Abstract
Purpose
To compare survival outcomes between chemoradiotherapy versus radiotherapy in patients with stage T1-2N0M0 small cell lung cancer (SCLC).
Materials and methods
SCLC patients from the Surveillance, Epidemiology, and End Results databases between 2000 and 2020 were investigated. Kaplan-Meier survival analysis was employed to assess cancer-specific survival (CSS) and overall survival (OS).
Results
Among 525 eligible patients, 371 (70.7%) received chemoradiotherapy, 64 (12.2%) underwent radiotherapy, and 90 (17.1%) received chemotherapy. While 5-year SCLC-specific mortality rates were comparable between chemoradiotherapy and radiotherapy groups (57.1% vs. 51.8%, P = 0.660), non-cancer mortality demonstrated significant reduction with chemoradiotherapy (13.3% vs. 30.2%, P = 0.004). After propensity score matching, median CSS was 27 months with chemoradiotherapy versus 26 months with radiotherapy (hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.57–1.52; P = 0.787). Multivariable analysis confirmed radiotherapy was not an independent prognostic factor for CSS (HR = 0.85, 95% CI: 0.52–1.41; P = 0.532). Median OS was 21.5 months for chemoradiotherapy and 20 months for radiotherapy (HR = 1.11, 95% CI: 0.76–1.64; P = 0.586). Multivariable analysis confirmed radiotherapy was not an independent prognostic factor for OS (HR = 1.03, 95% CI: 0.69–1.54; P = 0.888).
Conclusion
Radiotherapy demonstrates comparable survival outcomes to chemoradiotherapy in stage T1-2N0M0 SCLC patients.
Keywords: Small cell lung cancer, Stage T1-2N0M0, Radiotherapy, Chemotherapy
Introduction
Lung cancer remains the predominant cause of cancer-related mortality globally [1], with small cell lung cancer (SCLC) representing a particularly aggressive histological subtype accounting for approximately 15% of all cases [2]. Advancements in lung cancer screening have contributed to increased detection of early-stage SCLC [3]. For patients with limited-stage SCLC, concurrent chemoradiotherapy constitutes the current standard of care [4, 5].
Notably, patients with stage T1-2N0M0 SCLC represent a distinct clinical entity within limited-stage disease. This subgroup exhibits minimal primary tumor volume and absence of nodal involvement, suggesting potentially different treatment responsiveness compared to advanced limited-stage disease. Existing clinical trials reveal limited representation of this specific cohort [6–10]. This knowledge gap precludes definitive conclusions regarding optimal management strategies for this low-risk population.
The therapeutic equipoise between chemoradiotherapy and radiotherapy alone in T1-2N0M0 SCLC remains unresolved. While chemoradiotherapy demonstrates superiority in mixed-stage cohorts, its added benefit over radiotherapy in truly localized disease with favorable prognostic features warrants investigation. This retrospective cohort study addresses this critical unmet need by directly comparing survival outcomes between chemoradiotherapy and radiotherapy monotherapy in a rigorously defined T1-2N0M0 SCLC population. We hypothesize that radiotherapy alone may achieve equivalent therapeutic efficacy, with implications for treatment de-escalation strategies and future trial design.
Materials and methods
Patients
A retrospective cohort analysis was performed using data extracted from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database spanning the period 2000–2020. SCLC cases were identified according to International Classification of Diseases for Oncology, third edition (ICD-O-3) histological codes (8041/3, 8042/3, 8043/3, and 8044/3). Patient selection protocols have been previously described in our published work [11–13].
Eligible participants met the following criteria: (1) histopathological confirmation of SCLC diagnosis (2), absence of previous malignancies, and (3) clinical staging confirming T1-2N0M0 disease. Patients were excluded if they: (1) underwent surgical intervention, or (2) received no treatments.
Data collection and grouping
Baseline demographic variables included age, sex, and race. Tumor characteristics comprised primary site, laterality, histological grade, and T stage classification. Treatment modalities were categorized into three groups: chemoradiotherapy, radiotherapy alone, and chemotherapy alone.
Outcome measures
Overall survival (OS) served as the primary endpoint, defined as the interval from diagnosis to death from any cause as recorded in SEER. Cancer-specific survival (CSS) constituted the secondary endpoint, calculated as the time from diagnosis to SCLC-attributed mortality according to SEER coding.
Statistical analysis
Age was dichotomized at the median value for comparative analyses. Categorical variables were compared across treatment groups using χ² tests or Fisher’s exact tests where appropriate. Kaplan-Meier methodology with log-rank testing was employed for survival curve comparisons between groups. Univariate Cox proportional hazards regression identified potential prognostic factors, followed by multivariate analysis.
To mitigate confounding, propensity score matching (PSM) was implemented through a logistic regression framework. One-to-one nearest-neighbor matching without replacement was performed using calipers of width 0.05 standard deviations of the logit-transformed propensity scores to optimize balance precision. Results are presented as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs).
All statistical computations were performed using SPSS Statistics (Version 26.0; IBM Corp., Armonk, NY) and R software (version 4.2.2). Two-tailed P-values < 0.05 were considered statistically significant.
Results
Patient demographics and treatment allocation
As illustrated in Fig. 1, the study cohort comprised 525 patients with stage T1-2N0M0 SCLC. Treatment distribution revealed 371 patients (70.7%) received chemoradiotherapy, 64 (12.2%) underwent radiotherapy alone, and 90 (17.1%) were managed with chemotherapy alone. Baseline clinical characteristics are summarized in Table 1. Age and T stage were different between treatment groups.
Fig. 1.
Flowchart illustrating the patient selection process. SCLC Small cell lung cancer
Table 1.
Patient characteristics
| Chemoradiotherapy (n = 371) |
Radiotherapy (n = 64) |
Chemotherapy (n = 90) |
P | |
|---|---|---|---|---|
| Age | < 0.001 | |||
| < 70 | 200 (53.9%) | 9 (14.1%) | 37 (41.1%) | |
| ≥ 70 | 171 (46.1%) | 55 (85.9%) | 53 (58.9%) | |
| Sex | 0.435 | |||
| female | 194 (52.3%) | 39 (60.9%) | 49 (54.4%) | |
| male | 177 (47.7%) | 25 (39.1%) | 41 (45.6%) | |
| Race | 0.178 | |||
| white | 311 (83.8%) | 51 (79.7%) | 79 (87.8%) | |
| black | 42 (11.3%) | 6 (9.4%) | 5 (5.5%) | |
| others | 18 (4.9%) | 7 (10.9%) | 6 (6.7%) | |
| Site | ||||
| upper lobe | 215 (58.0%) | 33 (51.6%) | 49 (54.4%) | 0.077 |
| middle lobe | 24 (6.4%) | 6 (9.4%) | 9 (10.0%) | |
| lower lobe | 88 (23.7%) | 22 (34.4%) | 28 (31.1%) | |
| others | 44 (11.9%) | 3 (4.6%) | 4 (4.5%) | |
| Laterality | 0.336 | |||
| left | 170 (45.8%) | 31 (48.4%) | 49 (54.4%) | |
| right | 201 (54.2%) | 33 (51.6%) | 41 (45.6%) | |
| Grade | 0.498 | |||
| III/IV | 114 (30.7%) | 15 (23.4%) | 27 (30.0%) | |
| I/II/unknown | 257 (69.3%) | 49 (76.6%) | 63 (70.0%) | |
| T stage | < 0.001 | |||
| T1N0M0 | 154 (41.5%) | 48 (75.0%) | 40 (44.4%) | |
| T2N0M0 | 217 (58.5%) | 16 (25.0%) | 50 (55.6%) |
Median follow-up durations differed between groups: 28 months (interquartile range [IQR]: 12–65) for chemoradiotherapy, 20 months (IQR: 7–42) for radiotherapy, and 14 months (IQR: 6–22) for chemotherapy.
Cancer-specific survival
Median CSS reached 33 months in the chemoradiotherapy group, compared to 24 months with radiotherapy and 16 months with chemotherapy (Fig. 2A). Five-year CSS rates were 38.6%, 38.6%, and 13.9% for chemoradiotherapy, radiotherapy, and chemotherapy groups, respectively.
Fig. 2.
Cancer-specific survival between different treatment patterns A Kaplan-Meier survival curve of cancer-specific survival between chemoradiotherapy, radiotherapy, and chemotherapy B Multivariable proportional hazards regression analysis of cancer-specific survival, HR Hazard ratio, CI Confidence interval
Univariable Cox regression showed radiotherapy was not associated with CSS risk when compared to chemoradiotherapy (HR = 1.15, 95% CI: 0.80–1.64; P = 0.456). Conversely, chemotherapy demonstrated significantly worse CSS compared to chemoradiotherapy (HR = 2.24, 95% CI: 1.71–2.94; P < 0.001).
Multivariable analysis adjusting for age, sex, race, tumor characteristics, and treatment modality confirmed radiotherapy did not constitute an independent prognostic factor for CSS (HR = 1.16, 95% CI: 0.80–1.70; P = 0.435). Chemotherapy remained an independent risk factor for CSS (HR = 2.44, 95% CI: 1.83–3.24; P < 0.001) when referenced to chemoradiotherapy (Fig. 2B).
Overall survival
Median OS was 28 months for chemoradiotherapy, 20 months for radiotherapy, and 13.5 months for chemotherapy (Fig. 3A). Five-year OS rates were 29.5%, 18.1%, and 7.8% respectively.
Fig. 3.
Overall survival between different treatment patterns A Kaplan-Meier survival curve of overall survival between chemoradiotherapy, radiotherapy, and chemotherapy B Multivariable proportional hazards regression analysis of overall survival, HR Hazard ratio, CI Confidence interval
Univariable analysis revealed radiotherapy associated with increased mortality risk compared to chemoradiotherapy (HR = 1.43, 95% CI: 1.08–1.91; P = 0.011), while chemotherapy demonstrated the highest risk (HR = 2.19, 95% CI: 1.72–2.79; P < 0.001).
Multivariable adjustment attenuated the radiotherapy effect (HR = 1.35, 95% CI: 1.00-1.82; P = 0.054), though chemotherapy maintained significance as an independent OS predictor (HR = 2.29, 95% CI: 1.78–2.96; P < 0.001) when referenced to chemoradiotherapy (Fig. 3B).
Factors influencing treatment modality selection
Multivariable logistic regression identified clinically relevant predictors of treatment allocation (Fig. 4). Patients ≥ 70 years were significantly more likely to receive radiotherapy alone (odds ratio = 5.73, 95% CI: 2.81–12.94; P < 0.001). Conversely, patients with stage T2N0M0 were less likely to receive radiotherapy alone (odds ratio = 0.29, 95% CI: 0.15–0.53; P < 0.001).
Fig. 4.
Logistic regression analysis identifying factors that favor the selection of radiotherapy over chemotherapy
Causes of death
In the chemoradiotherapy cohort, 60.9% (226/371) of deaths resulted from progressive SCLC, while 22.9% (85/371) were attributed to non-tumor causes. The radiotherapy group exhibited a higher proportion of non-cancer mortality (34.4%, 22/64) with fewer SCLC related deaths (54.7%, 35/64).
Competitive risk analysis demonstrated comparable 5-year cumulative incidence of SCLC-specific mortality between groups (57.1% vs. 51.8%, P = 0.660, Fig. 5A). However, chemoradiotherapy was associated with a lower 5-year cumulative incidence of non-cancer mortality (13.3% vs. 30.2%, P = 0.004), driven predominantly by cardiovascular events (3.5% vs. 12.7%, P < 0.001, Fig. 5B).
Fig. 5.
Cumulative incidence functions of death between the chemoradiotherapy and radiotherapy groups, A Non-tumor death B Death due to heart disease
Propensity-matched cohort characteristics
After PSM, 58 patients were included in each treatment arm (Table 2). All the factors were balanced between the two treatment groups.
Table 2.
Patient characteristics after propensity score matching
| Chemoradiotherapy (n = 58) |
Radiotherapy (n = 58) |
P | |
|---|---|---|---|
| Age | 0.999 | ||
| < 70 | 8 (13.8%) | 9 (15.5%) | |
| ≥ 70 | 50 (86.2%) | 49 (84.5%) | |
| Sex | 0.999 | ||
| female | 34 (58.6%) | 33 (56.9%) | |
| male | 24 (41.4%) | 25 (43.1%) | |
| Race | 0.998 | ||
| white | 51 (87.9%) | 51 (87.9%) | |
| black | 4 (6.9%) | 3 (5.2%) | |
| others | 3 (5.2%) | 4 (6.9%) | |
| Site | 0.886 | ||
| upper lobe | 32 (55.2%) | 30 (51.7%) | |
| middle lobe | 4 (6.9%) | 6 (10.3%) | |
| lower lobe | 21 (36.2%) | 20 (34.5%) | |
| others | 1 (1.7%) | 2 (3.5%) | |
| Laterality | 0.458 | ||
| left | 32 (55.2%) | 27 (46.6%) | |
| right | 26 (44.8%) | 31 (53.4%) | |
| Grade | 0.835 | ||
| III/IV | 17 (29.3%) | 15 (25.9%) | |
| I/II/unknown | 41 (70.7%) | 43 (74.1%) | |
| T stage | 0.999 | ||
| T1N0M0 | 41 (70.7%) | 42 (72.4%) | |
| T2N0M0 | 17 (29.3%) | 16 (27.6%) |
Cancer-specific survival after PSM
Median CSS reached 27 months in the chemoradiotherapy group compared to 26 months with radiotherapy (Fig. 6A). Five-year CSS rates were 32.9% and 41.3% respectively. Both univariable (HR = 0.93, 95% CI: 0.57–1.52; P = 0.787) and multivariable (HR = 0.85, 95% CI: 0.52–1.41; P = 0.532, Fig. 6B) Cox analyses confirmed radiotherapy was not associated with CSS risk when compared to chemoradiotherapy.
Fig. 6.
Cancer-specific survival between chemoradiotherapy and radiotherapy groups after propensity score matching A Kaplan-Meier survival curve of cancer-specific survival between chemoradiotherapy and radiotherapy groups B Multivariable proportional hazards regression analysis of cancer-specific survival, HR Hazard ratio, CI Confidence interval
Overall survival after PSM
Median OS was 21.5 months for chemoradiotherapy versus 20 months for radiotherapy (Fig. 7A). Five-year OS rates were 20.7% and 18.2% respectively. Both univariable (HR = 1.11, 95% CI: 0.76–1.64; P = 0.586) and multivariable (HR = 1.03, 95% CI: 0.69–1.54; P = 0.888, Fig. 7B) Cox analyses confirmed radiotherapy was not associated with OS risk when compared to chemoradiotherapy.
Fig. 7.
Overall survival between chemoradiotherapy and radiotherapy groups after propensity score matching A Kaplan-Meier survival curve of overall survival between chemoradiotherapy and radiotherapy groups B Multivariable proportional hazards regression analysis of overall survival, HR Hazard ratio, CI Confidence interval
Discussion
Our analysis provides compelling evidence against the use of chemotherapy alone as initial therapy for stage T1-2N0M0 SCLC, with significantly inferior survival outcomes compared to both chemoradiotherapy and radiotherapy. Notably, radiotherapy demonstrated non-inferiority to chemoradiotherapy in CSS and OS endpoints, particularly in elderly patients (≥ 70 years).
Current guidelines recommend surgical resection for early-stage SCLC [5, 14]. Historical perspectives have evolved significantly. Early comparisons showing equivalent survival between radiation and surgery led to reduced surgical use [15], but late 20th century evidence demonstrated superior survival outcomes with resection. Cohort analyses revealed median OS improvements from 11 to 36 months to 22–68 months [16, 17], alongside 5-year OS increasing from 11.3 to 44.9% [18]. Database analysis confirmed these findings, showing 34–60 months median OS with surgery versus 16–31 months with chemoradiotherapy alone [19–22]. These data established surgery as standard care for T1-2N0M0 SCLC.
However, accurate preoperative staging remains critical due to frequent occult nodal metastases. While chest computed tomography shows only 60% accuracy for N0 staging [23–25], 18 F-flurodeoxyglucose positron emission tomography computed tomography improves N-staging (sensitivity 91%, specificity 87.5%) [26–29]. However, mediastinal lymph node assessment still requires invasive confirmation via mediastinoscopy or endobronchial ultrasound guided transbronchial needle aspiration to exclude N1/N2 disease, given its prognostic significance. These staging requirements contribute to the prevalence of concurrent chemoradiotherapy in clinical practice.
While CSS outcomes appeared comparable between chemoradiotherapy and radiotherapy groups, this finding warrants cautious interpretation. The inherent limitations of SEER database prevented us from distinguishing sequential radiotherapy-chemotherapy regimens from truly monotherapy approaches. As sequential therapy has been shown to compromise CSS compared to concurrent regimens [9], this potential misclassification may have attenuated observed survival differences.
The apparent OS advantage of chemoradiotherapy in univariable analysis was notably attenuated after multivariable adjustment (HR = 1.35, 95% CI: 1.00-1.82; P = 0.054), approaching statistical non-significance. This discrepancy prompted further investigation into confounding factors. Logistic regression revealed age as the predominant determinant of treatment selection, with patients ≥ 70 years having 5.73-fold odds of receiving radiotherapy alone. This selection bias likely explains the initial survival discrepancy, as elderly patients often harbor unrecorded comorbidities precluding aggressive systemic therapy.
Competing risk analysis of mortality causes provided critical insights. While 5-year SCLC-specific mortality rates were comparable, non-cancer mortality demonstrated a striking reduction with chemoradiotherapy (13.3% vs. 30.2%), driven predominantly by cardiovascular events. This finding suggests that while radiotherapy may offer comparable tumor control, survival benefit of chemoradiotherapy primarily stems from reduced non-cancer mortality in younger, fitter patients.
PSM further validated these observations. After balancing for age and T stage, both CSS and OS became statistically indistinguishable between treatment arms. This suggests that radiotherapy alone may represent a reasonable treatment de-escalation strategy for carefully selected elderly patients with potential comorbidities.
Notably, our chemoradiotherapy cohort demonstrated superior survival compared to historical controls [30, 31]. However, the survival outcomes are still unsatisfied. The ADRIATIC trial recently established consolidation durvalumab as the new standard after concurrent chemoradiotherapy, improving OS (HR = 0.73, 98.321% CI: 0.54–0.98; P = 0.01) and progression-free survival (HR = 0.76, 97.195% CI: 0.59–0.98; P = 0.02) in limited-stage SCLC [32]. However, less than 10% of ADRIATIC patients had stage I/II disease, highlighting the urgent need for immunotherapy validation specifically in T1-2N0M0 populations.
The KEYNOTE-799 trial suggested promising antitumor activity of pembrolizumab plus concurrent chemoradiotherapy and manageable safety in patients with stage III non-small cell lung cancer [33]. However, emerging data from PACIFIC-2 and NRG-LU005 trials raise important caveats about immunotherapy integration. Concurrent atezolizumab with chemoradiotherapy failed to improve survival endpoints in limited-stage SCLC, mirroring similar negative findings with durvalumab in stage III non-small cell lung cancer. These results suggest that immunotherapy may require specific sequencing or biomarker selection to demonstrate efficacy in early-stage disease.
For patient ineligible for chemoradiotherapy, the optimal treatment paradigm remains undefined. While our analysis showed non-inferior survival outcomes with radiotherapy alone compared to chemoradiotherapy, these findings require prospective evaluation. Notably, concurrent immunotherapy and radiotherapy show promise mechanism in killing cancer cells. Concurrent immunotherapy and radiotherapy may be a treatment option in patient ineligible for chemoradiotherapy. Key considerations include cost-effectiveness analyses and rigorous toxicity profiling, particularly in elderly populations where treatment tolerance is paramount.
In conclusion, our study challenges the traditional dominance of chemoradiotherapy in stage T1-2N0M0 SCLC, demonstrating comparable efficacy for radiotherapy alone in appropriately selected elderly patients. Future directions should focus on immunotherapy integration strategies tailored to early-stage disease biology and patient-specific factors.
Acknowledgements
The authors thank the Surveillance, Epidemiology, and End Results program for providing the data used in this study.
Abbreviations
- SCLC
Small cell lung cancer
- SEER
The surveillance, epidemiology, and end results
- ICD-O-3
International classification of diseases for oncology, third edition
- OS
Overall survival
- CSS
Cancer-specific survival
- PSM
Propensity score matching
- HR
Hazard ratio
- CI
Confidence interval
- IQR
Interquartile range
Authors’ contributions
Conceptualization: Juan LinMethodology: Huan-Wei Liang and Yang LiuFormal Analysis: Juan Lin and Huan-Wei LiangInvestigation: Juan LinResources: Juan Lin and Huan-Wei LiangValidation: Wei HuangWriting-Original Draft Preparation: Juan LinWriting-Review & Editing: Xin-Bin Pan.
Funding
None.
Data availability
The data are available from the corresponding author upon request.
Declarations
Ethics approval and consent to participate
Ethics approval was waived by the Ethics Committee/Institutional Review Board of Guangxi Medical University Cancer Hospital due to the retrospective cohort design based on the SEER database.
Informed consent was waived by the Ethics Committee/Institutional Review Board of Guangxi Medical University Cancer Hospital due to the retrospective cohort design 348 based on the SEER database.\
The study was conducted in compliance with the principles outlined in the Declaration of Helsinki.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data are available from the corresponding author upon request.