Correlation of Psychological Distress and Immune Checkpoint Inhibitors in Gastric Cancer

Summary

1. Background Gastric cancer (GC) is a leading global cause of cancer-related mortality, with over 1 million new cases and 769,000 deaths in 2020. In China, 80% of patients present with advanced disease, for whom perioperative chemotherapy, surgery, and lymphadenectomy are standard. Recent phase III trials (Checkmate-649, KEYNOTE-062, ORIENT-16) demonstrate that immune checkpoint inhibitors (ICIs) combined with chemotherapy improve progression-free survival (PFS: 2.8-10.5 months) and overall survival (OS: 11.1-18.4 months) compared to chemotherapy alone. However, outcomes remain suboptimal, necessitating exploration of novel predictive biomarkers and resistance mechanisms. Emerging evidence implicates chronic stress in cancer progression and treatment response. Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, elevating cortisol, catecholamines, and glucocorticoids. These hormones suppress immune function by reducing CD8+ T cells and natural killer (NK) cell activity while increasing immunosuppressive cells (e.g., regulatory T cells, myeloid-derived suppressor cells). Preclinical studies link chronic stress to metastasis via extracellular trap (NET) formation, impaired antitumor immunity, and resistance to PD-1/PD-L1 blockade. Clinically, chronic stress correlates with worse survival in non-small-cell lung cancer patients receiving ICIs. Despite these findings, psychological screening remains underutilized in oncology. This study aims to investigate the impact of chronic stress on ICI efficacy in advanced gastric cancer. 2. Objectives Primary Objective: Evaluate the association between chronic stress and tumor response (via Tumor Regression Grade, TRG) in advanced gastric cancer patients undergoing neoadjuvant immunotherapy. Secondary Objectives: Assess the effect of chronic stress on post-gastrectomy quality of life (QoL). Analyze correlations between chronic stress biomarkers and survival outcomes (PFS, OS). 3. Study Endpoints Primary Endpoint: Pathological response assessed by TRG (Mandard criteria). Secondary Endpoints: QoL (EORTC QLQ-C30/STO22 questionnaires). PFS and OS. Exploratory Endpoints: Dynamic changes in chronic stress biomarkers (serum cortisol, ACTH, epinephrine, norepinephrine, serotonin). Correlation of biomarker levels with TRG and survival. 4. Study Design Type: Single-center, prospective observational study. Duration: 36 months. Sample Size: 268 patients (134 high chronic stress, 134 low chronic stress). Inclusion Criteria: Age 18-75 years. Histologically confirmed gastric adenocarcinoma (per Japanese Gastric Cancer Guidelines, 2017). Scheduled for neoadjuvant immunotherapy + radical gastrectomy. Informed consent. Exclusion Criteria: Pregnancy/breastfeeding. Prior upper abdominal surgery (excluding cholecystectomy). Active infection, autoimmune disease, or corticosteroid use within 1 month. Psychiatric disorders or investigator-deemed unsuitability. Withdrawal Criteria: Patient request, loss to follow-up, or safety concerns. 5. Methods Chronic Stress Assessment: Validated psychological questionnaires (e.g., Hospital Anxiety and Depression Scale) at baseline and treatment milestones. Biomarker analysis: Serum cortisol, ACTH, epinephrine, norepinephrine, serotonin at key timepoints (pre-treatment, post-neoadjuvant therapy, post-surgery). Clinical Data Collection: TRG evaluation post-surgery. QoL assessments at 1, 3, 6, 12, 18, 24, and 36 months post-surgery. Survival tracking via hospital records and follow-up visits. Statistical Analysis: Stratification by baseline stress scores (high/low). Cox regression for survival outcomes; logistic regression for TRG-QoL correlations. Significance threshold: \*p\* \< 0.05. 6. Significance This study addresses a critical gap in understanding how psychological factors modulate ICI efficacy. By identifying chronic stress as a predictor of treatment response, results may guide personalized interventions (e.g., beta-blockers, behavioral therapy) to improve outcomes in advanced gastric cancer.

Eligibility

Inclusion Criteria:

* Voluntary signing of informed consent;
* 18≦ age ≦75 years;
* Sex: no limitation;
* Patients with gastric adenocarcinoma diagnosed according to the 15th edition of the Japanese gastric cancer statute, 2017, after endoscopic biopsy of the primary lesion;
* Patients requiring preoperative immune checkpoint inhibitor therapy at the discretion of the treating physician, followed by radical gastrectomy.

Exclusion Criteria:

* Women who are pregnant or breastfeeding;
* Serious mental illness;
* History of upper abdominal surgery (except for laparoscopic cholecystectomy) ;
* Patients with gastric cancer who do not wish to undergo neoadjuvant immunotherapy;
* Patients with a history of continuous systemic corticosteroid therapy within the past 1 month;
* Patients with active infection, active or refractory autoimmune disease, or uncontrolled systemic disease;
* Patients at the discretion of the investigator, were deemed unsuitable for participation in this study.

Conditions2

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