First-line serplulimab-based immunochemotherapy in elderly patients with extensive-stage small cell lung cancer: a multicenter, real-world study

Introduction

Lung cancer is one of the malignancies with the highest morbidity and mortality rates worldwide, of which small cell lung cancer (SCLC) is the most malignant and metastatic pathological type, accounting for approximately 10–15% of lung cancers, and has consistently been associated with a 5-year overall survival (OS) rate of less than 7% in the SCLC patient (1,2). Approximately 70% of SCLC is diagnosed as extensive-stage small cell lung cancer (ES-SCLC), which significantly worsens prognosis, with a median overall survival (mOS) of only 8–13 months (3).

As healthcare advances continue to extend human longevity, ES-SCLC is being delayed, especially in Asian countries where aging is increasing. The hallmarks of senescence in aged cells, including “proliferative senescence” and “immunosenescence” synergistically accelerate neoplastic growth and the rapid progression of cancer (4,5). Older patients often have a diminished response to current therapeutic regimens for ES-SCLC. As most clinical trials have enrolled patients younger than 65 years, the older patients, combined with more complex situations, have been screened out, and clinical efficacy data are lacking. Retrospective analyses have shown that elderly patients may derive less OS benefit from atezolizumab plus chemotherapy than their younger counterparts (6). This discrepancy raises critical questions regarding the applicability of immune checkpoint inhibitors (ICIs) in the geriatric population, particularly considering evidence suggesting that immunosenescence may limit the therapeutic benefit of ICIs. In addition, the elderly are at increased risk of toxicity, particularly an increased incidence and severity of immune-related adverse events (irAEs).

Another formidable hurdle in managing ES-SCLC is the absence of robust predictive biomarkers, which hinders the progress of precision medicine in this field. In contrast to non-small cell lung cancer (NSCLC), where programmed death ligand-1 (PD-L1) expression levels and tumor mutational burden (TMB) have been extensively studied (7), these markers have shown limited utility in SCLC (8,9). The neutrophil-to-lymphocyte ratio (NLR) reflects systemic inflammation and immune status. Its predictive capabilities have been substantiated across various solid tumors. Multiple studies (10,11) have explored NLR’s prognostic value in SCLC; however, consensus has yet to be reached. The role of NLR as a predictive biomarker in ES-SCLC, especially among the elderly population, requires further investigation and validation.

The advent of ICI has revolutionized the landscape of ES-SCLC therapy, breaking the long-standing reliance on chemotherapy alone (12-14). In particular, the ASTRUM-005 trial highlighted the exceptional efficacy of serplulimab among a plethora of PD-(L)1 inhibitors, achieving a milestone in ES-SCLC by extending mOS to over 15 months [15.4 vs. 10.9 months, hazard ratio (HR) 0.63, 95% confidence interval (CI): 0.49–0.82, P<0.001] (15). This led to the approval of serplulimab in combination with chemotherapy by the National Medical Products Administration (NMPA) on 17 January 2023 for the first-line treatment of ES-SCLC. Due to the strict inclusion criteria of clinical trials, the characteristics of enrolled patients often differ from those encountered in real-world settings. To our knowledge, there are only a few retrospective studies reporting basic efficacy or safety data after the application of immune-combination chemotherapy in elderly (≥70 years) patients with ES-SCLC, and there are no real-world data that exist regarding the use of serplulimab in combination with chemotherapy as first-line treatment in this group. To address this gap, we initiated a retrospective study and collected ≥70 years of patients with ES-SCLC from five institutions in China, evaluating the efficacy and safety of serplulimab plus chemotherapy as the first-line treatment for this population, and further investigating the predictive potential of NLR in this elderly cohort. We present the following article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1815/rc).

Methods

Patients selection

This retrospective study included patients who met the following criteria: (I) age ≥70 years; (II) histological or cytological diagnosis of ES-SCLC; (III) first-line treatment with serplulimab. Patients with incomplete clinical records, such as missing disease courses, pathological diagnoses, treatment details, and outcome observations, were excluded. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the institutional review board of the Fudan University Shanghai Cancer Center (No. 1612167-18), and individual consent for this retrospective analysis was waived. All participating hospitals/institutions were informed and agreed with this study.

Data collection and assessment of results

Information extracted from the medical records included: age, sex, smoking history, tumor VALG/TNM staging, Eastern Cooperative Oncology Group (ECOG) performance status (PS), number of lesions, recurrence/metastasis status, comorbidities (chronic obstructive pulmonary disease, emphysema, pneumonia, hypertension, diabetes, coronary heart disease, etc.), previous treatment history, first-line treatment regimen (including serplulimab), and adverse events (AEs).

Tumor assessments were performed by clinicians at each center based on the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. The primary endpoint was progression-free survival (PFS), defined as the period from the start of serplulimab treatment until the first documented disease progression (PD) or death from any cause. Secondary endpoints included OS, objective response rate (ORR), disease control rate (DCR), and adverse profile. OS was defined as the duration from the initiation of serplulimab therapy until death from any cause, with censored data for patients alive at the last follow-up visit or the end of the study, whichever occurred first. ORR was defined as the proportion of patients achieving complete response (CR) or partial response (PR). DCR was defined as the proportion of patients achieving CR, PR, or stable disease (SD). AEs during first-line treatment were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0, and we captured both all-grade AEs and those grade ≥3. This article also explores the prognostic utility of NLR in elderly patients with ES-SCLC.

Statistical analysis

Continuous variables were tested for normality using the Shapiro-Wilk method and reported as mean ± standard deviation (SD) for normally distributed measures and as median and range for skewed measures. Categorical variables were reported as frequency counts and percentages.

The two-sided 95% CIs of ORR and DCR were estimated using the Clopper-Pearson method. PFS and OS were analyzed by constructing Kaplan-Meier survival curves and compared between groups via the log-rank test. Univariate and multivariate Cox proportional hazards regression models were employed to assess the association between various variables and survival in patients with ES-SCLC. The Schoenfeld residuals test was used to validate the assumption of proportional hazards. Variables that did not meet the proportional hazards assumption were further analyzed using the accelerated failure time (AFT) model. The optimal AFT model was selected based on the minimum Akaike information criterion (AIC) and Bayesian information criterion (BIC) values. Graphical analyses included swimmer plots depicting tumor responses at each assessment point, forest plots based on subgroup analyses from univariate and multivariate models, and bar charts contrasting NLR differences pre- and post-treatment across different response categories. All statistical analyses were performed using R (v.4.3.2). Statistical significance was defined as a two-sided P value <0.05.

Results

Patients characteristic

From June 2022 to December 2023, a total of 43 patients with ES-SCLC were enrolled in five centers, with a median age of 73 years (range, 70–86 years) and 83.72% being male (n=36). Detailed baseline characteristics are shown in Table 1. Ten (23.26%) and 32 (74.42%) patients were diagnosed with stages III and IV at baseline, respectively. Notably, one patient with stage II at baseline progressed to ES-SCLC during treatment. Most patients had an ECOG PS score of 0 or 1 (93.02%, n=40) and were PD-L1 negative (74.42%, n=32). Bone, brain, and liver metastases were present in 11 (25.58%), 5 (11.63%), and 12 (27.91%) patients at baseline, respectively. Meanwhile, 12 (27.91%) and 5 (11.63%) patients received thoracic and brain radiotherapy, respectively. Almost half of the patients (44.19%, n=19) had hypertension. The median number of treatment cycles was 4 (range, 2–6).

Efficacy

Primary endpoint

The median follow-up duration in our study was 9.2 months. A total of 26 PFS events (60.47%) were observed, including PD in 17 patients and death in 12. The media PFS (mPFS) was 7.0 months (95% CI: 6.1–12.5), with a 6-month PFS rate of 69.4% (95% CI: 56.3–85.6%) and a 1-year PFS rate of 30.9% (95% CI: 18.3–52.3%) (Figure 1A).

Figure 1 Survival outcomes of all patients enrolled in this study. CI, confidence interval; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; OS, overall survival; PFS, progression-free survival.

The multivariate regression analysis revealed that compared to males, female patients had a significantly increased risk of PD (n=6/7, HR 4.92, 95% CI: 1.11–21.78, P=0.04). Similarly, compared to patients who hadn’t received brain radiotherapy, patients who received the brain radiotherapy also showed a significantly higher risk of PD (n=5/5, HR 26.16, 95% CI: 3.91–175, P<0.001). No significant differences were observed in the remaining subgroups (Figure S1). Results from the AFT model echoed these findings, indicating a significant increase in the risk of PD in female patients (Factor 0.51, 95% CI: 0.29–0.88, P=0.02) and in patients who received brain radiotherapy (Factor 0.25, 95% CI: 0.13–0.47, P<0.001) (Table S1).

Secondary endpoints

A total of 12 death events (27.91%) occurred, with the data still immature and mOS not yet reached (Figure 1B). The 6-month OS rate was 94.7% (95% CI: 87.9–100.0%), and the 1-year OS rate was 65.8% (95% CI: 50.0–86.5%), with ongoing follow-up. The univariate analysis showed a significantly elevated risk of death in female patients compared to males (HR 3.64, 95% CI: 1.02–12.96, P=0.046). The multivariate analysis indicated a significantly reduced risk of death in patients with a smoking history (HR 0.1, 95% CI: 0.01–0.96, P=0.046). Compared to patients with ECOG PS of 0, those with ECOG PS of 1 or 2 had a significantly increased risk of death (HR 18.64, 95% CI: 1.29–270.1, P=0.03). No significant differences were observed for the remaining variables (Figure S2). The AFT model demonstrated a significantly increased risk of death in patients aged ≥75 years (Factor 0.34, 95% CI: 0.15–0.75, P=0.008), those with ECOG PS of 1 or 2 (Factor 0.43, 95% CI: 0.25–0.73, P=0.002), patients who received thoracic radiotherapy (TRT) (Factor 0.41, 95% CI: 0.17–0.96, P=0.04), and those with brain metastasis (Factor 0.33, 95% CI: 0.13–0.86, P=0.02). Patients with a smoking history had a significantly decreased risk of death (Factor 1.78, 95% CI: 1.14–2.79, P=0.01) (Table S2).

A total of 28 patients achieved an objective response following first-line therapy (1 CR and 27 PR), resulting in an ORR of 65.12% (95% CI: 49.07–78.99%). Fourteen patients reached SD, yielding a DCR of 97.67% (95% CI: 87.71–99.94%) (Figure 2, Table 2).

Figure 2 Swimming pool image presents efficacy in each patient. CR, complete response; NE, not evaluable; PD, disease progression; PR, partial response; SD, stable disease.

Safety

A total of 19 patients (44.19%) experienced any grade AEs during the treatment, with most of them being grades 1–2 (14 patients, 32.56%). Grade ≥3 AEs occupied 11.63% (5 patients) of all AEs. Details of the safety profile are outlined in Table 3. The most frequent any-grade AE was anemia (9 patients, 20.93%), followed by elevated serum creatinine level (4 patients, 9.3%) and leukopenia (3 patients, 6.98%). Incidences of increased AST and ALT levels, pleural effusion, and allergic reaction were similar (2/43, 4.65%). Incidence rates for hyperthyroidism, hypothyroidism, urinary irritative symptoms, fever, bilirubin increase, asymptomatic elevation of amylase, and thrombocytopenia were equal (1/43, 2.33%). No other pneumonia was encountered except for one case of radiation pneumonitis. No AE-related death was reported.

Exploratory indicator of NLR

To investigate whether NLR has a similar prognostic value in ES-SCLC patients, especially in elderly patients, this retrospective study collected NLR levels at baseline and after four cycles of treatment. The aim was to evaluate both the prognostic significance of baseline NLR levels and changes in NLR during treatment. A total of 39 patients with measurable NLR values at both baseline and during treatment were included in the analysis.

As previous studies (16,17) had not found a precise value to differentiate NLR levels, and there was no consensus among researchers, we used the median NLR of patients at baseline, 3.086, as the threshold to define high/low NLR levels. The subgroup analysis showed that patients with lower baseline NLR [n=14/20, 9.2 months, 95% CI: 4.57–not reached (NR)] had numerically higher mPFS than patients with higher baseline NLR (n=11/19, 7.0 months, 95% CI: 6.03–NR), although the difference was not significant (HR 0.77, 95% CI: 0.35–1.70, P=0.52) (Figure 3A). Similarly, there was no statistically significant difference in mOS between patients stratified by baseline NLR levels (HR 1.24, 95% CI: 0.40–3.85, P=0.72) (Figure 3B).

Figure 3 Subgroup analysis of survival stratified by NLR level at baseline. CI, confidence interval; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; NR, not reached; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; PFS, progression-free survival.

After four treatment cycles, the NLR value had significantly increased compared to the baseline [4.19 (range, 0.86–20) vs. 3.09 (range, 1.38–7.27), P=0.04] (Figure 4A). Stratifying the patients based on their best overall response (BOR), we found that post-treatment NLR levels increased numerically in both the ORR group [4.19 (range, 0.86–12.69) vs. 3.04 (range, 1.38–7.27), P=0.07] and the non-ORR group [4.46 (range, 1.8–20) vs. 3.77 (range, 1.64–7.25), P=0.37], although these results had no statistical significance (Figure 4B, Table S3). Consistent with these findings, McNemar’s paired chi-squared test also showed no significant difference in NLR levels pre- and post-treatment (P=0.18) (Table S4).

Figure 4 Change of NLR in all patients and patients stratified by the best response. *, P<0.05 compared with the negative control. NLR, neutrophil-to-lymphocyte ratio; ORR, objective response rate.

Discussion

A previous study has demonstrated inferior survival benefits in elderly ES-SCLC patients compared to younger cohorts, regardless of the addition of ICIs to the standard first-line regimens (18). Moreover, age-related immunosenescence, complex comorbidities, and worse tolerance to multiple medications pose challenges in selecting appropriate treatments and maintaining patient compliance in this demographic. Optimal therapeutic strategies for this patient population remain a topic of ongoing investigation. In this report, elderly patients (≥70 years) with ES-SCLC treated with first-line serplulimab in combination with chemotherapy exhibited numerically superior mPFS (7.0 vs. 5.7 months) and 1-year PFS rates (30.9% vs. 23.6%) than the ASTRUM-005 study (15). Our findings indicated a notably increased risk of PD in female patients and those who received brain radiotherapy. However, given the small number of events in these subgroups (6/7 females progressed, 5/5 patients with brain radiotherapy progressed), the observed disparities require confirmation in larger cohorts. Otherwise, there were no significant PFS differences in other subgroups, suggesting that even though there is inherent heterogeneity in the real-world elderly population, most can benefit from serplulimab combination chemotherapy.

Due to the relatively short median follow-up time of 9.2 months in this study, the mOS has not yet been reached. Notably, our findings suggest that patients with a history of smoking experienced a survival benefit. Smoking has long been recognized as a major etiological factor for SCLC, and it is associated with poorer prognosis in patients with ES-SCLC. It has been posited that elderly patients exhibit ‘immunosenescence’, characterized by a decline in immune function that may contribute to their diminished responsiveness to immunotherapy relative to younger individuals. Conversely, smoking is linked to a higher TMB, leading to an increased presence of neoantigens and potentially a higher tumor load (19-22). This heightened immunogenicity may enhance the efficacy of immunotherapies in elderly patients (23,24).

Additionally, our study revealed that thoracic and/or brain radiotherapy may increase the risk of progression and/or death in patients. This observation might be skewed due to the small sample size, or it could indicate that radiotherapy does not necessarily confer a definitive advantage in the first-line treatment of ES-SCLC. Although numerous studies have suggested a synergistic effect between radiotherapy and immunotherapy, including radio sensitization and abscopal effects (25,26), particularly in NSCLC (27-30), the role of radiotherapy in SCLC remains uncertain. The brain is often the primary site of metastasis at diagnosis or soon after in SCLC patients, with an mOS of only 3–6 months (31). While many studies conclude that brain radiotherapy reduces the incidence of brain metastases and improves survival, some trials question its role in the first-line treatment of ES-SCLC. Partial studies have demonstrated that brain radiotherapy does not necessarily improve OS outcomes, regardless of whether brain metastases are present at diagnosis (32-36). Neurotoxicity resulting from cranial radiotherapy is another concern. Studies have shown that limited-stage SCLC (LS-SCLC) may benefit more from brain radiotherapy than ES-SCLC in terms of OS, PFS, and brain metastasis-free survival (BMFS) (37,38). Thus, the role of brain radiotherapy in ES-SCLC requires further clarification through prospective trials. The role of TRT in ES-SCLC is also ambiguous. In the era of immunotherapy, a comprehensive retrospective study and a meta-analysis have shown improved survival and enhanced survival rates under chemoimmunotherapy combined with concurrent thoracic radiotherapy (cTRT) (39,40). However, the RTOG 0937 study demonstrated that prophylactic cranial irradiation (PCI) plus TRT delayed progression but did not improve OS (41). The increased risk of death after chest radiotherapy in this study may be due to the increased likelihood of interstitial lung disease due to the combination of chest radiotherapy with immunotherapy. Discrepancies in the choice of ICIs, radiation dose, field of radiation, sequencing of therapies, and characteristics of the patient populations across studies contribute to these controversial results. Nowadays, two randomized controlled clinical trials, NCT04402788 and NCT04462276 are investigating the efficacy and safety of cTRT plus chemoimmunotherapy for ES-SCLC patients. We believe that the precise efficacy of cTRT, in addition to immunotherapy, would be revealed further.

The ORR in this study was numerically lower (65.12%) than the ASTRUM-005 trial of 80.2% (15). This discrepancy may be attributed to immunosenescence in the elderly population, usually characterized by T-cell dysfunction, decreased diversity of immune cells, and enhanced chronic inflammatory states, which can attenuate responses to ICIs. However, the observed ORR remains within an acceptable range. Notably, one patient (2.33%) in our cohort achieved CR. The DCR was 97.67%, suggesting that elderly patients can still experience favorable tumor responses when treated with serplulimab plus chemotherapy as a first-line therapy. Considering the aggressive nature of ES-SCLC, coupled with the complexity and refractoriness of the disease in elderly patients, enhancing quality of life and achieving long-term survival are paramount objectives for this patient population.

Even older patients with poorer ECOG PS scores and organ function experience more severe drug toxicity than younger patients (42-44). The incidence of bone marrow suppression induced by different ICIs varies and is generally low (45). In the ASTRUM-005 study (15), the incidence of any-grade bone marrow suppression (including anemia, thrombocytopenia, leukopenia, and neutropenia) exceeded 15%. In our study, only any-grade anemia was the most frequent event (more than 15%). The incidence of irAEs, such as thyroid dysfunction, was lower (2.33%) in elderly patients. Renal toxicity, manifested as increased creatinine levels, occurred more frequently (9.3%), consistent with the physiological degenerative changes typical of aging. All other TRAEs had an incidence of less than 10%, reaffirming the favorable safety profile of serplulimab, especially in the elderly population where drug toxicity is a major concern. The advantageous safety characteristics of serplulimab can potentially enhance patient adherence and thus improve clinical outcomes in this vulnerable group.

Regarding biomarker exploration, although the NLR has established its biomarker value in various solid tumors, including NSCLC (46,47), its predictive utility in SCLC remains uncertain. Neutrophils are generally associated with tumor promotion, whereas lymphocytes are linked to tumor suppression (48-50). Therefore, a lower baseline NLR and a decrease in NLR during treatment are typically thought to correlate with better outcomes. However, our study indicates that despite survival benefits, post-treatment NLR values significantly increased, and the NLR change had no correlation with tumor response, nor did the baseline NLR levels couldn’t predict survival outcomes. These findings collectively suggest that NLR may not serve as a suitable predictive biomarker for elderly patients with ES-SCLC. Such results are not surprising given the uncertainties surrounding NLR in our study. These uncertainties stem primarily from the small sample size, as well as the fact that immunosenescence in the elderly population inherently alters the composition and dynamics of the NLR components relative to those in standard clinical trial populations. Additionally, the timing of post-treatment NLR monitoring does not align with the timing of BOR assessment, which hinders the predictive accuracy. Besides, the selection of NLR cut-off values may influence its predictive value. In this study, we used the median baseline NLR of 3.086 as a cut-off, whereas other studies have utilized cut-offs ranging from 1.28 to 5 (51-57). Standardizing NLR thresholds in the future would aid in making more precise judgments about its predictive value. The choice of time points for measuring NLR may also affect its predictive value. For instance, changes in NLR and its level at two cycles after treatment have been shown to impact the prognosis in SCLC patients (56). Another study suggests that NLR level at 6 weeks post-immunotherapy offers better predictive value for patient outcomes (55). It is noteworthy that, despite differences in defining NLR thresholds and timing, the trend in most studies is consistent: a decrease in NLR levels correlates with improved survival, and lower baseline NLR levels are associated with better prognoses (57,58). However, some studies have presented contrasting conclusions. A recent large-scale analysis of ES-SCLC patients treated with ICIs indicated that patients with NLR ≥2.14 had better outcomes (59). Another study has shown that NLR is not a reliable predictor of prognosis in ES-SCLC patients (P=0.69) (60). As more studies emerge, the predictive utility of NLR in ES-SCLC becomes increasingly unclear, underscoring the need for more accurate biomarkers. Apart from NLR, lactate dehydrogenase (LDH), the lung immune prognostic index (LIPI, derived from the NLR and LDH), and the prognostic nutritional index (PNI, combining albumin and lymphocyte levels) also exhibit potential predictive roles in SCLC (57,59,61,62). It is anticipated that a combination of multiple biomarkers will offer a more precise approach to predicting outcomes in SCLC in the future.

Due to the limitations of retrospective studies, it was unable to provide sufficient baseline or treatment period data to support further investigation of NLR or other biomarkers. We eagerly anticipate that future researchers will use more advanced methods, such as next-generation sequencing (NGS) and proteomics, to explore the tumor characteristics of ES-SCLC patients across broader dimensions and to identify more reliable potential predictive markers. At the same time, due to the limited sample size and single-arm design of this cohort, direct comparisons could not be conducted between different age groups of patients. However, it is important to note that our study was conducted across five major tertiary hospitals in China, covering a geographically diverse patient population, which enhances the generalizability of our findings despite the sample size constraints. Furthermore, elderly patients (≥70 years) with ES-SCLC are often underrepresented in randomized controlled trials, and real-world data remain scarce. While acknowledging the limitations, our study provides valuable insights into the clinical feasibility of serplulimab-based first-line immunochemotherapy in this unique patient population. Additionally, as of the data cutoff, OS data remain immature, necessitating longer follow-up to obtain definitive long-term survival outcomes. Future prospective multicenter studies with larger cohorts and comparative designs will be crucial for validating our findings and further optimizing treatment strategies for elderly patients with ES-SCLC.

Conclusions

In conclusion, against the backdrop of therapeutic limitations and the historically inferior efficacy and safety of first-line treatment in older patients, this retrospective study yields encouraging findings. Specifically, the combination of serplulimab with chemotherapy demonstrates survival benefits in elderly patients aged 70 years and above with ES-SCLC, accompanied by a manageable toxicity profile. Our multicenter study design, involving five tertiary hospitals, enhances the representativeness of the patient population and mitigates some of the limitations associated with a smaller sample size. However, given the relatively short follow-up and immature OS data, continued monitoring is required to provide more definitive long-term survival outcomes. Nevertheless, our results suggest that NLR may not be a suitable biomarker for predicting prognosis in elderly patients with ES-SCLC. This highlights the need for further investigation into more accurate prognostic biomarkers for SCLC, especially for the more malignant type of ES-SCLC. Future well-powered, prospective trials are warranted to provide more robust evidence and refine treatment strategies for this unique and often vulnerable subgroup.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1815/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1815/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1815/prf

Funding: This work was supported by the Clinical Research Capacity Building and Human Research Participants Protection Practice Platform (CCHRPP) (No. CCHRPP-ZL-2023-Q-005), the Shanghai Anti-Cancer Association (No. SACA-AX202210), Shanghai Municipal Health Commission (No. 2020CXJQ02), and the Beijing Life Oasis Public Service Center (No. CPHCF-ZLKY-2023016).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1815/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Fudan University Shanghai Cancer Center (No. 1612167-18), and individual consent for this retrospective analysis was waived. All participating hospitals/institutions were informed and agreed with this 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/.

References

1. Oronsky B, Reid TR, Oronsky A, et al. What's New in SCLC? A Review. Neoplasia 2017;19:842-7. [Crossref] [PubMed]
2. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 2017;17:765. [Crossref] [PubMed]
3. Lim JU, Kang HS. A narrative review of current and potential prognostic biomarkers for immunotherapy in small-cell lung cancer. Ann Transl Med 2021;9:809. [Crossref] [PubMed]
4. Fernandez-Pol JA, Douglas MG. Molecular interactions of cancer and age. Hematol Oncol Clin North Am 2000;14:25-44. [Crossref] [PubMed]
5. Burns EA, Goodwin JS. Immunological changes of aging. Comprehensive Geriatric Oncology 1998;2:158-71.
6. Fujimoto D, Morimoto T, Tamiya M, et al. Outcomes of Chemoimmunotherapy Among Patients With Extensive-Stage Small Cell Lung Cancer According to Potential Clinical Trial Eligibility. JAMA Netw Open 2023;6:e230698. [Crossref] [PubMed]
7. Melosky B, Juergens R, Hirsh V, et al. Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer. Oncologist 2020;25:64-77. [Crossref] [PubMed]
8. Yu H, Chen P, Cai X, et al. Efficacy and safety of PD-L1 inhibitors versus PD-1 inhibitors in first-line treatment with chemotherapy for extensive-stage small-cell lung cancer. Cancer Immunol Immunother 2022;71:637-44. [Crossref] [PubMed]
9. Kowanetz M, Zou W, Gettinger SN, et al. Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci U S A 2018;115:E10119-26. [Crossref] [PubMed]
10. Drpa G, Sutic M, Baranasic J, et al. Neutrophil-to-lymphocyte ratio can predict outcome in extensive-stage small cell lung cancer. Radiol Oncol 2020;54:437-46. [Crossref] [PubMed]
11. Käsmann L, Bolm L, Schild SE, et al. Neutrophil-to-Lymphocyte Ratio Predicts Outcome in Limited Disease Small-cell Lung Cancer. Lung 2017;195:217-24. [Crossref] [PubMed]
12. Jett JR, Schild SE, Kesler KA, et al. Treatment of small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e400S-19S.
13. Liu SV, Reck M, Mansfield AS, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol 2021;39:619-30. [Crossref] [PubMed]
14. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-39. [Crossref] [PubMed]
15. Cheng Y, Han L, Wu L, et al. Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial. JAMA 2022;328:1223-32. [Crossref] [PubMed]
16. Chen D, Xu J, Zhao Y, et al. Prognostic value of pretreatment procalcitonin and neutrophil-lymphocyte ratio in extensive-stage small-cell lung cancer. Cancer Biol Ther 2024;25:2331273. [Crossref] [PubMed]
17. Lu Y, Jiang J, Ren C. The clinicopathological and prognostic value of the pretreatment neutrophil-to-lymphocyte ratio in small cell lung cancer: A meta-analysis. PLoS One 2020;15:e0230979. [Crossref] [PubMed]
18. Ma M, Wang M, Xu Y, et al. Zhongguo Fei Ai Za Zhi 2014;17:8-14. [First-line chemotherapy and its survival analysis of 394 patients with extensive-stage small cell lung cancer in a single institute].
19. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature 2013;500:415-21. [Crossref] [PubMed]
20. Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med 2017;377:2500-1. [Crossref] [PubMed]
21. Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. Clin Cancer Res 2016;22:3618-29. [Crossref] [PubMed]
22. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017;9:34. [Crossref] [PubMed]
23. Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol 2019;30:44-56. [Crossref] [PubMed]
24. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 2015;348:69-74. [Crossref] [PubMed]
25. Pitroda SP, Chmura SJ, Weichselbaum RR. Integration of radiotherapy and immunotherapy for treatment of oligometastases. Lancet Oncol 2019;20:e434-42. [Crossref] [PubMed]
26. Golden EB, Chhabra A, Chachoua A, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015;16:795-803. [Crossref] [PubMed]
27. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
28. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol 2022;40:1301-11. [Crossref] [PubMed]
29. Lin SH, Lin Y, Yao L, et al. Phase II Trial of Concurrent Atezolizumab With Chemoradiation for Unresectable NSCLC. J Thorac Oncol 2020;15:248-57. [Crossref] [PubMed]
30. Fitzgerald K, Flynn J, Zhang Z, et al. Patterns of Recurrence Among Higher-Risk Patients Receiving Daily External Beam Accelerated Partial-Breast Irradiation to 40 Gy in 10 Fractions. Adv Radiat Oncol 2020;5:27-33. [Crossref] [PubMed]
31. Hochstenbag MM, Twijnstra A, Wilmink JT, et al. Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis. J Neurooncol 2000;48:243-8. [Crossref] [PubMed]
32. Huang L, Chen S, Liu H, et al. PD-L1 inhibitors combined with whole brain radiotherapy in patients with small cell lung cancer brain metastases: Real-world evidence. Cancer Med 2024;13:e7125. [Crossref] [PubMed]
33. Gaebe K, Erickson AW, Li AY, et al. Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis. EClinicalMedicine 2024;67:102396. [Crossref] [PubMed]
34. Howlader N, Forjaz G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med 2020;383:640-9. [Crossref] [PubMed]
35. Ma J, Tian Y, Hao S, et al. Outcomes of first-line anti-PD-L1 blockades combined with brain radiotherapy for extensive-stage small-cell lung cancer with brain metastasis. J Neurooncol 2022;159:685-93. [Crossref] [PubMed]
36. Nosaki K, Seto T, Shimokawa M, et al. Is prophylactic cranial irradiation (PCI) needed in patients with extensive-stage small cell lung cancer showing complete response to first-line chemotherapy? Radiother Oncol 2018;127:344-8. [Crossref] [PubMed]
37. Chu X, Zhu Z. Prophylactic cranial irradiation in small cell lung cancer: an update. Curr Opin Oncol 2023;35:61-7. [Crossref] [PubMed]
38. Maroufi SF, Fallahi MS, Kankam SB, et al. Prophylactic cranial irradiation effect on survival in patients with small cell lung cancer: a comprehensive systematic review and meta-analysis. Neurosurg Focus 2023;55:E4. [Crossref] [PubMed]
39. Peng J, Zhang L, Wang L, et al. Real-world outcomes of PD-L1 inhibitors combined with thoracic radiotherapy in the first-line treatment of extensive stage small cell lung cancer. Radiat Oncol 2023;18:111. [Crossref] [PubMed]
40. Feng B, Zheng Y, Zhang J, et al. Chemoimmunotherapy combined with consolidative thoracic radiotherapy for extensive-stage small cell lung cancer: A systematic review and meta-analysis. Radiother Oncol 2024;190:110014. [Crossref] [PubMed]
41. Gore EM, Hu C, Sun AY, et al. Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937. J Thorac Oncol 2017;12:1561-70. [Crossref] [PubMed]
42. Schild SE, Zhao L, Wampfler JA, et al. Small-cell Lung Cancer in Very Elderly (&#x2265; 80 Years) Patients. Clinical Lung Cancer 2019;20:313-21. [Crossref] [PubMed]
43. Oshita F, Kurata T, Kasai T, et al. Prospective evaluation of the feasibility of cisplatin-based chemotherapy for elderly lung cancer patients with normal organ functions. Jpn J Cancer Res 1995;86:1198-202. [Crossref] [PubMed]
44. Jara C, Gómez-Aldaraví JL, Tirado R, et al. Small-cell lung cancer in the elderly--is age of patient a relevant factor? Acta Oncol 1999;38:781-6. [Crossref] [PubMed]
45. Michielin O, Lalani AK, Robert C, et al. Defining unique clinical hallmarks for immune checkpoint inhibitor-based therapies. J Immunother Cancer 2022;10:e003024. [Crossref] [PubMed]
46. Russo A, Russano M, Franchina T, et al. Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study. Adv Ther 2020;37:1145-55. [Crossref] [PubMed]
47. Fucà G, Galli G, Poggi M, et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 2019;4:e000457. [Crossref] [PubMed]
48. Zhao W, Wang P, Jia H, et al. Lymphocyte count or percentage: which can better predict the prognosis of advanced cancer patients following palliative care? BMC Cancer 2017;17:514. [Crossref] [PubMed]
49. Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology 2016;150:1646-1658.e17. [Crossref] [PubMed]
50. Fridlender ZG, Albelda SM. Tumor-associated neutrophils: friend or foe? Carcinogenesis 2012;33:949-55. [Crossref] [PubMed]
51. Mirili C, Guney IB, Paydas S, et al. Prognostic significance of neutrophil/lymphocyte ratio (NLR) and correlation with PET-CT metabolic parameters in small cell lung cancer (SCLC). Int J Clin Oncol 2019;24:168-78. [Crossref] [PubMed]
52. Templeton AJ, McNamara MG, Šeruga B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 2014;106:dju124. [Crossref] [PubMed]
53. Kang MH, Go SI, Song HN, et al. The prognostic impact of the neutrophil-to-lymphocyte ratio in patients with small-cell lung cancer. Br J Cancer 2014;111:452-60. [Crossref] [PubMed]
54. Suzuki R, Lin SH, Wei X, et al. Prognostic significance of pretreatment total lymphocyte count and neutrophil-to-lymphocyte ratio in extensive-stage small-cell lung cancer. Radiother Oncol 2018;126:499-505. [Crossref] [PubMed]
55. Xiong Q, Huang Z, Xin L, et al. Post-treatment neutrophil-to-lymphocyte ratio (NLR) predicts response to anti-PD-1/PD-L1 antibody in SCLC patients at early phase. Cancer Immunol Immunother 2021;70:713-20. [Crossref] [PubMed]
56. Bi H, Ren D, Xiao Y, et al. Prognostic implications of neutrophil-to-lymphocyte ratio in patients with extensive-stage small cell lung cancer receiving chemoimmunotherapy: A multicenter, real-world study. Thorac Cancer 2024;15:559-69. [Crossref] [PubMed]
57. Liu C, Jin B, Liu Y, et al. Construction of the prognostic model for small-cell lung cancer based on inflammatory markers: A real-world study of 612 cases with eastern cooperative oncology group performance score 0-1. Cancer Med 2023;12:9527-40. [Crossref] [PubMed]
58. Chen C, Yang H, Cai D, et al. Preoperative peripheral blood neutrophil-to-lymphocyte ratios (NLR) and platelet-to-lymphocyte ratio (PLR) related nomograms predict the survival of patients with limited-stage small-cell lung cancer. Transl Lung Cancer Res 2021;10:866-77. [Crossref] [PubMed]
59. Dang J, Xu G, Guo G, et al. Construction of a prognostic model for extensive-stage small cell lung cancer patients undergoing immune therapy in northernmost China and prediction of treatment efficacy based on response status at different time points. J Cancer Res Clin Oncol 2024;150:255. [Crossref] [PubMed]
60. Zhao J, He Y, Yang X, et al. Assessing treatment outcomes of chemoimmunotherapy in extensive-stage small cell lung cancer: an integrated clinical and radiomics approach. J Immunother Cancer 2023;11:e007492. [Crossref] [PubMed]
61. Yang Y, Ai X, Xu H, et al. Treatment patterns and outcomes of immunotherapy in extensive-stage small-cell lung cancer based on real-world practice. Thorac Cancer 2022;13:3295-303. [Crossref] [PubMed]
62. Sun B, Hou Q, Liang Y, et al. Prognostic ability of lung immune prognostic index in limited-stage small cell lung cancer. BMC Cancer 2022;22:1233. [Crossref] [PubMed]