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Use of an ultrasound imaging device within the applicator to evaluate placement and support treatment planning for breast brachytherapy and intraoperative radiation therapy

Published:October 08, 2020DOI:https://doi.org/10.1016/j.brachy.2020.08.004

      Abstract

      Purpose

      We evaluated the use of ultrasound imaging within a brachytherapy applicator as a method for applicator positioning, evaluation, and treatment planning in a series of in vitro, cadaver, and human studies.

      Methods and Materials

      We evaluated the performance of a prototype system comprising a small ultrasound imaging catheter inserted within the lumen of a balloon brachytherapy catheter. We tested the device in an ultrasound phantom, in human breast tissue, and in an endoscopic ultrasound catheter in cadaveric breast tissue. We evaluated the visualization of adjacent tissue to consider future development of a similar system for use in brachytherapy and intraoperative radiation therapy.

      Results

      Based on the ultrasound images obtained in an ultrasound phantom, cadaveric breast, and human participants, we observed that an ultrasound imaging catheter placed within the lumen of a brachytherapy applicator can effectively image adjacent tissue, ribs, and air voids, with appropriate quality to support clinical use. We observed high correlation in clinically useful information detected on ultrasound and comparative CT, with ultrasound spatial resolution near 1 mm (spatially variant).

      Conclusions

      The findings from our pilot work suggest that real-time ultrasound imaging, operated from within the applicator, is a promising technique for image guidance and treatment planning during brachytherapy and intraoperative radiation therapy. Further expansion of this technology for clinical use will require development of a cohesive system of components to suit specific clinical applications.

      Keywords

      Introduction

      Whenever possible, intraoperative imaging is recommended during brachytherapy applicator placement to confirm appropriate applicator positioning within or near the tumor [
      • Small W.J.
      • Strauss J.B.
      • Hwang C.C.
      • et al.
      Should uterine tandem applicators ever be placed without ultrasound guidance? No: A brief report and review of the literature.
      ,
      • Viswanathan A.N.
      • Erickson B.A.
      Seeing is saving: The benefit of 3D imaging in gynecologic brachytherapy.
      ]. For instance, the use of imaging confirmation with ultrasound or CT is recommended for cervical cancer brachytherapy to confirm applicator placement and avoid uterine perforation [
      • Small W.J.
      • Strauss J.B.
      • Hwang C.C.
      • et al.
      Should uterine tandem applicators ever be placed without ultrasound guidance? No: A brief report and review of the literature.
      ,
      • Viswanathan A.N.
      • Thomadsen B.
      American Brachytherapy Society Cervical Cancer Recommendations CommitteeAmerican Brachytherapy Society
      American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part I: General principles.
      ]. For breast radiation therapy, a prior study has demonstrated that intraoperative CT imaging leads to adjustment of applicator placement or other clinical actions in nearly 25% of patients treated with breast brachytherapy as a form of intraoperative radiation therapy (IORT). The observation that CT imaging identified a need for adjustment one-quarter of intraoperative breast brachytherapy applicators emphasizes the significance of image guidance for IORT and suggests a high, undetected rate of erroneous or imprecise IORT treatments when image guidance is not in use [
      • Trifiletti D.
      • Showalter T.N.
      • Libby B.
      • et al.
      Intraoperative breast radiation therapy with image guidance: Findings from CT images obtained in a prospective trial of intraoperative high-dose-rate brachytherapy with CT on rails.
      ,
      • Hassinger T.E.
      • Showalter T.N.
      • Schroen A.T.
      • et al.
      Utility of CT imaging in a novel form of high-dose-rate intraoperative breast radiation therapy.
      ]. In the present study, we report a preliminary study of ultrasound imaging for use during breast IORT with a breast brachytherapy technique.
      IORT is an emerging approach to breast conserving therapy in the treatment of early-stage breast cancer [
      • Tom M.C.
      • Joshi N.
      • Vicini F.
      • et al.
      The American Brachytherapy Society consensus statement on intraoperative radiation therapy.
      ], driven by strong patient interest in this form of adjuvant therapy [
      • Alvarado M.D.
      • Conolly J.
      • Park C.
      • et al.
      Patient preferences regarding intraoperative versus external beam radiotherapy following breast-conserving surgery.
      ,
      • Dutta S.W.
      • Mehaffey J.H.
      • Sanders J.C.
      • et al.
      Implementation of an HDR brachytherapy-based breast IORT program: Initial experiences.
      ]. IORT involves a single fraction of radiation to the tumor bed and adjacent breast tissue at the time of lumpectomy. IORT thus provides maximal patient convenience, low costs, and relatively low radiation doses to the heart, lungs, and skin [
      • Dutta S.W.
      • Showalter S.L.
      • Showalter T.N.
      • et al.
      Intraoperative radiation therapy for breast cancer patients: Current perspectives.
      ]. There are still concerns around the use of conventional IORT and possible increased risk of local recurrence as well as the technical methods—particularly the low radiation dose and lack of image guidance [
      • Tom M.C.
      • Joshi N.
      • Vicini F.
      • et al.
      The American Brachytherapy Society consensus statement on intraoperative radiation therapy.
      ,
      • Vaidya J.S.
      • Bulsara M.
      • Wenz F.
      • et al.
      Pride, prejudice, or science: Attitudes towards the results of the TARGIT-A trial of targeted intraoperative radiation therapy for breast cancer.
      ,
      • Vaidya J.S.
      • Joseph D.J.
      • Tobias J.S.
      • et al.
      Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): An international, prospective, randomised, non-inferiority phase 3 trial.
      ,
      • Vaidya J.S.
      • Wenz F.
      • Bulsara M.
      • et al.
      Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial.
      ]. Recently, investigators at our institution have developed a unique IORT technique (precision breast IORT; PB-IORT) that uses CT image guidance to assist with the optimization of radiation applicator positioning and to allow three-dimensional treatment planning for delivery of high-dose-rate (HDR) brachytherapy [
      • Jones R.
      • Libby B.
      • Showalter S.L.
      • et al.
      Dosimetric comparison of (192)Ir high-dose-rate brachytherapy vs. 50 kV x-rays as techniques for breast intraoperative radiation therapy: Conceptual development of image-guided intraoperative brachytherapy using a multilumen balloon applicator and in-room CT imaging.
      ,
      • Showalter S.L.
      • Petroni G.
      • Trifiletti D.M.
      • et al.
      A novel form of breast intraoperative radiation therapy with CT-guided high-dose-rate brachytherapy: Results of a prospective phase I clinical trial.
      ]. This method facilitated confirmation of appropriate catheter placement and allows for a higher dose of radiation to be delivered when compared with conventional IORT. Early results from treatment with PB-IORT demonstrated safety and feasibility and showed that the information from CT imaging leads to clinical changes in about one-quarter of cases [
      • Trifiletti D.
      • Showalter T.N.
      • Libby B.
      • et al.
      Intraoperative breast radiation therapy with image guidance: Findings from CT images obtained in a prospective trial of intraoperative high-dose-rate brachytherapy with CT on rails.
      ,
      • Showalter S.L.
      • Petroni G.
      • Trifiletti D.M.
      • et al.
      A novel form of breast intraoperative radiation therapy with CT-guided high-dose-rate brachytherapy: Results of a prospective phase I clinical trial.
      ].
      However, there are disadvantages to CT utilization for breast IORT. Obtaining intraoperative CT images increases the total procedure time and exposes the patient to ionizing radiation. The biggest logistical challenge to CT integration into breast IORT is the availability and cost of an appropriate facility. For a facility to consider implementing such an approach for brachytherapy, the need for in-room CT within a shielded vault where HDR brachytherapy can be delivered represents a significant burden on resources and space and an inefficient use of a CT unit given limited utilization. This burden limits the potential dissemination of PB-IORT, for example. Hanna et al. have previously reported leveraging the on-board imaging available on a linear accelerator, with use of implanted fiducial markers and the electronic portal imaging device for planar x-rays, for image guidance during IORT with electron beam therapy in a linear accelerator vault [
      • Hanna S.A.
      • de Barros A.C.
      • de Andrade F.E.
      • et al.
      Intraoperative radiation therapy in early breast cancer using a linear accelerator outside of the operative suite: An “image-guided” approach.
      ]. Surface ultrasound imaging has also been reported with electron beam breast IORT [
      • Garcia-Vazquez V.
      • Calvo F.A.
      • Ledesma-Carbayo M.J.
      • et al.
      Intraoperative computed tomography imaging for dose calculation in intraoperative electron radiation therapy: Initial clinical observations.
      ] and with a mobile superficial photon IORT unit [
      • Brodin N.P.
      • Mehta K.J.
      • Basavatia A.
      • et al.
      A skin dose prediction model based on in vivo dosimetry and ultrasound skin bridge measurements during intraoperative breast radiation therapy.
      ], but it should be noted that the use of surface ultrasound imaging is limited primarily to depth measurements for skin surface dose or dose depth estimates. Furthermore, surface ultrasound probes may cause tissue deformation of the target volume during imaging, which limits reliability for treatment planning. If a novel, volumetric imaging approach could be substituted for CT scanning, it would make image-guided IORT feasible with a smaller facility footprint and lower expense in terms of staffing and maintenance.
      To this end, our team developed and pilot-tested a novel method for integration of internal ultrasound imaging into our IORT procedures, with the idea that an inexpensive and portable ultrasound unit could be readily transported to an operating room to permit image evaluation of the brachytherapy applicator. By choosing a miniature ultrasound catheter that can be inserted into the channel of a breast balloon brachytherapy applicator, we have the ability to conduct real-time imaging of breast tissue while avoiding the tissue deformation that would be observed with a surface ultrasound probe. Internal ultrasound has other advantages over transcutaneous ultrasound. It is technically challenging to achieve proper spatial orientation between a handheld, transcutaneous, ultrasound probe and a brachytherapy applicator lying inside the breast tissue. In addition, using a transcutaneous ultrasound imaging approach risks blind spots on the distal side of the applicator in the event of any form of discontinuous acoustic path (e.g., due to proximal air voids). With a catheter-based imaging approach, the transducer is reliably located and oriented within the applicator lumen.
      In the future, the ultrasound technique reported here may aid in treatment planning and allow the physician to manipulate the breast and applicator until ideal positioning is obtained (e.g., adequate confirmation between the balloon applicator and the at-risk breast tissue and coverage of surgical clips). Additional potential benefits include customized treatment planning using the ultrasound images as well as remote monitoring of the source position of adjacent catheters during HDR brachytherapy. In this report, we detail the technology and procedure of the method and evaluate the images produced with internal ultrasound in a cadaver as well as through a breast balloon brachytherapy applicator in a pilot trial in humans.

      Methods and materials

      The potential use of internal ultrasound imaging for breast IORT with HDR brachytherapy was explored using soft-cured cadavers and in a pilot clinical trial. Institutional approvals were obtained before the cadaver study. The pilot clinical trial was designed as a substudy of an ongoing Phase II trial evaluating the efficacy of PB-IORT and was conducted with institutional review board approval and the informed consent of the patients.

      Cadaver study

      To simulate characteristics of ultrasound imaging within a lumpectomy cavity, we used a soft-cured cadaver preserved in the Thiel soft tissue embalming technique [
      • Eisma R.
      • Lamb C.
      • Soames R.W.
      From formalin to Thiel embalming: What changes? One anatomy department's experiences.
      ,
      • Healy S.E.
      • Rai B.P.
      • Biyani C.S.
      • et al.
      Thiel embalming method for cadaver preservation: A review of new training model for urologic skills training.
      ]. The soft-cured cadaver provides a useful model of the soft tissue properties of human tissue [
      • Healy S.E.
      • Rai B.P.
      • Biyani C.S.
      • et al.
      Thiel embalming method for cadaver preservation: A review of new training model for urologic skills training.
      ]. After surgical creation of a lumpectomy cavity within the cadaveric breast, an endoscopic ultrasound probe (GF-UE160-AL5 radial array, 7.5 MHz, ALOKA Prosound F7; Hitachi Healthcare Americas, Twinsburg, OH) was inserted into the cavity. Ultrasound images were obtained to verify visualization of adjacent breast tissue, chest wall (ribs), air cavities, and surgical instruments.

      Pilot clinical trial

      We conducted a pilot study of experimental ultrasound imaging as a substudy in patients who were enrolled in a Phase II clinical trial (NCT02400658). To acquire ultrasound images, an ultrasound imaging catheter was inserted within a standard breast brachytherapy balloon applicator. In this instance, we used an ultrasound catheter commonly used in intracardiac imaging because it had a near optimal imaging frequency and compatible dimensions. A single-lumen breast MammoSite brachytherapy balloon applicator (Hologic, Marlborough, MA) was placed into the lumpectomy cavity. Next, a 9 MHz ULTRA ICE PLUS ultrasound intracardiac imaging catheter (Boston Scientific, Marlborough, MA) was inserted into the treatment lumen of the brachytherapy balloon applicator. A continuous acoustic path was assured by injection of sterile water to displace any remaining air void within the lumen. Ultrasound images were obtained by translating the ultrasound catheter from the tip of the brachytherapy applicator to the other side of the brachytherapy balloon using an automatic catheter pullback device and the iLAB Ultrasound Imaging System (Boston Scientific, Marlborough, MA). A schematic of the method is shown in Fig. 1. Figure 2 is an image of the MammoSite applicator with the ultrasound catheter inside the balloon. An image of the ultrasound catheter tip is also shown. The images were stored on the iLAB system. Ultrasound images were reconstructed and analyzed offline using MATLAB (MathWorks, Natick, MA) and SLICER software (www.slicer.org) [
      • Fedorov A.
      • Beichel R.
      • Kalpathy-Cramer J.
      • et al.
      3D Slicer as an imaging computing platform for the quantitative imaging network.
      ]. For the purposes of image benchmarking, the ultrasound catheter was removed after ultrasound imaging, and a reference CT scan was acquired using a Siemens SOMATOM sliding gantry CT (Siemens AG, Berlin and Munich, Germany) using 1.5 mm slice thickness.
      Figure thumbnail gr1
      Fig. 1Schematic of catheter-based ultrasound imaging for breast intraoperative radiation therapy.
      Figure thumbnail gr2
      Fig. 2(Left) The MammoSite applicator with the ultrasound catheter inside the balloon. (Right) The image of the ultrasound catheter zoomed in on the transducer.

      In vitro testing with a Foley catheter

      An in vitro study was conducted to test the feasibility of ultrasound imaging with a Foley catheter, with the goal of evaluating the performance of the ultrasound transducer within a simple catheter. Any frictional problem between the ultrasound catheter and the lumen of the applicator can be overcome by using larger diameter catheters. 22 Fr Foley catheters were used in this study. The Foley catheter was filled with 30 mL water and placed on top of a tissue-mimicking phantom with embedded wires (Model 054 GS, CIRS, Norfolk, VA). The catheter was positioned on top of three wires that served as markers. A 9 MHz ULTRA ICE PLUS transducer was inserted to the center of the balloon and images were acquired. For comparison, images were also acquired using the same transducer with the MammoSite balloon applicator.

      Results

      Cadaver study

      When the endoscopic ultrasound probe was inserted into cadaveric breast tissue, the breast tissue could be identified up to a depth of 1.5 cm from the endoscopic probe. Furthermore, surgical instruments, ribs, skin surface, and air cavities in the tissue were readily visualized on ultrasound imaging. Representative ultrasound images are shown in Fig. 3a–c .
      Figure thumbnail gr3
      Fig. 3Endoscopic ultrasound images of cadaveric breast tissue. (a) Ribs, (b) Air cavity, (c) Surgical scissors inserted in tissue.

      Pilot clinical trial

      A total of 3 patients were enrolled in the pilot clinical trial. In the pilot clinical trial, translation of the internal ultrasound catheter was hindered by friction within the brachytherapy balloon applicator, limiting the consistency of imaging performance, and requiring offline processing and correction of the acquired images. Frictional issues were mostly related to the interface between the ultrasound catheter and the MammoSite lumen. This is an artifact of our limited choice of compatible devices and is not intrinsic to the underlying approach. Because of these challenges, imaging could be completed in only 1 of 3 patients.
      Representative ultrasound images are shown below. Figure 4 shows transverse images at different positions along the axis of the applicator, specifically at locations where gaps between the tissue and balloon were observed. Sagittal and coronal balloon cross-sections are shown in Fig. 5. CT images are shown in Fig. 6. Using this ultrasound device, in this experimental configuration (i.e., inside the MammoSite applicator), we achieved approximately 0.5 mm resolution in the range dimension and 2 mm in the angular dimension. The resolution in the angular dimension degrades with greater depth as is expected for a small aperture ultrasound source operating in its far field. This resolution is sufficient for the intended application and may be improved with further investment in design (i.e., using a higher frequency and modifications to the applicator that may include the use of thinner and/or softer polymer materials for the lumen and balloon).
      Figure thumbnail gr4
      Fig. 4Transverse images at different positions along the lumen of the applicator. The locations were at the following distances from the center: (a) 9 mm (distal end), (b) 5 mm (distal side), (c) Center, and (d) 1 mm (proximal). In (a) and (b), arrows denote locations where gaps between the tissue and balloon were observed. In (d), the arrow shows the presence of an air pocket inside the balloon.
      Figure thumbnail gr5
      Fig. 5Sagittal (left) and coronal (right) balloon cross-section echo images. The short red arrow denotes observed gaps between the balloon and tissue. The longer red arrow represents air pocket in the balloon. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Figure thumbnail gr6
      Fig. 6Breast CT images of the balloon applicator. Red contour indicates the balloon. Regions of poor tissue conformality (air voids) abutting the balloon surface appear dark on the image. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

      In vitro testing with a Foley catheter

      Ultrasound images of wire phantoms using Foley catheters (22 Fr) and MammoSite applicators are shown in Fig. 7. Wires were imaged up to a depth of 1 cm under both experimental setups. The Foley balloon exhibited lower acoustic reverberations from the wall than the applicator. Qualitative imaging performance of both methods was similar.
      Figure thumbnail gr7
      Fig. 7Ultrasound imaging of wires embedded in tissue-simulating phantoms using the Foley catheter (left) and MammoSite balloon applicator (right). Arrows indicate locations of wires.

      Discussion

      Our preliminary results suggest that the concept of internal ultrasound imaging within a brachytherapy applicator using an appropriately dimensioned ultrasound imaging device may be feasible for clinical use to evaluate applicator position and to support radiation treatment planning. The images produced by the ultrasound catheter placed within the brachytherapy applicator and lumpectomy cavity possess the necessary spatial resolution and contrast to allow for identification of applicator, chest wall, skin surface, and conformation between the balloon applicator and at-risk breast tissue, suggesting that this technique offers promising potential for clinical applications in brachytherapy and IORT. However, we observed technical performance limitations in the equipment we used for this purpose, and we emphasize that custom-designed materials will be needed to develop this technology further for comprehensive clinical validation in brachytherapy.
      The limitations of this technology in its current embodiment are not fundamental to the strategy itself; rather, they are related to limitations in the precise dimensions of system components adopted from their designed usage. There were compatibility issues between the ultrasound catheter and the breast balloon brachytherapy applicator, as these devices were not designed to function together as a cohesive unit. An integrated system of ultrasound and brachytherapy devices, with a linear motion stepper and imaging system to support the entire platform, would be preferable. Additional limitations of the current work include the small sample size of the patient substudy. The equivalent performance of the Foley catheter and the balloon applicator in the in vitro study suggests that at least some component materials are readily available at low cost and rapid technical development is feasible.
      This novel approach to image guidance during brachytherapy has the potential to expand the availability of image-guided high-dose IORT for early-stage breast cancer. It may also have a global impact on brachytherapy. Although we limit the current discussion to the application in breast IORT, the method may be applicable in other diseases including cervical and prostate cancer. Possible applications for clinical brachytherapy include applicator position verification, treatment planning, and source position verification during brachytherapy treatment delivery. Furthermore, the availability of internal ultrasound imaging for evaluation of applicator placement intraoperatively may reduce costs compared with other options, such as CT and MRI. Our method avoids the tissue deformation observed during breast imaging with a surface ultrasound probe, a key factor to consider if ultrasound images are to be used for brachytherapy treatment planning. Our findings support the feasibility of this method for ultrasound imaging during brachytherapy and IORT for the treatment of patients with early-stage breast cancer and suggest that further development of this technology for clinical use is appropriate and feasible. Although we limit the current discussion to application in breast IORT, the method may be equally applicable in other clinical environments. For example, the method may be adopted, and scaled up, to perform a similar function in placing a uterine tandem for cervical cancer or a needle during pelvic interstitial brachytherapy, or even monitoring source position during treatment delivery. Therefore, this overall approach warrants broader development for clinical application.

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