Malignant Airway Obstruction and the Use of Nd:YAG Laser: A Systematic Review on Its Efficacy and Safety

Endobronchial malignancies with significant airway obstruction can lead to multiple complications including pneumonia, and atelectasis over a period of time. Various intraluminal treatments have proven their value in palliative treatment for advanced malignancies. Nd:YAG (neodymium-doped yttrium aluminum garnet; Nd:Y3Al5O12) laser has established its role as a major palliative intervention due to its minimal side effects and improvement in quality of life by relieving local symptoms. The systematic review was conducted with the goal of elucidating the patient characteristics, pre-treatment parameters, clinical outcomes, and possible complications resulting from the use of the Nd:YAG laser. A thorough literature search for relevant studies was conducted on PubMed, Embase, and Cochrane Library from the inception of the idea to November 24, 2022. Our study included all original studies including retrospective studies and prospective trials, but excluded case reports, case series with less than 10 patients, and studies with incomplete or irrelevant data. A total of 11 studies were included in the analysis. The primary outcomes focused on the evaluation of pulmonary functional tests, postprocedural stenosis, blood gas parameters after the procedure, and survival outcomes. Improvement in clinical status, improvement in objective scale for dyspnea, and complications were the secondary outcomes. Our study shows that Nd:YAG laser treatment is an effective form of palliative treatment to provide subjective and objective improvement in patients with advanced and inoperable endobronchial malignancies. Due to the heterogeneous study populations in the studies reviewed and the presence of many limitations, more studies are still warranted to reach a definitive conclusion.


Introduction And Background
Endobronchial malignancy (and airway obstruction) is a common problem in small-cell lung cancer, nonsmall-cell lung cancer, and many other tumors that metastasize to the lungs from other parts of the body. The initial presentations of endobronchial malignancies are cough, hemoptysis, and dyspnea, which are distressing to the patients [1]. Among all lung cancer patients, 20-30% will develop complications, e.g., pneumonia, dyspnea, and atelectasis due to endotracheal and endobronchial diseases. Up to 40% of patients develop serious complications even after exhausting all treatment options including stenting, cryotherapy, mechanical dilation, and resection, photodynamic therapy (PDT), chemotherapy, and external beam radiotherapy [2,3]. Given the advancements in endoscopic treatment procedures along with their improved safety and effectiveness, laser treatment has become one of the most important endobronchial treatment procedures. Since the toxicity and side effects of chemotherapy and radiotherapy are very severe, patients seek alternative treatment options even if only for palliative purposes as they are well-tolerated with minimal side effects [4].
Nd:YAG (neodymium-doped yttrium aluminum garnet)-directed therapy for central airway obstruction (CAO) of the lungs has been a well-known treatment modality since the 1980s and has been well-established in the field [5]. It is most commonly used for palliative debulking procedures in metastatic obstructive diseases, where cardiothoracic surgery alone is not a suitable option or is not an option altogether. Initial data regarding the Nd:YAG laser was limited, partly due to the device's technical and mechanical limitations at the time. The 1064 nanometer (nm) wavelength available during the initial period significantly held back the data related to this topic as the laser was not able to provide sufficient cutting and coagulation capabilities to adequately perform resections. However, with the introduction of the 1318-nm wavelength, the data has shown improvement in symptoms in patients, and better survival rates in select patients [6]. Over the last few years, Nd:YAG laser has established itself as an important palliative treatment for patients with lung cancer [7]. Results from multiple studies have shown an improvement in quality of life and relieving local symptoms [8]. Treatment with Nd:YAG laser has led to significant improvement both objectively and subjectively in patients with endobronchial malignant obstruction. Interval response rate defined as tumor size at follow-up bronchoscopy performed at one week and one month was 53% and 23.5% in the Nd:YAG laser arm and 43% and 38.5% in the PDT arm, though the p-value was not significant [8]. The mean survival time after Nd:YAG laser treatment was 6.64 months [1]. It was also observed that the time for reintervention was longer in patients who received multimodal therapy where Nd:YAG laser was combined with either chemotherapy, radiotherapy, or brachytherapy than in those who received single modality treatment [1]. There was a significant improvement in the mean pulmonary function test after the procedure, which resulted in an improvement in the dyspnea index. Effective opening of the airway was achieved in 81% of the patients treated with Nd:YAG laser as compared to 75% of the patients who received photodynamic therapy (PDT) [9].
The aim of this article is to review current indications for and the role of endoscopic Nd:YAG laser therapy in the management of unresectable and advanced lung carcinoma, as well as to discuss overall survival rates and complications of the procedure.

Review Search strategy and study selection
This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses, which do not require protocol registration [10]. An electronic database search was conducted for relevant studies published from 11/20/2022 to 11/24/2022 on PubMed, Embase, and Cochrane using certain keywords.  Our search included all original studies (cohort, cross-sectional, and case-control studies) describing the characteristics of patients with airway obstruction in the setting of malignancy, pre-treatment evaluation (including pulmonary function testing, scoring systems deployed to assess the severity of dyspnea, arterial blood gas parameters, imaging and degree of obstruction, etc.), outcomes and complications associated with the use of Nd:YAG laser, and commentaries and case series with more than or equal to eight patients. With respect to case series, emphasis was laid on including studies that provided sufficient data on the outcomes and variables pertinent to our study design. The exclusion criteria included non-original reports, which were either reviews, letters to editors, or commentaries that did not include patient data; case reports or case series involving fewer than 10 patients; unextractable or irrelevant data; articles not published in English; duplicate records; animal studies; overlapping data; and full texts that were not available, unextractable, or irrelevant data.
The primary outcomes that were the focus of our review were as follows: post-procedure stenosis, evaluation of pulmonary function testing, and blood gas parameters after the procedure. Survival outcomes were also the primary focus of our study. Secondary outcomes that we focused on in our systematic review were as follows: improvement in clinical status after laser treatment, and improvement in dyspnea grade/additional scoring systems and scales post-procedure. We also evaluated the complications of the procedure as a secondary outcome. To ensure that we did not miss any relevant studies, we manually searched the references of our included papers. All original studies that reported malignant airway obstruction and the use of Nd:YAG laser were included in the study. Our systematic review was screened by two independent reviewers for titles and abstracts, followed by a full-text screening to ensure that relevant papers were included. We resolved disagreements by discussion and by referring them to the senior author when necessary.

Data extraction
We developed a data extraction sheet using Microsoft Excel (Microsoft® Corp., Redmond, WA). Two independent reviewers extracted data using the Excel sheet. Disagreements and discrepancies were resolved through discussions with the senior author.

Quality assessment
The risk of bias in the included studies was evaluated by one independent reviewer. A risk-of-bias assessment tool developed by the National Institutes of Health (NIH) was used to assess the quality of the included studies [11].

Search Results
A total of 139 records were identified. After the removal of two duplicate records, a total of 137 studies were included, which then underwent the screening process. After a thorough review of the study title and abstracts, 101 studies were excluded. It is noteworthy to mention that case reports were excluded during this phase.
A total of 36 reports became part of the secondary screening process. After the exclusion of case series with less than eight patients and no mention of mean/median values of variables pertinent to our study design, abstracts, and full-length papers not pertinent to the study, 11 studies were finally included in our systematic review ( Figure 1).

Study Characteristics, Quality of the Included Studies, and Risk of Bias of Included Studies
These 11 studies included four retrospective studies [1,5,9,12], two prospective [7,13] and one retrospective case series [14], and four prospective studies ( Table 2) [8,[15][16][17]. Based on the NIH tool, all the studies included scored at least a 9 on the assessment. We evaluated the risk of bias of the case series included in our study using the NIH risk assessment tool.

Baseline Patient Characteristics
The baseline patient characteristics are summarized in Table 2 [1,5,12,17]. The mean age of the patients in the partial obstruction group was 61 years and the mean age of the patients in the complete obstruction group was 66 years in the clinical investigation conducted by Gelb et al. [16].
The most common patient presentations were dyspnea, respiratory distress, cough, and hemoptysis. The prospective study by George et al. reports that some of the patients presented with malaise, weight loss, pneumonia, sputum production, and paresis of recurrent nerve [7]. The clinical investigation by Gelb et al.
reports unresolved atelectasis and pneumonia as the presenting findings in a few patients [16]. The wide variety of malignancies reported by the studies is listed in Table 2.
A total of 258 lesions were treated, 81 via PDT and 177 treated via laser therapy, in the study conducted by Furukawa et al. [9]. The PDT group had 78 cases (72 were males and six were females). There was a total of 29 patients in the clinical investigation conducted by Gelb et al.; 15 patients had a partial obstruction and 14 patients had a complete obstruction [16]. Ninety-seven patients were included in the retrospective study conducted by George et al. (62 males, of which 33 underwent laser therapy under local anesthesia while 29 underwent laser therapy under general anesthesia; 35 were females: 18 were treated under local anesthesia and 17 under general anesthesia [14].

Pre-intervention Assessment and Intervention Details
Pre-intervention parameters are summarized in Table 3.  In the prospective case series conducted by Gelb et al., the mean forced expiratory volume in one second (FEV1) was 49 ± 12% of predicted, and forced vital capacity (FVC) of 52% ± 18% of predicted [13]. In the retrospective study by George et al., the average peak expiratory flow rate (PEFR) was 201 liters/minute in patients undergoing laser therapy under local anesthesia and 185 liters/minute in patients undergoing laser therapy under general anesthesia [14]. The sites/locations of the obstruction in the setting of malignant lesions have been described in Table 3.
The malignant lesions caused more than 75% bronchial obstruction in 24 patients and less than 75% obstruction in the remaining seven patients in the study by Diaz-Jiménez et al. [8]. The prospective case series by Gelb et al. noted the mean main-stem bronchial diameter to be 1.9 mm ± 1.6 mm before laser therapy [13]. The retrospective study by George et al. observed partial obstruction in 64 patients and complete obstruction in 10 patients [14]. The retrospective case series by Moghissi et al. reported the overall degree of intraluminal tracheobronchial obstruction ranging from 60-100% [12]. Malignant endobronchial tumor obstruction ranged from 50-95% (mean 75%) in the prospective study conducted by Moghissi et al. [17].
Furukawa et al. observed that the patients had grade 2 (severe dyspnea) on the dyspnea scale [9]. Patients with a Karnofsky performance status of more than or equal to 40% were included in the study by Diaz-Jiménez et al. The Karnofsky performance status assessment was performed before treatment initiation, at one week, and one, two, three, six, 12, and 18 months thereafter [8]. The clinical investigation by Gelb et al. observed the average dyspnea index before laser treatment to be 3.4 ± 0.6 in patients with partial obstruction and 3.6 ± 0.5 in patients with complete obstruction [16]. The retrospective study by George et al. noted the mean Karnofsky performance index for patients undergoing local anesthesia for laser treatment to be 66 and 64 for patients undergoing general anesthesia for laser treatment [14]. The WHO performance status in patients in the retrospective case series by Moghissi et al. ranged from 2 to 3 with a mean of 2.24 [12]. Patients with an Eastern Cooperative Oncology Group (ECOG) ≤3 were included in the study by Perin et al. [5] The intervention details are described in Table 4. Toilet bronchoscopy was performed in all patients after Nd:YAG laser treatment in the study by Furukawa et al [9]. Toty et al. reported 48 recurrent cases of cancer undergoing radiotherapy prior to laser treatment. Some of the recurrent cancer patients underwent chemotherapy before the laser treatment; 18 patients with recurrent cancer had prior surgical intervention (six had pneumonectomies) [15]. Three patients in the PDT group received external radiotherapy prior to laser therapy in the study conducted by Diaz-Jiménez et al [8].

Outcomes
The primary and secondary outcomes that were the focus of our study are summarized in Table 5.      One patient with a moderately malignant tumor had a recurrence following laser therapy [15].
Airway obstruction improved from 79% to 62% in 27 patients post-therapy in the study conducted by Diaz-Jiménez et al. (both laser and PDT groups combined). At the one-week follow-up, the response rate (tumor size at follow-up bronchoscopy) was 53% in the patients who received laser treatment versus 43% in the patients who received PDT. The corresponding figures at one month were 23.5% and 38.5% respectively; however, the p-value was non-significant. In both groups, improvement in symptoms appeared to be similar [8].
As per the prospective study conducted by George et al., patients with both partial and complete obstruction showed symptomatic improvement and an improvement in the degree of stenosis following laser treatment. A 20% increase in FVC was seen in five out of eight (62%) patients with main bronchial obstruction and in three out of eight (38%) patients with intermediate/lobar bronchial obstruction; 50% of patients remained alive seven months after treatment. The overall morbidity was 6.6% of all treatments (12.7% of all patients), while the postoperative mortality was 1.8% of all treatments (3.6% of all patients) [7]. Han et al. reported a median survival of 6.64 months after Nd:YAG laser treatment. Patients were found to have an improvement in dyspnea, cough, and hemoptysis status post-treatment; 55% of the patients were rendered asymptomatic.
The study also mentions that the time to reintervene after multimodal treatment (Nd:YAG laser combined with either chemotherapy, radiotherapy, chemoradiotherapy, or brachytherapy) was longer than compared to the use of a single modality (Nd:YAG laser only) for the treatment of airway obstruction in the setting of malignancy [1].
The mean main-stem bronchial diameter improved from 1.9 ± 1.6 mm to 9.6 ± 1.0 mm in the participants of a prospective case series conducted by Gelb et al. [13]. The clinical investigation by Gelb et al. reported that the mean FEV1, FVC, and mid-expiratory flow rate (MMF) improved in patients with both partial and complete obstruction. Post-laser therapy, the dyspnea index was significantly better than the initial dyspnea index (p<0.05) and was associated with significant improvement in the Karnofsky score in patients with partial obstruction. The dyspnea index and the Karnofsky score did improve in patients with complete obstruction. The Karnofsky score and FVC were significant (p>0.05) when compared to patients with complete obstruction [16].
The retrospective study by George et al. noted a mean increase in PEFR of 86% in patients who received treatment under local anesthesia and 114% in patients who received treatment under general anesthesia; 27 out of 51 patients who received treatment under local anesthesia showed objective response whereas 31 out of 46 patients who received treatment under general anesthesia showed an objective response [14].
The mean improvement in FEV1 and FVC was noted to be 25% and 28% respectively among patients receiving Nd:YAG laser treatment, as demonstrated by the retrospective case series conducted by Moghissi et al. The median survival of the 10 patients who had died by the time of writing the study was 18.5 months (range: 5-39) [12]. A mean 15% increase and 27% increase in FEV1 and FVC were observed after laser treatment in the prospective study by Moghissi et al. [17]. A study of 17 patients showed a two-year survival of 47%. Unfortunately, Perin et al. did not report outcomes pertinent to our study apart from the complications of the laser treatment [5].

Discussion
The use of Nd:YAG laser treatment in patients with luminal obstruction of the trachea-bronchial respiratory tract due to malignancy has demonstrated positive outcomes in the form of subjective and objective improvement, regardless of the age group, type of malignancy, brand of laser, degree or location of the obstruction, or use of other modalities in conjunction with the laser treatment. The effectiveness of the treatment is largely dependent on complete resection of the lesion, if possible. As reported by Rolle A. et al., the prognostic capability of the traditional risk factors, such as solitary vs. multiple lesions, disease-free interval, and the number of metastases present, diminished in patients in whom complete resection was performed using the Nd:YAG laser. They found that 36% of the patients with four or more metastatic lesions were able to achieve confirmed five-year survival, whereas 28% of patients with 10 or more metastases, and 26% of patients with 20 or more metastatic lesions were able to achieve five-year survival, further elaborating the point that complete resection is arguably the most important prognosticating factor [6]. Another important factor that has impacted the effectiveness of this method is the tumor size and location; central, small tumors had more favorable outcomes than large, segmental tumors. Better outcomes have also been noted when using a higher wavelength of the laser instead of the conventional 1064-nm wavelength [7,9].
Multiple outcomes were used to assess objective improvement in the study conducted by Han et al. Patients experienced a subjective improvement in the form of an improvement in the presenting symptoms of dyspnea, hemoptysis, and cough, with some patients experiencing complete resolution of symptoms (after Nd:YAG laser intervention, 76% of patients reported improvement in dyspnea, 94% for hemoptysis, and 75% for cough; 55% of patients were rendered asymptomatic) [1].  [12]. Among all studies that reported post-procedure degree of stenosis, the prospective case series by Gelb et al. observed more than 50% of the patients showing an endoscopic reduction in the luminal obstruction with an increase in the luminal diameter (By direct bronchoscopy estimates, the mean main-stem bronchial diameter was 1.9 mm ± 1.6 mm before laser therapy; after laser therapy, the mean diameter increased to 9.6 mm ± 1.0 mm) [13]. An increase in post-procedure FEV1, FVC, and mid-expiratory and peak expiratory flow rates was noted in the clinical investigation conducted by Gelb et al. Dyspnea index and Karnofsky score showed improvement, more for partial obstruction as compared to complete obstruction [partial obstruction: mean dyspnea index before laser (3.4 ± 0.6) and after laser (2.6 ± 0.6); complete obstruction: mean dyspnea index before laser (3.6 ± 0.5) and after laser (3.4 ± 0.5). Partial obstruction: mean Karnofsky score (%) before laser (45.0 ± 15.0) and after laser (60.0 ± 15.0), Complete obstruction: mean Karnofsky score (%) before laser (28.0 ± 11) and after laser (29.0 ± 16.0)] [16].
Assessment of survival outcomes showed increased median survival among patients who received multimodality treatment as compared to those who received single modality treatment (median survival after Nd:YAG laser treatment was 6.64 months; median survival in patients who received single modality treatment was 3.79 months, while median survival in pts who received multimodality treatment was 6.99 months) [1]. The maximum survival was noted to be a 47% two-year survival rate in a small study of 17 patients [17]. The procedure is deemed safe for the most part and has seldom been associated with longterm adverse effects [7,18]. The theoretical adverse effects are mostly attributed to inadvertent exposure of healthy lung tissue to the laser, which may cause tissue damage and bleeding. However, in practice, this intervention is mostly done in terminally ill patients and has shown promising palliative properties and improved survival rates. Complications of the Nd:YAG laser treatment include, but are not limited to, pneumonia, hemorrhage/hemoptysis, respiratory distress and failure, pneumothorax, tracheal-esophageal fistula, tracheal stenosis, airway rupture, arrhythmias, myocardial infarction, and death [4,6].
Nd:YAG is a well-established, safe intervention that can be offered to patients with end-stage malignancies with significant endobronchial lesions that affect the quality of life. In clinical settings, there is some evidence that bronchoscopic electrocautery might have similar outcomes in a more cost-effective manner, but more research is needed in that regard. Overall, at present, Nd:YAG continues to be a safe method to provide effective palliation in terminally ill patients [19].

Limitations
Although Nd:YAG laser has been used in clinical practice for the last four decades, there is only a limited number of prospective trials conducted to compare the effectiveness of Nd:YAG laser with that of other therapeutic and palliative measures. Most of the data available are based either on case series, case reports, or retrospective studies. The lack of standardization in the reported data makes undertaking a systematic analysis and survival analysis difficult. A number of studies reported so far lack objective data on the reduction of the size of endobronchial obstruction, improvement in the pulmonary function tests, and results on survival over an extended follow-up period. Smoking status and imaging studies are important aspects of risk assessment for survival analysis; however, a significant number of studies have failed to report these aspects in the results. Similarly, the severity of dyspnea is an important aspect to gauge the impact of treatment on the quality of life of the patients, and several studies have either failed to report it or failed to use a standard scale of assessment for the same. Given the palliative aspect and the impact on the improvement of the quality of life of the survivors reported in the studies so far, there is a need to conduct a randomized controlled prospective trial comparing the Nd:YAG laser with other different available therapeutic and palliative measures, as well as to confirm the established risk factors and objective parameters to provide objective evidence of survival benefits.

Conclusions
The use of Nd:YAG laser treatment in patients with luminal obstruction of the trachea-bronchial respiratory tract due to malignancy has demonstrated positive outcomes in the form of subjective and objective improvement, regardless of the age group, type of malignancy, brand of laser, degree or location of the obstruction, or the use of other modalities in conjunction to the laser treatment. Patients experienced a subjective improvement in dyspnea, hemoptysis, and cough, with some patients experiencing complete resolution of symptoms. More than 50% of the patients showed an endoscopic reduction in the luminal obstruction with an increase in the luminal diameter. Assessment of survival outcomes showed increased median survival in patients who received multimodality treatment as compared to those who received single-modality treatment.
Based on the information currently available, Nd:YAG laser can be used as an effective form of palliative treatment to provide an improvement in symptoms and quality of life among patients with advanced-stage and inoperable endobronchial lung malignancies. There is potential for further studies that could compare median survival among patients receiving Nd:YAG laser treatment (alone or in conjunction with other modalities) in comparison to those receiving other treatments like PDT or those not receiving any treatment at all.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.