Accepted Manuscript Recent Advances in Bronchoscopic Treatment of Peripheral Lung Cancers Kassem Harris, MD, Jonathan Puchalski, MD, Daniel Sterman PII:
S0012-3692(16)49258-5
DOI:
10.1016/j.chest.2016.05.025
Reference:
CHEST 497
To appear in:
CHEST
Received Date: 4 February 2016 Revised Date:
9 May 2016
Accepted Date: 30 May 2016
Please cite this article as: Harris K, Puchalski J, Sterman D, Recent Advances in Bronchoscopic Treatment of Peripheral Lung Cancers, CHEST (2016), doi: 10.1016/j.chest.2016.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Recent Advances in Bronchoscopic Treatment of Peripheral Lung Cancers
Kassem Harris MD1,2, Jonathan Puchalski MD3, Daniel Sterman4 Roswell Park Cancer Institute, Department Of Medicine, Interventional
Pulmonary section. 2.
Division of Pulmonary, Critical Care and Sleep Medicine, Department of
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Medicine, State University of New York, Buffalo, New York. 3.
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1.
Division of Pulmonary, Critical Care and Sleep Medicine, Interventional
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Pulmonology section, Department of Medicine, Yale University, New Haven, CT, USA. 4.
Division of Pulmonary, Critical Care & Sleep Medicine, Department of
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Medicine, NYU School of Medicine New York, New York.
Corresponding author:
Kassem Harris MD, FCCP
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Roswell Park Cancer Institute Elm & Carlton Streets
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Buffalo, NY 14263
Email:
[email protected]
Running title: Bronchoscopic Treatment of Peripheral Lung Cancers Funding, Conflicts of Interest and Disclosures: No funding was provided for this review. KH is a consultant for Cook Medical.
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JP has no conflict of interest. DS is a consultant for Olympus Medical, Broncus Technologies, CSA Medical Spiration, Pinnacle Biologics, Ethicon Endosurgical/Johnson & Johnson, and Uptake Medical, Inc.
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Word counts: 4406
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Abbreviations List: CP-EBUS: Convex probe Endobronchial ultrasound
EMN: electromagnetic navigational systems FCFM: fibered confocal fluorescence microscopy HDR: high-dose rate
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NSCLC: non-small cell lung cancer
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PDT: Photodynamic therapy RFA: Radiofrequency ablation
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EBUS-TBNA: endobronchial ultrasound-guided transbronchial needle injection
RP-EBUS: radial-probe endobronchial ultrasound
RTRT: “real-time” tumor tracking radiation therapy
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SBRT: stereotactic body radiotherapy
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ABSTRACT: The detection of peripheral lung nodules is increasing due to expanded use of computed tomography (CT) and implementation of lung cancer screening recommendations.
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Although surgical resection of malignant nodules remains the treatment modality of choice at present, many patients are not surgical candidates, thus prompting the need for other therapeutic options.
Stereotactic body radiotherapy (SBRT) and percutaneous
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thermal ablation are emerging as viable alternatives to surgical resection. For safety, efficacy, and cost-effectiveness purposes, however, alternative bronchoscopic methods
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for treatment of peripheral lung cancer are currently under active exploration. We searched the Cochrane Library and Medline from 1990 to 2015 to provide the most comprehensive review for bronchoscopic treatment of malignant lung nodules. We used the following search terms: bronchoscopy; lung nodule; peripheral lung lesion; and
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bronchoscopic treatment. We focused on peripheral pulmonary nodules that are confirmed or highly likely to be malignant. Seventy-one articles were included in this narrative review. We provide herein an overview of advanced bronchoscopic modalities
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that have been utilized or are under active investigation for definitive treatment of malignant pulmonary nodules. We concisely discuss the use of direct intratumoral
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chemotherapy or gene therapies, transbronchial brachytherapy, bronchoscopy-guided radiofrequency ablation, placement of markers to guide real time radiation and surgery, cryotherapy and photodynamic therapy. We also briefly report on emerging technologies such as vapor ablation of lung parenchyma for lung cancers. Advances in bronchoscopic therapy will bring additional treatment options to patients with peripheral lung malignancies, with putative advantages over other minimally invasive modalities. 3
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INTRODUCTION: The National Lung Screening Trial (NLST) enrolled 53,454 subjects at high risk for lung cancer to investigate whether low-dose chest computed tomography (CT)
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decreases mortality from lung cancer. Twenty five percent of patients in this trial were
found to have lung nodules. It demonstrated that screening of high-risk individuals with low-dose chest CT led to a 20% decrease in lung cancer-specific mortality and 6.7 % in
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all cause mortality, compared to those screened with standard chest radiographs. Given
these findings, more peripheral lung nodules will be identified than ever before, although
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the vast majority (96.4%) of these will be benign in etiology.1
The need to accurately biopsy these lesions while minimizing risks has brought about an emergence of new bronchoscopic modalities that lead to higher diagnostic yields than conventional bronchoscopy. Coupled with advances in therapies, many of which can be
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delivered through the bronchoscope, we are upon a new era in which bronchoscopy may be used to not only diagnose early-stage lung cancer, but also to potentially treat it. In this review, we focus on peripheral pulmonary nodules that are confirmed or
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highly likely to be malignant. We searched the Cochrane Library and Medline from 1990 to 2015 to provide the most comprehensive review and propose roles for bronchoscopic
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treatment of malignant lung nodules. We used the following search terms: bronchoscopy; lung nodule; peripheral lung lesion; and bronchoscopic treatment. The aim of this article is to review current and emerging bronchoscopic technologies used for the treatment of peripheral lung cancers.
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BRONCHOSCOPIC APPROACHES FOR DIAGNOSING PERIPHERAL LUNG NODULES: Bronchoscopic modalities include the use of electromagnetic navigational systems
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(EMN), radial-probe endobronchial ultrasound (RP-EBUS), guide sheaths, thinner and more maneuverable bronchoscopes, as well as advanced imaging and virtual bronchoscopy.
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Other new techniques include optical coherence tomography (OCT), fibered confocal fluorescence microscopy (FCFM) and transparenchymal tissue sampling. OCT
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uses the backscattering of light to attain cross sectional images of tissue.2 FCFM obtains real-time images with a 1 mm fiberoptic probe and identifies structural properties of bronchial and alveolar tissue at 9-12 frames/second.3 More recently, Herth et al. reported a transparenchymal nodule access (BTPNA) approach to create a tunneled tract from the
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airway wall to the targeted nodule.4
Although all these technologies improve navigation and imaging of the peripheral lung nodules, the diagnostic yield remains lower than anticipated.5 Obtaining a diagnosis is
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crucial prior to providing bronchoscopy therapy for peripheral lung cancers. Significant improvement in the overall diagnostic yield of guided and navigational bronchoscopic
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approaches is needed before conducting larger trials of bronchoscopic treatment for peripheral lung nodules.
THE
BRONCHOSCOPIC
PLACEMENT
OF
MARKERS
TO
ASSIST
RESECTION OR RADIOTHERAPY:
2
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Surgical resection remains the treatment of choice for early-stage lung cancer. Alternatives include percutaneous image-guided therapies, as well as radiation therapy, particularly stereotactic body radiotherapy (SBRT). Currently, SBRT is considered the
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non-surgical standard of care for treating early-stage peripheral lung cancers. It has a low complication rate with similar overall mortality compared to lobectomy or sublobar resection.6 A recently published article suggested that SBRT could be a reasonable
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therapeutic option for operable stage I lung cancer.7 This study was limited by small sample size, wherein 58 patients were randomized to either SBRT (31 patients) or
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surgery (27 patients). The overall survival was better in the SBRT group, but larger randomized trials are needed to confirm these findings. Patients who are considered for local non-surgical treatment such as SBRT or other ablative therapies should be evaluated for both mediastinal and hilar nodal involvement, particularly the N1 lymph node
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stations. In a large retrospective study by Ong et al., patients with N0 lymph node station by CT and positive emission tomography (PET) were evaluated by convex probe endobronchial ultrasound (CP-EBUS).8 Out of 220 patients included in this study, the
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nodal staging was upgraded in 49 patients (22.3%) of patients. Eighteen of these patients were upstaged by CP-EBUS and the others by surgery, some at stations beyond the reach
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of CP-EBUS (stations 5 and 6). Despite an overall higher than expected false negative rate of 14.1% in this study, CP-EBUS remains the most useful modality to evaluate patients with radiographic N0 nodal staging, especially when non-surgical treatments are intended.
Bronchoscopy may serve an adjunctive role in minimally-invasive surgical techniques or in guiding focused radiotherapy. In these cases, bronchoscopy may be used 3
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in combination with the above navigational strategies to place markers in the target lesion. Bronchoscopic methods may ultimately prove safer than transthoracic methods to mark these lesions pre-operatively, as there may be a lower risk of pneumothorax, a
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significant concern in the medically-inoperable patient with underlying lung disease. 9-13 Newer planning technologies such as cone-beam and 3- or 4-dimensional radiotherapy have the ability to compensate for respiratory motion by gating during
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inspiration and expiration, and therefore obviate the need for fiducial markers. Fiducials are objects that are placed into or adjacent to a targeted lesion and used as a reference in
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the imaging field. In fact, fiducial markers may actually worsen planning by creating significant artifact and affecting the dose delivery to the targeted lesion.14,15
BRONCHOSCOPIC THERAPEUTIC OPTIONS FOR MALIGNANT LUNG
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NODULES:
Various bronchoscopic techniques have been used to treat central endobronchial tumors. These include, but are not limited to, heat modalities (argon plasma coagulation,
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electrocautery, laser phototherapy), cold modalities (cryotherapy), or the direct injection of chemotherapeutic agents.
New modalities are being investigated in ex vivo
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experiments with promising results. These thermal and non-thermal interventions, and variations of these techniques, are now being evaluated for the treatment of peripherally located lung tumors using the advanced diagnostic techniques already described. Direct tumor injection of chemo- or gene therapies Intratumoral injection of chemotherapeutic agents via a needle catheter system theoretically provides a directed means of anti-neoplastic therapy that enables higher 4
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intratumoral drug levels while minimizing systemic toxicity.16 For example, Jabbardarjani and colleagues conducted a study of bronchoscopic cisplatin injection with the goals of tissue debulking and alleviation of associated hemoptysis and post-
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obstructive pneumonia.17 Doses of 50mg/100 ml (4 mg/cm2) were injected weekly into tumors for up to 4 sessions with beneficial outcomes in ~ 80% of treated patients. Celikoglu, et al. used up to 40 mg of cisplatin for direct intratumoral injection into
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endobronchial tumors, observing clinical improvement in 83% of patients.18 In another study, five patients with symptomatic airway obstruction from endobronchial tumors
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were treated using intratumoral cisplatin. In addition, CP-EBUS was used to inject regional lymph nodes with cisplatin to minimize the risk of local recurrence. All tumors responded to therapy, and the procedure was found to be safe with no significant side effects.19 More recently, Khan et al. treated a patient with locally recurrent lung cancer in
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a hilar lymph node with endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) of cisplatin.20 The patient did not develop any complications, and the follow-up positron emission tomography/computed tomography (PET/CT) scan
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confirmed resolution of the fluorodeoxyglucose (FDG) avidity in the hilar node. Mehta et al. recently published a case series of 22 patients who were treated with bronchoscopic
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intratumoral cisplatin for malignant airway obstruction. The treatment was effective in achieving airway recanalization in the majority of patients (71.4%) and with minimal systemic or local toxicity.21 Several other studies have examined the use of other agents for endobronchial chemotherapy, as shown in Table 122-26, including bleomycin, methotrexate, fluorouracil and others. Although these were more centrally located tumors, the same treatment may 5
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conceptually be applied to peripherally-located lesions identified using the advanced bronchoscopic modalities previously described. Hohenforst-Schmidt et al. performed a pre-clinical experiment in murine models wherein tumors were implanted into the hind
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legs of mice. This study involved intratumoral cisplatin administration with and without microwave ablation to assess the synergistic effects of targeted thermal ablation with intralesional cytotoxic chemotherapy administration. Lipiodol, which is an oil-based
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agent, was also used to enhance drug penetration and diffusion within the tumor. In this pre-clinical study, however, the mouse cohort that received the combination of lipiodol,
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cisplatin, and microwave ablation had the most toxicity and the shortest survival 27. Another approach for bronchoscopic treatment of lung cancer is the delivery of therapeutic genes – most commonly intratumoral administration of normal (“wild-type”) copies of mutated tumor suppressor genes such as p53 via genetically-modified viral
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vectors. Bronchoscopic delivery of a recombinant adenovirus carrying the wild-type p53 (Adwt-p53) has been investigated in patients with non-small cell lung cancer who have a p53 gene mutation. After monthly injections of Adwt-p53 in 12 patients, 6 (50%) had
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improvement of more than >25% in airway obstruction and 3 (25%) fulfilled criteria for partial response.28 In another study of bronchoscopic gene therapy in lung cancer
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patients, three intratumoral Adwt-p53 injections were combined with 6 weeks of radiotherapy up to 60 Gy. All patients had follow up with bronchoscopy and chest CT imaging, with 63% of patients demonstrating biopsy-proven non-viable tumor on biopsy. 29
These and other studies of bronchoscopic gene delivery in central tumors provide the
rationale for combining wtp53 injections with radiation or other forms of therapy to improve treatment of p53-mutated lung cancers in the periphery of the lung parenchyma. 6
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Transbronchial Brachytherapy for Peripheral Lung Cancer Brachytherapy, a technique that involves localized intratumoral irradiation, has
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been utilized extensively in lung cancer patients. The procedure can be performed by direct implantation of radioactive seeds within or adjacent to a tumor using CT- or ultrasound guidance, or delivery of these seeds via an afterloading catheter inserted
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through the working channel or parallel to the flexible bronchoscope.30 In one paper, high-dose rate (HDR) transbronchial brachytherapy was used to treat two patients with
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peripheral lung cancers.31 Under moderate sedation, a cytology needle with the tip removed was advanced to the visceral pleura and high resolution CT imaging was utilized to verify the location. Barium (0.2 ml) was injected into the peripheral bronchus, allowing fluoroscopic guidance for placement of an applicator carrying a dummy source
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(Figure 2). Frontal and lateral X-rays provided coordinates for the brachytherapy planning software, PLATO-BPS (Planning Treatment Optimization-Brachytherapy Planning System, version 13.3). Seven days later, the applicator with dummy source was
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re-inserted bronchoscopically, confirmed fluoroscopically, and iridium-192 was inserted using the HDR afterloading system. Three fractions were delivered at one-week intervals
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with a radiation dose of 24 Gy at a 10 mm radius from the center of the applicator. The tumor size remained unchanged at 18 months follow-up. For the second patient, 15 Gy of radiation was administered in one dose via bronchoscopic HDR brachytherapy with a consequent 75% decrease in tumor size.31 Endoluminal
brachytherapy
has
also
been
used
in
conjunction
with
guided/navigational bronchoscopic approaches such as RP-EBUS and EMN. In one 7
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report, EMN with a dedicated catheter was used to localize a peripheral lung cancer, and RP-EBUS confirmed location at the lesion. A 6-Fr brachytherapy catheter was then inserted and brachytherapy planned by using CT 3D reconstruction with the catheter in
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place. HDR brachytherapy was performed using iridium-192 at a boost of 5 Gy three times weekly. At 12-month follow-up, there was a partial radiographic response as
biopsy specimens.32
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Bronchoscopy-Guided Radiofrequency Ablation
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determined by chest CT and RP-EBUS, with complete histopathological response in the
Radiofrequency ablation (RFA) uses an electromagnetic wave with a frequency band similar to that of a high-frequency surgical scalpel and an interchange radiofrequency electric current. Percutaneous image-guided thermal ablation of stage I-II
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non-small cell lung cancer (NSCLC) has been described using this technique (Figure 3). In one study, “technical failure” was encountered in 37.5% of patients receiving CTguided RFA, while 20% had “major complications,” including hemothorax and
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bronchopleural fistula.33 The most frequent complication of RFA performed by the percutaneous technique was pneumothorax, reported between 10% and 57% of cases.
In some patients with advanced underlying lung disease with peripheral lung cancers,
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36
34-
the risks of percutaneous RFA ablation may be more acceptable than those of standard external beam radiation therapy (EBRT) or surgical resection.37 The role of thermal ablation for lung cancer treatment has been recently elucidated by Jahangeer et al.38 in a thorough review.
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In addition to RFA, percutaneous microwave ablation has been described. In one series, a favorable treatment response - defined as a significant decrease in tumor size on chest CT scans -was reported in the majority of the 56 treated patients at 3- and 6- month
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follow up with 64 and 71 % decrease in maximum diameter respectively. In this study, however, 18 of the 56 patients (32%) treated with percutaneous microwave ablation of peripheral lung cancer developed pneumothoraces. 39
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Given the demonstrated anti-tumor effects of percutaneous RFA and microwave ablation of peripheral lung tumors, and the hypothesis that endobronchial approaches
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have a lower pneumothorax rates than transthoracic techniques, there have been concerted efforts to develop ablation technologies that can be delivered through the working channel of a flexible bronchoscope. In one study in healthy sheep, a standard, non-cooled RFA electrode was compared to an internal-cooled RFA probe.
It was
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determined that the ideal settings for the cooled-RFA were a power output of 30 W and a coolant flow rate of 30-40 ml/min. In addition, it was noted that the temperature of the electrode necessary for ablation of non-neoplastic lung tissue in the ovine model was 50
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degrees Celsius (C).40 The use of non-coolant RFA resulted in rapid necrosis formation around the catheter tip. This resulted in increase tissue impedance preventing appropriate
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necrosis of the targeted tumor. Cooling prevents the tissue temperature around the tip from reaching excessive temperatures, thus allowing wider zones of ablation with the same power output.
The technology of cooled-RFA probes for the ablation of lung tissue has been extended to humans. A total of 10 patients with stage IA lung cancer was treated using 9
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bronchoscopy-guided, internally-cooled RFA probes inserted within the tumors utilizing CT imaging guidance in advance of planned surgical resection.41 The investigators used a single 20-Watt power output with three types of catheters (5, 8 and 10 mm active tips) for
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RFA. The internal cooling lumen was infused with water at 4°C and 50 ml/min flow rate. Post RFA, all patients underwent surgical resection as planned, with close histopathological examination of the entire specimen, including the treated zone. A
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maximal ablated area of 12 mm x 10 mm, determined by demonstration of coagulation necrosis and destruction of alveolar space, was achieved using the 10 mm catheter tip
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with 5 beads and a total ablation time of 50 seconds. Ablation using the 5 mm catheter tip for 30 seconds or the 8 mm catheter tip for 40 seconds resulted in smaller ablated tumor areas. The coagulation necrosis area increased with larger tips and longer ablation times, but the resected tissue contained residual tumor cells in all patients. Except for two
pneumothorax.
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patients with mild chest pain, there were no complications such as bleeding or
In a follow-up report by the same group in Japan, two patients with medically
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A cooled-tip bronchoscopic ablation catheter with a 10-mm beaded end
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guided RFA.
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inoperable small peripheral lung cancers were successfully treated using bronchoscopy-
was used, with application of up to 50 W energy and temperature regulation not exceeding 70°C. The catheter was cooled using cold water at 4°C, which was infused into the internal lumen of the catheter at a continuous rate. This was the first description of longitudinal follow-up of bronchoscopic RFA in patients with peripheral lung cancer. In one patient, the peripheral lung cancer recurred at the treated site after 4 years and was 10
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retreated with bronchoscopic RFA and remained stable at 12 months of follow up. In the second patient, the treated peripheral lung cancer remained stable at 40 months of follow
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up. In their most recent paper, Koizumi et al. treated 23 peripheral lung lesions in 20 patients with early-stage NSCLC using CT-guided bronchoscopy cooled radiofrequency
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ablation.43 Local disease control was achieved in most patients (82.6%), and there were no reported serious complications. Three of the treated patients developed fever and chest
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pain and were managed conservatively with short-term hospitalization. Interestingly, the 5-year survival in these treated patients was 61.5%, which compares favorable to the 5year survival rates of less than 50% reported in early-stage cancers treated with SBRT. 4446
Given these recent efforts, it is plausible that RP-EBUS or EMN may have a potential
role in guiding radiofrequency ablation for lung cancers in patients who are not surgical
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candidates.47 Because of the putative significantly lower rates of complication – most notably decreased incidence of pneumothoraces, the bronchoscopic techniques used to
technologies.
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treat peripheral lung cancer with RFA probes may be favored over percutaneous RFA
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Bronchoscopically Placed Markers for Real-Time Radiation Therapy Various forms of radiation therapy have been implemented in the treatment of
lung cancer, including endobronchial radiation (brachytherapy, described above), conventional EBRT (low doses delivered in repeated sessions), and stereotactic radiotherapy (high doses of radiation applied in few sessions). In an effort to reduce uncertainties in organ motion and set-up error in external radiotherapy while minimizing 11
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toxicity to surrounding tissue, “real-time” tumor tracking radiation therapy (RTRT) was studied using bronchoscopically-placed gold markers placed into or adjacent to the target lesions. The 3-dimensional position of these markers was detected using two sets of The radiation treatment beam
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fluoroscopy images obtained every 0.03 seconds.
irradiated the tumor only when the marker coincided with its planned position using realtime imaging. The gold fiducial markers were successfully placed in the majority of the
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peripheral lung cancers (14 out of 16), but in none of the four centrally-located lung tumors. RTRT was possible in 13 of these 14 tumors. The overall RTRT success rate
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was 13 out of 20 tumors (65%). The study had a short median follow-up period of nine months, but local control was achieved in all successfully treated patients. Importantly, complications from radiation therapy were reduced using this guided technique.48 Stereotactic radiosurgery is an available option for patients who are unfit for
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surgical resection.49,50 The robotic device may require fiducial marker placement in or close to the target lesion to be able to compensate for changes related to respiratory variation and to precisely ablate the tumor. When performed percutaneously under CT-
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guidance, fiducial placement has a pneumothorax rate of 30%.50 When placed bronchoscopically, the pneumothorax rate is lower (0 to 6%).51-53 After bronchoscopic
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fiducial placement, a thin-cut chest CT scan is obtained and planning acquires tumor volume while treatment minimizes radiation to other intrathoracic structures (Figure 4). In one recent case series, stereotactic ablative body radiotherapy was used to treat 40 patients with a median nodule size of 2.6 cm. With a 3-year follow-up, they reported a favorable outcome compared to historical studies of wedge resection for the treatment of high-risk patients with stage I non-small cell lung cancer.54 12
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Cryotherapy Cryotherapy is the therapeutic local destruction of living tissue using intense cold (Figure 5). Bronchoscopic cryotherapy probes, which are typically cooled to -40°C, are
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sequentially applied to endobronchial lesions, inducing several cycles of cooling and thawing, and resulting in tumor necrosis.30 Some investigators have described using catheters that are cooled to around -165°C with tumor freezing times of 3 to 5 minutes
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followed by thawing.55 Unlike heat modalities that impart a risk of endobronchial fire, cryotherapy can be safely performed in high oxygen settings. Wang et el., published a
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large study on treating thoracic malignancy with percutaneous cryotherapy (PCT) using a 3 mm cryoprobe. The investigators enrolled 187 patients with 234 masses of which 196 were primary lung cancers.56 Of the 143patients with advanced stage lung cancers, most (89%) had previously undergone treatment with surgery and/or chemoradiation. 166 lung
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masses were peripheral with mean size of 4.3 cm and 68 masses were centrally located with mean size of 6.4 cm. Most tumors (76%) received a single PCT and the therapeutic response was satisfactory with 86% of tumors demonstrating reduced or stable size.56 In
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this study, complications included a 12% pneumothorax rate, brachial and recurrent laryngeal nerve damage in two patients, and procedure-related death in two other
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patients. In a retrospective study of 22 patients with 34 tumors treated with percutaneous cryoablation for non-operable stage I NSCLC, 2- and 3-year disease-free survival of 78% and 67% was reported. The complication rate was significant, however, as 28% of patients developed pneumothorax, 31% developed pleural effusions, and 24% had hemoptysis.57 There were no procedure-related deaths. Moreover, cryotherapy in combination of brachytherapy and percutaneous implantation of controlled-release drugs 13
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has been reported to be safe and effective for the treatment of lung cancer.55,58,59 A recent study of 625 patients with non-operative NSCLC showed 1, 2 and 3- year survival rates of 64%, 45% and 32% respectively. The investigators of this study noted the possibility
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that cryotherapy can also stimulate the immune system to trigger anti-tumor effects in 60
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Although the disease-free survivals for patients undergoing percutaneous cryoablation of lung cancer are encouraging, the high rate of complications from breaching the pleural
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surface imparts a theoretical advantage of bronchoscopic cryotherapy for peripheral lung cancers. In this scenario, small cryoprobes would be advanced after confirmation of tumor location by RP-EBUS or EMN. The major limitation of this approach would be the depth of penetration of cold delivery to parenchymal tumors via the endobronchial
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probes. Photodynamic Therapy
Photodynamic therapy (PDT) is based on local tumor activation of a
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photosensitizer that is administered systemically (or sometimes topically).61 This activation requires tissue illumination using monochromatic light of a proper wavelength
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(e.g. laser). The light application typically takes place 40-50 hours after photosensitizer injection. After many years of superficial and endoluminal therapeutic application, the use of PDT is currently being applied to parenchymal tumors.62 It is conceivable that special catheters, fibers and photosensitizers can be developed for interstitial PDT to treat various types of solid tumors.63 In rats using a single percutaneous fiber, necrosis appeared at sites of interstitial PDT, without damage to the surrounding lung.
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safety and efficacy of PDT on lung parenchyma was also demonstrated in pigs. Histologic findings revealed areas of necrosis surrounded by a granulation tissue area that was surrounded by normal lung tissue. An energy delivery of 100 J/cm2 led to a 5 mm
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necrotic area and energy of 200 J/cm2 resulted in a 10 mm necrotic area.65
Human application was demonstrated when 9 patients were enrolled to treat peripheral lung tumors using PDT through catheters placed percutaneously under CT
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guidance.66 Depending on tumor size, up to 6 catheters were placed into the tumor. In large tumors, more than one PDT session was conducted. All patients underwent
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histological assessment at 1- and 4-weeks post therapy using CT-guided needle biopsy and/or brush cytology. Seven of the nine patients (78%) demonstrated partial response and no patient had progressive disease at 4 weeks. Two of the nine patients developed pneumothorax with one patient requiring chest tube placement. Bronchoscopic PDT has
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been successfully used for the treatment of distal airway and peripheral cancers. 67,68 The development of thin and flexible laser fibers for illumination of the peripheral tumors using a guidesheath and guided by EMN and RP-EBUS have led to plans for clinical
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trials of PDT using Porfimer Sodium (PhotophrinTM). Other Therapeutic Modalities
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Ferguson et al. investigated a novel bronchoscopic technique that uses vapor
ablation of lung parenchyma for lung lesions in human ex vivo lung model.69 The theory behind this technique is that vapor can easily travel through the airways to the lung parenchyma. After treating ten lungs with different diseases including primary and metastatic lung cancers, they demonstrated that ablation of the lung was uniform and well
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defined to the targeted areas. There were no pleural ruptures or pneumatoceles. It is unclear whether this could reliably treat malignancy.
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Limitations and Future Directions
The development of bronchoscopic treatments for peripheral lung cancers faces significant challenges that stems in part from the slow progression and limited investment
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in new bronchoscopic technologies. SBRT is an effective, non-invasive intervention with a good safety profile, and remains the preferred treatment modality for patients who are
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unfit for surgery, but carries limitations of multiple treatments and significant cost. The downsides of SBRT include risk of radiation pneumonitis and fibrosis, particularly in those medically inoperable patients with underlying interstitial lung disease or other reasons for borderline lung function. In addition, SBRT can cause bronchial stenosis if
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utilized to treat central lesions. SBRT is also limited by the fact that it generally requires 5 daily treatments – much more onerous to patients and families than a single bronchoscopic treatment. In addition, SBRT is expensive with an average of $40.000.00
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for the serial treatments cost including the physician’ fees.70 The population most likely to benefit from bronchoscopic treatment consists of those who are not candidates for
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surgery because of poor lung function or other comorbidities. Bronchoscopic and transthoracic techniques are relatively invasive and must compete with SBRT for effectiveness and safety to justify a place in the management algorithm for peripheral lung cancers. Therapeutic bronchoscopic procedures require sedation or general anesthesia unlike SBRT. In addition current navigational bronchoscopic modalities provide a modest diagnostic yield, which preclude the application of transbronchial 16
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therapy in many of these patients. In comparison, percutaneous ablative techniques for peripheral lung cancers are associated with unacceptably high complication rates – primarily pneumothoraces
- which make such techniques difficult to pursue as an
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alternative to SBRT. It should be clear, however, that many of the bronchoscopic techniques presented in this narrative review are experimental, and require further investigation before proven effective and safe for clinical applications.
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The optimal scenario for successful bronchoscopic treatment of peripheral lung cancers would be to perform the diagnostic, staging, and therapeutic procedures in the
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same setting. This requires successful navigation to the targeted cancer and certainty of the malignant diagnosis with rapid on-site evaluation or frozen section to prevent the unnecessary treatment of non-malignant lesions, as well as for analysis of nodal sampling to exclude treatment of regionally advanced tumors. Emerging techniques such as intra-
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tumoral chemotherapy, immunotherapy, and combinations of both with local ablative technologies, need to be investigated further in early-phase clinical trials to ensure safety
Summary
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and to confirm findings from pre-clinical studies of anti-tumor efficacy and synergy.
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In the past decade, there have been significant advances in technology that are
facilitating the investigation of the therapeutic role of bronchoscopy for early-stage peripheral lung cancer. Through endobronchial ultrasound, electromagnetic navigation, ultrathin bronchoscopy and virtual bronchoscopy, the bronchoscopists’ ability to accurately reach peripheral lesions has markedly improved. Advanced therapies, such as local radiation, heat and cold therapies, and gene-based technologies, have now brought 17
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the capability of potentially curing malignant disease without surgery when combined with the tools used in diagnostic bronchoscopic to localize the tumor. These endoscopic
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same treatment modalities are applied.
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techniques may provide fewer complications than transthoracic approaches when the
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Acknowledgments:
Author contributions: KH, DS, and JP contributed substantially to the review design, data interpretation and writing of the manuscript. KH is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article.
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Financial/nonfinancial disclosures: No funding was provided for this review. KH is a consultant for Cook Medical. JP has no conflict of interest.
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SD is a consultant for Olympus Medical, Broncus Technologies, CSA Medical Spiration,
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Pinnacle Biologics, Ethicon Endosurgical/Johnson & Johnson, and Uptake Medical, Inc.
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Author
Number
(Year)
of
delivered
Patients
(volume)
40
(2000)
Agent
Advanced
Caroplatin 300
7 cases (35%)
bronchogenic
mg
were completely cured and 11
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carcinoma
Swisher et al 23
5
Unresectable NSCLC
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IIIb or IV NSCLC
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(1998)
15
Schuler et al 25 (2001)
5
cases (55%)
showed partial recovery
Adenoviral wt
86% of tumors
p53 cDNA (3
showed vector-
or 10 ml)
specific
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(1999)
Schuler et al. 24
Outcome
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Liu et al 22.
Target Lesion
adenovirus sequences
Adenoviral wt
Vector-specific
p53 cDNA
wild-type p53
(SCH 58500),
RNA sequences
1 ml)
was expressed in 40% of tumors
Unresectable NSCLC
Adenoviral wt
No additional
p53 cDAN
benefit in 31
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(SCH 58500)
patients
(10 ml)
receiving an effective first-
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line
chemotherapy
Griscelli et al
12
Unresectable NSCLC
Beta-
TG5327 (IL-2)
galactosidase
or RSV beta-
activity was
gal (LacZ)
detected in 66% of patients (dose related)
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(2003)
NSCLC
Adenoviral
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for advanced
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Table 1: Studies on intratumoral injection of various antitumor agents via bronchoscopy. Although mostly used for central and endoluminal lesions, new technologies are available
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that allow injection of these agents into peripheral lung lesions.
FIGURE LEGENDS:
Figure 1: A: Navigational bronchoscopy image showing the bronchial tree with airway
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(marked in pink) leading to the peripheral lung nodule in the apical segment of the right upper lobe (white arrow). B: Image showing the tip of the guide sheath proximal to the
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target. The green ball represents the right upper nodule in the apical segment. The red arrow showed the alignment of the guide sheath with the target at 0.3 cm distance. Figure 2: CT-assisted Transbronchial Brachytherapy for Small Peripheral Lung Cancer. a) Peripheral lung lesions (adenocarcinoma). b) A dummy source was inserted into the
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lesion. c) An applicator with a dummy source was stabilized between the pleura and the orifice of a tracheal tube in order to preserve accurate positioning of the radiation center throughout the procedure. d) CT scan after brachytherapy shows radiation fibrosis
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without apparent changes in the surrounding lung tissue. Jpn. J. Clin. Oncol. (2000) 30
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(2): 109-112 (with permission).
Figure 3: Salvage: Postradiation ablation. (A) PET and corresponding axial CT demonstrates a hypermetabolic lesion (black arrows) within the left upper lobe with surrounding radiation change—a difficult lesion to treat surgically. (B) RF electrode within target lesion (black arrow). (C) PET and corresponding axial CT after treatment demonstrating cavity in the region of prior ablation with smooth surrounding 33
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hypermetabolic rim—corresponding to expected postablation changes (black arrows). Semin Roentgenol. 2011 Jul;46(3):224-9 (with permission).
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Figure 4: CyberKnife® Robotic Radiosurgery for Early-Stage Non–Small-Cell Lung Cancer: A, B and C represent an example of radiation dose distribution in axial, sagittal and coronal images of a chest CT scan for a left peripheral lung cancer, respectively. D:
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Beam Configuration. A typical treatment plan for a 13-cm3 NSCLC lesion. Treatment
would deliver 60 Gy in 3 fractions to the 65% isodose level using 60 beams, resulting in a
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V(15) of 4.6%. Clinical Lung Cancer, Vol. 8, No. 8, 488-492, 2007 (with permission).
Figure 5: Cryotherapy for lung cancer. a) Preprocedural (left) and procedural (right) images of a 2-cm primary lung cancer in a patient who was not eligible for surgery show the initial needle placement (arrow). The tip was subsequently advanced to the far tumor
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margin. (b) Left: Image obtained 10 weeks after PCT shows resolution of the cavitary effect that developed (not shown), with a residual parenchymal reaction but a minimal
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underlying soft-tissue component. Right: Image obtained 6 months after PCT shows nearly complete resolution of the parenchymal reaction and minimal residual scarring.
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Radiology 2005; 235:289–298 (with permission).
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