Chronic stress impacts the prognosis of hepatocellular carcinoma patients after curative treatment by establishing a novel comprehensive classification: a cohort study and systematic review

Abstract

Aims

To investigate the impact of varying levels of chronic stress on the disease-free survival (DFS) and overall survival (OS) of patients with hepatocellular carcinoma (HCC) following curative treatment and establish a comprehensive evaluation index for chronic stress.

Methods

Ninety HCC patients who underwent curative treatment were assessed for chronic stress using hair cortisol concentration, Stress Score, and the Perceived Stress Scale (PSS-10). The optimal cut-off values for these markers were statistically determined, and correlations among them were analyzed to create the Chronic Stress Index (CSI), which classified patients into high or low chronic stress groups. DFS and OS were compared between the groups. Additionally, a systematic review of literatures on the effects of chronic stress and cancer recurrence was conducted.

Results

The optimal cut–off values of the Stress Score, PSS-10, and hair cortisol concentration were 15.30, 50.00 and 19.70 pg/mg, respectively. Patients with a CSI score of 3 to 4 were classified into the low chronic stress state (LCSS) group, whereas those scoring 5 to 6 were classified into the high chronic stress state (HCSS) group. Patients in the HCSS group had significantly reduced DFS (P < 0.001) and OS (P = 0.033) compared to the LCSS group. The systematic review identified only three clinical trials on chronic stress and cancer recurrence.

Conclusion

High chronic stress levels are associated with shorter DFS and OS in HCC patients. The CSI classification effectively categorized the chronic stress state, providing a novel tool for clinical evaluation.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12888-025-07288-z.

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1].China accounts for approximately 55% of new HCC cases globally [2].Although hepatectomy is recommended as the primary treatment for HCC according to several guidelines [3], the recurrence rate after curative treatment remains high, reaching up to 75% within five years [4]. Numerous studies have explored methods to prevent tumor recurrence following curative resection of HCC [5, 6]; however, a universally recognized treatment that, in addition to the IMBRAVE 050 results, leads to improved recurrence-free survival (RFS) has yet to be established. This highlights the urgent need to identify novel approaches to reduce recurrence rates and improve patient outcomes. The recurrence of HCC is influenced by various factors, including tumor size, microvascular invasion, vascular tumor embolism, the tumor microenvironment, and the patient’s psychological state [4, 7]. Among these, the psychological state of patients is a crucial element that significantly impacts the postoperative recurrence of HCC, as evidenced by numerous experimental studies and pilot clinical trials [8–12]. However, these factors have long been overlooked by doctors and researchers.

Stress can be categorized into acute stress and chronic stress based on the duration of the stimulus [13]. Cancer patients frequently experience chronic stress due to the prolonged and intense nature of their diagnosis and treatment, leading to symptoms such as insomnia, mental tension, and mild depression [14–16]. Chronic stress, in particular, has been shown to accelerate cancer progression and promote metastasis in various cancers, including breast, gastric, and lung cancers, through mechanisms such as sympathetic nervous system activation, angiogenesis, and immune modulation [17, 18]. We conducted a systematic review of the effects of chronic stress on cancer recurrence prior to implementation of our study. We found that there are few clinical studies on the effects of chronic stress on cancer prognosis. Therefore, research on the impact of chronic stress on the recurrence in patients following curative treatment holds significant clinical importance and addresses the academic gap in clinical research related to HCC. Additionally, our previous study confirmed that the sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through the activation of alpha-1 adrenergic receptors on Kupffer cells, thereby providing theoretical support for our research [12].

However, a standardized method for evaluating the chronic stress state of cancer patients and exploring the effects of different levels of chronic stress on the prognosis of HCC patients in a clinical setting has not yet been implemented. To address this gap, we propose a comprehensive evaluation index for assessing the chronic stress state in HCC patients after curative treatment. This study aims to explore how varying levels of chronic stress impact postoperative disease-free survival (DFS) and overall survival (OS), providing novel insights into the role of psychological factors in HCC recurrence and prognosis.

Patients and methods

Patient selection

The inclusion criteria for this study were as follows: (1) aged between 18 and 75 years; (2) diagnosed with HCC confirmed by postoperative pathology; (3) no absolute surgical contraindication prior surgery, no distant metastasis or major vascular invasion before surgery, and be able to achieve curative treatment of the tumor (hepatectomy or radiofrequency ablation) technically, with no residual tumor confirmed by imaging and pathology; (4) Child–Pugh class A or grade B (without ascites); (5) Barcelona Clinic Liver Cancer (BCLC) stage A or B; (6) Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1. (7) Patients who provided written informed consent to participate in the study. Patients were excluded if they met any of the following criteria: (1) a history of other malignancies; (2) patients with severe comorbidities, such as uncontrolled diabetes, cardiovascular disease, or chronic kidney disease, that could influence postoperative outcomes; (3) central nervous system disease, mental illness, psychiatric disorders or cognitive impairments that could interfere with the assessment of chronic stress; (4) long-term or currently taking foods and drugs that can alter the activity of the sympathetic nervous system; (5) insufficient hair in the posterior vertex area; (6) failure to scheduled follow-up appointments and testing.

This study was a single-center, prospective cohort investigation. Informed consent was obtained from all participants after they were providing detailed information regarding the study’s purpose, procedures, and potential risks. The study was approved by the Ethics Committee of the First Affiliated Hospital of Army Medical University, PLA (KY201747). Following enrollment, patients completed a questionnaire designed to assess any significant changes in their social education level, marital status, or family economic situation. This step was taken to exclude the potential interference of these factors in the assessment of their psychological stress state.

Chronic stress assessment method

Stress score

The Body-Checker detector (MEDICORE Company) was utilized to measure patients’ Stress Score, and both the heart rate variability (HRV) level and Stress Score were statistically analyzed. The Stress Score is derived from a comprehensive analysis of patients’ heart rate, heart rate variability, and other indicators, serving as an index to evaluate the stress level of patients. Studies have confirmed the Stress Score as a valid marker of sympathetic nervous system activity in healthy adults and athletes [19–21]. Our previous study has demonstrated that the Stress Score alone could effectively depict the chronic stress state of patients [22]. Patients were instructed to rest for 10 min before testing. After this period, they input their ID, sex, age and test times into the Body-Checker detector. The patient’s middle finger (either left or right hand) was then connected to the Body-Checker, and after waiting for 3–5 min, the Stress Score was recorded.

Hair cortisol concentration

Many studies have demonstrated that the hair cortisol concentration is a widely used marker for evaluating chronic stress [23, 24]. Hair samples were carefully cut from the posterior vertex position as close to the scalp as possible using fine scissors [25]. The total amount of hair collected was approximately equal to the thickness of a pencil. Hair samples were wrapped in aluminum foil and stored at room temperature in an envelope until analysis. Prior to analysis, the hair samples were washed with methanol twice and dried. The hair cortisol concentration was measured via liquid chromatography–tandem mass spectrometry (LC–MS/MS).

Perceived stress scale

The Perceived Stress Scale (PSS) is one of the most widely used tools for assessing stress perception [26, 27]. In 1983, Dr. Shelton Cohen, a psychologist at Carnegie Mellon University, compiled this scale [28]. The scale includes three editions: 14-item, 10-item and 4-item versions. The PSS-10 can reflect the stress state of patients over the past month. Each item is rated on a five-point scale from 0 = ‘never’ to 4 = ‘very often’. The 10-item version (PSS-10) consists of six negative and four positive items. The PSS-10 score is the sum of the scores of the 10 items (ranging from 0 to 40) [29]. Higher scores indicate higher levels of self-perceived stress in patients.

Establishing a comprehensive evaluation index of chronic stress

The cut-off values of the Stress Score, hair cortisol concentration, and PSS-10 were computed by evaluating their effects on the postoperative overall survival of HCC patients. The correlations among the three markers were explored, and a value assignment method was adopted to establish a comprehensive evaluation index of postoperative chronic stress in HCC patients. This chronic stress index was used to categorize HCC patients into different groups and to explore the differences in prognosis between patients with varying levels of chronic stress.

Literature review

Before the study, we conducted a literature search through three electronic databases: PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL).We utilized controlled terminology (MeSH and Emtree) and as well as free-text words to conduct the search. A combination of search terms and keywords included terms related to chronic stress (psychological stress, psychosocial stress, chronic stress, mental stress, distress, life events, job stress, work stress, death of a family member, loss of partner, depression, and anxiety) and outcomes (recurrence, relapse of neoplasm, cancer, tumor, carcinoma) and their combinations. We included all research articles published between 1950 and 2024 that involved human subjects, without limitations, provided they were written in English. The selection criteria were as follows: specific chronic stress assessment tools were used to evaluate chronic stress, and the study subjects needed to be divided into high- and low -stress groups. The impact of chronic stress on outcomes was required to be analyzed using effect measures such as hazard ratios (HRs) and relative risks (RRs). We excluded nonclinical studies, studies about the fear of tumor recurrence, and studies addressing the cancer-related biological aspects of chronic stress. Articles with no full text were excluded.

Data collection and follow‑up

Between June 2017 and January 2023, medical data were collected from 105 patients using the Advanced Southwest Hospital Scientific Research Platform. These data included demographic details and clinical parameters such as α-fetoprotein (AFP), indocyanine green retention rate at 15 min (ICGR-15), Child–Pugh grade, tumor size and number, presence of portal hypertension, severity of esophageal varices, splenomegaly, BCLC stage, and circulating tumor cell (CTCs) positivity. The patients’ Stress Score, PSS-10 scores, and hair cortisol concentrations were measured at 1, 3, and 6 months after the operation, and their mean values were calculated. The last follow-up date of this study was June 30, 2023. Contrast-enhanced MRI or CT were performed at intervals of four to eight weeks. Follow-up visits were systematically conducted bimonthly until disease progression or death occurred.

Statistics

Categorical data were analyzed using the chi-square test and Fisher’s exact test. Continuous data with a non-normal distribution were analyzed using the Mann–Whitney U test. The optimal cut-off values were calculated using the X-tile software. The Kaplan–Meier method was applied to generate survival curves, including those for cumulative overall survival (OS) and disease-free survival (DFS) for both groups. Additionally, the analysis of the effect of various stress markers on patient survival outcomes was also performed using the Kaplan–Meier method. Spearman’s rank correlation was employed to measure the monotonic relationship between two variables, which is often used for ordinal or non-normally distributed data. Since the PSS-10, hair cortisol concentration, and Stress Score were all non-normally distributed data, associations among these variables were explored using Spearman’s rank correlations. These correlations were classified as weak when the correlation coefficient (rho) was < 0.3, moderate if 0.3 to 0.49, or strong if > 0.5 [30]. The log–rank test was performed to evaluate the significance of the differences between the two groups. All p-values were two-sided, with p < 0.05 considered statistically significant. Statistical analyses were performed with SPSS 23.0 for Windows computer software (SPSS Inc., Chicago, IL) and GraphPad Prism software (version 9.0; GraphPad Prism Software Inc., San Diego, CA, USA).

Results

Characteristics of the study population

After screening, 105 patients diagnosed with primary HCC and who underwent hepatectomy or radiofrequency ablation were enrolled. Exclusions were made for various reasons: 3 patients were considered ineligible due to coexisting malignancies, 5 patients had insufficient hair in the posterior vertex area, 4 patients were lost to follow-up, and 3 patients had incomplete data. Consequently, 90 patients were included in the study, and their chronic stress states were assessed via hair cortisol concentration, Stress Score, and Perceived Stress Scale (PSS-10). Ultimately, 43 patients were classified into the low chronic stress group, while 47 patients were classified into the high chronic stress group. Progression-free survival and overall survival were analyzed in the two groups (shown in Fig S1). The characteristics, preoperative laboratory tests, and tumor characteristics of 90 patients are shown in Table S1. The parameters of the Stress Score, PSS-10, and hair cortisol concentration of the enrolled patients are shown in Table S2. Approximately 5% of follow-up data were missing. We employed multiple imputation as the primary method for handling missing data while adhering to the assumption of Missing At Random (MAR).

Chronic stress indicators were negatively correlated with DFS and OS in HCC patients

We utilized X-tile software to determine the optimal cut-off values of the Stress Score, PSS-10, and hair cortisol concentration in assessing the DFS of patients with HCC. The optimal cut-off values were found to be 15.30 for the PSS-10, 50.00 for the Stress Score, and 19.70 pg/mg for hair cortisol concentration, with corresponding p-values of 0.011, 0.035, and < 0.001, respectively (Table 1).

Table 1.

The optimal cut-off value of stress score, hair cortisol concentration and perceived stress scale to assess patients’ DFS

Variable		P
PSS-10
≤15.30(n = 54)	11.40 ± 2.76	0.011
>15.30(n = 36)	18.42 ± 2.40
Stress Score
≤50.00 (n = 41)	45.67 ± 5.62	0.035
>50.00 (n = 49)	56.48 ± 6.13
Hair cortisol concentration
≤19.70 pg/mg (n = 38)	16.06 ± 3.59	< 0.001
> 19.70 pg/mg (n = 52)	29.09 ± 7.15

Subsequently, the 90 patients were grouped according to these cut-off values, and the effects of the three chronic stress evaluation indices on the DFS and OS were analyzed. The results of Kaplan‒Meier survival analysis revealed that HCC patients with a Stress Score greater than 50 had reduced DFS (P = 0.035, HR 1.716, 95%CI: 1.030–2.860), and the OS in this group was significantly reduced than that in those with a Stress Score Less than 50 (P = 0.019, HR 2.204, 95%CI: 1.167–4.162). The median survival times were 48 months for the high Stress Score group and not reached for the low Stress Score group (shown in Fig. 1A, B). Significant differences in DFS and OS were also observed between HCC patients with a PSS-10 above 15.3 and those with a PSS-10 below 15.3 (P = 0.006, HR 1.979, 95%CI: 1.142–3.431, P = 0.002, HR 2.696, 95%CI: 1.377–5.282; shown in Fig. 1C, D). Patients whose hair cortisol concentration was exceeded than19.70 pg/mg experienced significantly reduced DFS (P < 0.001, HR 3.538, 95%CI: 1.142–3.431), and their OS was significantly reduced than that of patients with hair cortisol concentration below 19.70 pg/mg (P < 0.001, HR 3.538, 95%CI: 1.142–3.431, shown in Fig. 1E, F).

Fig. 1.

Stress Score, PSS-10 and hair cortisol concentration association with disease-free survival and overall survival in HCC patients A, B: Disease-free survival and overall survival curves for the high and low level stress score groups. C, D: Disease-free survival and overall survival curves for the high and low level PSS-10 groups. E, F: Disease-free survival and overall survival curves for the high and low level hair cortisol concentration groups

Establishment of a chronic stress index (CSI) system

Correlation analysis revealed that the PSS-10 was positively correlated with the Stress Score (R = 0.368, P < 0.001). The hair cortisol concentration was positively correlated with the PSS-10 (R = 0.334, P = 0.001) and also positively correlated with the Stress Score (R = 0.306, P = 0.003) (shown in Fig. S2A-C). Based on these findings, we propose the Chronic Stress Index (CSI) system. According to the above cut-off values, when the hair cortisol concentration was ≤ 19.7 pg/mg, PSS-10 was ≤ 15.3, and the Stress Score was ≤ 50.0, each parameter received 1 point. Conversely, when the cortisol concentration was > 19.7, PSS-10 was > 15.3, and the Stress Score > 50.0, each parameter received 2 points. Patients with a CSI score of 3 to 4 were classified as having a low chronic stress state (LCSS), and while those scoring 5 to 6 were classified as having a high chronic stress state (HCSS) (Table 2).

Table 2.

Chronic stress classification

Markers	Score
	1	2
Hair cortisol concentration(pg/mg)	≤ 19.7	>19.7
Perceived stress scale(PSS-10)	≤ 15.3	>15.3
Stress Score	≤ 50.0	>50.0

Chronic stress index Low chronic stress state: 3–4 Points, High chronic stress state: 5–6 Points

Patients in the HCSS group had shorter DFS and OS than those in the LCSS group did.

There were 43 patients in the LCSS groups and 47 and HCSS groups. No significant differences were observed in age, gender, laboratory test results, tumor size and number, internal diameter of the main portal vein, portal hypertension, esophageal varices, splenomegaly, BCLC stage, surgical method, or CTC positive rate between the two groups (all P values > 0.05). However, significant differences in PSS-10, Stress Score, and hair cortisol concentration were noted between the two groups (all P values < 0.001) (Table S3). The median follow-up time was 50.00 months for both the LCSS group and the HCSS group (P = 0.669). The DFS rates in the LCSS group were significantly better than those in the HCSS group (P < 0.001, HR 2.42, 95%CI: 1.44–4.07) (shown in Fig. 2A). The median DFS was 18 months for the HCSS group and 37 months for the LCSS group. A significant difference in the cumulative overall survival was also observed between the two groups (P = 0.033, HR 2.00, 95%CI: 1.06–3.79) (shown in Fig. 2B). The median OS was 50 months for the HCSS group and not reached for the LCSS group. If patients experienced tumor recurrence, treatment options included surgical resection, radiofrequency ablation, TACE, targeted therapies, and immunotherapies, depending on the specific circumstances of the patient [8, 14, 15].

Fig. 2.

Effects of different chronic stress states on disease-free survival and overall survival in HCC patients. A Disease-Free Survival (DFS) Curves: The blue and red lines represent the survival probabilities for the LCSS and HCSS groups, respectively. The log-rank test reported a p-value of < 0.001, suggesting a statistically significant difference between two groups. B Overall Survival (OS) Curves: The survival difference is significant with a log-rank p-value of 0.033. Additionally, the table below each graph indicates the number of patients remaining at risk at specified time intervals. Abbreviations: LCSS: low chronic stress state, HCSS: high chronic stress state, DFS: disease-free survival, HR: hazard ratio, CI, confidence interval, OS: overall survival

Systematic review results

Before conducting the study, we performed a systematic review of the relevant literature. The initial search across the three databases yielded a total of 632 studies: 262 from PubMed, 125 from Cochrane, and 245 from Embase. After excluding161 duplicates and 435 unrelated studies based on their abstracts, the remaining studies were considered for further review. Ultimately, 26 studies met the enrollment criteria; however, 23 studies were excluded for various reasons. Specifically, eight studies were excluded because they were not original research, which include four meta-analyses and four case reports.

The assessment methods for chronic stress are crucial to our study. Appropriate and well-standardized assessment methods are essential for obtaining accurate and reliable stress data. If a study does not clearly define its chronic stress assessment method, evaluating the validity and reliability of its results becomes challenging. Therefore, twelve studies that did not specify their stress assessment methods were excluded.

The core purpose of this research is to explore the relationship between stress and cancer recurrence, as well as the impact of stress management interventions on cancer recurrence. Consequently, four studies unrelated to cancer recurrence were also excluded. A total of three articles were included through screening: two focused on breast cancer and one on HCC (Table 3). Two studies on anxiety reported that anxiety promotes tumor recurrence in a breast cancer study (RR 1.19, p = 0.0281) [14] and another HCC study (HR 1.04, p = 0.040) [8]. One cohort study involving breast cancer patients reported a positive correlation between depression level and recurrence risk (RR 1.19, p = 0.1367), while it also indicated a reverse correlation between good emotional health and recurrence risk (RR 0.80, p = 0.0028) [27]. Another cohort study on breast cancer indicated that greater hostility predicted an increased number of breast cancer events (HR = 1.24, p = 0.005) [15].

Table 3.

Summary of the three selected studies

Author (Year), Country	Cancer Type N. of Participants	The type of chronic stress	Stress Measurement Tool	Timing of Stress Measurement	Follow-Up Period (Years)	Stress High vs. Low	N. of Recurrence	Adjusted HR or RR (95% CI)	Effect on the tumor recurrence
Groenvold et al. (2007), Denmark [14]	Breast cancer 1,588	Emotional health Anxiety Depression	EORTC QLQ-C30 HADS HADS	7 weeks after surgery	12.9	EORTC QLQ-C30 score: 83–100 vs. 0–75 HADS score: 8–21 vs. 0–7 HADS score: 8–21 vs. 0–7	761(No information on each group)	RR = 0.80 (0.69–0.93) RR = 1.19 (1.02–1.39) RR = 1.19 (0.95–1.50)	Promotion
Saquib et al. (2011), USA [15]	Breast cancer 2,967	Mental health Hostility	SF-36  CMHS	At first clinic visit	7.3	SF-36 score: 90.6–100 vs. 0–63.3 CMHS score: 6–13 vs. 0	492(No information on each group)	HR = 1.21 (0.85–1.72) HR = 1.24 (0.92–1.68)	Promotion
Liu et al. (2016), China	HCC, 110	Anxiety	HAMA	3 months after surgery	4.0	HAMA score: 17–56 vs 0–16	44 (High 31 vs. Low 13)	HR = 1.04 (1.00–1.10)	Promotion

HR hazard ratio, RR relative risk, CI confidence interval, EORTC QLQ-C30 European organization for research and treatment of cancer-quality of life, HADS hospital anxiety and depression scale, SF-36 short form 36-item health survey, CMHS Cook-Medley hostility scale, HAMA Hamilton rating scale for anxiety

Discussion

Our study demonstrated that HCC patients with HCSS had shorter DFS and OS compared to those with a lower chronic stress state. This finding is consistent with the results of previous studies. For instance, a study on anxiety in HCC patients revealed that individuals with higher Hamilton Anxiety Rating Scale (HAMA) scores had a worse prognosis [8]. In 1999, De Brabander B and Gerits P reported that chronic stress appeared to be a strong predictor of early recurrence in breast cancer patients [31]. Additionally, the systematic review indicated that two studies on the effect of stress on breast cancer prognosis found that a high stress state could promote tumor recurrence [14, 15]. While many related animal studies have been conducted, these studies also confirmed that chronic stress can promote the occurrence and development of various tumors. For example, long-term chronic stress has been shown to promote the metastasis of ovarian cancer by activating the sympathetic nervous system [32]. This activation can increase the serum levels of norepinephrine and IL-10, promoting tumor growth in a nude mouse model of ovarian carcinoma [33]. Another study identified that β-adrenergic activation of the cAMP–PKA signaling pathway is a major mechanism by which behavioral stress can increase tumor angiogenesis in vivo, thereby promote ovarian cancer growth [34]. Furthermore, a study on breast cancer demonstrated that chronic stress can restructure lymphatic networks within and around tumors, favoring the escape of tumor cells [35].

Although the aforementioned studies are primarily based on animal experiments, their conclusions align with the findings of our study. The conclusions regarding the effects of chronic stress on HCC are generally consistent with our results; however, the relevant mechanisms are different among these studies. For example, one study demonstrated that chronic stress can change the spleen structure, redistribute splenic myeloid cells to tumor tissues, and promote HCC growth [36]. Chronic stress induces the release of glucocorticoids, which promote the progression of HCC by upregulating PD-1 and inhibiting the activity of natural killer (NK) cells [11]. Additionally, another stress hormone, cortisol, can suppress p53 in HCC by increasing Bcl2L12 expression [37].

These studies demonstrated that chronic stress can promote cancer recurrence, however; how to categorize the chronic stress of cancer patients and the effects of different levels of chronic stress on the prognosis of HCC patients have not been reported. The quantitative evaluation of chronic stress in cancer patients is conducive to the development of targeted interventions and drugs and is beneficial for improving the prognosis of patients. To our knowledge, this is the first study to explore the impact of the chronic stress state on the prognosis of HCC patients and to establish a new comprehensive method to assess HCC patients’ chronic stress state after curative treatment. Since psychiatrist George Engel proposed the biopsychosocial medical model, which integrates biological, psychological, social, and behavioral dimensions in 1977, almost all scholars have accepted the conceptual framework [38]. Clinicians pay more attention to the impact of psychological factors on disease prognosis. The process of diagnosing and treating patients with malignancies, not only causes great trauma to the body, but also places enormous psychological pressure. Long-term stress causes patients to suffer from insomnia, mental tension, mild depression, and other manifestations, collectively referred to as chronic stress [39]. Chronic stress leads to sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) and the release of stress hormones, including catecholamines and glucocorticoids [40]. Chronic stress leads to disturbances in the neuroendocrine system. The disruption of neurotransmitters, stress hormones, and immune cells changes the tumor microenvironment, which is conducive to the occurrence, progression, metastasis, and multidrug resistance of tumors [41].

In the studies of De Brabander and Gerits [31], the chronic stress of breast cancer patients was measured using a Dutch version of the Hopkins Symptom Check List. The two studies on breast cancer and one study on HCC included in the systematic review also evaluated patients’ stress levels through various psychological scales. One of the key strengths of our study lies in its innovative approach to assessing the chronic stress state of HCC patients. We employed a unique combination of three indicators: hair cortisol concentration, a custom Stress Score, and the validated Perceived Stress Scale-10. This multifaceted evaluation strategy provides a more comprehensive and nuanced understanding of the stress experienced by HCC patients. The CSI system integrates hair cortisol concentration, a physiological marker; the Stress Score, an objective physiological marker; and the PSS-10, a subjective index, to comprehensively evaluate the chronic stress Level in HCC patients. To reduce bias, we measured chronic stress Levels three times at 1, 3, and 6 months after surgery. Compared to the single psychological scale used in previous studies, the CSI system evaluates the chronic stress level of cancer patients more comprehensively, scientifically, and objectively. Numerous studies have confirmed that the hair cortisol concentration is one of widely used biomarker for the evaluation of chronic stress [24]. While blood, urine, saliva, hair can be used to determine the cortisol levels, saliva, urine and blood are influenced by various substances and are easily affected by circadian rhythm, reflecting only the instantaneous cortisol level [23, 42]. In contrast, hair cortisol concentration has the potential to serve as an integral measure of cortisol production over 3 to 6 months [42]. Ramirez. et al. utilized hair cortisol concentrations to assess chronic stress in patients with breast cancer [43].

The PSS-10 has been confirmed to possess good reliability and validity across different populations, cultures, and institutions [44, 45]. It has been utilized in various cancers, including breast cancer and prostate cancer, to assess the chronic stress status of patients [46, 47]. Numerous studies have explored the relationship between hair cortisol concentrations and the PSS-10 to evaluate the chronic stress state in diverse populations. For instance, C.J. Gidlow investigated the correlation between hair cortisol concentrations and PSS-10 in healthy, working adults [48]. Additionally, hair cortisol concentrations and PSS score have been employed to assess chronic stress in patients with severe chronic pain [49]. In another study, hair cortisol concentrations and PSS scores were measured and correlated in 25 healthy pregnant women, revealing a significant correlation between hair cortisol concentration and PSS score (R = 0.47; P < 0.05). The concordance between the use of cortisol as a stress measure and the PSS suggests that combining hair cortisol concentration combination with the PSS may provide an effective method for assessing an individual’s chronic stress level [50]. Furthermore, a study examining the relationship between hair cortisol concentrations and insomnia and stress symptoms in 65 breast cancer survivors found a significant correlation between hair cortisol concentrations and the Stress Perception Scale score (Rho = 0.41, p = 0.001, Spearman’s correlation) [51].These results were consistent with our findings.

Heart rate variability (HRV), defined as the degree of fluctuation in the length of the intervals between successive heartbeats, is a representative marker of autonomic nervous system (ANS) status and has been widely used in both social science and biomedical fields [52]. For example, HRV has been utilized to study the effect of stress levels on distant metastasis in patients with breast cancer [53] and to assess stress in adolescents and young adults with cancer [54]. Our previous study demonstrated that Stress Score can serve as a simplified index for evaluating chronic stress level in HCC patients [22].

While previous studies have used PSS-10 or hair cortisol concentrations to evaluate chronic stress levels and their impact on cancer prognosis [43, 46, 47], our study is the first to combine the Stress Score, PSS-10 score, and hair cortisol concentration to quantitatively assess chronic stress in patients with HCC. The integration of these three indices allows for a more objective, comprehensive, and effective evaluation of chronic stress levels in HCC patients, providing a valuable tool for screening patients with high chronic stress levels and establishing a foundation for the development of targeted therapeutic drugs and interventions.

Limitations and future directions

It is important to acknowledge the limitations inherent in our research. First, this study is a single-center study. Second, due to time and financial constraints, our study has a relatively small sample study. Third, this study serves as a preliminary exploratory investigation into the impact of chronic stress on the postoperative prognosis of HCC patients, and whether these findings can be directly extended to other tumors requires further investigation. Lastly, the socioeconomic status, lifestyle, and comorbidities of the participants may influence their chronic stress levels. Additionally, individual differences in hair cortisol metabolism can affect the conclusions of the study.

To enhance the robustness and generalizability of our findings, future research should incorporate multicenter, large sample size, and randomized controlled trials. Such an approach would provide a more rigorous and extensive validation of our conclusions. In future research, we plan to explore the combined application of various intervention measures includng psychological interventions paired with lifestyle changes, as well as pharmacological treatments combined with social support interventions. Our goal is to develop more comprehensive and effective chronic stress management plans aiming to further reduce the impact of chronic stress on the prognosis of HCC.

Conclusion

Patients exhibiting elevated levels of chronic stress were observed to have significantly reduced postoperative disease-free and overall survival times. These findings underscore the detrimental impact of chronic stress on the prognosis of HCC patients. Furthermore, our established Chronic Stress Index (CSI) has demonstrated its efficacy in stratifying the stress profiles of HCC patients, providing an alternative tool for personalized medical strategies and interventions.

HR; hazard ratio, RR; relative risk, CI; confidence interval, EORTC QLQ-C30; European organization for research and treatment of cancer-quality of life, HADS; hospital anxiety and depression scale, SF-36; short form 36-item health survey, CMHS; Cook-Medley hostility scale, HAMA; Hamilton rating scale for anxiety.

Abbreviations

HCC

Hepatocellular carcinoma

DFS

Disease-free survival

OS

Overall survival

BCLC

Barcelona Clinic Liver Cancer

ECOG PS

Eastern Cooperative Oncology Group performance status

HRV

Heart rate variability

LC–MS/MS

Liquid chromatography tandem–mass spectrometry

PSS

Perceived Stress Scale

CSI

Chronic stress index

LCSS

Low chronic stress state

HCSS

high chronic stress state

CTC

Circulating tumor cell

HPA

Hypothalamic-pituitary adrenal

SNS

Sympathetic nervous system

TACE

Transarterial chemoembolization

SDNN

Norma1-to-normal R-R interval

RMSSD

Root mean square standard deviations of R-R intervals

LF

Low frequency

HF

High frequency

ADRB2

β2 adrenergic receptor

HR

Hazard ratio

RR

Relative risk

CI

Confidence interval

EORTC QLQ-C30

European organization for research and treatment of cancer-quality of life

HADS

Hospital anxiety and depression scale

SF-36

Short form 36-item health survey

CMHS

Cook-Medley hostility scale

HAMA

Hamilton rating scale for anxiety

Authors’ contributions

X. W., Y. D.Conceived and designed the experiments, Data curation, Investigation, Methodology, Software, Supervision, Validation, Analyzed and interpreted the data; Wrote the original draft. X. S., Y. S., L.S., H.D., P.Z., H.B., F. K., and K. M. Data curation, Investigation, Methodology, Supervision, Validation, Wrote the original draft. G. C. Software, Validation, Analyzed and interpreted the data; Funding acquisition; Wrote the original draft. F. X.Conceived and designed the experiments; Analyzed and interpreted the data; Writing-review & editing; Supervision; Funding acquisition; Wrote the original draft; Project administration.

Funding

This research is supported by Chongqing Natural Science Foundation of China general project (CSTB2023NSCQ-MSX0563) and special projects of Army Medical University for improving scientific and technological innovation capabilities (2019XLC1009).

Data availability

The datasets analyzed during the current study are not publicly available as they contain information that are sensitive to the study institution. They may be made available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Army Medical University, PLA (People’s Liberation Army), also known as Southwest Hospital. The decision reference number for this approval is KY2017047. Written informed consent was meticulously obtained from each participant. This consent process was conducted in compliance with the ethical guidelines set by the Ethics Committee of the First Affiliated Hospital of Army Medical University.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.