Associations of a Pre-Chemotherapy Anxiety-Sleep Disturbance Phenotype with Cellular Immunity and Quality of Life in Colorectal Cancer Patients: Statistical Mediation by Cortisol and IL-6.

BACKGROUND

Neuroimmunomodulation examines nervous-immune interactions via hormonal and inflammatory pathways. This study investigated whether the anxiety-sleep disturbance symptom cluster in colorectal cancer (CRC) patients undergoing chemotherapy is associated with neuroendocrine dysregulation, cellular immune alterations, and quality of life (QoL), and tested whether cortisol and interleukin-6 (IL-6) act as biological mediators.

METHODS

In this prospective baseline observational study, 268 CRC patients scheduled to initiate systemic chemotherapy were assessed within 24 hours before their first chemotherapy cycle. Anxiety (HADS-A), sleep quality (PSQI), and QoL (EORTC QLQ-C30) were assessed. Serum cortisol, IL-6, and TNF-α were quantified by ELISA. Lymphocyte subsets (CD3+, CD4+, CD8+, NK cells) and regulatory T cells (Tregs) were analyzed by flow cytometry. Patients with HADS-A ≥8 and PSQI >5 formed the Symptom Cluster group (n=118), while the remaining patients constituted the Non-cluster comparator group (n=150). Mediation analysis using bootstrapping tested cortisol and IL-6 as intermediaries.

RESULTS

The Symptom Cluster group showed significantly elevated cortisol, IL-6, and TNF-α (all P<0.001), higher Treg proportion (8.4% vs. 4.6%, P<0.001), and lower CD3+, CD4+, and NK cell counts (all P<0.001). Global QoL was reduced (36.4 vs. 69.5, P<0.001). Cross-sectional mediation models indicated that the association between symptom-cluster status and CD4+ T-cell count was statistically mediated by cortisol (indirect effect, -117.45; 95% bootstrap CI, -168.22 to -75.40), and the association with global QoL was statistically mediated by IL-6 (indirect effect, -13.85; 95% bootstrap CI, -18.50 to -9.80), accounting for 37.9% and 41.8% of the total effects, respectively.

CONCLUSION

The anxiety-sleep disturbance symptom cluster in CRC chemotherapy patients is associated with neuroendocrine-inflammatory dysregulation, effector immune suppression, Treg expansion, and impaired QoL. Exploratory mediation findings suggest that cortisol and IL-6 may be involved in statistical indirect associations between this pre-chemotherapy anxiety-sleep disturbance phenotype and immune/QoL outcomes; longitudinal studies are needed to determine temporal and causal relationships.