Best supportive care in stage I–III non-small cell lung cancer: survival by reason for curative treatment omission in a real-world study population

Introduction

Non-small cell lung cancer (NSCLC) represents the most common form of lung cancer, comprising approximately 85% of all lung cancer cases (1). Current main treatment modalities regarding local and regional NSCLC are curative resection, radiation therapy and chemoradiation followed by adjuvant immunotherapy (2-4). More recently, new treatment strategies involving neoadjuvant and perioperative immune checkpoint inhibitors (ICIs) have become standard of care in patients with resectable NSCLC (5-9). Despite these advances, a proportion of patients are considered not eligible for cancer treatment with curative intent. In addition, a subgroup of patients may choose not to pursue with active cancer therapy and instead prefer best supportive care (BSC). In a nationwide population-based study performed in the Netherlands, primary BSC alone was administered in nine, fifteen and twenty-five percent in clinical stage I, II and III NSCLC, respectively (10). These data are comparable to a recently published, large real-world English cohort whereof respectively, fourteen, fifteen and twenty-four percent of patients with stage I, II and III NSCLC did not receive curative-intent treatment (11).

Despite growing recognition of the importance of personalized patient-centered care, understanding outcomes and prognoses in patients with locoregional NSCLC receiving primary BSC remains a critical knowledge gap in current literature. Primary BSC decision-making is often based on individual patient characteristics and patient preferences (12). There is a growing emphasis on shared decision-making by healthcare providers, encouraged by for instance the Dutch Government (13,14). In this patient-centered approach, discussing primary BSC based on patient preference is also common in the context of locoregional NSCLC, even if curative treatment options are available. Recognition of detailed survival outcome data may improve the quality of clinical judgment in the outpatient setting.

In our study, we analyzed survival outcomes in patients with stage I–III NSCLC treated with primary BSC compared with patients treated with curative intent. Patients receiving primary BSC were stratified by main decisive factor for treatment omission, including patient preference, insufficient performance status or relevant comorbidities, to provide clinically relevant outcome data for shared treatment decision-making. The first main objective was to investigate median OS in the total curative-intent treatment cohort versus the total primary BSC cohort. The second objective was to compare median OS across the primary BSC cohort based on own preference versus other decisive factors. Finally, we calculated lung cancer-specific survival (LCSS) in the total curative treatment cohort, the total primary BSC cohort and across the BSC subcohorts. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0327/rc).

Methods

Study population

We performed a retrospective observational cohort study involving real-world data. Consecutive patients with stage I–III NSCLC diagnosed between 2015 and 2019 were included. Patients were diagnosed in regional hospitals within regional Lung Cancer Networks*, located in the South-Eastern part of the Netherlands. All included patients were registered in the Dutch Lung Cancer Audit (DLCA; https://dica.nl/). Missing data were traced and restored by inspection of local electronic patient files. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the review board of the Dutch Clinical Research Foundation (DCRF) (No. MK-3475/NIS101592). All participating hospitals were informed of and agreed to the study, which waived the requirement of individual informed consent due to its retrospective nature and inclusion of a large patient cohort.

Definitions and scope

BSC was defined as treatment administered to maximize health related quality of life (HR-QOL) without active anti-cancer treatment, representing the biological course of disease (15). Curative treatment was considered any main treatment strategy applied with curative intent. Locoregional NSCLC was defined as clinical stage IA until IIIC disease according to the Union for International Cancer Control/American Joint Committee on Cancer/International Association for the Study of Lung Cancer (UICC/AJCC/IASLC) Tumor-Node-Metastasis (TNM) classification 7th and 8th edition, depending on year of diagnosis (16). Follow-up duration was calculated by time between date of diagnosis and date of death, loss to follow-up or latest visit at the outpatient oncology clinic. Overall survival (OS) was defined as time from diagnosis until date of death. LCSS was defined as time from diagnosis to death due to lung cancer. Patients who were alive at latest follow-up or who died from causes other than lung cancer were censored. At least a period of 4 years of follow-up was endorsed: patients were diagnosed until 2019, and follow-up was realized until December 2023. Patients receiving primary BSC were typically referred to primary care, limiting follow-up data availability. For each included patient, tumor and patient characteristics, demographic information, diagnostic approach, type of treatment and the Charlson comorbidity index (CCI) were documented (17).

BSC and etiology

Although decision-making for BSC treatment is inherently multifactorial, a main single predominant determinant was identified for each patient: (I) an insufficient Eastern Cooperative Oncology Group performance score (ECOG PS); (II) relevant comorbidities; (III) patient preference; and (IV) unknown category. BSC based on patient preference was retrospectively defined as the request of primary BSC by the patient or their designated surrogate decision maker(s) as noted by the treating physician.

Statistical analysis

Continuous variables were summarized as mean ± standard deviation (SD) and median (range). Comparisons between groups were performed using Pearson’s Chi-squared test for categorical variables and Student’s t-test or analysis of variance (ANOVA) for continuous variables. OS and LCSS were estimated by treatment group. Survival outcomes were analyzed using the Kaplan-Meier method and compared with log-rank tests. In the LCSS analysis, deaths attributable to NSCLC were classified as events, while deaths from other causes and censored cases were considered non-events. The Cox proportional hazard regression model was used to determine hazard ratios (HRs) with adjustment for age at diagnosis, gender, smoking status, ECOG PS, CCI (manually categorized into mild, moderate and severe), clinical stage and histopathology. We designated these variables considered to be clinically relevant; these features did not arise from a univariate analysis process. Statistical analyses were conducted using SPSS version 29.0 and GraphPad Prism version 10.2.2. Two-sided P values of <0.05 were considered statistically significant.

Results

Baseline characteristics

In total, 1,943 patients diagnosed with clinical stage I to III NSCLC were included. Patients who received treatment with palliative intent were excluded from our study. The remaining 1,895 patients were divided into a primary BSC cohort (n=234) versus curative treatment cohort (n=1,661) (Table 1). BSC was administrated in 27 patients with clinical stage I disease (3.4%), 34 patients with clinical stage II disease (9.6%) and 173 patients with stage III disease (23.2%). Based on main decisive factor, the BSC cohort was divided into subgroups: insufficient ECOG PS (n=102, 44%), relevant comorbidities (n=43, 18%), patient preference (n=82, 35%) and unknown etiology (n=7, 3%) (see Figure 1 and Table S1). In the cohort of patients opting BSC, 25 patients were diagnosed with stage I–II disease and 57 with stage III disease.

Figure 1 Flowchart of the study. Patients participating in a clinical trial, being diagnosed before 2015 or patients with clinical stage 0 or IV NSCLC were excluded from the study. Patients with clinical stage I–III disease receiving palliative systemic treatment were excluded. BSC, best supportive care; ECOG PS, Eastern Cooperative Oncology Group performance score; NSCLC, non-small cell lung cancer.

OS in total study population

Median follow-up duration in the total study population (n=1,895) was 58.5 months. In total, 828 events of death were observed. The median OS was 44.6 months [95% confidence interval (CI): 40.9 to 48.3].

In the curative treatment cohort, median OS was 54.1 months compared to 5.9 months in the total BSC cohort (HR 0.12, 95% CI: 0.11 to 0.15; P<0.001) (Figure 2A). A significant survival gap was observed after OS comparison in the curative treatment versus the BSC cohort based on patient preference: 54.1 versus 9.6 months (HR 0.17, 95% CI: 0.13 to 0.22; P<0.001) (Figure 2B). This result remained significant after correction for relevant confounders (HR 0.39, 95% CI: 0.29 to 0.52 P<0.001). When comparing the BSC cohort based on patient preference (n=82) versus other decisive factors (n=152) median OS was significantly higher in the BSC patient preference cohort: 9.6 versus 4.3 months (HR 0.56, 95% CI: 0.42 to 0.75; P<0.001) (Figure 2C), persistent after correction for relevant covariables (HR 0.5895% CI: 0.41 to 0.80; P=0.001).

Figure 2 Overall survival in patients after curative treatment versus primary BSC. (A) OS in the total curative treatment cohort (n=1,661) versus the primary BSC cohort (n=234). (B) OS in the total curative treatment cohort (n=1,661) versus the primary BSC cohort based on patient preference (n=82). (C) OS in the primary BSC cohort based on patient preference (n=82) versus the BSC cohort based on other decisive factors (n=152). BSC, best supportive care; CI, confidence interval; HR, hazard ratio; mOS, median overall survival; OS, overall survival.

OS stratified to stage

Among patients with clinical stage I–II disease (n=1,150), median OS was longer in the curative treatment cohort than in the BSC cohort (66.6 versus 8.2 months; HR 0.13, 95% CI: 0.10 to 0.18; P<0.001). Similar findings were observed in the patient-preference analysis (66.6 versus 16.8 months; HR 0.17, 95% CI: 0.11 to 0.27; P<0.001) (Figure 3A). The survival gap remained significant after adjustment (HR 0.47, 95% CI: 0.28 to 0.78; P=0.004).

Figure 3 Survival rates between primary versus curative treatment cohort stratified to clinical stage. (A) OS in the total curative treatment cohort (n=1,089) versus the primary BSC cohort (n=25) in patients with stage I–II disease. (B) OS in the total curative treatment cohort (n=572) versus the primary BSC cohort (n=57) in patients with stage III disease. BSC, best supportive care; CI, confidence interval; HR, hazard ratio; mOS, median overall survival; OS, overall survival.

In the clinical stage III cohort (n=745), median OS was 31.8 versus 5.2 months in the curative treatment versus BSC cohort (HR 0.18, 95% CI: 0.14 to 0.21; P<0.001). The patient-preference analysis yielded comparable results (31.8 versus 8.8 months; HR 0.25, 95% CI: 0.18 to 0.33; P<0.001) (Figure 3B), persisting after adjustment (HR 0.33, 95% CI: 0.22 to 0.49; P<0.001).

LCSS comparison

In the curative treatment cohort, median LCSS was not reached compared to 8.9 months in the total BSC cohort (HR 0.11, 95% CI: 0.09 to 0.14; P<0.001) (Figure 4A) and 16.4 months in the BSC cohort based on patient preference (HR 0.15, 95% CI: 0.11 to 0.21; P<0.001) (Figure 4B). The survival disparity in the curative treatment cohort versus the BSC cohort by patient preference remained significant after correction for relevant confounders (HR 0.29, 95% CI: 0.20 to 0.44; P<0.001). When comparing the BSC cohort based on patient preference versus other decisive factors, median LCSS was significantly higher in the BSC patient preference cohort: 16.4 versus 7.2 months (HR 0.57, 95% CI: 0.40 to 0.83; P=0.003) (Figure 4C). However, this disparity was not pursued after correction for relevant covariables (HR 0.68, 95% CI: 0.44 to 1.063; P=0.09).

Figure 4 Lung cancer specific survival in patients with curative-intent therapy versus primary BSC. (A) LCSS in the total curative treatment cohort (n=1,661) versus the primary BSC cohort (n=234). (B) LCSS in the total curative treatment cohort (n=1,661) versus the primary BSC cohort based on patient preference (n=82). (C) LCSS in the primary BSC cohort based on patient preference (n=82) versus the BSC cohort based on other decisive factors (n=152). BSC, best supportive care; CI, confidence interval; HR, hazard ratio; LCSS, lung cancer-specific survival; NR, not reached.

Discussion

In our study population of 1,895 patients with confirmed stage I–III NSCLC disease, in 3.4%, 9.6% and 23.2% BSC was administrated in the stage I, II and III subcohorts, respectively. These proportions were consistently lower than those reported in a previous nationwide population-based study from the Netherlands (10), most pronounced in stage I and II disease.

A significant survival advantage was observed in patients treated with curative intent compared with those receiving primary BSC, even after correction for relevant confounding factors. These survival gaps were observed both in the overall study population and after stratification by clinical stage. Median OS was 5.9 months in the total BSC cohort, 8.2 months in the stage I–II cohort and 5.2 months in the stage III cohort. Similar results were observed in a Dutch retrospective cohort [2019]: median OS was 14 months (stage I) and 5.3 months (stage II) in patients with NSCLC treated with BSC (aged 64 to 75 years) (18). In our analyses, interpretation of stage-stratified multivariable analyses should be cautious due to the limited sample size of the BSC cohort.

We showed a survival benefit across patients treated with BSC by their own preference versus other main decisive factors. Stratifying patients based on the principal decisive factor facilitates a nuanced understanding of survival effects in the BSC population. Although BSC may be inevitable in certain cases within this subcohort, curative-intent therapy may not be absolutely contraindicated in a substantial proportion of patients. To our knowledge, this is the first report with a detailed analysis of patients with stage I–III NSCLC and primary BSC showing the potential loss of life years by absence of curative-intent treatment.

Several factors may have influenced treatment decisions in patients with stage I–III NSCLC who received primary BSC. First, in the patient preference subgroup, quality of life could have been preferred over life extension. Maintaining quality of life and independence were substantially higher valued than survival in a study of Sullivan and colleagues (19). A substantial part of patients was not willing to accept severe deficits affecting quality of life when considering treatment. Second, the medical culture in the Netherlands is generally known for its shared decision-making practice in general and in oncology health care (20). Patients suffering from lung cancer in the Netherlands can rely on a well-developed palliative care system and cultural openness toward discussing end-of-life decisions, possibly influencing early transitions to primary BSC (21,22). Other contributing factors in this decision-making process involve excessive anxiety for anticancer treatment, desire for control, skepticism on the likelihood of cure and spiritual beliefs emphasizing natural progression of illness (23).

Regarding the BSC cohort, a subgroup was deemed unfit for standard anticancer therapy. Clinical deterioration during routine work-up of lung cancer diagnostics and treatment preparation could play a substantial role. In our cohort, 104 patients received primary BSC due to an insufficient ECOG PS; however, 24 patients (23%) had an ECOG performance status of 0 or 1 at the initial outpatient presentation. Although inevitable in part of these cases, a structured and streamlined diagnostic pathway to minimalize treatment delay is indicated, particularly in a patient population with potentially curable NSCLC. Klarenbeek and colleagues [2023] found that patients with stage II NSCLC experienced OS benefit by fast initiation of surgical treatment, emphasizing the importance of an optimized diagnostic work-up (24).

There are limitations to our study. First, we scored etiological factors on BSC decision-making, based on a simplified model with a single option per case. In real-world though, these types of decisions are rather preceded by multiple underlying factors simultaneously. Second, a clear and concise rationale culminating in the final treatment decision is often lacking in medical records. Considerations of this nature should be documented more thoroughly. Third, among patients who preferred primary BSC, a small subset—for instance with a poor ECOG performance status (Table S1)—might have prompted the treating physician to select BSC as well. Finally, given the large differences in baseline characteristics, a propensity score matching would strengthen statistical analysis. However, it was not performed due to limited propensity score overlap between the BSC and curative-treatment cohorts, violating the positivity assumption and potentially excluding many BSC patients, thereby reducing representativeness.

The implications of our study are bifold. First, the reason for treatment omission appears to be an important prognostic marker in patients receiving primary BSC, with significant survival disparities observed between etiological subgroups. Second, the favorable survival outcomes observed in the patient-preference subgroup suggest that some patients declining treatment may still have a meaningful life expectancy, emphasizing the importance of individualized counseling and decision support.

Conclusions

In routine clinical practice, primary BSC was administered in twelve percent of patients diagnosed with stage I–III NSCLC due to clinical ineligibility or by patient preference. In either case, this resulted in a significantly reduced survival outcome. Our data facilitate tailored survival information to optimize well-informed treatment decision-making in the outpatient oncology clinic.

Acknowledgments

We would like to thank Dr. J.P.H. van den Bogart (Department of Pulmonology, Bernhoven, Uden, the Netherlands), Dr. L.C. Vermeer (Department of Pulmonology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands), Dr. H.M. van Groningen (Department of Pulmonology, Elkerliek Hospital, Helmond, the Netherlands), Dr. A. Mulders (Department of Pulmonology, Gelderse Vallei, Ede, the Netherlands), Dr. B. Biesma (Department of Pulmonology, Jeroen Bosch Hospital, ’s-Hertogenbosch, the Netherlands), Dr. M.C.M. Bunnik (Department of Pulmonology, Pantein, Boxmeer, the Netherlands) and Dr. F.H.W. Hermens (Department of Pulmonology, Slingeland Hospital, Doetinchem, the Netherlands) for facilitating data collection and data management.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0327/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0327/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0327/prf

Funding: This work was supported by Merck Sharp & Dohme (MSD) and the Radboud Oncology Fund (ROF1844)/Bergh in het Zadel.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0327/coif). All authors report study funding from Merck Sharp & Dohme. F.C. reports advisory board fees from TRIBVN Healthcare and shares in Aiosyn BV. M.M.v.d.H. reports research funding and speaker fees from multiple pharmaceutical companies, and has served as Chair of NVALT. The authors have no other 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the review board of the Dutch Clinical Research Foundation (DCRF) (No. MK-3475/NIS101592). All participating hospitals were informed of and agreed to the study. Individual informed consent was waived due to its retrospective nature and inclusion of a large patient cohort.

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/.

^*, Lung Cancer Net with participating centers Radboudumc Nijmegen, Canisius Wilhelmina Hospital Nijmegen, Pantein Boxmeer, Elkerliek Helmond, Jeroen Bosch Hospital ‘s-Hertogenbosch and Bernhoven Uden (https://www.longkankernet.nl/); Alliance Regional Top Care with participating centers Rijnstate Arnhem, Gelderse Vallei Ede and Slingeland Hospital Doetinchem.

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