In this study, we identified several clinical factors associated with the prognosis of ED-SCLC, including low DLco, large number of metastatic organs, and < 4 cycles of first-line chemotherapy. Our analysis showed that a lower DLco was an independent predictor of survival in patients with ED-SCLC. However, neither FEV1 nor FVC was associated with a poor prognosis of ED-SCLC. To our knowledge, this is the first study to identify a relationship between DLco and the prognosis of ED-SCLC.

DLco is a measure of gas transfer that reflects the complex interactions that occur at the alveolar-capillary interface. A low DLco is associated with destruction of the airspace secondary to emphysema and a lower pulmonary vascular volume (Balasubramanian et al. 2019). DLco provided insight into functional limitations in patients with COPD and lung cancer (Videtic et al. 2004; Balasubramanian et al. 2019; de-Torres et al. 2021). A low DLco is associated with reduced exercise performance, severe exacerbations, and all-cause mortality in patients with COPD (Balasubramanian et al. 2019; de-Torres et al. 2021).

DLco reflects the functional status of lung cancer patients and is a general indicator of patient performance (Ferguson et al. 1988, 2012; Brunelli et al. 2013; Videtic et al. 2004). A low preoperative DLco is a predictor of postoperative cardiopulmonary complications, mortality, and poor long-term survival in surgical patients, including those with a normal FEV1 (Ferguson et al. 1988, 2012; Brunelli et al. 2013). According to Videtic et al. (2004), a low DLco is a marker of treatment tolerance and poor OS in patients with limited-disease SCLC. However, Lee et al. (2019) reported that a low DLco was not associated with poor survival in patients with ED-SCLC. In our study, the DLco < 60% group underwent fewer first-line chemotherapy cycles compared with the DLco ≥ 60% group (5 vs. 4, P = 0.005). The proportion of patients who received < 4 cycles of first-line chemotherapy was significantly higher in the DLco < 60% than ≥ 60% group (48.6% vs. 21.9%, P = 0.002). The low DLco may have affected the treatment tolerance of ED-SCLC patients, and the relatively few chemotherapy cycles may have affected their survival.

Lee et al. (2021) analyzed the Korean Health Insurance Review and Assessment Service database and reported that COPD increases the risk of death 1.17-fold in ED-SCLC patients. Another study noted that FEV1 < 80% was associated with shorter survival in patients with ED-SCLC (Kang et al. 2018). However, COPD and airflow limitation were not associated with survival in our study.

The number of metastatic sites at baseline is the most important prognostic predictor for OS in patients with ED-SCLC (Albain et al. 1990; Foster et al. 2009), and patients who have ≥ 2 metastatic sites have a significantly worse OS (Foster et al. 2009). Hong et al. (2010) confirmed that the disease extent, including liver metastasis, is a poor prognostic factor for SCLC. In an analysis of real-world data from 988 SCLC patients, Ma et al. (2021) showed that ED-SCLC without liver, bone, or subcutaneous metastases has favorable clinical outcomes. Our study confirmed that a high disease burden, i.e., more metastatic organs, was an independent risk factor for short OS in patients with ED-SCLC.

The standard treatment for ED-SCLC over the past two decades has been 4–6 cycles of a platinum-based etoposide regimen (Ganti et al. 2021). Liu et al. (2015) reported that ≥ 4 chemotherapy cycles (OR, 0.486; 95% CI, 0.301–0.786, P = 0.003) was a favorable prognostic factor for OS in SCLC patients. Other studies also reported that < 4 cycles of first-line chemotherapy predicted a shorter survival time in patients with ED-SCLC (Lee et al. 2019; Kim et al. 2022). However, some SCLC patients cannot undergo four cycles of full-dose chemotherapy because of old age or poor performance status (Kim et al. 2022). Kim et al. (2022) reported that first-line EP dose-reduced chemotherapy offered no significant survival disadvantage over full-dose chemotherapy in elderly ED-SCLC patients if they received a minimum of four cycles (median OS, 10.9 vs. 9.4 months, P = 0.817). Thus, a minimum of four cycles of dose-reduced chemotherapy should be considered in patients with SCLC who cannot tolerate full-dose chemotherapy.

First-line chemotherapy EP showed a trend toward good OS in the univariate analysis of our study, but was not associated with good OS in the multivariate analysis. In East Asian studies, IP as first-line chemotherapy improved survival compared with EP (Noda and Saijo 2002), but no significant difference was reported in western populations (Lara et al. 2009). According to a Korean nationwide cohort study (Lee et al. 2021), patients who receive IP have better survival outcomes than those who receive etoposide-based platinum therapy. In our study, no significant prognostic differences were detected between chemotherapy drug regimens.

The overall response rate to first-line chemotherapy in our study (27.4%) was lower than previous studies (Hong et al. 2010; Ma et al. 2021). Although the RECIST ver. 1.1 represents an evolution of these radiographic criteria, it relies on human measurement (Villaruz and Socinski 2013). The median OS (9.3 months), and disease control rate to first-line chemotherapy (87.3%) in our study were similar or superior compared to previous studies (Hong et al. 2010; Ma et al. 2021). Therefore, the difference in overall response rate is seen as a problem simply due to the difference in measurement between researchers.

This study had several limitations. First, it was a retrospective, observational single-center study with a small number of patients, although 10 years of medical records were available. However, considering the low prevalence of SCLC, it is not a number to be underestimated. Second, we did not evaluate potential confounding factors, such as hemoglobin, emphysema, destructive tuberculosis changes, pneumoconiosis, and pulmonary fibrosis. Given the high prevalence and morbidity of tuberculosis in Korea, the impact of these factors on DLco may be considerable. Finally, the prognosis of patients treated with immune checkpoint inhibitors was not analyzed. Adding an immune checkpoint inhibitor to platinum-based doublet therapy is the new standard of care for first-line treatment of ED-SCLC (Ganti et al. 2021). In South Korea, atezolizumab combined with EC therapy has only been available since August 1, 2020, so the effect of immunotherapy could not be assessed. Nonetheless, to our knowledge, this is the first study showing that a low DLco is associated with a poor prognosis in patients with ED-SCLC. Further prospective cohort studies are needed to verify whether DLco is a poor prognostic factor in SCLC patients.