Impact of liver metastases status on survival outcomes of first-line immunotherapy in extensive stage small cell lung cancer: a systematic review and meta-analysis

Purpose: This study aims to assess the impact of liver metastases status on survival outcomes of first-line immunotherapy in extensive stage small cell lung cancer (ES-SCLC) patients. Materials and methods: Comprehensive searches were conducted in the Cochrane Library databases, Embase, PubMed, and abstracts from WCLC, ESMO, and ASCO from inception to December 2022. Randomized controlled trials reporting progression-free survival (PFS) and/or overall survival (OS) of first-line immunotherapy in ES-SCLC patients were included. Results: Six trials involving 3501 patients were analyzed, comprising 1350 patients with liver metastases and 2151 without. The quality of the included trials was consistently high. Pooled results revealed that immunotherapy plus chemotherapy did not significantly improve PFS (hazard ratio [HR] = 0.82, 95% confidence interval [CI]: 0.68-1.00, P = 0.05) and OS (HR = 0.89, 95% CI: 0.79-1.00, P = 0.05) in ES-SCLC patients with liver metastases compared to chemotherapy alone. However, immunotherapy plus chemotherapy improved PFS (HR = 0.66, 95% CI: 0.57-0.77, P < 0.01) and OS (HR = 0.74, 95% CI: 0.67-0.82, P < 0.01) in ES-SCLC patients without liver metastases compared to chemotherapy alone. Conclusions: First-line immunotherapy plus chemotherapy significantly improved PFS and OS in ES-SCLC patients without liver metastases compared to chemotherapy alone. However, patients with liver metastases did not experience comparable benefits.


INTRODUCTION
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy [1].The rapid growth rate of SCLC leads to about 75% of cases being diagnosed at an advanced stage with distant metastases [2,3].Among these cases, approximately 25% of extensive based on liver metastases status have raised important questions.This systematic review and meta-analysis aims to assess the survival outcomes of first-line immunotherapy in ES-SCLC patients, considering liver metastases status.

Trial search
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [13,14], two authors (Yan Lin and Wei Jiang) independently conducted thorough searches across various databases including the Cochrane Library, Embase, PubMed, as well as abstracts from World Conference on Lung Cancer, European Society of Medical Oncology, and American Society of Clinical Oncology, spanning from inception to December 2022.Key search terms included small cell lung cancer, SCLC, extensive stage, stage IV, randomized controlled trial, and RCT.Furthermore, references from significant clinical trials were also screened.

Trial selection
Trials meeting criteria including randomized controlled design, histologically/cytologically confirmed SCLC, extensive stage, reporting of immunotherapy and chemotherapy survival outcomes, and provision of hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival (PFS) and/or overall survival (OS) in patients with liver metastases were included.

Trial quality assessment
The methodological quality of trials was independently assessed by two authors (Yan Lin and Wei Jiang) using the Cochrane Risk of Bias tool [15].Any discrepancies were resolved through discussion or consultation with a third researcher (Xin-Bin Pan).

Data extraction
Data from included trials were extracted by two authors (Cui-Yun Su and Xin-Bin Pan), adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.

Statistical analysis
Estimated HRs of PFS and OS along with their respective 95% CI limits were calculated and illustrated through forest plots.Sensitivity analyses were carried out to gauge the impact of excluding specific trials.
Begg's and Egger's tests were used to assess publication bias.Random effect models were employed in the presence of statistical heterogeneity (I 2 ≥ 50%, P < 0.10), while fixed effect models were utilized in its absence.
Statistical analyses were performed using R software version 4.3.0 and SPSS Statistics Version 26.0 (IBM Co., Armonk, NY, USA).A significance level of P < 0.05 was adopted.

Characteristics of included trials
Following the evaluation of 8467 studies, 6 phase III randomized clinical trials were incorporated into the analysis [7,[9][10][11][12]16].The trial selection process is visually represented in Figure 1.These trials encompassed 3501 ES-SCLC patients, with 1350 having liver metastases and 2151 without.A detailed account of trial characteristics is presented in Table 1, while the methodological quality is delineated in Figure 2. The quality of the included trials was consistently high.
Sensitivity analyses confirmed the robustness of these findings.Figure 4A displays the sensitivity analyses of PFS for patients with liver metastases, while Figure 4B exhibits the sensitivity analyses of PFS for patients without liver metastases.No discernible publication bias was detected, as evidenced by the results of Egger's (P = 0.92) and Begg's (P = 0.98) tests across the three randomized clinical trials involving patients with liver metastases (Figure 5A).Similarly, among the three randomized clinical trials involving patients without liver metastases, Egger's (P = 0.90) and Begg's (P = 0.94) tests yielded no conspicuous indications of publication bias (Figure 5B).
Similarly, for patients without liver metastases, OS HR was reported in 6 trials as well [7,[9][10][11][12]16].No heterogeneity was detected (I 2 = 0.00%, P = 0.73), resulting in the utilization of a fixed effect model.Immunotherapy plus chemotherapy demonstrated improved OS compared to chemotherapy alone (HR = 0.74, 95% CI: 0.67-0.82,P < 0.01; Figure 6B).Sensitivity analyses confirmed the robustness of these findings.Figure 7A illustrates the sensitivity analyses of OS for patients with liver metastases, while Figure 7B presents the sensitivity analyses of OS for patients without liver metastases.There was no noticeable indication of publication bias, as indicated by the results of Egger's (P = 0.53) and Begg's (P = 0.65) tests across the six randomized clinical trials involving patients with     liver metastases (Figure 8A).Similarly, among the six randomized clinical trials involving patients without liver metastases, Egger's (P = 0.61) and Begg's (P = 0.65) tests revealed no apparent presence of publication bias (Figure 8B).

DISCUSSION
This systematic review and meta-analysis concluded that first-line immunotherapy plus chemotherapy significantly enhanced PFS and OS in ES-SCLC patients without liver metastases compared to chemotherapy alone.However, for patients with liver metastases, the benefits were not as pronounced.These findings emphasized the need for further exploration into the immunosuppressive microenvironment that characterized liver metastases, thereby shedding light on the observed divergence.
SCLC, with its high tumor mutational burden, is notably responsive to immunotherapy [17,18].Multiple trials have substantiated the survival benefits of blocking the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1) axis, either in conjunction with chemotherapy or as maintenance therapy, for ES-SCLC patients [19][20][21].However, several studies indicated that   immunotherapy did not improve OS and PFS of ES-SCLC patients with liver metastases [22][23][24].Consequently, disparities in the clinical advantages of immunotherapy in ES-SCLC patients with liver metastases have prompted thorough investigation.Our study contributed to the comprehension of this incongruity, demonstrating that first-line immunotherapy did not confer significant improvements in terms of PFS and OS to ES-SCLC patients with liver metastases.However, the observed P values of 0.05 suggested a potential trend towards improvement, warranting cautious interpretation and emphasizing the need for prospective studies.
The explanation for these findings may lie in the immunosuppressive microenvironment within liver metastases, which undermined the efficacy of immunotherapy [25].Liver non-parenchymal cells present antigens to T-cells in a tolerogenic manner [26], leading to the apoptosis of activated antigenspecific T-cells upon interaction with monocyte-derived macrophages [27].This phenomenon may account for the observed absence of immunotherapy benefits.Support for this explanation was found in a pooled analysis of non-small cell lung cancer patients with liver metastases, which revealed no discernible immunotherapy advantage (HR = 0.80, 95% CI: 0.49-1.31)[28].
A limitation of this study lies in its inability to differentiate patients with isolated liver metastases from those with metastases in other organs.This limitation underscored the necessity for judicious interpretation of the conclusions drawn.Additional research is indispensable to validate the findings presented in this systematic review and meta-analysis.
In conclusion, first-line immunotherapy plus chemotherapy significantly improved PFS and OS in ES-SCLC patients without liver metastases compared to chemotherapy alone.However, patients with liver metastases did not experience comparable benefits.

Figure 2 .
Figure 2. Risk of bias assessment for the included trials.

Figure 3 .
Figure 3. Forest plot displaying hazard ratios for comparing progression-free survival between immuno-chemotherapy and chemotherapy.(A) Patients with liver metastases.(B) Patients without liver metastases.

Figure 4 .
Figure 4. Sensitivity analysis for progression-free survival.(A) Patients with liver metastases.(B) Patients without liver metastases.

Figure 5 .
Figure 5. Assessment of publication bias for progression-free survival.(A) Patients with liver metastases.(B) Patients without liver metastases.

Figure 6 .
Figure 6.Forest plot illustrating hazard ratios for overall survival between immuno-chemotherapy and chemotherapy.(A) Patients with liver metastases.(B) Patients without liver metastases.

Figure 7 .
Figure 7. Sensitivity analysis for overall survival.(A) Patients with liver metastases.(B) Patients without liver metastases.

Figure 8 .
Figure 8. Assessment of publication bias for overall survival.(A) Patients with liver metastases.(B) Patients without liver metastases.