Characteristics of M1 lung cancerAt the time of initial diagnosis, SCLC exhibited the highest distant metastasis (DM) rate among histological subtypes (56.74%), succeeded by LCNEC (47.52%), ADC (43.36%), LCC (40.61%), ASC (36.69%), SCC (26.54%), and TC + AC (9.18%). A significant portion of lung cancer patients identified with distant metastases were over 50 years old and exhibited large tumor sizes. In metastatic lung cancer cases, the highest percentage of patients present with a primary tumor location in the upper lobe of the lung. Adenocarcinoma emerged as the predominant histological subtype, followed by small cell lung cancer and squamous lung cancer. Over two-thirds of the cases did not undergo surgical resection, and regional lymph node involvement was observed in most instances. Table 1 outlines the fundamental characteristics of the patients.Table 1 Characteristics of lung cancers with distant metastasis (DM) at presentation.Metastatic patterns in lung cancer subtypesIn adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma (ASC), and large cell carcinoma (LCC), bone metastases were the predominant site, comprising 35.15%, 33.26%, 38.51%, and 33.54%, respectively. The highest prevalence of brain metastases was observed in large cell neuroendocrine carcinoma (LCNEC) at 31.25%. Carcinoid tumors (typical and atypical combined, TC + AC) most frequently metastasized to the lungs, accounting for 32.95% of cases. Small cell lung carcinoma (SCLC) showed a significantly higher incidence of liver metastases at 35.35% compared to other subtypes (Fig. 1). Regarding multi-organ metastases at diagnosis, 38.25% of patients with distant metastasis had involvement of multiple organs, with the highest rates found in SCLC (42.30%), followed by ADC (39.52%), ASC (38.67%), LCNEC (37.21%), LCC (35.95%), SCC (29.10%), and TC + AC (28.71%). Liver was the sole metastatic site in 21.43% of SCLC and 21.45% of TC + AC cases, which was notably higher than other subtypes. Among single organ metastases, ADC and ASC had the highest percentages of bone metastases at 22.53% and 26.30%, respectively. Lung was the predominant single organ metastasis site in SCC, while brain was most frequent in LCC and LCNEC (Fig. 2).Fig. 1Bar chart depicting the percentage distribution of overall metastatic sites among various types of lung cancer. ADC adenocarcinoma, ASC adenosquamous carcinoma, SCC squamous cell carcinoma, LCC Large cell carcinoma, SCLC small cell lung cancer, TC typical carcinoid, ATC atypical carcinoid, LCNEC large cell neuroendocrine carcinoma.Fig. 2Pie chart depicting the percentage distribution of single-organ and multi-organ metastatic sites among various types of lung cancer. ADC adenocarcinoma, ASC adenosquamous carcinoma, SCC squamous cell carcinoma, LCC Large cell carcinoma, SCLC small cell lung cancer, TC typical carcinoid, ATC atypical carcinoid, LCNEC large cell neuroendocrine carcinoma.M1 lung cancer survival rate analysisUpon stratification by histological type, Kaplan-Meier (KM) curves revealed Small cell lung cancer (SCLC) exhibits the lowest cancer-specific survival (CSS) rates, followed by squamous cell carcinoma (SCC); whereas thymic carcinomas and adenocarcinomas (TC + AC) show the highest CSS. In terms of median survival times among different lung cancer subtypes with metastases, large cell carcinoma (LCC) has the shortest median survival time of 3 months. Metastatic squamous cell carcinoma (SCC) shows a median survival of 4 months, large cell neuroendocrine carcinoma (LCNEC) and adenosquamous carcinoma (ASC) both have 5 months, small cell lung cancer (SCLC) has 6 months, and adenocarcinoma (ADC) has 7 months. In contrast, metastatic typical and atypical carcinomas (TC + AC) exhibit the longest median survival time observed at 58 months, which is statistically significant (p < 0.001) (Fig. 3). Multivariable Cox regression assessment, accounting for variables including age, race, sex, and histological classification, primary tumor location, tumor size, regional lymph node status, radiotherapy, chemotherapy, systemic therapy, and surgical treatment, demonstrated that patients aged 50 years or older (HR = 1.2788; 95% CI (1.2321–1.3273)), male (HR = 1.1981; 95% CI (1.1798–1.2167)), those with large tumor diameter (HR = 1.0013; 95% CI (1.0012–1.0015)), positive lymph nodes (HR = 1.2585; 95% CI (1.2346–1.2830)), and multi-organ metastasis (HR = 1.4168; 95% CI (1.3945–1.4395)) experienced a negative impact on CSS in M1 lung cancer. Conversely, patients receiving radiotherapy (HR = 0.8536; 95% CI (0.8406–0.8668)), chemotherapy (HR = 0.3493; 95% CI (0.3435–0.3552)), systemic therapy (HR = 0.8004; 95% CI (0.7814–0.8199)), and surgery (HR = 0.5419. 95% CI (0.5136–0.5718)) had a positive impact on M1 lung cancer CSS, with a decreased mortality risk in comparison to those who remained untreated, and the most significant reduction in death risk observed in patients receiving chemotherapy, followed by surgery. Furthermore, multivariate analysis indicated that SCC, SCLC, LCC, LCNEC, and ASC adversely affected CSS in M1 lung cancer compared to ADC, with the highest death risk observed in SCLC (HR = 1.6295; 95% CI (1.5952–1.6646)). On the other hand, the mortality risk was notably reduced for the TC + AC group (HR = 0.2100; 95% CI (0.1769–0.2493)). Individuals with M1 lung cancer and primary tumor site in the main bronchus experienced an increased death risk compared to lung cancer with a primary location in the peripheral lung lobes (Table 2).When stratifying by age, sex, race, local lymph node involvement, and the number of organ metastases, unadjusted KM survival curves demonstrated superior survival outcomes for lung cancer patients under 50 years of age, of non-White, female, without lymph node involvement, and with single-organ metastasis (Fig. 4A-E). IPTW adjusted Kaplan-Meier analyses yielded consistent findings (Fig. 4F-J), with log-rank p-values below 0.001. Baseline data prior to and following IPTW adjustment can be found in Supplementary Table 1. The multivariate Cox proportional hazard regression model also corroborated these results. When stratified by chemotherapy, radiotherapy, systemic therapy, and surgical intervention, unadjusted Kaplan-Meier survival curves revealed enhanced survival rates for DM lung cancer patients who received chemotherapy, radiotherapy, systemic therapy, and surgical treatment (Fig. 5A-D). Upon IPTW correction, Kaplan-Meier analyses indicated that individuals with DM lung cancer who underwent chemotherapy, radiotherapy, and systemic therapy experienced improved survival outcomes, with log-rank p-values below 0.001. However, no significant difference emerged for surgical intervention (log-rank p = 0.5335; Fig. 5E-H). Baseline data before and after IPTW adjustment is delineated in Supplementary Table 2. The multivariable Cox proportional hazards regression analysis confirmed improved survival outcomes for DM patients with lung cancer who underwent chemotherapy, radiotherapy, systemic therapy, and surgical treatment both before and after IPTW adjustment.Fig. 3Kaplan–Meier curve illustrating the cancer-specific survival of different lung cancer subtypes with DM at time of diagnosis. ADC adenocarcinoma, ASC adenosquamous carcinoma, SCC squamous cell carcinoma, LCC Large cell carcinoma, SCLC small cell lung cancer, TC typical carcinoid, ATC atypical carcinoid, LCNEC large cell neuroendocrine carcinoma.Table 2 Multivariate analysis of cancer-specific survival (CSS) in patient with distant metastasis (DM) lung cancer.Fig. 4Kaplan–Meier cancer-specific survival curves depict the stratified survival status of distant metastatic (DM) lung cancer patients and their corresponding control group, both before and after adjustment using propensity score inverse probability weighting. The stratification is based on factors such as age, gender, ethnicity, local lymph node involvement, and the number of organ metastases. (A–E) Unadjusted; (G–J) Inverse Probability of Treatment Weighting (IPTW). Sex: group = 0 female; group = 1 male. Age: group = 0 < 50 years old; group = 1 ≥ 50 years old. Regional nodal involvement: group = 0 no lymph node metastasis; group = 1 distant lymph node metastasis. Race: race = 0 white people; group = 1 non-white people. Organ metastases: organmetastases = 0 single-organ; organmetastases = 1 Multiple-organ.Fig. 5Kaplan–Meier cancer-specific survival curves depict the stratified survival status of distant metastatic (DM) lung cancer patients and their corresponding control group, both before and after adjustment using propensity score inverse probability weighting. The stratification is based on factors such as chemotherapy, radiotherapy, systemic therapy, and surgery. (A–D) Unadjusted; (E–H) Inverse Probability of Treatment Weighting (IPTW). Chemotherapy: group = 0 No/Unknown chemotherapy; group = 1 received chemotherapy. Radiation therapy: group = 0 No/Unknown radiation therapy; group = 1 received radiation therapy. Systemic therapy: group = 0 No Systemic therapy; group = 1 received Systemic therapy. Surgery: group = 0 No surgery; group = 1 received surgery.Multi-organ metastasis risk factors and the impact of primary tumor resection on survival outcomes in lung cancer patients (excluding SCLC) with single- and multi-organ distant metastasesTable 3 outlines the relationships between single-organ and multiple-organ metastatic occurrences and assorted clinical aspects. Male sex, age below 50 years, primary tumor location (main bronchus and lower lobe of the lung), larger tumor diameter, pathological subtypes (ADC/SCLC/SCC), and regional lymph node involvement were identified as significant risk factors for multi-organ metastasis. Furthermore, we assessed the influence of initial tumor location surgery on survival results for patients with single- and multi-organ distant metastatic (DM) lung cancer (excluding small cell lung cancer, SCLC). Unadjusted KM curves and multivariate Cox proportional hazard regression models revealed that individuals who received surgical intervention at the initial tumor location for single-organ (log-rank p < 0.001, HR = 0.5275; 95% CI [0.8877–0.9275], p < 0.001) and multi-organ (log-rank p < 0.001, HR = 0.6982; 95% CI [0.6173–0.7896], p < 0.001) metastases experienced improved survival outcomes in the context of distant metastatic lung cancer (Fig. 6A and C). Intriguingly, no significant survival benefit was observed in patients with multiple-organ distant metastases who underwent primary tumor site surgery following IPTW adjustment (log-rank p = 0.358, HR = 0.8630; 95% CI [0.6961-1.0700], p = 0.179) (Fig. 6D). In contrast, a significant survival benefit was evident for patients with single-organ distant metastases who underwent surgical intervention at the initial tumor location (log-rank p < 0.001, HR = 0.6165; 95% CI [0.5468–0.6951], p < 0.001) (Fig. 6B). Baseline information for individuals with single-organ distant metastatic lung cancer before and after IPTW adjustment is provided in Supplementary Table 3. Similarly, baseline information for patients with multi-organ distant metastatic lung cancer before and after IPTW adjustment is presented in Supplementary Table 4.Table 3 Risk factors associated with the incidence of multi-organ metastasis.Fig. 6Kaplan–Meier cancer-specific survival curves delineate the impact of primary tumor site surgery on the survival outcomes of lung cancer patients (excluding small cell lung cancer (SCLC))with single-organ distant metastasis (DM) and multi-organ metastasis. These outcomes are presented both prior to and subsequent to adjustments implemented via propensity score inverse probability weighting (IPTW). Surgery: group = 0 No surgery; group = 1 received surgery. (A, C): Unadjusted. (B, D): IPTW.Impact of primary tumor site surgery on cancer-specific survival in patients with single organ metastatic lung cancer (excluding SCLC) at various metastatic sitesUpon conducting a more granular analysis of metastatic sites in lung cancer individuals (excluding small cell lung cancer, SCLC)with single-organ metastases, both KM survival curves and multivariate Cox proportional hazard regression analyses of the unadjusted cohort revealed that individuals with bone metastases who underwent surgery at the primary tumor site (log-rank p < 0.001, HR = 0.5773; 95% CI [0.5022–0.6638], p < 0.001), those with brain metastases (log-rank p < 0.001, HR = 0.6047; 95% CI [0.5466–0.6691], p < 0.001), those with liver metastases (log-rank p < 0.001, HR = 0.4827; 95% CI [0.3712–0.6276], p < 0.001), and those with intrapulmonary metastases (log-rank p < 0.001, HR = 0.50664; 95% CI [0.45448–0.5648], p < 0.001) all demonstrated enhanced survival outcomes (Fig. 7A-D). Notably, after applying inverse probability of treatment weighting (IPTW) adjustment, no significant survival benefit was observed for lung cancer individuals(excluding small cell lung cancer, SCLC) with liver metastases who received surgical intervention at the primary tumor location (log-rank p = 0.952, HR = 0.9242; 95% CI [0.7011–1.2182], p = 0.575) (Fig. 7G), and those with intrapulmonary metastases (log-rank p = 0.124, HR = 0.65316; 95% CI [0.53090–0.8036], p = 0.113) (Fig. 7H). However, individuals with brain metastases who received primary tumor site surgery exhibited a significant improvement in survival outcomes (log-rank p < 0.001, HR = 0.6467; 95% CI [0.5505–0.7596], p < 0.001) (Fig. 7F). In contrast, Kaplan-Meier curve analysis of individuals with bone metastases receiving surgery at the primary tumor location revealed no significant difference (log-rank p = 0.182), while multivariate Cox proportional hazard regression model analysis indicated a survival advantage for these patients (HR = 0.6289; 95% CI [0.50230–0.7873], p < 0.01) (Fig. 7E). Baseline characteristics of patients with single-organ distant metastatic lung cancer in diverse metastatic locations, both before and after IPTW adjustment, are presented in Supplementary Table 5.Fig. 7The Kaplan–Meier curve illustrates how the impact of primary tumor site surgery on cancer-specific survival (CSS) varies depending on the location of single organ metastasis in patients with lung cancer (excluding small cell lung cancer (SCLC)). surgery = 0: No surgery, surgery = 1: Received surgery. (A–D) Unadjusted cohort. (E–H) Inverse probability of treatment weighting (IPTW) cohort.
