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Recent Advances in Chest Medicine |

Recent Advances in Bronchoscopic Treatment of Peripheral Lung Cancers OPEN ACCESS

Kassem Harris, MD, FCCP; Jonathan Puchalski, MD, FCCP; Daniel Sterman, MD, FCCP
Author and Funding Information

aDepartment of Medicine, Interventional Pulmonary Section, Roswell Park Cancer Institute, Buffalo, NY

bDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, State University of New York, Buffalo, NY

cDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Interventional Pulmonology Section, Yale University, New Haven, CT

dDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, NYU School of Medicine New York, NY

CORRESPONDENCE TO: Kassem Harris MD, FCCP, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263


Copyright 2016, The Authors. All Rights Reserved.


Chest. 2017;151(3):674-685. doi:10.1016/j.chest.2016.05.025
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Published online

The detection of peripheral lung nodules is increasing because of the expanded use of CT imaging and implementation of lung cancer screening recommendations. 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 thermal ablation are emerging as viable alternatives to surgical resection. For safety, efficacy, and cost-effectiveness purposes, however, alternative bronchoscopic methods 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 of bronchoscopic treatment of malignant lung nodules. We used the following search terms: bronchoscopy, lung nodule, peripheral lung lesion, and 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 have provided an overview of advanced bronchoscopic modalities that have been used or are under active investigation for definitive treatment of malignant pulmonary nodules. We have concisely discussed the use of direct intratumoral chemotherapy or gene therapies, transbronchial brachytherapy, bronchoscopy-guided radiofrequency ablation (RFA), placement of markers to guide real time-radiation and surgery, cryotherapy, and photodynamic therapy. We have also briefly reported 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.

Figures in this Article

The National Lung Screening Trial (NLST) enrolled 53,454 subjects at high risk for lung cancer to investigate whether low-dose chest CT imaging 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 scanning led to a 20% decrease in lung-cancer-specific mortality and 6.7 % in all-cause mortality compared with patients screened with standard chest radiographs. Given these findings, more peripheral lung nodules will be identified than ever before, although the vast majority (96.4%) of these will be benign.

The need to obtain accurate biopsy samples for 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 delivered through the bronchoscope, we are upon a new era in which bronchoscopy may be used not only to diagnose early-stage lung cancer but also to potentially treat it.

In this review, we focus on peripheral pulmonary nodules that are confirmed or 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 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.

Bronchoscopic modalities include the use of electromagnetic navigational systems (EMNs), radial-probe endobronchial ultrasonography (RP-EBUS), guide sheaths, thinner and more maneuverable bronchoscopes, and advanced imaging and virtual bronchoscopy (Fig 1).

Figure 1
Figure Jump LinkFigure 1 A, Navigational bronchoscopy image showing the bronchial tree with airway (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 target. The green ball represents the right upper nodule in the apical segment. The red arrow shows the alignment of the guide sheath with the target at a 0.3-cm distance.Grahic Jump Location

Other new techniques include optical coherence tomography, fibered confocal fluorescence microscopy (FCFM), and transparenchymal tissue sampling. Optical coherence tomography uses the backscattering of light to attain cross-sectional images of tissue. FCFM obtains real-time images with a 1-mm fiberoptic probe and identifies structural properties of bronchial and alveolar tissue at 9 to 12 frames/s. More recently, Herth et al reported a bronchoscopic transparenchymal nodule access approach to create a tunneled tract from the airway wall to the targeted nodule.

Although all these technologies improve navigation and imaging of the peripheral lung nodules, the diagnostic yield remains lower than anticipated. Obtaining a diagnosis is crucial prior to providing bronchoscopic therapy for peripheral lung cancers. Significant improvement in the overall diagnostic yield of guided and navigational bronchoscopic approaches is needed before conducting larger trials of bronchoscopic treatment for peripheral lung nodules.

Surgical resection remains the treatment of choice for early-stage lung cancer. Alternatives include percutaneous image-guided therapies as well as radiotherapy, particularly stereotactic body radiotherapy (SBRT). Currently, SBRT is considered the nonsurgical standard of care for treating early-stage peripheral lung cancers. It has a low complication rate with overall mortality similar to that of lobectomy or sublobar resection. A recently published article suggested that SBRT could be a reasonable therapeutic option for operable stage I lung cancer. This study was limited by small sample size; 58 patients were randomized to either SBRT (31 patients) or 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 nonsurgical treatment such as SBRT or other ablative therapies should be evaluated for both mediastinal and hilar node involvement, particularly the N1 lymph node stations. In a large retrospective study by Ong et al, patients with N0 lymph node stations by CT and PET scanning were evaluated by convex probe endobronchial ultrasonography (CP-EBUS). Of 220 patients included in this study, the nodal staging was upgraded in 49 patients (22.3%). Eighteen of these patients were upstaged by CP-EBUS and the others by surgery, some at stations beyond the reach 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 nonsurgical 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 in combination with the navigational strategies discussed earlier to place markers in the target lesion. Bronchoscopic methods may ultimately prove safer than transthoracic methods to mark these lesions preoperatively, as there may be a lower risk of pneumothorax, which is a significant concern in the medically inoperable patient with underlying lung disease.,,,,

Newer planning technologies such as cone-beam and three- or four-dimensional radiotherapy have the ability to compensate for respiratory motion by gating during inspiration and expiration and therefore obviate the need for fiducial markers, which are objects that are placed into or adjacent to a targeted lesion and used as a reference in the imaging field. In fact, fiducial markers may actually worsen planning by creating significant artifact and affecting the dose delivery to the targeted lesion.,

Various bronchoscopic techniques have been used to treat central endobronchial tumors. These include, but are not limited to, heat modalities (argon plasma coagulation, electrocautery, laser phototherapy), cold modalities (cryotherapy), or the direct injection of chemotherapeutic agents. New modalities are being investigated in ex vivo experiments, with promising results. These thermal and nonthermal 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.

Intratumoral injection of chemotherapeutic agents through a needle catheter system theoretically provides a directed means of antineoplastic therapy that enables higher intratumoral drug levels while minimizing systemic toxicity. For example, Jabbardarjani et al conducted a study of bronchoscopic cisplatin injection with the goals of tissue debulking and alleviation of associated hemoptysis and postobstructive pneumonia. Doses of 50 mg/100 mL (4 mg/cm2) were injected weekly into tumors for up to four sessions, with beneficial outcomes in about 80% of treated patients. Celikoglu et al used up to 40 mg of cisplatin for direct intratumoral injection into endobronchial tumors, observing clinical improvement in 83% of patients. In another study, five patients with symptomatic airway obstruction from endobronchial tumors 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. More recently, Khan et al treated a patient with locally recurrent lung cancer in a hilar lymph node with endobronchial ultrasonographically guided transbronchial needle injection of cisplatin. The patient did not experience any complications, and the follow-up PET/CT scan confirmed resolution of the fluorodeoxyglucose avidity in the hilar node. Mehta et al recently published a case series of 22 patients who were treated with bronchoscopic intratumoral cisplatin for malignant airway obstruction. The treatment was effective in achieving airway recanalization in the majority of patients (71.4%), with minimal systemic or local toxicity.

Several other studies have examined the use of other agents for endobronchial chemotherapy, as shown in Table 1,,,,, including bleomycin, methotrexate, fluorouracil, and others. Although these were more centrally located tumors, the same treatment may conceptually be applied to peripherally located lesions identified using the advanced bronchoscopic modalities previously described. Hohenforst-Schmidt et al performed a preclinical experiment in murine models in which tumors were implanted in the hind 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 agent, was also used to enhance drug penetration and diffusion within the tumor. In this preclinical study, however, the mouse cohort that received the combination of lipiodol, cisplatin, and microwave ablation had the most toxicity and the shortest survival.

Table Graphic Jump Location
Table 1 Studies on Intratumoral Injection of Various Antitumor Agents Through Bronchoscopy

Although mostly used for central and endoluminal lesions, new technologies are available that allow injection of these agents into peripheral lung lesions.

Adwt-p53 = adenovirus carrying the wild-type p53; IL-2 = interleukin 2; LacZ = bacterial beta-galactosidase gene; NSCLC = non-small cell lung cancer; RSV = Rous Sarcoma Virus.

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 through genetically modified viral 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 (NSCLC) who have a p53 gene mutation. After monthly injections of Adwt-p53 in 12 patients, six (50%) had improvement of more than 25% in airway obstruction and three (25%) fulfilled criteria for a partial response. In another study of bronchoscopic gene therapy in patients with lung cancer, 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 nonviable tumor on biopsy. These and other studies of bronchoscopic gene delivery in central tumors provide the rationale for combining Adwt-p53 injections with radiation or other forms of therapy to improve treatment of p53-mutated lung cancers in the periphery of the lung parenchyma.

Brachytherapy, a technique that involves localized intratumoral irradiation, has been used extensively in patients with lung cancer. The procedure can be performed by direct implantation of radioactive seeds within or adjacent to a tumor using CT or ultrasonographic guidance or delivery of these seeds through an after-loading catheter inserted through the working channel or parallel to the flexible bronchoscope. In one paper, high-dose-rate (HDR) transbronchial brachytherapy was used to treat two patients with peripheral lung cancers. Under moderate sedation, a cytology needle with the tip removed was advanced to the visceral pleura, and high-resolution CT imaging was used 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 (Fig 2). Frontal and lateral radiographs provided coordinates for the brachytherapy planning software, PLATO-BPS (Planning Treatment Optimization-Brachytherapy Planning System, version 13.3, Nucletron Oldelft). Seven days later, the applicator with dummy source was reinserted bronchoscopically and confirmed fluoroscopically, and 192Ir was inserted using the HDR after-loading system. Three fractions were delivered at 1-week intervals 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 through bronchoscopic HDR brachytherapy, with a consequent 75% decrease in tumor size.

Figure 2
Figure Jump LinkFigure 2 CT-assisted transbronchial brachytherapy for small peripheral lung cancer. A, Peripheral lung lesions (adenocarcinoma). B, A dummy source was inserted into the lesion. C, An applicator with a dummy source was stabilized between the pleura and the orifice of a tracheal tube to preserve accurate positioning of the radiation center throughout the procedure. D, CT scan after brachytherapy shows radiation fibrosis without apparent changes in the surrounding lung tissue.Grahic Jump Location

Endoluminal brachytherapy has also been used in conjunction with guided/navigational bronchoscopic approaches such as RP-EBUS and EMNs. In one report, an EMN with a dedicated catheter was used to localize a peripheral lung cancer, and RP-EBUS confirmed location at the lesion. A 6F brachytherapy catheter was then inserted and brachytherapy planned by using three-dimensional CT reconstruction with the catheter in place. HDR brachytherapy was performed using 192Ir at a boost of 5 Gy three times weekly. At 12-month follow-up, there was a partial radiographic response as determined by chest CT scanning and RP-EBUS, with a complete histopathologic response in the biopsy specimens.

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 NSCLC has been described using this technique (Fig 3). In one study, “technical failure” was encountered in 37.5% of patients receiving CT-guided RFA, whereas 20% had “major complications,” including hemothorax and bronchopleural fistula. The most frequent complication of RFA performed by the percutaneous technique was pneumothorax, reported in between 10% and 57% of cases.,, In some patients with peripheral lung cancers and advanced underlying lung disease, the risks of percutaneous RFA may be more acceptable than those of standard external beam radiotherapy or surgical resection. The role of thermal ablation for lung cancer treatment recently has been elucidated by Jahangeer et al in a thorough review.

Figure 3
Figure Jump LinkFigure 3 Salvage: postradiotherapy ablation. A, PET and corresponding axial CT scans demonstrate a hypermetabolic lesion (black arrows) within the left upper lobe with surrounding radiation change—a difficult lesion to treat surgically. B, Radiofrequency electrode within target lesion (black arrow). C, PET and corresponding axial CT images after treatment demonstrating cavity in the region of prior ablation with smooth surrounding hypermetabolic rim—corresponding to expected postablation changes (black arrows).Grahic Jump Location

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 follow-up with 64% and 71% decreases in maximum diameter, respectively. In this study, however, pneumothoraces developed in 18 of the 56 patients (32%) treated with percutaneous microwave ablation of peripheral lung cancer.

Given the demonstrated antitumor effects of percutaneous RFA and microwave ablation of peripheral lung tumors and the hypothesis that endobronchial approaches have 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 noncooled RFA electrode was compared with an internally cooled RFA probe. It was determined that the ideal settings for the cooled RFA probe were a power output of 30 W and a coolant flow rate of 30 to 40 mL/min. In addition, it was noted that the temperature of the electrode necessary for ablation of nonneoplastic lung tissue in the ovine model was 50°C. The use of noncoolant RFA resulted in rapid formation of necrosis around the catheter tip. This resulted in increased tissue impedance, preventing appropriate 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. Ten patients with stage IA lung cancer were treated using bronchoscopy-guided internally cooled RFA probes inserted within the tumors using CT imaging guidance in advance of planned surgical resection. The investigators used a single 20-W power output with three types of catheters (5-, 8-, and 10-mm active tips) for RFA. The internal cooling lumen was infused with water at 4°C and a 50 mL/min flow rate. After RFA, all patients underwent surgical resection as planned, with close histopathologic examination of the entire specimen, including the treated zone. A maximal ablated area of 12 mm × 10 mm, determined by demonstration of coagulation necrosis and destruction of alveolar space, was achieved using the 10-mm catheter tip with five beads and a total ablation time of 50 s. Ablation using the 5-mm catheter tip for 30 s or the 8-mm catheter tip for 40 s 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 patients with mild chest pain, there were no complications such as bleeding or pneumothorax.

In a follow-up report by the same group in Japan, two patients with medically inoperable small peripheral lung cancers were successfully treated using bronchoscopy-guided RFA. A cooled-tip bronchoscopic ablation catheter with a 10-mm beaded end 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 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-up.

In their most recent paper, Koizumi et al treated 23 peripheral lung lesions in 20 patients with early-stage NSCLC using CT-guided bronchoscopic cooled RFA. Local disease control was achieved in most patients (82.6%), and there were no reported serious complications. Three of the treated patients experienced fever and chest pain and were managed conservatively with short-term hospitalization. Interestingly, the 5-year survival in these treated patients was 61.5%, which compares favorably to the 5-year survival rates of less than 50% reported in early-stage cancers treated with SBRT.,,,,,,,,,,,, Given these recent efforts, it is plausible that RP-EBUS or EMNs may have a potential role in guiding RFA for lung cancers in patients who are not surgical candidates. Because of the putative significantly lower rates of complication, most notably a decreased incidence of pneumothoraces, the bronchoscopic techniques used to treat peripheral lung cancer with RFA probes may be favored over percutaneous RFA technologies.

Various forms of radiotherapy have been implemented in the treatment of lung cancer, including endobronchial radiation (brachytherapy, described previously), conventional external beam radiotherapy (low doses delivered in repeated sessions), and stereotactic radiotherapy (high doses of radiation applied in a few sessions). In an effort to reduce uncertainties in organ motion and setup error in external radiotherapy while minimizing toxicity to surrounding tissue, real-time tumor tracking radiotherapy (RTRT) was studied using bronchoscopically placed gold markers in or adjacent to the target lesions. The three-dimensional position of these markers was detected using two sets of fluoroscopy images obtained every 0.03 s. The radiation treatment beam irradiated the tumor only when the marker coincided with its planned position using real-time imaging. The gold fiducial markers were successfully placed in the majority of the peripheral lung cancers (14 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 was 13 of 20 tumors (65%). The study had a short median follow-up period of 9 months, but local control was achieved in all successfully treated patients. Importantly, complications from radiotherapy were reduced using this guided technique.

Stereotactic radiosurgery is an available option for patients who are unfit for surgical resection., 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 guidance, fiducial placement has a pneumothorax rate of 30%. When placed bronchoscopically, the pneumothorax rate is lower (0%-6%).,, After bronchoscopic fiducial placement, a thin-cut chest CT scan is obtained, and planning acquires tumor volume while treatment minimizes radiation to other intrathoracic structures (Fig 4). In one 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 with historical studies of wedge resection for the treatment of high-risk patients with stage I NSCLC.

Figure 4
Figure Jump LinkFigure 4 CyberKnife robotic radiosurgery for early-stage non-small cell lung cancer (NSCLC). A-C, Example of radiation dose distribution in axial, sagittal, and coronal images, respectively, of a chest CT scan for a left peripheral lung cancer. D, Beam configuration. A typical treatment plan for a 13-cm3 NSCLC lesion. Treatment would deliver 60 Gy in three fractions to the 65% isodose level using 60 beams, resulting in a V(15) of 4.6%.Grahic Jump Location

Cryotherapy is the therapeutic local destruction of living tissue using intense cold (Fig 5). Bronchoscopic cryotherapy probes, which are typically cooled to –40°C, are sequentially applied to endobronchial lesions, inducing several cycles of cooling and thawing and resulting in tumor necrosis. Some investigators have described using catheters that are cooled to about –165°C with tumor freezing times of 3 to 5 min followed by thawing. Unlike heat modalities that impart a risk of endobronchial fire, cryotherapy can be safely performed in high-oxygen settings. Wang et al published a large study on treating thoracic malignancy with percutaneous cryotherapy (PCT) using a 3-mm cryoprobe. The investigators enrolled 187 patients with 234 masses, 196 of which were primary lung cancers. Of the 143 patients with advanced-stage lung cancers, most (89%) had previously undergone treatment with surgery or chemoradiation, or both. One hundred sixty-six lung masses were peripheral, with a mean size of 4.3 cm, and 68 masses were centrally located, with a mean size of 6.4 cm. Most tumors (76%) received a single session of PCT and the therapeutic response was satisfactory, with 86% of tumors demonstrating reduced or stable size. In this study, complications included a 12% pneumothorax rate, brachial and recurrent laryngeal nerve damage in two patients, and procedure-related death in two other patients. In a retrospective study of 22 patients with 34 tumors treated with PCT for nonoperable stage I NSCLC, 2- and 3-year disease-free survival of 78% and 67%, respectively, was reported. The complication rate was significant, however, as 28% of patients experienced pneumothorax, 31% experienced pleural effusions, and 24% had hemoptysis. There were no procedure-related deaths. Moreover, cryotherapy in combination with brachytherapy and percutaneous implantation of controlled-release drugs has been reported to be safe and effective for the treatment of lung cancer.,, A previous study of 625 patients with nonoperative NSCLC showed 1-, 2-, and 3-year survival rates of 64%, 45%, and 32%, respectively. The investigators in this study noted the possibility that cryotherapy can also stimulate the immune system to trigger antitumor effects in human lung cancer.

Figure 5
Figure Jump LinkFigure 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 margin. B, Image on left was obtained 10 weeks after percutaneous cryotherapy (PCT) and shows resolution of the cavitary effect that developed (not shown), with a residual parenchymal reaction but a minimal underlying soft-tissue component. Image on the right was obtained 6 months after PCT and shows nearly complete resolution of the parenchymal reaction and minimal residual scarring.Grahic Jump Location

Although the disease-free survival for patients undergoing percutaneous cryoablation of lung cancer is encouraging, the high rate of complications from breaching the pleural surface imparts a theoretical advantage for 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 through the endobronchial probes.

Photodynamic therapy (PDT) is based on local tumor activation of a photosensitizer that is administered systemically (or sometimes topically). This activation requires tissue illumination using monochromatic light of a proper wavelength (eg, laser). The light application typically takes place 40 to 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. It is conceivable that special catheters, fibers, and photosensitizers can be developed for interstitial PDT to treat various types of solid tumors. In rats, using a single percutaneous fiber, necrosis appeared at sites of interstitial PDT without damage to the surrounding lung. The 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 necrotic area, and energy of 200 J/cm2 resulted in a 10-mm necrotic area.

Human application was demonstrated when 9 patients were enrolled in a study to treat peripheral lung tumors using PDT through catheters placed percutaneously under CT guidance. Depending on tumor size, up to six catheters were placed in the tumor. In large tumors, more than one PDT session was conducted. All patients underwent histologic assessment at 1 and 4 weeks after therapy using CT-guided needle biopsy or brush cytology, or both. Seven of the nine patients (78%) demonstrated partial response, and no patient had progressive disease at 4 weeks. Two of the nine patients experienced pneumothorax, with one patient requiring chest tube placement. Bronchoscopic PDT has been successfully used for the treatment of distal airway and peripheral cancers.,

The development of thin and flexible laser fibers for illumination of the peripheral tumors using a guide sheath and guided by EMN and RP-EBUS have led to plans for clinical trials of PDT using porfimer sodium.

John et al investigated a novel bronchoscopic technique that uses vapor ablation of lung parenchyma for lung lesions in a human ex vivo lung model. The theory behind this technique is that vapor can easily travel through the airways to the lung parenchyma. After treating 10 lungs with different diseases, including primary and metastatic lung cancers, they demonstrated that ablation of the lung was uniform and well defined to the targeted areas. There were no pleural ruptures or pneumatoceles. It is unclear whether this could reliably treat malignancy.

The development of bronchoscopic treatments for peripheral lung cancers faces significant challenges that stem in part from the slow progression and limited investment in new bronchoscopic technologies. SBRT is an effective noninvasive intervention with a good safety profile and remains the preferred treatment modality for patients who are unfit for surgery, but it carries limitations of multiple treatments and significant cost. The downside of SBRT includes 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 used to treat central lesions. SBRT is also limited by the fact that it generally requires five daily treatments, which is much more onerous to patients and families than a single bronchoscopic treatment. In addition, SBRT is expensive, with an average of $40,000 for the serial-treatment cost, including physician fees. The population most likely to benefit from bronchoscopic treatment consists of those who are not candidates for 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 precludes the application of transbronchial 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 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 being proved effective and safe for clinical applications.

The optimal scenario for successful bronchoscopic treatment of peripheral lung cancers would be to perform the diagnostic, staging, and therapeutic procedures in the 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 nonmalignant lesions, as well as for analysis of nodal sampling to exclude treatment of regionally advanced tumors. Emerging techniques such as intratumoral chemotherapy, immunotherapy, and combinations of both with local ablative technologies, need to be investigated further in early-phase clinical trials to ensure safety and to confirm findings from preclinical studies of antitumor efficacy and synergy.

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 ultrasonography, EMN, ultrathin bronchoscopy, and virtual bronchoscopy, the bronchoscopist's ability to accurately reach peripheral lesions has markedly improved. Advanced therapies, such as local irradiation, heat and cold therapies, and gene-based technologies, have now brought the capability of potentially curing malignant disease without surgery when combined with the tools used in diagnostic bronchoscopy to localize the tumor. These endoscopic techniques may provide fewer complications than transthoracic approaches when the same treatment modalities are applied.

Author contributions: K. H. is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. K. H., D. S., and J. P. contributed substantially to the review design, data interpretation, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: K. H. is a consultant for Cook Medical. D. S. is a consultant for Olympus Medical, Broncus Technologies, CSA Medical Spiration, Pinnacle Biologics, Ethicon Endosurgical/Johnson & Johnson, and Uptake Medical, Inc. S. D. is a consultant for Olympus Medical, Broncus Technologies, CSA Medical Spiration, Pinnacle Biologics, Ethicon Endosurgical/Johnson & Johnson, and Uptake Medical, Inc. None declared (J. P.).

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Figures

Figure Jump LinkFigure 1 A, Navigational bronchoscopy image showing the bronchial tree with airway (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 target. The green ball represents the right upper nodule in the apical segment. The red arrow shows the alignment of the guide sheath with the target at a 0.3-cm distance.Grahic Jump Location
Figure Jump LinkFigure 2 CT-assisted transbronchial brachytherapy for small peripheral lung cancer. A, Peripheral lung lesions (adenocarcinoma). B, A dummy source was inserted into the lesion. C, An applicator with a dummy source was stabilized between the pleura and the orifice of a tracheal tube to preserve accurate positioning of the radiation center throughout the procedure. D, CT scan after brachytherapy shows radiation fibrosis without apparent changes in the surrounding lung tissue.Grahic Jump Location
Figure Jump LinkFigure 3 Salvage: postradiotherapy ablation. A, PET and corresponding axial CT scans demonstrate a hypermetabolic lesion (black arrows) within the left upper lobe with surrounding radiation change—a difficult lesion to treat surgically. B, Radiofrequency electrode within target lesion (black arrow). C, PET and corresponding axial CT images after treatment demonstrating cavity in the region of prior ablation with smooth surrounding hypermetabolic rim—corresponding to expected postablation changes (black arrows).Grahic Jump Location
Figure Jump LinkFigure 4 CyberKnife robotic radiosurgery for early-stage non-small cell lung cancer (NSCLC). A-C, Example of radiation dose distribution in axial, sagittal, and coronal images, respectively, of a chest CT scan for a left peripheral lung cancer. D, Beam configuration. A typical treatment plan for a 13-cm3 NSCLC lesion. Treatment would deliver 60 Gy in three fractions to the 65% isodose level using 60 beams, resulting in a V(15) of 4.6%.Grahic Jump Location
Figure Jump LinkFigure 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 margin. B, Image on left was obtained 10 weeks after percutaneous cryotherapy (PCT) and shows resolution of the cavitary effect that developed (not shown), with a residual parenchymal reaction but a minimal underlying soft-tissue component. Image on the right was obtained 6 months after PCT and shows nearly complete resolution of the parenchymal reaction and minimal residual scarring.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Studies on Intratumoral Injection of Various Antitumor Agents Through Bronchoscopy

Although mostly used for central and endoluminal lesions, new technologies are available that allow injection of these agents into peripheral lung lesions.

Adwt-p53 = adenovirus carrying the wild-type p53; IL-2 = interleukin 2; LacZ = bacterial beta-galactosidase gene; NSCLC = non-small cell lung cancer; RSV = Rous Sarcoma Virus.

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