Malignant pleural effusion is a negative prognostic factor for immunotherapy outcomes in non-small cell lung cancer: a single-center retrospective study

Introduction

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases (1-4). A common and serious complication of advanced NSCLC is malignant pleural effusion (MPE), which significantly worsens prognosis and complicates treatment. MPE often reflects disease progression and is associated with poor survival outcomes (5-8). Recent advancements in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have shown potential in improving the survival of metastatic NSCLC patients (9-12). Among the prognostic factors affecting NSCLC, host-related parameters are becoming increasingly important, such as the clinical characteristics of the patient, which predict the efficacy of immunotherapy. Examples include age, gender, tumor size, clinical stage, lymph node metastasis and distant metastasis (13,14).

While immunotherapy, particularly ICIs, has revolutionized the treatment landscape for metastatic NSCLC, its efficacy in patients with MPE remains poorly understood. Furthermore, the key factors influencing the outcomes of NSCLC patients with MPE have not been fully elucidated.

The objective of this study is to investigate the efficacy of immunotherapy in patients with NSCLC complicated by MPE. Specifically, we aim to assess the impact of immunotherapy on survival and treatment outcomes in this patient population. In addition, the study seeks to identify and define the key prognostic factors that influence the clinical outcomes and progression of NSCLC patients with MPE. Understanding these factors may provide insights into improving therapeutic strategies and enhancing survival rates for this challenging subgroup of lung cancer patients. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1999/rc).

Methods

Patients

This study included NSCLC patients treated with ICIs at Tianjin Medical University Cancer Institute & Hospital from January 2018 to August 2024. The inclusion criteria were as follows: (I) pathologically or cytologically confirmed NSCLC; (II) patients who received at least one cycle of ICI therapy in routine clinical practice; and (III) age >18 years. Clinical outcomes related to ICIs treatment, including progression-free survival (PFS) and overall survival (OS), were collected for all enrolled patients, along with baseline demographic and clinicopathological data prior to ICIs treatment initiation. Data collected included gender, age, histological types, clinical stage, previous treatment modalities, types and cycles of ICIs, presence of metastatic lesions, number and location of metastases, primary tumor resection, and prior systemic treatment for metastatic disease. In the MPE group, the pleural effusion was diagnosed using chest X-ray or computed tomography (CT). The effusion was obtained via thoracentesis, and malignancy was confirmed through cytological examination. The control group consisted of matched patients, but these patients did not have pleural effusions. The control group was designed to provide a baseline comparison to ensure that the observed differences between the two groups could be attributed to the presence of MPE rather than other confounding factors. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Committee of Tianjin Medical University Cancer Institute & Hospital (No. bc2020198) and individual consent for this retrospective analysis was waived.

Statistical analysis

PFS was defined as the time from the first ICIs administration to progressive disease or death from any cause, whichever occurred first. OS was defined as the time from the first dose to death from any cause. Baseline differences between groups were assessed using Pearson’s χ² test or Fisher’s exact test, as appropriate. Survival rates were analyzed using Kaplan-Meier and Cox proportional hazards regression analyses. Univariate Cox regression analysis was employed to assess the impact of different baseline factors on PFS and OS. Variables significantly associated with survival outcomes in univariate analysis were included in a multivariate Cox proportional hazards regression model to identify independent predictors of OS and PFS. The Cox regression model provided hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). All statistical tests were two-tailed, with P<0.05 considered statistically significant. Statistical analyses were performed using SPSS software, R Studio, R version 4.4.2.

Results

Baseline characteristics

A total of 167 patients were included in this study, with 84 patients in the MPE group and 83 in the control group. Figure 1 illustrates the flow. The baseline characteristics of the two groups are summarized in Table 1. Assessment of lymph nodes and distant tumor metastasis was performed for localization and confirmation using contrast-enhanced CT. The groups were comparable in terms of age, gender, and clinical stage. Specifically, 22.8% of the patients were female, and 77.2% were male, with no significant difference between the MPE and control groups (P=0.74). The majority of the patients had stage IV disease (99.4%), and the distribution of histology types was also similar between groups (P=0.45). Regarding metastasis patterns, lymph node metastasis was more prevalent in the MPE group (73.8%) compared to the control group (36.1%) (P<0.001). However, lung and liver metastasis were similarly distributed across both groups (P=0.24 and P=0.10, respectively).

Figure 1 Grouping flowchart. MPE, malignant pleural effusion.

Immunotherapy and treatment modalities

The ICIs used in this study included dual checkpoint inhibitors, as well as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, with PD-1 inhibitors being the most commonly administered (93.4%) (P=0.13, Fisher’s test). Regarding treatment, most patients received immunotherapy, with 85.6% undergoing combination therapy and 14.4% receiving single-agent treatment. Combination therapy refers to the administration of ICIs in conjunction with chemotherapy. Pre-immunotherapy treatment modalities were categorized into three groups: no medication, prior medication, and no prior treatment. In total, 62.3% of patients had received medication before starting immunotherapy, with a higher proportion in the control group (72.3%) compared to the MPE group (52.4%) (P=0.01). Additionally, 34.7% of patients had not received any prior treatment, with a significantly higher proportion in the MPE group (45.2%) compared to the control group (24.1%). The number of immunotherapy cycles administered varied among patients. The majority (76.6%) received between 5 and 35 cycles, while 18.0% received 1–4 cycles, and only 5.4% received more than 35 cycles (P=0.24, Fisher’s test). PD-L1 expression was assessed in NSCLC patients and categorized as negative, positive, or not available (NA). Of the total 167 patients, 15 (9.0%) had negative PD-L1 expression, 29 (17.4%) had positive expression, while the majority, 123 (73.7%), had an unknown PD-L1 status.

Survival outcomes

Figure 2 presents the optimal cut-off survival curves for the MPE and control groups. The presence of MPE was significantly associated with shorter PFS and OS (both P<0.05). The median follow-up time was 18 months. In the MPE group, the median PFS was 9.50 months (95% CI: 7.08–11.92). In contrast, the control group had a median PFS of 16.50 months (95% CI: 8.74–24.26). The median OS in the MPE group was 20.0 months (95% CI: 15.61–24.39). The control group demonstrated a significantly longer median OS of 32.0 months (95% CI: 18.11–45.89).

Figure 2 The optimal cut-off survival curves for the MPE and control groups. (A) Kaplan-Meier curves of PFS for the MPE group and the control group receiving ICIs therapy. (B) Kaplan-Meier curves of OS for the MPE group and the control group receiving ICIs therapy. ICI, immune checkpoint inhibitor; MPE, malignant pleural effusion; OS, overall survival; PFS, progression-free survival.

Whether in univariate or multivariate analysis, the presence of MPE is a significant risk factor. Especially in multivariate analysis, patients in the MPE group exhibited a significantly higher risk of disease progression (HR =1.865, 95% CI: 1.177–2.953, P=0.008) and worse OS (HR =2.419, 95% CI: 1.467–3.988, P=0.001) compared to the control group (Table 2).

Immune-related adverse events (ir-AEs)

ir-AEs were primarily observed in patients receiving combination immunotherapy, accounting for 91% of cases in this study. These adverse events occurred more frequently in the MPE group than in the control group. The types of adverse events were diverse and included dermatological reactions, gastrointestinal issues, and others. It is important to note that a single patient could experience multiple symptoms, such as rash and gastrointestinal reactions, which were recorded separately in Table 3. Specifically, 44% of patients in the MPE group (37/84) experienced ir-AEs, while 35% of patients in the control group (29/83) were affected. The most common ir-AEs in both groups were leukopenia and rash. The high incidence of these adverse events underscores the potential for significant side effects associated with combination immunotherapy, particularly in patients with advanced disease, such as those in the MPE group.

Discussion

In this study, we investigated whether there was a statistically significant difference in prognosis between patients in the MPE group, with cytologically confirmed MPE, and those in the control group following immunotherapy. Our findings indicate that, despite receiving immunotherapy, the PFS and OS in the MPE group remained significantly poorer than in the control group.

Our findings confirm that malignant effusion is a prognostic risk factor, even after immunotherapy. However, this study has several limitations. First, the small sample size (N=167) may affect the statistical validity of the results, emphasizing the need for larger-scale multicenter studies to validate our findings. Consequently, conducting larger-scale multicenter studies will help confirm our findings. Second, as this study primarily relies on retrospective data analysis, it may be subject to selection and information bias, highlighting the need for future prospective studies to overcome these limitations. Additionally, for unknown PD-L1 expression in some patients, we attempted to perform immunohistochemical staining on the missing sections, however time constraints led to poor sensitivity and limited reference value.

Consistent with our findings, Epaillard et al. identified MPE as an independent risk factor for poor prognosis in NSCLC. However, their study focused more on the clinical effects of ICI therapy, particularly early mortality (15). Additionally, Aarnink et al. reported that thoracic and abdominal metastases significantly reduce the response to immunotherapy in NSCLC patients, further supporting the association of pleural effusion with poor prognosis (16). Unlike our study, Hisakane et al. investigated the efficacy of atezolizumab combined with bevacizumab, carboplatin, and paclitaxel (ABCP) in patients with MPE, demonstrating that although this regimen provides short-term MPE control, MPE remains an unfavorable prognostic factor (17).

Existing studies have shown that the pleura is a common site of metastasis in lung cancer, especially in NSCLC, where pleural metastasis is closely associated with the formation of MPE. According to Li et al., eosinophils promote tumor cell migration through the CCL6-CCR1 signaling pathway and enhance bone metastasis (18). Similarly, pleural-associated cancer-associated mesothelial cells (CAMCs) enhance tumor cell migration through crosstalk with tumor epithelial cells, which provides strong support for pleural metastasis (19). Furthermore, Wu et al. found that alterations in the pleural microenvironment, particularly epithelial-mesenchymal transition (MesoMT) of mesothelial cells, promoted lung cancer metastasis in the pleura (20). These findings suggest that pleural metastasis is closely associated with alterations in the immune microenvironment, particularly the role of immunosuppressive cells such as tumor-associated macrophages (TAMs) in the metastatic process. The formation of MPE not only reflects the spread of the tumor, but also is closely related to the immune escape mechanism of the pleural microenvironment, which may be one of the reasons for the poorer outcome of immunotherapy in patients in the MPE group. Therefore, despite receiving immunotherapy, the immune tolerance of the pleural microenvironment caused by pleural metastasis resulted in a more limited therapeutic response in patients in the MPE group, which in turn affected their survival prognosis. This may contribute to the poor prognosis of MPEs.

In the treatment of MPE, all patients in this study received immunotherapy, including combination therapy (85.6%) and monotherapy (14.4%). Meanwhile, alternative and potentially more effective treatment options are under investigation. Liu et al. demonstrated that combining ICIs with local intrapleural injections of nanocarriers can significantly enhance immune responses in the pleural microenvironment, thereby improving the efficacy of anti-PD-L1 therapy and suggesting potential for local immune enhancement or combination therapy in MPE treatment (21). Several clinical trials have explored the potential benefits of early combination therapies targeting MPE (22,23).

Conclusions

In conclusion, this study demonstrated that pleural effusion remains a negative prognostic factor for clinical outcomes, even after immunotherapy. Future research should focus on optimizing treatment strategies and managing pleural effusion.

Acknowledgments

We would like to thank Tianjin Medical University Cancer Institute & Hospital for providing the patient data that made this study possible.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1999/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1999/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1999/prf

Funding: This study was funded by Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-009A), the National Natural Science Foundation of China (No. 81702268), and the Natural Science Foundation of Tianjin (No. 18JCYBJC93400).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1999/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 Committee of Tianjin Medical University Cancer Institute & Hospital (No. bc2020198) 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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