Effectiveness of Chemoimmunotherapy in Small-cell Lung Cancer Patients With a Poor Performance Status or Higher Neutrophil/Lymphocyte Ratio

Abstract

Background/Aim

Chemoimmunotherapy has improved overall survival in patients with extensive small-cell lung cancer (SCLC). However, the backgrounds of patients enrolled in clinical trials tend to differ from those of patients treated in clinical practice, and the effectiveness of chemoimmunotherapy may be unclear in some populations, including patients with poor performance status. This study aimed to evaluate the effectiveness of chemoimmunotherapy for SCLC patients in clinical practice while focusing on several subgroups.

Patients and Methods

We retrospectively analyzed the data of SCLC patients who received chemoimmunotherapy or chemotherapy. The association between chemoimmuno-therapy and overall survival was evaluated by adjusting for patient backgrounds using the Cox proportional hazards model, followed by a subset analysis.

Results

The chemoimmuno-therapy and chemotherapy groups included 43 and 71 patients, respectively. The Cox proportional hazards model showed that chemoimmunotherapy was significantly associated with improved overall survival (hazard ratio=0.47, 95% confidential interval=0.26-0.83). Furthermore, subgroup analysis showed that overall survival was significantly improved in patients with good performance status, lower neutrophil/lymphocyte ratio, and no liver metastases. However, overall survival with chemoimmunotherapy was similar to that with chemotherapy and was less than 12 months in patients with a poor performance status or higher neutrophil/lymphocyte ratio.

Conclusion

Chemoimmunotherapy was significantly associated with improved overall survival in clinical practice. However, the effectiveness was equivocal in SCLC patients with a poor performance status or higher neutrophil/lymphocyte ratio.

Systemic therapy is the standard of care for patients with extensive small-cell lung cancer (SCLC) (1). However, it is difficult to cure patients with extensive SCLC, and despite a good early response to cytotoxic agents, many patients experience relapse (2). Recently developed immune checkpoint inhibitors, when combined with platinum doublet chemotherapy—referred to as chemoimmunotherapy—have shown improved overall survival (OS) compared to conventional chemotherapy in small cell lung cancer (SCLC) patients with a poor prognosis in clinical trials (3,4).

However, patient backgrounds tend to differ between clinical trials and practice, and thus it is unclear whether the reported effectiveness can be expected in the real world. Although the real-world data have shown the comparable efficacy of the treatment to the previous clinical trials (5), it has also been shown that the effectiveness of chemoimmunotherapy is inferior in SCLC patients who are ineligible for clinical trials (6). Furthermore, poor prognostic factors, including liver metastasis (7) and a higher neutrophil/lymphocyte ratio (NLR), have been reported in malignancies such as SCLC (8-11). In addition, the efficacy of chemoimmunotherapy in patients with a history of prior cytotoxic agents was evaluated in a small number of patients in the IMpower 133 trial (12). Ultimately, it has not been clarified whether chemoimmunotherapy is expected to improve the outcome for SCLC patients with these backgrounds.

This study aimed to determine whether chemoimmuno-therapy has improved survival in SCLC patients in clinical practice, focusing on several subgroups in this retrospective study.

Patients and Methods

Patient selection. The following inclusion criteria were established for the chemoimmunotherapy group: 1) patients who were cytologically or histologically diagnosed as having SCLC, and 2) patients who were treated with chemoimmunotherapy between 2019 and 2023. The following inclusion criteria were established for the chemotherapy group: 1) patients who were cytologically or histologically diagnosed as having SCLC, and 2) patients who were treated with platinum doublet chemotherapy between 2010 and 2018. Patients with a history of prior treatment with platinum doublet chemotherapy as postoperative adjuvant chemotherapy or chemoradiotherapy were eligible in both groups. Patients missing important clinical information, such as performance status (PS), were excluded.

The present study was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Medical and Biological Research Involving Human Subjects (Ministry of Health, Labour and Welfare, Japan) and approved by the ethics committee at the University of Toyama (approval number: R2020067). Informed consent was waived and study information was provided to participants due to the retrospective and non-invasiveness nature of the study.

Clinical information and treatment. Clinical information, including age, sex, treatment history, PS, presence or absence of liver and brain metastases, interstitial lung disease, and NLR at the initiation of chemoimmunotherapy or chemotherapy, were retrieved from medical charts. NLR was calculated from the ratio of neutrophils and lymphocytes measured immediately before the start of the treatment. The treatment regimens and schedules were determined by the attending physician based on their clinical judgment.

Statistical analysis. The endpoint was the OS of patients with SCLC. OS was calculated from the start of frontline treatment, including chemoimmunotherapy or chemotherapy, until the day of death, or censored at the patients’ last visit.

Fisher’s exact test was used to compare patient characteristics. The association between chemoimmunotherapy and OS was analyzed using the Cox proportional hazards model, adjusting for potential prognostic factors, such as age, sex, PS, brain metastases, liver metastases, interstitial lung disease, NLR, and a prior history of treatment with platinum doublet. The NLR cutoff level was defined as 5 based on previous reports (9). The subset analysis was performed using the log-rank test. All statistical analyses were performed using JMP version 17 (SAS, Cary, NC, USA).

Results

Patient background. A total of 44 patients with SCLC were treated with chemoimmunotherapy between 2019 and 2023. Among them, one patient was excluded from the analysis because information on PS was not available, and 43 patients were included in the chemoimmunotherapy group. For the chemotherapy group, a total of 72 patients were treated with platinum doublet chemotherapy between 2010 and 2018. Among them, one patient was excluded because information on PS was not available, and 71 patients were included in the chemotherapy group.

Patient characteristics are shown in Table I. Male patients and a PS of 0-1 were predominant in both groups. The chemoimmunotherapy group included slightly more female patients than the chemotherapy group, as well as slightly more patients with a prior history of platinum doublet chemotherapy. Other demographics, including the proportion of patients with liver metastases, brain metastases, and interstitial lung disease, were not significantly different between the two groups. In the chemoimmunotherapy group, eight patients with interstitial lung disease received treatment. Of these patients, one showed honeycomb lung, and another showed mild honeycomb-like findings on lung computed tomography. In the six patients with PS ≥2 in the chemoimmunotherapy group, one received treatment with carboplatin plus etoposide, and then, an immune checkpoint inhibitor was added during the treatment.

Table I. Patient characteristics.

NLR: Neutrophil-lymphocyte ratio; PS: performance status.

Overall survival. To analyze the association between chemoimmunotherapy and OS in SCLC patients, the Cox proportional hazard model was performed by adjusting for age, sex, PS, brain metastases, liver metastases, interstitial lung disease, NLR, and a history of prior platinum doublet chemotherapy. Chemoimmunotherapy was associated with a reduction in the risk of death (hazard ratio=0.47, 95% confidential interval=0.27-0.83, p=0.010, Table II). Figure 1 shows the Kaplan-Meier curves of both patient groups. The chemoimmunotherapy group showed a higher OS rate (p=0.004, log-rank test).

Table II. Cox proportional hazard model for the association between overall survival and immune checkpoint inhibitor therapy.

CI: Confidential interval; HR: hazard ratio; NLR: neutrophil-lymphocyte ratio; PS: performance status.

Figure 1.

Overall survival (OS) of the chemoimmunotherapy and chemotherapy groups.

We then considered the OS of several subgroups in each treatment group (Figure 2). Chemoimmunotherapy showed significantly improved OS in patients with a good PS, lower NLR, no liver metastases, and no interstitial lung disease with or without brain metastases (log-rank test). In addition, chemoimmunotherapy showed a longer median OS in patients with liver metastases, although the difference was not significant. However, the median OS was similar in the chemoimmunotherapy and chemotherapy groups in patients with a poor PS and higher NLR.

Figure 2.

Subset analyses of overall survival (OS) according to the patient characteristics. Blue and red lines indicate chemoimmunotherapy and chemotherapy groups, respectively. Overall survival was compared using the log-rank test. NLR: Neutrophil-lymphocyte ratio; PS: performance status.

Discussion

We compared the OS from the initiation of chemoimmuno-therapy or chemotherapy by employing the Cox proportional hazards model and showed that chemoimmunotherapy was significantly associated with improved OS in clinical practice. Furthermore, PS, liver metastases, and NLR were independently associated with OS. The improvement of OS by chemo-immunotherapy was apparent in patients with a good PS, lower NLR, and no liver metastases, but the effectiveness was equivocal in patients with a poor PS or higher NLR.

The treatment strategy for SCLC patients with a poor PS is considered an important issue. Previous clinical studies have focused on chemoimmunotherapy in SCLC patients with a PS of 0-1 (4,12), and the effectiveness of the treatment for patients with PS ≥2 has been unclear. A phase II study of chemo-immunotherapy for SCLC patients with PS ≥ 2 is ongoing (13). Moreover, a previous retrospective study investigated the effectiveness of adding an immune checkpoint inhibitor to platinum doublet chemotherapy during treatment. In the study, 9/16 (56.3%) of the SCLC patients exhibited a PS ≥2, and the median OS of the 16 patients was reported to be 13.0 months (14).

NLR is considered to be a prognostic factor because a meta-analysis of several tumors showed the association between NLR and OS (8). Lymphocytes are associated with the exclusion of tumor cells, and increased neutrophils were reported to suppress the activity of lymphocytes (15). Furthermore, the peripheral NLR is related to the infiltration of T lymphocytes in tumor tissue (16). In the present study, the median OS was similar between the chemoimmuno-therapy and chemotherapy groups among patients with a higher NLR, suggesting that the prognosis after chemo-immunotherapy is poor in SCLC patients with a higher NLR. The development of a novel treatment strategy for SCLC with poor prognostic factors is needed.

Liver metastases are a poor prognostic factor in lung cancer after adjusting for the number of metastatic organs (7,17,18). The mechanisms of this association have been partially elucidated. In patients with non-SCLC with liver metastases, although 5 out of 7 patients (71.4%) showed CD8-positive T lymphocyte infiltration in the tumor tissue, programmed death-ligand 1 expression was not detected (18). This suggested that the T lymphocyte function was suppressed, considering that programmed death-ligand 1 expression is increased by interferon produced by T lymphocytes. The present study also showed the association between liver metastases and shortened OS in SCLC patients. Additionally, the median OS was longer in the chemoimmunotherapy group, although the difference was not significant, and there may have been insufficient statistical power. Therefore, it cannot be concluded that immune checkpoint inhibitor therapy cannot improve the prognosis of SCLC patients with liver metastases. In non-SCLC, Komiya et al. reported that immune checkpoint inhibitor therapy may improve OS in patients with liver metastases (19).

In the present study, chemoimmunotherapy showed prolonged OS compared with chemotherapy in SCLC patients with or without brain metastases, suggesting that immune checkpoint inhibitors can improve the prognosis in this population. Notably, a phase II study of chemoimmuno-therapy for SCLC patients with brain metastases is ongoing (20).

It is difficult to interpret the add-on effect of immune checkpoint inhibitors in SCLC patients with a history of platinum doublet chemotherapy or interstitial lung disease due to the small sample size in the present study. Given the lack of data on chemoimmunotherapy in patients with a history of platinum doublet chemotherapy, further investigation is necessary. Regarding interstitial lung disease, Shibaki et al. conducted a phase II study in SCLC patients with mild interstitial lung disease and concluded that immune checkpoint inhibitor therapy is feasible for this population (21).

Study limitations. First, due to its retrospective nature, the effect of potential confounders cannot be completely excluded, although the patient background was adjusted using the Cox proportional hazards model. Furthermore, patients who were enrolled in each treatment group were diagnosed and treated in different years. This difference may affect the OS analysis in the present study. In addition, the subset analysis may result in insufficient statistical power and/or accidental imbalance in patient backgrounds. Therefore, the results of the present study should be evaluated in further studies.

Conclusion

In summary, the present study showed that chemo-immunotherapy was associated with prolonged OS compared with chemotherapy in clinical practice, and the improvement was apparent in patients with a good PS, lower NLR, or no liver metastases. However, OS was less than 12 months in patients with a poor PS or higher NLR, even after chemoimmunotherapy. It is necessary to develop a novel treatment strategy for this population.

Conflicts of Interest

The Authors have no relevant financial or non-financial interests to disclose.

Authors’ Contributions

MI designed the study and wrote the original draft of the manuscript. MI, NT, ZS, NM, KT, SO, SI, TM, RH and SM contributed to the acquisition of data. MI, ZS, NM, KT, and SO contributed to the interpretation of data. All Authors have read and approved the final version of the manuscript.