World Association for Bronchology and Interventional Pulmonology (WABIP) guidelines on airway stenting for malignant central airway obstruction

Malignant Central Airway Obstruction (MCAO) encompasses significant and symptomatic narrowing of the central airways that can occur due to primary lung cancer or metastatic disease. Therapeutic bronchoscopy is associated with high technical success and symptomatic relief and includes a wide range of airway interventions including airway stents. Published literature suggests that stenting practices vary significantly across the world primarily due to lack of guidance. This document aims to address this knowledge gap by addressing relevant questions related to airway stenting in MCAO. An international group of 17 experts from 17 institutions across 11 countries with experience in using airway stenting for MCAO was convened as part of this guideline statement through the World Association for Bronchology and Interventional Pulmonology (WABIP). We performed a literature and internet search for reports addressing six clinically relevant questions. This guideline statement, consisting of recommendations addressing these six PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with expert experience when necessary. Panel members participated in the development of the final recommendations using the modified Delphi technique.


INTRODUCTION
Malignant Central Airway Obstruction (MCAO) is defined as a significant and symptomatic narrowing of the trachea, mainstem bronchi or the bronchus intermedius by a neoplastic process.While MCAO can be due to metastasis from various extrathoracic cancers, it is mainly seen in primary lung cancer.The estimated prevalence of MCAO at the diagnosis of lung cancer is 13%, with an additional 5% of patients developing it during follow-up. 1Airway invasion from oesophageal or thyroid cancer, lymphoma or metastasis from extra-thoracic malignancies may also cause MCAO.3][4] Patient presentations may range from mild shortness of breath to respiratory failure.Therapeutic bronchoscopy is associated with a high technical success in recanalizing a narrowed central airway, which often results in improvement of quality of life and symptoms. 2echanistically, MCAO can be caused by tumour that is purely extrinsic and compressing the airway, endoluminal (or intrinsic) or of mixed morphology. 5The type of obstruction affects bronchoscopic management, including the decision to stent.
Airway stents are primarily composed of silicone, metal or a combination of the two.Patients with symptoms or signs attributable to MCAO, such as dyspnoea, retained secretions or post-obstructive pneumonia, are usually stented after debulking endobronchial disease, if there is significant residual stenosis post debulking or if there is significant extrinsic airway compression.'Significant' stenosis is usually defined as narrowing exceeding 50%, 6 however, flow dynamics studies suggest that pressure drops across a stenosis have only been noticed to significantly increase when the stenosis exceeds 70%. 7Published literature suggest that stenting practices vary significantly across the world. 8This is primarily due to the lack of guidance in this space.Despite over 30 years of experience with airway stenting, 6 there are no large randomized, comparative trials of airway stenting in MCAO, and there are no guidelines or consensus statements.Published data are largely from retrospective and single-centre studies.
This document aims to address this knowledge gap by addressing relevant questions related to airway stenting in MCAO.Throughout this manuscript, the use of the term "metallic" stents refers to either partially covered or covered metallic stents, and not uncovered stents.Our recommendations, while potentially relevant to other patient populations, may not be extrapolated to non-malignant CAO and to MCAO in children, as these are distinct clinical entities.Throughout this document, recommendations and remarks for airway stenting for MCAO pertain to only those in whom airway stenting is 'indicated': such as those who are symptomatic from MCAO 6,7 of extrinsic or mixed morphology or those with recurrent intrinsic MCAO.The management of MCAO of intrinsic morphology, with therapeutic bronchoscopy using ablative or mechanical techniques, is beyond the scope of this document.We acknowledge that decisions on airway stenting often involve a complex interplay of patient and proceduredependent factors, and the extrapolation of our recommendations to a patient's unique scenario requires careful evaluation by qualified healthcare professionals.

Literature search
We used expert opinion to formulate six questions relevant to the use of airway stenting for the management of patients with MCAO.Questions were formulated using the patient, intervention, comparison and outcome (PICO) format.An electronic search of Medline (PubMed interface) was executed employing keywords "stent" OR "stenting" AND "airway obstruction" OR "tracheal stenosis" OR "bronchial stenosis" OR "laryngotracheal stenosis" OR "airway obstruction" AND "bronchoscopy" OR "airway obstruction" AND "stent" OR "malignant airway obstruction" OR "surveillance" OR "follow up" AND "airway obstruction" AND "stent," between 1985 and the present time (16 September 2022), applying an English language filter.A total of 5389 studies were returned using the above search strategy.Relevant studies including adult patients were evaluated based on the predefined questions.A total 315 full texts were evaluated, including manuscripts as well as their references, of which 77 articles were included in our final recommendations (Figure 1).We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to summarize relevant evidence and develop recommendations for clinical practice 9,10 (Table 1).We use expert consensus to grade recommendations for which no corresponding evidence was available.This approach incorporates two components-the strength of the recommendation and the certainty of the evidence.Summary of evidence tables for recommendations for the PICO questions is provided in Appendix in the Supporting Information.

Consensus methodology
A core writing group (UC, AA, JK, RO and SM) first drafted distinct statements and recommendations based on the table of evidence.The document was then circulated among all panel members, inviting both opinion and any additional recommendations.The panel included 17 pulmonologists with experience in using airway stenting for MCAO, from 17 different institutions in 11 countries.The document was revised based on comments from all members.The revised document was then shared with all members and subsequently discussed during a conference call with 88% participation.During the conference call, individual suggestions were reviewed and incorporated in real-time.The modified Delphi technique, a widely accepted method for the development of consensus among experts, was used to generate consensus. 11,12As part of this process, a priori decision was made to conduct up to three rounds of anonymous voting or until consensus was achieved for each question, whichever came first.The survey incorporating the questions and revised recommendations was sent to all panel members.The panel independently and anonymously rated the appropriateness of the recommendations on a fivepoint Likert scale.Consensus was defined a priori as agreement at ≥70% (4 or 5 on the Likert scale) with a minimal response rate of 80%.The results of the survey were tallied and reported to the group.There was 100% survey participation from the members and consensus was achieved on all recommendations (Tables 2 and 3).

PICO Question 1
In patients with MCAO, does airway stenting improve quality of life and performance status, compared to no stenting?

Recommendation
In patients with symptomatic MCAO, we suggest that airways stenting be performed to improve quality of life or performance status (Grade 2B).

Remark
There is no difference in outcomes between covered metallic and silicone stents.

Grade of recommendation
Risk/benefit Quality of evidence

Literature Review
Airway stenting in patients with attributable symptoms from MCAO, by re-establishing luminal patency, can lead to an improvement in these symptoms in greater than 90% of patients eligible for the intervention [13][14][15][16][17][18][19][20] The only randomized, controlled trial included 78 patients comparing silicone stenting to no stenting, and reported a longer duration of dyspnoea improvement in the stent group. 21Possibly, due to being able to achieve a larger demonstrable change, patients with worse dyspnoea and a lower functional status may benefit more from an airway intervention. 2A B L E 2 Survey data assessing agreement with recommendation (n = 17).

Recommendations
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree PICO Question 1: In patients with MCAO, does airway stenting improve quality of life and performance status, compared to no stenting?Recommendation: In patients with symptomatic MCAO, we suggest that airways stenting be performed to improve quality of life or performance status (Grade 2B) Small, retrospective studies including fewer than 100 patients have reported an improvement in Eastern Cooperative Oncology Group (ECOG) performance score (by at least 1; from 3-4 to 2), [22][23][24][25] Modified Medical Research Council (mMRC) dyspnoea scale (by at least 1 grade; in 97%), 13,14,24,26,27 oxygenation, [28][29][30][31] forced expiratory volume (FEV 1 ), peak expiratory flow (PEF), 19,25,[32][33][34][35][36] or 6MWD. 33ost studies utilized an endoscopy or operating room to perform the stenting procedure.Sicker patients and those requiring more complicated procedures may be better served by procedures under general anaesthesia in a dedicated procedure or operating room. 37Similar benefits have been reported with both silicone and metallic stents based on inter-study comparisons. 13,22,23,26,38tionale for Recommendations MCAO can cause symptoms ranging from dyspnoea with exertion to shortness of breath at rest, cough, haemoptysis and difficulty clearing secretions which may lead to post-obstructive and recurrent infections.4][15][16][17][18][19][20] It is important, however, to carefully select patients who may benefit from the intervention (i.e., those who have symptoms attributable to the MCAO).In addition, procedural and clinical success are not the same 2 ; opening an airway leading to little viable or poorly perfused parenchyma is likely to lead to no improvements in quality of life or performance status.The choice of airway stenting depends upon numerous institution, patient and providercentric factors and practices vary. 8There is no evidence that either quality of life or performance status will improve more with one stent type compared to another; however, no studies were specifically designed to evaluate for a difference between the two.

PICO Question 2
In patients with MCAO, does airway stenting impact mortality, compared to no stenting?

Recommendation
In patients with MCAO, airway stenting can lead to improvement in survival and therefore, we suggest that it T A B L E 3 PICO questions and recommendations.
PICO Question 1: In patients with MCAO, does airway stenting improve quality of life and performance status, compared to no stenting?Recommendations: • In patients with symptomatic MCAO, we suggest that airways stenting be performed to improve quality of life or performance status (Grade 2B) Remark: There is no difference in outcomes between covered metallic and silicone stents.
PICO Question 2: In patients with MCAO, does airway stenting impact mortality, compared to no stenting?Recommendations: • In patients with MCAO, airway stenting can lead to improvement in survival and therefore, we suggest that it be pursued in the presence of attributable symptoms (Grade 2C) Remark: There is no difference in outcomes between covered metallic and silicone stents.
PICO Question 3: In patients with respiratory failure requiring invasive mechanical ventilation due to MCAO, does airway stenting impact liberation from mechanical ventilatory support?Recommendations: • In patients with respiratory failure requiring invasive mechanical ventilation due to MCAO, we recommend airway stenting be considered, as it may lead to early liberation from ventilatory support (Grade 1C) Remark: Early intervention should be considered in patients with MCAO that causes respiratory failure requiring mechanical ventilation.
PICO Question 4: In patients with MCAO requiring airway stenting, do pulmonary hygiene measures reduce the incidence of stent-related complications, compared to no intervention?Recommendations: • In patients with MCAO requiring airway stenting, we suggest that pulmonary hygiene measures be implemented to reduce the incidence of stentrelated complications (Expert Consensus) Remark: Studies are needed to assess the optimal regimen and efficacy of pulmonary hygiene measures.
PICO Question 5: In patients with MCAO requiring airway stenting, do routine surveillance bronchoscopies reduce the incidence of stent-related complications, compared to only symptom-driven bronchoscopies?Recommendation: • In patients with MCAO requiring airway stenting, we suggest that surveillance bronchoscopies after stenting be performed to detect stent-related complications in asymptomatic patients (Grade 2C) Remark: Studies are needed to determine the ideal time for surveillance bronchoscopies.In the absence of quality evidence, we suggest that the first surveillance bronchoscopy be performed 4-6 weeks after stenting.
PICO Question 6: In patients with MCAO requiring airway stenting, does silicone stenting reduce the incidence of stent-related complications, compared to hybrid metallic stenting (fully or partially covered)?Recommendations: • In patients with MCAO requiring airway stenting, we suggest that either silicone or hybrid metallic stents be used (Grade 2B) Remark: The choice of airway stent should be based on local availability, expertise, patient and airway-related factors.
be pursued in the presence of attributable symptoms (Grade 2C).

Remark
There is no difference in outcomes between covered metallic and silicone stents.

Literature Review
No prospective study has directly compared the impact of airway stenting on survival versus no intervention.Given the acuity of presentation of patients with MCAO that may benefit from airway stenting, ethical and recruitment challenges may limit the feasibility of such trials in the future as well.Approximately 13% of patients with lung cancer have CAO, 1 which is associated with a higher hazard ratio (1.78) of death.Median survival in patients with MCAO is higher when the intervention (not limited to stenting) is successful. 39Survival curves for those who have MCAO that has been successfully intervened upon match those without MCAO. 4The only published randomized, controlled trial (N = 78) of silicone stenting versus no stent was terminated before their target enrollment (170 patients in each arm) and did not demonstrate any survival difference. 21Published data on outcomes of stenting in treatment naïve versus previously treated patients is limited and to date, no study has addressed this question in a comparative prospective study.A subgroup analysis of the SPOC trial, however, showed that in pure endoluminal MCAO, when compared to no stenting, silicone stenting showed a beneficial effect on local recurrence in patients on second or more lines of treatment but not in those recommended for the first line of therapy. 21atients with MCAO who require airway stenting represent a critically ill cohort with a survival likely in the order of months (even with an intervention).In a prospective, multicentre registry, 22% (72 of 326) of patients with stents died within 30 days of the procedure compared to 9.7% (46 of 474) of patients with no stents (p < 0.001) 2 ; patients with Y stents had higher mortality (OR 4.92 for Y stent vs. 1.72 for straight stent).This likely reflects how critical these patients are rather than an untoward complication of airway stenting, although causation cannot be excluded.][42][43] A recent retrospective study of 106 patients comparing survival after airway stenting reported a slightly better survival in the silicone stent group compared to the metallic stent group (5.6 vs. 3.2 months). 44Similar findings were noted in a 78 patients study comparing Y stents made of silicone or metal (Micro-Tech) (median survival 171 vs. 104 days). 45These studies, beyond their design, are limited by not controlling for cancer-type, which is likely one of the most important predictors of long-term patient outcomes.[49][50][51][52][53]

Rationale for Recommendations
Patient survival is dependent on numerous factors including their comorbidities, performance status and cancer type and treatment.The dearth of prospective data to control for these factors makes it hard to demonstrate a direct impact of airway stenting on survival.Extrapolating from retrospective data and our clinical practice, it does seem that the airway intervention impacts survival as many of these patients would not be able to leave the hospital without restoration of airway patency.Successful airway stenting, by improving patient performance status, may allow patients to receive systemic therapy.It is hard to determine how much of the survival benefit could be directly from the airway stenting as opposed to the subsequent antineoplastic therapy that the patient receives.With improving systemic and targeted therapies, it will become even more important to bring the patients to a performance level that makes them eligible to receive these directed treatments.The current limited evidence largely suggests no difference between metallic and silicone stents in regards to survival, but this question has not yet been addressed in prospective comparative trials.The impact of airway stenting on liberating patients from invasive mechanical ventilation, in patients with respiratory failure from MCAO, is discussed separately under PICO 3.

PICO Question 3
In patients with respiratory failure requiring invasive mechanical ventilation due to MCAO, does airway stenting impact liberation from mechanical ventilatory support?

Recommendation
In patients with respiratory failure requiring invasive mechanical ventilation due to MCAO, we recommend airway stenting be considered, as it may lead to early liberation from ventilatory support (Grade 1C).

Remark
Early intervention should be considered in patients with MCAO that causes respiratory failure requiring mechanical ventilation.

Literature Review
The largest study reporting on the success of airway stenting to liberate patients in respiratory failure from invasive mechanical ventilation included 30 patients 41 ; in this study, 93% (28 of 30) of patients were liberated from mechanical ventilation at 48 h.Other smaller studies, predominantly reported as sub-group analyses, report success rates ranging from 50% to 100%, 26,30,47,[54][55][56][57][58][59] with majority being liberated within 24 h of the intervention.Median reported survival in these studies ranged from 30 to 300 days and was better in those in whom the intervention was successful. 41,54,55

Rationale for Recommendations
In patients in respiratory failure from MCAO requiring invasive mechanical ventilation, the small body of published data demonstrates that airway stenting is an effective intervention to liberate patients from the mechanical ventilator.The results can be seen quickly after the intervention, with the majority of patients being liberated within 24-48 h.It is not unreasonable to extrapolate this success to patients requiring non-invasive ventilatory support for their MCAO-attributable respiratory failure. 26MCAO-related respiratory failure requiring invasive mechanical ventilation must be approached as a medical emergency warranting consideration for an intervention, if within the patient's pre-defined goals of care.The high success rate of airway stenting in these patients, however, may not be applicable to those presenting with a more chronic course to their respiratory failure, or those requiring prolonged periods of mechanical ventilation prior to airway stenting.
Despite the reported success, overall survival in these patients continues to remain poor, although in small series, it was several months.With improving systemic chemo, immuno-and targeted therapies, it remains to be seen whether survival will be significantly prolonged in this specific cohort of patients.However, weaning off mechanical ventilation is the first step to bridge patients to cancerdirected therapies or for palliative services for end-of-life care.

PICO Question 4
In patients with MCAO requiring airway stenting, do pulmonary hygiene measures reduce the incidence of stentrelated complications, compared to no intervention?

Recommendation
In patients with MCAO requiring airway stenting, we suggest that pulmonary hygiene measures be implemented to reduce the incidence of stent-related complications (Expert Consensus).

Remark
Studies are needed to assess the optimal regimen and efficacy of pulmonary hygiene measures.

Literature Review
There are no studies directly evaluating the impact of pulmonary hygiene measures on reducing airway stent-related complications.Only one study 60 explicitly reported the regimen used (i.e., normal saline nebulization) after airway stenting.However, given the lack of a control arm, firm conclusions cannot be drawn.

Rationale for Recommendations
Most experts on this panel use saline nebulization as their pulmonary hygiene intervention.Whether normal (0.9%) saline or other more concentrated forms of saline (3% or 7%) are better remains to be determined.Based on anecdotal evidence of higher rates of biofilm and mucus plugging in patients with airway stents who are not compliant with their pulmonary hygiene measures, and given that these carry a very low adverse effect profile, we suggest their use in every patient who undergoes airway stenting for MCAO.In practice, bronchoscopists use a variety of other measures including expectorants (guaifenesin), mechanical techniques (flutter valve) and mucolytics (N-acetyl cysteine-inhaled or oral).There is no published evidence pertaining to efficacy of each of these techniques and formulations, alone or in combination in patients with airway stents.

PICO Question 5
In patients with MCAO requiring airway stenting, do routine surveillance bronchoscopies reduce the incidence of stent-related complications, compared to only symptomdriven bronchoscopies?

Recommendation
In patients with MCAO requiring airway stenting, we suggest that surveillance bronchoscopies after stenting be performed to detect stent-related complications in asymptomatic patients (Grade 2C).

Remark
Studies are needed to determine the ideal time for surveillance bronchoscopies.In the absence of quality evidence, we suggest that the first surveillance bronchoscopy be performed 4-6 weeks after stenting.

Literature Review
The largest study assessing the impact of surveillance bronchoscopies at 4-6 weeks included 134 patients (147 stents). 61Sixty percent of asymptomatic patients were found to have at least one stent-related complication on follow-up bronchoscopy, although, the reported stentrelated complications did not correlate with respiratory symptoms.Another study of 88 patients (47 with cancers; 101 stents) reported a sub-group analysis comparing surveillance bronchoscopy at 2-3 months to 'emergency' bronchoscopy prompted by respiratory symptoms. 62Stent-related complications were noted in 84% (26 of 31) of patients undergoing emergency bronchoscopy and 29% (9 of 31) of asymptomatic patients undergoing surveillance bronchoscopy.Only four asymptomatic-surveillance bronchoscopy patients required a therapeutic intervention.Other studies have used more intense surveillance bronchoscopy regimens 63,64 ; however, in the absence of a comparison (nosurveillance) group, little can be inferred from the reported complication rates.

Rationale for Recommendations
The goal of surveillance bronchoscopies in asymptomatic patients with airway stents is to detect complications such as granulation tissue formation, earlier, at a time when it may be easier to intervene.A disadvantage of reactive interventions (i.e., after patients become symptomatic) is that immediate bronchoscopy for symptom palliation may not be feasible, and many patients may present acutely, occasionally in respiratory distress, requiring hospitalization (e.g., with a mucus plug or migrated stent).Limited published evidence favours the performance of surveillance bronchoscopies.Studies are needed to determine the true benefit of routine surveillance over symptom-driven bronchoscopies, and to determine the optimal time of the initial surveillance.The frequency of surveillance bronchoscopies after the initial surveillance is not standardized and is determined on a case-by-case basis.Institutional practices may vary based on ease of access to bronchoscopy and associated costs.Chest computerized tomography (CT) may detect some airway stent related complications and serve as an alternative to surveillance bronchoscopy.However, the performance of chest CT for surveillance is limited by what seems to be a lower sensitivity and specificity to detect endobronchial pathologies 65 ; under-recognition (e.g., of granulation tissue) or overcalls (e.g., of mucus as endobronchial tumour or granulation) may limit its routine application as a surveillance tool.At the very least, outpatient follow-up to interview and examine the patients, with or without in-office spirometry, should be pursued to determine the need for a bronchoscopy.

PICO Question 6
In patients with MCAO requiring airway stenting, does silicone stenting reduce the incidence of stent-related complications, compared to hybrid metallic stenting (fully or partially covered)?

Recommendation
In patients with MCAO requiring airway stenting, we suggest that either silicone or hybrid metallic stents be used (Grade 2B).

Remark
The choice of airway stent should be based on local availability, expertise, patient and airway-related factors.

Rationale for Recommendations
There is no conclusive evidence that the type of stent affects stent-related complications.Y stents, do however, expectedly migrate less often but may be associated with more mucus plugging.From the published data, is difficult to draw firm conclusions regarding stent-related complications, which in practice, are influenced by other provider (experience, stent choice/availability and sizing) and patient (cough-strength and CAO morphology)-related factors.

CONCLUSIONS AND FUTURE DIRECTIONS
This document intends to offer guidance regarding airway stenting in patients with symptomatic MCAO (Table 3).The strengths of this paper are its methodology, comprehensive literature review of all evidence on this topic and that it includes the opinions and perspectives of experts in the field from 17 institutions across 11 countries.The limitations of this work arise from the poor quality of existing evidence.Therefore, our recommendations are either supported by evidence of low-quality or based on expert consensus.There is only one randomized, controlled trial that assessed the benefits of airway stenting; however, this study could not recruit to the targeted enrollment. 21Ethical considerations, acuity of patient presentation, variability in type, location, extent and severity of MCAO, confounding comorbidities and treatments, as well as ensuring a suitable control group, are just a few of the challenges that researchers have to face when recruiting patients for studies of airway stenting in MCAO.
We expect better longer-term survival in patients with cancers obstructing the central airways due to improving anti-neoplastic therapies.Therefore, in future prospective studies, ability to undergo further anti-neoplastic therapy and ability and ease of subsequent stent removal should be incorporated as an individual or composite endpoint to accurately determine the overall impact of airway stenting in MCAO as part of multi-modal treatment strategies.Additional external beam radiation therapy after airway stenting may improve patient outcomes and survival. 38,43,79However, given the dearth of evidence, this strategy is not standard of practice.
Stent design improvements may lead to lower complication rates.CT and intraprocedural airway measurements suffice for airway stent selection in the vast majority of CAO scenarios.Rarely, morphologically complex stenoses, may benefit from patient-specific three-dimensional (3D) stents.3D printed stents using the patient's CT scan or an airway model have been recently used particularly for benign stenoses, [80][81][82][83] with only a few case reports of use in MCAO. 81,84With advances in technology (including standardization of material and manufacturing), particularly with the availability of on-site 3D printing, in the future, these stents may be used more commonly for complexmorphology MCAO.For a transient stenosis, such as MCAO from a potentially rapidly treatable tumour, biodegradable stents are theoretically appealing.However, the properties (including time to degradation) and complications with these stents must be studied before they are considered for routine use.In a case series of six post-lung transplantation airway stenoses treated with biodegradable stents, four needed further stenting. 85Drug-eluting stents, in principle, may reduce tumour-ingrowth, granulation tissue formation or biofilm formation; however, in-human testing remains to be conducted. 86,87uture studies must strive to demonstrate improvements in patient-centred outcomes, focusing on clinical rather than technical success.In multicentre studies, bronchoscopists should also aim to address comparisons between stent types and pulmonary hygiene measures.Studies should also investigate surveillance protocols including the timing, frequency and impact of follow up clinic visits, imaging (i.e., chest CT) and bronchoscopy in patients who have undergone airway stenting.We anticipate that as further evidence is generated in the current anticancer era, there will be a need to reassess stenting practices periodically, building on the recommendations presented in this manuscript.