Efficacy and safety of neoadjuvant chemotherapy with or without PD-L1/PD-1 inhibitors in surgically limited-stage small-cell lung cancer

Introduction

Small-cell lung cancer (SCLC) is an aggressive neoplasm marked by rapid proliferation and elevated rates of early local and distant metastases (1), representing approximately 13% of all lung malignancies (2). At diagnosis, approximately one-third of patients with SCLC exhibit cancer localized to one hemithorax, designated as limited-stage SCLC (LS-SCLC), which can be managed through a combination of chemotherapy and radiotherapy or surgical resection (3). As for now, only the patients with T1-2N0M0 stage SCLC are considered for surgical resection as per The National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) SCLC guidelines.

However, surgical resection of SCLC has consistently been underestimated, and more and more data indicate that surgery might play a critical role in the comprehensive treatment of the early stages of SCLC. A retrospective analysis of treatment data from the Surveillance, Epidemiology, and End Results (SEER) database showed that among patients with SCLC with localized lesions, patients receiving surgical treatment could obtain a better survival prognosis (4). Another retrospective study (5), which included 277 patients with LS-SCLC, suggested that for stage I SCLC, the 5-year survival rate of patients who underwent surgical resection was significantly higher than that of the other patients (62% vs. 25%, P=0.01).

Moreover, in the propensity score matching analysis of stage II and stage III LS-SCLC, patients who underwent surgery had a higher 5-year survival rate (P=0.04) (5). Selective surgeries in patients with stage I to stage IIIA SCLC were proven to have better local control rates and more prolonged survival. There were survival benefits in patients with nodal stage N0, N1, and N2 who underwent surgical resection (6). Similarly, Schreiber et al. reviewed surgery outcomes of LS-SCLC patients from the SEER database during 1988–2002. The results were that surgery was associated with a median survival compared with no surgery and a better 5-year overall survival (OS) rate in all LS-SCLC patients. Further, the survival benefit was not only in T1–2N0M0 patients but also in T3–4N0 patients. Subgroup analysis indicated OS benefits from surgery in patients with N0 and N1-2 (7). A retrospective analysis of 205 surgically resected patients showed that the survival of stage II SCLC patients who underwent surgical resection was similar to that of stage I patients. The results indicated that surgical resection should be considered for more LS-SCLC patients other than only stage I patients (8). All these studies indicated that the role of surgery in patients with LS-SCLC should be re-evaluated.

Immunotherapy is one of the most significant progress in lung cancer treatment in recent years. In the last two decades, many clinical trials have been performed in SCLC, but the results were frustrating until the programmed death-ligand 1/programmed death 1 (PD-L1/PD-1) antibodies were used for the extensive-stage SCLC (ES-SCLC). The combination of anti-PD-L1/PD-1 inhibitor and chemotherapy has already become the first-line treatment for ES-SCLC (9-12). However, the OS of the combination only brought two to four months of OS benefit compared with the control group in ES-SCLC (11,13). Moreover, results of the ADRIATIC trial in LS-SCLC demonstrated that durvalumab after chemoradiotherapy brought significantly longer OS (median, 55.9 vs. 33.4 months) and progression-free survival (PFS, median, 16.6 vs. 9.2 months) compared to placebo (14). In patients with resectable non-small-cell lung cancer (NSCLC), neoadjuvant nivolumab or pembrolizumab combined with chemotherapy led to significantly improved event-free survival (EFS) and a greater proportion of patients achieving a pathological complete response (pCR) compared to chemotherapy alone (15,16).

This study enrolled LS-SCLC patients who underwent neoadjuvant chemoimmunotherapy or chemotherapy alone, followed by surgical resection. Here, we report the results of this study in order to explore a new treatment in some selected LS-SCLC patients. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-438/rc).

Methods

Population of patients

A retrospective study was conducted between April 2019 and March 2023 on patients with surgically LS-SCLC who received preoperative chemoimmunotherapy (chemotherapy plus PD-L1/PD-1 inhibitor, neoCIT group) or chemotherapy alone (neoCT group) at Beijing Chest Hospital, Capital Medical University, China. The inclusion criteria were as follows: age 18 years or older, histological diagnosis of SCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, limited stage and clinical tumor, nodes, metastases (TNM) stage IIB–IIIB before treatment, two or more cycles of neoadjuvant therapy, normal organ function, and completion of surgical resection. The exclusion criteria included: receiving treatment prior to diagnosis, or lacking complete imaging or pathological data, or without neoadjuvant treatment, or without surgical treatment. Finally, 31 patients were included in the study (Figure 1). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Beijing Chest Hospital, Capital Medical University (No. 2023-LS-KY-53) and individual consent for this retrospective analysis was waived.

Figure 1 Flow diagram of patients in the study.

In the LS-SCLC neoadjuvant treatment in this study, all PD-L1/PD-1 inhibitors were off-label use. All patients provided informed consent prior to receiving neoadjuvant therapy. Given that neoadjuvant therapy for SCLC is not a standard treatment modality recommended by guidelines and is considered an individualized treatment plan, all included cases underwent multidisciplinary team (MDT) discussions. The MDT board in our center primarily consists of thoracic surgeons, radiation oncologists, medical oncologists, pathologists, radiologists, and pathologists. MDT discussions ensure a comprehensive treatment approach led by multidisciplinary experts. Additionally, these MDT discussions of neoadjuvant therapy took place prior to neoadjuvant treatment, following assessment of the efficacy of neoadjuvant treatment, prior to surgery, and during postoperative adjuvant therapy.

For staging SCLC, we used the eighth edition lung cancer staging system of the American Joint Committee on Cancer and the classic Veterans Administration (VA) staging system (17,18). According to the VA staging system, LS-SCLC disease is confined to the ipsilateral hemithorax, which can be safely encompassed within a radiation field (18). Clinical and pathological data collected from patients included gender, age, smoking history, ECOG PS, clinical TNM staging, neoadjuvant treatment regimen, treatment cycle, surgical treatment, imaging and pathological response assessment, survival status, and treatment-related adverse events (TRAEs).

Neoadjuvant treatment

All of the included patients were scheduled to receive surgery within 4–6 weeks after neoadjuvant therapy that consisted of 2–3 cycles of a standard etoposide-based doublet chemotherapy regimen, administered with or without a PD-L1/PD-1 inhibitor on the first day of each 21-day cycle. Patients were administered one of the following PD-L1/PD-1 inhibitors intravenously as neoadjuvant immunotherapy: atezolizumab (1,200 mg), durvalumab (1,000 mg), tislelizumab (200 mg), or camrelizumab (200 mg).

Surgery and postoperative treatment

All surgical resections were conducted in accordance with standard institutional procedures, utilizing either thoracotomy or video-assisted thoracoscopic surgery (VATS) with routine systematic lymph node dissection which encompassed a minimum of three groups of pulmonary lymph nodes and three groups of mediastinal lymph nodes, with the subcarinal lymph nodes being mandatorily included.

Postoperative adjuvant treatment was administered based on the patient’s postoperative pathological response, stage, performance status, and treatment preference.

Assessment of treatment

The primary endpoints of this retrospective study were to evaluate the pathological response to neoadjuvant chemotherapy with or without PD-L1/PD-1 inhibitors. The pathological response endpoints included pCR, described as the total absence of residual viable tumor cells in both the primary tumor and sampled lymph nodes, and major pathological response (MPR), characterized by having ≤10% residual viable tumor cells in the primary tumor and sampled lymph nodes. This pathological efficacy evaluation criterion was adapted from the criteria for neoadjuvant therapy in NSCLC (19).

Secondary endpoints were the imaging response, the radiographic downstaging rate, surgical outcome, EFS, OS, and the treatment’s toxicity profile.

Contrast-enhanced computed tomography (CT) scans were conducted again to evaluate the objective imaging response within seven days prior to surgery. The imaging responses were assessed for all patients according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (20), categorizing therapeutic responses as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The objective response rate (ORR) was a combined proportion of CR and PR. Surgical outcome included the operation time (minutes), hospitalization after surgery (days), the estimated intraoperative blood loss (mL), the residual tumor (R) classification of resection completeness including the proportion of patients who had complete resection (R0 resection with no residual tumor) or uncomplete resection (R1 resection with microscopic residual tumor and R2 resection with macroscopic residual tumor), the extent of resection, surgical methods, and perioperative mortality.

EFS was defined as the time from diagnosis to any progression of disease precluding surgery, progression or recurrence of disease after surgery, or death from any cause. OS was defined as the time from diagnosis to death from any cause. The safety endpoints comprised TRAEs as defined by the Common Terminology Criteria for Adverse Events (CTCAE, v.5.0).

Statistical analysis

Statistical analyses were conducted using R software, version 4.2.2, or GraphPad Prism, version 9.5. The frequency tabulation and summary of descriptive statistics for the patient’s baseline characteristics, surgical outcomes, and safety evaluation presented the data distribution characteristics. Continuous variables were reported as medians, along with their ranges. Categorical variables were represented as numerical values accompanied by their respective percentages. Statistical analysis was performed using appropriate methods, including descriptive statistics, Welch Two Sample t-test, Fisher’s exact test, Pearson’s Chi-squared test, Wilcoxon rank sum test, and survival analysis. Kaplan-Meier plots analyzed EFS and OS with differences calculated using the log-rank test. A two-sided P value less than 0.05 was considered statistically significant.

Results

Patients and treatment

This study included 31 patients diagnosed with stage IIB-IIIB LS-SCLC, comprising 16 patients in the neoCIT group and 15 patients in the neoCT group (Figure 1). The baseline characteristics of the study population were analyzed and summarized in Table 1. The table provides information on various characteristics, including age, gender, smoking status, ECOG performance status, tumor stage, nodal stage, clinical TNM stage (8th edition), neoadjuvant PD-L1/PD-1 inhibitor regimen, and neoadjuvant treatment cycles in the two groups. Notably, no significant differences were observed between the two groups (neoCIT and neoCT) regarding age, sex, smoking status, ECOG performance status, tumor stage, nodal stage, and clinical TNM stage. However, a statistically significant difference was noted in the number of treatment cycles received (P=0.01) between the two groups, with nine (56.3%) cases in the neoCIT group and two (13.3%) patients in the neoCT group receiving three cycles neoadjuvant treatment. These findings suggest that the baseline characteristics were well-balanced between the treatment groups, except for the number of neoadjuvant treatment cycles.

Two to three cycles of etoposide-based chemotherapy plus PD-L1/PD-1 inhibitors (16 cases in total, seven cases with durvalumab, four cases with atezolizumab, three cases with tislelizumab, and two cases with camrelizumab) or etoposide-based chemotherapy alone (15 cases) were administered prior to surgery (Table 1).

The results of surgical treatment are shown in Table S1. In both groups, the proportion of patients undergoing VATS was similar, at 50.0% and 53.3% in the neoCIT group and neoCT group, respectively. One patient in the neoCIT group underwent a change in surgical procedure from VATS to thoracotomy because the patient required a pneumonectomy to achieve curative intent. The most common surgical procedure was lobectomy. Among the two groups, 93.8% of those in the neoCIT group and 93.3% of those in the neoCT group had complete (R0) resection; 6.3% and 6.7%, respectively, had incomplete (R1) resection. The median duration of hospitalization after surgery operations was 9.5 (6.0 to 16.0) days in the neoCIT group and 9.0 (6.0 to 21.0) days in the neoCT group. The median operation time was 140 (75 to 280) minutes in the neoCIT group and 135 (70 to 240) minutes in the neoCT group. The median amount of estimated blood loss in the two groups was 150 (20 to 500) and 100 (50 to 600) mL, respectively. There were no perioperative deaths in the two groups.

In the neoCIT group, 14 patients received postoperative adjuvant treatment, 13 patients underwent 1–4 cycles of postoperative chemoimmunotherapy followed by immunotherapy maintenance (immunotherapy maintenance did not exceed 1 year), and one patient received only two cycles of adjuvant chemotherapy. In the neoCT group, 15 patients underwent 1–4 cycles of postoperative chemotherapy and did not receive immunotherapy. Additionally, two and three patients in the neoCIT and neoCT groups, respectively, received postoperative chest radiation therapy.

Pathological and radiological efficacy

A pCR was observed in eight cases (50.0%; 95% CI: 28.0 to 72.0) within the neoCIT group, compared to one patient (6.7%; 95% CI: 0.3 to 29.8) in the neoCT group. The odds ratio (OR) was 14.00 (95% CI: 1.71 to 164.20; P=0.02; see Table 2, Figure 2A). An MPR was observed in 14 cases (87.5%; 95% CI: 64.0 to 97.8) within the neoCIT group, compared to three patients (20.0%; 95% CI: 7.0 to 45.2) in the neoCT group. The OR was calculated at 28.00 (95% CI: 4.23 to 150.50; P<0.001; Table 2, Figure 2B). The waterfall plot illustrates pathological regression in the resected primary lung tumor following neoadjuvant treatment, according to the subgroup of neoadjuvant regimen and RECIST response (Figure 3). In the three patients in the neoCIT group and one in the neoCT group, the primary tumor disappeared (0% viable tumor cell). However, the regional lymph node involvement persisted, achieving an MPR in the final overall evaluation (Figure 3). The Sankey diagram illustrates the relationship between the pathological response to neoadjuvant therapy and the neoadjuvant regimen across various clinical stages (Figure S1).

Figure 2 Pathological assessment in the included patients. (A) Pathological complete response; (B) major pathological response. CI, confidence interval; neoCIT, neoadjuvant chemoimmunotherapy; neoCT, neoadjuvant chemotherapy; OR, odds ratio.

Figure 3 Waterfall plot of the pathological response to neoadjuvant treatment. Each bar indicates an individual patient. The upper rows present clinical characteristics and radiological responses. Orange dashed line: 90% change from baseline. ^#, the regional lymph node of dissection involvement persisted. CR, complete response; CT, chemotherapy; ICI, immune checkpoint inhibitor; MPR, major pathological response; pCR, pathological complete response; PR, partial response; RECIST, response evaluation criteria in solid tumors; SD, stable disease.

The clinical efficacy of the neoadjuvant treatment was assessed using the RECIST v.1.1 criteria. In particular, in the neoCIT arm of 16 patients, the radiological response rates of CR, PR, and SD were 6.3% (1/16), 81.3% (13/16), and 12.5% (2/16), respectively. In the neoCT arm, of 15 cases, the response rates of CR, PR, and SD were 0% (0/15), 86.7% (13/15), and 13.3% (2/15), respectively (Table 2). No patients in the two groups had a progressing imaging evaluation before surgery. No statistically significant difference was noted in the ORR between the two groups (87.5% in the neoCIT arm versus 86.7% in the neoCT arm, P>0.99). The incidence of radiographic primary tumor downstaging was 93.8% and 86.7% (P=0.60), respectively, and the incidence of radiographic nodal downstaging was 50.0% and 20.0% (P=0.14), respectively (Table 2).

Follow-up and survival

The last follow-up was in September 2024. The median duration of follow-up for EFS was 37.0 (range, 6.0–50.0) months in the neoCIT group and 33.0 (range, 6.0–58.0) months in the neoCT group. Disease progression was observed in nine patients (two in the neoCIT group and seven in the neoCT group). In the neoCIT group, one patient in the neoCIT group developed brain metastasis 17 months after surgery, and one patient developed multiple bone metastases 8 months after surgery. In the neoCT group, a total of five patients developed metastasis: one patient had paraesophageal and abdominal lymph node metastasis (26 months after surgery), one patient had right adrenal metastasis (10 months after surgery), one patient had subcutaneous metastasis (17 months after surgery), one patient had pleural metastasis (5 months after surgery), one patient had pleural and left adrenal metastasis(5 months after surgery), and the other two patients were unable to identify the specific site of metastasis prior to tumor-specific death. The median EFS was not reached with neoCIT and 19.0 months with neoCT (hazard ratio, 0.15; 95% CI: 0.04 to 0.62; Log-rank test, P=0.009, Figure 4A). The median duration of follow-up for OS was 37.0 months (range, 6.0–50.0 months) in the neoCIT group and 39.0 months (range, 6.0–58.0 months) in the neoCT group, eight patients died in the two groups (two in the neoCIT group and six in the neoCT group) by the time of data cutoff. The median OS was not reached with neoCIT and 39.0 months with neoCT (hazard ratio, 0.23; 95% CI: 0.06 to 0.95; Log-rank test, P=0.043, Figure 4B).

Figure 4 Event-free survival (A) and overall survival (B) among the included patients. neoCIT, neoadjuvant chemoimmunotherapy; neoCT, neoadjuvant chemotherapy.

Safety

TRAEs of any grade that occurred during neoadjuvant treatment were reported in 100% of patients in the two groups (Table 3). The majority of adverse events were classified as grades 1 to 2. Grade 3 or 4 adverse events during neoadjuvant treatment were noted in five patients (31.3%; some patients had different events) in the neoCIT group and five patients (33.3%) in the neoCT group, with no differences between the two groups. Neutrophil count decreased was the most common grade 3 or 4 adverse events in the two groups (25.0% and 20.0% of patients, respectively).

In the neoCIT group, the potentially immune-mediated adverse events were hypothyroidism (grade 1–2, three cases), rash (grade 1–2, two cases), hyperthyroidism (grade 1, one case), diarrhea (grade 1, one case) and increased serum amylase (grade 3, one case) in the neoadjuvant to surgery phase. No delays in surgery due to adverse events were noted.

Case presentation

A 59-year-old female patient, a nonsmoker, presented with a cough at our hospital. There was a mass (31 mm × 29 mm) in her right lower lobe and an enlarged interlobar node shown in positron emission tomography computed tomography (PET/CT) scan. A CT-guided percutaneous lung biopsy and bronchoscopic biopsy pathology proved SCLC. The stage of diagnosis was T2aN1M0, stage IIB. The tissue-based tumor mutation burden (TMB) was 18Muts/Mb by Foundation One CDx, and microsatellite status was stable. Besides, there were mutations in TP53 and RB1 and amplifications in KIT, Sox2, KDR, and BCL2L1. Atezolizumab plus chemotherapy with carboplatin and etoposide was given as the neoadjuvant therapy. After two cycles of immunotherapy plus chemotherapy, a CT scan of reevaluation indicated that the primary tumor mass was in remission and achieved a clinical partial response. A multi-disciplinary team discussion ensued, and it was recommended that surgery be considered. After full informed consent, the patient underwent right middle and lower lobectomy and mediastinal lymph node dissection. The pathological result after surgery proved R0 resection and was a pCR. Four cycles of atezolizumab plus chemotherapy were performed following surgery, and atezolizumab alone was maintained treatment for another 28 cycles every three weeks. Prophylactic cranial irradiation (PCI) was recommended after the six cycles of chemotherapy, but she refused. The last follow-up was in August 2024, and the EFS was 50 months (Figure S2). During the whole treatment, neutropenia (grade 2), vomiting (grade 1), and diarrhea (grade 2) were the treatment-related adverse effects. In addition, the diarrhea was recorded as an immune-related adverse event that caused one interruption of immunotherapy.

Discussion

Patients with LS-SCLC beyond stage T1-2N0 are currently treated with concurrent radiotherapy as the standard of care. Immunotherapy has been demonstrated to be an effective front-line treatment for extensive-stage SCLC (21,22). The impact of neoadjuvant chemoimmunotherapy in LS-SCLC has been rarely documented. This study retrospectively enrolled 31 patients diagnosed with stage IIB-IIIB LS-SCLC who received neoadjuvant chemoimmunotherapy or chemotherapy followed by radical surgery. Our study showed significant improvements in MPR, pCR, and EFS among patients who received neoadjuvant PD-L1/PD-1 plus etoposide-based chemotherapy followed by surgical resection compared to those who received neoadjuvant chemotherapy and surgery alone. In addition, no unexpected adverse effects were observed.

Stage I–IIA LS-SCLC may benefit from surgery. Available data show that 5-year survival rates range from 27% to 73% and 4% to 44% for patients in the surgical and non-surgical groups, respectively. In a propensity-matched analysis based on the National Cancer Data Base (23), Yang et al. found that surgical treatment significantly improved 5-year survival rates (47.6% and 29.8%, P<0.01) and prolonged the median OS (30.5 and 54.4 months). Regarding the surgical approach, subgroup analyses of several retrospective studies and meta-analyses showed that survival was better in the lobectomy group than in the wedge resection (23,24). In our study, no wedge resection was used among the patients enrolled, and most patients underwent lobectomy or bilobectomy.

The role of surgery is controversial in stage IIB to IIIA SCLC. Positive results were obtained in several retrospective studies. However, the median survival range obtained in these studies is 17.0 to 31.7 months, which is not a breakthrough improvement compared with 25 months in the CONVERT study with concurrent radiotherapy (25). Hence, the effectiveness of surgery for stage IIB-IIIA SCLC and the appropriate subgroups are still debatable. For stage IIIB-IIIC SCLC, surgery is not recommended because of the lack of valid evidence to prove the effectiveness of surgery. However, until now, no published randomized controlled trial has explored the role of neoadjuvant chemoimmunotherapy in LS-SCLC settings.

The cases included in our study were staged IIB-IIIB patients. In the neoCIT group, eight, six, and two were staged IIB, IIIA, and IIIB, respectively. After neoadjuvant chemoimmunotherapy and surgery in the neoCIT group, the MPR rates were 100% (8/8 in stage IIB), 66.7% (4/6 in stage IIIA), and 100% (2/2 in stage IIIB). The pCR rate was 50.0% in all three stages.

Immunotherapy has also been initially explored in LS-SCLC. In the STIMULI study (26), which compared the efficacy of immunotherapy consolidation and supportive therapy in patients with LS-SCLC after concurrent chemoradiotherapy (CCRT), the immunotherapy consolidation group was treated with four cycles of nivolumab and ipilimumab followed by up to 12 months of nivolumab maintenance therapy. The trial was terminated early due to slow enrollment and did not meet the primary endpoint, with PFS of 10.7 and 14.5 months in the immunotherapy consolidation and supportive therapy groups, respectively. In addition, 55.1% of patients in the immunotherapy consolidation group discontinued treatment due to adverse effects, and the proportion of patients with grade ≥3 AEs was 61.5% compared with 25.3% in the control group. Treatment discontinuation due to intolerable adverse reactions after short-term active treatment may have affected the efficacy evaluation of the entire trial. In a single-arm phase II study involving 50 patients with LS-SCLC, the median PFS was 14.4 months, with a 24-month PFS rate of 42.0%, and the 24-month OS rate reached 67.8% when treated with durvalumab in combination with CCRT (27). In the ADRIATIC study, the use of durvalumab after chemoradiotherapy significantly prolonged OS and PFS compared to placebo (14), and the results of this study have established the current standard of care for the LS-SCLC. However, another phase II clinical study suggested that atezolizumab therapy after chemoradiotherapy did not improve PFS or OS in patients with LS-SCLC (28). Moreover, the results of other ongoing immunotherapy studies in LS-SCLC, such as the ML41257 study, the MK7339-013 study, and the NRG-LU005 study, are expected. It is worth re-emphasizing that in our exploratory study, radical surgical treatment after 2–3 cycles of neoadjuvant chemoimmunotherapy achieved a 50% pCR rate and 87.5% MPR rate, whereas, in the control group of patients (n=15) undergoing surgery after 2–3 cycles of chemotherapy alone, only one case (6.7%) of pCR and three cases of MPR (20.0%) were identified. At the same time, the neoadjuvant immunotherapy group had prolonged EFS and OS compared with the control group. Several other small-sample retrospective studies have been published on neoadjuvant therapy for SCLC, suggesting that neoadjuvant immunotherapy combined with chemotherapy can improve surgical resection rates and the feasibility of surgery (29-31). However, the published studies have small sample sizes (less than 20 cases) and lack long-term follow-up data on EFS and OS.

The immunotherapeutic agents used in our study included the PD-L1 inhibitors atezolizumab (n=4) and durvalumab (n=7), in addition to 5 cases of the PD-1 inhibitors tislelizumab (n=3) and camrelizumab (n=2). Of these patients receiving PD-L1 inhibitor combination chemotherapy, 81.8% (9/11) achieved MPR or pCR, and all patients (5/5) who received PD-1 inhibitor combination chemotherapy achieved MPR or pCR. No statistical differences were found in the pathological response to PD-L1 and PD-1 inhibitors (Fisher’s exact test, P>0.99). Since this is a retrospective study, the use of immunotherapy drugs among patients was inconsistent. The selection of immunotherapy drug types was influenced by factors such as efficacy, safety, availability, and economic considerations in SCLC. To address this inconsistency and selection bias, we are conducting an investigator-initiated prospective study (ChiCTR2100042367) to evaluate the efficacy and safety of neoadjuvant atezolizumab in combination with chemotherapy in SCLC. Another investigator-initiated clinical study evaluating the neoadjuvant tislelizumab is also underway in LS-SCLC (NCT06375109). Our team and collaborators conducted a single-arm study examining neoadjuvant atezolizumab combined with chemotherapy for resectable SCLC. In the per-protocol cohort, a pCR was observed in eight out of thirteen patients (61.5%), while an MPR was noted in twelve out of thirteen patients (92.3%) (32).

In our study, 2–3 cycles of neoadjuvant treatment were based on clinical practice and experience with neoadjuvant treatment for NSCLC to balance efficacy, reduce potential toxicity, and minimize the impact on surgery. In our study, although there was a disparity in the number of cycles between the neoadjuvant chemotherapy group and the neoadjuvant immunotherapy group, it is worth noting that the ORR of the imaging efficacy evaluation before surgery was similar between the two groups (86.7% in the chemotherapy group vs. 87.5% in the immunotherapy group). There was no difference in tumor reduction between the two groups, as determined by imaging. In addition, previous neoadjuvant studies of NSCLC suggest that there is no significant correlation between the number (two versus three) of cycles of neoadjuvant therapy and MPR (33,34). A meta-analysis of 29 studies reported MPR rates of 43% with two cycles and 33% with three cycles of neoadjuvant immunotherapy (34).

Circulating tumor DNA (ctDNA) has emerged as a promising tool for the detection of minimal residual disease (MRD) in lung cancer (35). In SCLC specifically, several studies supported the feasibility of using ctDNA to assess MRD after systemic treatment in SCLC (36-38). By providing a real-time reflection of tumor burden and clonal evolution, ctDNA assays may enable earlier detection of relapse, inform risk stratified surveillance strategies, and facilitate prompt adjustments in therapy. In LS-SCLC, Future studies should focus on integrating ctDNA-guided MRD monitoring into prospective clinical trials to establish its impact on patient outcomes.

The limitations of this study encompass the inherent bias associated with retrospective analyses, the limited sample size of participants, and the absence of long-term survival follow-up data. Therefore, larger prospectively randomized controlled studies are necessary to minimize bias and assess the efficacy of neoadjuvant chemoimmunotherapy in LS-SCLC. Furthermore, long-term follow-up of these studies will be necessary to define the role of neoadjuvant PD-L1/PD-1 blockade in reducing recurrences and curing resectable SCLC. In addition, this study did not report biomarkers related to predicting efficacy, such as tumor PD-L1 expression, tumor mutational burden and MRD from ctDNA, commonly used in NSCLC, and neoadjuvant chemoimmunotherapy requires adequate biomarker studies to identify the best predictive response biomarkers.

Conclusions

Among the resectable SCLC patients, neoadjuvant PD-L1/PD-1 inhibitors combined with chemotherapy followed by surgery significantly improved pathological response, EFS, and OS as compared with neoadjuvant chemotherapy alone followed by resection.

Acknowledgments

We thank patients and their families for their support and participation in this study. Parts of this work were presented as a poster at 2021 World Conference on Lung Cancer and 2024 European Lung Cancer Congress.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-438/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-438/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-438/prf

Funding: This study was supported by Beijing Municipal Administration of Hospitals Incubating Program (No. PX2023057), Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (No. JYY2023-14), and Beijing Tongzhou District High Level Talent Project (Nos. YH201910 and YH201916).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-438/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 study was approved by the Institutional Review Board of Beijing Chest Hospital, Capital Medical University (No. 2023-LS-KY-53) and 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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