Palliative external beam radiotherapy for lung cancer patients with malignant airway obstruction

Background Significant proportion of lung cancer patients suffer from malignant airway obstruction (MAO). Palliative external beam radiotherapy (EBRT) is often attempted to control symptoms caused by MAO. In this study, we report the effect of palliative EBRT on lung cancer with MAO and analyze the factors that influence it. Methods This study included 75 patients with MAO in lung cancer who underwent palliative EBRT, between 2009 and 2018 and were analyzed retrospectively. Change of dyspnea, tumor response, and overall survival (OS) were recorded. Univariate and multivariate analyses were done to find the prognostic factors for treatment outcomes. Results The median follow-up duration was 2.5 months, and the median OS was 2.3 months. Out of 75 patients, dyspnea was improved in 46 patients (61.3%), and tumor was partially decreased in 39 patients (52%). The symptom improvement was significantly affected by tumor response and radiation dose. The tumor response was significantly affected by disease status, radiation dose, and time to EBRT. Conclusions Palliative EBRT MAO lung and can improve results. the with EQD2 42.2 Gy was irradiated, 61.3% of patients showed improvement of dyspnea, and 52% of patients showed partial tumor response. The tumor response was good in patients with untreated disease status, high-dose irradiation, or short time to RT. Symptom improvement was better in patients with good tumor response and high-dose irradiation (EQD2 ≥ 42.2 Gy). The OS of all patients was poor, but that was relatively high in patients with good performance status or good tumor response.

Various palliative-intent treatments are attempted to improve symptoms and penetrate blocked airways [4,6]. External beam radiotherapy (EBRT) is a preferred treatment option for MAO because it is non-invasive, safe, and simpler than other methods such as a bronchoscopic procedure, laser ablation, and intraluminal brachytherapy [7,8]. However, there are several limitations in EBRT in that there is no standardized guideline (radiation dose, fractionation, and time for EBRT) and the result data are insufficient.
Therefore, in this study, we report our institutional experience and treatment outcomes of treating lung cancer patients with MAO by palliative EBRT. We analyze how treatment by EBRT is better for symptom relief, good tumor response, and survival.

Patient selection
For this study, the inclusion criteria were as follows: 1) patients with histologically proven primary lung cancer, 2) patients suffering from dyspnea with a radiographic finding of MAO on chest X-ray or computed tomography (CT), and 3) patients treated by palliative-intent EBRT for the obstructive pulmonary mass. Patients who received prior systemic chemotherapy were included in this analysis.
In contrast, patients who had any of following conditions were excluded from this study: 1) no followup image data for showing the treatment response, 2) no follow-up medical records for showing the change of symptoms, and 3) a previous history of RT and surgery at chest. Among those patients who received palliative EBRT at Gyeongsang National University Hospital (GNUH) and Gyeongsang National University Changwon Hospital (GNUCH) between November 2009 and December 2018, we selected 75 patients who fully fulfilled the above criteria for analysis and retrospectively reviewed their medical charts, treatment records, and the results of image work-up.
This study was retrospective, with no informed consent from individual patients, but was done in accordance with relevant guideline; the study protocol was approved by the Institutional Review Boards (IRBs) at GNUH (IRB No. GNUH 2020-03-009) and GNUCH (IRB No. GNUCH 2020-03-020).

Radiotherapy
For radiotherapy (RT), all patients were immobilized in the supine position and had received CT simulations. The scanned images were imported into the Eclipse treatment-planning system. Total or partial lung mass including conglomerated metastatic lymph nodes presumed by clinicians to induce airway obstruction was delineated as gross tumor volume. The clinical target volume was not delineated, because treatment was delivered with palliative intent. Subsequently, a volumetric margin of 10 mm was applied to make the planning target volume (PTV). Three-dimensional conformal RT plans were created and used to prescribe a median dose of 39 Gy (range, 24-59 Gy), 2-3 Gy per fraction, equal to a median equivalent dose in 2 Gy per fraction (EQD2) 42.2 Gy (range, 26 -62.2 Gy). All plans were normalized so that 100% of PTV received more than 90% of the prescribed dose.
If the changes in atelectasis or airway position were observed by means of daily chest x-rays during RT, the previous procedure was repeated from CT scanning to RT planning. We then continued with the remaining RT with the new RT plan.

Statistical analysis
The severity of dyspnea was recorded by radiation oncologists based on the American Thoracic Society (ATS) score, and the differences in score before, during, and after RT was used to assess symptom improvement [9]. We defined time for EBRT as the period from the day of dyspnea with an ATS score of 2 or higher to the day of RT start. In simulated chest CT images, the degree of obstruction, presence of carina involvement, and length of the tumor blocking the airway were measured. On mean 27 days (range, 4 -90 days) after the end of RT, all patients had scanned chest CT for treatment response evaluation. Tumor response was divided into complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, and we defined CR or PR in the RT field area as the responding group [10]. Acute toxicity was evaluated by National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [11].
Simple and multivariate logistic regression analyses were done to identify prognostic factors of symptom relief and tumor response. The overall survival duration was defined as the period from the date of end of RT to the date of any death. Kaplan-Meier method and Log-rank test were used for survival curves. All analyses were done using the SPSS program, and a p value < 0.05 was considered statistically significant.

Patient characteristics
Patient characteristics are summarized in Table 1 cm). The patients' dyspnea level before RT was divided into 2, 3, and 4 points based on ATS score, for 9, 32, and 34 patients, respectively. Time for EBRT was mean 24 days (range, 1-112 days).

Treatment outcomes
The median follow-up duration was 2.5 months (range, 0.2-32.2 months), and 71 patients (94.7%) died at the end of the follow-up period. The median overall survival (OS) was 2.3 months, and 1-year OS rate was 8%. The degree of symptomatic change in dyspnea was divided based on the difference in ATS scores before and after RT, as shown in Table 2. According to the ATS score gap, the number of patients with 3, 2, and 1 was 8 (10.7%), 18 (24%), and 20 (26.7%), respectively. In 46 patients (61.3%), the symptoms of dyspnea improved, although there was a difference in degree. On the other hand, 24 patients (32%) had no change in symptoms, and 5 patients (6.7%) had worsened symptoms despite treatment. Tumor response was classified into CR, PR, SD, and PD and the number of patients was 0 (0%), 39 (52%), 29 (36%), and 7 (9.3%), respectively. A total of 52% of patients showed a tumor response after RT. The tumor response in one patient who underwent Palliative EBRT is shown in Figure 1 by comparing chest CT images before and after treatment. Based on CTCAE criteria, acute toxicity was grade 1 esophagitis in 21 patients, grade 2 esophagitis in 10 patients, and grade 1 radiation dermatitis in 3 patients. No patient suffered from grade 3 or higher toxicity.

Prognostic factors
We used logistic regression analyses to find factors that could affect the treatment outcomes. Among palliative treatment methods, EBRT has some advantages that can be easily applied. First, palliative EBRT is effective in lung cancer patients with MAO. Lee et al. [7] gave a median 30 Gy EBRT to 95 patients with airway obstruction in lung cancer. They defined responders as patients with improved chest x-rays or symptoms and reported a total response rate of 78.9%. They also reported that a higher response was observed in patient with a biologically effective dose ≥ 39 Gy or tumor length ≤ 6 cm. Another investigator, Nihei et al. [12], gave 30 Gy in 10 fractions EBRT to 24 patients with airway stenosis in non-small-cell lung cancer. They assessed treatment response by chest images and reported a response rate of 54.2%, which lasted for a median of 116 days, corresponding to about 66% of the patient's remaining survival. Our study showed a satisfactory therapeutic effects (symptom response, 61.3%; tumor response, 52%) similar to those of these previous studies. In addition, the effects may be improved by controlling factors such as high-dose irradiation and short time to RT. Second, palliative EBRT is noninvasive and safe in lung cancer patients with MAO. In MAO patients, therapeutic bronchoscopic procedures are often attempted for palliation. Ernst el al. [13] reported procedure-related toxicity in 554 patients who received therapeutic bronchoscopy at four hospitals. They reported that general anesthesia was needed in 65.3% of patients and adverse events, such as hypoxia, pneumothorax, escalation of care, bleeding, and hypotension, were found in 25% of patients with malignant tumors. Another study reported the side effects of therapeutic bronchoscopy in 15 institutions and 947 MAO patients [14]. They reported that side effects could differ depending on the institution and skill of the operator, and if side effects occur, more than 50% of patients develop additional severe adverse events, such as permanent disability or death. On the other hand, in previous studies with EBRT and in our study, grade 3 or higher acute toxicity was not observed in any patients. Although chronic toxicity has not been evaluated, late effects are often less concerning because of their short lifespan in most palliative therapy.
However, there are several disadvantages of palliative EBRT. First, it cannot immediately improve symptoms in MAO patients. Lee et al. [7] reported that median time for resolving the symptom or radiologic findings was 7 days after EBRT, and for Nihei et al. [12] it was 24 days. EBRT alone is not effective in patients with acute phases of respiratory distress or requiring dramatic and immediate symptomatic improvement. This shortcoming can be overcome by combining the bronchoscopic procedure with early effects and the EBRT with delayed effects. Combined treatment studies have reported good results in improving symptom-free survival and progression-free survival as well as symptom improvement [15,16]. Second, palliative EBRT has a relatively long duration of treatment.
Because of the short survival of patients with MAO, a long time spent on treatment can be a disadvantage. To overcome this shortcoming, hypofractionated RT can be considered. Theoretically, the risk of late complications increases, but considering the short life expectancy, a faster tumor response can be expected. Additional studies are needed to find proper RT schedules that increase response rates and reduce treatment duration while maintaining low side effects.
The limitation of this study is its retrospective nature, where the patient characteristics and outcome data are not well controlled. However, our study is relatively consistent because both institutions have the same medical staff with the same principles.

Conclusions
In patients with lung cancer with MAO, palliative EBRT is effective and safe. High-dose irradiation (EQD2 ≥ 42.2 Gy) and prompt treatment (time to RT ≤ 14 days) may improve the response rate.
Finding an optimal dose schedule, to reduce treatment duration and increase response while maintaining toxicity, should be investigated in future studies.

Ethics approval and consent to participate
This study was retrospective, with no informed consent from individual patients, but was done in accordance with relevant guideline; the study protocol was approved by the Institutional Review Boards (IRBs) at GNUH (IRB No. GNUH 2020-03-009) and GNUCH (IRB No. GNUCH 2020-03-020).

Consent for publication
Not applicable because this analysis has retrospective nature

Availability of data and material
Raw data may be available on request from the corresponding author.

Competing interests
The authors declare that they have no competing interests

Funding
This study was not funded by any organizations or companies.

Authors' contributions
Conception and design of the study: HSC, and KMK. Acquisition of data: HSC, BKJ, and IBH. Analysis and interpretation of the data: HSC, HJ, and KMK. Writing and revision of the manuscript: HSC, and KMK. All authors read and approved the final manuscript.        Overall survival according to (a) performance status and (b) tumor response.