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ORIGINAL ARTICLE

Fibrotic airway stenosis following radiotherapy in patients with adenoid cystic carcinoma JUNG SEOP EOM,1 BOKYONG KIM,2 HOJOONG KIM,1 KYEONGMAN JEON,1 SANG-WON UM,1 WON-JUNG KOH,1 GEE YOUNG SUH,1 MAN PYO CHUNG1 AND O JUNG KWON1 1

Division of Pulmonary and Critical Care Medicine, Department of Medicine, and 2Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

ABSTRACT Background and objective: Radiotherapy is usually administered to the central airway in patients with unresectable adenoid cystic carcinoma (ACC). The purpose of this study was to describe the outcomes of endobronchial intervention in patients with airway stenosis following radiotherapy for ACC. Moreover, we investigated the incidence and contributing factors for airway stenosis following radiotherapy for ACC. Methods: Forty-seven patients with ACC, who underwent radiotherapy of the tracheobronchial tree from January 1995 to December 2011, were reviewed retrospectively. Fibrotic airway stenoses were diagnosed using three-dimensional computed tomography, flexible bronchoscopy or both. Results: Eleven (23%) of the 47 patients with ACC suffered fibrotic airway stenosis following radiotherapy and received bronchoscopic intervention. The median interval from radiotherapy to diagnosis of fibrotic airway stenosis was 7 months. Low forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity and brachytherapy were verified as factors contributing to radiotherapy-induced airway stenosis. Bronchoscopic intervention provided both symptomatic relief and improvement of lung function, and no procedurerelated death or major complication was observed. Insertion of a straight silicone stent was required in 10 patients (91%), and 4 (36%) eventually received Y-shaped silicone stents. The stents, once implanted, could not be removed in any of the patients; stents were well-tolerated for a prolonged period in all patients. Conclusions: Fibrotic airway stenosis following radiotherapy in patients with ACC is often found. Bronchoscopic intervention, including silicone airway stenting, was a safe and useful method for treating radiotherapy-induced fibrotic airway stenosis in patients with ACC. Correspondence: Hojoong Kim, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul 135-710, Korea. Email: [email protected] Received 16 November 2013; invited to revise 2 January and 8 February 2014; Revised 19 January and 25 March 2014; Accepted 13 April 2014 (Associate Editor: Chi Chiu Leung). Article first published online: 17 June 2014 © 2014 Asian Pacific Society of Respirology

SUMMARY AT A GLANCE Patients with inoperable adenoid cystic carcinoma (ACC) of the central airway may often develop symptomatic fibrotic airway stenosis after radiotherapy. Our results show that bronchoscopic intervention is a safe and effective strategy to restore airway patency in patients with ACC who experience this complication.

Key words: adenoid cystic carcinoma, airway obstruction, bronchoscopy, radiotherapy, stents. Abbreviations: ACC, adenoid cystic carcinoma; EBRT, external beam radiotherapy; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IQR, interquartile range; RBS, radiation bronchitis and stenosis.

INTRODUCTION Adenoid cystic carcinoma (ACC) is a rare intrathoracic malignancy, representing less than 0.2% of all lung cancers.1 It is usually considered a slow-growing neoplasm with relatively long survival of patients compared with that of other types of lung cancer.2 While surgical resection of the primary tumour is the treatment of choice in patients with ACC, radiotherapy is a reasonable alternative therapy in inoperable patients with a larger tumour size or comorbidities.3,4 Various airway toxicities occur following radiotherapy.5–8 These adverse effects are defined as radiation bronchitis and stenosis (RBS) and have been divided into four grades: grade 1, mild mucosal inflammatory response; grade 2, whitish fibrinous membrane with exudates; grade 3, severe inflammatory response with a marked membranous exudate; and grade 4, significant airway narrowing due to fibrotic stenosis.5 Of the various RBS grades, grade 4 is the most difficult to control and the most clinically problematic. These patients usually present with severe dyspnea or respiratory failure and undergo bronchoscopic intervention to restore airway patency. Respirology (2014) 19, 914–920 doi: 10.1111/resp.12336

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Figure 1 Spectrum of radiation bronchitis and stenosis (RBS) on bronchoscopy. (a) Grade 1 RBS was characterized by mild mucosal inflammation. (b) A whitish, fibrinous membrane with exudates was found in patients with grade 2 RBS within the area of prior radiotherapy. (c) Grade 3 changes consisted of a severe inflammatory response with marked membranous exudates and mild fibrotic changes. (d) A greater degree of fibrosis leading to significant luminal narrowing was found in patients with grade 4 RBS.

High-dose radiotherapy in patients with unresectable ACC has been suggested as an effective and safe treatment strategy.9 However, little information is available on fibrotic airway stenosis after radiotherapy, i.e. grade 4 RBS, in patients with ACC. Most ACCs in the thoracic cage are endobronchial malignancies that arise within the central airway; therefore, radiotherapy is usually administered to the trachea, carina or main stem bronchus. Based on the anatomical location of ACC, ACC may have a higher incidence of radiation-induced airway toxicity than that of other lung cancers. The purpose of the present study was to describe the clinical and treatment outcomes of endobronchial intervention in patients with symptomatic grade 4 RBS following external beam radiotherapy (EBRT) for ACC.

METHODS Study subjects Patients with ACC were identified using the International Classification of Disease code (ACC (M8200/3) and ACC, metastatic (M8200/6)) at Samsung Medical Center, Seoul, Korea. We selected 47 patients with unresectable ACC on the tracheobronchial tree who received EBRT (three-dimensional conformal radiation therapy) through a retrospective medical record review. We investigated patients with symptomatic grade 4 RBS who received therapeutic bronchoscopy. © 2014 Asian Pacific Society of Respirology

The study was approved by the Institutional Review Board (No. 2013-09-061). Informed consent was waived because of the retrospective nature of the study. Some of the clinical data for patients were included in an article published in 2012.10

Diagnosis and definition of RBS RBS was diagnosed using three-dimensional computed tomography, flexible bronchoscopy or both. According to the Speiser and Spratling grading system,5 RBS was classified into four grades (Fig. 1). Multiple forceps biopsies were performed at the RBS site when it was difficult to distinguish cancer recurrence from benign airway inflammation and stenosis on gross bronchoscopic findings. Bronchoscopic intervention Rigid bronchoscopy was performed to restore airway patency using the standard techniques of Colt and Dumon11 and Kim.12 A representative case of grade 4 RBS is shown in Supporting Information Figure S1. Natural silicone stents (TNO, Seoul, South Korea) were implanted for the following indications: (i) malacia of the tracheobronchial tree >180 of the dilated lumen; (ii) longitudinal stenotic segment >2 cm; or (iii) restenosis after an initial intervention without stenting. Y-shaped Natural silicone stents were indicated when: (i) a stenosis of the carina was observed with involvement of the main bronchus; Respirology (2014) 19, 914–920

916 (ii) stenosis of the carina recurred despite the use of a straight Natural silicone stent; or (iii) diffuse airway narrowing extended from the trachea to the main bronchi.13 The appropriate diameter and length of stent were selected by an interventional pulmonologist. Patients were usually discharged from the hospital 24 h after the intervention and followed at 1, 3, 6, 9 and 12 months after intervention. Symptom relief after intervention was defined as an improvement in previous respiratory symptoms caused by airway obstruction, such as dyspnea, cough or sputum retention, during the day following the intervention. Elective stent removal was planned when the patients had been stable for >12 months. Successful stent removal was defined as no respiratory symptoms related to airway obstruction after stent removal. Restenosis after stent removal, i.e. stent removal ‘failure’ was defined as the occurrence of airway obstruction after stent removal that required additional intervention.

Factors contributing to the development of symptomatic grade 4 RBS To identify factors associated with the development of airway stenosis following EBRT, analysis between the RBS group and the no RBS group was conducted in 47 patients who received EBRT for ACC. The RBS group comprised patients who received bronchoscopic intervention for symptomatic grade 4 RBS; the no RBS group included all other patients. Statistical analysis All results are presented as numbers (percentages) for categorical variables and medians (interquartile range (IQR)) for continuous variables. The Mann– Whitney U-test was used for continuous variables and Pearson’s chi-square test or Fisher’s exact test was performed to compare the proportions of categorical variables. The Wilcoxon signed-rank test was used to compare initial lung function test results with lung function tests after stenting. The Kaplan–Meier method was used to estimate the overall survival, and differences in survival between the two groups were analysed using the log–rank test. A P-value 12 months. In addition, seven patients were still alive with a silicone airway stent and in stable status.

Factors contributing to the development of symptomatic grade 4 RBS The analysis of factors contributing to the development of symptomatic grade 4 RBS is presented in Table 3. A significant difference in baseline lung function tests was observed between the RBS group and the no RBS group. The RBS group had lower FEV1 and FEV1/FVC than those in the no RBS group (P = 0.007 for FEV1 and P = 0.024 for FEV1/FVC). In addition, the RBS group had more patients with brachytherapy added to EBRT (64% vs. 8%, P < 0.001).

DISCUSSION The present study demonstrated that the incidence of fibrotic airway stenosis following radiotherapy in patients with ACC was relatively high and that bronchoscopic intervention, including silicone airway stenting, was a useful method for treating patients with ACC and grade 4 RBS. Moreover, low initial FEV1, FEV1/FVC, and combined radiotherapy with EBRT and brachytherapy were verified contributing factors for the development of RBS. This is the first report regarding the outcomes of bronchoscopic intervention in patients with ACC with symptomatic grade 4 RBS. Speiser and Spratling showed that the incidence of grade 4 RBS was 4% in 342 patients with lung cancer who received brachytherapy.5 Gollins et al. reported that only 1 of 406 patients with non-small-cell lung Respirology (2014) 19, 914–920

cancer developed grade 4 RBS after brachytherapy.6 In addition, Miller et al. described that 8 (8%) of 106 patients with non-small-cell lung cancer suffered airway narrowing after EBRT.7 However, the incidence of grade 4 RBS was 23% after EBRT with or without brachytherapy in the 47 patients with ACC in the present study. The study populations in previous studies were restricted to non-small-cell lung cancers with or without small-cell lung cancer, and ACC was excluded.5–7 Approximately 80% of ACC presents in the trachea, carina or main stem bronchi of the thoracic cage, and radiotherapy is administered to the central airway.2 The high incidence of fibrotic airway stenosis following radiotherapy in the ACC population may be due to its primary anatomical location. Outcomes of bronchoscopic intervention for RBS have been reported sporadically with a relatively small number of patients in previous studies and case reports. Miller and Harrell reported successful laser ablation of a fibrous endobronchial band in one patient with small cell lung cancer.14 Dechambre et al. reported a successful clinical outcome of one patient who received a silicone stent for bronchial stenosis with fibrosing mediastinitis that developed after radiotherapy.15 Speiser and Spratling described several patients who received silicone stenting for >1 year; however, no detailed description regarding the clinical course after silicone stent placement was provided.5 Gollins et al. reported on two patients with grade 3 RBS who received bronchoscopic intervention without stent placement; one patient who underwent bronchoscopic debridement and another who received mechanical dilatation only.6 Miller et al. described three RBS patients who underwent bronchoscopic intervention; one received balloon dilatation and a silicone stent; however, that patient © 2014 Asian Pacific Society of Respirology

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Table 3 Factors contributing to the development of radiation-induced fibrotic airway stenosis in patients with adenoid cystic carcinoma

Age, years Female gender Weight, kg Height, cm Body surface area, m2 Body mass index, kg/m2 Initial pulmonary function tests* FEV1, % predicted FVC, % predicted FEV1/FVC, % Patients with brachytherapy Total radiation dose, Gy Tumor resection prior to radiotherapy† Tumor location, overlapped Trachea Main bronchi or bronchus intermedius Initial CT findings before radiotherapy Shortest airway diameter‡, mm Tumor length in airway, mm

RBS group (n = 11)

No RBS group (n = 36)

P-value

46 (40–54) 6 (55) 66 (47–74) 162 (154–168) 1.73 (1.45–1.85) 23.1 (20.1–27.0)

49 (42–57) 16 (44) 61 (56–72) 165 (158–172) 1.65 (1.58–1.82) 22.7 (20.8–25.7)

0.719 0.557 0.757 0.227 0.683 0.872

71 (59–95) 90 (80–105) 67 (52–75) 3 (8) 60 (60–66) 13 (36)

0.007 0.280 0.024

Fibrotic airway stenosis following radiotherapy in patients with adenoid cystic carcinoma.

Radiotherapy is usually administered to the central airway in patients with unresectable adenoid cystic carcinoma (ACC). The purpose of this study was...
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