Extensive-stage small cell esophageal carcinoma: a retrospective analysis of treatment modalities

Abstract

Background

This study aimed to investigate the clinicopathological features, treatment strategies and outcomes, failure patterns, and prognostic factors impacting progression-free survival (PFS) and overall survival (OS) in patients with extensive-stage primary small cell esophageal carcinoma (ES-SCEC).

Methods

This retrospective study included consecutive patients with ES-SCEC diagnosed and treated at Fudan University Shanghai Cancer Center from January 2006 to December 2024. Clinicopathological data related to diagnosis, staging, and follow-up were collected. In patients with available tumor specimens, immunohistochemistry (IHC) was performed to assess the expression of POU2F3 (POU class 2 homeobox 3), standard neuroendocrine markers, thyroid transcription factor-1 and Ki-67. Univariate and multivariate Cox proportional hazards models were used to identify prognostic factors, with statistical significance defined as a two-sided p value < 0.05.

Results

Among the 112 patients with ES-SCEC, the median PFS was 5.0 months (95% CI: 4.4–5.6), and the median OS was 9.0 months (95% CI: 7.9–10.1). Liver metastasis was the most common metastatic site at initial diagnosis (58.9%). The use of immune checkpoint inhibitors (ICIs), the number of chemotherapy (CT) cycle and T stage were identified as independent prognostic factors for OS. Independent predictors of PFS included T stage, CT cycle, and thoracic radiotherapy (TRT). The overall response rate (RR) was 52.7%, and the disease control rate (DCR) was 90.2%. Patients receiving CT combined with ICIs (n = 33) achieved significantly longer median OS than those who not treated with ICIs (n = 72) (13.8 months vs. 8.8 months, p = 0.029). Patients treated with TRT (n = 36) demonstrated improved local control and longer median PFS compared with those not receiving TRT (n = 69) (7.9 months vs. 4.1 months, p < 0.001). The combination of CT, ICIs, and TRT was associated with favorable outcomes, with median PFS and OS of 10.1 and 16.9 months, respectively.

Conclusion

The addition of ICIs to CT may be associated with improved survival in patients with ES-SCEC. This findings warrant validation in larger cohorts and prospective randomized studies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-026-16189-7.

Introduction

Primary small cell esophageal carcinoma (SCEC) is characterized by high malignancy, rapid progression, early metastasis, and an extremely poor prognosis. SCEC accounts for 0.5–2.8% of all esophageal malignancies [1, 2], with a rising incidence over the past decade. In regions with a high prevalence of esophageal cancer, the number of reported SCEC cases is substantially higher than in Western countries, and the absolute number of SCEC patients remains considerable [3].

The clinical manifestations, endoscopic and imaging features of SCEC are not obviously different from those of esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC). Due to the highly aggressive behavior and strong propensity for distant metastasis of SCEC, approximately half of patients are diagnosed at the extensive stage (ES), with a median survival time (MST) ranging from 3.4 to 13.0 months [4, 5]. The 5-year survival rate for limited-stage (LS) patients is approximately 10%, whereas that for ES patients is nearly zero [6–8]. However, owing to the low incidence of SCEC, prospective randomized controlled trials are not feasible; consequently, no specific TNM staging system or treatment guidelines have been established. Given the similarities between SCEC and small cell lung cancer (SCLC) in clinical course [7, 9, 10], morphology [11] and immunohistochemistry (IHC) staining [2], SCEC is generally staged according to the SCLC staging criteria proposed by the Veteran’s Administration Lung Cancer Study Group (VALSG), and most management strategies are extrapolated from those used for SCLC [12]. Nevertheless, the current therapeutic options for ES-SCEC remain unsatisfactory, and patient outcomes are generally poor. In addition, most published evidence consists of case reports or small retrospective series; systematic studies focusing specifically on ES‑SCEC are scarce. Consequently, the clinicopathological features, prognostic factors, and optimal treatment strategies for ES‑SCEC remain largely undefined.

The introduction of immunotherapy has substantially improved outcomes in SCLC. In the IMpower 133 trial [13], the addition of atezolizumab to etoposide-carboplatin chemotherapy achieved a 5-year survival rate of 12%, compared with 1–5% in the pre-immunotherapy era. In contrast, the role of immunotherapy in ES-SCEC remains largely unexplored.

In summary, this study retrospectively analysed the clinicopathological data of patients with ES-SCEC diagnosed and treated at our institution over an 18-year period, aiming to understand their survival status, prognostic factors, failure patterns, and to identify effective therapeutic modalities, which could provide a basis for the clinical management of ES-SCEC patients.

Materials and methods

Patient selection

Patients with pathologically confirmed primary SCEC who were diagnosed and treated at Fudan University Shanghai Cancer Center (FUSCC) between January 2006 and December 2024 were retrospectively reviewed. The exclusion criteria included: (1) patients with SCEC originating from other sites, such as the lungs; (2) mixed esophageal tumors with nondominant small cell carcinoma components (small cell component < 50%); and (3) incomplete medical or follow-up records. Disease stage was defined according to the VALSG staging system. Extensive-stage disease was defined as tumor spread beyond locoregional boundaries, based on clinical and imaging evaluations including contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, ultrasonography, or positron emission tomography/computed tomography (PET/CT). All patients were also staged via the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for esophageal cancer [14] and had distant lymph node or organ metastasis (cTanyNanyM1).

The present study was approved by the institutional review board and the independent ethics committee of FUSCC (approval number: 2202251-5) with the Helsinki Declaration (as revised in 2013). Owing to the retrospective and anonymized nature of the analysis, informed consent was waived.

Treatment

First-line treatment modalities included chemotherapy (CT) alone, thoracic radiotherapy (TRT) alone, CT combined with immune checkpoint inhibitors (ICIs) (CT + ICIs), CT + TRT, CT + ICIs + TRT, and CT combined with surgery (CT + S). In the CT + TRT group, intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) were allowed. The gross tumor volume (GTV) included primary tumor and involved regional lymph nodes. Surgical procedures included open or minimally invasive esophagectomy.

Endpoints definition and follow-up

Clinicopathological variables including demographic characteristics, performance status (PS), tumor length and location, imaging and pathological findings, treatment details, response to therapy, failure patterns, and survival outcomes were collected. Immunohistochemical analysis of POU2F3 (POU class 2 homeobox 3), synaptosomes (Syn), chromogranin A (CgA), CD56, thyroid transcription factor-1 (TTF-1), and Ki-67 were performed in 87 accessible samples. Tissue samples collected during gastroscopy prior to treatment were routinely processed and then embedded in paraffin. All the specimens were immunohistochemically examined using the EnVision 2-step method.

The routine examination during follow-up included physical, blood, and imaging examinations. If the patient had specific symptoms, the examination was performed as soon as possible for a more careful assessment. Disease recurrence/progression was categorized as local (esophagus and anastomotic), regional (regional lymph nodes) or distant (distant lymph nodes or organs, including supraclavicular lymph nodes). The last follow-up was performed on June 30, 2025, or upon patient death. Patients were followed up at the institution or by phone. Overall survival (OS) was defined as the interval from initiation of treatment to death from any cause, and progression-free survival (PFS) as the time from treatment initiation to disease progression or death. Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria [15].

Statistical analysis

All data from this study were entered and analyzed using SPSS 26.0 (SPSS Inc., Chicago, IL). The mean values were presented as mean ± standard deviations (SDs). Continuous data were compared using the Student’s t-test, and categorical variables were analysed using the Chi-square test or Fisher’s exact test. Survival analysis was performed by the Kaplan-Meier method, and survival rates were compared via the log-rank test, with 95% confidence intervals (CIs) reported. The relationships between survival and clinicopathological variables were determined by Cox proportional hazards regression by calculating the hazard ratio (HR) and 95% CI in multivariate analyses. A 2-sided probability value of less than 0.05 was considered statistically significant.

Results

Patient demographic and baseline characteristics

The detailed baseline clinicopathological characteristics of the 112 patients with ES-SCEC are summarized in Table 1. The median age was 64 [interquartile range (IQR), 66–70] years old. Most patients were male (77.7%), had a PS of 1 (72.3%), were smokers (56.3%), and had tumors located in the middle or lower esophagus (middle thoracic 36.6%; lower thoracic 48.2%). Pure SCEC accounted for 92.0% of cases (n = 87), whereas the remaining patients had mixed histology, including squamous cell carcinoma (n = 6), adenocarcinoma (n = 1) or large cell neuroendocrine carcinoma (n = 2). Immunohistochemical analysis demonstrated positive staining rates of 95.4% for CD56, 88.5% for synaptophysin, 75.9% for TTF-1, 57.5% for chromogranin A, and 8.0% for POU2F3 (Fig. S1 and Fig. S2) .

Table 1.

The clinicopathological characteristics of 112 patients with ES-SCEC

Characteristics	Number	(%)
Sex
Male	87	77.7
Female	25	22.3
Age
< 70	82	73.2
≥ 70	30	26.8
Performance status
1	81	72.3
2	31	27.7
Comorbidity
Yes	57	50.9
No	55	49.1
Family history
No	82	73.2
Yes	30	26.8
Length of disease
≤ 7 cm	87	73.2
> 7 cm	25	26.8
Primary site
Cervical	0	0.0
Upper thoracic	12	10.7
Middle thoracic	41	36.6
Lower thoracic	54	48.2
Overlap	5	4.5
Smoking history
Yes	63	56.3
No	49	43.8
Heavy drinking
Yes	41	36.6
No	71	63.4
Food habit
Yes	27	24.1
No	85	75.9
Second tumor
Yes	7	6.3
No	105	93.8
BMI
< 18.5 kg/m2	10		8.9
18.5–25 kg/m2	85			75.9
> 25 kg/m2	17	15.2
Pathology
Pure SCEC	103	92.0
Mixed SCC	6	5.3
Mixed ADC	1	0.9
Mixed large cell NEC	2	1.8
POU2F3
Positive	7	8.0
Negative	80	92.0
Syn
Positive	10	11.5
Negative	77	88.5
CgA
Positive	50	57.5
Negative	37	42.5
CD56
Positive	83	95.4
Negative	4	4.6
TTF1
Positive	66	75.9
Negative	21	24.1
T stage (8th)
T1a	0	0.0
T1b	0	0.0
T2	12	10.7
T3	45	40.2
T4a	20	17.9
T4b	35	31.2
N stage (8th)
N0	0	0.0
N1	9	8.0
N2	47	42.0
N3	56	50.0

Abbreviations: ES-SCEC Extensive-stage small cell esophageal carcinoma, BMI Body mass index, SCC Squamous cell carcinoma, ADC Adenocarcinoma, NEC Neuroendocrine carcinoma, POU2F3 POU class 2 homeobox 3, Syn Synaptosomes, CgA Chromogranin A, TTF1 Thyroid transcription factor-1

According to the 8th edition of the TNM staging system, most patients were classified as T3 (40.2%) or T4 (49.1%) stage. All the patients had lymph node metastases, including 9 (8.0%) with N1, 47 (42.0%) with N2, and 56 (50.0%) with N3 disease. Comorbid conditions were well controlled at the initiation of anticancer treatment.

All patients presented distant lymph node and/or distant organ metastasis at baseline. Liver metastasis was the most common distant metastatic organ (58.9%), followed by bone metastasis (31.3%), retroperitoneal lymph node metastasis (25.0%) and lung metastasis (23.2%). Only 3 patients (2.7%) had brain metastasis at initial diagnosis. Detailed information on metastatic patterns at diagnosis is provided in Table S1.

Survival and treatment failure

As of the last follow-up on June 30, 2025, 99 patients died, and 13 patients remained alive. The median PFS for the entire cohort was 5.0 months (95% CI: 4.4–5.6), with a 6-month PFS rate of 35.7% and a 1-year PFS rate of 3.6%. The median OS was 9.0 months (95% CI: 7.9–10.1), with 12-, 18-, and 24-month OS rates of 32.9%, 11.9%, and 3.6%, respectively.

At the time of analysis, one patients remained disease stable, 97 patients experienced disease progression, and the pattern of failure was unknown in 14 patients. As summarized in Table 2, distant metastasis was the predominant pattern of failure, occurring in 86 patients (88.7%) as the first site of recurrence. The most common sites of distant metastasis during disease progression were the liver (n = 59), brain (n = 20), and bone (n = 18), as detailed in Table 3.

Table 2.

Recurrence/progression pattern after first line treatment in ES-SCEC patients

Failure pattern	Number	%
Locoregional only	11	11.3
Local only	1	1.0
Regional only	8	8.2
Both	2	2.1
Distant only	57	58.8
Both	29	29.9
Regional + distant	16	16.5
Locoregional + distant	13	13.4

Abbreviations: ES-SCEC Extensive-stage small cell esophageal carcinoma

Table 3.

Metastatic sites after first line treatment of ES-SCEC patients

Pattern of failure	Number
Liver metastasis	59
Brain metastasis	20
Bone metastasis	18
Lung metastasis	12
Supraclavicular lymph node metastasis	11
Retroperitoneal lymph node	11
Adrenal metastasis	2

Abbreviations: ES-SCEC Extensive-stage small cell esophageal carcinoma

Prognostic factors for PFS and OS

The results of the multivariate Cox proportional hazards analysis of PFS and OS are shown in Table 4. Univariate analysis identified tumor length, CT cycle, TRT and T stage as factors significantly associated with PFS (Table S2). Several factors were included in the multivariate Cox proportional hazards model after univariate analysis, and tumor length lost their significance as independent prognostic factor of PFS in ES-SCEC patients. The survival curves are shown in Fig. 1.

Table 4.

The results of multivariate analysis in different prognostic factors for all patients

Variables	OS			PFS
	HR	95%CI	p value	HR	95%CI	p value
ICIs (Yes vs. No)	0.60	0.37–0.92	0.030*	-	-	-
CT cycle (< 4 vs. ≥ 4)	1.97	1.28–3.04	0.002*	2.98	1.91–4.54	< 0.001*
TRT (Yes vs. No)	-	-	-	0.31	0.20–0.75	< 0.001*
T stage (2-4a vs. 4b)	0.43	0.27–0.69	< 0.001*	0.48	0.31–0.75	0.001*

Abbreviations: OS Overall survival, PFS Progression-free survival, CT Chemotherapy, ICIs Immune checkpoint inhibitors, TRT Thoracic radiotherapy

Fig. 1.

PFS curves stratified by T stage (A), CT cycle (B) and TRT (C) in patients with ES-SCEC. Abbreviations: PFS, progression-free survival; TRT, thoracic radiotherapy; CT, chemotherapy; ES-SCEC, extensive-stage small cell esophageal carcinoma

For OS, univariate analysis demonstrated significant associations with tumor length, POU2F3 expression, CT cycle, use of ICIs and T stage (Table S3). Multivariate Cox regression analysis revealed that T4b disease, absence of ICI, and receipt of fewer than four CT cycles were independent predictors of inferior OS (Fig. 2).

Fig. 2.

OS curves stratified by T stage (A), CT cycle (B) and ICIs (C) in patients with ES-SCEC. Abbreviations: OS, overall survival; ICIs, immune checkpoint inhibitors; CT, chemotherapy; ES-SCEC, extensive-stage small cell esophageal carcinoma

Treatment outcomes

First-line treatment modalities for patients with ES-SCEC included TRT alone (2, 1.8%), CT alone (43, 38.4%), CT + ICIs (26, 23.2%), CT + TRT (29, 25.9%), CT + ICIs + TRT (7, 6.2%), and CT + S (5, 4.5%). Fifty-nine patients achieved partial response (PR) and 42 achieved stable disease (SD) as the best response after first-line treatment, with a response rate (RR) of 52.7% and a disease control rate (DCR) of 90.2%. Eleven patients experienced progressive disease (PD) during treatment. The most common CT regimen was etoposide plus platinum (n = 94, 86.3%), of whom 79 received cisplatin and 15 received carboplatin. Other CT regimens included: paclitaxel + cisplatin (10.1%), S1 + cisplatin (0.9%), S1 + oxaliplatin (0.9%), epirubicin + oxaliplatin + capecitabine (0.9%), oral etoposide (0.9%). None of the patients received prophylactic cranial irradiation. Survival outcomes by treatment group are illustrated in Fig. S3, with corresponding median PFS and OS summarized in Table S4.

TRT alone was associated with poor outcomes (median PFS 1.8 months; median OS 3.0 months). Among patients treated with CT alone (mean, 3.9 ± 1.9 cycles), ORR and DCR were 46.5% and 86.0%, respectively. In CT + ICIs group, ORR was 53.8% and DCR was 92.3%. Three patients received programmed cell death ligand 1 (PD-L1), and the remaining patients received PD-1 antibodies. Patients treated with CT + TRT achieved an ORR of 51.7% and a DCR of 96.6%. All seven patients who received CT combined with ICIs and TRT achieved PR as their best response. This group demonstrated a median PFS of 10.1 months (95% CI, 6.8–13.4) and a median OS of 16.9 months (95% CI, 14.0-19.8).

To further evaluate the impact of immunotherapy, patients treated with TRT alone or CT + S were excluded. The remaining patients were categorized into CT alone (n = 72) and CT + ICIs groups (n = 33). Baseline characteristics, including use of TRT, CT cycle, tumor length, and T stage, were well balanced between groups (Table S5). Compared with CT alone, the addition of immunotherapy was associated with significantly prolonged OS (13.8 months vs. 8.8 months, p = 0.029; Fig. 3A), while there was no significant difference in PFS (5.3 months vs. 4.0 months, p = 0.052). To exclude the influence of era effects, we further analyzed survival data of patients from the same era after the introduction of immunotherapy, following the methods described above. Compared with the CT group (n = 41), the CT + ICIs group (n = 33) was also associated with prolonged OS (13.8 months vs. 7.0 months, p = 0.002; Fig. S4), and the baseline parameters between the two groups were balanced and comparable (Table S6). Similarly, patients were stratified into CT alone (n = 69) and CT + TRT (n = 36). Baseline characteristics were comparable between groups (Table S7). The addition of TRT to CT significantly improved PFS (7.9 months vs. 4.1 months, p < 0.001; Fig. 3B), although no significant difference in OS was observed (11.0 vs. 8.8 months, p = 0.063).

Fig. 3.

OS curves in ICIs vs. non-ICIs (A) and PFS curves in TRT vs. non-TRT (B) groups in patients with ES-SCEC (n = 102). Abbreviations: OS, overall survival; PFS, progression-free survival; ICIs, immune checkpoint inhibitors; TRT, thoracic radiotherapy; ES-SCEC, extensive-stage small cell esophageal carcinoma

Discussion

Primary SCEC is an aggressive and rare carcinoma with a strikingly poor prognosis. Owing to its marked biological heterogeneity, nonspecific clinical presentation, and limited awareness, most patients are diagnosed at an advanced stage, and evidence guiding the management of extensive-stage disease remains scarce. In this large single-center retrospective cohort, we systematically evaluated the clinicopathological characteristics, treatment patterns, survival outcomes, and prognostic factors of patients with ES-SCEC. Our findings indicate that disease burden (T stage), treatment intensity (number of CT cycle), and treatment modality—particularly the use of ICIs and TRT—are key determinants of clinical outcomes in this population.

Patterns of failure observed in this study underscore the aggressive metastatic potential of ES-SCEC. Brain metastasis (BM) is typically associated with poor prognosis in cancer patients, and ES-SCEC patients with BM have an even worse prognosis [16]. In this study, although BMs were uncommon at initial diagnosis (n = 3, 2.7%), they emerged as the second most frequent sites of disease progression during follow-up (n = 20, 17.9%). Owing to the scarcity of studies reporting on BMs in SCEC, the exact incidence of BM in SCEC patient remains unclear. This finding is consistent with prior reports suggesting a higher propensity for BM in SCEC (6.7–12.0%) [16, 17] compared with ESCC (0.34–1.4%) [18, 19]. The relatively high incidence of brain involvement after first-line treatment highlights the need for heightened clinical vigilance and may support more frequent neuroimaging surveillance in selected patients, although the role of prophylactic cranial irradiation in ES-SCEC remains undefined.

The prognostic significance of IHC markers in SCEC has been controversial. In the present study, conventional, individual neuroendocrine markers and TTF-1 expression were not associated with survival outcomes, which is consistent with several previous reports [20, 21]. POU2F3 (POU class 2 homeobox 3) a transcription factor defining a distinct molecular subtype of SCLC, was expressed in a small proportion of SCLC tumors [22–24]. We observed strong nuclear POU2F3 expression in 8.0% (7/87) of SCEC specimens, accompanied by absent or minimal expression of TTF-1 and conventional neuroendocrine markers, a pattern consistent with prior reports in SCLC [25]. Univariate analysis indicated that ES-SCEC patients with POU2F3-positive tumors had significant poorer OS than those without POU2F3 expression (6.0 months vs. 10.1 months, p = 0.012); however, this association did not persist in multivariate analysis. Currently, there is a lack of definitive evidence regarding the impact of molecular subtyping on the prognosis of SCLC, and data on POU2F3 in SCEC are extremely rare. The findings in our study are merely explorative, further studies integrating molecular profiling with functional analyses are warranted to clarify the biological and clinical relevance of this marker.

To date, few studies have systematically evaluated treatment strategies for ES-SCEC, and available evidence suggests that current modalities confer only limited survival benefit. Small retrospective series have reported that CT prolongs survival compared with best supportive care in patients with ES-SCEC (9.5 months vs. 6.0 months) [26]. In patients with stage IV disease, CT has been shown to significant improve survival (MST 12.5 vs. 4.0 months, p < 0.001), and the CT combined with radiotherapy appears superior to CT alone (MST 13.2 vs. 8.9 months, p = 0.014) [27]. In the era of immunotherapy, the corporation of ICIs into platinum-etoposide CT has become the standard first-line approach for ES-SCLC [28–30]. Given the similarities between SCEC and SCLC in clinical behavior, histopathology, and molecular features [2, 31], immunotherapy represents a biologically plausible therapeutic option for ES-SCEC; nevertheless, its clinical efficacy in this setting remains insufficiently characterized.

Emerging translational studies indicate that most SCEC tumors exhibit an immunosuppressive tumor microenvironment characterized by limited infiltration of T cells and CD8⁺ cytotoxic T lymphocytes [4, 5, 31], a phenotype also prevalent in SCLC and other small cell carcinomas [32]. Notably, PD-L1 expression is infrequently detected on tumor cells but is present on tumor-infiltrating immune cells in a substantial proportion of SCEC specimens (44.2%). Prior studies have demonstrated that PD-L1 expression on immune cells and increased CD8⁺ T-cell infiltration are independently associated with improved OS in SCEC [4]. Moreover, a subset of SCEC tumors displays features of immune activation and adaptive immune tolerance, suggesting potential sensitivity to immunotherapy in selected patients [31]. Similarly, Wu et al. found SCEC showed higher CD8_c14_CXCL13 infiltration than healthy tissue, which was considered as immune reactive T cells accounting for response of immunotherapy [5]. Additionally, Jiang et al. described a case of ES-SCEC with microsatellite instability and high tumor mutational burden in which the patient achieved complete response after three months of treatment with anlotinib combined with toripalimab (an anti-PD-1 antibody) following first-line CT failure [33]. Consistent with these observations, our study demonstrated that the use of ICIs was independently associated with improved OS, yet this requires validation in prospective clinical trials.

Importantly, the survival advantage associated with immunotherapy was more evident for OS than for PFS. On the one hand, given the rarity of small cell SCEC, the resulting limited sample size may also contribute to insufficient statistical power for detecting a difference in PFS. On the other hand, pivotal phase III randomized trials in ES‑SCLC have demonstrated a delayed separation of survival curves between ICI‑containing regimens and CT alone, with PFS benefits emerging only after several months of follow‑up [28, 29, 34, 35]. A similar phenomenon in ES‑SCEC may partially explain the absence of a statistically significant improvement in PFS in our cohort. Future large‑scale prospective studies are needed to further elucidate this matter.

Prior to the incorporation of ICIs into the treatment paradigm for ES-SCLC, consolidative TRT has been shown to improve thoracic control and survival outcomes [36–39]. Given the rarity of SCEC, the role of TRT in ES-SCEC remains poorly defined. In the present study, both concurrent (40%) and consolidative TRT (60%) were utilized and the optimal timing of local intervention could not be further delineated given the limited sample size, the addition of TRT to CT was independently associated with improved PFS, although no significant improvement in OS was observed. This finding potentially imply that TRT may enhanced local disease control thus primarily influence intrathoracic tumor burden without substantially altering the course of systemic disease; more definitive conclusions and underlying mechanistic analyses await confirmation in future studies.

First-line CT combined with ICIs has demonstrated only modest efficacy in ES-SCLC, yielding a median survival improvement of approximately 3 months, the addition of consolidative TRT in selected patients may potentially enhance this outcome. Several retrospective and early-phase studies suggest that such a combined approach is feasible and safe, and prospective randomized phase III trials are currently ongoing. Furthermore, evidence indicates that ICIs can synergize with radiotherapy to enhance antitumor efficacy, a phenomenon attributed to the immunomodulatory effects of radiotherapy [40, 41]. Notably, in this study, seven SCEC patients received first-line consolidative TRT in addition to etoposide-platinum CT combined with immunotherapy. This group achieved a median PFS of 10.1 months and a median OS of 16.9 months, suggesting a favorable treatment response. TRT was not associated with severe toxicities, and no cases of grade 3 or higher pneumonitis occurred. Nevertheless, given the retrospective nature of the analysis and the small number of patients treated with this combined modality, these results should be interpreted with caution and require confirmation in prospective studies. Meanwhile, the mechanisms underlying the immunomodulatory effects of radiotherapy in SCEC warrant further investigation.

Several limitations of this study should be acknowledged. First, the retrospective design, the single-center setting and the extended time span inherently introduce selection bias. Second, the sample size, particularly for subgroup analyses involving immunotherapy and combined-modality treatment, was relatively small. Third, differences between anti-PD-1 and anti-programmed death ligand 1 (PD-L1) agent were not explored. Fourth, routine brain MRI surveillance was not performed in all SCEC patients, which may have led to underestimation of the true incidence of brain metastases. Despite these limitations, this study represents one of the largest dedicated analyses of ES-SCEC to date and provides clinically relevant insights into prognostic factors and contemporary treatment strategies. Nonetheless, more effective systemic therapies are urgently needed to reduce the risk of distant metastasis and improve long-term survival in this aggressive disease.

Conclusion

This study identified key prognostic factors in patients with ES-SCEC and suggests that the corporation of ICIs into CT may be associated with improved survival outcomes, while the addition of TRT may enhance PFS. Although limited by its retrospective design and sample size, this analysis provides clinically relevant evidence to inform future prospective studies and treatment strategies for ES-SCEC.

Author contributions

Di Liu and Yiliang Zhang conceived and designed the study. Di Liu and Xiaofei Zhang drafted the manuscript. Di Liu, Xiaofei Zhang and Junhua Zhang analysed and interpreted all the data. Di Liu and Xiaofei Zhang prepared the figures and tables. Jiaqing Xiang, Zhen Zhang, Kuaile Zhao and Di Liu reviewed and revised the manuscript. All authors have read and approved the manuscript for publication.

Funding

The study is supported partially by National Natural Science Foundation of China (NNSF: 82303695) and Wu Jieping Medical Foundation (320.6750.2025-13-34).

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The present study was approved by the institutional review board and the independent ethics committee of Fudan University Shanghai Cancer Center (FUSCC, approval number: 2202251-5) with the Helsinki Declaration (as revised in 2013). Owing to the retrospective and anonymized nature of the analysis, informed consent was waived.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.