Lung cancer continues to be the leading cause of cancer-related deaths worldwide. In 2013, an estimated 228,000 individuals in the United States will be diagnosed with lung cancer, leading to close to 160,000 deaths.1 Stereotactic body radiation therapy (SBRT) has been shown to be an effective treatment modality for early-stage inoperable non–small cell lung cancers.2,3 SBRT is a technique in which dose-intensive radiation is delivered using targeted methods, thereby allowing substantial tumor ablation while sparing normal surrounding tissues. With increasing adoption of imaged-guided radiation therapy (IGRT), the therapeutic index of radiotherapy has vastly improved. However, the lung presents particular challenges in IGRT.
Unlike other disease sites, pulmonary lesions do not have a fixed relationship with skeletal anatomy, as they are highly mobile secondary to normal respiratory motion. In addition, multiple radiation centers provide lung SBRT treatments utilizing the Cyberknife Synchrony system, which uses dynamic tumor tracking based on automated detection and trajectory modeling of implanted fiducial markers.4,5 Given these factors, fiducial makers as surrogates for lung tumor position are being increasingly used.
Commonly, transthoracic-placed gold fiducial markers, which have been shown to be stable and quite effective in other subsites,6 have been utilized in the lung. However, owing to their very smooth surface, they are frequently dislodged from the lungs, usually by coughing. Even in experienced hands, gold seed fiducial marker dislocation rates as high as 10% to 20% have been reported for lung malignancies.7 Given this major disadvantage of gold fiducial markers, embolization coils, which have been traditionally used for vascular occlusion procedures, are being increasingly used with improved retention rates.7 Embolization coils are perceived to have a very high retention rate secondary to better ability to conform and anchor in small bronchi and soft tissues.
In addition to the importance of fiducial marker type, the method of fiducial placement has serious implications. Traditionally, percutaneous transthoracic approaches have been utilized as the main placement modality; however, pneumothorax rates as high as 25% to 30% have been reported with transthoracic procedures.8 In addition, a large pneumothorax may be fatal in elderly patients with already poor lung function. Transbronchial approaches have been associated with a better side-effect profile9; however, peripheral tumors may be impossible to visualize.
Electromagnetic navigational bronchoscopy (ENB) is a minimally invasive, computed tomography (CT)-based localization technology that navigates the bronchoscope to peripheral lesions previously inaccessible to traditional bronchoscopy. ENB consists of 2 phases: the planning phase and the navigation phase. In the planning phase, previously acquired CT scans are utilized to mark and plan pathways to targets within the lung. In the navigation phase, these previously planned targets and pathways are displayed and can be utilized for navigation and access deep within the lung.10
The specific aims of our study were to assess the feasibility and safety of ENB-guided embolization coil fiducials, to assess the accuracy of ENB for placing fiducial markers, and to assess the stability of embolization coil fiducial markers throughout a 5-fraction SBRT treatment course.
PATIENTS AND METHODS
Patients who underwent ENB-guided fiducial placement followed by lung SBRT between January 2010 and November 2012 at our institution were selected for review. Those with easily discernable pulmonary nodules (minimal consolidation, atelectasis, or CT artifact surrounding the lesion) as assessed on cone-beam CT (CBCT) were selected to ensure reproducibility of nodule contours. The study was approved by the Institutional Review Board. All nodules were deemed medically or surgically unresectable. A retrospective analysis of medical records was conducted to collect relevant demographic, clinical, and procedural data.
ENB-guided Fiducial Placement and Periprocedural Care
Patients being considered for SBRT underwent bronchoscopy with linear-array endobronchial ultrasound (Olympus, Center Valley, PA) for assessment of mediastinal/hilar adenopathy and electromagnetic navigation bronchoscopy (iLogic System; SuperDimension, Minneapolis, MN) to the nodule. These procedures were performed as an outpatient by a pulmonologist (M.D.) under general anesthesia. Total procedure time was between 60 and 90 minutes.
First, mediastinal and hilar nodal examination was performed by endobronchial ultrasound. Any nodes >5 mm were sampled with rapid on-site evaluation. If any nodes demonstrated malignant cells on rapid on-site evaluation, ENB to the nodule was not performed, no fiducial markers were placed, and the patient was referred for management of a greater than stage I lung cancer.
The process of electromagnetic navigation to a peripheral lesion has been previously described in multiple publications.10–15 Briefly, before ENB, all patients underwent a planning noncontrast CT scan of the chest with slice thickness of 1 mm at overlapping 0.8 mm intervals with arms at the side. Digital Imaging and Communications in Medicine (DICOM) information from the CT scan was uploaded into the iLogic software system. Using iLogic software with multiplanar reconstructions and generation of a 3-dimension airway tree, an airway path to the target nodule was identified. Bronchoscopy was performed with the patient lying supine on an electromagnetic location board. Patient anatomy was registered with the CT data using either predefined anatomic landmarks or automatic registration during a continuous endobronchial examination. During navigation to the target lesion, several representations of the endobronchial location were used to guide a catheter containing the electromagnetic probe to the target lesion: virtual bronchoscopy, multiplanar reconstructions of the planning CT, local view, tip-view, and maximum intensity projection representations of local landmarks. Once navigation to the target lesion was accomplished, the lesion was confirmed using radial ultrasound (Olympus, Natick, MA). After electromagnetic navigation, biopsies were performed followed by fiducial marker placement.
Fibered platinum coils (4 mm) (VortX-35 fibered platinum coil, Ref. No. 373204; Boston Scientific, Natick, MA) were used as fiducial markers. After ENB localization and placement of the working channel at the target lesion a “hockey stick” catheter (marker placement kit; SuperDimension, Center Valley, PA) was passed through the working channel under fluoroscopy. A fibered coil was inserted into the external end of the marker placement catheter and passed using a wire and deployment was observed by fluoroscopy. Two hours after the procedure, a chest x-ray was obtained to assess for pneumothorax and location of markers.
Patient Simulation Methods and CBCT Acquisition
After fiducial placement, a 4-dimensional simulation CT (4DCT) scan (Brilliance CT Big-bore Configuration; Philips Medical Systems, Cleveland, OH) was obtained with the patients immobilized in a double-vacuum whole-body immobilization system (BodyFix; Medical Intelligence, Schwabmuenchen, Germany). Ten volumetric image sets were constructed retrospectively to match the 10 patient-specific respiratory phases and were exported to an Eclipse treatment-planning platform (Varian Medical Systems, Palo Alto, CA). The reconstructed slice thickness was 3 mm with an in-plane resolution of 1.37 mm by 1.37 mm.
All patients were treated with a Novalis Tx treatment platform (Varian Medical Systems). CBCT scans were acquired on daily basis using the low-dose thorax scan mode (reconstructed slice thickness of 2.5 mm and in-plane pixel resolution of 1.17 mm by 1.17 mm).
Assessment of Fiducial Retention, Placement, and Migration
To assess for retention of all ENB-guided fiducial markers, the total number of fiducial markers that were reported by the pulmonary procedure note and the postprocedure plain film chest radiography was compared with the number of fiducial markers manually counted on 4DCT scan obtained for radiation treatment planning.
Proximity of fiducial placement to the surface of the nodule was also assessed in Eclipse. Incremental 3-dimensional shells of 0.5 cm were created from the nodule surface utilizing the 0% breath phase on 4DCT (Fig. 1). Each individual fiducial marker was scored according to which nearest shell to the nodule the fiducial marker resided.
Fiducial migration was assessed in Eclipse radiation-planning software. On the untagged average simulation 4DCT images and all daily CBCTs, the nodule and all surrounding fiducial markers were contoured as separate structures (all fiducial markers contoured as a single structure). In Eclipse, the coordinates of the geometric center, or centroid, of the both the nodule and the contoured fiducial makers were obtained for the simulation CT scan and each daily CBCT. The 3-dimensional (Euclidian) distance between these 2 centroids were calculated and the change in this distance in each CBCT as compared with the simulation CT was evaluated (Fig. 2).
A total of 37 patients with 44 nodules received ENB-guided fiducial placement during the analyzed time period. All patients subsequently received lung SBRT. Ten nodules were excluded from analysis given the inability to have reproducible tumor contours on daily CBCT (secondary to consolidation, atelectasis, or CT artifact). Therefore, 31 patients with 34 nodules were analyzed. Patient and procedural characteristics are listed in Table 1. The median age of the patients was 74 years (range, 58 to 87 y). The average size of treated nodules was 2.27 cm (range, 0.8 to 4.4 cm) and were located in the right upper lobe (38%), right middle lobe (3%), right lower lobe (6%), left upper lobe (38%), and left lower lobe (15%) of the lung.
Thirty-one ENB-guided biopsies were performed, with 10 of 31 biopsies (32%) showing suspicious cells, atypia, or definite malignancy. Two (6%) patients incurred asymptomatic pneumothoraces identified only on post-ENB plain film chest radiography. Neither patient required a chest tube and both were discharged from the hospital in good condition the following day. One patient incurred hemoptysis requiring hospitalization, red blood cell transfusion, and further workup with diagnostic CT scan 1 week from ENB. The patient was discharged in stable condition following conservative inpatient management. The etiology of hemoptysis or pneumothorax in each patient remained unclear, as complications can arise from transbronchial biopsies and/or fiducial placement.
The mean number of fiducials placed per patient was 3.09 for a total of 105 fiducials. CT simulation for radiation therapy treatment planning occurred on a median of 24 days (range, 5 to 110 d) following ENB. Of the 105 fiducials placed, 103 were identified on simulation CT (retention rate of 98.1%).
Fiducial Proximity to Nodule Surface
Utilizing the proximity shell measurement as described above, the estimated proximity of the each fiducial marker to the nodule surface was analyzed. This proximity measurement served as a surrogate to the accuracy of the pulmonologist in placing the fiducial markers utilizing ENB guidance. A representative example of implanted fiducials in near vicinity to a peripheral nodule is shown in Figure 3. For 1 patient, the 0% breath phase of the 4DCT was unaccounted for. Of the 100 analyzed fiducials, 86 fiducials (86%) were placed within ≤1 cm of the nodule surface, with 52 fiducials (52%) being placed directly on the nodule surface (Fig. 4). For the 2 patients with fiducial marker placement >5 cm from the nodule surface, 1 patient was noted to have a difficult ENB secondary to collapsed airways. The other patient incurred a subclinical pneumothorax, which could have resulted in dissimilarity of the planning CT to the real-time patient anatomy.
CBCTs from 166 SBRT treatments were analyzed for fiducial migration (1 CBCT was not analyzed secondary to very poor image quality, 3 CBCTs were missing from the database). During SBRT, the median daily displacement of the centroids of the fiducial markers as compared with the nodule was 1.5 mm (range, 0.01 to 10.2 mm). Fiducial displacement was <7, 5, and 2 mm in 98%, 96%, and 67% of CBCTs, respectively (Fig. 5). For the 2 nodules with a daily displacement of >7 mm, 1 had fiducial placements >5 cm from the nodule surface, whereas the other exhibited retraction of the nodule to the chest wall.
As lung SBRT treatments are highly ablative with potential of serious toxicities, reliable and stable fiducial markers as surrogates for nodule position are extremely important. This retrospective study identified the safety, feasibility, and accuracy of ENB-guided placement of fibered platinum embolization coils as fiducial markers in very close proximity to the primary nodule. Our study is the first to describe the stability of ENB-guided, commercially available, embolization coil fiducial markers throughout a lung SBRT treatment course utilizing information obtained from daily CBCTs.
Multiple studies of other disease sites have examined the stability of fiducial markers throughout a radiation treatment course as seen on electronic portal imaging or CBCT.6,16–19 In a study by Hong et al,20 the centroid of transthoracic-placed lung fiducial gold seed and coil markers were analyzed for migration comparing an immediate postimplantation CT and simulation CT. They reported that between these 2 scans, the centroid of the gold seed and coils fiducials shifted, on average, <1.3 mm; however, migration between postimplantation and simulation is not of much clinical use.
In another study, the stability of percutaneously placed platinum fiber (made in-house) fiducial markers were assessed utilizing daily pretreatment CT scans throughout SBRT treatment.21 Congruent to our results, van der Voort van Zyp and colleagues identified a median marker migration of 1.3 mm. However, their study reported the change in the centroid of the fiducial markers without taking into account the relationship of the fiducial markers to the nodule as nonsynchronous nodule-marker motion may add additional uncertainty to their findings. Our methodology of assessing fiducial migration builds on their findings, in that it captured the relationship of the nodule to the markers by analyzing the daily displacement of the distance between the nodule centroid and the fiducial marker centroid (Fig. 2). Nonetheless, our study shows that fiducial stability is not sacrificed by utilizing more minimally invasive placement techniques.
In our analysis, only 2 SBRT treatment courses exhibited daily fiducial displacement of >7 mm. For one of these treatment courses, fiducial placement was >5 cm from the nodule (collapsed airways leading to a difficult procedure). The differences in lung compliance directly adjacent to and far from a nodule may explain this aberrancy, thus reinforcing the fact that fiducial placement in close proximity to the nodule surface is optimal. Another nodule exhibited retraction to the chest wall during treatment, out of proportion to the migration of the fiducials.
Previous studies have evaluated the safety of fiducial marker placement utilizing ENB,11,13 as many patients undergoing SBRT for early-stage lung cancers have chronic obstructive pulmonary disease secondary to tobacco use. History of tobacco use and chronic obstructive pulmonary disease has been shown in previous studies to be associated with a higher risk of pneumothorax requiring chest tube placement following transthoracic procedures, which entails distress and hospital stays of up to 5 days.22 As such, iatrogenic pneumothoraces as a result of fiducial implantation may have serious consequences.
In a decision tree analysis, Dale et al23 reported that for a hypothetical cohort of 100 patients, use of ENB lung biopsy resulted in 13.4 fewer pneumothoraces, 5.9 fewer chest tubes, 0.9 fewer significant hemorrhagic episodes, and 0.6 fewer respiratory failure episodes as compared with a CT-guided biopsy technique. In addition, when examining specifically fiducial placement, Hong et al7 reported an incidence of all pneumothoraces, including asymptomatic, to be 23% for transthoracic-placed embolization coil fiducial markers and 54% for transthoracic-placed gold seed markers. For our cohort of patients we reported a very low rate of asymptomatic pneumothorax and hemoptysis (6% and 3%, respectively) when taking into account both ENB-guided biopsy and placement of up to 4 fiducials per patient.
There are a couple of potential limitations to the utilization of ENB-guided fiducial placement and embolization coils in general. First, although ENB has been shown to have a decreased rate of iatrogenic pneumothoraces, ENB may be more costly than uncomplicated transthoracic approaches secondary to the additional equipment used and operating room fees. However, further population-based cost-effectiveness analyses needs to be conducted, as avoided hospital stay costs by an uncomplicated ENB may supercede the up-front cost of the procedure. Moreover, as general anesthesia is typically used at our institution for ENB-guided fiducial placement, the medical risks of general anesthesia should be taken into account. In addition, our positive pathology rate from ENB-guided biopsy of the peripheral nodules was lower than expected at only 32%, with a time-dependent clustering of positive results as the operator gained further experience, showing that there is a learning curve. Finally, a notable drawback to the utilization of embolization coils is their relative low density when compared with gold seed markers, limiting their use to only kilovoltage IGRT. Limitations of our study included the poor resolution of CBCT and frequent CT artifact from the embolization coils, which in turn impacted our contouring accuracy of the nodule and fiducial markers.
In summary, we have shown that ENB-guided placement of embolization coils as surrogates for tumor position for lung SBRT is feasible and is associated with a better toxicity profile as compared with published transthoracic approaches. We have also shown that ENB-guided placement of the embolization coil fiducial markers in very near proximity to the tumor is possible, with most importantly, minimal migration of fiducial markers throughout a 5-fraction SBRT treatment course.
The authors would like to acknowledge the professionalism, expertise and dedication of the radiation therapists at the Oregon Health & Science Knight Cancer Institute with special thanks to Dorothy J. Hargrove, M.S., R.T.(R)(T), Andrea M. Dale, R.T.(R)(T), James O. Price, R.T.(T), Scott A. Madsen, R.T.(R)(T), Linette R. Chapman, R.T.(R)(T), Erica H. Ryu, R.T.(T), JoAnne M. Reasoner, R.T.(R)(T), and Andrea J. Tewson, R.T.(T).
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