SCLC is an aggressive neuroendocrine tumor with rapid growth, high malignancy and early metastasis.4 About 42.8%-52.7% of patients with SCLC comorbid COPD have been reported in the literature,5–8 but related studies of such patients are few. And the studies are limited to the analysis of the impact of COPD or airflow limitation on the prognosis of SCLC, in which most scholars believe that COPD did not affect the prognosis of SCLC. Sunmi5 found that COPD had no effect on OS in patients with SCLC receiving first-line chemotherapy. Kang7 also noted that prognosis in SCLC patients receiving first-line chemotherapy was not associated with COPD, but airflow limitation (FEV1 < 80%) was an independent risk factor for OS shortening in patients with ED-SCLC; however, Lee8 pointed out that neither COPD nor airflow limitation (FEV1 < 80%) was associated with OS in patients with ED-SCLC receiving first-line chemotherapy, and that was not affected by the severity of COPD.
In this study, we found that COPD did not lead to significant OS shortening in patients with SCLC, which was consistent with the findings of Sunmi5; Subgroup analysiss found that this conclusion was not affected by clinical stage and severity of COPD, and multivariate analysis further supported the above view, which was basically consistent with the conclusion of Lee8, but not consistent with Kang7, who point out that FEV1 < 80% was an independent risk factor for OS shortening in patients with ED-SCLC. However, previous studies have indicated that a reduced FEV1 is not only the marker of severity of airflow limitation, but also a predictor of increased risk of lung cancer, cardiovascular disease and premature death from all causes in the general population.7 The mean age of population in our study was younger and the rate of cardiovascular disease was lower that may also be responsible for this difference.
COPD was not correlated with OS shortening in SCLC patients who received chemotherapy suggesting that COPD is not a contraindication for SCLC patients comorbid COPD to receive chemotherapy. In addition, Lee8 also suggested that chemotherapy was a prior treatment option for patients with ED-SCLC, which we hold the same opinion. In our study, the subjects is all SCLC patients receiving first-line chemotherapy, including ED-SCLC, which was broader than Lee’s. To some extent, it does showed that chemotherapy was a preferred option as first-line treatment for patients with SCLC comorbid COPD. Although there was no sufficient data to demonstrate that first-line chemotherapy is superior to optimal supportive care.
Although this study does not suggest that COPD is a risk factor for OS of SCLC patients, the role of COPD in SCLC still deserves attention, because COPD is the second common cause of non-cancer death in lung cancer patients.17 However, at present, the treatment rate of COPD in lung cancer patients is relatively low (only 28–35%18). Previous studies of our team have found that received both anti-tumor therapy and COPD treatment was effective in prolonging OS in patients with NSCLC comorbid COPD14; It is not clear that COPD treatment could improve OS of patients with NSCLC comorbid COPD, a similar exploration was made to explore it. In this study, COPD treated group had longer OS than COPD untreated group and the difference was statistically significant, which further suggested the necessity of COPD treatment in the process of anti-tumor treatment. Unfortunately, the differences in subgroup analysis (ED-SCLC and LD-SCLC) were not statistically significant, and multivariate analyses did not identify COPD treatment as an independent predictor of OS in SCLC patients. But we believe that the importance of COPD treatment would be further confirmed by increasing the sample size or conducting prospective multicenter studies. It was easy to note that ECOG PS status of the patients in the COPD treated group deteriorated more slowly during anti-tumor therapy. We hypothesized that the effect of COPD treatment on improving OS may be achieved by improving ECOG PS status in order to create conditions for patients to receive longer term antitumor therapy. The recently published international experts consensus of severe lung cancer20 pointed out that the combination of COPD is one of the main causes of severe lung cancer, and improper treatment of COPD will lead to a decrease in quality of life, therapeutic efficacy, and prognosis, which provides a theoretical basis for our hypothesis.
Extensive stage was identified as independent prognostic factors for short OS in patients with SCLC comorbid COPD. A large number of studies have confirmed that the prognosis is worse in ED-SCLC than in LD-SCLC,21, 22 and estimated that the one-year survival rate for LD-SCLC and ED-SCLC who received chemotherapy was about 60.7–73% and 26.2–38%, respectively. In this study, the one-year survival rate of patients with LD-SCLC was about 65.4% and ED-SCLC was about 32.9%, which was consistent with previous research;21, 22 and the one-year survival rate of patients with LD-SCLC comorbid COPD was about 56.9% and ED-SCLC with COPD was about 28.6%, which mean that COPD does not significantly reduce one-year survival rate of patients with SCLC received chemotherapy, further suggesting that chemotherapy was a preferred option as first-line treatment for SCLC patients with COPD.
In addition, we also found that thoracic radiotherapy is a protective factor of long OS in SCLC patients comorbid COPD. Thoracic radiotherapy is an effective adjunct method for LD-SCLC patients receiving chemotherapy, which can effectively prolong the survival time of patients compared with chemotherapy alone.23 Meta-analysis21 also revealed that, compared with chemotherapy alone, adding chest radiotherapy could improve the overall survival rate and progression-free survival rate when patients with ED-SCLC receiving first-line chemotherapy whose tumor achieved CR or PR. In this study, whether comorbid COPD or not, chest radiation was an independent predictor of OS prolongation in SCLC patients, which was consistent with previous studies.21, 23 However, there was controversial that COPD patients could be treated with radiation therapyat present. Some studies24–27 have suggested that COPD is a risk factor for radiation pneumonitis, Kayoko’s study28 suggests that COPD does not affect the incidence of radiation pneumonitis. Even some studies29–31 have reported a lower incidence of radiation pneumonitis in COPD patients than in non-COPD patients, and a lower incidence of radiation pneumonitis in patients with severe COPD than in patients with mild COPD or normal pulmonary function. In this study, no difference in the incidence of radiation pneumonitis was observed between the COPD and non-COPD groups (14.8% vs 18.8%, p = 0.97), similar to Kayoko’s findings28. Therefore, we speculated that COPD may not be a contraindication for SCLC patients receiving radiotherapy, and the benefits of radiotherapy may outweigh the adverse effects.
Instability and high mutation of the genome make the SCLC genome highly heterogeneous, and the lack of tissue samples for analysis results in the slow progress of the research on the SCLC genome.32 In this study, 10 patients completed relatively comprehensive genetic testing, of whom 6 were SCLC with COPD and the remaining 4 were SCLC without COPD. The genomic changes of 10 patients showed high heterogeneity, but a series of inactivation mutations of tumor suppressor genes, such as TP53, RB1 and PTEN, were found in different degrees, and the activation of oncogenes PIK3CA, EGFR, Kras (Deta sheet1) is consistent with the earlier work of the authors33–37. Although clinical studies of targeted drugs such as BCR-ABL TKI, bevacizumab, sorafenib, and sunitinib have not shown better efficacy than chemotherapy in treating SCLC38, however, these complex genetic changes may still provide cancer cells with continuous oncogene signals, thus providing a candidate therapeutic target for SCLC treatment.
There are several limitations of this study. Firstly, this is a retrospective study with a small sample and involves a large time span. Secondly, a significant number of patients were excluded for unavailable lung function, and there were only six women, which could lead to selection bias. Thirdly, without the diffusion function date, we can not exclude the influence of diffusion dysfunction on the conclusion.