A retrospective real-world single-arm study evaluating the efficacy and safety of neoadjuvant chemotherapy in patients with selected limited-stage small-cell lung cancer

Introduction

Globally, lung cancer continues to be the predominant cause of cancer-related mortality, constituting an estimated 18% of all such deaths (1). Small-cell lung cancer (SCLC), a neuroendocrine tumor characterized by high invasiveness and propensity for metastasis, accounts for approximately 15% of all lung cancer cases (2,3). Based on the Veterans Administration Lung Study Group classification, SCLC is classified into limited and extensive stages, with approximately one-third diagnosed as limited-stage SCLC (LS-SCLC) (4).

Over the past six decades, the treatment for LS-SCLC has been extensively explored in clinical settings, including surgery, radiotherapy, and medical treatments (5). In the 1960s, prospective randomized controlled trials (RCTs) indicated that radiotherapy offered better outcomes than surgery (6). Lad et al. investigated the efficacy of neoadjuvant chemotherapy followed by surgery for LS-SCLC and found that did not extend survival compared to chemoradiotherapy (7). In light of the failures from earlier surgical trials, subsequent research has largely concentrated on the development of novel drugs and improvements in radiotherapy modalities, with surgery-related trials being rare (5). The National Comprehensive Cancer Network (NCCN) guidelines establish concurrent or sequential chemoradiotherapy as the standard of care for LS-SCLC, with surgery being recommended only for patients with T1–2N0M0 staging (8). Nevertheless, the majority of patients experience disease recurrence within 2 years following standard thoracic chemoradiotherapy, with a 5-year survival rate of approximately 30% (9-11). Therefore, more effective alternative treatments are warranted.

Recently, great improvements have been achieved in surgical techniques (12). Thoracoscopic surgery approaches, such as video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS), offer a minimally invasive alternative to traditional open surgery (13). Compared to open thoracotomy, thoracoscopic surgery offers benefits such as reduced postoperative pain, shorter hospital stays, and lower complication rates, while providing comparable oncologic outcomes (14-16). Notably, a growing body of real-world evidence suggests that for selected LS-SCLC, surgery-based treatment modalities may have superior outcomes compared to standard chemoradiotherapy (17-20). Therefore, the feasibility of surgery for the treatment of selected LS-SCLC merits renewed consideration. Furthermore, existing evidence indeed suggests that neoadjuvant therapy can enhance surgical opportunities, increase the rate of radical resection, reduce postoperative recurrence and distant metastasis, and ultimately extend patient survival (21). Therefore, the therapeutic strategy integrating neoadjuvant therapy with surgery is likely to improve clinical outcomes for selected LS-SCLC, and clinical evidence is warranted to ascertain its efficacy and safety.

In this study, we conducted a retrospective, real-world, single-arm trial to evaluate the efficacy and safety of the combined treatment modality of neoadjuvant chemotherapy with surgery for selected LS-SCLC, with the objective of identifying enhanced therapeutic strategies for these patients. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-209/rc).

Methods

Study design and participants

This clinical trial was conducted as a retrospective, single-center, single-arm study at Shanghai Pulmonary Hospital from December 2015 and December 2022. This retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Research Ethics Committee of Shanghai Pulmonary Hospital (No. K18-203). Informed consent requirements were waived due to the use of anonymized and deidentified data for this retrospective study. Our study aimed to evaluate the efficacy and safety of neoadjuvant chemotherapy combined with surgery in patients diagnosed with potentially resectable LS-SCLC. The inclusion and exclusion criteria for patients are presented in Table S1.

Data collection

We conducted an exhaustive compilation of demographic and clinical information from the medical files of the patients included in the study. Baseline characteristics such as age, sex, smoking history, clinical stage, and histological subtype were meticulously recorded. Clinical staging was established based on pre-neoadjuvant treatment imaging, encompassing positron emission tomography (PET)-computed tomography (CT), CT, brain magnetic resonance imaging (MRI), or endobronchial ultrasound (EBUS) results. Detailed information on the neoadjuvant treatment procedure, including the regimen, treatment cycles, and the time from the last treatment dose to surgery, was also retrieved. In addition, we collected comprehensive surgical data, including the approach and duration, extent of resection, operative time, estimated blood loss, margin status, postoperative complications, and other operative details, as well as information on adjuvant treatments such as chemotherapy regimens and cycles, and the frequency and dosage of radiotherapy. Patients were followed up until October 02, 2024, or until death. The data collection process was conducted by two medical oncologists and reviewed by the chief oncologist to ensure accuracy and reliability. Only data that passed the final quality control checks were included in the analysis.

Clinical outcomes evaluation

The radiologic response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (22). A partial response (PR) was defined as a reduction of at least 30% in the sum of diameters of all measurable target lesions compared to baseline. Stable disease (SD) was characterized by neither sufficient shrinkage to qualify for PR nor an increase of 20% or more in the sum of diameters of all measurable target lesions from baseline. The overall response rate (ORR) is the proportion of patients with complete response (CR) or PR. Following the International Association for the Study of Lung Cancer’s guidelines for pathological assessment post-neoadjuvant therapy, complete pathological response (CPR), major pathological response (MPR), and non-MPR (N-MPR) were categorized based on the percentage of residual viable tumor cells in the primary tumor and sampled lymph nodes, with thresholds of 0%, ≤10%, and >10%, respectively (23). Event-free survival (EFS) was calculated from the commencement of neoadjuvant therapy until any instance of disease progression, postoperative recurrence, or death from any cause. The metric for overall survival (OS) spanned from the onset of the initial treatment to the time of death due to any cause. Lung cancer was deemed to have achieved complete resection (R0) if it met all the criteria listed in Table S2 (24). Adverse events were assessed by the Common Terminology Criteria for Adverse Events, version 5.0 (25).

Statistical analysis

In our study, all statistical analyses were conducted using R software (version 4.2.2). Categorical variables were reported as frequencies and percentages, while continuous variables were expressed as median with interquartile range (IQR). Survival analyses were performed using the Kaplan-Meier estimator and compared with the log-rank test. The relationship between individual factors and survival was evaluated using univariate Cox regression analysis, and the independence of these factors was assessed with multivariate Cox regression. The impact of various clinicopathological characteristics on pathological response was analyzed using univariate and multivariate logistic regression models. The correlation between radiologic and pathologic remission was determined using Pearson’s correlation coefficient, denoted as Pearson’s r, with a corresponding P value. A two-sided P value of less than 0.05 was considered to indicate statistical significance.

Results

Patient characteristics and neoadjuvant therapy

Between December 2015 and December 2022, a total of 47 patients were enrolled in the study (Table 1). Of these, 40 (85.11%) were male, and 21 (44.68%) had a history of smoking. The cohort consisted of 39 (82.98%) patients with pure SCLC (P-SCLC) and 8 (17.02%) with combined SCLC (C-SCLC). The median age of the patients was 61.00 years, with an IQR of 55.50–67.50 years. Regarding preoperative clinical staging, 6 patients were in stage I, 9 in stage II, and 32 in stage III. All patients received 2–6 cycles of platinum-based combination chemotherapy before surgery, with the majority undergoing a regimen of etoposide plus carboplatin for 2–3 cycles (Table S3). Detailed demographics, including baseline characteristics, clinical staging, and neoadjuvant treatment information for each patient, are presented in Figure 1A. The median interval between the completion of neoadjuvant chemotherapy and subsequent surgery was 33 days (Table S3).

Figure 1 Overview of clinicopathological characteristics. (A) Overview of baseline characteristics and neoadjuvant information for the neoadjuvant SCLC. Baseline characteristics including sex, age, smoking history, histology, and clinical stage were annotated for each patient. (B) Overview of surgical information and adjuvant therapy for the neoadjuvant SCLC. AC, abraxane + carboplatin; C-SCLC, combined small-cell lung cancer; EC, etoposide + carboplatin; EL, etoposide + lobaplatin; EN, etoposide + nedaplatin; EP, etoposide + cisplatin; IP, irinotecan + cisplatin; N, lymph nodes; P-SCLC, pure small-cell lung cancer; PC, paclitaxel + carboplatin; RATS, robotic-assisted thoracoscopic surgery; STAS, spread through air spaces; T, tumor; VATS, video-assisted thoracoscopic surgery.

Surgical information and adjuvant therapy

Comprehensive surgical profiles for each patient, encompassing the surgical approach, extent of resection, postoperative pathological staging, the assessment of high-risk factors in the surgical specimens, and details of adjuvant therapy, including both adjuvant chemotherapy and radiotherapy, are illustrated in Figure 1B. The median time from surgery to the initiation of adjuvant chemotherapy was 38 days (Table S4). The surgical approaches varied, with the majority of procedures performed using VATS in 38 cases (80.85%), followed by thoracotomy in 8 cases (17.02%), and RATS in 1 case (2.13%) (Table S4). The extent of surgical resection was predominantly lobectomy, which was performed in 27 patients (57.45%). Other resection types included bilobectomy in 6 patients (12.77%), sleeve resection in 9 patients (19.15%), and segmentectomy in 2 patients (4.26%) (Table S4). The median surgery time was 2.00 hours (IQR, 1.56–3.00 hours), with a median blood loss of 50.00 mL (IQR, 50.00–115.00 mL). In terms of resection completeness, R0 resection was achieved in 32 patients (68.09%), while the remaining patients had R1 resection. Regarding the assessment of surgical specimens: all margins were negative, nerve infiltration was positive in 2 (4.26%), intravascular cancer embolus in 10 (21.28%), spread through air spaces (STAS) in 8 (17.02%), and vascular invasion in 4 (8.51%) (Table S4). Postoperative adjuvant chemotherapy was administered to 40 patients (85.11%), while postoperative adjuvant radiotherapy was given to 16 patients (34.04%). The specific chemotherapy regimens, cycles, and radiotherapy doses are detailed in Tables S5,S6, respectively. Table S7 provides a summary of the total cycles of neoadjuvant and adjuvant chemotherapy administered.

Outcomes regarding radiologic and pathologic response

Figure 2A,2B depict tumor regression depths on both radiologic and pathologic levels for each patient. Among the 47 patients, 33 (70.21%) achieved PR and 14 (29.79%) had SD as their best response according to the RECIST criteria (Table S8). In terms of pathologic response, 5 patients (10.64%) achieved CPR, and an additional 6 patients (12.77%, excluding those with CPR) achieved MPR (Table S8). Univariate and multivariable logistic regression analyses revealed no significant differences in pathologic remission across subgroups stratified by sex, age, smoking history, clinical stages, or neoadjuvant cycles; however, a trend toward higher MPR rate in smokers was observed (Figure 2C). No significant positive correlation was found between radiologic and pathologic remission (R=0.171, P=0.31) (Figure S1).

Figure 2 Radiological and pathological remission. (A) Waterfall plots of radiological regression of target lesions for patients after neoadjuvant chemotherapy treatment (n=47). (B) Waterfall plots of pathologic tumor regression (percentage reduction of viable tumor cells) in resected tumors and lymph nodes following neoadjuvant treatment with chemotherapy (n=47). (C) Multivariable logistic regression analysis of the pathologic response MPR vs. N-MPR across subgroups including sex, age, smoking history, pathology subtype, clinical stage, and neoadjuvant cycle. C-SCLC, combined small-cell lung cancer; CI, confidence interval; CPR, complete pathological response; Inf, infinity; MPR, major pathological response; N-MPR, non-major pathological response; OR, odds ratio; PR, partial response; PT, patient; SD, stable disease.

Survival outcomes

With a median follow-up of 35.367 months [IQR, 26.367 months–not reached (NR)], the median EFS was 16.27 months [95% confidence interval (CI): 12.20–30.53] (Figure 3A). The 1-, 2-, and 3-year EFS rates were 66.64% (95% CI: 54.14–82.02%), 37.44% (95% CI: 25.21–55.60%), and 28.16% (95% CI: 16.85–47.05%), respectively (Figure 3A). As of the data cutoff on October 2, 2024, the median OS had not been reached, with 2-, 3-, and 4-year survival rates of 79.96% (95% CI: 68.36–93.52%), 71.39% (95% CI: 57.12–89.22%), and 64.90% (95% CI: 48.52–86.82%), respectively (Figure 3B).

Figure 3 Kaplan-Meier survival curves. (A) Kaplan-Meier estimates of the duration of EFS. (B) Kaplan-Meier estimates of the duration of OS. EFS, event-free survival; OS, overall survival.

Subgroup analysis for survival

Pathologic response and adjuvant therapy

Patients were categorized into CPR, MPR (excluding CPR), and N-MPR based on pathologic response. The median EFS was NR for patients with CPR and was 42.23 months (95% CI: 26.10–NR) for those with MPR, both of which were significantly longer than the median EFS of 12.20 months (95% CI: 9.60–19.93, P=0.02) for patients with N-MPR (Figure 4A). A similar trend was also evident in the analysis of OS (Figure S2A). Survival analysis stratified by CPR status revealed that patients with CPR exhibited prolonged EFS and OS compared to those with non-CPR (N-CPR) (Figure 4B and Figure S2B). Additionally, the MPR-based subgroup survival analysis demonstrated a median EFS of 42.23 months (95% CI: 26.10–NR) for patients with MPR (including the CPR), significantly exceeding that of 12.20 months (95% CI: 9.60–19.93) for N-MPR (P=0.008) (Figure 4C). A trend of prolonged OS was also observed in the MPR (Figure S2C).

Figure 4 EFS analysis based on pathologic response and adjuvant therapy. (A) Kaplan-Meier estimates of the duration of EFS among the CPR, the MPR (excluding CPR), and the N-MPR. (B) Kaplan-Meier estimates of the duration of EFS between the CPR and the N-CPR. (C) Kaplan-Meier estimates of the duration of EFS between the MPR (including CPR) and the N-MPR. (D) A comparison of EFS based on adjuvant radiotherapy in overall patients. (E) A comparison of EFS based on adjuvant chemotherapy in overall patients. (F) A comparison of EFS based on adjuvant cycle in overall patients. (G) A comparison of EFS based on adjuvant radiotherapy in patients achieving MPR. (H) A comparison of EFS based on adjuvant chemotherapy in patients achieving MPR. (I) A comparison of EFS based on adjuvant cycle in patients achieving MPR. (J) A comparison of EFS based on adjuvant radiotherapy in patients not achieving MPR. (K) A comparison of EFS based on adjuvant chemotherapy in patients not achieving MPR. (L) A comparison of EFS based on adjuvant cycle in patients not achieving MPR. CI, confidence interval; CPR, complete pathological response; EFS, event-free survival; HR, hazard ratio; Inf, infinity; MPR, major pathological response; N-MPR, non-major pathological response; RT, radiotherapy.

Stratified survival analyses based on postoperative adjuvant treatment were conducted. There was a trend toward improved EFS (21.00 vs. 12.37 months) and OS in patients who underwent adjuvant radiotherapy compared to those who did not (Figure 4D and Figure S2D). Conversely, the receipt of adjuvant chemotherapy did not significantly extend survival (Figure 4E and Figure S2E). Further analysis was conducted by categorizing patients based on the number of adjuvant cycles and the cumulative cycles of both neoadjuvant and adjuvant chemotherapy. No significant difference in EFS was noted between patients receiving 4–6 cycles of adjuvant therapy and those with fewer cycles (Figure 4F), but a trend toward longer OS was observed with 4–6 cycles (Figure S2F). Patients completing 7–10 total cycles of therapy showed a trend toward improved EFS and OS (Figure S2G,S2H).

Furthermore, we conducted a stratified assessment of the efficacy of adjuvant therapy in patients with MPR and N-MPR. For patients achieving MPR, no significant trends in EFS extension were observed across groups stratified by adjuvant radiotherapy, adjuvant chemotherapy, or the number of adjuvant cycles (Figure 4G-4I). Given that no mortality events have occurred among patients with MPR, a comparison of OS is not feasible (Figure S2I). For patients who did not achieve MPR, adjuvant radiotherapy showed a trend toward longer EFS (17.50 vs. 9.77 months, P=0.08) and OS (NR vs. 30.63 months, P=0.17), but it was not statistically significant (Figure 4J and Figure S2J). Adjuvant chemotherapy significantly prolonged survival (Figure 4K and Figure S2K), with 4–6 cycles of chemotherapy being particularly effective in extending both EFS and OS (Figure 4L and Figure S2L). Patients who received 7–10 cycles of chemotherapy (neoadjuvant cycle plus adjuvant cycle) had longer EFS and OS compared to those who received fewer cycles (Figure S2M,S2N). Subgroup analyses based on the median time from the end of neoadjuvant chemotherapy to surgery and the median time from surgery to the start of adjuvant therapy shown no significant impact on pathological response (Tables S9,S10).

Pathologic stage and adjuvant therapy

Firstly, we conducted survival analysis based on the pathological T stage, pathological N stage, and comprehensive pathological staging. Patients at the T1 stage demonstrated superior EFS compared to those at the T2 stage (Figure 5A), with their OS curves nearly coinciding (Figure S3A). Patients without lymph node involvement (N0 stage) experienced significantly improved EFS compared to those with lymph node metastasis (N1 and N2 stages) (26.10 vs. 12.20 vs. 13.10 months, P=0.01) (Figure 5B). Regarding OS, both N0 and N1 stages exhibited a notably longer trend compared to the N2 stage (NR vs. NR vs. 44 months) (Figure S3B). The comparison based on comprehensive pathological staging showed that patients at stages 0 (NR), I (19.93 months), and II (25.83 months) had longer EFS than those at stage IIIA (12.37 months), while statistical comparison for stage IIIB was not possible due to having only one patient (Figure 5C). A similar trend was observed in OS (Figure S3C).

Figure 5 EFS analysis based on pathologic stage and adjuvant therapy. (A) A comparison of EFS based on pathological T stage in overall patients. (B) A comparison of EFS based on pathological N stage in overall patients. (C) A comparison of EFS based on comprehensive pathological staging in overall patients. (D) A comparison of EFS based on adjuvant chemotherapy in patients with pathologically negative lymph nodes. (E) A comparison of EFS based on adjuvant cycle in patients with pathologically negative lymph nodes. (F) A comparison of EFS based on adjuvant radiotherapy in patients with pathologically negative lymph nodes. (G) A comparison of EFS based on adjuvant chemotherapy in patients with pathologically positive lymph nodes. (H) A comparison of EFS based on adjuvant cycle in patients with pathologically positive lymph nodes. (I) A comparison of EFS based on adjuvant radiotherapy in patients with pathologically positive lymph nodes. CI, confidence interval; EFS, event-free survival; HR, hazard ratio; N, lymph nodes; RT, radiotherapy; T, tumor.

Further exploration into the efficacy of postoperative adjuvant therapy in patients with pathologically negative lymph nodes was conducted. The results showed no EFS or OS benefit from adjuvant chemotherapy over no chemotherapy (Figure 5D and Figure S3D), with 4–6 cycles offering similar outcomes to fewer cycles (Figure 5E and Figure S3E). While 7–10 cycles of perioperative chemotherapy showed a trend towards longer EFS compared to 4–6 cycles (Figure S3F), there was no OS difference (Figure S3G). Adjuvant radiotherapy, however, was associated with improved EFS (23.27 months vs. NR) and OS (NR vs. NR) (Figure 5F and Figure S3H).

Ultimately, the prognostic outcomes of patients with pathologically positive lymph nodes were evaluated based on receipt of adjuvant therapy. The result demonstrated a significant extension in EFS among patients who underwent adjuvant chemotherapy (7.52 vs. 13.10 months, P=0.02) (Figure 5G); however, no difference was observed in OS (Figure S3I). Adjuvant chemotherapy of 4–6 cycles was superior to fewer cycles in terms of prolonging both EFS and OS (Figure 5H and Figure S3J). As for the total cycles of chemotherapy administered perioperatively, those ranging from 7 to 10 cycles were identified as optimal for both EFS and OS (Figure S3K,S3L). Compared to patients with N0, those with N+ experienced a more evident prolongation of EFS (10.13 vs. 16.27 months, P=0.18) and OS (17.70 months vs. NR, P=0.12) with the use of adjuvant radiotherapy (Figure 5I and Figure S3M). Both univariate and multivariate Cox regression analyses yielded similar results, yet neither achieved statistical significance (Figure S4A,S4B).

Neoadjuvant cycle

When stratified by the number of neoadjuvant chemotherapy cycles, no significant differences were observed in either EFS (Figure S5A) or OS (Figure S5B). However, a trend toward improved EFS and OS was noted in the group that underwent a greater number of neoadjuvant chemotherapy cycles.

High-risk factors in pathology reports

Analyses were conducted by stratifying patients according to high-risk features including STAS, intravascular cancer embolus, nerve infiltration, vascular invasion, etc. (Figures S6,S7). Patients positive for these factors tended to have shorter survival (Figures S6A-S6D,S7A-S7D), particularly in those with intravascular cancer embolus (median EFS: 17.50 vs. 12.65 months, P=0.047; median OS: NR vs. 30.63 months, P=0.09) (Figures S6B,S7B). Further comparison revealed no significant differences in EFS or OS between inflammation levels (Figures S6E,S7E) or pathological subtypes (Figures S6F,S7F).

Surgery

Among different surgical approaches—RATS, thoracotomy, and VATS—patients exhibited similar EFS and OS (Figure S8A,S8B). R0 resection emerged as a critical prognostic factor, with patients undergoing R0 resection experiencing longer EFS (23.27 vs. 12.37 months, P=0.01) and OS compared to those with R1 resection (Figure S8C,S8D).

Relapse reason

Patients were categorized based on postoperative recurrence patterns into three groups: local recurrence group (L group), distant metastasis group (M group), and combined group (M + L group). The specific sites of distant metastasis and the corresponding number of patients are presented in Table S11. Survival comparison revealed that patients in the M group had a significantly longer survival than those in the L group (12.65 vs. 8.28 months, P<0.001) (Figure S9). The M + L group’s smaller sample size and shorter follow-up period diminished the credibility of the statistical comparison.

Baseline characteristics

Subgroup survival analyses were conducted based on baseline characteristics of median age, sex, and smoking history. No significant difference was identified in EFS and OS between the < median age and the ≥ median age (Figure S10A,S10B). Sex-based survival analysis revealed significant differences in EFS, with the female exhibiting a shorter EFS of 10.43 months (95% CI: 8.43–NR) compared to the male [19.93 months (95% CI: 13.73–NR)] (Figure S10C). However, an opposite trend was observed in terms of OS, potentially due to the immature data (Figure S10D). Unexpectedly, the smoking subgroup analysis revealed that smokers had a significantly longer EFS [smoker vs. non-smoker: 26.10 (95% CI: 17.50–NR) vs. 11.43 months (95% CI: 9.60–25.83), P=0.02] and exhibited a similar trend in OS (Figure S10E,S10F).

Treatment‑related adverse events during neoadjuvant treatment

Treatment-related adverse events are summarized in Table S12. Grade 3 and 4 adverse events that occurred during neoadjuvant treatment were noted in 8 patients (17.02%) and 2 patients (4.26%), respectively. Treatment-related adverse events of grade 3–4 with the most frequent occurrences being a decrease in neutrophil count (12.77%), followed by a decrease in platelet count (8.51%), and a decrease in white blood cell count (4.26%). Regarding surgery-related adverse events, no grade 2 or higher events were observed. The most common event was a grade 1 lung infection. Additionally, one patient experienced grade 1 pulmonary embolism. There were no cases of perioperative death or postoperative pneumothorax.

Discussion

In this single-arm retrospective clinical study, we included 47 patients with LS-SCLC who underwent surgery following neoadjuvant chemotherapy and systematically evaluated the efficacy and safety of this regimen. Compared to previous data from trials of thoracic chemoradiotherapy, this regimen appears to offer patients a longer survival period. We speculate that the treatment strategy of neoadjuvant chemotherapy combined with surgery could be a more effective option for potentially resectable LS-SCLC, warranting exploration in large-sample, prospective clinical trials.

Concurrent thoracic chemoradiotherapy is the current standard of care for LS-SCLC, with surgery not considered except for T1–2N0M0 staging (5). Nevertheless, the role of surgery in the SCLC remains a contentious issue. Two large, prospective, randomized, controlled trials conducted by the British Medical Research Council in the 1960s and 1970s found that surgery, either alone or following neoadjuvant chemotherapy, did not confer a survival advantage over chemoradiotherapy for LS-SCLC (6,26); thereby, establishing chemoradiotherapy as the standard treatment strategy for LS-SCLC. Subsequently, there has been a scarcity of prospective clinical studies focusing on surgical intervention for SCLC, with the focus shifting towards systemic therapies and radiotherapy approaches (27). Notably, in real-world settings, some patients with LS-SCLC still undergo surgical treatment. A retrospective comparison by Takenaka et al. of 88 surgically treated and 189 non-surgically treated SCLC patients revealed a significantly higher 5-year survival rate in the surgery group (28). Similar conclusions have been echoed in other recent retrospective studies (18,29,30). Compared with surgery alone, neoadjuvant therapy combined with surgery is a more effective therapeutic strategy to increase the R0 resection rate and reduce the postoperative recurrence or metastasis rate (31). Considering the highly aggressive and metastatic properties of SCLC, preoperative neoadjuvant therapy could be even more essential (32). Currently, there are fewer studies on neoadjuvant therapy combined with surgery for SCLC, with most being case reports (33-35). In our retrospective study, 47 SCLC patients who underwent surgery following neoadjuvant chemotherapy were included. As of the cutoff date, the median EFS was 16.27 months, and the median OS had not been reached, with a 2-year survival rate of 79.96%. The ADRIATIC study has demonstrated that the treatment strategy of “chemoradiotherapy followed by durvalumab maintenance” significantly enhances survival outcomes in LS-SCLC (36). Specifically, this approach achieved a 2-year OS rate of 68%, which is a substantial improvement over traditional chemoradiotherapy (36). While our study reported a 2-year survival rate of 79.96%, which appears higher than that observed in the ADRIATIC study, we acknowledge that differences in patient characteristics limit the direct comparability of these results. We speculate that for LS-SCLC patients with potentially resectable tumors, neoadjuvant chemotherapy followed by surgery may be a preferred treatment option. However, for patients with more advanced disease (e.g., N3 involvement) where surgery is not feasible, chemoradiotherapy followed by durvalumab maintenance, as demonstrated in the ADRIATIC study, may be a more optimal approach. There have been several trials exploring the combination of neoadjuvant chemotherapy and immunotherapy in resectable LS-SCLC. For instance, Duan et al. reported an MPR rate of 92.3% in 13 patients treated with this combination, which is significantly higher than the 23.4% observed in our study (37). This suggests the feasibility of neoadjuvant combined surgery strategies for LS-SCLC, particularly the combination of neoadjuvant chemotherapy and immunotherapy. Our study provides a rationale for the design and conduct of prospective clinical trials on neoadjuvant therapy plus surgery in SCLC, which could potentially advance the optimization of treatment strategies for LS-SCLC.

Pathologic response is recognized as a crucial indicator for evaluating the effectiveness of neoadjuvant treatments (38). NSCLC patients who achieve an MPR or a CPR have improved survival outcomes (39). Our investigation aligns with these findings, observing that SCLC achieving MPR or CPR experienced more favorable survival durations compared to those who did not. In the context of NSCLC, consensus guidelines recommend 4 to 6 cycles of neoadjuvant and adjuvant chemotherapy, with adjuvant radiotherapy generally not administered due to evidence suggesting it does not enhance survival outcomes (40). Given the distinct aggressiveness, invasiveness, and metastatic potential of SCLC in contrast to NSCLC, the perioperative treatment model may differ from that of NSCLC. Current protocols advocate for four cycles of postoperative adjuvant chemotherapy for incidentally resected SCLC, with the inclusion of adjuvant radiotherapy for cases with lymph node involvement (41). However, there is a lack of evidence on how to optimize treatment in the context of neoadjuvant therapy followed by surgery for SCLC. Our study delved into the effects of various adjuvant treatment modalities on the prognosis of patients with different characteristics. It was revealed that neither adjuvant chemotherapy nor radiotherapy improved outcomes for patients with MPR, but they did prolong survival for those with N-MPR, and a total of 7–10 cycles of preoperative and postoperative chemotherapy were superior to a lower number of cycles. Intriguingly, analysis based on lymph node involvement demonstrated that survival was extended in patients receiving adjuvant radiotherapy or chemotherapy, irrespective of lymph node status. Therefore, for SCLC, it is hypothesized that the degree of pathologic remission is a pivotal determinant in the decision-making process for postoperative adjuvant therapies, with both adjuvant chemotherapy and radiotherapy being essential for patients with N-MPR, irrespective of lymph node status. Furthermore, different from the four-cycle chemotherapy protocol for NSCLC, SCLC might necessitate an extended chemotherapy regimen.

Local recurrence and distant metastasis are the main factors affecting the prognosis of SCLC after surgery. In our study, we observed that the L group had a poorer prognosis compared to the M group. This finding is somewhat counterintuitive, as distant metastasis is generally considered to have a worse prognosis than local recurrence. Of note, our data suggest that the majority of distant metastases in our cohort were oligometastatic. Oligometastatic lesions, particularly those confined to specific sites such as the brain, bone, or liver, are often associated with a more favorable prognosis compared to widespread metastatic disease (42). Therefore, we speculate that the relatively better prognosis observed in the M group may primarily be due to the fact that the distant metastases were predominantly oligometastatic lesions. Additionally, the sample size in our study is relatively small, and further validation in larger cohorts is needed. Various factors, including STAS, intravascular cancer embolus, nerve infiltration, and vascular invasion, are considered high-risk pathological factors for postoperative recurrence and metastasis (43,44). Our study’s findings are in alignment, demonstrating a reduction in survival for patients with positive results for any of these factors. Furthermore, an R0 resection, which signifies the complete removal of the tumor without residual disease, is a critical benchmark in surgical oncology. In lung cancer surgery, an R0 resection is specifically defined by the extent of lymph node dissection, the number of lymph nodes removed, and the status of surgical margins (24). Our research revealed that individuals with R0 resection experienced superior EFS and OS compared to those without, further highlighting the importance of aiming for R0 resection in lung cancer treatment.

Recent studies have noted an increasing incidence of SCLC among female non-smokers, potentially reflecting a unique pathogenesis and divergent responses to treatment and survival outcomes (45,46). Our research did reveal a disparity in prognosis between female and male patients, with females experiencing a reduced EFS compared to males. The OS was paradoxical, a discrepancy that may stem from immature data. Moreover, smoking patients tend to have better survival outcomes compared to non-smoking patients, which requires further investigation.

In summary, this retrospective clinical study has put forth that the combination of neoadjuvant chemotherapy with surgery may represent a more effective and safe treatment strategy for selected LS-SCLC, deserving of further validation through prospective clinical trials. In addition, we systematically explored the potential influencing factors for the efficacy of the treatment modality, particularly delving into the significance of adjuvant therapy in different pathological response statuses and lymph node involvement states, thereby laying the foundation for the design of more standardized and potent treatment models in subsequent clinical trials. However, there are still some limitations. First, this study is a retrospective, single-arm analysis that compared outcomes with historical data, lacking a control group, necessitating head-to-head efficacy comparisons in prospective, RCTs. Second, our study is limited by the small sample size, which may affect the generalizability of our findings. Future studies with larger cohorts are needed; Third, the OS data in this study are still immature, necessitating further follow-up to ascertain the treatment regimen’s efficacy.

Conclusions

Neoadjuvant chemotherapy combined with surgery may represent a potential treatment strategy for potentially resectable LS-SCLC, with a high proportion of patients achieving an MPR and manageable safety profile that did not compromise surgical resection. Further prospective clinical trials are warranted to delineate the benefits of neoadjuvant chemotherapy and optimize LS-SCLC treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-209/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-209/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-209/prf

Funding: This study was supported in part by a grant of the National Key Research and Development Program of China (No. 2022YFF0705300), the National Natural Science Foundation of China (Nos. 52272281 and 52473144), the Aeronautical Science Foundation of China (No. XJZ-20240017), the Shanghai Municipal Science and Technology Major Project (No. 2021SHZDZX0100), the Fundamental Research Funds for the Central Universities, Shanghai Municipal Health Commission Health Industry Clinical Research Project, Clinical Research Project of Shanghai Pulmonary Hospital (No. FKLY20010), the Research Physician Innovation and Translational Capability Training Program of Shanghai Shenkang Hospital Development Center (No. SHDC2023CRD017), the Science and Technology Innovation Action Plan Medical Innovation Research Special Program (No. 23Y11908500), the Research Physician Talent Program (No. LYRC202403), the Young Talents in Shanghai (No. 2019 QNBJ), the Shanghai Shuguang Scholar, 2021 Science and Technology Think Tank Youth Talent Plan of China Association for Science and Technology, ‘Dream Tutor’ Outstanding Young Talents Program (No. fkyq1901), and the National Key Research and Development Program of China (Nos. 2021YFF1201200 and 2021YFF1200900).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-209/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 and was approved by the Research Ethics Committee of Shanghai Pulmonary Hospital (No. K18-203), with informed consent requirements waived due to the use of anonymized and deidentified data for this retrospective study.

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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