Association between emotional distress and efficacy of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a multicentre, prospective observational study protocol.

Abstract

Hepatocellular carcinoma is the sixth most common malignancy worldwide, with immune checkpoint inhibitors transforming treatment paradigms despite modest response rates of approximately 30%. Emotional distress, encompassing depression and anxiety symptoms, affects 30-50% of cancer patients and may influence immunotherapy efficacy through immune system modulation. Recent studies in lung cancer, gastric cancer and melanoma demonstrate associations between pretreatment emotional distress and worse immunotherapy outcomes. However, this relationship remains unexplored in patients with hepatocellular carcinoma, who may be particularly vulnerable due to underlying chronic liver disease and associated stigma. This study protocol describes a prospective investigation of the association between emotional distress and immune checkpoint inhibitor efficacy across different hepatocellular carcinoma treatment settings. This multicentre, prospective, observational cohort study will enrol 700 patients with hepatocellular carcinoma across three cohorts: unresectable disease receiving first-line therapy (n=400), adjuvant therapy following curative resection (n=200) and neoadjuvant therapy with conversion intent (n=100). Three tertiary hospitals in China will serve as study sites, with recruitment commencing in October 2024 and study completion anticipated by October 2027. Emotional distress will be assessed using validated self-report measures (Patient Health Questionnaire-9, Generalised Anxiety Disorder 7) and clinician-administered scales (Hamilton Depression Rating Scale-17, Hamilton Anxiety Rating Scale), with comprehensive biomarker analysis including stress hormones, inflammatory cytokines and immune markers. Primary endpoints are cohort-specific: progression-free survival in Cohort 1, disease-free survival in Cohort 2 and pathological complete response rate in Cohort 3. Secondary endpoints include overall survival, objective response rate, quality of life and biomarker correlations. Statistical analysis will employ Kaplan-Meier survival analysis and Cox proportional hazards modelling, with participants followed for up to 36 months. The study has received ethical approval from the Medical Ethics Committee of the First Affiliated Hospital of Guilin Medical University (LXIIT2024051), the Ethics Committee of Shaoyang Central Hospital (SYCH2025012) and the Ethics Committee of the Second Affiliated Hospital of Guangdong Medical University (PJKT2025035), and complies with Declaration of Helsinki guidelines. Results will be published in peer-reviewed journals and presented at international conferences. NCT07141056.