Association Between Chronic Psychological Stress and Disease Course Outcomes in Pancreatic Cancer

Official title

A Prospective Cohort Study on the Association Between Chronic Psychological Stress and Disease Course Outcomes in Pancreatic Cancer: A Comprehensive Analysis Based on Multidimensional Dynamic Psychological Assessment (MIND-PANC)

Overview

This is a prospective, observational cohort study (MIND-PANC) to explore the associations of chronic psychological stress with disease progression, treatment outcomes, and prognosis of pancreatic cancer. Researchers will ask participants to fill out simple questionnaires about their mood, worries, and sleep at the start of the study and at regular follow-up visits. The study will also collect a small blood sample (leftover from routine care) to measure stress-related markers. Investigators hypothesize that pancreatic cancer patients who have higher levels of ongoing psychological stress (such as anxiety, depression, or poor sleep) tend to have shorter survival times, a higher chance of recurrence, and a poorer response to treatment, compared to patients with lower stress levels.

Detailed description

Study Design and Population This is a multicenter, prospective, observational cohort study designed to investigate whether chronic psychological stress (anxiety, depression, and sleep disturbance) is independently associated with disease course outcomes in patients with pancreatic cancer.

Study Procedures At baseline (day 0), participants complete validated self-report instruments: the Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Pittsburgh Sleep Quality Index (PSQI). Clinical data are extracted from medical records (demographics, tumor stage, CA19-9, treatment history, comorbidities, etc.). A 2 mL remnant peripheral blood sample (collected during routine morning phlebotomy) is obtained for serum separation and storage at -80 °C; samples will be shipped to the central laboratory (Zhongshan Hospital) for batch analysis of biomarkers.

Follow-up assessments occur at key clinical time points (neoadjuvant therapy mid-point, adjuvant therapy mid-point, end of adjuvant therapy, 12-month long-term follow-up, and at disease progression/recurrence). Psychological scales are repeated at each time point. Clinical outcomes (recurrence, progression, treatment modifications, adverse events, survival status) are captured every 3 months via medical records or telephone contact.

Quality Assurance and Data Management

Quality assurance plan: All sites receive standardized training on study procedures, scale administration, and GCP principles. Regular multicenter meetings and annual on-site monitoring/remote auditing by the coordinating center (Fudan University Zhongshan Hospital) are conducted.

Data validation: A web-based electronic data capture (EDC) system is used with automated range and logic checks. Queries are generated for out-of-range or inconsistent entries.

Source data verification (SDV): A random sample of 10% of participants will undergo SDV against original medical records. For key endpoints (OS, PFS, and psychological scores), 100% SDV will be performed.

Data dictionary: A comprehensive data dictionary defines all variables, including coding dictionaries (MedDRA for adverse events, WHO Drug Dictionary for concomitant medications).

Standard Operating Procedures (SOPs): SOPs govern recruitment, informed consent, psychological assessment, biospecimen handling, data entry, adverse event reporting, and protocol amendments.

Sample Size Assessment The sample size of 320 patients was calculated based on the primary outcome (OS) using a two-sided alpha of 0.05, power of 80%, a hazard ratio (HR) of 1.5 (high vs. low psychological stress), an event rate of 67.5%, and 10% loss to follow-up. The Schoenfeld formula yields at least 192 death events and 285 completed patients; after accounting for dropouts, 317 patients are needed, rounded to 320. The HR of 1.5 is justified by recent literature and represents a clinically meaningful medium effect size while maintaining feasibility.

Handling of Missing Data For OS, missing survival dates are minimized by active follow-up. For covariates and scale items with random missingness (\<15%), multiple imputation (MI) will be used, with complete-case analysis as sensitivity.

Statistical Analysis Plan

Primary analysis: Kaplan-Meier curves, log-rank tests, and multivariable Cox proportional hazards models (adjusting for study center, age, TNM stage, surgery, ECOG score, etc.) will be used to estimate the HR for OS. The proportional hazards assumption will be tested by Schoenfeld residuals.

Secondary analyses: Similar Cox models will be applied to PFS. Longitudinal trajectories of psychological scores (HADS, PHQ-9, GAD-7, PSQI) will be modeled using generalized estimating equations (GEE).

Subgroup and sensitivity analyses: Pre-specified subgroups (by TNM stage, surgery type, age, site) will be examined with interaction tests. Sensitivity analyses will use alternative definitions of psychological stress (e.g., continuous z-score) and different missing data methods.

Bias assessment: E-values will be calculated for unmeasured confounding. Selection bias will be assessed by comparing completers vs. dropouts; worst-case scenario sensitivity analyses will be performed.

Ethics and Dissemination The protocol (version V1.4, dated 20260302) has been approved by the ethics committees of all participating centers. Results will be published in peer-reviewed journals regardless of outcome direction.

Primary outcome measures

• overall survival [Time frame: 3 years]

Secondary outcome measures (4)

• progression-free-survival [Time frame: 3 years]
• disease-free-survival [Time frame: 3 years]
• The prevalence of depression and/or anxiety among participants as assesed by HADS and PSQI questionnaire [Time frame: 3 weeks]
• recurrence rate of different types and sites [Time frame: 3 years]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years.
• Histologically or cytologically confirmed diagnosis of pancreatic cancer, or other pancreatic diseases.
• Conscious, with basic reading/writing or communication skills, able to understand and complete the questionnaire assessments (either independently, with assistance from research staff, or with help from a family member).
• Voluntarily agree to participate in this study and sign a written informed consent form.

Exclusion criteria

• Presence of severe cognitive impairment (e.g., dementia, disturbance of consciousness) or a definite history of psychiatric disorders, judged by the investigator as unable to comply with the study assessments, and without a family member who can help complete the questionnaire assessments.
• Presence of other severe, uncontrolled systemic diseases (e.g., severe heart, lung, or kidney failure), with an estimated life expectancy < 3 months as judged by the investigator.
• Inability to understand Chinese or presence of severe visual/hearing impairment that affects completion of the questionnaire assessments, and without a family member who can help complete the questionnaire assessments.

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 · 3 centers

• the Third Xiangya Hospital of Central South University — Changsha
• Zhongshan Hospital Affiliated to Fudan University — Shanghai
• The First Affiliated Hospital of Xi'an Jiao Tong University — Xi’an

Publications

• Peng F, Lu J, Su K, Liu X, Luo H, He B, Wang C, Zhang X, An F, Lv D, Luo Y, Su Q, Jiang T, Deng Z, He B, Xu L, Guo T, Xiang J, Gu C, Wang L, Xu G, Xu Y, Li M, Kelley KW, Cui B, Liu Q. Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis. Cell Metab. 2024 Jul 2;36(7):1598-1618.e11. doi: 10.1016/j.cmet.2024.04.018. Epub 2024 May 20. PMID 38772364
• Pariollaud M, Ibrahim LH, Irizarry E, Mello RM, Chan AB, Altman BJ, Shaw RJ, Bollong MJ, Wiseman RL, Lamia KA. Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer. Sci Adv. 2022 Sep 30;8(39):eabo1123. doi: 10.1126/sciadv.abo1123. Epub 2022 Sep 28. PMID 36170373
• Peng Z, Song J, Zhu W, Bao H, Hu Y, Shi Y, Cheng X, Jiang M, Fang F, Chen J, Shu X. Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1alpha axis in tumor lipid metabolism and metastasis. Mol Metab. 2025 Mar;93:102109. doi: 10.1016/j.molmet.2025.102109. Epub 2025 Feb 6. PMID 39920992
• Liu JL, Xu X, Rixiati Y, Wang CY, Ni HL, Chen WS, Gong HM, Zhang ZL, Li S, Shen T, Li JM. Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells. Cell Metab. 2024 Jun 4;36(6):1320-1334.e9. doi: 10.1016/j.cmet.2024.04.019. PMID 38838643
• Li Y, Yu H, Li ZM, Yin KW, Jin SY, Chen CC, Tan MS, Zhang CJ, Liu XH, Li WP, Yang JM, Zhou AJ, Zhang X, Ni ED, Wang ML, Mo H, Qin C, Hu J, Li SJ, Gao TM, Li JM. Colorectal cancer cells hijack a brain-gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth. Nat Cancer. 2025 Nov;6(11):1800-1820. doi: 10.1038/s43018-025-01033-x. Epub 2025 Aug 21. PMID 40841473
• Zhou R, Li K, Hu X, Fan S, Gao Y, Xue X, Bu Y, Zhang H, Wang Y, Wei C, Zhang S, Xie Z, Liu C, Chen P, Yin Z, Ren D. Sleep Deprivation Activates a Conserved Lactate-H3K18la-RORalpha Axis Driving Neutrophilic Inflammation Across Species. Adv Sci (Weinh). 2025 Oct;12(38):e04028. doi: 10.1002/advs.202504028. Epub 2025 Jul 21. PMID 40686333
• Cui B, Luo H, He B, Liu X, Lv D, Zhang X, Su K, Zheng S, Lu J, Wang C, Yang Y, Zhao Z, Liu X, Wang X, Zhao Y, Nie X, Jiang Y, Zhang Z, Liu C, Chen X, Cai A, Lv Z, Liu Z, An F, Zhang Y, Yan Q, Kelley KW, Xu G, Xu L, Liu Q, Peng F. Gut dysbiosis conveys psychological stress to activate LRP5/beta-catenin pathway promoting cancer stemness. Signal Transduct Target Ther. 2025 Mar 5;10(1):79. doi: 10.103 PMID 40038255
• Zeng Y, Hu CH, Li YZ, Zhou JS, Wang SX, Liu MD, Qiu ZH, Deng C, Ma F, Xia CF, Liang F, Peng YR, Liang AX, Shi SH, Yao SJ, Liu JQ, Xiao WJ, Lin XQ, Tian XY, Zhang YZ, Tian ZY, Zou JA, Li YS, Xiao CY, Xu T, Zhang XJ, Wang XP, Liu XL, Wu F. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med. 2024 Jun;30(6):1680-1688. doi PMID 38740994

Identifiers

NCT: NCT07529626 · B2026-092R

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗