Reproducibility of a novel, vacuum‐assisted immobilization for breast stereotactic radiotherapy

Abstract A novel, breast‐specific stereotactic radiotherapy device has been developed for delivery of highly conformal, accelerated partial breast irradiation. This device employs a unique, vacuum‐assisted, breast cup immobilization system that applies a gentle, negative pressure to the target breast with the patient in the prone position. A device‐specific patient loader is utilized for simulation scanning and device docking. Prior to clinical activation, a prospective protocol enrolled 25 patients who had been or were to be treated with breast conservation surgery and adjuvant radiotherapy for localized breast cancer. The patients underwent breast cup placement and two separate CT simulation scans. Surgical clips within the breast were mapped and positions measured against the device’s integrated stereotactic fiducial/coordinate system to confirm reproducible and durable immobilization during the simulation, treatment planning, and delivery process for the device. Of the enrolled 25 patients, 16 were deemed eligible for analysis. Seventy‐three clips (median, 4; mean, 4.6; range, 1–8 per patient) were mapped in these selected patients on both the first and second CT scans. X, Y, and Z coordinates were determined for the center point of each clip. Length of vector change in position was determined for each clip between the two scans. The mean displacement of implanted clips was 1.90 mm (median, 1.47 mm; range, 0.44–6.52 mm) (95% CI, 1.6–2.20 mm). Additional analyses stratified clips by position within the breast and depth into the immobilization cup. Overall, this effort validated the clinically utilized 3‐mm planning target volume margin for accurate, reliable, and precise employment of the device.

Breast conservation therapy has emerged as the preferred approach to mastectomy, with comparable disease control and improved quality of life. 3 This approach has traditionally employed lumpectomy (partial mastectomy) or removal of the breast tumor with a small rim of normal surrounding breast tissue, followed by adjuvant radiotherapy. Breast radiotherapy has most often been delivered to encompass the whole ipsilateral breast tissue (i.e., whole-breast radiotherapy [WBRT]) while avoiding deep underlying organs at risk. Standard fractionated radiotherapy involved 5.5-6 weeks of treatment. In an effort to reduce side effects and improve quality of life related to radiotherapy, accelerated partial breast irradiation (APBI) has been advocated in a select group of patients. [4][5][6] This has proven as effective as WBRT while substantially reducing the volume of tissue irradiated and the duration of therapy to 1 week or less depending on the technique of therapy. [7][8][9][10][11][12] External-beam radiotherapy (EBRT) has become the technique preferred by both patients and clinicians for delivery of APBI. 13 This is probably the result of its familiarity to physicians, ease of use, completely noninvasive nature, and wide availability. This has most commonly been used in clinical trials with three-dimensional conformal radiotherapy (3DCRT) techniques. Early reports from these trials indicate that 3DCRT APBI, although similar in oncologic efficacy to WBRT, has produced unexpectedly high rates of fair/poor cosmetic outcomes. [14][15][16] Dosimetric analyses from several single-institution experiences implicated the volume of normal breast tissue exposed to each of several dose prescription levels as predictive of these fair/poor cosmeses. 14,15 At our institution, several strategies have been explored to reduce normal breast tissue exposure during APBI. We have previously reported our institutional results utilizing preoperative 3DCRT APBI to decrease target volume, because the in vivo tumor is uniformly and powers of magnitude smaller than the eventual lumpectomy cavity with margin. 17,18 This work led to a prospective, phase II clinical trial of preoperative 3DCRT APBI with excellent disease control rates so far and promising cosmetic outcomes. 19 In parallel, a novel breast-specific stereotactic radiotherapy (BSRT) device (Gam-maPod; Xcision Medical Systems, LLC, Columbia, MD) was developed at our academic medical institution. This device employs nonoverlapping, non-coplanar 60 Co beams that rotate around the breast as the patient, in the prone position, is translated over the apertures employing a dynamic dose-painting technique. [20][21][22][23][24][25] We have recently reported in silico results demonstrating improvements in dose fall-off and conformity in comparison with traditional APBI techniques (e.g., 3DCRT, intensity-modulated radiation therapy, etc). 26,27 The purpose of this study was to establish the setup accuracy for this stereotactic system that allows for a substantial reduction in planning target volume (PTV) for APBI. The BSRT delivery system is coupled with a device-specific, vacuum-assisted breast immobilization cup by which a slight, comfortable negative pressure (150 mm Hg) is applied to the breast and through which a stereotactic registration fiducial system is established. This cup can be registered to both the simulation and treatment tables. Prior to activation of the BSRT device on clinical trial, we completed this reproducibility study for the immobilization system and report the results here.

| MATERIALS AND METHODS
Twenty-five patients were enrolled on a prospective Institutional Review Board-approved protocol (GCC 1047) at the University of Maryland School of Medicine in the Greenebaum Comprehensive Cancer Center. Eligible patients were those who had previously undergone, were planned to undergo, or were undergoing WBRT by EBRT following partial mastectomy and who could tolerate the prone position.
One physician completed breast-cup fitting on all participating patients. The three outer cup sizes (small, medium, and large) vary in the width of the base (Fig. 1). Each outer cup, in turn, has 9 or 10 sets of inner cups with varying height (apex-to-base) sizes. The outer cup also has an incorporated fiducial system that acts to establish the stereotactic coordinate system. The edge of the inner cup is inserted into a groove along the rim of the silicon flange, which then also locks into the outer cup, forming the combined breast cup immobilization device. The area between the inner and outer cups is subjected to negative pressure with a vacuum device. Through the perforations on the inner cup, the breast is subjected to the gentle pulling of negative pressure and fills the inner cup volume. This immobilizes the breast tissue within the cup. This system has been described previously in greater detail. 21 Despite the application of negative pressure, the anatomy of some patients did not allow the entire breast to fill the inner cup because the cup's geometry reflects a regular and round surface.
This was exacerbated in patients who had prior radiation and some loss of breast elasticity. Where large (>1 cm) gaps were visible between the breast and inner cup, a silicone filler was inserted into the inner cup to close the gap. The silicone fillers are akin to commercially available silicone bra inserts and are intended to comfortably fill negative space within the inner cup with appropriate rigidity; size/fitting for these was individualized. This was adhered to the inner cup with adhesive prior to repeat placement of the cup.  Pressure seal was not obtained as a result of patient body habitus. 2 No appropriate breast cup size was found. 3 Procedure was aborted because of discomfort. 4 No appropriate clips for vector measurement. 5 Clips mobile within a lumpectomy seroma.
potential multi-fraction applications of the device, the cup would be re-fitted and the patient resimulated for each delivery; therefore, interfractional variability in breast cup placement is of less concern.
Both CT simulations were transferred to the institutional treat-    with clips displaced more than 3 mm also had other clips that were less than 3 mm from their original positions.

| DISCUSSION
This BSRT device represents a novel, breast stereotactic radiotherapy system with two key advantages over other external-beam delivery platforms: a unique dynamic dose-painting delivery technique and a device-specific breast stereotactic immobilization cup. Based on results from the current study, the immobilization cup offers excellent reproducibility both within and above the cup's brim (at level of treatment table top) up to 1 cm, which coincides with the geometric limit of the device's delivery. Our analysis of internal marker localization accuracy indicates that 86% of markers could be localized with an uncertainty of less than 3 mm. In patients without breast cup pressure loss or substantially different arm position at CT2, 93% of clips were displaced less than 3 mm. In this group, all  Although PTV margin should take into account other applicable uncertainties (mechanical and dose delivery uncertainties, etc.), localization uncertainty is deemed a major component driving PTV margin. As such, we have concluded that it is reasonable to utilize a PTV margin of 3 mm in treatment planning with this device. This is substantially less than the 10 mm recommended on previous APBI trials. 13,16 It should be noted that for cases in which the target is close to or extends slightly above the treatment table and, therefore, outside F I G . 4. Patient with substantial positioning difference between CT1 and CT2 examinations. Note the folded right arm (blue arrow) in CT2 (b and d) vs. initial CT1 position (a and c) on two representative axial slices (a vs. b, c vs. d), which has substantially changed the external contour (green, all images) and rotated the patient. Also note that the clips immediately surrounding the lumpectomy cavity remain relatively unchanged (a and b) SNIDER ET AL. | 13 of the immobilization cup, care must be taken to prevent differences in patient positioning between simulation and treatment specifically as it pertains to arm positioning. Such changes can lead to significant alterations in target positioning, as seen in Fig. 4. For targets that extend outside the cup, additional upper-body or thoracic immobilization techniques, which were not included in this study, might be considered. In addition, a room or unit-mounted laser localization or optical guidance system could also be utilized to improve the reproducibility of upper-body positioning.
A relatively high incidence (7/25% or 28%) of pressure loss was In this prospective study the immobilization technique and breast cup system were well tolerated by patients, with generally minimal discomfort or side effects. Small, asymptomatic superficial skin blisters were encountered in one case that self-resolved. Otherwise, the majority of patients underwent CT1, waited for 30 min, and underwent CT2 without significant issue or pain.
In summary, limiting the exposure of normal tissue to radiation dose is appropriately prioritized in patients with early-stage breast cancer, where high rates of cure predominate. While keeping local control rates relatively similar to whole-breast irradiation, APBI approaches can offer measurable reductions in dose to normal tissues, including the lung, heart, chest wall, breast skin, and uninvolved breast tissue. As previously noted, several efforts have detailed unexpectedly poor cosmetic outcomes with APBI delivered with traditional EBRT techniques. 14-16 These outcomes have been clearly linked to the amount of normal breast and skin tissue exposed to radiotherapy. In silico work at our institution has demonstrated improved dose conformality and substantial reductions in breast and other organ-at-risk exposure with the BSRT device. 26,27 The current work has verified the appropriateness of margins utilized for setup uncertainty. The device has been activated clinically at two institutions with four additional sites projected within the next 2 years. [22][23][24][25]28

| CONCLUSION
The device-specific negative-pressure breast cup evaluated here offers excellent immobilization and reproducibility, with an average setup uncertainty of ≤3 mm. This serves as the recommended PTV margin for utilization of the device on currently activated and planned clinical trials as well as in general clinical practice. Further work is underway to improve manufacturing and application of the immobilization cup to prevent pressure losses and further reduce uncertainty.

ACKNOWLEDG MENTS
Snider contributed the most to data collection, authorship/drafting of the manuscript, analysis, and review of this offering. Mutaf, Molitoris, Diwanji, Becker, Nichols, Feigenberg, Chen all contributed to data analysis, authorship/drafting/editing, and review of this offering.
Feigenberg acted as the primary mentor and director of this effort. Healthineers, and the Society for Thermal Medicine. Snider reports an unrelated patent regarding a proton radiotherapy planning methodology.

CONFLI CTS OF INTEREST
All above sources of bias have been effectively mitigated in this investigation through systematic methodology for data collection and analysis.