The Impact of Emotional Stress on Immunotherapy Outcomes in Liver Cancer Patients: A Multi-Cohort Study

Official title

Impact of Emotional Stress on Immune Checkpoint Inhibitor Treatment Outcomes in Hepatocellular Carcinoma: A Multicohort Clinical Study

Overview

The goal of this observational study is to learn if emotional distress affects how well liver cancer treatment works in people receiving immunotherapy. Emotional distress means feeling anxious or depressed. The study aims to answer whether having emotional distress before treatment or changes in emotional distress during treatment affect how well immunotherapy works to treat liver cancer. Researchers will compare participants with and without emotional distress to examine differences in how long the cancer stays under control, treatment response, and overall survival time. Study participants will complete mood and quality of life questionnaires, meet with mental health specialists for emotional assessments, undergo regular blood tests to measure stress hormones, have routine medical check-ups and scans to monitor their cancer status, and be followed for up to 3 years. The study includes three groups of people with liver cancer: those starting immunotherapy for cancer that cannot be removed by surgery, those receiving immunotherapy after surgery, and those receiving immunotherapy before surgery. To be eligible for participation, individuals must be 18 years or older, diagnosed with liver cancer, about to start immunotherapy treatment, and able to complete mood questionnaires.

Detailed description

This multi-center prospective cohort study investigates the relationship between emotional distress (ED) and treatment outcomes in patients receiving immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (liver cancer). Recent research suggests that emotional distress may influence how well cancer treatments work, particularly immunotherapy, but this connection hasn't been well studied in liver cancer patients.

Scientific Background: Liver cancer is a major global health concern, with increasing cases worldwide. While immunotherapy has emerged as a promising treatment option, not all patients respond equally well to this therapy. Understanding factors that might influence treatment success is crucial for improving patient care. Recent studies have shown that emotional distress can affect immune system function, which may impact how well immunotherapy works.

Study Design: The study includes three distinct cohorts of liver cancer patients:

Cohort 1: Patients with unresectable liver cancer starting first-line ICI therapy Cohort 2: Patients receiving ICI therapy after surgery (adjuvant therapy) Cohort 3: Patients receiving ICI therapy before surgery (neoadjuvant therapy)

Comprehensive Assessment Approach:

Emotional distress will be evaluated through multiple methods:

Self-reported questionnaires (PHQ-9 for depression and GAD-7 for anxiety) Professional clinical assessments (Hamilton Depression Scale, Hamilton Anxiety Scale, and Clinical Global Impression Scale) Quality of life measurements Biological markers of stress measured through blood tests

Treatment Monitoring: Participants will receive standard-of-care immunotherapy according to their treating physician's recommendations. The study will not influence treatment decisions but will carefully monitor:

Treatment response through regular imaging Side effects Quality of life Changes in emotional well-being Biological markers of stress and immune function Expected Outcomes and Impact: This study aims to: Determine if emotional distress affects treatment outcomes, Identify which patients might benefit from additional psychological support Understand the biological mechanisms linking stress and treatment response, Develop better strategies for supporting patients during immunotherapy Patient Safety and Support: While this is an observational study that doesn't change standard treatment, we recognize that discussing emotional health can be sensitive. The study includes: Regular monitoring of participants' emotional well-being, Access to mental health professionals if needed, Clear protocols for handling any psychological concerns that arise, Protection of patient privacy and confidentiality Long-term Goals: The findings from this study could lead to: Better ways to identify patients who might need extra support during treatment, New strategies to improve treatment effectiveness, More personalized approaches to cancer care that consider both physical and emotional health, Improved understanding of how psychological factors affect cancer treatment Duration and Follow-up: The study will enroll participants over three years, with each participant followed for up to three years. This allows us to understand both immediate and long-term relationships between emotional well-being and treatment outcomes.

Study Innovation: This is one of the first large-scale studies to: Examine the impact of emotional distress on immunotherapy outcomes in liver cancer, Use both patient self-assessments and professional clinical evaluations, Study this relationship across different stages of treatment.

Interventions

• Other Psychological Stress Status
  Psychological stress status will be assessed using both self-reported and clinician-rated measures. Participants will be categorized into stressed and non-stressed groups based on the following criteria: Self-reported measures (either): PHQ-9 score ≥ 5 (depression symptoms) and/or; GAD-7 score ≥ 5 (anxiety symptoms) Clinician-rated measures (either): HAMD score ≥ 7 (mild depression) and/or HAMA score ≥ 7 (mild anxiety) Additional assessments: Clinical Global Impression Scale (CGI) EORTC QLQ-C30
• Other Psychological Stress Status
  Psychological stress status will be assessed using both self-reported and clinician-rated measures. Participants will be categorized into stressed and non-stressed groups based on the following criteria: Self-reported measures (either): PHQ-9 score ≥ 5 (depression symptoms) and/or; GAD-7 score ≥ 5 (anxiety symptoms) Clinician-rated measures (either): HAMD score ≥ 7 (mild depression) and/or HAMA score ≥ 7 (mild anxiety) Additional assessments: Clinical Global Impression Scale (CGI) EORTC QLQ-C30
• Other Psychological stress status
  Psychological stress status will be assessed using both self-reported and clinician-rated measures. Participants will be categorized into stressed and non-stressed groups based on the following criteria: Self-reported measures (either): PHQ-9 score ≥ 5 (depression symptoms) and/or; GAD-7 score ≥ 5 (anxiety symptoms) Clinician-rated measures (either): HAMD score ≥ 7 (mild depression) and/or HAMA score ≥ 7 (mild anxiety) Additional assessments: Clinical Global Impression Scale (CGI) EORTC QLQ-C30

Primary outcome measures

• Progression-Free Survival (PFS) [Time frame: Up to 24 months]
• Disease-Free Survival (DFS) [Time frame: Up to 36 months]
• Pathological Complete Response (pCR) Rate [Time frame: At time of surgery (approximately 6-8 weeks after neoadjuvant therapy)]

Secondary outcome measures (9)

• Overall Survival (OS) [Time frame: Up to 36 months]
• Objective Response Rate (ORR) [Time frame: Up to 2 years (assessed every 6-8 weeks from from treatment initiation until disease progression or death from any cause)]
• Stress Biomarker Levels [Time frame: From baseline up to 36 months (assessed every 3 months until study completion, disease progression, or death from any cause, whichever occurs first)]
• Safety and Adverse Events [Time frame: Throughout study duration (up to 36 months)]
• Health-Related Quality of Life measured by EORTC QLQ-C30 Total Score [Time frame: Baseline, 6 weeks, 9 weeks, then every 12 weeks through study completion (up to 3 years).]
• Changes in Depression Scores (PHQ-9) [Time frame: Baseline, 6 weeks, 9 weeks, then every 12 weeks through study completion (up to 3 years)]
• Changes in Anxiety Scores (GAD-7) [Time frame: Baseline, 6 weeks, 9 weeks, then every 12 weeks through study completion (up to 3 years)]
• Changes in Depression Scores (HAMD) [Time frame: Baseline, 6 weeks, 9 weeks, then every 12 weeks through study completion (up to 3 years)]
• Changes in Anxiety Scores (HAMA) [Time frame: Baseline, 6 weeks, 9 weeks, then every 12 weeks through study completion (up to 3 years)]

Eligibility criteria

Cohort 1 (SOLACE-1):

Inclusion criteria

• Age ≥ 18 years
• Able to complete psychological questionnaires
• Child-Pugh liver function class A
• ECOG performance status ≤ 1
• Signed informed consent
• Expected survival > 3 months
• Diagnosed with unresectable HCC by pathology or imaging
• BCLC stage B or C
• Has at least one measurable lesion (mRECIST)
• About to receive first-line ICI treatment

Exclusion criteria

• Currently taking antidepressant or anti-anxiety medications
• Previous diagnosis of psychiatric disorders
• Concurrent malignancy
• Unable to complete psychological assessments
• Previous systemic anti-tumor therapy
• Symptomatic brain metastases
• Child-Pugh score > 7

Cohort 2 (SOLACE-2):

Inclusion criteria

• Age ≥ 18 years
• Able to complete psychological questionnaires
• Child-Pugh liver function class A
• ECOG performance status ≤ 1
• Signed informed consent
• Expected survival > 3 months
• Pathologically confirmed HCC after curative surgery
• Pathological stage II or III (AJCC 8th edition)
• Will start adjuvant ICI therapy within 4-6 weeks after surgery
• Expected survival > 12 months

Exclusion criteria

• Currently taking antidepressant or anti-anxiety medications
• Previous diagnosis of psychiatric disorders
• Concurrent malignancy
• Unable to complete psychological assessments
• Residual lesions after surgery
• Child-Pugh score B or C

Cohort 3 (SOLACE-3):

Inclusion criteria

• Age ≥ 18 years
• Able to complete psychological questionnaires
• Child-Pugh liver function class A
• ECOG performance status ≤ 1
• Signed informed consent
• Expected survival > 3 months
• Diagnosed with resectable HCC by pathology or imaging
• Has at least one measurable lesion (RECIST 1.1)
• About to receive neoadjuvant ICI treatment
• Expected survival > 12 months

Exclusion criteria

• Currently taking antidepressant or anti-anxiety medications
• Previous diagnosis of psychiatric disorders
• Severe cardiac, pulmonary, or renal dysfunction
• Concurrent malignancy
• Unable to complete psychological assessments
• Previous systemic anti-tumor therapy
• Symptomatic brain metastases
• Child-Pugh score B or C

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

China · 5 centers

• The Second Affiliated Hospital of Guangdong Medical University — Zhanjiang
• The Affiliated Hospital of Guilin Medical University — Guilin
• The Second Affiliated Hospital of Guilin Medical University — Guilin
• Shaoyang Central Hospital — Shaoyang
• The First Affiliated Hospital of Shaoyang College — Shaoyang

Publications

• Ye L, Liao J, Lin K, Chen X, Su Y, Shi H, Wang T, Mo Q, Weng J, Li R, Jiang Z, Yu Y. Association between emotional distress and efficacy of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a multicentre, prospective observational study protocol. BMJ Open. 2026 Jul 22;16(7):e110148. doi: 10.1136/bmjopen-2025-110148. PMID 42486514

Identifiers

NCT: NCT07141056 · 2024IITLL-51

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗