Neoadjuvant immunochemotherapy in potentially resectable small cell lung cancer: a real-world retrospective analysis

Introduction

Small cell lung cancer (SCLC) is one of the most aggressive malignancies, and accounts for approximately 15% of all lung cancer cases (1). Globally, there are approximately 250,000 new cases of SCLC and 200,000 SCLC-related deaths annually (2). Under the Veterans Administration Lung Study Group staging system, SCLC is typically classified as limited-stage SCLC (LS-SCLC) or extensive-stage SCLC (ES-SCLC), which corresponds to stage I–III and stage IV of the American Joint Committee on Cancer-International Association for the Study of Lung Cancer tumor-node-metastasis (TNM) staging system, respectively (3,4). According to the National Comprehensive Cancer Network (NCCN) guidelines, only a small number of patients with negative pathologic mediastinal staging T1–2N0M0 (stage I–IIA) LS-SCLC are eligible for surgery (4). For the majority of patients, the standard treatment comprises radiotherapy combined with systemic chemotherapy. The recent ADRIATIC trial demonstrated that consolidation therapy with durvalumab after chemoradiotherapy significantly extended the median overall survival to 56 months; however, the need to explore superior treatment modalities persists (2,5).

Neoadjuvant therapy has evolved as a multidisciplinary approach in the treatment of malignant tumors. It aims to shrink tumors and reduce surgical trauma, thereby improving patient prognosis. Currently, systemic neoadjuvant therapy has become a standard treatment for various solid tumors, including early-stage non-SCLC (6,7). However, the application of neoadjuvant therapy in SCLC, which is prone to early resistance, remains controversial (8).

Recent advancements in immunotherapy have revolutionized the treatment landscape of SCLC, significantly improving the prognosis of patients with ES-SCLC (9-12). Although immunotherapy combined with chemotherapy using programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors was not shown to significantly improve the objective response rate (ORR) compared to chemotherapy alone, it was shown to extend median progression-free survival (PFS), indicating its potential to overcome early resistance in SCLC, and suggesting that neoadjuvant therapy may have a role in the treatment of LS-SCLC (13). We previously reported the case of a stage IIIB SCLC patient who achieved a pathological complete response (pCR) after five cycles of neoadjuvant therapy with serplulimab [an anti-PD-1 monoclonal antibody (mAb)] combined with etoposide plus cisplatin, and remained disease-free for over two years (updated follow-up) (14). However, all of these studies have reported outcomes from single cohorts. It is not yet known whether neoadjuvant therapy is suitable for SCLC patients and whether the addition of immunotherapy to neoadjuvant therapy can further improve patient prognosis.

Based on the existing evidence and clinical challenges in the treatment of LS-SCLC, we conducted a single-center, real-world, two-arm retrospective analysis. This study aimed to explore the feasibility of neoadjuvant therapy for potentially resectable LS-SCLC and assess whether the addition of immunotherapy to neoadjuvant therapy further improves the prognosis of LS-SCLC patients. By analyzing real-world data, we aimed to provide evidence to guide treatment strategies for these patients and suggest future research directions. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1422/rc).

Methods

Patients and treatments

We retrospectively reviewed the medical records of SCLC patients treated at the West China Hospital of Sichuan University between January 2018 and March 2024. This study focused on potentially resectable patients receiving neoadjuvant therapy. According to the clinical practice at our center, for patients with LS-SCLC staged as IIB–III (based on the 8th edition TNM staging), if the multidisciplinary team assessment deemed an R0 resection technically feasible and the patient’s performance status (PS) tolerable for surgery, a strategy of neoadjuvant therapy followed by surgery would be considered. Patients who underwent surgery following neoadjuvant therapy were included in the analysis. Patients were included in the study if they: (I) were aged 18 years or older and had a histologically confirmed diagnosis of SCLC; (II) had potentially resectable stage IIB–III disease with no distant metastasis; (III) had undergone surgical resection after receiving systemic neoadjuvant therapy; and (IV) had not undergone systemic anti-tumor therapy before neoadjuvant treatment. Patients were excluded from the study if they: (I) had another primary malignancy; (II) had a histologic diagnosis of combined SCLC; and/or (III) had incomplete medical records (specifically, missing key data such as details of neoadjuvant therapy regimen, surgical pathology report, or survival follow-up information). Patients were further divided into the following two groups based on the neoadjuvant treatment regimen: the chemotherapy-only group (Group A) and the immunochemotherapy group (Group B). The chemotherapy regimen comprised etoposide in combination with either cisplatin or carboplatin, while the immunochemotherapy regimen included the addition of a PD-1 or PD-L1 monoclonal antibody to the chemotherapy regimen. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The human investigations were performed after approval by the Institutional Review Board of West China Hospital of Sichuan University (No. 2024-1015). Individual consent for this retrospective analysis was waived.

Data collection and outcome assessment

Data on the baseline characteristics of the patients, including sex, age, smoking status, comorbidities, Eastern Cooperative Oncology Group (ECOG) PS, and tumor TNM stage, were collected from the electronic medical records. We also thoroughly reviewed detailed information on neoadjuvant treatment and surgical procedures, including treatment cycles, type of surgery, resection status, status of postoperative pathological residual disease, and safety data. All surgeries aimed for systematic lymph node dissection (including cases with N3 involvement). Postoperative pathological assessment was independently reviewed by two senior pathologists. Postoperatively, patients were followed up to collect information on adjuvant therapy, survival outcomes, and other relevant prognostic data.

The primary endpoints of this study were pCR and disease-free survival (DFS). pCR was defined as the absence of residual tumor cells in the primary tumor site and lymph nodes. DFS was defined as the time from the initiation of neoadjuvant therapy to disease recurrence or death from any cause. The secondary endpoints included the R0 resection rate, major pathological response (MPR), tumor response to neoadjuvant therapy, and safety. R0 resection was defined as the absence of microscopic residual tumor cells at the surgical margin. MPR was defined as ≤10% residual viable tumor cells in the resected tumor bed, regardless of the presence of residual tumor cells in the lymph nodes. Tumor response was assessed according to RECIST 1.1 based on contrast-enhanced chest computed tomography (CT). A small subset of patients underwent positron emission tomography (PET)-CT restaging after neoadjuvant therapy (with similar proportions between groups). For cases of suspected pseudoprogression, a comprehensive judgment was made through multidisciplinary discussion, considering patient symptoms, tumor markers, and a comparison with prior imaging. The safety analysis was based on the adverse events (AEs) recorded in the patients’ medical records and evaluated independently by two investigators, K.L.H. and D.P., according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All AEs, including expected ones such as postoperative pain, were recorded in accordance with standard reporting guidelines. In cases of disagreement, a third investigator, T.W., made the final decision.

Statistical analysis

Statistical analyses were performed with R software (version 4.3.2). Continuous variables were tested for normality using the Shapiro-Wilk test. Normally distributed variables were expressed as the mean ± standard deviation (SD), whereas non-normally distributed variables were expressed as the median and range. Categorical variables were summarized as the frequency and percentage (%). Differences in the baseline characteristics between Group A and Group B were assessed using Chi-squared tests or Fisher’s exact tests as appropriate. The Kaplan-Meier method was used to estimate DFS and OS, and comparisons were made using the log-rank test. Subgroup analyses were conducted to explore the consistency of treatment effects across clinically relevant subgroups. For DFS, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) comparing neoadjuvant chemo-immunotherapy with chemotherapy alone within each subgroup. For pCR, logistic regression models were applied to estimate odds ratios (ORs) and corresponding 95% CIs. In addition, exploratory analyses were performed to identify potential factors associated with DFS and pCR. Univariate Cox and logistic regression analyses were conducted for DFS and pCR, respectively, and variables with a P value <0.10 were considered for inclusion in the corresponding multivariable models. The proportional hazards assumption for Cox regression models was assessed using Schoenfeld residuals. Safety characteristics were summarized descriptively. All statistical tests were two-sided, with the significance level set at P<0.05.

Results

Patient baseline and treatment characteristics

We retrospectively reviewed the medical records of 173 patients with LS-SCLC who were treated at West China Hospital, Sichuan University between January 2018 and March 2024. A total of 59 patients with stage IIB–III disease who underwent surgery following neoadjuvant therapy were included in the final analysis (Figure 1). The mean age of the enrolled patients was 57.6 years, and more than 70% of the patients were younger than 65 years and male. Overall, the patients had good PS; 94.9% had ECOG-PS scores of 0–1. In total, 16 patients (27.1%) had a comorbid chronic disease at the time of diagnosis (Table 1). Nearly half of the patients (n=25, 42.4%) were diagnosed with stage IIIA disease. The median primary tumor diameter was 4.7 cm. In terms of lymph node involvement, 74.6% of the patients had N2 disease, and 5.1% (n=3) had N3 disease. The patients were further categorized based on whether they received immunotherapy in the neoadjuvant setting, resulting in two groups: Group A, which included patients who received chemotherapy alone (n=27), and Group B, which included patients who received a combination of anti-PD-1 or anti-PD-L1 monoclonal antibodies and chemotherapy (n=32). The baseline clinicopathologic characteristics were generally well-balanced between the two groups (Table 1).

Figure 1 Study profile. Group A, patients receiving neoadjuvant chemotherapy. Group B, patients receiving neoadjuvant immunochemotherapy. EC, etoposide + cisplatin; EP, etoposide + carboplatin; EPC, etoposide + cisplatin + carboplatin; MPR, major pathological response; pCR, pathological complete response; PD-1, programmed death 1; PD-L1, programmed death-ligand 1.

All patients included in the analysis received a doublet regimen of etoposide combined with a platinum agent. The use of carboplatin and cisplatin was generally consistent across the cohort (Table 2), as was the use of anti-PD-L1 and anti-PD-1 monoclonal antibodies for the patients in Group B. The anti-PD-L1 monoclonal antibodies included atezolizumab, durvalumab, and adebrelimab, while the PD-1 inhibitor used was serplulimab. The median number of neoadjuvant therapy cycles was three, and the median time from the last dose of neoadjuvant therapy to surgery was 41 days [interquartile range (IQR): 33.0–59.0 days]. The vast majority of patients (88.1%) underwent open thoracotomy. Lobectomy was the most common type of resection (83.1%). There were no statistically significant differences between Groups A and B in terms of the surgical approach or type of resection. More than 90% of the patients achieved an R0 resection (n=55, 93.2%), and no statistically significant difference in R0 resection rates was observed between Groups A and B (Table 2).

A total of 54 patients (91.5%) received systemic adjuvant therapy after surgery, including 23 of 27 patients in Group A and 31 of 32 patients in Group B (Table 2). In Group B, only one patient received chemotherapy alone as adjuvant therapy, while all the other patients underwent an adjuvant strategy that included immunotherapy. Conversely, of the patients in Group A who received adjuvant therapy, only four chose an immunotherapy-based regimen, while the remainder received a platinum-based chemotherapy regimen. In addition, 31 patients received postoperative radiotherapy, of whom 11 received thoracic consolidation radiotherapy and 28 received prophylactic cranial irradiation.

Tumor response after neoadjuvant therapy

Based on radiological assessments, 47 of the patients included in the analysis achieved an objective response, resulting in an ORR of 79.7% (95% CI: 67.2–89.0%). Among these, six patients achieved a radiologic complete response (CR) during neoadjuvant therapy, all in Group B. Additionally, the ORR in Group B was 96.9% while that in Group A was 59.3%. The patients who received immunotherapy combined with chemotherapy had a better tumor response to neoadjuvant therapy than those who received chemotherapy alone (P<0.001, Table 3).

A total of 18 patients (30.5%) achieved pCR, including three patients (11.1%) in Group A and 15 patients (46.9%) in Group B, resulting in an absolute difference of 35.8% between the two groups. Thus, the neoadjuvant strategy of combining immunotherapy with chemotherapy significantly increased the pCR rate (P=0.006; OR =7.06, 95% CI: 1.76–28.24) (Table 3 and Figure 1). The subgroup analysis showed that the neoadjuvant immunochemotherapy strategy was more efficacious across almost all patient subgroups, with statistically significant characteristics including age <65 years, absence of comorbidities, and lower tumor T stage. However, due to the small sample size of this study, the wide CIs of the ORs suggest that these results should be interpreted with caution, and further validation in larger clinical trials is warranted (Figure 2A). MPR was observed in 25 patients (42.4%), including five patients (18.5%) in Group A and 20 patients (62.5%) in Group B. In addition, 40 patients (67.8%) experienced tumor T-stage downstaging after neoadjuvant therapy, including 12 patients (44.4%) in Group A and 28 patients (87.5%) in Group B (Figure 2B). Additionally, 27 patients experienced N2/3 downstaging (45.8%), including 8 patients (29.6%) in Group A and 19 patients (59.4%) in Group B (Figure 2C).

Figure 2 Overview of pathological outcomes in patients treated with neoadjuvant therapy. (A) Subgroup analysis of pCR stratified by clinical characteristics. (B) Changes in T stage after neoadjuvant therapy. (C) Changes in N stage after neoadjuvant therapy. Group A, patients receiving neoadjuvant chemotherapy. Group B, patients receiving neoadjuvant immunochemotherapy. CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group performance status; N, node; OR, odds ratio; pCR, pathological complete response; T, tumor.

Univariable logistic regression analysis (Table S1) revealed that patients with an ECOG PS of 1–2 had a significantly lower likelihood of achieving pCR compared to those with ECOG PS 0 (OR =0.13, 95% CI: 0.02–0.7, P=0.02), and patients receiving neoadjuvant immunochemotherapy had a significantly higher pCR rate than those receiving chemotherapy alone (OR =7.06, 95% CI: 1.96–34.02, P=0.006). Other variables did not show significant influence in univariable analysis. In the multivariable logistic regression, which included only variables with P<0.10 from the univariable analysis, ECOG PS remained an independent predictor of pCR (OR =0.08, 95% CI: 0.01–0.55, P=0.02). Neoadjuvant immunochemotherapy continued to be significantly associated with an increased pCR rate in the multivariable model (OR =9.72, 95% CI: 2.3–68.21, P=0.006), suggesting a higher probability of preoperative tumor CR in patients with good baseline PS and those receiving immunotherapy combined with chemotherapy.

Survival prognosis of patients

As of August 2024, we had completed a median follow-up of 18.9 months (range, 4.4–35.7 months) for all patients. The median DFS of all patients was 13.7 months (95% CI: 11.7–18.9), with a median DFS of 11.6 months (95% CI: 9.7–17.1) for Group A patients and 15.3 months (95% CI: 13.7–not reached) for Group B patients. The difference in DFS between the two groups was statistically significant (P=0.03; HR =0.49, 95% CI: 0.26–0.94) (Figure 3A). The subgroup analysis of DFS showed that the neoadjuvant immunochemotherapy strategy was more efficacious across almost all patient subgroups, with statistically significant characteristics including age <65 years, male gender, non-N2/N3 status, stage IIB disease, and receipt of adjuvant therapy (Figure 3B).

Figure 3 Survival outcomes of patients treated with neoadjuvant therapy. (A) Kaplan-Meier curves for DFS. (B) Subgroup analysis of DFS stratified by clinical characteristics. (C) Kaplan-Meier curves for OS. Group A, patients receiving neoadjuvant chemotherapy. Group B, patients receiving neoadjuvant immunochemotherapy. CI, confidence interval; DFS, disease-free survival; ECOG-PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; N, node; NR, not reached; OS, overall survival; T, tumor.

A total of seven patients had died by the data cut-off date (six in Group A and one in Group B). The OS data were immature, with the median OS not yet reached and the lower bound of the 95% CI at 32.0 months. The OS survival curves for Groups A and B began to diverge approximately 10 months after the initiation of neoadjuvant therapy; however, there was no statistically significant difference in OS between the two groups (Figure 3C).

Univariable Cox regression analysis (Table S2) showed that patients receiving neoadjuvant immunochemotherapy had a significantly reduced risk for DFS events (HR =0.49, 95% CI: 0.26–0.94, P=0.03), while other variables showed no significant effect. In the multivariable Cox regression model, which included only variables with P<0.10 from the univariable analysis, immunochemotherapy still showed a trend towards a protective effect on DFS, although it did not reach statistical significance.

Safety

All patients experienced at least one AE during the neoadjuvant and perioperative periods. Fortunately, all AEs were grade 1–2, and no patients experienced grade 3 or higher AEs. During neoadjuvant therapy, the incidence of AEs was 100% in both groups. The most common AEs in all patients were leukopenia (44.1%), pancytopenia (39.0%), and fatigue (33.9%). In Group A, the most frequent AEs were leukopenia (48.2%), pancytopenia (40.7%), and fatigue (37.0%), while in Group B, the most common AEs were leukopenia (40.6%), pancytopenia (37.5%), fatigue (31.3%), and neutropenia (31.3%) (Table 4).

The incidence of AEs during the perioperative period was also 100%, with all patients experiencing at least one procedure-related pain event (100%). In addition, infectious pneumonia (37.0%) and wound complications (11.1%) were relatively common in Group A, whereas infectious pneumonia (28.1%) and anemia (18.8%) were more common in Group B (Table 4). These results suggest that SCLC patients tolerate neoadjuvant therapy well, whether they receive chemotherapy alone or in combination with immunotherapy, and the safety profile of the therapy was manageable.

Discussion

Immunotherapy has revolutionized the treatment paradigm for SCLC; however, the indications and feasibility of radical surgery and neoadjuvant/adjuvant therapy for early-stage patients have not been clearly defined (15). Historically, several guidelines, including the NCCN guidelines, and lung cancer experts worldwide have stated that surgical intervention is not appropriate for SCLC (4). This conclusion was based on two prospective randomized controlled trials conducted in the last century (16,17). In the 1960s, the United Kingdom Medical Research Council (MRC) conducted a trial involving 144 resectable SCLC patients, who were randomly assigned to receive either surgery or radical radiotherapy (16). The results showed that the mean survival time of the surgical patients was 199 days, while that of those receiving radiotherapy was 284 days (P=0.05). The 2-year survival rates of the groups were 4% and 10%, respectively, while the 5-year survival rates were 1% and 4%, respectively, indicating that radical radiotherapy was more suitable for these patients. The Lung Cancer Study Group (LCSG) conducted another randomized controlled trial of 328 patients with non-metastatic SCLC who received five cycles of cyclophosphamide, doxorubicin, and vincristine chemotherapy (17). The patients who achieved an objective response (CR + partial response) were then randomized to receive surgery (70 patients) or not (76 patients). The results showed no difference in the median OS between the two groups, with 2-year survival rates of 20% in both groups. As a result, for decades, the international medical community viewed radical surgery as an option only for stage I–IIA patients, who typically represent less than 5% of all SCLC cases (18).

However, from the perspective of rapidly advancing medical science, these two prospective studies conducted in the last century have clear limitations. For example, the MRC study did not include neoadjuvant or adjuvant chemotherapy, and the neoadjuvant treatment regimen in the LCSG study did not include platinum-based agents. Moreover, in recent decades, there have been significant advancements in cancer treatment technologies. Beyond the revolutionary impact of immunotherapy, perioperative management has also improved considerably, allowing patients to derive greater benefits from surgery. These developments underscore the substantial unmet clinical need in the treatment of early-stage SCLC and compel us to re-evaluate curative treatment strategies for these patients. Expanding the indications for radical surgery may provide a new avenue for improving survival in this population.

Our study retrospectively analyzed the data of SCLC patients who received neoadjuvant therapy followed by surgery at the West China Hospital of Sichuan University over a 6-year period from 2018 to 2024. The results showed that all the patients tolerated the treatment well, with a pCR rate of 30.5%. Notably, the pCR rate of the patients who received neoadjuvant immunochemotherapy was significantly higher than that of those who received chemotherapy alone (46.9% vs. 11.1%, P=0.006). The survival follow-up also showed that median DFS was significantly better in the immunochemotherapy group than the chemotherapy-only group (15.3 vs. 11.6 months, P=0.03). Further, the safety of the treatment was manageable; the AEs were limited to grades 1–2 and were reversible. These findings indicate that neoadjuvant therapy is a safe and feasible option for patients with potentially resectable stage IIB–III SCLC. Moreover, neoadjuvant immunochemotherapy offers a clear advantage over chemotherapy alone in terms of the pathological response and survival outcomes, warranting further investigation and validation.

These results are consistent with findings from other small clinical studies. A prospective study conducted by Duan et al. (19), which included 17 patients with stage I–IIIB SCLC, demonstrated that the majority of patients achieved R0 resection following neoadjuvant treatment with atezolizumab combined with a platinum-based doublet, with a pCR rate of 61.5% (12/13, 92.3% achieved R0 resection). Similarly, retrospective studies by Lu et al. (20) and Liu et al. (8), which included six and 19 patients, respectively, also supported the feasibility of neoadjuvant immunochemotherapy. In the study by Lu et al. (20), all patients achieved a partial pathologic response, while Liu et al. (8) reported a pCR rate of 30% (3/10). Another study comparing the efficacy of neoadjuvant chemotherapy and adjuvant chemotherapy in terms of survival outcomes in LS-SCLC patients found that neoadjuvant chemotherapy significantly improved median OS and 5-year survival (21). In a phase 3, double-blind, randomized, placebo-controlled trial, consolidation durvalumab after chemoradiotherapy prolonged OS and PFS to 55.9 months (median, 95% CI: 37.3–not reached) and 16.6 months (median, 95% CI: 10.2–28.2), respectively, in patients with ES-SCLC (5).

Compared to some earlier small-scale studies focusing solely on the neoadjuvant phase, our study collected more comprehensive perioperative treatment data, including specific details of adjuvant therapy (chemotherapy, immunotherapy, or chemoradiotherapy), thereby providing efficacy and safety information that more closely reflects real-world clinical scenarios. The larger sample size and real-world clinical context of our study provide stronger evidence for the potential expansion of curative treatment strategies for SCLC. These results provide valuable real-world historical data that can serve as a reference for future research.

We previously reported the case of a 51-year-old female patient with stage IIIB SCLC (T4N2M0) (14). Despite the large size of the primary tumor at diagnosis (approximately 9.0 cm × 6.9 cm) and the presence of a 3.4 cm × 3.2 cm positive mediastinal lymph node, the patient achieved significant tumor shrinkage after five cycles of neoadjuvant immunochemotherapy with serplulimab combined with etoposide and cisplatin. Radiological imaging revealed a reduction of the primary tumor to 1.5 cm during neoadjuvant therapy, and postoperative pathology confirmed a pCR, with no residual tumor cells in the resected specimens. Given the subgroup analysis results from this study, factors such as the patient’s relatively young age, absence of comorbidities, and N2 lymph node status, in addition to the benefits derived from the immune checkpoint inhibitor (ICI), may have contributed to the achievement of pCR.

Our analysis has preliminarily confirmed the efficacy and feasibility of neoadjuvant therapy, particularly immunochemotherapy, in potentially resectable SCLC patients; however, several critical issues need to be addressed. Notably, research needs to be conducted on the optimal number of neoadjuvant therapy cycles, long-term survival outcomes, and the use of different immunotherapy agents. Due to limitations related to the study sample size, we could not address all of these clinically relevant questions in our study. The findings from this analysis require further exploration and validation in studies with larger sample sizes.

The goal of immunotherapy is to induce a cellular immune response, specifically T-cell-mediated cytotoxicity directed against tumor-specific antigens and tumor-associated antigens, thereby selectively destroying tumor cells (22). In addition, immunomodulators can combat cancer cells by increasing the levels of tumor-specific antibodies, natural killer cells, dendritic cells, macrophages, and cytokines (23). Unfortunately, in this retrospective study, we were unable to further elucidate the mechanisms by which immunotherapy enhances the efficacy of neoadjuvant treatment. However, in our previous research, we observed that patients who achieved a pCR after neoadjuvant immunotherapy had increased infiltration of T cells and monocytes in the tumor bed, but decreased infiltration of myeloid-derived suppressor cells and macrophages (14).

Lung cancer was once considered unsuitable for immunotherapy due to its weak immune response; however, technological advances have gradually elucidated the types and densities of immunogenic molecules relevant to lung cancer, paving the way for various immunotherapies (24,25). The aggressiveness of SCLC can be attributed to its high tumor mutation burden (TMB), which includes the biallelic inactivation of tumor suppressor genes associated with almost all tumorigenic processes, such as p53 and Rb1 (26). A high TMB generates more neoantigens, enhancing T-cell presentation and potentially leading to more effective immunotherapies (27). SCLC has long been considered immunogenic, as it is associated with paraneoplastic syndromes like Lambert-Eaton myasthenic syndrome (LEMS) that are linked to immune responses against specific antigen targets (HuD, HuC, and Hel-N1) expressed on both SCLC and normal neuronal cells (28-30). SCLC patients with LEMS may achieve better outcomes with immunotherapy, as the immune response targeting the nervous system may also target tumor cells (31). Currently, the use of ICIs as neoadjuvant anti-tumor therapy has garnered significant attention across the oncology field. Immune checkpoints, such as CTLA-4, PD-1, B7-H3, and B7x, attenuate antigen-specific immune responses by limiting the scope and duration of T-cell immunity (32). The use of ICIs acts as a co-stimulatory factor and plays a critical role in the immunoregulation mediated by antigen-specific T-cell responses (33). Further, the subgroup analysis in this study suggests that adjuvant therapy, particularly when it includes immunotherapy, may further improve patient survival. This finding underscores the need to develop comprehensive perioperative immunotherapy strategies for these patients in future clinical practice to maximize their potential benefits.

Our study had several limitations. First, as a retrospective study, our inclusion criterion of having undergone surgery inevitably introduces selection bias, as it excludes patients who experienced disease progression during neoadjuvant therapy or whose PS deteriorated, precluding surgical intervention. This may lead to a study population with a more favorable prognosis than the broader patient cohort. Additionally, retrospective studies rely on real-world clinical data, where the principles of clinical management may evolve over time. For example, in our study, the patients in the chemotherapy group had their medical records documented relatively earlier than those in the immunotherapy group, which might have led to differences in the clinical management techniques. In this study, patients in the chemotherapy group were treated at a relatively earlier time, when the clinical accessibility and insurance coverage for immunotherapy were both limited. This may reflect how real-world treatment choices evolve over time and with policy changes. These factors could potentially influence the efficacy and safety outcomes of the treatments. Despite stable disease on radiological assessment, some patients still underwent surgery based on a comprehensive MDT evaluation of tumor biology, the patient’s strong preference, and the potential for R0 resection. This clinical decision-making reflects the complexity of real-world practice but may also introduce selection bias. Furthermore, there were differences in the postoperative adjuvant treatment regimens received by the two groups, particularly in the proportion of immunotherapy use. This may have introduced confounding effects on the observed difference in DFS and represents another limitation of this retrospective analysis. Despite these limitations, our study has significant clinical value and provides important insights for future research. By comparing the efficacy and safety of different treatment regimens, we provide valuable information for clinicians regarding neoadjuvant therapy for SCLC. Moreover, our findings provide data to support further exploration of the role of immunotherapy in the neoadjuvant treatment of SCLC, which may help guide future clinical practice and research directions.

Conclusions

Our study suggests that the addition of immunotherapy to neoadjuvant treatment regimens for LS-SCLC could represent a significant advancement in the treatment paradigm. Larger multi-center prospective studies with more diverse patient populations need to be conducted to validate and extend our findings. Further research should also focus on identifying biomarkers that predict response to neoadjuvant immunotherapy, enabling more personalized treatment approaches.

Acknowledgments

The authors would like to thank Lung Cancer Center, West China Hospital of Sichuan University for helpful discussions on topics related to this work.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1422/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1422/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1422/prf

Funding: This work was partially supported by Sichuan Science and Technology Program (No. 2021YFQ0029), and Research Program of West China Hospital, Sichuan University (Nos. HX-H2105128, HX-H2112318, and HX-H2204070).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1422/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The human investigations were performed after approval by the Institutional Review Board of West China Hospital of Sichuan University (No. 2024-1015). Individual consent for this retrospective analysis 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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(English Language Editor: L. Huleatt)