Effects of Managing Cancer and Living Meaningfully on Cancer-Related Fatigue and Cytokine Levels in Gastrointestinal Cancer Patients

Abstract

Objective:

To evaluate the effects of managing cancer and living meaningfully (CALM), a psychological intervention with semi-structured interviews, on cancer-related fatigue (CRF), quality of life (QOL), and sleep quality in patients with gastrointestinal (GI) cancer, which may be accompanied by changes in cytokine levels.

Methods:

A total of 152 GI cancer patients with CRF were enrolled in the study during treatment. Patients were randomly assigned to CALM or usual care (UC) groups. Patients in the CALM group received 12 weeks of CALM plus usual care, and patients in the UC group received usual care plus usual health education. All study participants were evaluated at baseline and at 12 weeks using the Revised Piper Fatigue Scale, the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30, and the Pittsburgh Sleep Quality Index scale, while cytokine levels were measured.

Results:

At 12 weeks, the differences in total CRF, QOL, sleep quality, IL-6, IL-4, and TNF-α levels were statistically significant not only in the CALM group compared to patients in the UC group (t = −7.902, t = 2.163, t = −2.187, t = 3.313, t = −4.120, t = −3.853, respectively; P < .05), but also in the CALM group compared to baseline (t = 11.331, t = −5.492, t = 5.450, t = −2.418, t = 2.186, t = 2.699, respectively; P < .05). Additionally, the total CRF at 12 weeks was correlated with IL-4, IL-6, and TNF-α levels (r = −.30, r = .31, r = .32, respectively; P < .001).

Conclusions:

CALM alleviated CRF and improved QOL and sleep quality in patients with GI cancer, and these improvements were accompanied by changes in IL-4, IL-6, and TNF-α levels.

Introduction

Gastrointestinal (GI) cancer has become the most common cancer worldwide, and the incidence and mortality rates of esophageal, gastric, and colorectal cancers are among the top 10 in China, according to the National Cancer Center. ¹ The percentage of cancer survivors continues to grow as advances in early detection and treatment techniques have led to improved cancer survival rates. However, patients often suffer from long-term side effects from the cancer itself or its treatment, which may affect their quality of life by causing fatigue, sleep disturbances, anxiety, depression, etc.^2-4

Cancer-related fatigue (CRF) is one of the most prevalent and distressing symptoms among cancer patients; it is defined by the National Comprehensive Cancer Network (NCCN) as a subjective experience of physical, emotional, and/or cognitive tiredness or fatigue associated with cancer or cancer treatment that is disproportionate to recent activity and interferes with normal functioning.^5,6 Depending on the patient demographics, the type of medication taken, and the evaluation technique, it is estimated that the prevalence of CRF might range from 25% to 99%.^7-13 CRF might emerge as generalized weakness, poor or impaired focus, indifference in everyday tasks, and negative emotional tendencies. An abnormal decline in physical and mental energy is the most important feature of CRF, which does not allow patients to feel completely rested (in contrast to healthy individuals), and the patient’s degree of fatigue is usually not proportional to their activity and energy levels.^6,14 Numerous studies have revealed that CRF slows the completion of cancer medication therapy and restricts patient participation in significant activities before, during, and after treatment, thereby lowering the patient’s overall quality of life and potentially shortening overall survival.^7,8,15,16

Despite the prevalence and negative effects of CRF, there is evidence that both patients and clinicians underestimate the symptoms leading to underdiagnosis and under-treatment of CRF.^6,17 This might reflect the difficulty in treating CRF, which may be caused by barriers to properly assessing and managing fatigue due to the lack of understanding regarding the underlying mechanisms, risk factors and effective treatments for this condition. Exercise and psychosocial therapies are evidence-based CRF interventions during primary cancer therapy. ⁶ However, appropriate treatments to better manage CRF in cancer patients are still unclear. ¹⁸ Other types of severe fatigue may be associated with peripheral immune responses and inflammation as evidenced by elevated levels of proinflammatory cytokines; examples of conditions with a comparable pathogenesis that cause pathogenic fatigue include rheumatic diseases, autoimmune type 1 diabetes, inflammatory bowel disease, systemic autoimmune diseases, and infections,^19-22 and of which IL-2, IL-4, IL-6, and TNF-α levels have received the most attention. A longitudinal study on breast cancer showed an association between IL-6 and TNF-α and fatigue, ²³ and a linear trend between IL-2, IL-4, and IL-6 and chronic fatigue was also shown by Montoya et al ²⁴ and Lattie et al. ²⁵ Thus, it is reasonable to assume that CRF may have a similar pathogenesis to other pathogenic fatigue.

This study is a clinical case-control study using CALM, a psychological intervention, in patients with gastrointestinal cancer with CRF. CALM is a structured, short-term, and expression-supporting psychosocial intervention devised by Rodin et al^26-28 to prevent psychological disorders and increase well-being.^26-28 Prior research has demonstrated that CALM can help with both the avoidance and treatment of negative psychological reactions while having positive effects on fatigue, anxiety, depression and quality of life.^26,27,29 Based on the limited number of studies investigating the impact of CALM during GIL cancer treatment, there is a need to explore the effectiveness of CALM in GI cancer patients with CRF and also to analyze the correlation of cytokines and CRF to provide further evidence for the ability of cytokines as early predictors of CRF onset. In this paper, we report the effects of CALM on CRF, QOL, and sleep quality in patients with GI cancer during cancer treatment, while analyzing the relationship between changes in CRF and cytokine levels.

Methods

Study Design

Eligible subjects were identified and recruited through prescreening of the oncology outpatient list, using 2 trial conditions: CALM and usual care (UC) (1:1). Over the course of a 12-week period, every cancer patient received a minimum of 6 individual face-to-face sessions in the hospital; the biweekly session lasted between 60 and 70 minutes. We evaluated patients at baseline and at 12 weeks (ie, before the intervention, and after 6 sessions of intervention). Cancer patients were required to complete questionnaires, including the Revised Piper Fatigue Scale (PFS-R), the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), and the Sleep Quality Index scale (PSQI), as well as blood tests to determine IL-2, IL-4, IL-6, and TNF-α levels. Patients in the CALM group received CALM intervention in addition to usual care, while patients in the UC group received usual care with usual health education and stress relief for the same frequency and duration as participants in the CALM group. All patients received cancer treatment according to the national guidelines of the Chinese Cancer Organization. The study was approved by the Research Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (Ethics number 2012088), and all patients provided written informed consent. The design of the experiment was evaluated by research experts in the field to ensure the feasibility, practicality and scientificity of the experiment.

Participants

The inclusion criteria were as follows: (1) ≥18 years old, proficient in Chinese, and sufficient listening and speaking skills for test participation; (2) mobile and well behaved (Karnofsky ≥80); (3) no prior psychological interventions; (4) pathologic diagnosis of malignancy, including esophageal cancer (International Classification of Diseases, 10th revision [ICD-10]: C15), gastric cancer (ICD-10: C16), and colorectal cancer (ICD-10: C18-C20), and treated with chemotherapy, immunotherapy, and targeted therapy, which may be combined with surgery and/or radiotherapy; and (5) reported moderate to severe fatigue (Checklist Individual Strength, PFS-R score >3), with no known somatic cause other than cancer and its therapy, and a life expectancy of 6 months according to the patient’s oncologist. The exclusion criteria were as follows: a diagnosis of other cancers, symptomatic brain metastases, cognitive impairment, poor status (Karnofsky <70) or diagnosed for psychiatric disorders.

Sample Recruitment

Our study was conducted at the Department of Oncology, Second Hospital of Anhui Medical University, from January 1, 2022 to September 1, 2022, using the PFS-R scale to screen patients with GI cancers for fatigue severity and provide study information to eligible patients. The same researcher who collected baseline information also consulted patients who consented to the trial, and a rigorous, standardized registration process was used to reduce bias. Thereafter, consenting patients were regularly scheduled for a 12-week psychological intervention at the hospital. Detection of clinically significant differences in CRF between the CALM and UC groups required enrollment of 60 patients per group, with a 90% power and a 2-sided alpha of .05 used to correct for both comparisons. Therefore, we aimed to enroll 160 patients, assuming an attrition rate of 30%.

Randomization and Blinding

An independent biostatistician randomly assigned eligible study subjects to the CALM and UC groups in a 1:1 ratio using a computer-generated randomization table and stratified using HADS and EORTC-QLQ-C30 scores to ensure a balance of symptoms of heart distress between the 2 groups at baseline. Corresponding authors included patients in the randomized group list via sealed envelopes containing randomized serial numbers and informed research assistants of treatment options, but they were not involved in the conduct of the trial. Block size was variable. Information on the grouping of these patients for treatment tasks was not known to the person collecting the questionnaire data or to the independent investigator analyzing the data, but was not concealed from the patients, the interventionist, or the research assistant administering the study assessment. The final data set was exported to the analysis group (rather than part of the pilot group) for analysis and validation.

Neuropsychological Tests

The PFS-R is a validated multidimensional self-assessment scale for assessing perceived fatigue in patients with chronic diseases, especially in cancer patients, and it has been validated in a Chinese population.^29,30 The scale consists of 22 items which span the 4 dimensions of fatigue: behavioral/daily life (6 items), cognitive (6 items), affective/emotional meaning (5 items), and sensory/physical (5 items). Respondents are able to score items from 0 to 10 according to the following rating scale: 0 = none; 1 to 3 = mild; 4 to 6 = moderate; and 7 to 10 = severe fatigue. This study assessed total fatigue and its 4 dimensions, with higher item scores indicating more severe fatigue.

The EORTC-QLQ-C30 is a cancer-specific scale that is valid and reliable for all types of cancer. ³¹ It can be broken down into fifteen different categories, including 5 functional categories (somatic, role, cognitive, emotional, and social functioning), 3 symptom categories (fatigue, pain, nausea, and vomiting), 1 general health status/quality of life category, and 6 single entries. This study assesses overall quality of life, with higher scores indicating better overall quality of life.

The PSQI is the most widely used method of measuring sleep quality in clinical and research settings.^32,33 It is used to evaluate a patient’s quality of sleep during the previous month, and it consists of 19 self-assessments and 5 other review entries, in which the 19th self-rated entry and 5 other review entries do not influence the total score. The scores of all parts are summed to attain the total PSQI score, which ranges from 0 to 21; higher scores indicate poorer sleep quality.

Cytokine Measurements

To control for potential circadian rhythm abnormalities, peripheral blood samples from all of the participants were arranged to be taken between 5 and 6 am the morning before treatment. A 2 ml blood sample was drawn using ethylenediaminetetraacetic acid (EDTA) tubes at baseline and at 12 weeks. All samples were centrifuged at 2500 and 4000 RPM for 10 within 60 minutes of collection. The plasma fraction of the blood samples was separated after centrifugation, and at least 600 μl of each sample was retained and stored under sterile −80°C conditions until analysis.

Interventions

CALM Patients assigned to CALM receive 6 face-to-face individual sessions at the hospital over a 12-week period. CALM is a psychological intervention tailored to cancer patients that addresses 4 main areas: symptom management and communication with health care providers, changing the self and the self’s relationship with others, courage to live and consider the future, and spiritual well-being and a sense of meaning.^27,34 The CALM intervention is done by the Department of Oncology at the Second Affiliated Hospital of Anhui Medical University by staff who are qualified as psychotherapists. Prior to conducting the study, clinical investigators trained participating therapists for 2 weeks and were continuously supervised as the study progressed, and our therapists were unanimously deemed competent to deliver CALM.

UC Although cancer patients assigned to the usual care group do not receive CALM interventions, depending on clinical judgment and patient needs, health care providers (eg, psychologists, oncologists, nursing staff) provide health education or stress management, which includes modifying work and rest, improving meals, counseling on diagnosis and treatment options, and providing brief, non-standardized psychological guidance.^12,28

Statistical Analysis

Statistical analysis was performed using SPSS statistical software, version 22.0 (version 22.0, http://spss.en.softonic.com/; Chicago, IL, USA). No interim analysis was performed. Baseline information, scale scores and cytokine levels were compared between and within the 2 groups. The t test and Mann‒Whitney U test were used for normal and nonnormal distributions of continuous variable data, respectively. All results are expressed as the mean ± standard deviation (SD). Differences in categorical variables between baseline data of the 2 groups were analyzed using the chi-square (χ²) test. The correlation analysis between CRF and cytokine levels in the CALM and UC groups was based on Spearman correlation analysis. In addition, we used multiple interpolation to fill in the missing values according to the degree of sample missingness and performed a sensitivity analysis to explore the robustness of our results. ¹² In the analysis of the results, we considered statistical significance to be set at a bilateral P < .05.

Results

Demographic and Clinical Characteristics

Of the 213 patients with CRF that were contacted between January 1, 2022 and September 1, 2022, 152 (71.4%) were included in the study and randomly assigned to the CALM (n = 76) and UC (n = 76) groups (Figure 1). All patients were required to complete 6 interventions for inclusion in the final outcome analysis. About 11 patients (7.2%) withdrew from the study for various reasons during the study period, 10 patients (6.6%) failed to complete all UC or CALM interventions, and 5 patients (3.3%) had missing cytokine data at 12 weeks. The attrition rate was 19.7% in the CALM group and 14.5% in the UC group, and the overall attrition rate of 17.1%, with 80.3% and 85.5% of CALM and UC participants meeting final analysis requirements, respectively. In the final analysis, 61 patients were assigned to the CALM group, and 65 patients were assigned to the UC group. Table 1 shows patient characteristics at baseline; no significant differences (P > .05) were found for age, KPS, sex, education level, cancer type, treatment modality, cancer stage, tumor pathology type, or meeting time.

Figure 1.

Research flowchart.

Table 1.

Demographics and Characteristics of Study Participants.

Characteristic	CALM (n = 61)	UC (n = 65)	t/x 2	P
Age (y)
Mean ± SD	66.39 ± 10.73	64.38 ± 11.87	.998	.320
Sex, n (%)			.382	.676
Male	45 (46)	51 (53)
Female	16 (53)	14 (47)
Education, n (%)			5.070	.076
Low (ISCED 0-1)	37 (61)	31 (48)
Medium (ISCED 2-5)	21 (34)	23 (35)
High (ISCED 6-8)	3 (5)	11 (17)
KPS	88.44 ± 5.44	86.69 ± 7.03	1.531	.132
Diagnosis, n (%)			.153	.949
Esophagus cancer	22 (37)	23 (35)
Gastric cancer	23 (38)	23 (35)
Colorectal cancer	16 (26)	19 (29)
Cancer stage, n (%)			.663	.471
Stage I	1 (2)	2 (3)
Stage II	13 (21)	12 (18)
Stage III	19 (31)	13 (20)
Stage IV	28 (46)	38 (59)
Current treatment type, n (%)			.712	.407
Chemotherapy	16 (26)	15 (23)
Targeted therapy	6 (10)	5 (8)
Immunotherapy	3 (5)	1 (2)
Radiation therapy	5 (8)	6 (9)
Surgery	6 (10)	7 (11)
Chemo + targeted	9 (15)	10 (15)
Immuno + targeted	7 (12)	10 (15)
Other a	9 (15)	11 (17)
Meeting time (minutes)
Mean ± SD	63.66 ± 2.37	64.11 ± 2.37	−1.069	.287

Abbreviations: CALM, managing cancer and living meaningfully; KPS, Karnofsky performance status; ISCED, international standard classification of education; SD, standard deviation.

^aIncluding: Chemo + immunotherapy; chemo + radiation therapy; chemo + targeted + immunotherapy.

Comparison of the Symptom Assessment Results and the Cytokine Levels Before and After Intervention Periods Between Groups

The results of the analysis in Table 2 and Figure 2 show that there were no test group differences at baseline and that participants in the CALM group reported lower fatigue severity (T-CRF, D-CRF, A-CRF, P-CRF, and C-CRF) than those in the UC group at 12 weeks (t = −7.902, t = −6.358, t = −7.853, t = −6.666, t = −7.412, respectively; P < .001). Compared with the UC group, the CALM group improved quality of life and sleep quality at 12 weeks (t = 2.163, t = −2.187, respectively; P < .05). In addition, the differences in cytokine IL-2, IL-6, IL-4, and TNF-α levels between the 2 groups at 12 weeks were statistically significant (t = 2.536, t = 3.313, t = −4.120, t = −3.853, respectively; P < .05).

Table 2.

Comparison of the Symptom Assessment Results and the Cytokine Levels Before and After Intervention Periods Between Groups.

	Before: CALM vs UC (n = 61) (n = 65)					After: CALM vs UC (n = 61) (n = 65)
Measure	CALM (mean ± SD)	UC (mean ± SD)	95% CI	t	P	CALM (mean ± SD)	UC (mean ± SD)	95% CI	t	P
T-CRP	5.40 ± 1.04	5.45 ± 1.14	(−0.44 to 0.33)	−.276	.783	3.80 ± 1.04	5.24 ± 1.00	(−1.80 to −1.08)	−7.902	<.001
D-CRF	5.56 ± 1.22	5.73 ± 1.42	(−0.64 to 0.29)	−.729	.467	3.87 ± 1.30	5.32 ± 1.26	(−1.91 to −1.00)	−6.358	<.001
A-CRF	5.61 ± 1.02	5.68 ± 1.13	(−0.45 to 0.31)	−.354	.724	3.93 ± 1.18	5.45 ± 0.98	(−1.90 to 1.14)	−7.853	<.001
P-CRF	5.39 ± 1.13	5.40 ± 1.15	(−0.41 to 0.39)	−.042	.967	4.01 ± 1.01	5.27 ± 1.12	(−1.64 to −0.89)	−6.666	<.001
C-CRF	5.04 ± 1.26	5.00 ± 1.27	(−0.41 to 0.48)	.147	.883	3.41 ± 1.21	4.93 ± 1.09	(−1.93 to 1.11)	−7.412	<.001
E-QoL	61.69 ± 11.81	61.22 ± 11.54	(−3.65 to 4.59)	.227	.821	69.61 ± 12.96	65.03 ± 10.58	( 0.39 to 8.77)	2.163	.033
PSQI	11.38 ± 3.41	10.55 ± 3.18	(−0.34 to 1.99)	1.399	.164	8.41 ± 3.07	9.71 ± 3.59	(−2.48 to −0.12)	−2.187	.031
IL-2	2.74 ± 2.43	2.07 ± 2.05	(−0.12 to 1.47)	1.673	.097	3.22 ± 2.19	2.31 ± 1.78	( 0.20 to 1.61)	2.536	.013
IL-4	0.96 ± 0.96	0.81 ± 1.02	(−0.19 to 0.51)	.891	.375	1.35 ± 0.96	0.87 ± 0.63	(−0.19 to 0.76)	3.313	.001
IL-6	9.97 ± 15.79	9.69 ± 12.94	( 4.83 to 5.39)	.108	.914	6.01 ± 5.21	17.51 ± 21.21	(−17.03 to 5.98)	−4.120	<.001
TNF-a	3.29 ± 4.25	2.18 ± 2.97	(−0.18 to −0.93)	1.701	.091	1.86 ± 1.48	3.76 ± 3.59	(−2.89 to −0.93)	−3.853	<.001

Abbreviations: CALM, managing cancer and living meaningfully; UC, usual care; T-CRF, total cancer-related fatigue; D-CRF, behavior/daily life cancer-related fatigue; CRF, emotional/affective cancer-related fatigue; A-P-CRF, sensory/physical cancer-related fatigue; C-CRF, cognitive cancer-related fatigue; E-QoL, European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30; PSQI, Pittsburgh sleep quality index; SD, standard deviation.

P < .05 indicates significance for outcomes.

Figure 2.

Histogram showing the symptom assessment results in the CALM and UC groups at 12 weeks.

Comparison of the Symptom Assessment Results and the Cytokine Levels Before and After Intervention Periods Within Groups

As shown in Table 3 and Figure 3. We found significant exploratory differences in fatigue severity (T-CRF, D-CRF, A-CRF, P-CRF, and C-CRF) at 12 weeks compared with baseline for participants in the CALM group (t = 11.331, t = 11.188, t = 9.817, t = 9.128, t = 8.432, respectively; P < .001), whereas for participants in the UC group at 12 weeks, only D-CRF reflected a difference. There was a difference in quality of life and sleep quality reported by patients in the CALM group at 12 weeks compared to baseline (t = −5.492, t = 5.45, respectively; P < .001). Additionally, there was a statistically significant difference in quality of life reported by patients in the UC group between baseline and week 12 (t = −2.676, P < .05); however, the difference in sleep quality between baseline and week 12 was not statistically significant (t = 1.656, P > .05).

Table 3.

Comparison of the Symptom Assessment Results and the Cytokine Levels Before and After Intervention Periods Within Groups.

	CALM (n = 61)					UC (n = 65)
Measure	Baseline (mean ± SD)	12 weeks (mean ± SD)	95% CI	t	P	Baseline (mean ± SD)	12 weeks (mean ± SD)	95% CI	t	P
T-CRF	5.39 ± 1.04	3.80 ± 1.04	(1.31 to 1.88)	11.331	<.001	5.45 ± 1.14	5.24 ± 0.99	(−0.06 to 0.48)	1.537	.129
D-CRF	5.56 ± 1.21	3.86 ± 1.30	(1.39 to 2.00)	11.188	<.001	5.73 ± 1.42	5.32 ± 1.26	(0.09 to 0.73)	2.549	.013
A-CRF	5.61 ± 1.02	3.93 ± 1.18	(1.34 to 2.03)	9.817	<.001	5.68 ± 1.23	5.45 ± 0.98	(−0.07 to −0.54)	1.553	.125
P-CRF	5.38 ± 1.13	4.01 ± 1.01	(1.08 to 1.68)	9.128	<.001	5.40 ± 1.15	5.27 ± 1.12	(−0.20 to 0.45)	.761	.449
C-CRF	5.04 ± 1.26	3.41 ± 1.21	(1.24 to 2.01)	8.432	<.001	5.00 ± 1.27	4.93 ± 1.09	(−0.22 to 0.36)	.484	.630
E-QoL	61.69 ± 11.81	69.61 ± 12.96	(−10.80 to −5.03)	−5.492	<.001	61.22 ± 11.54	65.03 ± 10.58	(−6.66 to −0.97)	−2.676	.009
PSQI	11.38 ± 3.41	8.30 ± 2.71	(1.95 to 4.21)	5.45	<.001	10.55 ± 3.18	9.71 ± 3.59	(−0.18 to 1.87)	1.656	.103
IL-2	2.74 ± 2.43	3.22 ± 2.19	(−0.98 to 0.03)	−1.899	.062	2.07 ± 2.05	2.31 ± 1.79	(−0.80 to 0.31)	−.877	.384
IL-4	0.96 ± 0.96	1.35 ± 0.96	(−0.71 to −0.07)	−2.418	.019	0.81 ± 1.02	0.87 ± 0.63	(−0.35 to 0.22)	−.455	.650
IL-6	9.97 ± 15.79	6.01 ± 5.21	(0.34 to 7.59)	2.186	.033	9.69 ± 12.94	17.51 ± 21.21	(−12.79 to −2.85)	−3.142	.003
TNF-a	3.29 ± 4.25	1.85 ± 1.48	(0.37 to 2.50)	2.699	.009	2.18 ± 2.97	3.76 ± 3.59	(−2.63 to −0.53)	−3.010	.004

Abbreviations: CALM, managing cancer and living meaningfully; UC, usual care; T-CRF, total cancer-related fatigue; D-CRF, behavior/daily life cancer-related fatigue; A-CRF, emotional/affective cancer-related fatigue; P-CRF, sensory/physical cancer-related fatigue; C-CRF, cognitive cancer-related fatigue; E-QoL, European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30; PSQI, Pittsburgh sleep quality index; SD, standard deviation.

P < .05 indicates significance for outcomes.

Figure 3.

Histogram showing symptom assessment within the CALM group at baseline and at 12 weeks.

In contrast, there was a significant difference in the cytokines IL-6 and TNF-α at 12 weeks in the CALM and UC groups compared to baseline (IL-6: t = 2.186, t = −3.142, respectively; P < .05; TNF-α: t = 2.699, t = −3.010, respectively; P < .05), with no significant difference in IL-2 levels (t = −1.899, t = −.877, respectively; P > .05). Meanwhile, cytokine IL-4 levels were significantly different at 12 weeks in the CALM group (t = −2.418, P = .019) but they were not significantly different in the UC group (t = −.455, P = .65).

Correlation Between Symptom Assessment Results and the Cytokine Levels

In the final outcome analysis, the total fatigue severity in all patients at 12 weeks was positively correlated with IL-6 and TNF-α levels (r = .31, r = .32, respectively; P < .001), negatively correlated with IL-4 levels (r = −.30, P < .001), and not correlated with IL-2 levels (r = −.24, P = .007). Additionally, total fatigue was positively correlated with sleep quality (r = .50, P < .001) and negatively correlated with quality of life (r = −.48, P < .001). This is shown in Figure 4.

Figure 4.

Linear correlation between total CRF and the symptom assessment results and the cytokine levels at 12 weeks.

Discussion

The CALM intervention significantly reduced the severity of fatigue at 12 weeks in GI cancer patients with fatigue during treatment and improved their quality of life and sleep quality, with accompanying changes in IL-4, IL-6, and TNF-α levels. Our study further validated the correlation between total fatigue and cytokine IL-4, IL-6, and TNF-α levels. This study not only shows that the CALM intervention has a significant positive impact on CRF, quality of life and sleep quality in GI cancer patients during the 3-month intervention period but also provides evidence for understanding the biological mechanisms of CRF.

CALM is a psychological intervention that can target interventions for cancer survivors’ subjective feelings of fatigue as well as descriptions of their fatigue and accompanying symptoms. Our findings add to evidence from a systematic review which described consistent findings of psychological interventions as an effective tool for CRF in the cancer setting.^13,18 The possible benefits of CALM for cancer patients have attracted the attention of researchers, as studies have reported that CALM can alleviate cognitive impairment, anxiety, fatigue, etc., in cancer patients.^26,29,34,35 In a large randomized controlled trial, Rodin et al ²⁸ reported the effectiveness of CALM on depressive symptoms in patients with advanced cancer. However, there are limited studies on CALM, and our findings provide further evidence supporting the positive benefits of utilizing CALM interventions for cancer patients.^26,28,29 Our findings suggest that CALM is an effective psychological intervention for patients with GI cancer with CRF.

In this study, we explored changes in cytokine levels in GI cancer patients with CRF. The improvement in fatigue severity by CALM intervention was accompanied by a decrease in IL-6 and TNF-α levels as well as an increase in IL-4 levels. Although the differences in IL-6 and TNF-α levels were statistically significant in the UC group at 12 weeks compared to baseline, there was no statistically significant difference in the severity of fatigue. The etiology of CRF is unclear, but some possible biological mechanisms have been hypothesized, with proinflammatory cytokines receiving the most empirical attention and garnering the most supporting evidence.^13,36,37

CRF, a symptom of cancer cachexia, has been reported to be induced by a variety of mediators, and its prevalence and severity correlate with serum inflammatory cytokine levels, such as IL-6 and TNF-α.^38-40 Furthermore, in a longitudinal study of ovarian cancer patients receiving initial treatment, a decrease in IL-6 levels in peripheral blood was found to be significantly associated with reduced self-reported fatigue severity. ⁴¹ Consistent with our findings, reduced levels of IL-6 and TNF-α may attenuate or prevent the development of CRF, where the mechanism underlying CRF may be activation of the peripheral blood proinflammatory cytokine network by cancer cells, their treatment or other factors, which produces CRF symptoms through cytokine signaling pathways in the central nervous system. ³⁸ However, our findings indirectly reflect a negative effect of IL-4 levels on CRF, which is contrary to the hypothesized biological mechanism of CRF. The impact of IL-4 levels on CRF is still unclear, and its role in fatigue requires further exploration.

In terms of fatigue, CALM significantly reduced scores in all subdomains of CRF, including behavioral/daily living, sensory/physical, affective/emotional meaning, and cognition. Although patients assigned to the UC group had reduced total fatigue severity and scores in all subdomains at 12 weeks, their behavioral/daily living domain differed, which was consistent with their improved quality of life. These data support clinical practice recommendations that advise exercising and other psychological techniques to help adult cancer survivors feel less worn out and enhance their quality of life. ¹⁰

Our study provides further evidence to support the relationship between exhaustion level, quality of life, and sleep quality. Based on the WHO definition of quality of life as “the overall satisfaction of individuals from different cultures,” ³⁵ we consider quality of life to be a composite measure of the physical, psychological and social adaptability of an individual or group. We employ CALM as a systematic approach to reducing the negative emotions of cancer patients by addressing the practical and existential issues faced by cancer patients, restoring their hope in life, increasing their meaning and purpose to improve quality of life and improve fatigue symptoms.

The relationship between sleep and CRF may be bidirectional; CRF is often accompanied by sleep disturbances ¹³ and cancer patients report significantly disturbed sleep patterns, which may cause or exacerbate fatigue. Our study found that fatigue severity was positively associated with sleep quality, and as previously reported, and breast cancer patients reported higher levels of CRF when their self-assessed sleep quality remained below standard. ³⁹ Although this clinical presentation has been extensively reported, the underlying mechanisms are not yet clear, and further mechanistic studies are warranted.

We explored the study of CALM, a psychological intervention, on fatigue severity, quality of life, and sleep quality in patients with GI cancer. Furthermore, we explored the correlation between fatigue severity, quality of life, and sleep quality. Clinicians must understand and manage potentially preventable fatigue risk factors to reduce the burden of CRF.

We also investigated the possible relationship between the degree of fatigue and cytokine levels. It is critical for researchers to identify factors that increase the risk of inflammation and fatigue. We focused on factors associated with the fatigue process that may influence fatigue through the pathway of inflammation. Our findings provide evidence for the relationship between elevated inflammatory processes and changes in associated fatigue symptoms during treatment. Moreover, our findings suggest that the CALM intervention may be an effective approach for GI cancer patients with CRF and that cytokine IL-4, IL-6, and TNF-α levels may be potential biomarkers for predicting CRF development. However, further studies are needed to explore changes in these positive psychological and physiological responses over time, to gain access to highly effective CALM interventions and to provide more robust evidence for potential biological markers of CRF.

Strengths and Limitations

This study had several limitations. We included 3 cancer types due to slow participant recruitment, resulting in increased sample heterogeneity. This study was not followed up at a later stage, and the long-term effects of CALM on CRF should be further investigated. Finally, the study was conducted at a single site in a large city in China; therefore, the sample may not be representative of other settings, which may limit the generalizability of the findings. Nevertheless, recruitment rates to the oncology clinic were comparable to other psychotherapy interventions taken in similar settings.

This experiment also had several advantages. The interventions we evaluated were theoretically consistent with guidelines for lowering fatigue and raising quality of life while receiving cancer therapy. In addition, the trial had relatively high intervention compliance and completion rates, with less than 20% of patients assigned to the CALM intervention dropping out or not completing the final blood test for various reasons, primarily due to disease progression.

Conclusions

This study showed that the CALM intervention reduces CRF and improves quality of life and sleep quality in patients with GI cancer during cancer treatment. Additionally, the study demonstrated a correlation between CRP and IL-4, IL-6, and TNF-α levels. This suggests that CALM may be used as a supportive care approach for GI cancer patients with CRF; furthermore, the levels of IL-4, IL-6, and TNF-α may correlate with the severity of CRF in patients with GI cancers.