminary evidence supports the short-term stability and accuracy of the anchored transponders. 13 Fixation of the transponders for up to 60 days was similar to that of spherical gold markers in a canine model, 14  Rates of acute pneumothorax exceeding 20% were initially described in early series that utilized trans-thoracic fiducial placement techniques, 17,18 but this has become rare in the era of bronchoscopic placement. The fact that no patient in this series developed a pneumothorax is consistent with recent reports. 19