Lung cancer remains the primary cause of cancer incidence and mortality worldwide, including in China. Approximately 15% of newly diagnosed lung cancer cases are classified as small cell lung cancer (SCLC) (1, 2). SCLC is a highly aggressive, poorly differentiated, high-grade neuroendocrine carcinoma. In the United States, the 2021 incidence rate was 4.7 cases per 100,000 population, with a dismal five-year overall survival (OS) rate of 12% to 30% (3). In clinical practice, SCLC is categorized into two types: extensive stage (ES)-SCLC and limited stage (LS)-SCLC (4). At diagnosis, approximately 70% of patients present with ES-SCLC, while LS-SCLC accounts for the remaining 30% (5). Unlike non-small cell lung cancer (NSCLC), therapeutic advancements for SCLC have progressed relatively slowly. Although SCLC demonstrates high initial sensitivity to chemotherapy and radiotherapy, responses are typically not durable (6). Current guidelines define curative intent as the treatment goal for LS-SCLC. The standard of care consists of concurrent thoracic radiotherapy (TRT) with 4 to 6 cycles of platinum-etoposide chemotherapy (cisplatin or carboplatin plus etoposide), followed by prophylactic cranial irradiation (PCI) for patients achieving a favorable response (7). Despite this aggressive multimodal treatment strategy, the five-year survival rate for LS-SCLC remains modest, at only 30–35% (8).

In recent years, immune checkpoint inhibitors (ICIs) have shown significant advancements in the management of ES-SCLC. Multiple clinical trials, such as IMpower133 and CASPIAN, have incontrovertibly demonstrated that the combination of chemotherapy and ICIs (atezolizumab or durvalumab) can effectively extend the survival of patients with ES-SCLC (9, 10). However, for patients with LS-SCLC, there remains insufficient clinical evidence to support the routine use of immunotherapy. Notably, several preclinical studies have indicated a potential synergistic effect between chemoradiotherapy (CRT) and ICIs (11, 12). Furthermore, findings from the ADRIATIC clinical trial revealed that adjuvant treatment with durvalumab following CRT in LS-SCLC significantly improved both OS and progression-free survival (PFS) (13). In addition, a phase 1/2 clinical trial demonstrated that the combination of concurrent CRT with pembrolizumab was well tolerated and yielded promising improvements in median OS and median PFS among patients with LS-SCLC (14). Although the above-mentioned clinical trials have established the position of ICIs in LS-SCLC, several important knowledge gaps still exist. For instance, real-world evidence in LS-SCLC chemotherapy ± ICIs controlling for radiotherapy is limited, and there is almost no ‘head-to-head’ evidence directly comparing the efficacy and safety of PD-1 inhibitors and PD-L1 inhibitors.

Immunity and inflammation assume a crucial role in the immunotherapy of SCLC. At present, several novel comprehensive immune indicators, including the lung immune prognostic index (LIPI), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and prognostic nutrition index (PNI), have been closely linked to poor unfavorable outcomes in the immunotherapy of NSCLC and ES-SCLC (15, 16). Nevertheless, the significance of these indices in the immunotherapy of LS-SCLC remains elusive.

Since the approval of the immunotherapy for ES-SCLC in China in 2020, immunotherapy has occasionally been implemented in clinical practice for LS-SCLC patients. Consequently, we gathered data of LS-SCLC patients from 2020 to 2022 at a large-scale medical center in China. Propensity score matching (PSM) was employed to evaluate the clinical implications of the combination of chemotherapy and immunotherapy for LS-SCLC. Additionally, the treatment response and safety were assessed. A multivariate Cox regression analysis was also performed to investigate the prognostic value of these newly developed comprehensive immune and nutritional indicators in LS-SCLC patients undergoing immunotherapy.

Drawing upon high-quality evidence, encompassing systematic reviews, guidelines, and meta-analyses, the current standard treatment for LS-SCLC involves CCRT with platinum and etoposide (19–21). Patients who exhibit an intermittent disease response to this treatment are considered suitable candidates for PCI, as it can significantly enhance the three-year survival rate (22). Nevertheless, the effectiveness of these standard treatment modalities remains constrained. At present, chemotherapy combined with ICIs is recommended as the standard first-line treatment for ES-SCLC in the United States, Europe, China, and other countries (23–25). Prior to the ADRIATIC trial, there was a lack of evidence to support the use of immunotherapy in LS-SCLC (13). Demonstrating that immunotherapy can notably improve OS and PFS, it holds the potential to reshape the treatment paradigm of LS-SCLC. The approval of durvalumab for LS-SCLC by both the US Food and Drug Administration (FDA) and the China National Medical Products Administration (NMPA) represents a significant milestone (26, 27). Consequently, prior to the widespread clinical implementation of ICIs in combination with CCRT or chemotherapy alone, it is of great significance to explore their efficacy, safety, and the prognostic biomarkers associated with the combined treatment approach.

In this retrospective study, data were collected from patients diagnosed with LS-SCLC who received treatment at the First Affiliated Hospital of Zhengzhou University from 2020 to 2022, followed by follow-up evaluations. K-M curve analyses, conducted both before and after PSM, indicated that patients with LS-SCLC who were treated with a combination of chemotherapy and ICIs experienced improved mOS and mPFS compared to those treated with chemotherapy alone. It is worth noting that, unlike the ADRITIC trial, this study did not make CRT a mandatory requirement. Moreover, In addition, both therapies maintained acceptable safety profiles, and there was no statistically significant difference in the rates of grade ≥3 adverse events between the two groups. PSM effectively minimized the disparities in baseline variables between the two groups. Consequently, following PSM, alterations were observed in the mOS and mPFS of the chemotherapy group. This could potentially be attributed to the reduction of potential confounding factors achieved by PSM (28).

Prior to this, several clinical trials have also underscored the importance of integrating CRT with ICIs A single-center, open-label phase 1/2 clinical trial reported that the concurrent administration of CRT and pembrolizumab in patients with LS-SCLC was well tolerated. Among the 40 enrolled patients, there were only three grade 4 events, and the incidence of pneumonia was 15%. At a median follow-up of 23.1 months, the mPFS was 19.7 months (14). Another phase 3 clinical trial demonstrated that consolidation treatment with durvalumab administered every 4 weeks during CRT significantly extended the mPFS and mOS without elevating the incidence of grade 3/4 AEs such as pneumonia (3.1% vs 2.6%) (13). Conversely, the STIMULI trial showed that consolidation immunotherapy with ipilimumab plus nivolumab after CRT in LS-SCLC patients did not enhance PFS compared to the control group and failed to reach the primary endpoint. This might be attributed to the high dropout rate (35%) induced by severe AEs during the trial (29). In conclusion, these studies indicate that the combination of CRT and ICIs in the treatment of LS-SCLC patients can significantly improve OS and PFS compared to CRT alone, with favorable tolerability.

It is noteworthy that during the collection of information on LS-SCLC cases, some patients presented with complex conditions and did not adhere strictly to the drug recommendations outlined in the Chinese CSCO guidelines. Clinicians frequently tailored medical strategies according to the actual circumstances. Consequently, a significant number of LS-SCLC patients did not undergo strict concurrent or sequential CRT, but rather received chemotherapy alone. The reasons for declining chest radiotherapy can be multifaceted, encompassing concerns regarding severe side effects associated with combined treatments, pulmonary fibrosis, and economic constraints. Moreover, an even smaller proportion of LS-SCLC patients received sequential CRT treatment. The most plausible explanation is the complexity of the treatment process, wherein patients often need to be transferred to the radiology department for treatment, and the treatment cycle is relatively protracted. In light of these considerations, we adjusted the inclusion criteria for SCLC patients, including only LS-SCLC patients who received chemotherapy and/or immunotherapy. CRT treatment was not incorporated as an inclusion criterion; instead, it was regarded as one of the covariates to be balanced in PSM. Such an analysis can offer more practical recommendations for clinicians in the real world when formulating treatment strategies for LS-SCLC patients. Nevertheless, in the treatment of stage III NSCLC, consolidation treatment with durvalumab following CRT could significantly enhance PFS (30). Subsequently, expert consensus also advocated the combination of durvalumab and CRT in NSCLC (31, 32). Likewise, the real-world study (SOLUTION) reported concordant findings (33), presumably due to the fact that the combination of radiotherapy and ICIs could induce alterations in the tumor immune microenvironment within the body (34). In the treatment of SCLC, it is essential to compare the clinical impact of CRT combined with ICIs against that of CRT alone in the future.

Regarding the combination of chemotherapy with various types of ICIs, our findings demonstrate that there are no statistically significant disparities in OS, PFS, and AEs between PD-1 inhibitors and PD-L1 inhibitors. In the treatment of ES-SCLC with chemotherapy in combination with ICIs, a network meta-analysis based on randomized controlled trials reveals that the efficacy and safety of PD-L1 inhibitors in combination with chemotherapy are comparable to those of PD-1 inhibitors combined with chemotherapy (35). Nevertheless, in NSCLC, treatment regimens incorporating anti-PD-1 agents confer better OS benefits compared to anti-PD-L1 therapy (36). Considering these inconsistent results, for LS-SCLC, with the clinical approval of durvalumab, further research is warranted in the future to elucidate the differences between PD-1 and PD-L1 when combined with chemotherapy.

Conventional factors, including smoking habits, gender, age, ECOG and TNM staging, along with other clinical indicators, are associated with the prognosis of SCLC (37). Systemic inflammation also exerts a crucial influence on tumor promotion and progression. Thus, it is plausible that markers of systemic inflammation are linked to the prognosis of SCLC. At present, certain novel systemic immune indicators, such as LIPI, can serve as prognostic factors for ES-SCLC in first-line chemotherapy and immunotherapy (38). Similarly, in studies of LS-SCLC without differentiating treatment modalities, the LIPI stratification results are key determinants affecting the prognosis of LS-SCLC patients (39). Our findings indicate that in LS-SCLC patients who received only chemotherapy plus ICIs, LIPI cannot be utilized as a prognostic factor, whereas the SII and PLR can be employed as independent predictors of OS. SII is a comprehensive immune parameter that incorporates neutrophils, lymphocytes, and platelets. Typically, an elevation in neutrophil levels, an increase in platelet count, and a decline in lymphocytes contribute to an increase in SII. A meta-analysis exploring the prognostic implications of SII in SCLC revealed a significant correlation between high SII and poor OS. Nevertheless, subgroup analysis indicated that different cut-off values of SII and the adjustment of confounding factors could influence the outcomes. In studies where the SII cut-off was set at < 700, high SII was not significantly associated with poor OS, with an odds ratio (OR) of 1.54 (95% CI: 0.83 - 2.85). Hence, multiple factors may account for the discrepancies between the findings of this study and those of the meta-analysis, including variations in cut-off values, adjustment for confounding variables, and differences in treatment modalities (40). PLR represents a composite outcome of platelets and lymphocytes, concurrently reflecting the equilibrium between the inflammatory response and the adaptive immune response. Our research findings demonstrate that a high PLR is correlated with poor OS. This is in accordance with the results of a meta-analysis, which reveals a notable decrease in OS among patients with LS-SCLC in the high PLR group (41). Our research is distinguished by its concentrated examination of LS-SCLC patients who received concurrent treatment with chemotherapy and immunotherapy.

The tumor microenvironment, consisting of the vascular system, extracellular matrix, and inflammatory cells, assumes a pivotal role in cancer progression. An increased PLR implies a surge in the inflammatory response, and it is accompanied by the regulation of immune cells and vascular signaling within the tumor microenvironment. Consequently, calculating the PLR prior to initiating chemotherapy combined with immunotherapy in LS-SCLC patients can aid in identifying those who are likely to have a poor prognosis.

Our research has certain limitations that warrant attention. One key limitation is the currently limited number of patients with LS-SCLC who underwent combined chemotherapy and immunotherapy (n = 66). This limited sample size may undermine both the statistical power and the generalizability of the findings. Additionally, the relatively wide 95% CI may give rise to concerns regarding the precision of the estimates. Secondly, the relatively short follow-up duration could have an impact on the outcomes. By the conclusion of the follow-up period, some patients had not yet reached the primary clinical endpoints, namely OS and PFS. Furthermore, given that durvalumab has been approved for the treatment of LS-SCLC for a relatively brief period, future research will necessitate a larger number of cases and more extended follow-up intervals to obtain more comprehensive and reliable data. Thirdly, owing to the retrospective nature of this study, despite the use of PSM to balance the baseline characteristics between the two treatment groups, there remains a possibility that some potential confounding factors may still be present.

In summary, our results indicate that the combination of first-line chemotherapy and ICIs can significantly improve OS and PFS in patients with LS-SCLC, while maintaining an acceptable safety profile. Moreover, radiotherapy, PLR > 261.39, and SII > 666.29, emerge as independent predictors of prognosis in LS-SCLC patients receiving combined treatment modalities. These results offer reliable references for clinicians when formulating treatment strategies for LS-SCLC patients and also provide support for future clinical trials. It should be noted that, owing to the retrospective study design, limited follow - up, and other factors, these findings should be referred to with caution.