Hepatocellular carcinoma (HCC) is a leading global cancer burden and a major cause of cancer mortality. The introduction of immune checkpoint inhibitors (ICIs), including combination regimens such as atezolizumab plus bevacizumab, has changed treatment paradigms for HCC, but objective response rates remain modest at about 30%. The protocol presents a prospective investigation into whether emotional distress—operationalised as clinically significant symptoms of depression or anxiety—affects ICI efficacy in HCC across different clinical settings.
Emotional distress (ED) affects an estimated 30–50% of patients with cancer and is prevalent in HCC because of factors such as underlying chronic liver disease and disease-related stigma. Preclinical and clinical evidence suggests chronic psychological stress may modulate immune function via activation of the hypothalamic–pituitary–adrenal axis and sympathetic nervous system, increasing cortisol and catecholamines and potentially impairing antitumour immunity. Prior observational studies in lung cancer, gastric cancer and melanoma have reported associations between pretreatment ED and worse immunotherapy outcomes, but the relationship has not been systematically studied in HCC.
This protocol aims to fill that gap by prospectively assessing psychological states, serial biomarkers and clinical outcomes in HCC patients receiving ICIs across three treatment settings to evaluate associations between ED and treatment efficacy.
This is a multicentre, prospective, observational cohort study enrolling 700 patients with HCC across three cohorts: unresectable disease receiving first-line ICI therapy (n=400), adjuvant ICI after curative resection (n=200) and neoadjuvant ICI with conversion intent (n=100). Three tertiary hospitals in China are registered as study sites. Recruitment commenced in October 2024 and study completion including follow-up assessments is anticipated by October 2027. The observational design captures real-world clinical practice while adding standardised psychological and biomarker assessments.
Eligible patients will receive verbal and written information about study objectives, procedures, risks, benefits and their rights. Consent will be obtained by qualified investigators and will emphasise that participation will not change standard cancer treatment. Consent forms will be available in local languages and culturally appropriate formats. Procedures for referral to mental health services will be in place if assessments identify clinically significant distress. Participants retain the right to withdraw at any time without affecting clinical care.
Inclusion criteria require age ≥18 years; histological or radiological confirmation of HCC according to Chinese Guidelines for Primary Liver Cancer; planned initiation of ICI therapy (monotherapy or combinations) per routine care; ECOG performance status 0–2; Child–Pugh class A or B (≤7); adequate organ function as defined by blood counts and biochemistry thresholds; ability to complete psychological assessments; and ability to provide informed consent.
Exclusion criteria include mixed hepatocellular–cholangiocarcinoma histology; prior systemic therapy for HCC (except permitted in the adjuvant cohort); active psychiatric illness requiring hospitalisation or severe cognitive impairment preventing questionnaire completion; symptomatic brain metastases; expected survival <3 months; pregnancy or lactation; and concurrent enrolment in interventional trials.
The study uses a dual assessment approach combining validated self-report instruments and clinician-rated scales. Self-report measures are the Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder 7 (GAD-7). Clinician-administered scales include the Hamilton Depression Rating Scale-17 (HAMD-17) and Hamilton Anxiety Rating Scale (HAMA). ED is operationally defined as PHQ-9 ≥5 or GAD-7 ≥5.
Serial blood sampling will assess stress and immune biomarkers, including morning cortisol (08:00–10:00), adrenocorticotropic hormone (ACTH), inflammatory cytokines (interleukin-6, tumour necrosis factor-α, C-reactive protein) and immune cell markers such as CD8+ T-cell and natural killer (NK) cell counts. Quality of life will be measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).
Treatment decisions remain at treating clinicians’ discretion and reflect routine care; ICI regimens may include atezolizumab plus bevacizumab, durvalumab plus tremelimumab, single-agent PD-1/PD-L1 inhibitors or other evolving standard regimens. The study limits procedures to data collection and assessments without altering treatment.
Participants will undergo follow-up evaluations every 6 weeks during active treatment and every 3 months during post-treatment surveillance. Follow-up includes repeated psychological assessments, quality of life questionnaires, biomarker sampling and documentation of clinical outcomes. Radiological response will be evaluated per RECIST v1.1 and modified RECIST for HCC, typically every 6–9 weeks during treatment and every 3 months thereafter. Participants will be followed for up to 36 months to capture long-term survival and quality-of-life outcomes.
Primary endpoints are cohort-specific:
Cohort 1 (unresectable, first-line ICIs): progression-free survival (time from treatment initiation to radiological progression by RECIST v1.1 or modified RECIST, or death), assessed up to 24 months.
Cohort 2 (adjuvant after resection): disease-free survival (time from surgery to recurrence or death), assessed up to 36 months.
Cohort 3 (neoadjuvant conversion intent): pathological complete response rate (absence of viable tumour in surgical specimen) assessed by standardised pathological criteria.
Secondary endpoints include overall survival, objective response rate, quality of life measures and correlations between psychological measures, biomarker dynamics and clinical outcomes.
The protocol specifies use of Kaplan–Meier survival analysis for time-to-event endpoints and Cox proportional hazards models to evaluate associations between ED measures and clinical outcomes. Analyses will account for cohort-specific endpoints and standard covariates. Participants will be followed up to 36 months to capture survival outcomes. Specific sample size calculations and power assumptions were described in the source protocol text; any additional analytic details beyond those reported were not provided in the source summary.
Key strengths include the prospective, multicohort design enabling comparisons across unresectable, adjuvant and neoadjuvant settings; the dual psychological assessment approach combining PHQ-9, GAD-7, HAMD-17 and HAMA; and serial biomarker sampling linking stress and immune measures to clinical outcomes. Limitations include the observational design, which precludes causal inference, and recruitment limited to three Chinese tertiary hospitals, which may affect external generalisability to other populations and healthcare settings.
Ethics approvals have been obtained 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). The study adheres to the Declaration of Helsinki. The trial is registered under NCT07141056. Results will be submitted to peer-reviewed journals and presented at international conferences. The source indicates that data sharing and dissemination will follow standard academic routes; specific data access plans beyond publication were not detailed in the source.