Therapeutic bronchoscopy for both endobronchial tumors and peripheral lung cancer is rapidly evolving. The expected increase in early stage lung cancer detection and significant improvement in near real-time imaging for diagnostic bronchoscopy has led to the development of bronchoscopy-delivered ablative technologies. Therapies targeting obstructing central airway tumors for palliation and as a method of local disease control, patient selection and patient-centered outcomes have been areas of ongoing research. This review focuses on patient selection when considering therapeutic bronchoscopy and new and developing technologies for endobronchial tumors and reviews the status of bronchoscopy-delivered ablative tools for peripheral lung cancers.
Key points
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Patients with central airway obstruction should be evaluated by individuals trained in interventional pulmonology to achieve the best outcome based on patient selection and the intended objectives of the procedure.
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Relief of central airway obstruction improves clinically important outcomes such as health-related quality of life, lung function, functional status, and, in some cases, survival. Spray cryotherapy, endobronchial injection of chemotherapy drugs, photodynamic therapy, and monopolar radiofrequency ablation catheter are emerging techniques that may achieve durable treatment responses in the correct patient population.
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Bronchoscopic treatment of peripheral lung cancers is a rapidly evolving area with microwave ablation, radiofrequency ablation, laser, and thermal vapor ablation currently being studied.
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The patient population suitable for endobronchial ablative technologies, both for central and peripheral airway lesions, has yet to be defined.
Introduction
With the advent of lung cancer screening and the increase of incidentally discovered pulmonary nodules, it is expected that the number of early stage lung cancers identified will continue to increase. Current guideline recommendations for the management of early stage lung cancer include surgical resection and stereotactic body radiation therapy (SBRT) for high-risk surgical patients. Percutaneous radiofrequency ablation is also recommended as an alternative to SBRT in selected patients with lesions in a suitable anatomic location and who have met maximal radiation doses in the course of their treatment. Recent developments in percutaneous ablation techniques include cryotherapy and microwave ablation. However, all percutaneous techniques carry a substantial complication rate (pneumothorax, hemorrhage, and hemoptysis), which has hindered widespread adoption. As a result, and in conjunction with the recent explosion of more accurate diagnostic bronchoscopy platforms, some with near real-time imaging and localization, the delivery of bronchoscopy-guided ablation procedures is generating considerable interest, aiming for similar efficacy at a lower complication rate.
In addition, it is estimated that up to 30% of patients diagnosed with lung cancer will initially present with central airway obstruction (CAO). Although surgical resection of the airway tumor is considered the definitive management option, this is often not possible because most patients presenting with an endobronchial mass have advanced stage of disease, poor performance status, complete or partial atelectasis of the affected lung, and are not suitable to undergo an operation. Although most of the endobronchial ablation techniques are used primarily to relieve symptoms of obstruction and improve quality of life (QOL), there is emerging evidence that therapeutic bronchoscopy can also improve survival when used alone or in combination with systemic therapy and is effective at controlling and palliating locally advanced disease.
In this review, the authors attempt to address 5 practical clinical questions that arise when considering therapeutic bronchoscopy for patients with endobronchial tumor or peripheral lung cancer ( Box 1 ). Although many therapies have been around for decades, this review focuses on recent evidence on patient selection, outcomes, and developing technologies in the areas of endobronchial and peripheral lung ablation that would be of interest to the pulmonologist.
What patients benefit from therapeutic interventions to the central airways?
Does relieving CAO improve clinically meaningful outcomes?
What are the new and emerging therapies available for treatment of endobronchial tumors?
What options are available for treatment of peripheral lung cancers by bronchoscopy?
What patients benefit from therapeutic interventions to the central airways?
When considering an endoscopic intervention for CAO, it is of first importance to clearly define the goals of the procedure, as appropriate patient selection will be directly related to these objectives. Is the goal to liberate a patient with CAO from the ventilator? Alternatively, is the objective to relieve dyspnea, clear postobstructive pneumonia, or treat hemoptysis, thus improving performance status and permitting a patient to undergo systemic therapy? Or is the goal to relieve the obstruction and simultaneously provide definitive local treatment of the disease? It is worth pointing out that in the absence of such indications, attempts at endobronchial ablation have inherently little utility.
In clinical practice, it is common for patients with malignant CAO, respiratory failure, and mechanical ventilation to be transitioned to hospice and comfort care without consideration of therapeutic bronchoscopy, and this is particularly true in the absence of dedicated interventional pulmonology (IP) services. With the recent development and accreditation of more than 30 specialized IP training programs in the United States, it is expected that advanced therapeutic bronchoscopy will become increasingly available. It is also incorrectly assumed that patients with advanced lung cancer and CAO have a uniformly poor clinical course and that further intervention would have no impact on QOL or clinical outcome. Published literature contradicts such nihilism. Recent data suggest that CAO adequately managed bronchoscopically may not portend a worse survival prognosis than similarly staged patients without CAO. It is also imperative that patients presenting with acute respiratory failure requiring mechanical ventilation be evaluated for the possibility of rigid bronchoscopy to restore luminal patency. This intervention allows rapid relief of the obstruction, improvement in symptoms, and reduction in the level of care in 71% to 94% of patients. , Although this can be performed with flexible bronchoscopy techniques, rigid bronchoscopy allows a broader range of therapeutic options, better airway control, and safety, as these procedures are often complicated by significant endobronchial bleeding. Therapeutic bronchoscopy should be also considered as a purely palliative intervention, as it was demonstrated to significantly improve QOL even in the terminally ill.
Although external beam radiation therapy (XRT) is often a reasonable option for these patients, bronchoscopic intervention should be attempted when possible before radiation treatment. Although comparative data are sparse, one study of patients who only received radiation therapy and who were mechanically ventilated due to CAO showed that only 27% (7/26) of patients were successfully extubated with time to extubation ranging from 4 to 22 days. In an older study from Desai and colleagues, the survival benefit of laser ablation compared with XRT alone was evaluated using a historical control of patients with CAO who only underwent XRT. Patients who underwent emergency laser ablation had a better survival than those who underwent XRT alone (267 days vs 150 days, P = .04); however, there was no difference in overall survival when patients with nonurgent malignant CAO were analyzed (312 days vs 258 days, P = .44). These patients frequently have coexisting atelectasis or postobstructive pneumonia, which complicates simulation plans by making it difficult to distinguish atelectatic lung from tumor, potentially exposing healthy lung tissue to the toxic effects of radiation. In addition, because these tumors are in central airways, radiation injury to adjacent vascular structures and noninvolved airways are more likely. Because radiation therapy is not immediately effective, rigid bronchoscopy facilitates relief of the obstruction and liberation from mechanical ventilation more quickly than radiation therapy, thus, in theory, reducing the daily incremental risk of ventilator-associated pneumonia. Once the obstruction has been treated bronchoscopically, the lung reinflated, and any postobstructive purulent secretions removed, the patient can then undergo more effective radiation therapy, chemotherapy, or even possibly surgery.
Patient selection is straightforward in most circumstances. There is little doubt that the symptomatic patients with CAO, and either dyspnea, hemoptysis, or, obviously, impending suffocation are prime candidates for therapeutic bronchoscopy, and this approach is supported by current guidelines. Some data suggest that early intervention may improve survival, although this may admittedly represent lead-time bias resulting from the selection of patients with less severe disease and higher performance status. However, patients with minimal symptoms, who are asymptomatic, or who have significantly reduced performance status can be a more challenging situation. Limited data exist to guide the pulmonologist in these types of situations. In general, it is unlikely that a moribund patient with poor performance status will benefit from general anesthesia and therapeutic bronchoscopy. It is also often claimed that once a lobe has been atelectatic for 4 to 6 weeks, the probability of recovery of this lobe is low. In actuality, lung that has been atelectatic for more than 6 weeks is occasionally reexpandable ( Fig. 1 ), although this is difficult to predict until after the time of bronchoscopy. As such, it is important that these patients be evaluated by interventional pulmonologists to ascertain the probable success of an intervention.
Endoluminal obstruction does not necessarily entail that a tumor is unresectable. Based on updated tumor classification (T) for lung cancer staging, a tumor with invasion of the bronchus is classified as T2a tumor regardless of distance from the main carina or if partial or complete atelectasis is observed. As such, if neither lymph node involvement (N0) nor hilar disease is identified (N1), the patient could be classified from stage IB through IIB, assuming no metastatic disease and no features consistent with T3 or T4 status. Thus, proper assessment of staging should be done around the time of the procedure, defining as accurately as possible the location of the tumor in relation to the secondary carinas, main carina, and any mucosal involvement. This intervention and localization will allow the patient the best benefit not only from a symptomatic palliative standpoint but in providing optimal staging to guide therapy.
Recent data have provided more insight into who may benefit from a therapeutic intervention. The multicenter registry AQuIRE investigators reported on the technical success and predictive factors of success and health-related QOL (HRQOL) in more than a thousand therapeutic procedures. They defined technical success of the procedure as greater than 50% recanalization of the airway, which was achieved in 93% of patients with a combination of different techniques (rigid bronchoscopy, flexible bronchoscopy, thermal therapies, and airway stenting). Predictors of success were an endobronchial obstruction and stent placement. Factors associated with failure included an American Society of Anesthesiology (ASA) score of greater than 3, renal failure, tracheal esophageal fistula, left main disease, and primary lung cancer. The greatest improvement in HRQOL occurred in individuals with the highest baseline Borg scores (dyspnea scale), a higher ASA, and higher Zubrod scores (performance status metric). Those least likely to notice an improvement in symptoms were those with lobar obstruction. Interestingly, although greater than 90% of patients had a successful procedure, only 48% noticed an improvement in their dyspnea, implying that technical success does not necessarily translate into clinically meaningful patient-centered outcomes. Complications were low (3.9%), and procedure-specific mortality was less than 1%. Although patients with an ASA score greater than 3 and Zubrod score greater than 1 had a noticeable improvement in their HRQOL following bronchoscopy; they were also the most likely to experience complications.
Does relieving central airway obstruction improve clinically meaningful outcomes?
Although the relief of impending suffocation and liberation from mechanical ventilation are obvious clinical benefits derived from therapeutic bronchoscopy, the benefit is less certain in the minimally symptomatic patient. However, recent data have confirmed that therapeutic bronchoscopy in patients with functional and symptomatic limitations can experience an improvement in lung function, QOL, and survival ( Table 1 ).
| Variables | ||||||
|---|---|---|---|---|---|---|
| Study | Type of Study | HRQOL | Dyspnea | FEV1 | 6-Minute Walk | Survival |
| Chhajed et al, , 2006 | Retrospective | NR | NR | Increased by 0.5 L | NR | 8.4 mo a |
| Ost et al, 2015 | Retrospective, multicenter registry | Δutility,0.023 ± 0.107 b | ΔBorg−0.9 ± 2.2 c | NR | NR | NR |
| Oviatt et al, 2011 | Prospective observational | Improved at days 90, 180 d | Improved at 30, 90, and 180 d e | Increased by 0.4 L at 30 d | Improved by 99.7 m at 30 d | NR |
| Ong et al, 2019 | Prospective observational | Δutility,0.047 (0.23–0.71) b | ΔBorg −1.8 (−2.2 to −1.3) c | NR | NR | 109 quality-adjusted life days |
| Amjadi et al, 2008 | Prospective observational | No improvement in global QOL d | ΔBorg −2.5 c | NR | NR | NR |
| Mahmood et al, 2015 | Prospective observational | Improved at 8 wk f | Improved at 8 wk g | Increased by 0.4 L | NR | 242 d a |
| Stratakos et al, 2016 | Prospective observational | Improvement up to 6 mo c | Improved up to 6 mo c | NR | NR | 10 mo h |
| Venuta et al, 2002 | Retrospective | Improvement noted, P <.001 d | NR | Increased by 0.8 L | NR | 12 mo i |
| Jeon et al, 2006 | Retrospective | NR | Improved in 94% (34/36) j | NR | NR | 38 mo k |
b SF-6D measure used, statistically significant.
c Negative changes in Borg score indicate improved dyspnea, statistically significant.
d European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and lung cancer–specific module (LC13) were used.
e Resting and 6-minute walk test, Borg scale, lung cancer module questionnaire (LC13), and C30 dyspnea scale were used.
g University of California San Diego Shortness of Breath Questionnaire (SOBQ) used.
i Palliation only and no chemotherapy or radiation.
j Dyspnea scale used not reported.
k Reported as median, when combined with chemotherapy ± radiation
In a prospective study by Mahmood and colleagues, 67 patients were observed who had both benign and malignant CAO (defined as a central airway through which a therapeutic bronchoscope [outer diameter 6.3 mm] could not be passed—trachea, right and left mainstem, bronchus intermedius, and lobar bronchi) and who underwent therapeutic rigid bronchoscopy with ablative therapy with or without stent placement. The technical success of the procedure was defined as luminal patency of greater than 50%, which was achieved in 90.5% (43/53). Study subjects performed spirometry, dyspnea, and QOL evaluations (Shortness of Breath Questionnaire [SOBQ] and the Short Form Health Survey questionnaire [SF36]) both pre- and postbronchoscopy. The forced expiratory volume in the first second of expiration and forced vital capacity improved by 0.4 L and 0.5 L, respectively ( P = .002 and P = .009). Patients had improvements in most domains of the SF36 (physical functioning, role limitations—physical health and energy/fatigue). Dyspnea score (SOBQ) also showed a significant improvement (55.8–37.9, P = .002). In addition, overall survival was better in those patients with malignant CAO who underwent successful therapeutic bronchoscopy versus those who had a nonsuccessful intervention with a difference in survival of 114 days (229 vs 115).
Similarly, a study performed by Oviatt and colleagues demonstrated an improvement in 6-minute walk distance of more than 100 m following a therapeutic bronchoscopy that persisted up to 6 months postprocedure. They also observed sustained and clinically significant improvements in dyspnea scores, QOL, and spirometry.
In a detailed study analyzing the magnitude of therapeutic bronchoscopy on quality-adjusted survival, investigators reviewed data on 102 patients with malignant CAO. Median survival was 179 days, and the number of quality-adjusted life days was 109. This effect was maintained from the baseline prebronchoscopy up to and beyond 180 days. Factors that were associated with quality-adjusted survival included better baseline performance status, treatment naive tumor, less baseline dyspnea, follow-up chemotherapy, and endobronchial disease. The investigators highlighted that this improvement in HRQOL was one and half times that observed following placement of indwelling pleural catheters for malignant pleural effusions, an intervention that is widely considered an excellent choice at improving QOL in metastatic malignancy.
High-quality, comparative studies demonstrating improved outcomes with therapeutic bronchoscopy alone or in combination with additional therapies (chemotherapy, radiation, surgery, or other ablative techniques) are lacking. However, the available data do suggest that there may be a potential survival benefit when endobronchial intervention is combined with conventional therapies. For example, in the study mentioned earlier by Ong and colleagues, sustained HRQOL was achieved by a multimodality approach to treatment and resulted in a prolonged control in dyspnea that was originally achieved with bronchoscopy. In a retrospective study by Han and colleagues, 110 patients underwent 153 laser treatments; patients were allocated to 2 groups: laser therapy alone (30 patients) and neodymium:yttrium aluminum garnet (Nd:YAG) laser combined with multimodality therapy (66 patients; stent, chemotherapy, radiation therapy). Median length of survival was longer with multimodality therapy versus single modality therapy (6.99 months vs 3.77 months, P = .002) for all types of malignancies. This was also observed for non-small cell lung cancer, with survival favoring a multimodality approach (7.17 vs 2.27 months, P <.001).
It is clear that therapeutic bronchoscopy improves clinically important outcomes. Dyspnea, hemoptysis, functional status, lung function, HRQOL, and survival can all be positively affected in properly selected patients and, in most instances, via a combination of modalities.
What new and emerging therapies are available for the treatment of endobronchial tumors?
Several therapies, many of which have been around for decades, are available to the pulmonologist when managing an endobronchial tumor ( Table 2 ). These ablative technologies have well-established safety and efficacy profiles for the palliation of malignant CAO. The choice of modality will depend on the size and location of the tumor, provider experience, training, institutional availability, and goals of the procedure.
