---
title: "Emotional distress and immune checkpoint inhibitor efficacy in hepatocellular carcinoma: multicent"
id: "bmj-open-1-association-between-emotional-distress-and-efficacy-of-immune-checkpoint"
canonical_url: "https://medichelpline.com/clinical-feed/bmj-open-1-association-between-emotional-distress-and-efficacy-of-immune-checkpoint"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "BMJ Open"
source_url: "http://bmjopen.bmj.com/cgi/content/short/16/7/e110148?rss=1"
published_at: "2026-07-22T08:50:16.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Emotional distress and immune checkpoint inhibitor efficacy in hepatocellular carcinoma: multicent
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/bmj-open-1-association-between-emotional-distress-and-efficacy-of-immune-checkpoint
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** BMJ Open
- **Source URL:** [Original Journal Publication](http://bmjopen.bmj.com/cgi/content/short/16/7/e110148?rss=1)
- **Published At:** 2026-07-22T08:50:16.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This protocol describes a multicentre, prospective observational cohort study assessing the association between **emotional distress** and the efficacy of **immune checkpoint inhibitors (ICIs)** in patients with **hepatocellular carcinoma (HCC)**. - The study will recruit 700 patients across three cohorts: unresectable HCC receiving first-line ICI therapy (n=400), adjuvant ICI after curative resection (n=200) and neoadjuvant ICI with conversion intent (n=100). - Recruitment began in October 2024 with anticipated completion of follow-up by October 2027; three tertiary hospitals in China are study sites. - Emotional distress is defined by validated thresholds (PHQ-9 ≥5 or GAD-7 ≥5) and will be measured with both self-report (PHQ-9, GAD-7) and clinician-administered scales (HAMD-17, HAMA), plus serial biomarker sampling. - Biomarker analysis includes morning cortisol, ACTH, inflammatory cytokines (IL-6, TNF-α, CRP) and immune markers (CD8+ T-cell and NK cell counts). - Primary endpoints differ by cohort: progression-free survival for unresectable disease, disease-free survival for adjuvant therapy, and pathological complete response rate for neoadjuvant therapy. - Secondary endpoints include overall survival, objective response rate, quality of life (EORTC QLQ-C30), and correlations between biomarkers, psychological measures and outcomes. - Statistical methods include Kaplan-Meier survival analysis and Cox proportional hazards models; follow-up up to 36 months. - The observational design enables real-world data collection but cannot establish causality; site selection limited to three Chinese tertiary hospitals may limit generalisability. - Ethical approvals have been obtained from three institutional ethics committees and the trial is registered (NCT07141056). Results will be published and presented at conferences.
## Clinical Analysis & Structured Key Points
Skip to main content Intended for healthcare professionals Log In Basket Search for this keyword Advanced search Latest content Archive For authors About Browse by collection You are here Home Archive Volume 16, Issue 7 Email alerts Article Text Article info Citation Tools Share Rapid Responses Article metrics Alerts PDF Oncology Protocol Association between emotional distress and efficacy of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a multicentre, prospective observational study protocol http://orcid.org/0009-0006-8664-5548Lin Ye1,2, Jiaye Liao3, Kangqiang Lin1,2, Xuanting Chen4, Yuanying Su5, Hao Shi1,2, Tao Wang1, Qingrong Mo1, Jun Weng1, Renjian Li1,2, Zhao Jiang1,2, Yaqun Yu1 Correspondence to Dr Yaqun Yu; yyq0129@glmc.edu.cn Abstract Introduction 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. Methods and analysis 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. Ethics and dissemination 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. Trial registration number NCT07141056. https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/. https://doi.org/10.1136/bmjopen-2025-110148 Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Request permissions STRENGTHS AND LIMITATIONS OF THIS STUDY Prospective three-cohort design enables comparison of emotional distress effects across unresectable, adjuvant and neoadjuvant hepatocellular carcinoma treatment settings. Dual assessment approach combines validated self-report instruments (Patient Health Questionnaire-9, Generalised Anxiety Disorder 7) with clinician-administered scales (Hamilton Depression Rating Scale-17, Hamilton Anxiety Rating Scale) and serial biomarker sampling. Observational design precludes causal inference regarding the relationship between emotional distress and immunotherapy outcomes. Recruitment limited to three Chinese tertiary hospitals, which may restrict generalisability to other populations and healthcare settings. Introduction Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of cancer-related deaths, with over 900 000 new cases annually, of which China accounts for more than half of global cases.1 The introduction of immune checkpoint inhibitors (ICIs) has fundamentally transformed HCC treatment, with the approval of atezolizumab plus bevacizumab as standard first-line therapy for advanced disease marking the beginning of a new therapeutic era2 . This milestone has catalysed widespread adoption of ICI-based combination strategies across all stages of HCC, with such regimens now dominating clinical investigation and treatment paradigms. Despite these advances, objective response rates remain modest at approximately 30%, underscoring the critical need to identify predictive factors that influence treatment efficacy and patient selection.3 Emotional distress (ED), operationally defined in this study as clinically significant symptoms of depression or anxiety (Patient Health Questionnaire-9 (PHQ-9) ≥5 or Generalised Anxiety Disorder 7 (GAD-7) ≥5), affects 30–50% of patients with cancer and is particularly prevalent in HCC due to the associated stigma of underlying liver disease and poor prognosis.4–6 Beyond its impact on quality of life, emerging evidence suggests that ED may directly influence cancer treatment outcomes through immune system modulation.7–9 Chronic psychological stress activates the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, leading to elevated cortisol and catecholamine levels. These stress hormones can suppress immune function by reducing T-cell proliferation, impairing natural killer cell activity and promoting regulatory T-cell expansion—mechanisms that may compromise the efficacy of immunotherapy.10–12 Despite these emerging data, the relationship between ED and immunotherapy outcomes in HCC remains poorly characterised. Patients with HCC may be particularly vulnerable to the immunosuppressive effects of chronic stress due to the underlying chronic liver disease and associated systemic inflammation. Furthermore, the optimal timing and methods for assessing ED in this population are unclear, as is the potential for psychological interventions to improve treatment outcomes. Recent clinical studies have provided compelling evidence for this relationship. The landmark STRESS-LUNG-1 study demonstrated that pretreatment ED was independently associated with shorter progression-free survival (7.9 vs 15.5 months) and lower objective response rates (46.8% vs 64.9%) in patients with advanced non-small cell lung cancer receiving first-line ICIs.13 Similar findings have been reported in patients with gastric cancer, where ED was associated with worse treatment response and survival outcomes. 14 In patients with melanoma receiving neoadjuvant immune checkpoint blockade, an exploratory post hoc analysis of the phase 2 PRADO trial demonstrated that pretreatment emotional distress was significantly associated with reduced major pathological responses (46% vs 65%) and reduced 2-year relapse-free survival (74% vs 91%), even after adjusting for established biomarkers such as interferon-gamma signature and tumour mutational burden; however, the post hoc and exploratory nature of this analysis warrants cautious interpretation.15 Recent studies have established high prevalence of emotional distress among patients with HCC, with systematic reviews showing pooled global prevalence rates of 22% for depression and 22% for anxiety. 16 A multicentre study of 100 patients with advanced HCC found anxiety and depression incidence rates of 64% and 65%, respectively, with significant negative associations between emotional distress and quality of life measures. 17 These findings underscore the substantial psychological burden faced by patients with HCC and provide compelling rationale for investigating the potential impact of emotional distress on treatment outcomes.18 19 This study aims to address these knowledge gaps by conducting a comprehensive, multicohort investigation of ED and immunotherapy outcomes in patients with HCC. We hypothesise that pretreatment ED will be associated with worse clinical outcomes across different treatment settings, and that changes in ED during treatment will correlate with treatment response. The findings may inform the development of integrated psycho-oncological care strategies to optimise immunotherapy efficacy in patients with HCC. Methods and analysis Study design This is a multicentre, prospective, observational cohort study investigating the association between emotional distress and clinical outcomes in patients with HCC receiving ICI therapy. The study employs a three-cohort design to comprehensively evaluate the relationship between emotional distress and treatment outcomes across different clinical scenarios: unresectable disease receiving first-line therapy, adjuvant therapy following curative resection and neoadjuvant therapy with conversion intent. Three tertiary hospitals in China have been registered as study sites, each capable of providing ICI therapy for HCC and willing to implement the study’s psychological assessment protocols. Patient recruitment commenced in October 2024, with study completion including follow-up assessments anticipated by October 2027. This observational design allows for real-world evidence generation by studying patients receiving routine clinical care while adding standardised research assessments to evaluate the relationship between emotional distress and treatment outcomes. Informed consent All eligible patients will receive detailed verbal and written information about the study objectives, procedures, potential risks and benefits and their rights as research participants. The informed consent process will be conducted by qualified investigators with expertise in oncology and research ethics, ensuring patients have adequate time to consider participation and ask questions. The consent documentation will explicitly outline the observational nature of the study, emphasising that participation will not alter their standard cancer treatment but will involve additional psychological assessments and blood sampling for research purposes. Patients will be informed about data confidentiality measures, their right to withdraw from the study at any time without affecting their clinical care and procedures for accessing psychological support services if distress is identified during assessments. Special attention will be given to ensuring patients understand that psychological assessment results may identify mental health concerns requiring clinical attention, and clear pathways for referral to appropriate mental health services will be established. Written informed consent will be obtained from all participants before any study-specific procedures, with consent forms available in local languages and culturally appropriate formats. Inclusion and exclusion criteria The inclusion criteria are designed to capture a representative population of patients with HCC initiating ICI therapy while ensuring participants can meaningfully contribute to study objectives. The inclusion criteria are as follows (1): age ≥18 years; (2) histologically or radiologically confirmed HCC according to the Chinese Guidelines for Primary Liver Cancer; 20 (3) planned for initiation of ICI therapy, either as monotherapy or in combination regimens, according to standard clinical practice and institutional protocols; (4) Eastern Cooperative Oncology Group performance status 0–2; (5) Child-Pugh class A or B (score ≤7); (6) adequate organ function, defined by absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥75×10⁹/L, haemoglobin ≥85 g/L, total bilirubin ≤3.0 mg/dL, alanine aminotransferase ≤5 times the upper limit of normal and creatinine clearance ≥30 mL/min; (7) ability to complete psychological assessment questionnaires; (8) ability to provide signed informed consent. The exclusion criteria are as follows: (1) mixed hepatocellular-cholangiocarcinoma histology; (2) previous systemic therapy for HCC except in the adjuvant cohort where prior therapy may be part of the treatment sequence; (3) active psychiatric illness requiring hospitalisation, severe major psychiatric disorders or cognitive impairment precluding questionnaire completion; (4) symptomatic brain metastases; (5) expected survival less than 3 months; (6) pregnancy or lactation; (7) concurrent participation in interventional clinical trials. Study procedures The study procedures encompass comprehensive baseline assessment, standardised treatment monitoring and systematic follow-up evaluations designed to capture the relationship between emotional distress and clinical outcomes. At study entry, participants will undergo detailed baseline characterisation including demographic information, medical history, disease staging according to Barcelona Clinic Liver Cancer classification, performance status evaluation and laboratory assessments. Emotional distress will be evaluated through both self-reported questionnaires and clinician-administered scales, with the PHQ-9 and GAD-7 providing standardised self-assessment tools.21 22 While the HAMD-17, HAMA offer clinical validation of psychological status. 23 24 Quality of life assessment will be conducted using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.25 Blood samples will be collected for stress biomarker analysis, including cortisol levels measured from morning samples collected between 08:00 and 10:00, adrenocorticotropic hormone levels, inflammatory cytokines including interleukin-6, tumour necrosis factor-α and C-reactive protein, as well as immune markers encompassing CD8+T cell and natural killer cell counts. During the treatment phase, participants will receive ICI therapy according to their treating physician’s recommendations and institutional protocols, which may include atezolizumab plus bevacizumab, durvalumab plus tremelimumab, single-agent programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, or other combination regimens representing evolving standard of care. Since this is an observational study, all treatment decisions remain at the discretion of the clinical team, with study procedures limited to data collection and assessment activities. Follow-up evaluations will occur every 6 weeks during active treatment and every 3 months during post-treatment surveillance, incorporating repeated psychological assessments, quality of life evaluations, biomarker sampling and clinical outcome documentation. Radiological assessments will be performed according to institutional standards, typically every 6–9 weeks during treatment and every 3 months during follow-up, with response evaluation conducted according to Response Evaluation Criteria in Solid Tumours V.1.1 and modified RECIST criteria for HCC.26 Participants will be followed for up to 36 months to capture long-term survival and quality of life outcomes, with procedures designed to minimise patient burden while maintaining comprehensive data collection for meaningful analysis. The flow of the study is illustrated in figure 1. Download figure Open in new tab Download powerpoint Figure 1 Flowchart of study design. ACTH, adrenocorticotropic hormone; BCLC, Barcelona Clinic Liver Cancer; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; ED, emotional distress; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; GAD-7, Generalised Anxiety Disorder 7-item scale; HAMD-17, Hamilton Depression Rating Scale-17; HAMA, Hamilton Anxiety Rating Scale; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; IL-6, interleukin-6; NK, natural killer; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PHQ-9, Patient Health Questionnaire-9; TNF-α, tumour necrosis factor-α. Study endpoints This multicohort study employs cohort-specific primary endpoints tailored to the most clinically relevant outcome for each treatment setting. In Cohort 1 (unresectable HCC receiving first-line ICIs), the primary endpoint is progression-free survival, defined as the time from treatment initiation to disease progression according to Response Evaluation Criteria in Solid Tumours V.1.1 or modified RECIST for HCC, or death from any cause, whichever occurs first, assessed up to 24 months. This endpoint was selected based on its clinical relevance in advanced HCC and established precedent from studies demonstrating associations between emotional distress and progression-free survival in other cancer types receiving ICI therapy. For Cohort 2 (adjuvant therapy following curative resection), the primary endpoint is disease-free survival, defined as the time from surgical resection to disease recurrence or death from any cause, whichever occurs first, assessed up to 36 months. This endpoint reflects the curative intent of the adjuvant setting and aligns with standard oncological practice for evaluating adjuvant therapies in HCC. Disease-free survival provides the most clinically meaningful assessment of treatment benefit in patients who have achieved complete resection and are receiving therapy to prevent recurrence. In Cohort 3 (neoadjuvant therapy with conversion intent), the primary endpoint is pathological complete response rate, defined as the percentage of patients achieving complete absence of viable tumour cells in the surgical specimen following neoadjuvant ICI therapy. This endpoint was selected because pathological complete response represents the optimal outcome of neoadjuvant therapy and has been established as a strong surrogate for long-term survival benefit in other cancer types. Assessment will be conducted by experienced pathologists using standardised criteria for HCC pathological response evaluation. The rationale for employing different primary endpoints across cohorts reflects the distinct therapeutic objectives and clinical contexts of each treatment setting. In unresectable disease, the goal is disease stabilisation and progression delay, making progression-free survival the most appropriate measure. In the adjuvant setting, the objective is prevention of recurrence following complete resection, for which disease-free survival provides the most relevant assessment. For neoadjuvant therapy, the immediate goal is tumour response to facilitate surgical resection, with pathological complete response serving as the optimal measure of treatment efficacy. Secondary endpoints are designed to provide comprehensive assessment of clinical benefit, patient experience and treatment safety across all three cohorts. Overall survival, measured as time from treatm
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