Clinical impact and prognostic factors of early radiotherapy in limited-disease small-cell lung cancer cohort

Introduction

Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma that accounts for approximately 10–15% of all lung cancers (1). It predominantly affects men in their 60s and 70s, with cigarette smoking as the primary risk factor, and is characterized by rapid progression, high metastatic potential, and high mortality (2,3). In recent years, global research has focused on the transcriptional and inflammatory characteristics of SCLC, generating growing interest in novel clinical approaches such as targeted therapy and immunotherapy, similar to those used in non-small cell lung cancer (NSCLC) (4,5). Advances in radiotherapy (RT) techniques and supportive care have improved overall survival (OS) for patients with SCLC (6). Although the introduction of immune checkpoint inhibitors has changed treatment guidelines for extensive-disease (ED) SCLC, concurrent platinum-based chemotherapy and thoracic RT remain the standard first-line therapy for limited-disease (LD) SCLC. Several studies comparing outcomes according to the initiation timing of thoracic RT have reported improved prognosis with early thoracic RT (ERT) (2,7-9). However, since 2010, relatively few investigations have examined the optimal timing of thoracic RT, and evidence supporting superior outcomes with ERT remains limited (Table 1) (10-17).

Prophylactic cranial irradiation (PCI) has been established as a standard treatment option for patients with SCLC, although its efficacy and associated risk factors are not fully established (18,19). Previous meta-analyses demonstrated that PCI reduces the incidence of brain metastasis in LD-SCLC; however, its effect on OS has been inconsistent and may not adequately reflect recent advances in diagnostic and therapeutic strategies (20).

This study aimed to retrospectively analyze a single-institution cohort of patients with SCLC to evaluate treatment outcomes and toxicities according to thoracic RT timing, identify prognostic factors influencing outcomes in LD-SCLC, and assess the efficacy of PCI. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2719/rc).

Methods

Study design and participants

This single-center, retrospective observational study was conducted at Asan Medical Center in Republic of Korea and included patients with LD-SCLC. Adult patients aged ≥19 years who were diagnosed and treated at the institution between January 2018 and December 2022 were included. Clinical data, including treatment history, disease progression, and survival outcomes, were collected. Among these patients, those who received concurrent chemoradiotherapy (CCRT) were evaluated to compare prognostic differences according to the timing of RT initiation. Patients with LD-SCLC were assessed through multidisciplinary discussion, and CCRT was generally considered the standard treatment strategy when clinically feasible.

ERT was defined as the initiation of thoracic RT within 9 weeks after the start of chemotherapy or during the first three cycles of chemotherapy. Late thoracic RT (LRT) was defined as initiation of thoracic RT more than 9 weeks after chemotherapy initiation or after three or more cycles of chemotherapy, consistent with previous studies summarized in Table 1, which adopted a 9-week cutoff. Because this study was retrospective, the timing of thoracic RT was not determined by a predefined protocol but rather through multidisciplinary clinical decision-making, considering factors such as patient performance status, pulmonary function, treatment tolerance during chemotherapy, tumor burden, and logistical aspects of RT planning. Initial staging was routinely performed using chest and abdominal computed tomography (CT), positron emission tomography-CT (PET-CT), and brain magnetic resonance imaging (MRI) to evaluate disease extent and exclude brain metastases. Invasive mediastinal staging using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was selectively performed when further pathological confirmation of mediastinal lymph node involvement was clinically indicated (21). During follow-up, chest CT and brain MRI were routinely performed to monitor disease recurrence and detect intracranial metastases.

The primary outcome was treatment efficacy according to the thoracic RT schedule. Secondary outcomes included prognostic factors affecting survival in LD-SCLC and treatment outcomes according to PCI administration.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2023-1160). Because this was a retrospective observational study, all clinical data were anonymized, and the requirement for informed consent was waived.

Data collection

Data on age, sex, body mass index (BMI), smoking history, Eastern Cooperative Oncology Group (ECOG) performance status scale, pulmonary function test results, and comorbidities were retrospectively collected from medical records. Information related to SCLC treatment, including chemotherapy, RT, and surgery, was also obtained.

Treatment outcome data included OS, progression-free survival (PFS), and brain metastasis-free survival (BMFS). OS was defined as the time from treatment initiation to death or the last follow-up, whichever occurred first. PFS was defined as the time from treatment initiation to disease progression, initiation of subsequent therapy, or death, whichever occurred first. BMFS was defined as the time from treatment initiation to the diagnosis of brain metastasis. Treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), including overall response rate (ORR) and disease control rate (DCR) (22). Among patients who experienced disease recurrence, differences between locoregional recurrence and distant recurrence were evaluated to further characterize post-treatment relapse patterns. The frequency and severity of treatment-related adverse events were compared between the ERT and LRT groups.

Statistical analysis

Continuous variables are presented as mean and standard deviation. Normally distributed data were compared using the independent t-test, whereas non-normally distributed data were analyzed using the Mann-Whitney U test. Categorical variables are presented as numbers and percentages, and differences between groups were analyzed using the Chi-squared test or Fisher’s exact test, as appropriate.

Propensity score matching (PSM) was performed to reduce potential selection bias and balance covariates between groups, comparing ERT with LRT and PCI recipients with non-recipients. Matching was conducted using a 1:1 nearest-neighbor algorithm with a caliper of 0.2. Covariates included in the PSM were age, ECOG performance status, diffusing capacity of the lung for carbon monoxide (DLCO), tumor-node-metastasis (TNM) stage, and smoking status.

Survival and disease progression data (OS, PFS, BMFS) were analyzed using Kaplan-Meier survival curves. Risk factors associated with mortality and disease progression were evaluated using the Cox proportional hazards model. Analyses were performed using complete cases in the PSM cohort, as no substantial missing data were present for the variables of interest. All statistical analyses were performed using SPSS version 21.0 software (IBM Corp., Armonk, NY, USA) and R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value <0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 122 patients with LD-SCLC were enrolled between January 2018 and December 2022. After excluding patients who did not receive CCRT or had unclear classification into ERT or LRT, 99 patients were analyzed, comprising 74 in the ERT group and 25 in the LRT group. Among these, 22 patients received PCI. Following PSM, 16 patients were retained in each of the ERT and LRT groups, and 13 patients were matched between the PCI and non-PCI groups (Figure 1).

Figure 1 Flow chart of the study. CCRT, concurrent chemoradiotherapy; CTX, chemotherapy; ERT, early thoracic radiotherapy; LD, limited disease; LRT, late thoracic radiotherapy; PCI, prophylactic cranial irradiation; PSM, propensity score matching; SCLC, small cell lung cancer.

Table 2 presents the baseline characteristics of the overall cohort and stratified by ERT and LRT groups. The mean age of the entire LD-SCLC cohort was 66.0 years; 87.9% were male, and 89.9% had a history of smoking. Patients in the ERT group had a lower mean age (64.2±8.2 vs. 71.3±6.6 years, P<0.001) and had a higher BMI (24.1±3.2 vs. 22.8±2.7 kg/m², P=0.02) than those in the LRT group. Pulmonary function, measured by forced vital capacity (FVC) (82.7%±14.5% vs. 76.1%±9.4% predicted, P=0.01) and DLCO (71.1%±15.1% vs. 57.5%±13.7% predicted, P<0.001), was superior in the ERT group. No significant differences were observed in T stage, N stage, or overall TNM stage between the two groups. Most patients who received PCI were in the ERT group (95.5%). After PSM, previously imbalanced variables were adequately adjusted.

Survival analysis

The median OS for the entire cohort was 30.0 months [95% confidence interval (CI): 19.7–40.3]. Figure 2 compares survival outcomes between the ERT and LRT groups. Figure 2A shows OS, with 5-year survival rates of 37.8% in the ERT group and 10.7% in the LRT group. The median OS was 41.0 months (95% CI: 32.4–49.6) for the ERT group and 12.0 months (95% CI: 5.5–18.5) for the LRT group (P<0.001). Figure 2B compares PFS according to the time of RT. The median PFS was significantly longer in the ERT group (23.0 months; 95% CI: 14.9–31.1) than in the LRT group (8.0 months; 95% CI: 5.9–10.1) (P<0.001). Figure 2C compares OS after PSM, showing that the median OS remained longer in the ERT group (20.0 months; 95% CI: 16.1–23.9) than in the LRT group (12.0 months; 95% CI: 6.1–17.9) (P=0.041). Similarly, Figure 2D compares PFS after PSM; the median PFS was longer in the ERT group (16.0 months; 95% CI: 10.1–21.9) than in the LRT group (8.0 months; 95% CI: 5.6–10.4) (P=0.01). No significant difference in BMFS was observed between the two groups (P=0.32).

Figure 2 Survival outcomes according to ERT and LRT. (A) OS. (B) PFS. (C) OS after PSM. (D) PFS after PSM. ERT, early thoracic radiotherapy; LRT, late thoracic radiotherapy; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.

Figure 3 presents survival outcomes according to PCI status. Patients who received PCI had superior OS (P=0.001; Figure 3A) and PFS (P=0.009; Figure 3B), whereas BMFS did not differ between the PCI and non-PCI groups (P=0.34; Figure 3C). However, after PSM, PCI status was no longer associated with OS (P=0.14; Figure 3D) or PFS (P=0.16; Figure 3E), whereas BMFS showed significant improvement in the PCI group (P=0.048; Figure 3F).

Figure 3 Survival outcomes according to PCI status. (A) OS. (B) PFS. (C) BMFS. (D) OS after PSM. (E) PFS after PSM. (F) BMFS after PSM. BMFS, brain metastasis-free survival; OS, overall survival; PCI, prophylactic cranial irradiation; PFS, progression-free survival; PSM, propensity score matching.

Prognostic factor

Table 3 presents the Cox proportional hazards analysis of factors influencing OS. In univariate analysis, age [hazard ratio (HR) =1.039; 95% CI: 1.014–1.065; P=0.002], ECOG 2–4 (HR =2.082; 95% CI: 1.105–3.920; P=0.02), DLCO (HR =0.964; 95% CI: 0.950–0.979; P<0.001), LRT (HR =3.397; 95% CI: 2.016–5.723; P<0.001), and PCI (HR =0.315; 95% CI: 0.152–0.653; P=0.002) were significantly associated with mortality. Among TNM stages, only stage IIIB (HR =1.880; 95% CI: 1.121–3.154; P=0.01) was significant. In multivariate analysis, age, DLCO, and LRT remained significant prognostic factors. Table 4 shows Cox regression results after PSM. In univariate analysis, age (HR =1.092; 95% CI: 1.043–1.143; P<0.001) and LRT (HR =2.212; 95% CI: 1.162–4.209; P=0.01) were significantly associated with increased mortality, whereas DLCO did not show a significant association (P=0.31). In multivariate analysis adjusted for age and DLCO, LRT (HR =2.752; 95% CI: 1.268–5.972; P=0.01) and age (HR =1.133; 95% CI: 1.078–1.191; P<0.001) remained independent predictors of OS.

Table 5 presents factors influencing PFS. In univariate analysis, age (HR =1.037; 95% CI: 1.014–1.061; P=0.002), ECOG 2–4 (HR =2.408; 95% CI: 1.339–4.332; P=0.003), DLCO (HR =0.971; 95% CI: 0.958–0.985; P<0.001), LRT (HR =3.256; 95% CI: 1.935–5.478; P<0.001), and PCI (HR =0.391; 95% CI: 0.208–0.735; P=0.004) were significantly associated with mortality. Among TNM stages, only stage IIIC (HR =2.346; 95% CI: 1.206–4.566; P=0.01) was significant. In multivariate analysis, age and LRT remained significant predictors of PFS. Table 6 summarizes the Cox regression analysis of factors associated with progression after PSM. In the univariate analysis, age (HR =1.055; 95% CI: 1.021–1.090; P=0.001) and LRT (HR =2.793; 95% CI: 1.293–6.033; P=0.009) were significantly associated with an increased risk of disease progression, whereas DLCO was not statistically significant (P=0.46). In multivariate analysis adjusted for age and DLCO, LRT (HR =3.062; 95% CI: 1.370–6.846; P=0.006) and age (HR =1.079; 95% CI: 1.046–1.114; P<0.001) remained independent predictors of shorter PFS.

Treatment response and adverse events

Table 7 summarizes treatment outcomes according to RT timing. The ERT group showed a higher ORR (91.9% vs. 83.3%) and DCR (97.3% vs. 92.0%) than the LRT group, although these differences were not statistically significant. During the study period, disease recurrence occurred in 44.4% of patients, with no significant difference in the patterns of locoregional or distant recurrence according to the timing of thoracic RT (P=0.71).

Table 8 presents treatment-related adverse events. Grade 3 or higher adverse events occurred in 56% of patients in the ERT group and 50% in the LRT group, with no significant difference between the groups (P>0.99). Neutropenia was the most frequent adverse event, and no treatment-related deaths were observed.

Discussion

This retrospective study evaluated prognostic differences according to thoracic RT timing and the use of PCI in patients with LD-SCLC who received CCRT. Patients who received ERT demonstrated superior OS and PFS, and these findings remained consistent after PSM. No significant difference in BMFS was observed according to ERT status. In contrast, patients who received PCI demonstrated significant improvement only in BMFS after PSM. Multivariate Cox regression analysis revealed that age at diagnosis and timing of thoracic RT were independently associated with prognosis. Treatment response and treatment-related adverse events did not differ according to thoracic RT timing.

These findings reflect contemporary treatment outcomes in patients with LD-SCLC and reinforce the clinical value of ERT, consistent with previous studies (12,13,16). Evidence from randomized trials and meta-analyses suggests that earlier initiation of thoracic RT may improve survival outcomes in patients with LD-SCLC (2,7-9,17). Among patients receiving platinum-based chemotherapy combined with thoracic RT, ERT has generally been favored, as indicated by the meta-analysis by Fried et al. (2). However, subsequent studies have reported that LRT does not necessarily result in inferior survival outcomes and may be associated with reduced toxicity, leaving the optimal timing of thoracic RT an ongoing point of debate (23). The treatment paradigm for SCLC has recently evolved with the introduction of immunotherapy (24,25). Although immunotherapy has been incorporated into the treatment paradigm for SCLC, the optimal integration of immunotherapy with CCRT, including the timing of thoracic RT, remains unclear. In addition, sequential thoracic RT following induction chemotherapy has demonstrated favorable outcomes in selected populations such as older adults with LD-SCLC (26). In this context, the prognostic findings of the present study provide additional evidence supporting the efficacy of ERT.

Although patients in the ERT group were younger and exhibited better baseline pulmonary function, multivariate analyses adjusting for these factors confirmed the independent prognostic value of ERT, which demonstrated the strongest association with survival among all predictors. Moreover, after PSM for age, pulmonary function, and TNM stage, both univariate and multivariate analyses consistently identified ERT as a significant prognostic factor. Notably, the median OS (41.0 months, 95% CI: 32.4–49.6) and median PFS (23.0 months, 95% CI: 14.9–31.1) in the ERT group were substantially longer than those reported in most previous studies, which may reflect improvements in treatment strategies and supportive care (10,11,14,17).

Several poor prognostic factors for SCLC have been reported, including advanced age, poor performance status, ED, and elevated serum lactate dehydrogenase levels; however, real-world data remain limited, and findings have been inconsistent across studies (27-29). Kim et al. identified low DLCO as a poor prognostic factor in patients with ED-SCLC (30). Similarly, Videtic et al. reported a significant association between low DLCO and treatment interruptions due to toxicity, although DLCO was not statistically correlated with survival duration (31). DLCO is a key physiological parameter that quantitatively assesses pulmonary gas exchange capacity and reflects both structural and functional abnormalities of the lungs (32). Although several studies have shown that reduced forced expiratory volume in 1 second (FEV₁) negatively affects SCLC prognosis, research examining the relationship between DLCO and SCLC outcomes remains limited (32-34). Previous studies in NSCLC have reported that lower baseline DLCO or a greater decline in DLCO is associated with an increased risk and severity of treatment-related pneumonitis (35-39). In the present study, DLCO was not identified as a significant prognostic factor after PSM; however, based on evidence research, it may still represent a potential pulmonary function parameter influencing the clinical course of SCLC. Further prospective studies are warranted to clarify the prognostic role of DLCO in patients with SCLC.

Since the 1999 meta-analysis demonstrating that PCI reduces intracranial metastasis and improves 3-year survival, PCI has been widely regarded as a standard treatment for SCLC (40). Before the widespread adoption of routine brain MRI follow-up, a randomized trial comparing standard-dose PCI (25 Gy) with high-dose PCI (36 Gy) demonstrated that the higher-dose PCI did not significantly reduce the incidence of brain metastases and was associated with increased overall mortality (41). Consequently, 25 Gy PCI has remained the standard of care for LD-SCLC. However, this paradigm has evolved with the increased implementation of routine brain MRI surveillance. A Japanese randomized controlled trial reported that when brain MRI was performed every 3 months, PCI did not improve OS (42). Similarly, a 2020 U.S. multicenter study found that PCI after thoracic RT was not significantly associated with a reduced risk of brain metastasis or improved survival (43). As a result, although PCI continues to be recommended as a standard treatment, concerns regarding neurotoxicity have led some clinicians to omit PCI in clinical practice. Recently, a multicenter, prospective, randomized trial was initiated to test the hypothesis that, in patients with LD-SCLC who achieve a complete response after CCRT and have no evidence of brain metastasis, regular MRI surveillance without PCI may represent a feasible management strategy (44). In the present study, post-PSM survival analysis suggested that PCI may improve BMFS; however, further evidence is needed to elucidate its long-term impact on clinical outcomes in SCLC.

Several studies have reported higher incidences of neutropenia and esophagitis in patients receiving ERT (10,11,45). In the present study, consistent with previous reports, neutropenia was the most frequent treatment-related adverse event. However, no significant difference in toxicity was observed according to the timing of thoracic RT. Furthermore, the overall frequency of grade 3–4 adverse events was relatively low, suggesting improvements in the management of chemotherapy-related toxicities.

This study has some limitations. First, as a single-center retrospective analysis, potential selection bias and incomplete information regarding the RT field could have influenced the results. Because treatment timing was determined during routine clinical practice rather than according to a predefined protocol, immortal time bias related to thoracic RT timing cannot be completely excluded. Furthermore, quantitative tumor volume was not systematically recorded and therefore could not be directly analyzed. Because tumor burden may influence the timing of thoracic RT, this represents a potential limitation. To partially address this issue, we examined tumor-related staging variables that may indirectly reflect tumor burden, including T stage, N stage, and overall TNM stage, that may indirectly reflect tumor burden and found no significant differences between groups. Nevertheless, residual confounding related to tumor volume cannot be completely excluded. Second, the number of patients in the PSM cohort was relatively small, which may limit the statistical power of the analysis. In addition, only a minority of patients received PCI in this cohort; therefore, conclusions regarding the survival benefit of PCI should be interpreted with caution. Finally, because this was a retrospective observational study, post-PCI neurotoxicity could not be evaluated. Despite these limitations, this study provides additional evidence regarding the timing of thoracic RT and prognostic factors in LD-SCLC, serving as a valuable basis for future research.

Conclusions

In conclusion, among patients with LD-SCLC who received CCRT, ERT was associated with improved survival outcomes and was identified as a favorable prognostic factor, with no significant differences in treatment-related toxicity. Although PCI was not clearly associated with OS or disease progression, it may contribute to improved BMFS. Further research is warranted to clarify the role of PCI and its associated complications.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2719/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2719/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2719/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2719/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2023-1160). Because this was a retrospective observational study, all clinical data were anonymized, and the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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