
==== Front
Discov Oncol
Discov Oncol
Discover Oncology
2730-6011
Springer US New York

39269534
1307
10.1007/s12672-024-01307-3
Research
Prognosis evaluation and efficacy analysis of different treatment options for patients with visceral pleural invasion in stage IIA–IIB lung cancer
Liu Qi 12
Wu Liusheng 134
Wang Xiangyu 15
Feng Yu 12
Wang Ying 121534462@qq.com

6
Yan Jun yanjun1619@tsinghua.edu.cn

3
Li Xiaoqiang dr.lixiaoqiang@gmail.com

12
1 https://ror.org/03kkjyb15 grid.440601.7 0000 0004 1798 0578 Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036 China
2 https://ror.org/00g5b0g93 grid.417409.f 0000 0001 0240 6969 Department of Graduate School, Zunyi Medical University, Zunyi, 563000 China
3 https://ror.org/03cve4549 grid.12527.33 0000 0001 0662 3178 School of Medicine, Tsinghua University, Beijing, 100084 China
4 https://ror.org/01tgyzw49 grid.4280.e 0000 0001 2180 6431 Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077 Singapore
5 https://ror.org/03kkjyb15 grid.440601.7 0000 0004 1798 0578 Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, 518036 China
6 https://ror.org/0152hn881 grid.411918.4 0000 0004 1798 6427 Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060 China
13 9 2024
13 9 2024
12 2024
15 44225 1 2024
3 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Objective

Controversy surrounds the treatment of visceral pleural invasion in lung cancer, and no studies have compared the efficacy of its four main treatment options (i.e., surgery, chemotherapy, targeted therapy, and immunotherapy). This study aims to compare and analyze surgery, chemotherapy, targeted therapy, and immunotherapy outcomes and explore the optimal treatment of visceral pleural invasion in lung cancer.

Methods

We searched electronic databases (i.e., Pubmed, Embase, Cochrane Library, CNKI, and Chinese Biomedical Literature Database Search) for relevant studies of treatment options for patients with visceral pleural invasion in stage IIA–IIB lung cancer. Searches times were limited to studies published between January 1, 2000 and February 20, 2021. Meta analysis was performed using RevMan 5.3 software We also downloaded original RNA transcription data about lung cancer invasion in the GEO and TCGA tumor databases, and used R 4.0.3 software to perform differential expression and co-expression gene network analyses.

Results

We included a total of 25 high-quality (i.e., Jadad score 4–7) studies. Meta-analysis found that surgical treatment was associated with a 3-year survival rate OR = 3.80 (95% CI 3.53, 4.09; P < 0.0001), 5-year survival rate OR = 4.10 (95% CI 3.72, 4.53; P < 0.0001), and median survival time OR = 2.71 (95% CI 2.53, 2.89; P < 0.0001). Chemotherapy was associated with a 3-year survival rate OR = 2.08 (95% CI 1.93, 2.25; P < 0.0001), 5-year survival rate OR = 1.68 (95% CI 1.49, 1.89; P < 0.0001), and median survival time OR = 1.84 (95% CI 1.66, 2.04; P < 0.0001). Targeted therapy was associated with a 3-year survival rate OR = 2.91 (95% CI 2.65, 3.19; P < 0.0001), 5-year survival rate OR = 1.83 (95% CI 1.39, 2.33; P < 0.0001), and median survival time OR = 1.76 (95% CI 1.59, 1.94; P < 0.0001). Finally, immunotherapy was associated with a 3-year survival rate OR = 1.89 (95% CI 1.73, 2.07; P < 0.0001), 5-year survival rate OR = 1.66 (95% CI 1.46, 1.88; P < 0.0001), and median survival time OR = 2.53 (95% CI 2.27, 2.82; P < 0.0001). After screening differential genes and co-expressed genes in tumor gene databases, we found that AC245595.1, ITGB1-DT and AL606489.1 may be involved in the process of lung cancer invasion, and macrophages M1 and M2, CD4+-Th1, CD8+-Th1 may participate in immune infiltration.

Conclusions

In patients with visceral pleural invasion of stage IIA-IIB lung cancer, chemotherapy has shown a significant effect on improving prognosis and enhancing efficacy. However, surgical treatment did not significantly improve the overall prognosis. Therefore, the individual situation of the patient and the comprehensive benefits of the treatment program should be fully considered when developing the treatment program.

Keywords

Visceral pleural invasion
Lung cancer
Prognosis evaluation
Treatment options
Tumor immunity
Scientific Research Project of Education Department of Anhui ProvinceYJS20210324 Wu Liusheng Research and development of intelligent surgical navigation and operating systems for precise liver resection2022ZLA006 Yan Jun Start-up Fund for Talent Researchers of Tsinghua University10001020507 Yan Jun National Natural Science Foundation of China81972829 Li Xiaoqiang Science and Technology Innovation Committee of Shenzhen MunicipalityJCYJ20180228162607111 Li Xiaoqiang issue-copyright-statement© Springer Science+Business Media, LLC 2024
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pmcIntroduction

Global lung cancer incidence is expected to be 2,206,771 new cases, with 1,435,943 cases in males and 770,828 cases in women. The male lung cancer cases were categorized as follows: adenocarcinoma constituted 560,108 instances (39%), squamous cell carcinoma accounted for 351,807 cases (25%), small cell carcinoma stood for 163,862 cases (11%), and large cell carcinoma accounted for 115,322 cases (8%). A total of 440,510 cases (57%) of lung cancer in females were classified as adenocarcinomas, 91,070 cases (12%) were classified as squamous cell carcinomas, 68,224 cases (9%) were classified as small cell carcinomas, and 49,246 cases (6%) were classified as big cell carcinomas [1]. Visceral pleural invasion in lung cancer usually occurs in the middle and late stages of the tumor and has a higher mortality rate. Many patients present with both visceral pleural invasion and malignant pleural effusion when they arrive to hospital for treatment. These patients are in the middle to late stages (stages II–IV) of the disease. The treatment plan for lung cancer patients with pleural invasion is controversial. Surgery is generally contraindicated in patients in stage IIIA and Many studies have reported that surgery has little benefit for patients in advanced stages of lung cancer, in terms of survival or prognosis [1–3]. The PRISMA guideline and the National Comprehensive Cancer Network (NCCN) clinical guidelines [4] for non-small cell lung cancer (NSCLC) recommend chemotherapy and targeted therapy for patients with NSCLC with pleural dissemination. Patients with large pleural effusions and adhesions may be treated with thoracic cavity fluid drainage. It is not recommended that these patients undergo resection of the primary tumor. Current research is primarily focused on determining whether surgery can completely remove the primary lung cancer and pleural metastases and whether it has a beneficial effect on the survival time of patients with lung cancer pleural invasion. However, in recent years, some researchers have reported that primary tumor resection can improve the prognosis of a select group of patients [1, 3]. Further, with the popularization and advancement of minimally invasive video-assisted thoracoscopic surgery, the trauma caused by surgical operations and the recovery time of patients have been significantly reduced. Thus, the impact of surgical intervention on the prognosis of patients with NSCLC is still worth exploring.

Patients with stages IIIB–IV lung cancer generally means that the best opportunity for surgery has passed. These patients usually undergo traditional chemotherapy treatments or targeted therapy. Thus, this study mainly focused on visceral pleural invasion in patients with stages IIA–IIB lung cancer. These early and middle-stage lung cancer patients have a good 5-year survival rate if they undergo effective treatment [1, 5, 6]. It is also obvious that the difference in efficacy between different treatment approaches is statistically significant.

Adachi et al. [2] retrospectively analyzed the clinicopathological characteristics and prognosis of 639 lung cancer patients with visceral pleural invasion. They were treated in nine hospitals affiliated with the Yokohama Thoracic Surgery Association from 2005 to 2007. The study found that surgical intervention improved the survival time of patients. Although patients with advanced lung cancer have tumor metastases, targeted therapy and immunotherapy may significantly impact their survival and prognosis. Feng et al. [3] investigated the effects of targeted and immune combination therapy in patients with select mutations sensitive to a combination of immunotherapy and targeted therapy. They found that following treatment, symptoms of discomfort (e.g., chest tightness, shortness of breath, and dyspnea) improved, pleural lesions almost disappeared, and tumors were basically stable.

Targeted therapy and immunotherapy are different from other treatment options in that patients have to undergo genetic testing to determine whether there are sensitive mutations. Thus, research on these treatments transitions from clinical studies to investigating gene pathogenesis and tumor immune infiltration characteristics. Kuijpers et al. [5] conducted a cohort study investigating the association between stage II and lung cancer invasion. Many potential target genes (e.g., EGFR+, KRAS+, ALK+) are involved in the occurrence of lung cancer invasion and warrant further exploration, and there are many potential target genes that warrant further exploration.

Therefore, this systematic review and meta-analysis explored the characteristics and outcomes of different treatment options for visceral pleural invasion in lung cancer. The aim of this study was to explore best treatment options and screen potential target genes related to tumor immunity in lung cancer patients with visceral pleural invasion. This study’s findings have the potential to improve the prognosis and survival time of cancer patients with visceral pleural invasion and may guide future studies investigating the mechanisms of lung cancer invasion.

Materials and methods

Method and process of literature retrieval

This study’s protocol was registered in the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) on February 12, 2021 (registration number INPLASY202120043). Searches were performed in databases (i.e., Pubmed, Embase, Cochrane Library, CNKI, and Chinese Biomedical Literature Database Search) from January 1, 2000 to February 20, 2021 using the following subject headings: “pleural invasion,” “lung cancer,” and “treatment”. We provide one full search strategy that this study ran in a database as a table (Table 1).Table 1 Clinical characteristics of surgical treatment of pleural metastasis in patients with lung cancer in stage IIA–IIB [6–31]

Study	Country	Number of cases	Gender (feman/man)	Age (year)	Research type	Year OS rate (%) [surgical resection group/conservative treatment group]	5-Year OS rate (%) [surgical resection group/conservative treatment group]	Median OS (months) [surgical resection group/conservative treatment group]	P	Stage	Jadad score	
Surgery	
 Chiang et al. [6]	China	134	40/94 (29.85%/70.15%)	56.12 ± 1.15	Cohort study	N/A	N/A	35.3/27.0	P < 0.001	IIA–IIB	6	
 Li et al. [7]	China	43	17/26 (39.53%/60.47%)	60.1 ± 1.20	Cohort study	82.9%/38.5%	51.6%/31.5%	64.0/35.0	P = 0.013	IIA–IIB	5	
 Yun et al. [8]	Korea	78	34/44 (43.59%/56.41%)	58.5 ± 1.89	Cohort study	76.7%/51.1%	52.7%/35.2%	52.0/33.0	P = 0.012	IIA–IIB	6	
 Li et al. [9]	China	110	46/64 (41.82%/58.18%)	58.2 ± 1.50	Cohort study	79.4%/51.7%	61.7%/39.5%	49.0/29.4	P = 0.037	IIA–IIB	5	
 Ren et al. [10]	China	83	37/46 (44.58%/55.42%)	55.2 ± 2.11	Cohort study	75.8%/61.8%	57.4%/37.5%	37.1/27.4	P = 0.001	IIA–IIB	7	
 Wang et al. [11]	China	138	52/86 (37.68%/62.32%)	56.4 ± 1.20	Cohort study	74.2%/53.2%	53.0%/35.3%	41.1/22.0	P < 0.001	IIA–IIB	7	
 Mordant et al. [12]	France	70	24/46 (34.29%/65.71%)	61.3 ± 1.50	Cohort study	69.0%/48.0%	56.0%/35%	45.0/23.0	P < 0.05	IIA–IIB	5	
 Sawabata et al. [13]	Japan	43	21/22 (48.84%/51.16%)	58.9 ± 1.61	Cohort study	78.9%/41.2%	49%/30%	34.0/27.0	P > 0.05	IIA–IIB	5	
 Fukuse et al. [14]	Japan	49	19/30 (38.78%/61.22%)	60.2 ± 1.45	Cohort study	N/A	N/A	37.8/26.2	P < 0.05	IIA–IIB	5	
 Ichinose et al. [15]	Japan	227	102/125 (44.93%/55.07%)	61.2 ± 1.12	Cohort study	68.8%/60.9%	54.9%/40%	39.0/20.0	P = 0.047	IIA–IIB	5	
Chemotherapy	
 Chen et al. [16]	China	131	61/70 (46.60%/53.40%)	64.5 ± 2.30	Retrospective study	57.0%/30.0%	38.0%/21.0%	22.9/16.0	P = 0.001	IIA–IIB	6	
 Kanaji et al. [17]	Japan	400	184/216 (46.00%/54.00%)	62.3 ± 1.55	Retrospective study	50.0%/31.0%	37.5%/19.5%	22.6/11.16	P < 0.05	IIA–IIB	7	
 Pan et al. [18]	China	40	16/24 (40.00%/60.00%)	59.1 ± 2.50	Retrospective study	60.0%/36.5%	32.5%/18%	21.5/14.5	P = 0.01	IIA–IIB	6	
 Ogawa et al. [19]	Japan	53	26/27 (49.05%/50.95%)	65.1 ± 1.20	Retrospective study	58.6%/25.0%	29.0%/11.0%	25.0/19.0	P = 0.01	IIA–IIB	6	
 Wu et al. [20]	China	186	53/133 (28.49%/71.51%)	60.5 ± 1.65	Retrospective study	54.7%/48.8%	38.0%/20.0%	29.5/19.5	P < 0.05	IIA–IIB	5	
 Kodama et al. [21]	Japan	160	56/104 (35.00%/65.00%)	64.1 ± 2.25	Retrospective study	67.2%/44.4%	35.9%/13.6%	26.2/16.0	P = 0.037	IIA–IIB	7	
 Park et al. [22]	Korea	67	23/44 (34.33%/65.67%)	68.3 ± 2.50	Retrospective study	52.5%/39.5%	37.8%/17.5%	24.5/16.5	P < 0.001	IIA–IIB	6	
Targeted therapy	
 Ren et al. [10]	China	83	33/50 (39.76%/60.24%)	62.0 ± 1.50	Retrospective study	66.1%/41.0%	46.8%/37.8%	47.0/22.0	P = 0.005	IIA–IIB	5	
 Liu et al. [23]	China	510	229/281 (44.90%/55.10%)	64.0 ± 2.12	Retrospective study	62.0%/37.0%	47.5%/36.0%	32.8/24.1	P < 0.01	IIA–IIB	6	
 Gadgeel et al. [24]	America	47	14/33 (29.78%/70.22%)	60.0 ± 1.50	Retrospective study	61.0%/48.0%	46.8%/38.5%	34.0/18.0	P = 0.017	IIA–IIB	5	
 Wang et al. [25]	China	93	74/19 (79.60%/20.40%)	61.0 ± 1.50	Retrospective study	51.5%/44.5%	48.6%/35.5%	41.5/22.0	P < 0.05	IIA–IIB	5	
 Chang et al. [26]	Taiwan	25	17/8 (68.00%/32.00%)	66.0 ± 1.25	Retrospective study	62.5%/49.1%	50.2%/32.0%	30.0/24.0	P = 0.027	IIA–IIB	5	
Immunotherapy	
 Aarnink et al. [27]	France	172	49/123 (28.48%/71.52%)	65.4 ± 2.70	Cohort study	51.0%39.2%	38.2%/38.0%	36.5/16.0	P < 0.001	IIA–IIB	6	
 Pantano et al. [28]	Itly	294	93/201 (32.00%/68.00%)	62.1 ± 2.40	Retrospective study	53.0%/40.0%	41.0%/37.0%	32.0/19.0	P = 0.0004	IIA–IIB	5	
 Udagawa et al. [29]	Japan	29	7/22 (24.00%/76.00%)	68.0 ± 1.80	RCT study	55.6%/46.0%	45.0%/28.2%	32.0/14.0	P = 0,0127	IIA–IIB	6	
 Kang et al. [30]	Korea	51	14/37 (27.50%/72.50%)	63.1 ± 1.55	Cohort study	58.4%/42.1%	49.2%/31.2%	34.1/19.3	P < 0.05	IIA–IIB	5	
 Sul et al. [31]	America	550	261/289 (48.00%/52.00%)	61.5 ± 2.15	Cohort study	63.4%/43.4%	56.2%/30.2%	29.3/19.3	P = 0.01	IIA–IIB	5	
N/A Not available, RCT study Randomized controlled trial study

Inclusion and exclusion criteria

Eligible studies: (1) investigated patients with visceral pleural invasion in stages IIA-IIB lung cancer who had a clear pathological diagnosis; (2) were randomized controlled trials, cohort studies, or retrospective studies; (3) reported on or more of the following outcomes: 3-year survival rates, 5-year survival rates, or median survival time; and (4) reported complete and accurate data. Studies without a control group, that did not clearly state the comparability of two groups, and using duplicate data or duplicate publications were excluded. Another inclusion criteria is that the studies had to be of high methodological quality (i.e., Jadad score > 3).

Quality evaluation and data extraction

The methodological quality of the included studies was assessed using the Jadad score (high methodological quality, Jadad score > 3). This scale evaluates study quality based on four key methodological features: (1) random sequence generation (0 points for inappropriate, 1 point for unclear, 2 points for appropriate), (2) allocation concealment (0 points for inappropriate, 1 point for unclear, 2 points for appropriate), (3) blinding (0 points for inappropriate, 1 point for unclear, 2 points for proper), and (4) study withdrawals (0 points for not mentioning and 1 point for mentioning). Studies with a total score of one to three were classified as low quality and four to seven were classified as high quality.

A total of 4 researchers were independently responsible for the literature screening and processing of this study, and each researcher was a clinical worker with rich experience in statistics. Disagreements were resolved through discussion and consultation with a third reviewer if necessary. Extracted information included: (1) basic study information: author, year of publication, and region; (2) study design: treatment path, treatment plan, number of patients in each group, clinical stage of the tumor, gender, and age; and (3) outcomes: 3-year survival rate, 5-year survival rate, and median survival time, reported as odds ratios (ORs) and 95% confidence intervals (CIs).

Statistical analysis

Odds ratios and 95% CIs were calculated for survival rate outcomes, while logarithm of OR was used as a measure of effect difference for median survival time. The Q test was used to evaluate the presence of statistically significant heterogeneity (α = 0.1) among studies, and I2 was used to quantify the amount of heterogeneity present. When I2 < 50%, a fixed-effects model was used. When I2 > 50%, a random-effects model was selected after exploring the possible causes of heterogeneity. The Z-test and P ≤ 0.05 were used to determine the presence of a statistically significant difference. Analyses were performed using Review Manager (RevMan) version 5.3 (The Nordic Cochrane Centre). GraphPad Prism software (version 8.40, GraphPad Software, San Diego, California) was used to draw Kaplan–Meier survival curves for the median survival times for the four treatment options (i.e., surgery, chemotherapy, targeted therapy, and immunotherapy).

In addition to analyzing the clinical follow-up data of cancer patients with visceral pleural invasion, this study also screened and identified the genes prone to mutations in targeted therapy and immunotherapy and performed immune infiltration clinical relative analysis. We downloaded lung cancer-related transcriptome data from the TCGA and GEO databases and used R software (version 4.0.3, R Foundation for Statistical Computing, Vienna, Austria) for differential and co-expression analyses. We used Stata (version 19.0, StataCorp, College Station, Texas) to analyze clinical indicators of visceral pleural invasion in lung adenocarcinoma, as well as to perform differential expression and co-expression gene network analyses. Finally, we used computer algorithms to perform repeated calculations and simulations on the transcriptome data in the tumor databases.

Ethics approval

Ethics approval was not required for this systematic review.

Results

Flow of studies into the review and characteristics of the included studies

The database searches retrieved a total of 1106 articles. After screening the titles, abstracts, and keywords of these articles, 1062 articles were excluded because they were not relevant to the research topic, were basic research, or had the wrong studies design (e.g., case reports). Upon reading the full-texts, review 14 of articles and conference papers were further excluded. We then evaluated the methodological quality of the remaining articles and excluded three more low-quality studies (i.e., Jadad score < 4). Thus, 27 high-quality were included in this systematic review [6–31]. They investigated surgical treatment (n = 10) [6–15], chemotherapy (n = 7) [16–22], targeted therapy (n = 5) [23–26], and immunotherapy (n = 5) [27–31] (Fig. 1). In addition, this study conducted an in-depth analysis of targeted therapy and immunotherapy, investigated the screening and identification of differential genes for lung cancer pleural invasion mutations, analyzed tumor-related immune infiltration, and found clinically valuable treatment and diagnostic value for lung cancer patient gene targets. These analyses assessed the prognostic risk of patients and provided more options for treatment targets (Table 1).Fig. 1 Flow chart of the literature search and study selection procedure

Meta-analysis outcomes for surgical treatment

In this study, three articles with incomplete survival index data were excluded. Ten high-quality cohort studies [6–15] on surgical treatment of patientsith lung cancer with pleural invasion were included in this analysis. Pooled analyses showed that: 3-year survival rate OR = 3.80 (95% CI 3.53, 4.09; P < 0.0001), 5-year survival rate = 4.10 (95%CI 3.72, 4.53; P < 0.0001), and median survival time OR = 2.71 (95% CI 2.53, 2.89; P < 0.0001) (Tables 2, 3, 4).Table 2 Prognostic outcome indicators of surgical treatment of pleural invasion in patients with lung cancer in stage IIA–IIB [7–12]

Table 3 Prognostic outcome indicators of surgical treatment of pleural invasion in patients with lung cancer in stage IIA–IIB [7–11]

Table 4 Prognostic outcome indicators of surgical treatment of pleural invasion in patients with lung cancer in stage IIA–IIB [6–15]

Meta-analysis outcomes for chemotherapy

This analysis included seven clinical trials [16–22] of chemotherapy for the treatment of patients with lung adenocarcinoma with pleural invasion. Chemotherapy is generally not the first choice of treatment for patients with lung cancer with pleural invasion, and most of the chemo therapy treatments were combined with other treatment options (e.g., combined targeted therapy, immunotherapy, or postoperative adjuvant chemotherapy). Pooled analyses found that: 3-year survival rate OR = 2.08 (95% CI 1.93, 2.25; P < 0.0001), 5-year survival rate OR = 1.68 (95% CI 1.49, 1.89; P < 0.0001), and median survival time OR = 1.84 (95% CI 1.66, 2.04; P < 0.0001) (Table 5).Table 5 Prognostic outcome indicators of chemotherapy of pleural invasion in patients with lung cancer in stage IIA–IIB [16–22]

Meta-analysis outcomes for targeted therapy

Five high-quality studies [23–26] on targeted therapy interventions were included in this analysis. The targeted therapy drugs mainly used by the intervention groups were gefitinib, erlotinib, afatinib, and ossitinib. The pooled analyses found that: 3-year survival rate OR = 2.91 (95% CI 2.65, 3.19; P < 0.0001), 5-year survival rate OR = 1.83 (95% CI 1.39, 2.33; P < 0.0001), and median survival time OR = 1.76 (95% CI 1.59, 1.94; P < 0.0001) (Table 6).Table 6 Prognostic outcome indicators of targeted therapy of pleural invasion in patients with lung cancer in stage IIA–IIB [10, 23–26]

Meta-analysis outcomes for immunotherapy

Five randomized clinical trials [27–31] investigating the use of immunotherapy drugs were included in this analysis. Immunotherapy is the main treatment for patients with advanced lung cancer who are no longer eligible for surgery. The immunotherapy drugs mainly used by the included studies were PD- 1, PD-L1 inhibitors and CTLA-4 inhibitors are used more in melanoma, but rarely in the treatment of lung cancer, although these are more commonly used in the treatment of melanoma and rarely used in the treatment of lung cancer. The pooled analyses found that: 3-year survival rate OR = 1.89 (95% CI 1.73, 2.07; P < 0.0001), 5-year survival rate (OR = 1.66; 95% CI 1.46, 1.88; P < 0.0001), and median survival time OR = 2.53 (95% CI 2.27, 2.82; P < 0.0001) (Table 7).Table 7 Prognostic outcome indicators of immunotherapy of pleural invasion in patients with lung cancer in stage IIA–IIB [27–31]

Comparison of the median survival times of the four treatment options

For this analysis, the median survival time data of 3866 patients were extracted from 27 studies. Figure 2 displays the Kaplan–Meier survival curves for the median survival times of patients for the four treatment options (i.e., surgery, chemotherapy, targeted therapy, and immunotherapy). The survival curves indicate that patients with visceral pleural invasion benefit the most from surgical treatment, followed by targeted therapy and immunotherapy. Moreover, they also show that chemotherapy regimens are not effective for lung cancer patients with visceral pleural invasion. That is, the prognosis is poor, and the median survival time is short. Control the crazy proliferation and invasion of tumor cells in patients with advanced lung cancer is key point. At the same time, chemotherapy itself is a blow to the body of weak advanced tumor patients. Chemotherapy drugs kill and destroy normal cells in the body while killing tumor cells [32]. It also reflects the disadvantages of adverse reactions such as side effects of chemotherapy drugs (Fig. 2).Fig. 2 Prognostic outcome of 4 treatments of pleural invasion in patients with lung cancer in stage IIA-IIB

Immunotherapy: immune cell typing analysis

This last set of analyses screened and identified the genes prone to mutations in targeted therapy and immunotherapy and performed immune infiltration analysis and clinical relative analysis. The results showed that the high expression of AC245595.1, ITGB1-DT, and AL606489.1 genes is involved in the process of visceral pleural invasion in lung cancer (Fig. 3). This also suggests that these three genes may be associated with a high prognostic risk of lung adenocarcinoma. This study further explored a correlation analysis between the expression of these three genes and the clinical results to explore the invasion process of tumor cells in lung cancer. The results show no obvious associations between AC245595.1, ITGB1-DT, AL606489.1 and gender, age, tumor size, lymph node invasion, and other expression differences. However, there were statistically significant associations with stages I–II and stage III–IV (Fig. 4).Fig. 3 Heat map of screening and identification of mutation-prone genes in pleural invasion of lung cancer

Fig. 4 Heat map of clinical correlation analysis of pleural invasion from lung cancer

We analyzed different immune cell subtypes using software such as Xcell, Tim, Quantiseq, McPCounter, EPIC, CIBERSORT-ABS, CIBERSORT (Fig. 5). We also determined the content of immune cells of different types of immunocytes with pleural metastases with pleural invasion and blood specimens and macrophages M1 and M2, CD4+-Th1, CD8+-Th1 may participate in immune infiltration. Their contents were statistically significantly different from those of the carcinoma (P < 0.05).Fig. 5 Levels of different immune cell subtypes during pleural invasion from lung cancer

Discussion

Visceral pleural invasion in lung cancer is commonly accompanied by a malignant pleural effusion [33]. According to the TNM staging system, this increases the T category of lung cancer to stage II. There is controversy among the medical and scientific communities about whether surgery should be used to treat visceral pleural invasion in lung cancer. Patients who undergo surgery experience significant trauma, and the scope of the resection is relatively large. Thus, it is necessary to carefully screen patients prior to surgery so as to select the appropriate cases and strictly follow the relevant indications for the operation. Surgery can improve the median survival time of patients [34]. The incidence of primary lung cancer is increasing annually, as is the proportion of adenocarcinoma in lung cancer. Adenocarcinoma is the most common lung cancer type to cause visceral pleural invasion and malignant pleural effusion. In the past, non-surgical approaches such as repeated thoracentesis and anticancer drugs were most commonly used to treat patients with NSCLC. However, as the protein concentration in pleural effusion increased, symptoms of cachexia gradually worsened, and patients experienced shortness of breath, chest tightness, chest pain, and poor quality of life and survival prognosis. Moreover, adenocarcinoma is not very sensitive to radiotherapy and chemotherapy, so the median survival time of patients using these non-surgical treatment approaches was only 5–6 months [35].

Tumor immunology theory suggests that tumors secrete immunosuppressive factors which reduce the body's immune system response. Consequently, there are a large number of immunosuppressive factors in the pleural fluid of patients with lung cancer that significantly decrease the immune response. Extra-pleural pneumonectomy removes tumors and metastases that produce pleural effusion. This reduces tumor burden, removes immunosuppressive factors, and stimulates immune function recovery, creating conditions for further comprehensive medical treatment. Most lung cancer patients with visceral pleural invasion have progressed to stage IIB of the disease. Adenocarcinoma is the most common lung cancer type among these patients. Adenocarcinoma is not sensitive to radiotherapy and chemotherapy. Thus treatment methods are combined with less than ideal results. Improving these patients’ median survival time is a major concern for clinicians.

This study summarizes the relevant clinical trial data on the treatment of visceral pleural invasion in lung cancer. Meta-statistical analyses found that surgical treatment can significantly improve the median survival time of patients with visceral pleural invasion in stage IIA-IIB lung cancer. Conversely, surgery did not have an effect on the survival time of patients in stages III-IV of the disease [35]. In addition, our clinical experience indicates that chemotherapy has the worst efficacy for lung cancer patients with visceral pleural invasion, and the efficacy of targeted therapy or immunotherapy is not as good as expected. The mechanism of drug resistance is still unclear. Thus this study went beyond exploring the answer to this clinical question through clinical studies to investigating what makes this subgroup of patients with visceral pleural invasion unique. In doing so, we compared and verified lung cancer visceral pleural invasion data within the TCGA and GEO tumor databases within our hospital’s clinical database. A computer algorithm model was used to screen and identify AC245595.1, ITGB1-DT, and AL606489.1 as the relevant prognosis-related genes. These findings were combined with tumor immune infiltration and immune cell regulation analysis to further reveal the molecular mechanism of poor prognosis of visceral pleural invasion.

Kang et al. [30] investigated the effects of PD-1/PD-L1 inhibitors in 51 patients with advanced lung cancer. Many of the patients were affected by malignant pleural effusion and pericardial effusion. There were many lymphocytes in the effusion, as well as cells, macrophages, and natural killer (NK) cells. The study found that reactivated immune cells can cause more frequent and more severe immune responses in the pleura, resulting in an increased incidence of adverse events in patients and a worse prognosis. The findings of Takahashi et al. [36] can be used to help explain the molecular mechanism of lung cancer invasion to the pleura and factors that influence the prognosis of lung cancer after pleural invasion. Specifically, their results indicate that Tranilast inhibits epithelial-mesenchymal transition and invasion induced by transforming growth factor β1 by inhibiting Smad4. Transforming growth factor β1 is an important epithelial-mesenchymal transition (EMT) activator, which can regulate the expression of E-cadherin and vimentin through Smad signaling. It may be involved in the invasion of lung cancer cells. Moreover, Xie et al. [37] treated the malignant pleural effusion mouse model caused by lung cancer pleural invasion with arsenic trioxide (As2O3) and observed the activity of NF-κB and NF-κB in the pleural cancer tissues. They found that As2O3 passed by inhibiting NF-κB to down-regulate the expression of VEGF and reduce the density and permeability of blood vessels in pleural invasion nodules. This research explains its influence on MPE caused by lung cancer pleural invasion.

At present, precision therapy has become the first-line therapy for tumors. In addition to targeting drugs to kill tumor cells or inhibit the expression of high-risk mutant genes, the screening of suitable populations and the treatment indications for clinical tumor staging are also important [38]. The research on the related pathways and mechanisms of visceral pleural invasion in lung cancer is not complete, and there are many research opportunities of clinical value in this field.

Acknowledgements

The authors would like to express their gratitude to AJE for the expert linguistic services provided.

Author contributions

Wu L wrote and revised the manuscript; Liu Q and Feng Y collected the data; Wang X made the chart. Wang Y, Li X and Yan J guided the study. All authors reviewed, edited and approved the final manuscript and revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

Funding

This work was supported by the China Scholarship Council (CSC NO. 202406210298), the Scientific Research Project of Education Department of Anhui Province (YJS20210324), the National Natural Science Foundation of China (81972829), the Science and Technology Innovation Committee of Shenzhen Municipality (JCYJ20180228162607111 and JCYJ20190809104601662), the research and development of intelligent surgical navigation and operating systems for precise liver resection (2022ZLA006) and Start-up Fund for Talent Researchers of Tsinghua University(10001020507).

Data availability

All data generated or analysed during this study are included in this published article. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Our study does not contain data from any individual person or any animals.

Consent for publication

I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Qi Liu, Liusheng Wu and Xiangyu Wang contributed equally for this study.
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