Image-guided navigation systems for interstitial brachytherapy

Interstitial brachytherapy has shown quite promising therapeutic effects in the treatment of tumors in various body regions. Prior to the navigation techniques with quantitative imaging feedback during the procedure, the safety and accuracy of interstitial brachytherapy mainly depended upon the operator's experience, spatial skills and mind reconstruction of the anatomical structures. Different navigation systems have been reported to be experimented on various phantoms and clinically applied in the brachytherapy of many anatomic sites. The numerous advancements of navigation systems integrated with multiple imaging modalities increase accuracy and standardization of the brachytherapy procedure, guarantee clinical effects and even enable less experienced operators to deliver a precise procedure. This article reviews the existing navigation systems and techniques for brachytherapy and discusses the relevant clinical applications.


INTRODUCTION
Brachytherapy is a form of radiotherapy which places radioactive sources permanently into the tumor or region of interest or temporarily into body cavities using afterloading techniques.In the past 20 years, interstitial brachytherapy has shown quite promising therapeutic effects in the treatment of tumors in various body regions.When tumors are unresectable, recurrent, with positive surgical margins or located nearby risk structures, interstitial brachytherapy can be used as a complementary therapy for surgery, chemotherapy, external beam radiotherapy and interventional techniques such as RFA (Radiofrequency Ablation), MWA (Microwave Ablation) and TACE (Transhepatic Arterial Chemotherapy Embolization) [1][2][3][4][5].The most widely used form of interstitial brachytherapy is probably the transrectal ultrasound (US)-guided prostate brachytherapy [6,7].5-10 years of follow-up shows that the clinical outcomes of interstitial brachytherapy for early-stage prostatic cancer are comparable to those of surgery [8][9][10].
However, the accuracy of brachytherapy can be decreased by many factors.For example, the transperitoneal needle insertion may cause organ movement and distortion, which often leads to seed misplacement and dosimetry errors [11,12] Prior to the navigation techniques with quantitative imaging feedback during the procedure, the safety and accuracy of brachytherapy mainly depend upon the operator's experience, spatial skills and mind reconstruction of the anatomical structures.Therefore, image-guided navigation systems, which can provide the spatial orientation of the tumor and the structures buried or beside the tumor in interstitial brachytherapy, is of higher demand.Nowadays, more and more navigation systems have been developed and put into use in clinical procedures, such as conventional and robotic surgery, endoscopy, laparoscopy, radiotherapy and interventional procedure.On the basis of existing and newly developed navigation technologies, different navigation systems have been reported to be experimented on various phantoms and clinically introduced into the brachytherapy treatment of many anatomic sites, such as prostate, endometrium and cervix [13], head and neck [14], breast [15], lung [16], liver, etc.The numerous advancements of navigation systems integrated with multiple imaging modalities increase accuracy and standardization of brachytherapy, guarantee clinical effects and even enable less experienced operators to deliver a precise procedure.
A literature search was performed on PubMed, EMbase for papers between January, 2000 and March, 2016 with no language restrictions.We used ''brachytherapy", "seed implantation", "navigation",

Clinical Research Paper
brachytherapy could decrease the standard deviation in TRE to 1 mm.As shown in Figure 1, the typical workflow for abdominal and cervical seed implantation procedure was mapped.

Treatment planning systems
Before brachytherapy procedure, a treatment planning system (TPS) can be used to identify safe and operable needle trajectories and determine the location and number of radioactive seeds so as to achieve the calculated dosimetric goals.It is a software system which enables the anatomy visualization of the patient by 3D reconstruction and image fusion of the pre-acquired, imaging information from MR (magnetic resonance) or CT (computed tomography) scanners.After the procedure of brachytherapy, TPS can also be used to execute imagebased postimplant dosimetric analysis.Currently, both the AAPM (American Association of Physicists in Medicine) and ABS (American Brachytherapy Society) recommend the evaluation of postimplant dosimetry for all patients undergoing prostate brachytherapy [26][27][28].A number of treatment planning systems are now commercially available.However, the weaknesses such as requirement for manual sketch, not applicable to all body parts, and not providing standard dose models for corresponding lesions limit their applications.Thus, future TPS that can handle tissue composition and density, applicator geometry, body shape and dose calculation is expected [29][30][31][32].
A simple optimization method, presented by Deufel et al. [33], was able to gain similar results compared with more complex optimization algorithms found in commercial treatment planning systems for high dose rate brachytherapy.Fonseca et al. [34] proposed a Medical Image-based Graphical platform Brachytherapy module (AMIGOBrachy), a software module capable of integrating clinical treatment plans with Monte Carlo (MC) simulations with increased accuracy and creates an efficient and powerful user-friendly graphical interface which is able to be incorporated in clinical practice.This simple method optimized conformal target coverage using an exact, variance-based, algebraic approach.It was able to acquire similar metrics such as dose volume histogram, conformity index, and total reference air kerma compared with complex optimizations for cervix, breast, prostate, and planar applicators.However, image-based conformal treatment planning is still largely constrained by the nature of dwell locations even though we can sculpt/ customize radiation dose distribution to meet different requirements and patient anatomy.In addition, there is a lack of clinical evidence which can provide a standard and optimal dose model for corresponding lesions with different therapeutic goals.Therefore, it calls for combined efforts to develop a conformal treatment planning system for various body parts supported by clinical validation of optimal dose.

Registration
Image registration is the process of aligning preoperative coordinate systems with an intraoperative one.The overall goal of image registration applied to image-guided brachytherapy is to fuse imaging information acquired at different points in time, treatment planning and post-processing results into an integrated view during the procedure.Broadly there are two types of registration: rigid registration in which rotations between the data sets are allowed, a small shape change between acquisitions has occurred and deformations are not considered and non-rigid registration, which is required in unstable anatomical structure with elasticity and mobility such as lung, liver and cervix [13,35].
In clinical practice, rigid models are widely used especially in anatomical structures enclosed by a rigid structure such as the brain or with bony landmarks such as the spine [36][37][38].Detailed methodology for testing and quantifying the systemic accuracy of the rigid registration results is well established [39], and for all marker configurations, the automatic technique displayed subvoxel accuracy of marker localization (less than 0.8 mm).Therefore, rigid registration tools have been included in some navigation products such as a neuronavigation system named BrainLab VectorVision which is used for implanting radioactive particles into the cranial base and orbital ape [40,41].However, these rigid registration tools are not suitable for compensating the deformations observed in the soft tissues, which requires the use of deformable or non-rigid registration methods.Over the past 20 years, a large number of non-rigid registration (NRR) models have been developed.However, NRR approaches have only been applied in some research systems with preliminary results due to the challenges in algorithms, computational requirements and validation for NRR [42].In addition, patient motion such as respiration and cardiac motion which may cause tissue deformation is also a confounding factor [43,44].Respiratory motion greatly affects thoracic procedures such as brachytherapy and tumor ablation during which the lung is usually deflated, thus preoperative images are rendered ineffective for targeting the tumor.To address this issue, Naini et al. [45] presented a novel image construction technique which could predict the deformation of the lung and process the pre-operative CT images in order to obtain the CT images of deflated lung.
The diversity of imaging technologies being registered is another confounding factor that inhibits the maturity of the available NRR approaches for clinical applications.Modalities such as CT and magnetic resonance imaging (MRI) sample volumetric data in three spatial dimensions while other technologies such as B-mode US, X-ray and fluoroscopy sample imaging data in two spatial dimensions.Registration between images of different spatial dimensionality necessitates transformation [41,46,47].
In the context of a common procedure of seed implantation, pre-procedural volumetric CT data and 2D US data, which represents a slice through a 3D volume will be acquired.Then an intraoperative navigation system will be applied to track the location of the US probe and slice plane relative to the three-dimensional volume, a non-rigid registration will be finally accomplished by performing either 3D-3D registration via creating a 3D US volumetric image from US slices [44] or 2D-3D registration via aligning 2D slice data directly with the 3D volume [48,49].Ali et al. [35] proposed a fully automatic technique to enhance the poor quality of intraoperative US images during a lung brachytherapy procedure by preprocessing the preoperative 4D-CT respiratory sequence and constructing a CT image to the lung's deflated state.They used a deformable registration/air volume estimation/ extrapolation pipeline and the output of the CT-enhanced US image was located and oriented accurately in its preoperatively processed CT counterpart.Sub-millimeter accuracy was achieved on ex vivo phantom experiments.
Numerous challenges remain to be solved for the mature applications of NRR in navigated brachytherapy.Even though the concepts and methodologies are common, the possibility of developing a single registration method is precluded by the variety of imaging modalities, involved organs and clinical applications.Research in registration, segmentation, visualization methods, and tracking for image-guided navigation systems has continued in academic and industry laboratories.The clinical demands are the mighty power to motivate refinement of the registration technology.

Tracking
The operators used to mentally register the anatomic information from offline imaging modalities to modality used for actual guiding of the procedure which might lead to inaccuracies and human errors.Tracking systems provide the major function to track the spatial position of devices relative to a patient's anatomy, thus enabling therapies and relevant devices to be accurately positioned.The two widely used techniques for brachytherapy are optical tracking and electromagnetic (EM) tracking.The commercially available tracking systems in medical use for image-guided navigation are reviewed as shown in Table 1.
The optical tracking system uses cameras to localize visual markers with a large field of view and high measurement accuracy.It is a well-established tracking modality [50].However, the requirement for a free line-of-sight kept between the tracking devices and instruments to be tracked is its main drawback.For procedures that instruments such as needle tips, flexible endoscopes and catheters must be tracked inside the body, the applications of optical tracking systems are limited due to limited monitoring depth because of tissue absorption and scattering.Hamming et al. [51] presented a conebeam CT-guided, automatic image-to-world registration method based on an optical tracking system.This technique acquired a subvoxel accuracy (< 0.8 mm) of marker localization for all marker configurations and decreased the standard deviation in target registration error (TRE) from 0.34 mm for the manual technique to 0.2 mm for the automatic technique (p = 0.001).The automatic registration of surgical tracking in 3D images was acquired within ~20 s.The results are inspiring and indicate that automatic registration has a great potential to replace conventional manual technique in image-guided navigation.
EM tracking systems localize small sensor coils, which are embedded in medical devices for tracking inside the body, in a magnetic field of known geometry provided by a field generator (FG).The advantage of EM tracking is that it can reside inside the body without requiring "line-of-sight".Boutaleb et al. [52] demonstrated the accuracy performance of an electromagnetic tracking system (EMTS), Aurora ((R)) V1 Planar Field Generator (PFG) EMTS, in brachytherapy procedures.Their experimental results showed that the positional errors were 2 +/-1 mm in a tracking zone restricted to the first 30 cm, the orientation errors remained low at +/-2 degrees for most of the measurements and the presence of typical brachytherapy components nearby the EMTS had little influence on tracking accuracy.Unfortunately, EM tracking also has some drawbacks.Some additional hardware components, such as the EM field generator, are required to place next to the patients or even be attached to them.A lot of electromagnetic tracking systems have a dynamic registration patch which can correct for organ shifts and some also provide respiratory gating which corrects for respiratory motion.The accuracy of the EM tracking system can also be compromised by metallic objects because of magnetic field distortion [53].
To address these issues, different EM tracking systems can be customized for specific clinical applications so as to minimize the drawbacks, and mental devices can be replaced by other materials such as wood or plastic or kept away from the magnetic field as far as possible [54].Technical evaluation shows that precise EM tracking errors can be minimized to less than 1 mm in a suitable environment [55].Furthermore, to increase the tracking accuracy, some research teams proposed integrating EM sensors with other technologies [53].It is possible to use an optical tracking technique for data fusion when lineof-sight is available.For example, Matthias et al. [56] presented a new method of evaluating surgical margins intraoperatively based on (PET/CT) image fusion, using four electromagnetic trackable spheres as well as three infrared cameras.
However, most of the commercial tracking systems are still very complex to operate, hindering widespread applications in clinical workflow.Therefore, the main challenge is the development of simple and practical tracking systems that are feasible in clinical practice.Our team has developed an EM navigation system for permanent seed implantation.Equipped with a tracked ultrasound probe and sensor coils embedded in the needle tip (Figure 2), this system can provide real time feedback of the position of the seeds in relation to the fused modalities, which assist the operators to implant the seeds accurately as planned.

Imaging modalities
Imaging is a fundamental tool in navigated brachytherapy.It is essential in every aspect of the procedure including preoperative diagnosis and staging, treatment planning, real-time guidance, quantitative imaging feedback, postoperative qualitative evaluation of dosimetry and follow-up observations [71,72] (Figure 3).
The most commonly used imaging modality for brachytherapy is CT, while other imaging modalities such as US, fluoroscopy and MRI can be applied intraoperatively for imaging guidance or used for treatment planning refinement in conjunction with CT [71,73,74].However, information provided by each of these modalities alone, due to their own limitations, does not meet all the requirements for brachytherapy, thus it necessitates image fusion so as to take full advantage of acquired information.Image fusion and image co-registration is the technique to merge multiple images from different imaging modalities or from the same imaging modality but acquired at different time points, to one display and align them  [17,[76][77][78].A review of recent representative applications of navigated brachytherapy in different imaging modalities is shown in Table 2.

US or 3D Ultrasound
Ultrasound imaging provides fast, intraoperative, real-time, and both qualitative and quantitative imaging information for treatment planning and treatment delivery in brachytherapy procedure.Developments in US imaging such as 3D US, power Doppler US or elastography [72,83] and in US-based image fusion techniques open a door for the sonographer to perform interventional procedures more precisely according to the treatment plan with both anatomical and functional information.Scott et al. [84] proposed a prostate biopsy approach using real time MRI-US fusion and an adaptive focus deformable registration model on a commercially available 3D US prostate biopsy system on 29 male patients who had suspicious prostate lesions identified by Multiparametric MRI (MP-MRI).Li et al. [83] compared the accuracy of the Elekta ClarityTM 3D US system and kilo-voltage cone beam computed tomography (CBCT) (seed-and bone-based positioning) for prostate positioning in patients with prostate cancer and found out that 3D US appeared comparable to CBCT in image guidance in this retrospective study.

Functional imaging modalities
Functional imaging modalities (e.g.PET, SPECT, power Doppler US imaging, optical imaging, and MRI-MRS), which have become increasingly popular in recent years, enable the assistance in target delineation, modulation of the dose and assessment of the response to the radiotherapy in radiation oncology [56,77,78,85,86].With anatomical, functional and metabolic information, these functional imaging modalities open a new dimension to resolve ambiguities in anatomical imaging, map tumor cells, quantify partial organ function, and sculpt the dose of radiation in the treated volume precisely [87].
The Key Laboratory of Molecular Imaging, Chinese Academy of Science (CAS) has recently developed an advanced Optical Multimodality Molecular Imaging system for Small Animal Imaging.A crucial feature of this system is the capability to acquire multimodality image data including BLT, FMT, PET, MRI and CT and reveal the anatomical, functional and metabolic activity simultaneously in the same device.Using this device, operators can localize viable tumor tissue preoperatively and ensure the complete treatment by visualization of any residual cancer tissue.The fast development of new multi-modality molecular probes or PET tracers also raise the possibility of a shift from anatomical imagingbased to molecular imaging-based boundary delineation, which contributes to an improvement of curative effects in interventional practice [56,78].
Take optical-CT dual-modal molecular imaging probe for example, the local injection of this fluorescent probe can increase the enhancement of CT images, resulting in accurate segmentation, reconstruction and registration because of the clear delineation of the irregular tumor margin.Besides, fluorescence imaging-navigated brachytherapy can assist the operators to deliver the brachytherapy procedure with real-time adjustment of the planning according to the process of the procedure, precise localization of tumor margins that can be seen through the skin (especially for superficial malignancies such as cervical lymph node metastases) and accurate identification of metastatic lymph nodes [88], resulting in reduced number of needle puncture, operating time, incidence of complications and increased one-treatment successful rate.Therefore, fluorescence imaging-navigated brachytherapy, with tremendous potential for navigated brachytherapy, might become the future trend of the development.

MRI
MRI provides a 3D dataset, excellent soft tissue contrast, function of staging and arbitrary multiplanar reconstruction, allowing a superior delineation of normal tissues and tumors over CT and US [89].MRI has been reported to be used in many interventional procedures such as biopsies, thermal therapy or brachytherapy in many sites [40,71,84,90,91].A few articles have reported various experiences using MRI for brachytherapy and the major indications are for gynecologic and prostate cancers [91][92][93][94][95]. Findings of a study by Buch et al. suggested that the volume contours derived from CT was overestimated compared to that from high resolution contrast enhanced magnetic resonance imaging (HR-CEMRI) in 11 postbrachytherapy prostate cancer patients [92].Viswanathan et al. reported that CT-based scans at brachytherapy showed wider target contours than MRI in cervical cancer [96].Thus, MRI remains the gold standard for tumor contouring in image-guided brachytherapy [96,97].
However, it is challenging to ensure that all the devices for brachytherapy are safe for use in high magnetic field and the acquisition of MR image is acceptable due to the different optimal pulse sequences between the soft tissue and the applicators [98].Current solutions are to make MR compatible paramagnetic or some

Optical tracking system
Nsclc = Non-small cell lung cancer; SIRPS = Seed Interstitial Radiotherapy Planning System; 3D = Three-dimensional; SPECT = single photon emission computed tomography.nonmetallic (plastic) devices and titanium applicators and seeds [91].Further efforts to exploit alternative MR compatible materials, MR compatible markers, new sequences and reconstruction methods of applicator and seed visualization are required for MRI-based guidance and postimplant dosimetry assessment [92,[99][100][101].So far, real-time MRI guidance is not generally used except at some major medical centers that have MR scanners available for brachytherapy procedures.

CBCT
CBCT is an imaging technique which consists of a C-arm equipped with a flat panel detector and a cone beam X-ray.This imaging modality, which allows low radiation exposure doses, accurate 3D volumetric datasets and the possible use of dedicated planning and navigation software, is increasingly accessible in navigated brachytherapy.
Various experiences of the implementation of CBCT in brachytherapy have been reported, including 3D planning, assistance in needle placement, intraoperative dosimetric assessment and reconstruction of implanted seed positions and orientations [102][103][104][105][106][107].Amat di San Filippo et al. [107] introduced a new method to obtain the precise segmentation of the implanted radioactive seeds in C-arm images which was validated to be suitable for integration in the dynamic dosimetry workflow during prostate brachytherapy by the clinical datasets.The implanted seeds were delineated by a region-based implicit active contour approach.The iodine implants were segmented by a template-based matching whereas the palladium seed clusters were resolved by a K-means algorithm.The results suggested that the automatically detected rates of the implanted iodine and palladium seeds were both 98.7% and the false-positive rates of iodine and palladium seeds were 1.7% and 2.0%, respectively.Li et al. [83] found out that the discrepancy between bonematch in CBCT and 3D US for prostate positioning was not significant and the discrepancy between seed-match in CBCT and 3D US was significant only in the longitudinal direction which is -1.9 +/-2.3 mm.Experiences of other CBCT-based interventional procedures such as ablation and biopsy [108,109] can be borrowed in performing navigated brachytherapy in many other sites such as the liver, lungs and metastatic lymph nodes.

DISCUSSION
As one of the minimally invasive surgeries, interstitial brachytherapy is of increasing importance in the treatment of cancer [1,14].At present, the emerged commercial navigation systems are not mature and have their own limitations.Most of the preoperative treatment planning is completed manually, which is time-consuming, non-repeatable and with subjective.Once the deviation of seed placement occurs in the middle of the procedure, it is difficult to adjust the original treatment planning in real time, leading to treatment failure.Another important issue with clinical relevance is the dosimetric uncertainty which renders intraoperative dosimetric update difficult and inaccurate.This is because some implanted radioactive seeds are unidentified or hidden due to overlapping or poor imaging, making captures of the coordinates of the seeds unavailable.We can solve this problem by making segmenting algorithms more precise, using novel image fusion techniques, or making seeds more visible for the guiding image modality.For soft tissues or organs, new algorithms are required to calculate respiratory displacement and incorporate these parameters to the whole navigation system.Registration is the key to ensure the precision, but the time needed for registration is the longest.Thus, increasing registration speed is another problem that needs to be solved in the future.In addition, to improve the interoperability of devices and software for image-guided therapy (IGT) and promote the transition from research prototypes to clinical use, a need for standardized communication among devices and software to share data such as target locations, images and device status is highlighted.There have been sporadic efforts to standardize the interconnections between medical devices and software.Tokuda et al. [110] proposed a new, open, extensible yet simple network communication protocol named OpenIGTLink.It was designed for use in the Application Layer on the TCP/IP stack, while allowing developers to implement it for other network models, such as the User Datagram Protocol.The results of performance tests and use-case evaluations showed that this protocol was capable of handling data with sufficient time resolution and latency.It transferred position data with submillisecond latency up to 1024 fps and images with latency of < 10 ms at 32 fps.
To date, with the development of molecular imaging (MI) technology, we believe that image-guided brachytherapy will be moving into a new phase.Molecular imaging and image-fusion techniques can synthesize anatomical, metabolic, and functional information to guide clinicians in their decision-making [111].The combination of full-course molecular imaging and intraoperative navigation can assist clinicians to achieve complete elimination of tumors by defining tumor extent and visualizing any residual tumor tissue.
In the future, our goals are to merge the multimodality-based images into a single model, to incorporate the use of novel MI agents to detect tumors, to increase accuracy of navigation systems, and to perform real-time evaluation of seed placement and dosimetry update.To accelerate clinical translation and evaluate the real effectiveness of these techniques, further clinical trials with quantitative clinical data are necessary.

CONFLICTS OF INTEREST
None.

Figure 1 :
Figure 1: Typical workflow for an intraoperative navigation system for seed implantation procedure.

Figure 2 :
Figure 2: Electromagnetic tracking navigation system.(A) Components of image-guided navigation system incorporating electromagnetic tracking for seed implantation procedure.(B-D) User interface of the treatment planning system showing the axial, sagittal, coronal, and 3D views with radioactive seeds (red) and 100% isodose lines (green).The treatment volume (green) covers the tumor volume (yellow) which was automatically segmented at the beginning of the planning procedure.(E) The simulation ultrasound image of the reconstructed CT image.

Figure 3 :
Figure 3: Role of imaging in image-guided brachytherapy procedure.

Table 1 : Representative applications of commercial tracking systems for image-guided navigation today
[75,76]uided surgery spatially to each other[75,76].Therefore, by the overlay of one dataset with additional second dataset or functional dataset (functional MR, SPECT, PET), multimodality image fusion can provide additional information without the physical presence of MRI, CT, PET or SPECT during brachytherapy procedure with navigation.Recently, novel imaging techniques are being developed (3D US, power Doppler US imaging, PET, MRI-MRS and CBCT are among them) and being increasingly applied in medical practice