Prognosis evaluation and efficacy analysis of different treatment options for patients with visceral pleural invasion in stage IIA–IIB lung cancer

Abstract

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.

Introduction

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 [Images not available. See PDF.]

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 [Images not available. See PDF.]

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 [Images not available. See PDF.]

Heat map of screening and identification of mutation-prone genes in pleural invasion of lung cancer

Fig. 4 [Images not available. See PDF.]

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 [Images not available. See PDF.]

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.

References

1. Zhang, Y; Vaccarella, S; Morgan, E; Li, M; Etxeberria, J; Chokunonga, E; Manraj, SS; Kamate, B; Omonisi, A; Bray, F. Global variations in lung cancer incidence by histological subtype in 2020: a population-based study. Lancet Oncol; 2023; 24, 11 pp. 1206-1218. [DOI: https://dx.doi.org/10.1016/S1470-2045(23)00444-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37837979]

2. Adachi, H; Tsuboi, M; Nishii, T et al. Influence of visceral pleural invasion on survival in completely resected non-small-cell lung cancer. Eur J Cardio-thor Surg; 2015; 48, 5 pp. 691-697. [DOI: https://dx.doi.org/10.1093/ejcts/ezu515]

3. Feng, D; Yang, Y; Han, P; Wei, X. The preliminary outcome of the combination of immunotherapy and targeted therapy after recurrence and metastasis for hereditary leiomyomatosis and renal cell cancer-a case report. Transl Androl Urol; 2020; 9, 2 pp. 789-793. [DOI: https://dx.doi.org/10.21037/tau.2019.12.37] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32420185][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215000]

4. Ettinger, D; Wood, D; Aggarwal, C et al. NCCN guidelines insights: non-small cell lung cancer, Version 1.2020. J Natl Comp Cancer Netw JNCCN; 2019; 17, 12 pp. 1464-1472. [DOI: https://dx.doi.org/10.6004/jnccn.2019.0059]

5. Kuijpers, C; Hendriks, L; Derks, J et al. Association of molecular status and metastatic organs at diagnosis in patients with stage IV non-squamous non-small cell lung cancer. Lung Cancer (Amsterdam, Netherlands); 2018; 121, pp. 76-81.[COI: 1:STN:280:DC%2BC1MbivV2itw%3D%3D] [DOI: https://dx.doi.org/10.1016/j.lungcan.2018.05.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29858031]

6. Chiang, CL; Wang, LC; Ho, HL et al. Effect of postoperative systemic therapy on pulmonary adenocarcinoma with unexpected pleural spread detected during thoracotomy or thoracoscopy. Oncotarget; 2018; 9, 4 pp. 5435-5444. [DOI: https://dx.doi.org/10.18632/oncotarget.23686] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29435191]

7. Li, C; Kuo, S; Hsu, H; Lin, M; Chen, J. Lung adenocarcinoma with intraoperatively diagnosed pleural seeding: Is main tumor resection beneficial for prognosis?. J Thorac Cardiovasc Surg; 2018; 155, 3 pp. 1238-1249.e1231. [DOI: https://dx.doi.org/10.1016/j.jtcvs.2017.09.162] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29254636]

8. Yun, J; Kim, M; Choi, C et al. Surgical outcomes after pulmonary resection for non-small cell lung cancer with localized pleural seeding first detected during surgery. Thorac Cardiovasc Surg; 2018; 66, 2 pp. 142-149. [DOI: https://dx.doi.org/10.1055/s-0035-1564928] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26669768]

9. Li, S; Zhang, S; Huang, M; Ma, Y; Yang, Y. Management of occult malignant pleural disease firstly detected at thoracotomy for non-small cell lung cancer patients. J Thorac Dis; 2017; 9, 10 pp. 3851-3858. [DOI: https://dx.doi.org/10.21037/jtd.2017.09.112] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29268394][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723903]

10. Ren, Y; She, Y; Dai, C; Jiang, G; Fei, K; Chen, C. Primary tumour resection showed survival benefits for non-small-cell lung cancers with unexpected malignant pleural dissemination. Interact Cardiovasc Thorac Surg; 2016; 22, 3 pp. 321-326. [DOI: https://dx.doi.org/10.1093/icvts/ivv353] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26705302]

11. Wang, B; Wu, Y; Hung, J et al. Prognosis of non-small-cell lung cancer with unexpected pleural spread at thoracotomy. J Surg Res; 2011; 169, 1 pp. e1-5. [DOI: https://dx.doi.org/10.1016/j.jss.2011.02.028] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21529842]

12. Mordant, P; Arame, A; Foucault, C; Dujon, A; Le Pimpec, BF; Riquet, M. Surgery for metastatic pleural extension of non-small-cell lung cancer. Eur J Cardio-thorac Surg; 2011; 40, 6 pp. 1444-1449.

13. Sawabata, N; Matsumura, A; Motohiro, A et al. Malignant minor pleural effusion detected on thoracotomy for patients with non-small cell lung cancer: is tumor resection beneficial for prognosis?. Ann Thorac Surg; 2002; 73, 2 pp. 412-415. [DOI: https://dx.doi.org/10.1016/S0003-4975(01)03426-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11845851]

14. Fukuse, T; Hirata, T; Tanaka, F; Wada, H. The prognostic significance of malignant pleural effusion at the time of thoracotomy in patients with non-small cell lung cancer. Lung Cancer (Amsterdam, Netherlands); 2001; 34, 1 pp. 75-81.[COI: 1:STN:280:DC%2BD3MrhtVWrtA%3D%3D] [DOI: https://dx.doi.org/10.1016/S0169-5002(01)00228-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11557116]

15. Ichinose, Y; Tsuchiya, R; Koike, T et al. The prognosis of patients with non-small cell lung cancer found to have carcinomatous pleuritis at thoracotomy. Surg Today; 2000; 30, 12 pp. 1062-1066.[COI: 1:STN:280:DC%2BD3M7jvFSnsg%3D%3D] [DOI: https://dx.doi.org/10.1007/s005950070002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11193736]

16. Chen, Y; Tang, W; Lin, H et al. Wait-and-see treatment strategy could be considered for lung adenocarcinoma with special pleural dissemination lesions, and low genomic instability correlates with better survival. Ann Surg Oncol; 2020; 27, 10 pp. 3808-3818. [DOI: https://dx.doi.org/10.1245/s10434-020-08400-1] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32239339]

17. Kanaji, N; Tadokoro, A; Watanabe, N; Inoue, T; Kadowaki, N; Ishii, T. Association of specific metastatic organs with the prognosis and chemotherapeutic response in patients with advanced lung cancer. Respir Investig; 2019; 57, 5 pp. 472-480. [DOI: https://dx.doi.org/10.1016/j.resinv.2019.06.004] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31327681]

18. Pan, Y; Wang, Y; Wang, Y; Wang, D. The pathological characteristics and outcomes of 40 surgically treated stage M1b non-small cell lung cancer patients. Zhonghua zhong liu za zhi Chin J Oncol; 2019; 41, 1 pp. 63-67.[COI: 1:STN:280:DC%2BB3cjkvFejtQ%3D%3D]

19. Ogawa, H; Uchino, K; Tanaka, Y et al. Efficacy of adjuvant chemotherapy for lung adenocarcinoma patients with positive pleural lavage cytology findings. Interact Cardiovasc Thorac Surg; 2015; 21, 1 pp. 34-39. [DOI: https://dx.doi.org/10.1093/icvts/ivv098] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25911680]

20. Wu, X; Huang, X. Screening for patients with non-small cell lung cancer who could survive long term chemotherapy. Asian Pac J Cancer Prevent APJCP; 2015; 16, 2 pp. 647-652. [DOI: https://dx.doi.org/10.7314/APJCP.2015.16.2.647]

21. Kodama, K; Higashiyama, M; Okami, J et al. Cytoreductive surgery and post-operative heated pleural chemotherapy for the management of pleural surface malignancy. Int J Hyperthermia; 2013; 29, 7 pp. 653-662. [DOI: https://dx.doi.org/10.3109/02656736.2013.829247] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24028146]

22. Park, D; Hwang, K; Shim, H et al. Elevated survivin is associated with a poor response to chemotherapy and reduced survival in lung cancer with malignant pleural effusions. Clin Exp Metas; 2012; 29, 2 pp. 83-89.[COI: 1:CAS:528:DC%2BC38XnvFynug%3D%3D] [DOI: https://dx.doi.org/10.1007/s10585-011-9431-7]

23. Liu, Y; Hao, X; Li, J et al. Survival of patients with advanced lung adenocarcinoma before and after approved use of gefitinib in China. Thorac Cancer; 2015; 6, 5 pp. 636-642. [DOI: https://dx.doi.org/10.1111/1759-7714.12267] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26445613][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567010]

24. Gadgeel, S; Gandhi, L; Riely, G et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol; 2014; 15, 10 pp. 1119-1128.[COI: 1:CAS:528:DC%2BC2cXhsVSmt77K] [DOI: https://dx.doi.org/10.1016/S1470-2045(14)70362-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25153538]

25. Wang, B; Zhang, X; Lin, L et al. Progressive patterns of gifitinib treating advanced non-small cell lung cancer after obtained resistance. Zhongguo fei ai za zhi Chin J Lung Cancer; 2013; 16, 10 pp. 510-513.[COI: 1:CAS:528:DC%2BC2cXhsFant7rF]

26. Chang, C; Chi, K; Kao, S et al. Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a mono-institutional experience. Lung Cancer (Amsterdam, Netherlands); 2011; 73, 2 pp. 189-194. [DOI: https://dx.doi.org/10.1016/j.lungcan.2010.12.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21247653]

27. Aarnink, A; Fumet, J; Favier, L; Truntzer, C; Ghiringhelli, F. Role of pleural and peritoneal metastasis in immune checkpoint inhibitors efficacy patients with non-small cell lung cancer: real-world data from a large cohort in France. J Cancer Res Clin Oncol; 2020; 146, 10 pp. 2699-2707.[COI: 1:CAS:528:DC%2BB3cXhtVOjs7nM] [DOI: https://dx.doi.org/10.1007/s00432-020-03262-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32474752]

28. Pantano, F; Russano, M; Berruti, A et al. Prognostic clinical factors in patients affected by non-small-cell lung cancer receiving Nivolumab. Expert Opin Biol Ther; 2020; 20, 3 pp. 319-326.[COI: 1:CAS:528:DC%2BB3cXitlCntrc%3D] [DOI: https://dx.doi.org/10.1080/14712598.2020.1724953] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32011207]

29. Udagawa, H; Akamatsu, H; Tanaka, K et al. Phase I safety and pharmacokinetics study of rovalpituzumab tesirine in Japanese patients with advanced, recurrent small cell lung cancer. Lung Cancer (Amsterdam, Netherlands); 2019; 135, pp. 145-150. [DOI: https://dx.doi.org/10.1016/j.lungcan.2019.07.025] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31446987]

30. Kang, D; Chung, C; Kim, J et al. Pleural or pericardial metastasis: a significant factor affecting efficacy and adverse events in lung cancer patients treated with PD-1/PD-L1 inhibitors. Thorac Cancer; 2018; 9, 11 pp. 1500-1508.[COI: 1:CAS:528:DC%2BC1cXitFSiurnL] [DOI: https://dx.doi.org/10.1111/1759-7714.12877] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30253080][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209802]

31. Sul, J; Blumenthal, G; Jiang, X; He, K; Keegan, P; Pazdur, R. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist; 2016; 21, 5 pp. 643-650.[COI: 1:CAS:528:DC%2BC28XhvFGnurzK] [DOI: https://dx.doi.org/10.1634/theoncologist.2015-0498] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27026676][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861368]

32. Hartner, L. Chemotherapy for oral cancer. Dent Clin North Am; 2018; 62, 1 pp. 87-97. [DOI: https://dx.doi.org/10.1016/j.cden.2017.08.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29126496]

33. Kaiser D. [Special diagnosis of pleural metastasis]. Langenbecks Archiv fur Chirurgie. Supplement II, Verhandlungen der Deutschen Gesellschaft fur Chirurgie. Deutsche Gesellschaft fur Chirurgie. Kongress; 1990. p. 775–778.

34. Waller, D; Tenconi, S. Surgery as part of radical treatment for malignant pleural mesothelioma. Curr Opin Pulm Med; 2017; 23, 4 pp. 334-338. [DOI: https://dx.doi.org/10.1097/MCP.0000000000000389] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28590338]

35. Chen, D; Fu, R; Shi, P; Qin, S; Chen, C. Latest progress of intraoperative pleural lavage cytology in lung cancer surgery. Zhongguo fei ai za zhi Chin J Lung Cancer.; 2018; 21, 9 pp. 719-726.

36. Takahashi, K; Menju, T; Nishikawa, S et al. viaTranilast inhibits TGF-β1-induced epithelial-mesenchymal transition and invasion/metastasis the suppression of smad4 in human lung cancer cell lines. Anticancer Res; 2020; 40, 6 pp. 3287-3296.[COI: 1:CAS:528:DC%2BB3cXitFSqs7zO] [DOI: https://dx.doi.org/10.21873/anticanres.14311] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32487624]

37. Xie, S; Yang, M; Chen, K et al. Efficacy of arsenic trioxide in the treatment of malignant pleural effusion caused by pleural metastasis of lung cancer. Cell Biochem Biophys; 2015; 71, 3 pp. 1325-1333.[COI: 1:CAS:528:DC%2BC2cXhvFKlurbE] [DOI: https://dx.doi.org/10.1007/s12013-014-0352-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25413961]

38. Prasad, V; Fojo, T; Brada, M. Precision oncology: origins, optimism, and potential. Lancet Oncol; 2016; 17, 2 pp. e81-e86. [DOI: https://dx.doi.org/10.1016/S1470-2045(15)00620-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26868357]