Research ArticleClinical Studies

Overall Survival of Small-cell Lung Cancer Patients With Malignant Central Airway Obstruction Who Received Chemotherapy Without Undergoing Transbronchial Interventions: A Single-institution Retrospective Study

KOSUKE KASHIWABARA, SHINJI FUJII, SHINSUKE TSUMURA and KAZUHIKO SAKAMOTO
Anticancer Research December 2022, 42 (12) 6113-6119; DOI: https://doi.org/10.21873/anticanres.16124

Abstract

Background/Aim: This study aimed to determine whether the prognosis of small-cell lung cancer (SCLC) patients with malignant central airway obstruction (MCAO) who receive chemotherapy without undergoing transbronchial intervention (TBI) is not inferior to that of SCLC patients without MCAO. Patients and Methods: We compared overall survival (OS) from the time of SCLC diagnosis between stage III or IV SCLC patients with MCAO (MCAO group, n=22) and those without MCAO (non-MCAO group, n=88). MCAO is generally defined as >50% obstruction of the trachea or mainstem bronchi. Results: The median interval from the time of SCLC diagnosis until the initiation of anticancer therapy and the median number of chemotherapy regimens were 6 days and 2 regimens, respectively, in the MCAO group and 15 days and 2 regimens in the non-MCAO group. During the median follow-up period of 11.7 months after SCLC diagnosis, 95% of the patients in the MCAO group and 85% of the patients in the non-MCAO group died. No difference in the median OS (11.9 months vs. 12.4 months, p=0.455) was seen between the MCAO group and the non-MCAO group. A multivariate analysis showed that the presence of MCAO was not associated with an increased risk of death in SCLC patients who received chemotherapy (p=0.664). Conclusion: The prognosis of SCLC patients with MCAO who receive chemotherapy without undergoing TBI is not inferior to that of SCLC patients without MCAO.

Key Words:

Malignant central airway obstruction (MCAO) is a serious and life-threatening complication that can cause death from suffocation, if left untreated. Among patients with advanced non-small cell lung cancer (NSCLC) or with lung metastases from primary malignant tumors at other sites, transbronchial intervention (TBI) can relieve respiratory distress in patients with MCAO (1-3) and additional anticancer therapy after TBI has been reported to improve the quality of life in these patients (4, 5). Laser ablation, electrocautery and argon plasma coagulation are commonly used ablative procedures in MCAO patients with endoluminal obstruction caused by the ingrowth of tumors into the lumen of the airway, and stent placement (STP) is used in patients with extraluminal obstruction caused by growing tumors that externally compress the airway (6-8).

However, advanced small-cell lung cancer (SCLC) patients with MCAO empirically receive cytotoxic chemotherapy without undergoing TBI, although some reports have described the use of TBI in SCLC patients with MCAO (9-13). The reason is that chemotherapy can decrease the tumor volume and improve patient symptoms more immediately in SCLC patients than in NSCLC patients. However, whether overall survival (OS) of SCLC patients with MCAO who received chemotherapy without undergoing TBI is not inferior to that in SCLC patients without MCAO remains unclear. Therefore, we conducted this retrospective study to evaluate the difference in OS between advanced SCLC patients who received anticancer therapy with MCAO and those without MCAO.

Patients and Methods

This single-institute retrospective study was approved by the Institutional Review Board of the Kumamoto Regional Medical Center (approval date, September 1, 2022; approval number, 22-007). All procedures were in compliance with the principle of the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained prior to each procedure.

Eligible patients had an Eastern Cooperative Oncology Group performance score (PS) score of 0-3; had been diagnosed as having stage III or IV SCLC by bronchoscopy at our institute; had undergone staging body computed tomography (CT), brain magnetic resonance imaging (MRI), and bone scintigraphy or F-18 fluorodeoxyglucose positron emission tomography examinations; and had received chemotherapy or concurrent chemoradiation therapy as first-line anticancer therapy. Patients who received best supportive care (BSC) alone and patients with insufficient data were excluded from this retrospective study. Disease staging for NSCLC was performed according to the 8th edition of the guidelines of the Union for International Cancer Control TNM classification of malignant tumors (14) (re-staging was performed using the 8th edition in NSCLC patients whose disease staging had previously been based on the 7th edition).

The endpoint of the study was to evaluate the differences in OS between SCLC patients with MCAO and those without MCAO. MCAO is generally defined as >50% obstruction of the trachea or mainstem bronchi (6-8). OS was defined as the period from the time of SCLC diagnosis until the death of the patient. Progression-free survival (PFS) was defined as the period from the time of SCLC diagnosis until a diagnosis of disease recurrence or patient death. The comorbidities at the time of SCLC diagnosis were evaluated according to the Charlson comorbidity index (15). The presence of respiratory failure was defined as a ratio of the partial pressure of oxygen in the arterial blood to the inspired oxygen fraction (PaO2/FiO2) of <300.

The statistical analysis was performed using the Stat View J 5.0 statistical program (SAS, Institute Inc., Berkeley, CA, USA). Differences in clinical data between two independent samples were tested using the unpaired t-test or the Mann–Whitney U-test. Categorical data were analyzed using the χ2 test or the Fisher exact probability test. The log-rank test was performed to identify clinical variables potentially associated with OS. Variables identified as being significant with p-values of <0.10 were entered into a Cox proportional-hazards model for multivariate analysis. The PFS and OS were estimated using the Kaplan–Meier method. A two-tailed p-value of less than 0.05 was considered to indicate a statistically significant difference.

Results

Data on 126 stage III or IV SCLC patients were retrieved from our medical records database for the period from November 1, 2013, to December 31, 2021. Nine patients who received BSC alone because of a PS score of 4, four patients who refused anticancer therapy, and three patients with insufficient data were excluded from the study. A total of 110 untreated stage III or IV SCLC patients with a PS score of 0-3 and who received first-line anticancer therapy were included in this study; 22 patients had MCAO (MCAO group), and 88 patients did not have MCAO (non-MCAO group) (Figure 1).

Figure 1.
Figure 1.

Study flowchart.

Patient and disease characteristics (Table I). No differences in patient or disease characteristics were seen between the MCAO group and non-MCAO group, except for the proportion of men (50% vs. 78%, p=0.008) and the proportion of patients with comorbid interstitial pneumonia (IP) (5% vs. 20%, p=0.078). The percentage of patients who had dyspnea at the time of SCLC diagnosis was higher in the MCAO group than in the non-MCAO group (32% vs. 11%, p=0.018). The most common site of MCAO and the most common bronchoscopic appearance of the MCAO was the right main bronchus (55%) and extraluminal obstruction (68%).

View this table:
Table I.

Patient and disease characteristics.

Anticancer therapies (Table II). The median interval from the time of SCLC diagnosis until the initiation of anticancer therapy was shorter in the MCAO group than in the non-MCAO group (6 days vs. 15 days). Among the MCAO group, all the patients received first-line chemotherapy, and 2 of the 4 patients with stage III disease underwent additional thoracic radiotherapy after the completion of the first-line chemotherapy. Among the non-MCAO group, 15 (50%) of the 30 patients with stage III disease received concurrent chemoradiotherapy (CCRT). In the remaining 15 patients with stage III disease, 2 patients underwent additional thoracic radiotherapy because of an advanced age, and 13 patients received chemotherapy alone because of the coexistence of IP (n=7), the presence of contralateral hilar nodes metastasis (n=4), or the judgment of their doctors (n=2). Fifty-eight patients with stage IV disease in the non-MCAO group received first-line chemotherapy (including immune oncology drugs). Second-line chemotherapy was performed in 16 patients (73%) in the MCAO group and 58 patients (66%) in the non-MCAO group, and there was no difference in the median number of anticancer therapy regimens between the two groups (2 regimens vs. 2 regimens).

View this table:
Table II.

Anticancer therapies and prognosis.

Survival. During the median follow-up period of 11.7 months (range=0.3-115.2 months) after the time of SCLC diagnosis, 95% of the patients in the MCAO group and 85% of the patients in the non-MCAO group died (Table II). There was no difference in the median OS time (11.9 months vs. 12.4 months, p=0.455) or PFS (5.8 months vs. 6.1 months, p=0.438) between the MCAO group and the non-MCAO group (Figure 2A and Figure 3A). Similar results were observed in patients with stage IV disease (Figure 2B and Figure 3B). Among the patients with stage III disease, the median OS time (18.6 months vs. 22.6 months, p=0.248) and PFS (5.0 months vs. 10.0 months, p=0.131) were shorter in the MCAO group than that in the non-MCAO group (no statistical difference between the two groups). There was a difference in the percentage of patients who received CCRT between the two groups (0% vs. 17%, p=0.038), and few stage III patients in the non-MCAO group who had completed CCRT survived for relatively long periods (Figure 2C and Figure 3C).

Figure 2.
Figure 2.

Overall survival in the malignant central airway obstruction (MCAO) and non-MCAO groups: in all the patients (A), patients with stage IV disease (B) and patients with stage III disease (C).

Figure 3.
Figure 3.

Progression-free survival in the malignant central airway obstruction (MCAO) and non-MCAO groups: in all the patients (A), patients with stage IV disease (B) and patients with stage III disease (C).

Univariate and multivariate analyses to identify factors influencing OS (Table III). Six variables associated with the OS time when examined using log rank tests (p<0.10) were included into the multivariate analysis as follows: patients with a PS score of 1-3, patients with stage IV disease, the presence of brain metastasis or acute respiratory failure and the coexistence of IP. A Cox proportional-hazards model analysis identified patients with a PS score of 1-3 (p=0.072), patients with stage IV disease (p<0.001), the presence of acute respiratory failure (p<0.001) and the coexistence of IP (p<0.001) as factors that tended to be independently associated with an increased risk of death, whereas the presence of MCAO at the time of SCLC diagnosis was not found to be associated with an increased risk of death (p=0.664).

View this table:
Table III.

Multivariate analysis to identify factors influencing the overall survival time.

Discussion

Our results showed that there was no difference in the OS between the MCAO group and the non-MCAO group (11.9 months vs. 12.4 months, p=0.455), and long-term survival was observed in stage III SCLC patients of the non-MCAO group who had completed CCRT.

Among the stage IV SCLC patients, no differences in OS (11.4 months vs. 11.1 months, p=0.350) and PFS (5.0 months vs. 5.0 months, p=0.319) were seen between the MCAO group and the non-MCAO group. Reportedly, the median OS and PFS reportedly ranges from 9.2 to 12.8 months and 4.1 to 6.9 months, respectively, in extensive-stage SCLC patients who have received chemotherapy with cisplatin plus irinotecan or cisplatin plus etoposide (16-19). As our results in this study were similar to these previously reported results, we suggest that stage IV SCLC patients with MCAO might be able to receive chemotherapy without undergoing TBI.

Among the stage III SCLC patients, the median OS (18.6 months vs. 22.6 months, p=0.248) and PFS (5.0 months vs. 10.0 months, p=0.131) were shorter in the MCAO group compared to those in the non-MCAO group. None of the patients in the MCAO group received CCRT. Many patients in the MCAO group required chemotherapy immediately after the diagnosis of SCLC (before the completion of the distant metastasis evaluation), and there was no time to evaluate whether CCRT was indicated. However, the number of stage III patients in the MCAO group was very small (n=4), since SCLC is a rapidly progressive disease and most SCLC patients with MCAO have distant metastases. The small number of stage III patients with MCAO did not affect our results.

We previously reported that among 61 advanced NSCLC patients with MCAO, 31% of the patients had extraluminal obstruction, and 66% had dyspnea (20). In the present study, 68% of the SCLC patients with MCAO had extraluminal obstruction, and 32% had dyspnea. Since normal endobronchial mucosa is maintained in patients with extraluminal obstruction, symptoms arising from airway stenosis are less likely to occur. For this reason, TBI before chemotherapy is less of a priority in SCLC patients with MCAO.

However, some case reports have described the use of TBI in advanced SCLC patients with MCAO (9-11). Oki et al. (12) reported that the median OS after TBI was 1.7 months in 21 SCLC patients with MCAO who received STP. Ozdemir et al. (13) reported that 43% of SCLC patients with MCAO died during the first month after the first TBI. Although our patients with MCAO did not receive TBI, the median OS in the MCAO group was not inferior to the above-mentioned results. STP can be performed more quickly and safely, compared with ablative procedures, and is the most suitable procedure for MCAO patients with extraluminal obstruction. However, long-term complications associated with the presence of a foreign body in the airway, including bacterial pneumonia, mucus plugging of the stent, stent migration, or massive hemoptysis have also been reported after STP (21, 22). In particular, stent migration can occur once chemotherapy improves the airway obstruction in SCLC patients. As long-term complications after STP can interfere with additional anticancer therapy in patients with MCAO (20), STP should be avoided in SCLC patients with MCAO who are scheduled to receive first-line anticancer therapy.

The sample size in our study was relatively small because this was a retrospective study performed at a single institute. However, our study is the first report to suggest that performing TBI prior to chemotherapy is less of a priority in SCLC patients with MCAO. Secondly, we did not evaluate the difference in OS between SCLC patients with MCAO who underwent TBI and those who did not. The best way to evaluate whether TBI is useful for SCLC patients with MCAO is to perform randomized prospective studies. However, randomly assigning patients to receive TBI might be considered unethical, since STP possibly interferes with additional anticancer therapy in patients with MCAO (20).

In conclusion, the prognosis of SCLC patients with MCAO who received chemotherapy without undergoing TBI is not inferior to that of SCLC patients without MCAO.

Footnotes

  • Authors’ Contributions

    Kosuke Kashiwabara: Conceptualization, data curation, methodology, investigation, formal analysis, visualization, writing - original draft, writing - review & editing; Shinji Fujii: Investigation, visualization, writing - review & editing; Shinsuke Tsumura: Investigation, writing - review & editing; Kazuhiro Sakamoto: Investigation, writing - review & editing.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received October 18, 2022.
  • Revision received October 25, 2022.
  • Accepted October 26, 2022.

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Overall Survival of Small-cell Lung Cancer Patients With Malignant Central Airway Obstruction Who Received Chemotherapy Without Undergoing Transbronchial Interventions: A Single-institution Retrospective Study
KOSUKE KASHIWABARA, SHINJI FUJII, SHINSUKE TSUMURA, KAZUHIKO SAKAMOTO
Anticancer Research Dec 2022, 42 (12) 6113-6119; DOI: 10.21873/anticanres.16124
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