Increased mortality in lung cancer patients with same-lobe, multi-lobe, or mixed nodules: a retrospective study of 166,097 participants from the SEER database

Introduction

Lung cancer remains a major global health concern, ranking among the leading causes of cancer-related deaths. According to the World Health Organization (WHO), lung cancer accounts for approximately 1.82 million fatalities annually, representing nearly 18.7% of all cancer-related deaths globally (1). In 2022, China recorded the highest number of new lung cancer cases among all cancers (1.06 million) and the highest number of lung cancer-related deaths (730,000) (2). Despite advancements in early detection and treatment, the prognosis of lung cancer remains poor, with a 5-year survival rate of approximately 19% in the United States (3).

This low survival rate is primarily because most lung cancer cases are diagnosed at later stages when treatment options are less effective. Despite advances in diagnostic and therapeutic strategies, lung cancer is poorly treated, primarily because many cases are diagnosed at advanced stages when treatment options are ineffective (4). Lung cancer has multiple subtypes, each with distinct molecular signatures and varying responses to treatment (5). Moreover, resistance to chemotherapy, targeted therapies, and immunotherapies may develop over time (6,7). Surgical resection remains the mainstay of curative treatment for lung cancer (8). Significant challenges persist in the diagnosis, staging, and treatment of lung cancer with independent nodules within the same lobe or multiple independent nodules across different lobes (9-12).

The Surveillance, Epidemiology, and End Results (SEER) database serves as the definitive source of cancer statistics in the United States. The SEER program provides cancer statistics to support efforts to reduce the cancer burden in the U.S. population. SEER collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 48% of the U.S. population. These data encompass all cancer cases reported in 22 geographic regions of the United States. As these regions are representative of the demographics of the entire U.S. population, SEER accounts for diverse populations across the country.The SEER also reports mortality data provided by the National Center for Health Statistics. This database includes detailed demographic, clinical, and tumor characteristics, making it an important resource for epidemiological studies and cancer research (13-15).

This study aimed to assess the survival rates of patients with lung cancer by focusing on overall survival (OS) and disease-specific survival (DSS). It also provides survival data for clinical research involving multiple independent nodules occurring within the same or different lobes of the ipsilateral lung. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-445/rc).

Methods

Data sources

Data for this study were obtained from the SEER database (https://seer.cancer.gov/), specifically the Incidence SEER Research Plus Data [17 registries, November 2021 Sub (2000–2019)]. This dataset represents approximately 26.5% of the U.S. population based on the 2020 Census, covering regions such as San Francisco-Oakland, Connecticut, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta. This study focused on cases of lung and bronchial cancers categorized under the Site Recode International Classification of Diseases for Oncology, 3rd Edition, WHO 2008 (https://seer.cancer.gov/siterecode/icdo3_dwhoheme/index.html). After excluding records with missing or unassessed data, the final sample comprised 166,097 participants. The details of the data screening process are provided in Figure S1. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All the multiple nodules included in this study were confirmed to have the same histological type and were located in the same lung (ipsilateral presentation).

Variables

The main independent variable was the occurrence of separate tumor nodules in the ipsilateral lung, which were classified into four categories: (I) single tumors without intrapulmonary metastasis; (II) multiple nodules in different lobes; (III) multiple nodules in the same-lobe; and (IV) multiple nodules across both the same and different lobes. Eight covariates were analyzed: age, sex, race, histologic type, grade, surgery, radiation, and chemotherapy.

Data processing and statistical analysis

Statistical analyses were performed using SPSS version 24 (IBM) for frequency analysis and GraphPad Prism 8 to visualize survival curves, including overall survival and subgroup-specific survival. To assess survival data, life table analysis, Kaplan-Meier survival analysis, and both univariate and multivariate Cox proportional hazards models were employed. Survival distributions across groups were compared using log-rank (Mantel-Cox), Breslow (generalized Wilcoxon), and Tarone-Ware tests. The mean survival times and survival rates at 1, 2, 3, 5, and 10 years were calculated for patients with lung cancer. EmpowerStats software and R (version 4.2.0) were used for multivariate analysis, with adjustments for eight covariates: age, sex, race, histological type, grade, surgery, radiation, and chemotherapy. An adjusted II model was used to account for these covariates in the analysis.

Results

Survival curve

Figure 1A shows the overall survival curve of patients with lung cancer, and Figure 1B shows the disease-specific mortality curve of patients with lung cancer. Figure 1C shows OS stratified by tumor burden. Survival ranked from highest to lowest as follows: single-tumor, same-lobe, multi-lobe, and mixed groups. Figure 1D depicts DSS by tumor group. DSS ranked: single-tumor > same-lobe > multi-lobe > mixed. Figure 2 depicts the Kaplan-Meier survival curves (OS and DSS) for patients with lung cancer stratified by eight covariates: age, sex, race, histologic type, grade, surgery, radiation, and chemotherapy. Figure 2, A2 and B2 illustrate that the survival curves (OS and DSS) of female patients with lung cancer were higher than those of the male patients. Similarly, Figure 2, A4 and B4 show that the survival curves (OS and DSS) for patients with lung adenocarcinoma were higher than those for patients with squamous cell lung carcinoma.

Figure 1 Kaplan-Meier survival curves of lung cancer patients (OS and DSS). (A) OS curve. (B) DSS curve. (C) Prognosis of tumor nodules in different lobes and in the same lobe of the ipsilateral lung for lung cancer (OS). (D) Prognosis of tumor nodules in different lobes and in the same lobe of the ipsilateral lung for lung cancer (DSS). DSS, disease-specific survival; Hist, histological; mets, metastases; OS, overall survival.

Figure 2 Kaplan-Meier survival curves of lung cancer patients stratified by covariates (OS and DSS). (A1) Age stratification (OS); (A2) sex stratification (OS); (A3) race stratification (OS); (A4) histologic type stratification (OS); (A5) grade stratification (OS); (A6) surgery stratification (OS); (A7) radiation stratification (OS); (A8) chemotherapy stratification (OS). (B1) age stratification (DSS); (B2) sex stratification (DSS); (B3) race stratification (DSS); (B4) histologic type stratification (DSS); (B5) grade stratification (DSS); (B6) surgery stratification (DSS); (B7) radiation stratification (DSS); (B8) chemotherapy stratification (DSS). DSS, disease-specific survival; OS, overall survival.

Basic situation and univariate analysis

Table 1 presents the baseline characteristics of each variable, with the data stratified by the early OS and DSS columns. A total of 166,097 participants were included in this study. Table 1 details the stratification for the tumor group variable and the eight covariates. Table 2 presents the univariate analysis results (OS and DSS) for the independent variable, separate tumor nodules in the ipsilateral lung, and eight covariates. Compared to patients with lung cancer aged <60 years, no statistically significant difference was observed in the survival risk of those aged 65–69 years [OS: hazard ratio (HR) =1.016, 95% confidence interval (CI): 0.993–1.040, P=0.18]. However, male patients with lung cancer exhibited increased mortality risks of 29.8% (OS) and 31.8% (DSS). Compared to patients with lung cancer who were identified as white, those who were identified as black had 8.4% and 7.2% higher mortality risks for OS and DSS, respectively. Patients with lung cancer who were identified as Asian and Pacific Islander showed a 9% reduced mortality risk (OS) and a 12% reduction in DSS-related mortality compared to those who were identified as white. Compared with patients with lung adenocarcinoma, those with squamous cell lung carcinoma had a 24% and 32% increased mortality risk for OS and DSS, respectively. Compared with patients with well-differentiated lung cancer, those with undifferentiated, poorly differentiated, and moderately differentiated lung cancers exhibited increased mortality risks of 434.8% (OS) and 319.3% (DSS), 267.1% (OS) and 201.2% (DSS), and 94.3% (OS) and 74.6% (DSS), respectively.

Multivariate analysis (OS and DSS)

Table 3 presents the multivariate analysis of the tumor group variables (OS and DSS). Three covariate adjustment models were used: unadjusted and adjusted for age, sex, race, histological type, grade, surgery, radiotherapy, and chemotherapy. Multivariate analysis, adjusted for eight covariates (age, sex, race, histological type, grade, surgery, radiotherapy, and chemotherapy), revealed that compared to a single tumor without metastasis, the mortality risk increased in the following scenarios: (I) multiple nodules in different lobes, 22.5% (OS) and 27.7% (DSS); (II) multiple nodules in the same lobe, 16.2% (OS) and 17.9% (DSS); and (III) multiple nodules across both the same and different lobes: 35.7% (OS) and 41.8% (DSS).

Tables 4,5 present the stratified multivariate analysis (OS and DSS) of the “separate tumor nodule ipsilateral lung” variable. Tables 4,5 show that, relative to the single-tumor reference, the mixed group carried the highest mortality risk, followed by the multi-lobe and same-lobe groups: (I) male patients exhibited a higher mortality risk [39.3% (OS), 46.4% (DSS)] than female patients [32.2% (OS) 37.3% (DSS)]; (II) Patients who identified as white had a higher mortality risk [38.7% (OS), 45.3% (DSS)] than those who identified as black [31.0% (OS), 37.3% (DSS)] and those who identified as Asian or Pacific Islander [25.8% (OS), 33.7% (DSS)]; (III) patients with squamous cell lung cancer [58.1% (OS), 62.1% (DSS)] exhibited a higher mortality risk than patients with adenocarcinoma [34.5% (OS), 40.9% (DSS)]; (IV) patients with moderately differentiated lung cancer had the highest mortality risk [57.3% (OS), 65.0% (DSS)]; (V) patients who underwent surgery had a substantially higher mortality risk [137.9% (OS), 198.4% (DSS)] than those who did not undergo surgery [30.1% (OS), 35.8% (DSS)]. The mortality risk in patients who received radiotherapy [90.9% (OS), 98.2% (DSS)] was higher than that in those who did not receive radiotherapy [17.5% (OS), 22.0% (DSS)]. The mortality risk in patients with lung cancer who did not receive chemotherapy [51.7% (OS) and 64.0% (DSS)] was higher than that in those who did [19.4% (OS) and 21.9% (DSS)].

Survival rates

Table 6 presents the 1-, 2-, 3-, 5-, and 10-year OS and DSS rates of patients with lung cancer. For the single-tumor group, the OS and DSS rates at 1, 2, 3, 5, and 10 years were 56% and 62%, 43% and 49%, 35% and 43%, 27% and 36%, and 16% and 28%, respectively. For the multi-lobe group, the 1-, 2-, 3-, 5-, and 10-year OS and DSS rates were 39% and 44%, 25% and 29%, 18% and 22%, 12% and 16%, and 5% and 9%, respectively. For patients with separated nodules of the same histological type present in the same lobe of the lung on the same side, the OS and DSS rates were 47% and 53%, 33% and 38%, 25% and 31%, 17% and 23%, and 9% and 17%, respectively. In the mixed group, the OS and DSS rates were 34% and 38%, 20% and 24%, 14% and 17%, 7% and 10%, and 3% and 5%, respectively. For female patients with lung cancer, the OS and DSS rates at 1, 2, 3, 5, and 10 years were 59% and 63%, 45% and 51%, 35% and 44%, 29% and 37%, and 17% and 29%, respectively. For male patients with lung cancer, the 1-, 2-, 3-, 5-, and 10-year OS and DSS rates were 49% and 54%, 35% and 41%, 27% and 34%, 19% and 28%, and 11% and 21%, respectively. The OS and DSS rates at 1, 2, 3, 5, and 10 years for each category of the other variables are detailed in Table 6.

Mean and median survival time

Table 7 presents the mean and median survival times of patients with lung cancer. The single-tumor group showed a mean OS/DSS of 38.988/49.720 months and a median OS/DSS of 17.000/24.000 months. The multi-lobe group showed a mean OS/DSS of 21.572/26.677 months and a median OS/DSS of 8.000/10.000 months. The same-lobe group showed a mean OS/DSS of 28.726/36.366 months and a median OS/DSS of 11.000/14.000 months. The mixed group showed a mean OS/DSS of 16.975/20.288 months and a median OS/DSS of 6.000/7.000 months. The median OS and median DSS of patients with lung cancer aged 65–69 years were longer than those of patients aged 60–64 years. The mean DSS and median DSS of patients with lung cancer aged 65–69 years was longer than that of patients aged 60–64 years. The mean OS and mean DSS of female patients with lung cancer were 41.300 and 50.907 months, respectively, whereas the median OS and median DSS were 20.000 and 26.000 months, respectively. The mean OS and mean DSS of male patients with lung cancer were 30.829 and 40.653 months, respectively, whereas the median OS and median DSS were 12.000 and 16.000 months, respectively. The mean OS and mean DSS of patients with lung adenocarcinoma were 43.967 and 53.060 months, respectively, whereas the median OS and median DSS were 23.000 and 31.000 months, respectively. The mean OS and mean DSS for patients with squamous cell carcinoma were 32.318 and 44.027 months, respectively, whereas the median OS and median DSS were 14.000 and 19.000 months, respectively.

Comparison of overall survival and survival between strata within each variable

Table 8 presents the overall comparison of the variables and the comparison between the categories within each variable using the Kaplan-Meier survival analysis, including the log-rank (Mantel-Cox), Breslow (Generalized Wilcoxon), and Tarone-Ware tests. Pair-wise Kaplan-Meier tests for the tumor group variable were all significant: (I) single-tumor vs. multi-lobe; (II) single-tumor vs. same-lobe; (III) single-tumor vs. mixed; (IV) multi-lobe vs. same-lobe; (V) multi-lobe vs. mixed; and (VI) same-lobe vs. mixed. No significant difference was observed in the survival analysis between patients aged <60 years and those aged 65–69 years. No significant difference was observed in the survival analysis results between patients aged 60–64 years and those aged 70–74 years.