Association of baseline hormone levels with outcomes of first-line immunotherapy in extensive-stage small cell lung cancer

Introduction

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by rapid proliferation, early metastasis and spread, and an inferior prognosis. Approximately 70% of patients are diagnosed with extensive-stage SCLC (ES-SCLC), for which systemic therapy remains the primary treatment method (1,2).

The emergence of immune checkpoint inhibitors (ICIs) targeting programmed death ligand 1 (PD-L1) and the programmed cell death 1 (PD-1) pathway represents a significant breakthrough in the treatment of ES-SCLC. The landmark Phase III clinical trial demonstrated that the addition of ICIs to platinum-etoposide chemotherapy could significantly increase overall survival (OS), making this regimen the current first-line standard treatment for extensive-stage SCLC (3-10). Despite these advancements, the benefits in survival remain insufficient: compared with chemotherapy alone, the improvement in median OS is only 2 to 3 months. The 2-year survival rate of most regimens is still less than 50%, suggesting the need for breakthrough treatment strategies to improve long-term prognosis (3-10). Furthermore, only a small proportion of patients achieved lasting survival benefits, which highlights the significant heterogeneity among patients. Reliable prognostic biomarkers are urgently needed to guide patients’ treatment choices and improve treatment outcomes.

Traditional biomarkers of ICI efficacy confirmed in other malignant tumors, including PD-L1 expression and tumor mutational burden (TMB), have limited predictive efficacy in SCLC. Most SCLC patients show negative PD-L1 expression. Furthermore, the correlation between the expression level of PD-L1 and the response to ICIs is not tight (11,12). At present, reliable markers to determine which patients will benefit from immunotherapy are still lacking. This restriction hinders personalized treatment for patients. Therefore, people’s attention has shifted to alternative and easily measurable biomarkers that reflect the host environment of the system and its interaction with the tumor microenvironment (TME). The indicators of neuroendocrine stress response seem very promising. In our previous study on non-small cell lung cancer (NSCLC), we demonstrated that chronic psychological stress was closely associated with the efficacy of ICIs. Notably, patients with stress-induced elevated baseline cortisol exhibited significantly poorer survival outcomes. These findings suggest that cortisol may serve as a biological link between stress-related neuroendocrine alterations and treatment efficacy (13).

SCLC, however, is a distinct malignancy with prominent neuroendocrine characteristics, in which endocrine dysregulation may exert an even greater influence on disease progression and therapeutic response (14). Despite this, the prognostic relevance of baseline endocrine hormones in the setting of SCLC immunotherapy remains largely unexplored.

The hypothalamic-pituitary-adrenal axis (HPA) and the hypothalamic-pituitary-thyroid axis (HPT) are key regulatory systems that coordinate metabolic balance, stress response, and immune function (15-18). Glucocorticoids (GCs), especially cortisol, exert immunosuppressive effects through genomic and non-genomic pathways. These mechanisms include T-cell apoptosis, inhibition of cytokine production, and impaired dendritic cell (DC) maturation (19). The increase in cortisol is also associated with poor prognosis for various tumor immunotherapy treatments (20,21), however, in SCLC, there were only 8 cases with relevant evidence (11). In the context of chronic stress and advanced malignancy, circulating cortisol levels regulated by adrenocorticotropic hormone (ACTH) are often elevated and are associated with a poor prognosis (15). Meanwhile, thyroid hormones [free triiodothyronine (FT3), free thyroxine (FT4)] and thyroid-stimulating hormone (TSH) play key roles in immune regulation. The dysregulation of these axes is not only a common immune-related adverse event, but may also reflect a physiological state that is conducive to tumor immune escape (22). In urothelial carcinoma and metastatic melanoma, thyroid hormones also demonstrate the value in predicting the prognosis of immunotherapy (23,24). Given that SCLC is a typical neuroendocrine malignant tumor, stress-related endocrine disorders may have a particularly strong impact on immune escape and treatment response, providing a theoretical basis for this study.

Clarifying the association between baseline hormone levels (cortisol, ACTH, FT3, FT4, and TSH) and clinical outcomes may provide insights into host-tumor interactions. This retrospective study evaluates their prognostic value in ES-SCLC patients receiving first-line immunotherapy. These biomarkers may help stratify patients and inform strategies targeting the neuroendocrine environment to improve immunotherapy efficacy and support personalized treatment. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0928/rc).

Methods

Research design and patients

This retrospective multicenter study included adult patients with histologically confirmed SCLC, who were classified as extensive-stage according to the Veterans Administration Lung Study Group (VALSG) staging system. A total of 377 patients received first line immunotherapy from January 2020 to December 2024. The patients were respectively from The Second Xiangya Hospital, Central South University (262 cases), the First Hospital of Changsha (50 cases), Union Hospital, Huazhong University of Science and Technology (43 cases), and The Affiliated Changsha Central Hospital, Hengyang Medical School (22 cases). All patients received at least one cycle of chemotherapy combined with first-line treatment with ICIs. Imaging procedures such as chest computed tomography (CT), upper abdominal CT, and magnetic resonance imaging (MRI), including their types and times, shall be carried out in accordance with clinical practice guidelines.

Data collection

Manually extract demographic, clinical [age, gender, smoking history, stage, cortisol level, ACTH level, FT3 level, FT4 level, TSH level, performance status (PS) score, etc.], radiological and treatment-related data from the hospital’s electronic medical records. The hormone levels of each center were standardized using Z-score normalization. The data consistency of each center was verified by independent investigators. OS is defined as the time from the start of chemotherapy and immunotherapy to death from any cause. Progression-free survival (PFS) is defined as the time from the start of treatment to the first recorded disease progression or death. Researchers at each center evaluated the tumor response according to the Solid Tumor Response Evaluation Criteria (RECIST) version 1.1. The following are the inclusion and exclusion criteria:

Selection criteria:

• Age ≥18 years old
• It was pathologically confirmed as SCLC
• Receive first-line immunotherapy
• There is at least one measurable baseline lesion according to RECIST 1.1
• Clear past medical history and personal history

Exclusion criteria:

• Pregnant or lactating women
• At the same time, diagnose other malignant tumors
• Known endocrine disorders that may affect hormone levels, including primary hypothyroidism, hyperthyroidism, adrenal insufficiency, or other clinically significant disorders of the hypothalamic-pituitary-adrenal or thyroid axis

Ethical consideration

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Second Xiangya Hospital, Central South University (No. LYEC2025-K0262). All participating hospitals were informed of and agreed to the study. Individual consent for this retrospective analysis was waived.

Standardization of hormone levels

Because reference ranges for endocrine hormones differed across participating centers, hormone levels were standardized using Z-scores prior to analysis. Z-scores were calculated for each hormone by subtracting the center-specific mean and dividing by the corresponding standard deviation (SD). Standardized Z-scores were subsequently used for survival and mediation analyses to minimize inter-center variability. Z = (X − μ_center)/SD_center, where μ center and SD_center represent the mean and SD of each hormone within the corresponding center.

Statistical analysis

Continuous variables were expressed as mean ± SD or median interquartile range (IQR), and categorical variables were analyzed using the χ² test. Survival curves were generated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazards regression models were applied to evaluate the association between baseline endocrine parameters and survival outcomes. Variables with clinical relevance or statistical significance in univariable analyses were included in multivariable Cox regression models, and hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were reported. Multivariable Cox regression analyses were performed using SPSS software (version 26.0; IBM Corp., Armonk, NY, USA).

All statistical tests were two-sided tests, and a P value <0.05 was considered statistically significant. Kaplan-Meier survival curves were generated using RStudio (version 4.2.3).

Results

Patient characteristics and baseline endocrine profiles

From January 2020 to December 2024, 377 ES-SCLC patients receiving first-line immunotherapy were retrospectively analyzed. The median age was 63 years (IQR 57–69), and 88.6% were male; 70.0% had Eastern Cooperative Oncology Group (ECOG) PS 1, and 40.3% were aged ≥65. Common metastatic sites included bone (24.9%), liver (29.9%), and brain (12.7%). PD-1 inhibitors were used in 55.7% of patients (Table 1). The baseline characteristics of patients stratified by cortisol levels are summarized in Table 2. Baseline endocrine parameters included ACTH, cortisol, FT3, FT4, and TSH. Hormone levels were standardized as Z scores and dichotomized into high and low groups based on median values.

PFS and OS in the study population

With a median follow-up of 20.4 months, the median PFS and OS for the entire cohort were 9.7 months (95% CI: 8.8–10.9 months) and 16.7 months (95% CI: 14.8–21.4 months), respectively. Kaplan-Meier survival curves for PFS and OS are shown in Figure 1.

Figure 1 Kaplan-Meier curves for the entire cohort showing PFS and OS. CI, confidence interval; OS, overall survival; PFS, progression-free survival.

Association between baseline cortisol levels and survival outcomes

Patients with high baseline cortisol levels exhibited significantly shorter PFS and OS compared with those with low cortisol levels (Figure 2A,2B). The median PFS was 8.9 months in the high cortisol group vs. 11.7 months in the low cortisol group (P=0.02), while the median OS was 15.2 vs. 26.0 months, respectively (P=0.003). In univariate Cox proportional hazards analyses, elevated baseline cortisol levels were significantly associated with worse OS (HR =1.70, 95% CI: 1.19–2.44, P=0.003), along with older age, advanced disease stage, and the presence of liver or bone metastases (all P<0.05). In the multivariable Cox proportional hazards regression model including age (<65 vs. ≥65 years), sex, smoking status, disease stage, and metastatic burden as covariates, elevated baseline cortisol remained independently associated with poorer OS (HR =1.50, 95% CI: 1.04–2.15, P=0.03; Table 3).

Figure 2 Kaplan-Meier survival curves stratified by baseline COR levels. (A) Progression-free survival and (B) overall survival. COR, cortisol.

Associations between other baseline endocrine hormones and survival outcomes

The associations between other baseline endocrine hormones and survival outcomes were further explored. No significant differences in PFS were observed according to baseline ACTH, FT3, FT4, or TSH levels (Figure 3A-3D). Similarly, none of these hormones showed a significant association with OS (Figure 4A-4D). These findings suggest that, among the assessed endocrine parameters, baseline cortisol may have a predominant association with survival outcomes in patients receiving immunotherapy.

Figure 3 Kaplan-Meier curves showing PFS according to baseline levels of other endocrine parameters, including ACTH, FT3, FT4, and TSH. ACTH, adrenocorticotropic hormone; FT3, free triiodothyronine; FT4, free thyroxine; PFS, progression-free survival; TSH, thyroid-stimulating hormone.

Figure 4 Kaplan-Meier curves showing OS according to baseline levels of ACTH, FT3, FT4, and TSH. ACTH, adrenocorticotropic hormone; FT3, free triiodothyronine; FT4, free thyroxine; OS, overall survival; TSH, thyroid-stimulating hormone.

Association between baseline cortisol levels and ACTH levels

A significant association between baseline cortisol and ACTH levels was observed. When patients were stratified by baseline cortisol status, the distribution of ACTH differed significantly between the low- and high-cortisol groups (P=0.005; Figure 5A). Consistently, categorical analysis demonstrated that a higher proportion of patients in the high-cortisol group exhibited elevated ACTH levels compared with the low-cortisol group (62.7% vs. 39.8%). This association remained statistically significant in Fisher’s exact test (P=0.001; Figure 5B).

Figure 5 Association between baseline cortisol and ACTH levels. (A) ACTH levels according to baseline cortisol status (high vs. low). (B) Distribution of ACTH categories between cortisol groups. ACTH, adrenocorticotropic hormone; COR, cortisol.

Discussion

In this study, we evaluated baseline endocrine hormones and immunotherapy outcomes in ES-SCLC. Elevated baseline cortisol was significantly associated with shorter PFS and OS, suggesting that HPA axis activation and stress-related endocrine alterations may influence ICI efficacy. These findings provide clinical evidence linking systemic hormonal status to immunotherapy outcomes in SCLC and support the role of neuroendocrine-immune interactions in treatment response.

The hypothalamic axis is a key mediator of the body’s response to chronic psychological and physiological stress, leading to the continuous secretion of cortisol (25,26). Cortisol is a GC that exerts broad immunosuppressive effects by inhibiting T cell activation, impairs antigen presentation, and regulates cytokine production (27,28). Chronically elevated cortisol has been proven to be associated with tumor immune evasion and poor anti-tumor immune response (29). The GC response mediated by the HPA axis is the main pathway connecting psychological stress and immunosuppression. Under chronic or acute stress, elevated cortisol activates the GC receptor (GR) signaling in DCs, upregulates TSC22D3/GILZ, and selectively inhibits type I interferons and interleukin-12 (IL-12) programs. This leads to defects in antigen presentation and impaired T cell initiation (28,30). In our cohort, patients with higher baseline cortisol levels had significantly poorer survival outcomes, which was consistent with this biological mechanism. Although previous study have shown that high expression of cortisol is associated with a poorer prognosis for various tumor immunotherapy, only 8 patients with SCLC were involved in the previous research (11), lacking statistical power to draw definitive conclusions. In contrast, we focused more on the first-line immunotherapy for ES-SCLC and the sample size was much larger (377 patients). These findings are consistent with the results of our recent stress-lung study, which previously indicated that emotional distress (characterized by depression and anxiety) was associated with a poorer prognosis in patients with advanced NSCLC treated with ICIs (13). Importantly, the study found that patients with emotional distress had significantly higher serum cortisol levels, which was associated with lower PFS (7.9 vs. 15.5 months, HR =1.73, P=0.002) and OS (HR =1.82, P=0.02). Our research results show that elevated cortisol can predict poor PFS and OS in SCLC patients, which supports the prevalence of this phenomenon in the histological subtypes of lung cancer and also suggests a close connection between psychological stress, cortisol and immunotherapy. Together, these clinical data from SCLC and NSCLC suggest that the activation of the HPA axis, whether triggered by psychological stress or tumor-related systemic stress, may serve as a biomarker for the efficacy of immunotherapy.

The immunosuppressive effect of cortisol involves innate and adaptive immune compartments. Cortisol can tilt the polarization of macrophages towards the M2 phenotype, inhibit the presentation of DC antigens, and down-regulate pro-inflammatory cytokines such as IL-12 and interferon-gamma (IFN-γ) (30,31). In T cells, GCs promote the apoptosis of effector subsets and simultaneously expand regulatory T cells, jointly inhibiting the anti-tumor response (32). Elevated cortisol also interferes with PD-1/PD-L1 signaling by altering the metabolic pathways necessary for T cell activation, which may explain the reduced sensitivity to ICIs observed in patients with high cortisol.

ACTH, as an upstream regulator of cortisol secretion, reflects the activation status of the pituitary gland in the stress response (33,34). In our study, the positive correlation between cortisol and ACTH suggests intact HPA axis activity, indicating that elevated cortisol likely reflects endogenous stress rather than exogenous steroid exposure. However, ACTH was not independently associated with PFS or OS, implying that downstream cortisol activity may be the key driver of immunological effects. Consistently, our previous NSCLC data showed no significant difference in ACTH between emotionally distressed and non-distressed patients, despite higher cortisol levels in the distressed group. This suggests that chronic stress may alter adrenal sensitivity to ACTH, leading to disproportionate cortisol release, while ACTH may primarily reflect transient acute stress responses.

Although thyroid hormones (FT3, FT4, and TSH) have been linked to immune regulation and immune-related adverse events in previous studies, we found no significant association between baseline thyroid hormones and survival outcomes. These findings suggest that the thyroid axis may play a secondary role compared with the HPA axis in SCLC chemoimmunotherapy. Thyroid hormone changes may occur in the later stage of treatment or as part of thyroiditis caused by delayed immunotherapy, rather than as a reliable baseline predictor (24). Dynamic changes, such as subclinical hypothyroidism, transient thyrotoxicosis or thyroid storm, can occur, usually influenced by previous treatments or comorbidities (35). Future longitudinal studies should evaluate thyroid hormone dynamics during treatment and their associations with immune-related toxicity, treatment response, and survival to clarify the role of thyroid function in treatment outcomes.

Clinical implications

Clinically, baseline cortisol may serve as an accessible biomarker for identifying ES-SCLC patients at higher risk of poor outcomes after first-line immunotherapy. Early recognition of these patients may support closer monitoring and individualized supportive strategies alongside standard oncologic care.

Limitations and future directions

This study has several limitations, including its retrospective design, baseline-only hormone measurements, and lack of direct psychological distress assessment. Additionally, although center-specific Z-score standardization was used to address inter-center variability (36-39), it reflects relative rather than absolute hormone levels and may limit direct clinical interpretation and the establishment of universal clinical thresholds. In addition, all participants were Chinese patients, and validation in larger, multiethnic cohorts is needed.

Conclusions

In conclusion, elevated baseline cortisol was associated with poorer progression-free and OS in patients with ES-SCLC receiving immunotherapy. Baseline cortisol may serve as a stress-related biomarker with potential prognostic value, whereas ACTH and thyroid-related hormones were not independently associated with survival outcomes.

Acknowledgments

The authors thank all individuals and institutions that contributed to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0928/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0928/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0928/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-2026-0928/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Second Xiangya Hospital, Central South University (No. LYEC2025-K0262). All participating hospitals were informed of and agreed to the study. Individual consent for this retrospective analysis was waived.

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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