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* From Interventional Pulmonology (Drs. Anantham, Feller-Kopman, and Ernst), Radiation Oncology (Drs. Shanmugham and Berman), and Thoracic Surgery (Drs. DeCamp and Gangadharan), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and Department of Pneumology and Critical Care Medicine (Drs. Eberhardt and Herth), Thoraxklinik, University of Heidelberg, Heidelberg, Germany.
Correspondence to: Armin Ernst, MD, FCCP, Chief, Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston MA 02215; e-mail: aernst{at}bidmc.harvard.edu
Abstract
Background: Stereotactic radiosurgery (Cyberknife; Accuray Incorporated; Sunnyvale, CA) is a treatment option for patients who are medically unfit to undergo lung tumor resection. For precise tumor ablation, the Cyberknife requires fiducial marker placement in or near the target tumor. Fiducial placement under transthoracic CT guidance is associated with a high risk of iatrogenic pneumothorax. Electromagnetic navigation bronchoscopy (ENB) may offer a less morbid alternative to accurately deploy fiducials to bronchoscopically invisible peripheral lung lesions.
Objective: Open-label, feasibility study to assess fiducial placement in peripheral lung tumors by ENB.
Method: Consecutive patients with peripheral lung tumors and who were evaluated to be nonsurgical candidates underwent fiducial placement under ENB. This procedure was considered successful if fiducials were placed in or near the tumors and remained in place without migration for radiosurgery to proceed. The need for alternative or additional intrathoracic fiducial placement was documented as procedure failure.
Results: A total of 39 fiducials markers were successfully deployed in eight of nine patients (89%). Of these eight successful cases, seven had fiducials placed directly within the tumor (88%). At Cyberknife planning, 7 to 10 days after fiducial placement, 35 of 39 fiducial markers (90%) were still in place and were adequate to allow radiosurgery to proceed. No immediate bronchoscopic complications were observed. One patient had a COPD exacerbation. Another patient returned within 1 day with transient, self-limiting fever.
Conclusions: ENB can be used to deploy fiducial markers for Cyberknife radiosurgery of lung tumors safely and accurately without the complications associated with transthoracic placement.
Key Words: Cyberknife • electromagnetic navigation bronchoscopy • fiducial • lung cancer • robotic stereotactic radiosurgery
Patients who have potentially resectable lung tumors may be considered inoperable because of advanced age, comorbidities, or poor pulmonary function. Stereotactic radiosurgery (Cyberknife; Accuray Incorporated; Sunnyvale, CA) is an alternative to external beam radiotherapy in such patients. The Cyberknife is a frameless and image-guided device that has a 6-megavolt linear accelerator mounted on a robotic arm (Fig 1 ), Consequently, the Cyberknife can administer radiation to a tumor from different trajectories while minimizing dosage to adjacent normal tissue. When used with the Synchrony System (Accuray Incorporated), the Cyberknife avoids the need for breath holding because it compensates for changes in tumor position during the normal respiratory cycle. However, this system requires the insertion of fiducials in or near the tumors to enable accurate tracking. Fiducials are radiographically visible markers that precisely identify the location of a tumor during Cyberknife therapy.
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Electromagnetic navigation bronchoscopy (ENB) is designed to guide bronchoscopic tools to predetermined locations within the periphery of the bronchial tree. ENB consists of four components: an electromagnetic location board, a locatable sensor probe with an eight-way steering mechanism that is able to navigate the bronchial tree, an extended working channel (EWC) that can carry either the sensor probe or a flexible forceps/brush/needle, and computer software that converts CT scans into multiplanar images with three-dimensional virtual bronchoscopy reconstruction. This system enables real-time navigation guidance within the lungs to endobronchially invisible targets. The diagnostic yield from ENB-guided biopsies of peripheral lung lesions ranges from 69 to 74% and is independent of target size.678 Therefore, ENB-guided fiducial placement is likely to be more accurate than standard bronchoscopy.
We hypothesized that ENB could be used as a vehicle to precisely place fiducials into peripheral lung tumors. An open-label, feasibility study was conducted to test this hypothesis.
Materials and Methods
Nine consecutive patients who were referred for bronchoscopic fiducial placement were recruited between September 2005 and April 2006. All patients had peripheral lung tumors and no CT evidence of endobronchial pathology. The cases were reviewed at a multidisciplinary thoracic oncology clinic, and seven were deemed inoperable. Two additional patients declined surgery when informed of the potential surgical risks and complications due to their medical comorbidities. The indications for all nine patients for Cyberknife radiosurgery are listed in Table 1 . Patients with implantable pacemakers or defibrillators were excluded from ENB. The Institutional Review Board of Beth Israel Deaconess Medical Center approved the data collection and analysis.
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The patient was then placed on an electromagnetic location board. Bronchoscopy was performed under moderate sedation via the oral route with an adult therapeutic bronchoscope (Olympus IT160; Olympus; Tokyo, Japan) with a 2.8-mm working channel. Endobronchial mapping was achieved when the virtual registration points were linked to the actual position in the patient’s thorax by a sensor probe. The software then documented the registration error, which represents the radius of the expected difference in location between the tip of the sensor probe in the actual patient and where the tip is expected to be. The registration error could then be reduced by either repositioning a misplaced registration point or by eliminating the registration points with the greatest deviation. Navigation began by wedging the bronchoscope in the suspected bronchial segment and steering the sensor probe with the EWC to the lesion using the multiplanar CT images and the "tip-view" orientation (Fig 2 ). At the end of navigation, the navigation error was documented. The navigation error is defined as the closest distance between the sensor probe and the lesion center.
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-Omega Services; Bellflower, CA) were used as fiducial markers. The dimensions are 0.8 mm by 5 mm. The gold seeds were wedged into the wax tip of a microbiology specimen brush (catalogue No. 1650; Boston Scientific; Natick, MA) [Fig 3
]. The proximal end of the microbiology brush was marked with a strip of paper tape to prevent overshoot beyond the distal end of the EWC. After successful ENB navigation to the tumor, the sensor probe was removed and the microbiology brush with the loaded fiducial was placed through the EWC. When the brush catheter reached the distal end of the EWC, the brush was pushed through the wax tip to deploy the fiducial into the distal airways/lung parenchyma. After each fiducial placement, the EWC was navigated to a different area of the tumor before the next gold seed was deployed. Ideally, fiducials must have a minimum spatial separation of 20 mm and an angular separation between any groupings of three fiducials of 15°.9 A postprocedure radiograph was obtained to exclude iatrogenic pneumothorax and confirm fiducial placement. All ENB-guided fiducial placement were performed as outpatient procedures and no fluoroscopy was used.
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50 to 60 mm)9 to the tumor center for Cyberknife targeting to proceed was deemed an ENB success. The need for alternative or additional intrathoracic fiducial placement was documented as ENB failure. Patients were tracked for 30 days for possible ENB-related complications.
Cyberknife Radiosurgery
Cyberknife planning was done 7 to 10 days after fiducial placement to determine beam number, trajectory, and intensity to provide appropriate radiation dose distribution for radiosurgery (Fig 4
). A waiting period of 7 to 10 days allowed for any movement or displacement of fiducials. Evidence suggests that once the fiducials are deployed appropriately, minimal migration occurs after the first week because these markers are fixed in place by airway edema and subsequent fibrosis.10
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Thirty-nine fiducial markers were placed in nine patients. Mean age of these patients was 69 ± 13 years (range, 46 to 92 years). Histology, size, and stage of the tumors are listed in Table 1. Majority of these patients had multiple comorbidities and poor pulmonary function. Mean FEV1 was 39 ± 10% of predicted.
During ENB, the mean number of registration points used was 6 ± 1 (range, 5 to 7). Mean registration error was 6.1 ± 0.2 (range, 5.9 to 6.5 mm), while the documented navigation error was 14 ± 5 (range, 10 to 18 mm). Mean target size was 35.8 ± 16.7 (range, 20 to 67 mm). None of the patients had any evidence of endobronchial abnormalities on bronchoscopic evaluation.
Fiducial markers were successfully placed in eight of nine patients (89%). Navigation to the lesion with ENB was unsuccessful for the remaining patient (case 8) despite multiple attempts. It was believed that this patient did not have an airway leading to the tumor and ENB was aborted. Subsequently, this patient had fiducials placed transthoracically under CT guidance.
Mean number of fiducials placed in each patient was 4.9 ± 1.0 (range, 4 to 6). Some fiducials were placed directly within the tumor in seven of eight patients (88%). In the remaining case, the fiducials were located 15 mm adjacent to the tumor. Observations during Cyberknife planning, 1 week after fiducial placement, showed that 35 of 39 fiducials (90%) were still in place (Table 2 ). Although data on spatial and angular separation of fiducials were not collected, all patients had sufficient number and location of intrathoracic fiducials for radiosurgery planning and therapy to proceed.
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Discussion
Cyberknife radiosurgery has emerged as an alternative for patients with lung cancers who are inoperable for medical reasons.11 Bronchoscopic fiducial placement in the thorax is more attractive than either transthoracic or intravascular deployment because of the improved side effects profile. Transthoracic fiducial placement has a reported pneumothorax rate of 13%.11 This percentage may not be representative of the actual incidence because the pneumothorax rate for transthoracic CT-guided biopsies has been reported to be as high as 23 to 38%.1213 Clearly, pneumothorax can be a potentially serious complication in patients with already compromised pulmonary function. Intravascular coils have pleurisy (13 to 33%), pulmonary infarcts (5%), and groin hematoma (3%) as documented complications.1415 Bronchoscopic fiducial placement is limited by either gold seed migration and inadvertent deployment in the proximal airways.39
ENB-guided fiducial placement for Cyberknife radiosurgery of lung tumors is a viable alternative to the other methods of fiducial placement. ENB is accurate and can be performed as an outpatient procedure under moderate sedation. Although duration of the procedure was not recorded in this study, our previous data on ENB showed that mean procedure time was only 26.9 ± 6.5 min. The technique is safe despite the advanced age, comorbidities, and poor pulmonary function of most of the patients who require radiosurgery.
Fiducial placement via standard flexible bronchoscopy has limitations. Placement using a transbronchial aspiration needle may result in the fiducials dropping into the airway before deployment with a reported frequency of 22%.3 One incidence of embolization to the pulmonary artery after a fiducial was deployed into a subcarinal lymph node via a 19-gauge transbronchial aspiration needle has also been reported.3 Alternatively, a dedicated polytetrafluoroethylene catheter has been used to deploy fiducials in peripheral tumors via bronchoscopy.2 However, 26% of these fiducials were not seen at the planning phase and are believed to have dropped out of the target airways.9 There is an inverse relationship between size of bronchial lumen and successful fiducial placement without subsequent migration.9 Fiducial gold seeds must be wedged in small peripheral airways or lung parenchyma to avoid migration. However, when the fiducials are placed by standard bronchoscopy, they are often deployed in the more proximal airways and tend to dislodge. ENB, in contrast, enables the operator to navigate to small peripheral airways beyond the reach of standard bronchoscopy. The majority of fiducials (35 of 39; 90%) remained in place for use during Cyberknife planning and subsequent treatment of our patients. We hypothesized that the remaining four fiducial markers may have migrated and were coughed out. We therefore recommend placement of more than the required three fiducials to avoid the need for alternative or repeat fiducial deployment should any of these markers migrate.
The primary limitation of ENB-guided fiducial placement is the inability to navigate to the target when there are no airways that lead directly to the tumor. The airways may be either distorted or not patent. However, positioning the fiducials strictly within the target is not required for Cyberknife and fiducial markers can be placed adjacent to rather than within the tumor. Although, we found no ENB-related pneumothoraces, there is a reported pneumothorax rate of approximately 3% when ENB was used to obtain transbronchial lung biopsy specimens.678 There are no data to suggest that ENB without performing lung biopsies causes iatrogenic pneumothoraces. It is debatable whether to attribute the single COPD exacerbation in our study directly to ENB because the patient was successful discharged back to home after the procedure and was only subsequently readmitted for dyspnea. Nevertheless, the comorbidities and cardiopulmonary reserve of the group of patients who are likely to be candidates for radiosurgery is such that similar complications could be anticipated regardless of the modality of fiducial placement.
ENB-guided fiducial marker placement for Cyberknife treatment of peripheral lung tumors is a feasible and safe alternative to the other transthoracic, intravascular, or bronchoscopic modalities that are currently available. The steering mechanism of the locatable guide and the ability to "road map" a lesion has made it possible for ENB to accurately navigate to bronchoscopically invisible lesions. Larger, prospective, randomized trials are still needed before definite conclusions can be reached about which modality of fiducial placement is indeed superior. A dedicated catheter to deploy the fiducials via ENB is an area for future product development. Issues of equipment costs and reimbursement for ENB also need to be addressed. Despite these limitations, ENB is rapidly gaining an increasing number of applications from targeted biopsies of mediastinal and lung lesions678 to therapeutic interventions like radiosurgery fiducial placement.
Acknowledgements
Arthur Dea and Robert Garland from Interventional Pulmonology, Beth Israel Deaconess Medical Center, Boston, assisted with manuscript editing and data collection.
Footnotes
Abbreviations: ENB = electromagnetic navigation bronchoscopy; EWC = extended working channel
The locatable sensor probes for electromagnetic navigation bronchoscopy were provided free of charge by superDimension. superDimension has supported continuing medical education courses at Harvard University through unrestricted educational grants. Dr. Ernst was a member of the Scientific Advisory Board of superDimension and has been reimbursed for time and travel expenses related to that function. Dr. Ernst also had stock options in superDimension, which have been returned in the past. Dr. DeCamp is a member of the Scientific Advisory Board of superDimension and Accuray and has been reimbursed for time and travel expenses related to that function. Neither Dr. Ernst nor Dr. DeCamp were involved in the consenting process. Drs. Anantham, Feller-Kopman, Shanmugham, Berman, Gangadharan, Eberhardt, and Herth have no conflict of interest to report.
A portion of this data was presented as an abstract at the European Respiratory Society Congress, Munich, Germany, 2006.
Received for publication February 27, 2007. Accepted for publication May 22, 2007.
References
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