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World Journal of Oncology

Original Article

Volume 14, Number 6, December 2023, pages 529-539

Efficacy of First-Line Immunotherapy Combined With Chemotherapy in Extensive-Stage Small Cell Lung Cancer Patients With Different Brain Metastases Status: A Systematic Review and Meta-Analysis

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases [1]. It is a highly aggressive neuroendocrine malignancy, ranking among the leading causes of cancer-related mortality [2]. Within the spectrum of SCLC, extensive-stage disease (ES-SCLC) constitutes a significant portion, accounting for approximately 70% of cases [3]. Notably, 10-18% of ES-SCLC cases present with brain metastases at the time of diagnosis [4].

Extensive evidence supports the notion that the integration of first-line immunotherapy with chemotherapy leads to enhanced treatment outcomes for ES-SCLC patients [5-12]. However, it is important to recognize that several studies have suggested that various clinical factors and combined agents might influence prognosis in this context [13, 14]. Moreover, clinical trials, when subjected to subgroup analysis, have demonstrated variable efficacy in the combination of immunotherapy with chemotherapy for ES-SCLC patients who already have brain metastases [5-11].

Given the potential incidence of adverse events associated with immunotherapy [15], it becomes imperative to determine whether ES-SCLC patients with brain metastases can derive maximal benefit from this treatment approach. The existing inconsistencies in the literature underscore the necessity for a systematic review aimed at evaluating the treatment outcomes of first-line immunotherapy combined with chemotherapy in ES-SCLC patients with varying brain metastasis statuses.

Two authors (Wen Hua Zhao and Shou Feng Wang) independently conducted data retrieval. The search spanned multiple databases, including PubMed, EMBASE, and the Cochrane Library, from their inception up to December 2022. Additionally, abstracts from key oncology conferences such as the European Society of Medical Oncology, World Conference on Lung Cancer, and American Society of Clinical Oncology were screened by the same authors. The data search strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [16, 17].

Our search strategy involved a range of terms, including “small cell lung cancer”, “SCLC”, “stage IV”, “extensive stage”, “chemotherapy”, “immunotherapy”, and “immune checkpoint inhibitor”. Furthermore, relevant randomized controlled trials were identified by reviewing references in significant literature.

The included studies were required to meet specific inclusion criteria, which are as follows: 1) patients with histopathologically confirmed SCLC; 2) clinical stage classified as extensive stage based on the Veterans Administration Lung Study Group (VALG) definition or stage IV according to the International Association for the Study of Lung Cancer (IASLC) staging system; 3) patients received first-line immunotherapy combined with chemotherapy; 4) study design was a randomized controlled trial; and 5) randomized controlled trials reported treatment outcomes regarding progression-free survival (PFS) and/or overall survival (OS). Case reports, reviews, comments, editorials, letters, and animal studies were excluded from this systematic review and meta-analysis.

The selection of studies was carried out independently by two authors (Wen Hua Zhao and Shou Feng Wang). Initially, titles and abstracts of studies were assessed, and for potentially eligible studies, full manuscripts were reviewed. Duplicate studies were eliminated by combining the results of the two authors’ selections. In cases of disagreement during the selection process, a third author (Xin Bin Pan) was consulted for resolution.

Following the selection process, data extraction was performed by two independent authors (Cui Yun Su and Xin Bin Pan), adhering to the PRISMA guidelines. The following information was extracted from each included randomized controlled trial: 1) authors and trial names; 2) publication year; 3) patient geographical area; 4) trial design; 5) total number of participants; 6) immunotherapy and chemotherapy regimens; 7) number of patients with brain metastases; 8) number of patients without brain metastases; and 9) hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and/or OS in patients treated with immunotherapy combined with chemotherapy and those receiving chemotherapy alone.

Two independent authors (Wen Hua Zhao and Shou Feng Wang) assessed the methodological quality of included randomized controlled trials. In cases of disagreement, a third author (Xin Bin Pan) was involved for discussion and consensus. Methodological quality assessment of included randomized clinical trials was performed using the Cochrane Risk of Bias tool [18], which evaluated seven domains: 1) random sequence generation; 2) blinding of participants and personnel; 3) allocation concealment; 4) incomplete outcome data; 5) blinding of outcome assessment; 6) selective reporting; and 7) other bias.

Heterogeneity between the included randomized controlled trials was evaluated using the I² statistic and the Q Chi-squared test. P ≥ 0.10 or I² < 50% indicated no significant heterogeneity between the included randomized controlled trials. In contrast, P < 0.10 or I² ≥ 50% indicated significant heterogeneity between the included randomized controlled trials. The random-effect model was used in cases of significant heterogeneity between the included randomized controlled trials; otherwise, the fixed-effect model was used when no significant heterogeneity was observed.

The primary endpoint was PFS, and the secondary endpoint was OS. This systematic review and meta-analysis presented pooled analyses using forest plots. HRs with 95% CIs for PFS and OS were calculated to compare the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone in patients with varying brain metastasis statuses. Sensitivity analyses were performed to assess the influence of each study by omitting one study at a time. Publication bias was assessed using funnel plots with Begg’s and Egger’s tests.

This systematic review and meta-analysis utilized R software version 4.3.0 and SPSS Statistics Version 26.0 (IBM Co., Armonk, NY, USA) for statistical analyses. A statistically significant difference was considered at P < 0.05 (two-tailed).

Ethics approval and informed consent were waived by the Ethics Committee of Guangxi Medical University Cancer Hospital.

The study selection process is illustrated in Figure 1. Initially, 8,466 studies were identified, and after abstract screening, 8,420 were excluded. Upon a thorough examination of full-text articles, 20 studies were considered potentially eligible. Among the 20 studies, two were not focused on first-line treatment, eight were duplicative trials, and three did not provide information on brain metastases. Ultimately, seven randomized controlled trials were included in this systematic review and meta-analysis [5-11].

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Figure 1. Flowchart illustrating trial selection.

Table 1 provides a summary of the characteristics of the included trials. All seven randomized controlled trials were classified as phase III trials. Of these, six trials had a global scope, while one was conducted exclusively in China. In total, these trials encompassed 3,931 ES-SCLC patients, comprising 398 patients with brain metastases and 3,533 without. The methodological quality assessment consistently indicated high quality for the seven included randomized controlled trials (Fig. 2).

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Table 1. Characteristics of Included Trials

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

Two randomized controlled trials reported PFS data for patients with brain metastases [6, 11]. Heterogeneity was not observed between these two trials (P = 0.85, I² = 0.00%). Therefore, the fixed-effects model was applied. The pooled analysis indicated that immunotherapy combined with chemotherapy did not significantly improve PFS compared to chemotherapy alone in patients with brain metastases (HR = 1.03, 95% CI: 0.66 - 1.61; P = 0.887) (Fig. 3a).

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Figure 3. Forest plot displaying hazard ratios (HRs) for comparing progression-free survival between immunotherapy combined with chemotherapy and chemotherapy alone. (a) Patients with brain metastases. (b) Patients without brain metastases. CI: confidence interval.

Similarly, for patients without brain metastases, the analysis of two randomized controlled trials revealed no significant heterogeneity (P = 0.60, I² = 0.00%). Therefore, the fixed-effects model was used. The pooled analysis showed that immunotherapy combined with chemotherapy improved PFS compared to chemotherapy alone in these patients (HR = 0.72, 95% CI: 0.62 - 0.84; P < 0.001) (Fig. 3b).

Sensitivity analyses confirmed the robustness of these findings. For patients with brain metastases, the pooled HRs for PFS ranged from 0.98 to 1.07 (Fig. 4a). In patients without brain metastases, the pooled HRs for PFS ranged from 0.69 to 0.75 (Fig. 4b). No significant publication bias was detected in the two randomized controlled trials (Fig. 5).

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Figure 4. Sensitivity analysis for progression-free survival. (a) Patients with brain metastases. (b) Patients without brain metastases. HR: hazard ratio; CI: confidence interval.

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Figure 5. Assessment of publication bias for progression-free survival. (a) Patients with brain metastases. (b) Patients without brain metastases.

Six randomized controlled trials reported OS data for patients with brain metastases [5-9, 11]. These trials did not exhibit significant heterogeneity (P = 0.12, I² = 43.00%), leading to the application of the fixed-effects model. The pooled analysis indicated that immunotherapy combined with chemotherapy did not improve OS compared to chemotherapy alone in patients with brain metastases (HR = 1.03, 95% CI: 0.82 - 1.31; P = 0.776) (Fig. 6a).

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Figure 6. Forest plot illustrating hazard ratios for overall survival between immunotherapy combined with chemotherapy and chemotherapy alone. (a) Patients with brain metastases. (b) Patients without brain metastases. HR: hazard ratio; CI: confidence interval.

In contrast, seven randomized controlled trials reported OS data for patients without brain metastases [5-11]. These trials demonstrated significant heterogeneity (P = 0.01, I² = 64.00%), leading to the use of the random-effects model. The pooled analysis indicated that immunotherapy combined with chemotherapy improved OS compared to chemotherapy alone in patients without brain metastases (HR = 0.77, 95% CI: 0.67 - 0.88; P < 0.001) (Fig. 6b).

Sensitivity analyses supported the stability of these results, with pooled HRs for OS in patients with brain metastases ranging from 0.87 to 1.10 (Fig. 7a), and in patients without brain metastases ranging from 0.73 to 0.79 (Fig. 7b). While no publication bias was detected among the six randomized controlled trials involving patients with brain metastases (Egger’s test: P = 0.133, Begg’s test: P = 0.352) (Fig. 8a), publication bias was identified among the seven randomized controlled trials involving patients without brain metastases in the Egger’s test (P = 0.001), but not in the Begg’s test (P = 0.051) (Fig. 8b).

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Figure 7. Sensitivity analysis for overall survival. (a) Patients with brain metastases. (b) Patients without brain metastases. HR: hazard ratio; CI: confidence interval.

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Figure 8. Assessment of publication bias for overall survival. (a) Patients with brain metastases. (b) Patients without brain metastases.

This systematic review and meta-analysis have provided valuable insights into the treatment outcomes of ES-SCLC patients with and without brain metastases when undergoing first-line immunotherapy combined with chemotherapy. The findings highlight clear distinctions in the efficacy of this combined treatment based on brain metastasis status.

In ES-SCLC patients without brain metastases, the addition of immunotherapy to chemotherapy as a first-line treatment led to substantial benefits. The significant improvements in both PFS and OS in this subgroup underscore the clinical efficacy of this combination therapy. These results align with existing evidence supporting the role of immunotherapy in improving outcomes for ES-SCLC patients.

Conversely, for ES-SCLC patients with brain metastases, the incorporation of immunotherapy into chemotherapy did not result in a significant enhancement of PFS or OS. This observation raises critical questions about the management of this particular subgroup, indicating that more aggressive therapeutic strategies, such as radiotherapy and surgery, might be needed in the era of immunotherapy for patients with brain metastases.

Historically, the brain has been considered an immune-privileged organ [19]. However, recent insights into the tumor microenvironment within brain metastases challenge this notion. Emerging evidence suggests that the brain can be a viable target for immunotherapy, with promising results seen in controlling brain metastases from melanoma [20]. This has prompted discussions about the potential effectiveness of immunotherapy in lung cancer brain metastases, with some studies indicating improved treatment outcomes for lung cancer patients with brain metastases when immunotherapy is combined with chemotherapy [21-26].

However, this meta-analysis suggests that immunotherapy combined with chemotherapy as a first-line treatment did not improve PFS in ES-SCLC patients with brain metastases. One possible explanation is that many of these patients may have been asymptomatic, and some might have received radiotherapy before being included in the randomized controlled trials. Additionally, the use of prophylactic cranial irradiation following immunotherapy and chemotherapy remains unclear in all of the included trials. As such, it is essential to exercise caution when translating the results of this meta-analysis into clinical practice.

Moreover, the study indicates that immunotherapy combined with chemotherapy did not result in improved OS compared to chemotherapy alone in patients with brain metastases. This finding may be attributed to the fact that all the included trials recommended second-line systemic treatments for patients experiencing recurrences, and the primary patterns of first progression were thoracic and brain metastases [8]. None of the trials allowed for consolidation or salvage local treatments such as surgery or radiotherapy on brain metastases, thoracic disease, or other metastases. Notably, thoracic radiotherapy and brain irradiation have demonstrated the potential to improve OS in ES-SCLC patients when used as consolidation or salvage local treatments [27, 28].

Several limitations of this systematic review should be acknowledged. First, four of the randomized controlled trials did not stratify patients randomly based on brain metastasis status [5, 6, 8, 9], potentially introducing imprecision in subgroup analyses. Second, the small sample size of ES-SCLC patients with brain metastases may have limited the statistical power for analysis.

In conclusion, this study highlights the significant benefit of first-line immunotherapy combined with chemotherapy in ES-SCLC patients without brain metastases, leading to improvements in both PFS and OS. However, this benefit is not observed in patients with brain metastases. The intricate nature of ES-SCLC with brain metastases, combined with the challenges of balancing systemic therapy and localized treatments, underscores the imperative need for further research to optimize the management of this specific subgroup.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

The authors declare no conflict of interest.

Informed Consent

Not applicable.

Author Contributions

Conceptualization: Xin Bin Pan. Methodology: Wen Hua Zhao and Shou Feng Wang. Formal analysis: Cui Yun Su. Validation: Wen Hua Zhao and Shou Feng Wang. Writing - original draft preparation: Wen Hua Zhao. Writing - review and editing: Xin Bin Pan.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

SCLC: small cell lung cancer; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses; RCT: randomized controlled trial; HR: hazard ratio; CI: confidence interval; PFS: progression-free survival; OS: overall survival

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