Prognostic significance of the 9th TNM lung cancer staging system in SCLC

Introduction

Small cell lung cancer (SCLC) is a fatal subtype of lung cancer, accounting for about 15% of all lung cancers, characterized by short tumor doubling time, strong aggressiveness, and easy early spread (1,2). About 60–70% of patients present with distant metastases at the time of diagnosis (1,3). Similar to other solid tumors, treatment strategies and prognosis for SCLC are determined by the anatomic involvement at diagnosis. Initially, in the 1950s, SCLC was divided into limited stage and extensive stage by the Veterans’ Administration Lung Study Group (VALSG) classification system based on whether the tumor was confined to one hemithorax and could be included in one radiation field (4). Chemoradiotherapy remains the primary treatment modality for limited-stage SCLC (LS-SCLC), while chemotherapy is the main treatment for extensive-stage SCLC (ES-SCLC). However, in 1989, the International Association for the Study of Lung Cancer (IASLC) revised the VALSG classification to include patients with unilateral hemithoracic tumors with hilar, ipsilateral and contralateral mediastinal, and ipsilateral and contralateral supravicular lymph node metastases as LS-SCLC (5). Moreover, patients with ipsilateral pleural effusion should be considered as LS-SCLC if no extrinsic metastasis is detected, regardless of cytology results. However, modern imaging and treatment approaches have provided growing evidence that the VALSG classification system has limited prognostic and therapeutic utility. Hence, a more precise definition of lymph node involvement may facilitate the development of precise radiotherapy plans for SCLC (6-9). In addition, some LS-SCLC patients could benefit from surgical treatment. Notably, some studies suggested that LS-SCLC patients with pathological stage N₀ exhibited a longer survival than those with N₁ and N₂, suggesting that the TNM classification system was also applicable to SCLC patients (6,10).

The 7th edition of the tumor-node-metastasis (TNM) classification for lung cancer was published in 2007, which was recommended for SCLC, and stage I–III was recommended as a stratification factor in clinical trials of LS-SCLC (11,12). The 8th edition of TNM classification for lung cancer mainly brought revisions to the T and M categorization, based primarily on data from non-small cell lung cancer (NSCLC) cases. Notably, the analysis included 5,002 patients with SCLC, which showed that the classification was also applicable to SCLC (13,14). The 9th edition of the TNM classification was officially launched in 2024. Compared with the 8th TNM classification, one of the major changes in the 9th TNM classification is the subdivision of N₂ into N_2a (single ipsilateral mediastinal or subcarinal nodal station) and N_2b (involvement of multiple ipsilateral mediastinal nodal stations) (15). Another change is the subdivision of the eighth version of M_1c into M_1c1 (multiple extrathoracic metastases in one organ system) and M_1c2 (multiple extrathoracic metastases in multiple organ systems) (15). In the 9th edition, 87,043 patients were evaluated, including 73,197 patients with NSCLC and 5,530 patients with SCLC. Compared with the data of the 8th edition, the number of NSCLC patients was roughly similar, while the number of SCLC patients was slightly lower (16). Among NSCLC patients, 58,193 patients were subjected to clinical staging, and 39,192 patients had pathological staging. Among the SCLC patients, 4,453 were subjected to clinical staging, while only 583 patients had pathological staging (16). Furthermore, differences in the composition ratios of each stage of NSCLC and SCLC were observed. According to the classification of the 9th edition, in terms of clinical staging, stage I_A accounted for 40%, while stages IV_A and IV_B accounted for 14% and 13% of NSCLC, respectively. In SCLC, stage I accounted for 11% of cases, and stage VI accounted for 64% (16). The major changes in the 9th edition—the subcategories of N₂ and M_1c—were proposed based on the data analysis of NSCLC and were also confirmed in SCLC. The major revisions in the 9th edition for NSCLC were supported by significant differences in overall survival (OS) between the two new subcategories (N_2a and N_2b), both in terms of clinical staging and pathological staging. The 5-year OS rate of the N_2a and N_2b subcategories showed a difference exceeding 10%. In SCLC, due to the limited patients with pathological staging, the newly proposed N₂ subcategories were only confirmed by the clinical staging. A significant difference in the median OS was observed between N_2a and N_2b. However, the difference in the 2-year OS rate was only 5% (17). In NSCLC, the median OS of M_1c1 and M_1c2 was 1.0 year and 0.6 year, respectively. The 2-year OS rates were 27% and 19%, respectively, showing a significant difference (15). In SCLC, the median OS of M_1c1 and M_1c2 was 0.7 years and 0.6 years, respectively. The 2-year OS rates were 10% and 5%, respectively (17). Despite the significant difference in the median OS, the clinical significance of this difference remains questionable. However, compared with the clinical stage data of 58,108 patients with NSCLC (16), the data of SCLC remain limited, with only 2,244 Asian patients with SCLC (17). Therefore, additional data are needed to evaluate the prognostic accuracy of the 9th edition for SCLC patients, especially Asian-Chinese patients. This study aimed to evaluate prognostic utility of the 9th edition of the TNM classification in a retrospective SCLC cohort. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1031/rc).

Methods

Patients

This is a retrospective analysis of SCLC patients with histological or cytological diagnoses and complete imaging staging between January 2014 and December 2021. The main exclusion criteria were: (I) lack of follow-up information; (II) no adequate imaging examination; (III) patients with malignant tumors other than SCLC; (IV) the patient had not received anti-tumor treatment at this center, and it was impossible to obtain information about the patient’s anti-tumor treatment at other centers. Patients who underwent surgical treatment were reclassified into pathological stages based on the pathological results. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and only de-identified patient data were analyzed. This study was approved by the Ethics Committee of Jilin Cancer Hospital (No. 202505-002-01). Informed consent was waived due to the retrospective nature of the study.

Statistical analysis

All statistical analyses were performed using SPSS software, version 26, and bar charts were generated using GraphPad Prism 10.1.2. The enumeration data were expressed as numbers and percentages (%). Kaplan-Meier methodology and log-rank statistics were utilized to estimate OS. Cumulative survival rates were calculated by the life table method, and the multivariable Cox regression analysis was performed by the Forward: LR method. A two-sided P value of less than 0.05 was considered statistically significant. Missing data were excluded from the analysis.

Results

Patient characteristics

A total of 2,043 patients diagnosed with SCLC were identified and subjected to initial screening. Based on exclusion and inclusion criteria, 1,329 patients were eligible (Figure S1). All patients underwent clinical staging, and pathological staging was available on 51 patients. The characteristics of the patients are summarized in Table 1. The median age at diagnosis was 62 years. Among all patients, 834 (62.8%) were male, and 862 patients (64.9%) were smokers. A total of 309 patients underwent positron emission tomography-computed tomography (PET-CT) examination as part of staging. All patients received medication, and 32.3% patients received thorax radiotherapy. Only a very small number of patients (n=51) underwent surgery. At diagnosis, 717 (54.0%) patients were classified as LS-SCLC and 612 (46.0%) as ES-SCLC. The median follow-up time was 39.67 months (95% CI: 36.28–43.06), and the median OS in the general population was 15.40 months (95% CI: 14.45–16.35). The median OS for LS-SCLC and ES-SCLC was 21.77 months (95% CI: 19.86–23.69) and 12.00 months (95% CI: 11.20–12.80), respectively (Figure 1). Immunotherapy has emerged as the most significant advancement in the treatment of SCLC in recent years, establishing a new treatment paradigm. Therefore, based on the Food and Drug Administration (FDA) approval of atezolizumab in combination with chemotherapy as a first-line treatment for ES-SCLC, the survival outcomes of patients before 2019 and those after 2019 were analyzed. However, before 2022, only atezolizumab and durvalumab were approved for first-line treatment of ES-SCLC in China. Due to the high cost of these two drugs, the number of patients receiving immunotherapy combined with chemotherapy was very limited in our center before 2022. Before 2019, a total of 586 patients were included, with a median OS of 15.33 (95% CI: 14.04–16.62). After 2019, a total of 743 patients were included, with a median OS of 15.47 (95% CI: 14.11–16.83). The median OS of patients after 2019 was longer compared to that of patients before 2019 (P=0.002). Moreover, the survival of patients was analyzed based on different treatment regimens (Figure S2 and Table S1).

Figure 1 Overall survival of LS-SCLC and ES-SCLC. CI, confidence interval; ES-SCLC, extensive-stage small cell lung cancer; LS-SCLC, limited-stage small cell lung cancer; mOS, median overall survival.

The distribution of patients according to the 8th and 9th editions is shown in Table 2. No significant difference in the proportion of stage I and IV patients was observed between the two editions. The proportion of stage II patients increased from 4.6% in the 8th edition to 5.3% in the 9th edition, in which the proportion of stage IIA patients increased and the proportion of stage IIB patients decreased. Compared with the 8th edition, the proportion of stage III patients in the 9th edition decreased slightly (45.4% and 44.8%, respectively). Specifically, the proportion of stage IIIA patients decreased, and the proportion of stage IIIB patients increased. A total of 90 stage IIIC patients were found. Moreover, the cohort included 402 patients with M_1c, 202 patients with M_1c1, and 200 patients with M_1c2 according to the 9th edition.

T-component

In this cohort, no patients had primary tumors classified as T₀ and T_X. A total of 74 patients had T₂ tumors that could not be measured and could not be further classified into T_2a or T_2b due to obstructive pneumonitis or atelectasis. The proportion of patients with primary tumor T₁ in SCLC was very small (10.1%), with most patients having primary tumor T_3–4 (24.9% and 34.2%) (Table S2).

N-component

In terms of N categorization, the majority of patients were classified as N₂ and N₃, with N₂ accounting for 52.1%, further divided into N_2a (193 patients, 14.5%) and N_2b (500 patients, 37.6%). N₃ was found in 31.7% of patients. Only 10.7% of patients had no lymph node involvement. In addition, the proportion of patients with N₁ was also only 5.5% (Table S3).

Survival analysis indicated that the median survival showed a decreasing trend with higher N-classification. Patients with N₂/N₃ demonstrated a poorer prognosis compared to those with N₀/N₁. Notably, N₂ was subdivided into N_2a and N_2b in the 9th edition. The median OS of patients with N_2a and N_2b was 20.00 months (95% CI: 16.14–23.86) and 14.53 months (95% CI: 12.88–16.18), respectively. Moreover, the 3-year survival rate was 22.9% and 14.6%, respectively. Patients with N_2b exhibited a poorer prognosis (P=0.002), as shown in Figure 2.

Figure 2 OS according to the detailed clinical N categories by the 8th (A) and 9th (B) edition. mOS, median OS; OS, overall survival; cTNM, clinical tumor-node-metastasis stage.

M-component

In our cohort, 46.0% (612) of patients had distant metastases, most of whom were M_1c (402/596). In the 9th edition, M_c1 was subdivided into M_1c1 and M_1c2. A total of 202 patients were categorized as M_1c1 and 200 patients as M_1c2 (Table S4). In both the 8th and 9th editions, the median OS gradually decreased as the M-category increased, but no significant difference in median OS was observed between M_1c1 and M_1c2 in the 9th edition (P=0.13) (Figure 3).

Figure 3 OS according to the detailed clinical M categories by the 8th (A) and 9th (B) edition. mOS, median OS; OS, overall survival; cTNM, clinical tumor-node-metastasis stage.

TNM stages

In the 8th and 9th TNM editions, the median OS, 1-, 2-, and 3-year OS rates gradually decreased with advancing stages. The median OS of patients with stage I was numerically longer than that of stage II in the 9th edition, but the results did not reach statistical significance. OS showed a progressively deteriorating trend with advancing TNM stages in the ninth edition, except for stages II_A and IV_A. However, only III_B and III_C, IV_A and IV_B demonstrated significant differences in median OS. The 3-year survival rate decreased gradually from IA₂ to IV_B (Figure 4).

Figure 4 OS according to (A) the 8th edition and (B) the 9th edition of clinical TNM stage grouping. mOS, median OS; OS, overall survival; TNM, tumor-node-metastasis.

SCLC-pathologic stage

Clinical and pathological staging data were available for 51 patients. The results revealed 22 cases in stage p-I, 15 cases in stage p-II, and 14 cases in stage p-III according to the 8th and 9th TNM editions (Table S5). Due to the very limited sample size, survival staging based on the TNM classification system was not conducted, and the OS of 51 patients was 45.77 months (95% CI: 18.06–73.48) (Figure S3). The median DFS was 25.90 months (95% CI: 15.86–35.94).

Univariate and multivariate analysis of clinical characteristics

The univariate analysis indicated that age ≥65 years, smoking history, ECOG PS score ≥2, stage III, and stage IV were significantly associated with OS. Patients who underwent PET-CT showed a significant association with better survival compared to patients who did not undergo PET-CT. In the multivariate analysis, age ≥65 years, ECOG PS score ≥2, stage III, and stage IV were independent adverse prognostic factors, and the later the stage, the higher the risk of death (Table 3).

Discussion

The TNM classification system is the most widely used tumor classification system and has become an international standard for conveying information about the extent of lung cancer invasion and prognosis. As an important consideration in clinical decision-making and clinical research, the TNM classification has been recommended for use in SCLC cases since the 7th edition. The staging systems in the 7th and 8th editions have been validated using the IASLC database and external datasets specific to SCLC, respectively. The 9th edition of the TNM classification of lung cancer was published in 2023, and the results of IASLC database analysis support the recommendation of TNM classification for SCLC, especially clinical classification (17). However, the applicability of the 9th edition of the TNM classification for SCLC lacks external validation using large samples, particularly in Chinese SCLC patients. Therefore, data from 1,329 SCLC patients from a single center were collected and re-staged according to the 9th edition. External validation was conducted to evaluate the applicability of the 9th edition of the TNM classification in Chinese SCLC patients. To our knowledge, the present study is the largest external validation study for the 9th edition of the TNM classification in SCLC patients.

In clinical practice, the N classification impacts treatment selection and prognosis assessment. The number, location, and fusion of involved lymph nodes contribute to the complexity and heterogeneity of the N classification. In the 8th edition update, stratification was further divided based on the number of involved lymph nodes, with N₁ representing single sites and N₂ indicating multiple sites. The number of lymph nodes involved affected prognosis in the pathological stage, but this finding could not be confirmed in the clinical stage (18). One of the major revisions in the 9th edition of the TNM classification is that N₂ and M_1c are divided into new subgroups. Among patients with NSCLC, the 9th edition introduces the subgroups N_2a and N_2b, which identify prognostically distinct groups of tumors based on the analysis of the IASLC database of the 9th edition (19). The survival curves of SCLC patients showed clear separation between the N_2a and N_2b subgroups based on the N classification data (17). However, similar evaluation for patients with pathologic N data could not be conducted due to the small sample size (17). Our study confirmed a significant difference in survival between patients with single-station nodal involvement (N_2a) and multi-station nodal involvement (N_2b), consistent with results from the IASLC database.

The N2 category encompasses a wide range of clinical scenarios, including the number of involved lymph nodes, the number of metastatic nodal stations, the external lymph node invasion, the size of metastatic lymph nodes, and the presence or absence of skip metastasis. Differentiating between the N_2a and N_2b categories in NSCLC may lead to different treatment decisions. Nonetheless, single-site or multi-site N₂ lymph node involvement has not been included in clinical decision-making for SCLC in current clinical practice. However, a retrospective study reported that the number of p-N₂ lymph nodes was strongly associated with time to recurrence (P=0.001) and OS (P<0.001), the pN₂ patients with multi-station lymph node metastases showing shorter DFS (20). In our study, for both the 8th and 9th editions of the TNM classification, the median OS and 1-, 2-, and 3-year survival rates demonstrated a gradually worsening trend with advancing N stage, regardless of the 8th or 9th edition. However, no statistically significant difference was observed between the median OS of N_2a and N₁. This may be partly attributable to the small sample of patients with stage N₁ and partly to the presence of skip metastases within the N_2a subgroup. A retrospective study analyzed 176 SCLC patients with pathological stage T_1–4N_1–2M₀ (21). After propensity score matching (PSM), cancer-specific survival was assessed in 32 pairs of patients with the N₂ and skip-N₂ stages, and 34 pairs of patients with the N₁ and skip-N₂ stages. The study revealed that the cancer-specific survival of patients with skip-N₂ was better than that of patients with non-skip-N₂. No significant difference in survival rate was observed between pN₁ and skip-N₂ patients (21). In addition, another study revealed that patients with pN₂-SCLC with involved subcarinal lymph node had shorter survival times (22). These studies suggest that additional data are needed to further evaluate the effect of skip metastases and subcarinal lymph node involvement on the prognosis of SCLC categorized as stage N₂.

Furthermore, the 9th edition introduces the division of the M_1c stage into two subcategories, namely M_1c1 (multiple metastases in a single extrathoracic organ system) and M_1c2 (metastases in multiple extrathoracic organ systems) (15). The analysis of the data of the 8th edition TNM classification suggests that patients with single-site metastasis (SSM) without pleural effusion or patients with brain metastases only in SCLC have better survival than patients with multi-site lesions or pleural effusion (13). However, whether this difference is due to the greater opportunity for SSM patients with brain metastases to receive radiotherapy for metastases, or whether the prognosis is different due to the extent of disease metastasis, remains undetermined. This also suggests that even patients with metastatic SCLC may benefit from local treatment, but such patients should be highly selective. In our study, the median OS of M_1c of M_1c1 was longer than that of M_1c2, and the 1-, 2-, and 3-year survival rates were higher, but it did not reach statistical significance. A recent retrospective study of 439 patients with ES-SCLC did not confirm a significant difference in progression-free survival (PFS) and OS between M_1c1 and M_1c2 (23). The sample size of our study was very limited compared to the SCLC database of the 9th edition of the TNM classification of lung cancer. In addition, previous studies also reported that patients with no more than 5 metastases in a single organ had significantly different OS from SCLC patients with more than 5 metastases in a single organ and multiple organ metastases (24). Oligometastasis (25), in which tumor metastasis is still confined to one organ and the number of metastases is small (usually 1 to 5), may also be a factor for future staging. The combination of systemic treatment and local treatment may achieve long-term disease control and even clinical cure (26). For SCLC patients with oligometastasis, the addition of local treatment to drug therapy has gradually attracted attention, and related studies are also in progress (27). Although distant metastasis is fatal, chemotherapy combined with thoracic radiotherapy can improve the 2-year survival rate of ES-SCLC (28). Considering the availability of immunotherapy, studies have reported that thoracic radiotherapy plus immunotherapy and chemotherapy show promising efficacy and acceptable safety (29), suggesting that the addition of local treatment to drug therapy for selected ES-SCLC patients may enhance survival outcomes. In addition to the analysis of biological characteristics, distinguishing patients with single metastasis or limited metastasis in a single organ from patients with single other diffuse metastasis or multiple organ metastasis may represent a simple method to screen patients with ES-SCLC eligible for drug therapy in combination with local therapy. Moreover, whether oligometastases can be included in future TNM classification to guide prognosis assessment and treatment strategy selection of SCLC is also worth further exploration.

Nevertheless, the limitations of the present study should be acknowledged. First, our study is a single-center retrospective study with unavoidable selective bias. Second, the sample size of some subcategories is limited. Patients with I_A1 stage were lacking in our study, and no significant difference in prognosis was found between stage I_A2–II_B patients. Furthermore, only 90 patients with stage III_C were included in the analysis, and the prognosis of these patients requires further evaluation. Third, our study included patients from 2014 to 2021, during which the treatment options for SCLC have changed. For example, after 2018, phase 3 studies of programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor plus chemotherapy for first-line treatment of ES-SCLC were published, and PD-1/PD-L1 inhibitor plus chemotherapy emerged as the new standard treatment for ES-SCLC. In addition, anlotinib, a multi-target angiogenesis inhibitor, was approved as third-line and post-line treatment of SCLC in China in 2019; these treatment options have enhanced OS in SCLC. Our study did not have uniform protocol requirements for patients’ treatment choices, and no year-by-year survival analysis was conducted. Fourth, only the correlation between TNM classification and OS was analyzed, while the correlation between TNM classification and cancer-specific survival was not studied. These factors should be further improved in future studies.

Conclusions

The results from this retrospective study further validate a significant difference in prognosis between the N_2a and N_2b subgroups in the 9th edition of the TNM classification. In this cohort, no statistical difference was found between the stages M_1c1 and M_1c2, which suggests that the 9th edition of the TNM classification requires further external validation. We hold the opinion that incorporating limited metastasis in a single organ as a factor in the future staging system may prove beneficial.

Acknowledgments

We thank the Home for Researchers editorial team (www.home-for-researchers.com) for language editing service.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1031/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1031/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1031/prf

Funding: This work was supported by the National Cancer Center Climbing Fund (No. NCC202407004).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1031/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Jilin Cancer Hospital (No. 202505-002-01). Informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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