Characteristics of patients with non-small cell lung cancer and either limited or extensive synchronous metastatic spread in Germany—a population-based cancer registry cohort study

Introduction

Background

In Germany, approximately 57,000 individuals are diagnosed with lung cancer [International Classification of Diseases, 10th Revision (ICD-10) C33 and C34] each year. About half of these patients present with distant metastases at initial diagnosis (1). In 1995, Hellman and Weichselbaum (2) were the first to postulate the existence of an oligometastatic stage of the disease in which a limited number of metastases occur in a limited number of organs. Patients with oligometastatic lung cancer represent a highly heterogeneous group. This has repeatedly led to inconsistent definitions of oligometastasis in the many small retrospective analyses. The literature describes at least three different classification approaches: (I) classification of patients with oligometastasis according to synchronous and metachronous oligometastasis in combination with the extent of mediastinal lymph node involvement (3); (II) classification of patients according to tumour volume and histological subgroup (4); (III) classification according to the number of metastases and the number of organs involved. The third classification approach was used in the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project (5), which ultimately led to a change in the 8^th edition of the tumour-node-metastasis (TNM) classification. The revised metastasis (M) category distinguishes between pulmonary and extrapulmonary metastases and, for the first time, between patients with single versus multiple metastases.

Considering the available literature, such as the consensus report on oligometastatic disease by Dingemans et al. (4) and the American Society for Radiation Oncology (ASTRO)/European Society for Radiotherapy and Oncology (ESTRO) guidelines (6) on the use of local therapy in extracranial oligometastatic non-small cell lung cancer (NSCLC), oligometastatic disease is defined as the presence of at least one up to a maximum of five metastases in up to three organs.

However, it remains unclear to what extent these definitions and subclassifications can be applied to a large real-world dataset, and whether subgroups of patients with oligometastases can be reliably identified. Furthermore, it is also uncertain whether survival benefits associated with specific treatments for these subgroups can be evaluated outside of clinical trials.

Rationale and knowledge gap

Numerous (predominantly) retrospective studies have been published describing the impact of local ablative therapies on survival in patients with oligometastatic NSCLC (5)—including only a few with German patients (7-10). However, in the majority of these studies, the sample sizes were rather small, the definitions of oligometastasis (due to the lack of a uniform definition until the year 2020/2019) and the patient populations were heterogeneous, and finally, the generalizability of the results to the entire population of oligometastatic patients is limited due to inclusion criteria, especially in the case of clinical trials.

Objective

This study is part of a series aiming to describe characteristics, treatment patterns, and survival outcomes of patients with stage IV NSCLC with either limited (LMS) or extensive metastatic spread (EMS), based on population-based cancer registry data from Germany. In this first paper, we focus on the characterization of patient subgroups according to the extent of metastatic spread. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-342/rc).

Methods

Study design and data source

The study is registered with the German Register for Clinical Studies under the reference DRKS00028698. This is a retrospective cohort study using data from population-based cancer registries in Germany: Bavaria (South), Hesse (Central), and Schleswig-Holstein (North). Together, these registries cover approximately 27% of the German population. They were selected to ensure regional diversity, thereby enhancing the representativeness of the dataset and supporting the generalizability of the findings.

Cancer registration in Germany is governed by federal law, which was significantly expanded by the Cancer Screening and Registry Act that came into force in April 2013 (11). This legislation mandated the establishment of clinical cancer registries in all 16 federal states, following the recommendations of the National Cancer Plan (12). Since then, all registries have been required to collect standardized information on diagnosis, staging, treatment, and disease progression on the population level (13,14).

The de facto anonymous data were requested from the three cancer registries in March 2022. After receipt (Bavaria: October 2022, Hesse: November 2022, Schleswig-Holstein: March 2022), the data were harmonised, checked for plausibility and pooled.

As cancer registry data does not yet provide information on the exact number of metastases in one location, Dingemans et al.’s definition (4) (a maximum of five metastases in a maximum of three organs) cannot be applied exactly. Instead, we approximated oligometastatic disease (which we termed LMS) and polymetastatic/extensive metastatic spread (EMS) using the number of organ systems involved and the M-categories as defined in 8^th edition of the TNM classification (15).

The following inclusion criteria were defined for the data request: patients diagnosed in the years 2016–2020, age at diagnosis 18 years or older, male or female sex, diagnosis of lung cancer (ICD-10 C34) and place of residence of the patient at the time of diagnosis in the respective federal state.

Patients reported solely by death certificate (DCO cases) were excluded due to zero days of follow-up. Vital status was last updated in June 2021 (Bavaria), May 2020 (Hesse), and February 2022 (Schleswig-Holstein).

For the present analyses, the data were further restricted to NSCLC (see Appendix 1). In addition, coding of tumour stage according to the 8^th edition of the TNM classification system (15) was required, as it is the first to distinguish between patients with single versus multiple metastases. Information on the location of the metastases and their date of diagnosis had to be available. Cases in which the date of first metastasis occurred after the last documented vital status check at the residents’ registration office were also excluded (see Figure 1).

Figure 1 Flow chart. ^†, TNM-M unclear: patients with M1 status and a documented metastasis site, but who cannot be clearly assigned to M1b or M1c. EMOI, extensive multi-organ involvement; ET-LMS, extra-thoracic limited metastatic spread; IT-LMS, intra-thoracic limited metastatic spread; LMOI, limited multi-organ involvement; NSCLC, non-small cell lung cancer; TNM, tumour-node-metastasis; UICC, Union for International Cancer Control.

Definition of synchronous metastatic spread and identification of episodes of metastatic spread during follow-up

Synchronous metastatic disease was defined as the presence of distant metastases diagnosed either at the time of initial tumour diagnosis or within 92 days thereafter. This time frame allowed for the inclusion of cases in which metastases were identified with some delay due to extended staging procedures, thereby ensuring a consistent classification of synchronous disease.

All metastases reported within a 92-day period were combined into a ‘metastases block’. A second ‘metastases block’ was defined if more than 92 days had elapsed between the last reported metastasis in the first block and the first newly reported metastasis in the subsequent block. This approach ensured a clear distinction between patients with up to three organ system involvement and those with more EMS.

Definition of patients with LMS and extensive, polymetastatic spread (EMS) as an approximation of oligo- and polymetastatic disease

The subgroup definition was based on the 8^th edition of the TNM staging system (15) and the information on the site affected by metastasis. It was adapted from the definition proposed in the NSCLC consensus report (4), which considers metastatic disease involving up to three organ systems to be potentially oligometastatic. Based on this framework, patients were grouped as follows:

• Intra-thoracic LMS (IT-LMS): patients with metastases confined to the thoracic cavity, including tumour nodule in the contralateral lung lobe, pleural metastasis or malignant pleural or pericardial effusion. This category corresponds to TNM stage M1a.
• Extra-thoracic LMS (ET-LMS): patients with a single metastasis outside the thoracic region. This category corresponds to TNM stage M1b.
• Limited multi-organ involvement (LMOI): patients with multiple distant metastases involving up to three different organ systems. This category is based on TNM stage M1c and represents a limited metastatic burden.
• Extensive multi-organ involvement (EMOI): patients with metastases in more than three organ systems or those classified as having generalised metastatic disease [coded “GEN” (16)]. This category is based on TNM stage M1c and represents an extensive metastatic burden.

Subgroups 1 to 3 represent an approximation of oligometastatic disease and are collectively referred to as patients with LMS, while subgroup 4 reflects an extensive, polymetastatic disease (EMS).

Statistical analyses

The basic description of the cohort was stratified according to four predefined subgroups reflecting the extent of metastases. We use medians and the interquartile ranges (i.e., the 25^th and 75^th percentiles) to summarize metric data and use absolute and relative frequencies (%) to describe the distribution of nominal and ordinal data. The proportion of missing information for each variable is also reported. Potential sources of bias (e.g., misclassification, limited clinical data) are discussed in section “Strengths and limitations”.

For visualization we use a flow chart and a Sankey diagram.

As the intent of our analysis was mainly descriptive, neither a priori formal sample size calculation nor statistical testing of hypothesis was applied. Data management, analysis and visualization was performed in R (version 4.1.3) (17). The main packages used were tidyverse (version 2.0.0) (18) and ggalluvial (version 0.12.5, Sankey plot) (19).

Ethics

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. In Germany, there is an obligation to register cancer patients. At the time of diagnosis, patients are informed by their doctors about the registration of information on their disease, treatment and the course of the disease in the cancer registry of the respective federal state. The cancer registry laws of the federal states permit the transfer of de facto anonymous data to third parties for the purpose of health services research (11,20-23). At the time of data retrieval from the cancer registries, no ethics vote was required in Germany for analyses based on de facto anonymous data without patient contact. Nevertheless, we reported the research project to the ethics committee of the University of Lübeck. The ethics committee approved the study protocol (file number: Az 22-083).

Results

Data source—applying in- and exclusion criteria

A total of 44,437 individuals diagnosed with lung cancer between 2016 and 2020 were reported to the cancer registries, including 31,180 cases of NSCLC. Of these, about half had distant metastases at the time of diagnosis. After applying the exclusion criteria (see Figure 1), 8,033 patients remained eligible for analysis. Of these, 1,767 had intra-thoracic metastases (IT-LMS), 1,314 had a single extra-thoracic metastasis (ET-LMS), 4,196 had multiple metastases limited to a maximum of three organ systems (LMOI), and 756 had multiple metastases in more than three organ systems (EMOI).

The overall cohort of 44,437 individuals with lung cancer had a median follow-up of 7 months (IQR, 2–18 months), the subgroup NSCLC patients had a median follow-up of 7 months (IQR, 3–16 months). Patients with LMS (i.e., the subgroups IT-LMS, ET-LMS and LMOI) had a median follow-up time of 9 months (IQR, 4–18 months), compared to 5 months (IQR, 2–12 months) in the EMOI group.

During follow-up, 67% patients with LMS and 81.6% patients with EMOI died.

Characteristics of synchronous metastatic NSCLC patients by metastatic extent

A total of 8,033 patients with synchronous metastases were included in the analysis. Of these, 22.0% had intra-thoracic spread (IT-LMS), 16.4% had one single extra-thoracic metastasis (ET-LMS), 52.2% had LMOI and 9.4% of patients had extensive multi-organ or generalised metastases (EMOI). Compared to LMS group (IT-LMS, ET-LMS and LMOI), patients with extensive, polymetastatic disease (EMOI) were younger (median age: 64 years vs. 66–70 years), more often female (45.0% vs. 40.6–41.4%), and had a higher proportion of adenocarcinomas (83.7% vs. 72.2–78.7%). The proportion of patients with N3 lymph node involvement was also higher in the EMOI group (37.8% vs. 22.9–30.4% in the LMS group) (Table 1).

A little more than half of the patients with IT-LMS disease was diagnosed with pleural metastases (54.3%). Among the patients with ET-LMS isolated brain metastases (30.0%) and bone metastases (28.7%) were most common.

In patients with up to three organ systems involved (LMOI), the most common metastatic sites were bone (49.3%), brain (34.4%) and lung (23.6%), patients in the EMOI group presented most often with osseous (75.3%), cerebral (50.8%) and/or pulmonal (53.0%) metastasis. In addition, the adrenal glands (52.0%) and liver (56.3%) were frequently involved in this group.

Median follow-up varied between subgroups, ranging from 10.0 months in the IT-LMS group to 8.0 months (ET-LMS), 7.0 months (LMOI) and 4.0 months in the EMOI group (Table 1).

Characteristics of patients with a second metastatic event after initial synchronous metastatic disease

Approximately one quarter of patients with synchronous LMS (IT-LMS 26.8%; ET-LMS 27.5%; LMOI 25.1%) and one-fifth of patients in the EMOI group (19.7%) developed a second metastatic event during the follow-up period. Among patients with a second LMS event, the proportion of female patients was slightly higher in most subgroups when compared to all patients with initial LMS (differences in proportions ranged between 2.2% and 4.1%), while the difference in the ET-LMS subgroup was marginal (0.1%). On average, patients with a second metastatic event were 2–4 years younger and showed higher proportions of adenocarcinoma and large cell carcinoma with regard to histological subtype (see Table S1).

Sites of second metastatic events after initial synchronous metastatic disease

More than half of patients with a second metastatic event (53.4–56.8%) had metastases outside the thoracic region. However, due to missing TNM-M information—which was only available for the time of the initial diagnosis in our dataset—these cases could not be further classified as either ET-LMS (one metastasis in one organ system) or LMOI (one or more metastases in up to three organ systems). Intra-thoracic manifestation was observed in 23.4% of patients initially classified as IT-LMS and less frequently in other subgroups (ET-LMS: 12.5%, LMOI: 13.2%, EMOI: 12.8%). Metastatic spread to more than three organ systems (EMOI) during follow-up was rare, occurring in only 2.5% to 5.4% of cases (see Figure 2). In most patients, the second metastasis occurred in a different organ than the initial event—regardless of subgroup (see Table S1).

Figure 2 Type of second metastatic event, stratified by extent of synchronous metastasis. EMOI, extensive multi-organ involvement; ET-LMS, extra-thoracic limited metastatic spread; IT-LMS, intra-thoracic limited metastatic spread; LMOI, limited multi-organ involvement.

In all subgroups, the most common sites for second metastatic events were brain and bone. In the IT-LMS group, pleura (18.1%) and lung (17.7%) were also common. Brain metastases predominated in ET-LMS (26.6%) and LMOI (28.2%), while in the EMOI group, brain and bone metastases were equally common (25.5%; see Table S1).

Discussion

Using a real-world data source based on three population-based German cancer registries, we aimed to comprehensively describe the characteristics and the metastatic spread of 7,277 NSCLC patients with synchronous LMS and of 756 NSCLC patients with synchronous extensive, polymetastatic spread.

Key findings and comparison to similar researches

We believe that these are the four most important:

First, the definition of ‘limited metastatic spread” in patients with synchronous metastasis and a clinically meaningful stratification of these patients can be applied to cancer registry data.

While previous studies—which contributed to the revision of the M-category in the 8^th edition of the TNM classification (5)—have highlighted the clinical relevance of distinguishing between intra- and extra-thoracic metastatic patterns, this is, to our knowledge, the first study to describe a large and unselected, population-based cohort of NSCLC patients with either synchronous LMS (subdivided into IT-LMS, ET-LMS and LMOI) as an approximation of oligometastatic disease or with EMOI, which serves as a proxy for extensive, polymetastatic disease. Our study provides a further subdivision of the M1c category according to the number of organ systems involved.

The literature on oligometastatic disease in lung cancer consists mainly of small retrospective studies or meta-analyses derived from these studies. Oligometastatic disease is often defined as the presence of a single synchronous metastasis (7,8). In addition, many clinical trials evaluating treatment options have significant limitations in patient selection, particularly with regard to the location of metastases. For example, the studies by Palma et al. [2020] (24) and De Ruysscher et al. [2018] (25) excluded patients with manifestations of pleural metastases, while the study by Petty et al. [2018] (26) excluded patients with a single pulmonary metastasis. The studies by Hong et al. [2018] (27) and Wang et al. [2023] (28) excluded patients with brain metastases. These limitations are not present in our analysis.

With the introduction of the 9^th edition of the TNM classification (29), published by the Union for International Cancer Control (UICC) in January 2024, the M1c stage was subdivided into M1c1 (multiple extra-thoracic metastases in a single organ) and M1c2 (multiple extra-thoracic metastases in multiple organs). This refinement reflects growing recognition of the clinical relevance of metastatic burden and distribution, and may help to better capture oligometastatic and polymetastatic patterns in future studies. The clinical relevance of the proposed subgroups—that is the question whether this classification is associated with different survival outcomes—both overall survival (OS) and progression-free survival (PFS)—will be discussed elsewhere (REF Bertram et al., companion paper survival, also submitted to TLCR, under review) (30).

However, it should be noted that even with the updated TNM 9^th edition (29), oligometastatic disease is not explicitly defined. While the subdivision of M1c is a step forward, further refinements may be needed to reflect clinically relevant oligometastatic disease criteria, such as the total number of metastases, lesion size, location, and synchronous vs. metachronous presentation.

Second, the baseline characteristics differ across the groups with limited and EMS.

Overall, our NSCLC cohort is comparable to the general lung cancer patient population in Germany in terms of age and sex distribution (1). Overall, about 52% of all incident NSCLC cases in Germany are diagnosed as stage IV. This proportion increases to 59% in the case of adenocarcinomas and reduced to 37% in squamous cell carcinoma (31). In our study with incident NSCLC cases, adenocarcinoma was the most frequent histology subgroup.

When the synchronous LMS subgroups are considered separately the baseline characteristics at the time of primary tumour diagnosis differs in comparison to the EMOI subgroup. Regarding the sex distribution, we observed that the proportion of females was lowest among patients with IT-LMS (40.6%) and highest among patients with EMOI (45%). Patients with EMOI tended to be younger (median 64 years) than patients with LMS (median 66–70 years).

The nodal involvement of the disease increased with the increasing spread of metastases. The majority of patients with synchronous LMS and EMOI had T3/4 or N2/3 disease across all risk groups, with synchronous EMOI patients being up to 14.9% more likely to have N3 disease than synchronous LMS patients. Xie et al. (32) showed in their Surveillance, Epidemiology, and End Results (SEER) database analysis of 77,827 lung cancer patients that higher T and N stages were associated with an increased risk of distant metastases.

Regarding the T stage a study by Shan et al. (33) found in an unselected cohort of 40,196 lung cancer patients that tumour sizes of 3–7 cm were associated with an increased risk of liver metastases, while tumour sizes >7 cm were associated with an increased risk of bone metastases. In addition, the risk of brain and lung metastases increased continuously with increasing primary tumour size. In our dataset, the EMOI group showed a higher incidence of bone and liver metastases, despite having a T-stage distribution comparable to the LMS groups—suggesting that this observation cannot be attributed to differences in primary tumour size alone.

Xie et al. (32) also identified bone metastases as the predominant site. In their review Gobbini et al. (8) found brain metastases in 52% and an osseous manifestation in 27% in patients with synchronous oligometastatic disease. A pattern of metastatic spread that is a little more comparable to that of our ET-LMS group, but with an overall lower prevalence of metastatic spread was described in IASLC (5) with 35.6% osseous, 24.9% brain, 20% adrenal and 12% hepatic metastases in synchronous oligometastatic disease. However, in the IASLC patient group with more than one metastasis (LMOI and EMOI according to our definition), a shift towards osseous metastases was observed. In our high-risk group we observed also a high frequency of osseous metastases, but also a broader distribution across all metastatic sites with no specific organ/site being clearly the most frequently involved site.

It should be noted that the performance status (PS) in our cohort [i.e., Eastern Cooperative Oncology Group (ECOG)] was reported as ‘unknown’ in approximately 50–60% of LMS and EMS patients. When ECOG is reported than the general condition of our patients at the time of the initial diagnosis seems to be reduced (ECOG >2 most frequently reported). In a study by Käsmann et al. (34) investigating PS in patients with UICC stage III lung cancer, the majority of patients had PS 0 (33%) and PS 1 (46%).

Thirdly, approximately one in four patients with synchronous LMS develop a second metastatic event over time, typically presenting as limited extra-thoracic spread. The most common sites involved in the second metastatic event were bones and brain. Given the potential for repeated local ablative therapy, this subset of patients remains of particular clinical interest.

Our analysis suggests that a meaningful proportion of patients with initially synchronous metastatic NSCLC developed a second episode of limited metastatic disease during follow-up. To date, only a few, mostly small case series have been published on secondary oligometastatic disease, typically categorised as either oligorecurrent disease (recurrence of a limited number of metastases after initial curative treatment) or oligoprogressive disease (isolated progression of one or a few metastases during ongoing systemic therapy) (8,35). The systematic review by Gobbini et al. (8) [2021] analysed 31 studies with a total of 2,208 patients with oligometastatic NSCLC. Three of the studies included reported the incidence of oligoprogressive disease, which ranged from 10% to 49%. However, these studies focused primarily on oncogene-addicted subgroups (e.g., EGFR- or ALK-positive patients) and used different definitions of oligoprogressive disease, generally based on a maximum of four or five progressive metastases. For oligorecurrent disease, two studies reported an incidence between 13% and 28%, although these analyses mainly included patients after surgical treatment for early-stage disease (stage I–III). Regarding the organs involved, Gobbini et al. (8) reported that the brain (56%) and bone (33%) were the most common sites of oligoprogressive disease. This distribution is broadly consistent with our findings, in which brain and bone metastases were also the most common sites of second episode of metastases with limited spread.

Our results indicate that approximately 25% of patients developed a second episode of LMS during follow-up. This is in the mid-range of the incidence reported by Gobbini et al. (8) and confirms that secondary limited metastasis is a common event even in an unselected, population-based cohort of synchronously metastatic NSCLC patients.

In addition, studies included in the review suggest that patients with oligoprogressive disease may benefit from local ablative therapies. Weickhardt et al. [2012] (36) described in a cohort of NSCLC patients treated with tyrosine kinase inhibitors that local ablative treatment significantly prolonged PFS (6.2 vs. 2.2 months; P<0.001).

Similarly, Yu et al. [2013] (37) confirmed that targeted local treatment of limited progression could prolong systemic therapy and improve survival.

Although we are not yet able to conclusively distinguish between oligoprogression and oligorecurrence in our cohort due to pending analyses of treatment interventions, it should be emphasised that the subgroup of patients with a second LMS represents a clinically relevant group, both because of its frequency and the potential for subsequent local ablative treatment. In future analyses, we plan to use available treatment data from cancer registries to better differentiate between oligorecurrent and oligoprogressive disease.

Strengths and limitations

Clinical cancer registration is mandatory in Germany (11). In principle, cancer registries are organized on the level of the federal states of Germany. The data (items) collected are standardized throughout Germany (38). Patient follow-up is ensured by physicians reporting disease events such as progression, recurrence or death, by regular comparison/linkage of the cancer registry data with the database of the residents’ registration offices and by reviewing all death certificates of the respective federal state. We used data from three population-based cancer registries for this retrospective cohort analysis. The inclusion of data from three population-based cancer registries covering federal states of different sizes and geographical locations supports the generalisability of our findings.

To our knowledge, this is the first study to characterize a large, unselected population of NSCLC patients with synchronous metastases that approximates oligo- and extensive, polymetastatic disease based on real-world, population-based cancer registry data. The main limitation of using the cancer registry data is that the number of metastases per organ is not consistently recorded in the cancer registries dataset. As a result, it is not possible to (I) accurately determine the metastatic burden, except in cases of ET-LMS at diagnosis, where classification according to the 8^th edition of the TNM system allows this distinction, and (II) to apply the recently published definition of oligometastasis (4,6) directly to our dataset, which would facilitate the transferability of our results and a comparison with other (future) studies.

Due to data protection issues, the cancer registries provided the dates (diagnosis, distant metastasis during the course of the disease, last follow-up date) in the form of month and year. This may introduce bias, as we use a time window of 92 days after initial diagnosis to differentiate between synchronous and late metastatic (metachronous) disease. This temporal inaccuracy can lead to misclassification between synchronous and metachronous disease, although in metachronous cases the median time to first diagnosis is at least 11 months (IQR, 7–17 months; data not shown), so this is likely to affect only a small proportion. However, as the maximal potential inaccuracy is only one month, the overall impact on survival estimates is small. In most cases, survival probabilities are only minimally affected.

The completeness of the dataset is essential for the analysis, as—when using cancer registry data—it is not possible to follow-up individual patients and supplement missing information by reviewing individual patient record files. A substantial number of patients had to be excluded from the analysis because of missing information on treatment and metastatic location. Further, one cancer registry provided information on subsequent metastases (one or more) during follow-up with only one date. This may have led to misclassification of patients with second metastases. Due to limited date resolution in one registry—where multiple metastases in the second metastatic event were recorded with a common date rather than individual time stamps—some patients with a second limited metastatic event may have been misclassified as having EMOI. A sensitivity test excluding this registry resulted in a nearly identical proportion of EMOI cases in the second metastatic event (3.51% vs. 3.67%), suggesting a limited impact of this potential misclassification.

Finally, another limitation of our analysis is the lack of PS (ECOG) data for the majority of patients and the lack of information on molecular tumour characteristics (e.g., EGFR, ALK, KRAS nutation status) for all patients. In addition, the standardised oncology baseline dataset does not include information on other clinically relevant variables such as smoking history, socioeconomic status or comorbidities. All of these factors may have an influence on disease presentation, treatment pathways and survival prospects.

Implications and actions needed

Using real-world data, we identified and characterised a small but therapeutically relevant subgroup of NSCLC patients with limited or EMS. The impact of stratification into four subgroups with different extent of metastatic spread on OS and PFS—as well as the potential benefit of different follow-up treatment strategies after a second metastatic event—requires further investigation.

A modification of the oncological basic data set which would allow to report the exact number of metastases in addition to the organ systems involved, would make the use of population-based cancer registry data even more valuable for the identification and characterization of patients with oligometastatic disease.

Recently, the therapeutic landscape for non-metastatic and metastatic NSCLC has expanded with the emergence of new treatment options and modalities. Consequently, it is necessary to verify whether the results obtained in clinical trials can be confirmed by real-world data. It would also be useful to establish a baseline description prior to the new therapy being used more widely, for comparison purposes. As part of the current research project, a detailed analysis of treatment strategies and their correlation with results is planned. An initial description of patient distribution across different primary treatment types, similar to that of Greystoke et al. (39), can be found on the Open Science Framework (https://osf.io/zrv82/).

Future perspectives

Future research should focus on how cancer registry data can be improved to better support the study of oligometastatic disease in real-world populations. In particular, the exact number of metastases in each organ, as well as the organ systems involved, should be documented more consistently. This would enable a more precise characterisation of metastatic burden and facilitate comparability across studies and with evolving international definitions of oligometastatic disease.

Conclusions

This population-based study demonstrates that it is feasible to stratify NSCLC patients with synchronous metastatic disease into those with limited or EMS using cancer registry data. Our findings reveal that baseline characteristics vary across these subgroups and that approximately one in four patients with LMS at baseline develop a second metastatic event, most commonly involving the brain or bones, but often remaining limited in extent. These findings highlight the importance of refining classification systems for metastatic NSCLC and emphasise the need to further explore treatment strategies and survival outcomes in this therapeutically relevant subgroup. Further analyses of treatment patterns and survival outcomes will be presented in forthcoming papers from this study series.

Acknowledgments

We would like to thank the cancer registries in Bavaria, Hesse and Schleswig-Holstein for providing the data for this research project.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-342/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-342/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-342/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. The study was approved by the Ethics Committee of the University of Lübeck, Germany (No. Az 22-083).

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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