Identifying relevant factors influencing cancer-related fatigue in patients with diffuse large B-cell lymphoma during chemotherapy

Abstract

BACKGROUND

Diffuse large B-cell lymphoma (DLBCL) is a rapidly growing malignant tumor, and chemotherapy is one of the treatments used to combat it. Although advancements of science and technology have resulted in more and more patients being able to receive effective treatment, they still face side effects such as fatigue and weakness. It is important to thoroughly investigate the factors that contribute to cancer-related fatigue (CRF) during chemotherapy.

AIM

To explore the factors related to CRF, anxiety, depression, and mindfulness levels in patients with DLBCL during chemotherapy.

METHODS

General information was collected from the electronic medical records of eligible patients. Sleep quality and mindfulness level scores in patients with DLBCL during chemotherapy were evaluated by the Pittsburgh Sleep Quality Index and Five Facet Mindfulness Questionnaire-Short Form. The Piper Fatigue Scale was used to evaluate the CRF status. The Self-Rating Anxiety Scale and Self-Rating Depression Scale were used to evaluate anxiety and depression status. Univariate analysis and multivariate regression analysis were used to investigate the factors related to CRF.

RESULTS

The overall average CRF level in 62 patients with DLBCL during chemotherapy was 5.74 ± 2.51. In 25 patients, the highest rate of mild fatigue was in the cognitive dimension (40.32%), and in 35 patients the highest moderate fatigue rate in the behavioral dimension (56.45%). In the emotional dimension, severe fatigue had the highest rate of occurrence, 34 cases or 29.03%. The CRF score was positively correlated with cancer experience (all P < 0.01) and negatively correlated with cancer treatment efficacy (all P < 0.01). Tumor staging, chemotherapy cycle, self-efficacy level, and anxiety and depression level were related to CRF in patients with DLBCL during chemotherapy.

CONCLUSION

There was a significant correlation between CRF and perceptual control level in patients. Tumor staging, chemotherapy cycle, self-efficacy level, and anxiety and depression level influenced CRF in patients with DLBCL during chemotherapy.

Key Words: Diffuse large B-cell lymphoma; Chemotherapy; Cancer-related fatigue; Anxiety; Depression; Mindfulness

Core Tip: The study aimed to explore the factors related to cancer-related fatigue (CRF), anxiety, depression, and mindfulness level in patients with diffuse large B-cell lymphoma (DLBCL) during chemotherapy. Univariate analysis and multivariate regression analysis were used to investigate the related factors of CRF. The overall average level of CRF in 62 patients with DLBCL during chemotherapy was 5.74 ± 2.51. There was a significant correlation between CRF and perceptual control level in patients with DLBCL during chemotherapy. Tumor staging, chemotherapy cycle, self-efficacy level, and anxiety and depression level influenced CRF in patients with DLBCL during chemotherapy.

INTRODUCTION

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). DLBCL is characterized by progressive destruction of lymphoid structures or diffuse infiltration of large B lymphoid cells[1]. It is the most common NHL in adults, accounting for 30%-40% of all new cases. The cause of the disease is related to genes, the environment, viruses, and the aging population[2]. In 2020, 544352 new cases of NHL were reported worldwide, which ranked it as the 13^th most common malignant tumor[3]. The incidence of DLBCL has increased worldwide in recent decades, including in China[4].

The molecular genetics and immunophenotype of DLBCL are highly heterogeneous, and chemotherapy is the primary clinical treatment[5]. However, the prolonged treatment cycle, high cost, and frequent adverse reactions associated with chemotherapy, along with patient concerns related to illness, can lead to prolonged periods of anxiety and depression. Cancer symptoms and the side effects of chemotherapy drugs make patients prone to negative emotions, fatigue, and other adverse reactions[6]. Cancer-related fatigue (CRF) is a common symptom in patients with DLBCL[7]. It is complex, and if severe it may affect quality of life, activities of daily life, and ultimately, survival. Fatigue is seldom an isolated condition and is typically accompanied by sleep disorders, unhealthy sleeping habits, emotional conditions (like depression and anxiety), or pain[8]. CRF usually lasts for a long time. It may begin at diagnosis and continue until several years after the end of treatment[9]. CRF and emotional disorders may be more uncomfortable for patients than symptoms like nausea, vomiting, and pain, which can be controlled by drugs[10]. Continuous CRF and emotional disorders not only affect quality of life and lead to delay or termination of antitumor therapy but also make patients unable to return to work and a normal life after curative treatment[11]. These destructive emotions seriously impact the effectiveness of treatment and quality of life and place a heavy burden on the patient’s family. Thus, it is important to identify the variables that impact CRF, anxiety, and depression in DLBCL patients undergoing chemotherapy, from a clinical standpoint. That was the aim of this study.

MATERIALS AND METHODS

Study design and patients

We evaluated the data of 62 patients who were. diagnosed with DLBCL and admitted to the Fourth Hospital of Hebei Medical University between January 2020 and December 2022. The Ethics Committee of the Fourth Hospital of Hebei Medical University approved the study (No. 2020ky022) and it was performed following the ethical guidelines of the Declaration of Helsinki. All participants signed a written informed consent form.

Eligible patients were ≥ 20 years of age with DLBCL and symptoms of CRF and emotional disorders. All had been treated with similar chemotherapy regimens. Patients with any of the following were excluded: (1) Functional injuries of the heart, liver, lung, and other organs; (2) A previous history of mental illness or mental disorders; (3) Cognitive impairment; or (4) Incomplete clinical records or lack of follow-up.

Data collection

The clinical data of eligible patients, including sex, age, marital status, education level, disease diagnosis, tumor type, chemotherapy cycle, and family history, among others, were collected from their electronic medical records. During the course of radiotherapy, nursing staff evaluated the patient's fatigue and psychological state.

Diagnostic criteria of CRF

The CRF status of the patients was evaluated with the Chinese edition of the Piper Fatigue Scale (PFS)[12]. The PFS is a subjective self-evaluation scale of perceived fatigue. It comprises 27 items across four behavioral dimensions, namely behavioral (six items), emotional (five items), cognitive (six items), and perceptual (five items). Each item uses a 0-10 score scale. The score for each item represents the severity of fatigue, 0-3 for no or mild fatigue, 3-6 for moderate fatigue, and 6-10 for severe fatigue.

Evaluation of anxiety and depression

The Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS)[13] were used to evaluate the anxiety and depression status of patients. The SDS scale includes 20 items related to depression, with a score of 1-4 for each item. The higher the score, the more serious the item. The total score multiplied by 1.25 is converted into a percentile, and a total score > 53 indicated depression. The SAS scale includes 20 anxiety-related items, scoring 1-4 for each item. The higher the score, the more serious the item. The total score multiplied by 1.25 was converted into a percentile, and a total score > 50 indicated anxiety.

Evaluation of mindfulness awareness and sleep quality

The Chinese edition of the Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF)[14] was used to assess the mindfulness awareness level, which encompasses awareness, description, conscious action, nonjudgment, and nonreaction. Each dimension contains four items, each was scored from 1-5 points, and the total score is 20-100 points. The higher the score, the higher the level of mindfulness awareness. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI)[15]. The total PSQI score ranges from 0-21. The higher the score, the worse the sleep quality.

Evaluation of perceptual control

The Chinese version of the cancer experience and efficacy scale (CEES)[16] was used to evaluate the perceptual control ability of patients. The scale consists of two subscales, experience and efficacy, and each subscale includes three dimensions. The experience subscale is divided into personal experience (4 items), social experience (6 items), and emotional experience (6 items). The efficacy subscale is divided into individual efficacy (5 items), collective efficacy (5 items), and medical effectiveness (3 items). A total of 29 items are scored on a Likert scale, with responses ranging from "strongly disagree" to "strongly agree" with corresponding scores of 0 to 5. A high experience score indicates a more significant negative cancer experience. A high efficacy score indicates more effective dealing with cancer.

Statistical analysis

Continuous variables were reported as means ± SD or medians and interquartile range. Between-group differences were compared using the Mann-Whitney U test. Categorical variables are reported as n (%) and were compared using the χ² test or Fisher's exact test. Cox regression analysis was used to analyze the factors related to CRF in patients with NHL. P < 0.05 was regarded as statistically significant.

RESULTS

General patient information

Between January 2020 and December 2022, 662 DLBCL patients were treated in our department, and 304 were not enrolled because they did not meet the inclusion criteria. Of those, 86 were less than 18 years of age; 149 were excluded because they refused to participate, and 61 were excluded because of incomplete data. The remaining 62 participants were eligible and were included in the study analysis (Figure 1). Table 1 shows the demographic and clinical characteristics of the eligible patients.

Figure 1 Flow diagram of the selection of study participants. DLBCL: Diffuse large B-cell lymphoma.

Table 1 Demographic and clinical characteristics of study-eligible patients.

Characteristics	Eligible, n = 62
Sex
Male	29
Female	33
Age in years
≤ 65	49
> 65	13
Education
High school or less	23
College	20
Bachelor’s degree	15
Graduate degree	4
ECOG performance status
< 2	8
≥ 2	7
BMI in kg/m2, median (IQR)	25.4 (22.2-28.7)
High serum LDH	9
High serum β2m	11

BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; LDH: Lactate dehydrogenase; β2m: β2-microglobulin.

Psychological symptoms of patients with DLBCL during chemotherapy

As shown in Table 2, the incidence of psychological symptoms in the 62 patients during chemotherapy was the highest for restless sleep (93.55%), followed by sadness (91.94%), forgetfulness (80.65%), distress (93.55%), and numbness (48.39%). The psychological symptom scores are shown in Figure 2A.

Figure 2 Psychological symptom scores and cancer-related fatigue-related symptom scores during chemotherapy. A: Psychological symptom scores during chemotherapy; B: Cancer-related fatigue-related symptom scores during chemotherapy.

Table 2 Psychological symptom scores in patients with diffuse large B-cell lymphoma during chemotherapy.

Item	Eligible, n = 62	Score
Restless sleep	58 (93.55)	4.51 ± 1.38
Sadness	57 (91.94)	4.77 ± 1.40
Forgetfulness	50 (80.65)	3.48 ± 1.12
Distress	58 (93.55)	4.53 ± 1.37
Numbness	30 (48.39)	3.47 ± 1.08

Data are n (%).

Sleep quality and mindfulness level scores in patients with DLBCL during chemotherapy

The sleep quality and mindfulness level scores during chemotherapy were evaluated by the PSQI and FFMQ-SF. The results are shown in Table 3.

Table 3 Pittsburgh Sleep Quality Index and Five-Facet Mindfulness Questionnaire-Short Form of patients with diffuse large B-cell lymphoma during chemotherapy.

Assessment measure	Scores
PSQI	10.49 ± 1.28
FFMQ-SF	49.85 ± 10.67

PSQI: Pittsburgh Sleep Quality Index; FFMQ-SF: Five-Facet Mindfulness Questionnaire-Short Form.

CRF status of patients with DLBCL during chemotherapy

The CRF status of these 62 patients with DLBCL was investigated based on data from their electronic medical records (Table 4). The results showed that during chemotherapy the overall average CRF was 5.74 ± 2.51. In 25 patients (40.32%) the highest rate of mild fatigue was in the cognitive dimension, in 35 patients (56.45%). the highest rate of moderate fatigue was in the behavioral dimension, and in 34 patients (29.03%) the highest rate of severe fatigue was in the emotional dimension.

Table 4 Cancer-related fatigue status of patients with diffuse large B-cell lymphoma, n = 62.

Dimension	Average score	Mild fatigue, n (%)	Moderate fatigue, n (%)	Severe fatigue, n (%)
Behavior fatigue	6.57 ± 2.43	18 (29.03)	35 (56.45)	9 (14.52)
Emotional fatigue	5.25 ± 2.14	15 (24.19)	29 (46.78)	34 (29.03)
Perceived fatigue	6.39 ± 2.36	20 (32.26)	32 (51.61)	10 (16.13)
Cognitive fatigue	5.37 ± 2.48	25 (40.32)	21 (33.87)	16 (25.81)
Total CRF score	5.74 ± 2.51	24 (38.71)	26 (41.94)	12 (19.35)

CRF: Cancer-related fatigue.

Univariate analysis of CRF in patients with DLBCL during chemotherapy

Univariate analysis was conducted to evaluate the factors related to CRF in patients with DLBCL. The results showed that pain, tumor stage, degree of anxiety and depression, chemotherapy cycle, and self-efficacy affected CRF in these patients during chemotherapy (all P < 0.05, Table 5).

Table 5 Univariate analysis of cancer-related fatigue in patients with diffuse large B-cell lymphoma.

Influencing factors	Eligible, n = 62	Average PFS score	P value
Sex			0.543
Male	29	5.44 ± 2.32
Female	33	5.74 ± 2.20
Age in years			0.095
≤ 65	49	4.59 ± 1.25
> 65	13	5.15 ± 2.42
Marital status			0.206
Married	21	5.57 ± 2.34
Unmarried	40	5.95 ± 2.53
Others	1	6.54 ± 2.32
Education			0.390
High school or less	23	4.39 ± 1.60
College	20	4.37 ± 1.38
Bachelor’s degree	15	5.07 ± 2.21
Graduate degree	4	5.93 ± 2.52
Self-efficacy level	26		0.031
High	26	4.66 ± 1.71
Medium	9	5.56 ± 2.30
Low		5.90 ± 2.51
Anxiety and depression degree			0.033
Mild	20	4.72 ± 1.32
Moderate	29	5.50 ± 2.53
Severe	13	5.97 ± 2.85
Tumor staging			0.001
Stage I	25	4.34 ± 1.55
Stage II	14	5.64 ± 2.19
Stage III	13	5.82 ± 2.44
Stage IV	10	6.78 ± 3.13
Chemotherapy cycle			0.006
First cycle	23	4.09 ± 1.13
Second cycle	19	4.52 ± 1.40
Third cycle	11	5.72 ± 2.37
Fourth cycle	9	6.46 ± 3.50
Pain degree			0.004
Mild	15	4.54 ± 1.75
Moderate	37	5.48 ± 2.44
Severe	10	6.31 ± 3.47

CRF-related symptoms of patients with DLBCL during chemotherapy

As shown in Table 6, the incidence of CRF-related symptoms in these 62 patients was fatigue (95.16%), pain (82.26%), dry mouth (88.71%), lethargy (87.10%), and shortness of breath (45.16%). The symptom scores are shown in Figure 2B.

Table 6 Cancer-related fatigue-related symptoms during chemotherapy in the study patients.

Items	Eligible, n = 62	Score
Fatigue	59 (95.16)	4.48 ± 1.47
Pain	51 (82.26)	4.42 ± 1.48
Dry mouth	55 (88.71)	4.35 ± 1.32
Lethargy	54 (87.10)	4.08 ± 1.34
Shortness of breath	28 (45.16)	3.52 ± 1.16

Data are n (%).

Perceptual control scores of patients with DLBCL during chemotherapy

The perceptual control scores of the 62 study patients are shown in Table 7.

Table 7 Perceptual control scores in patients with diffuse large B-cell lymphoma during chemotherapy.

Items	Score
Cancer experience
Personal experience	13.71 ± 1.98
Social experience	24.01 ± 3.02
Emotional experience	21.51 ± 3.12
Cancer efficacy
Personal efficacy	15.71 ± 4.66
Collective efficacy	18.28 ± 4.72
Medical care efficacy	11.63 ± 2.03

Correlation analysis between CRF and perceptual control

The correlation between CRF and perceptual control in patients with DLBCL during chemotherapy is shown in Figure 3. The CRF score was positively correlated with cancer experience (all P < 0.01) and negatively correlated with cancer treatment efficacy (all P < 0.01).

Figure 3 Correlation analysis between cancer-related fatigue and features of perceptual control in patients with diffuse large B-cell lymphoma during chemotherapy. A: Personal experience; B: Social experience; C: Emotional experience; D: Personal efficacy; E: Collective effectiveness; F: Medical care efficiency. CRF: Cancer-related fatigue.

Factors influencing CRF in patients with DLBCL during chemotherapy

As shown in Table 8, tumor stage, chemotherapy cycle, self-efficacy level, and anxiety and depression level were related to CRF in patients with DLBCL during chemotherapy.

Table 8 Factors influencing cancer-related fatigue in patients with diffuse large B-cell lymphoma during chemotherapy.

Factor	Regression coefficient	Wald χ2 value	P value	OR
Tumor staging	0.459	5.440	0.015	1.583
Chemotherapy cycle	0.233	4.629	0.003	1.339
Self-efficacy level	0.559	8.429	0.004	1.274
Anxiety and depression level	0.460	8.340	0.001	1.674

OR: Odds ratio.

DISCUSSION

CRF is a subjective feeling of lack of passion, weakness, lack of concentration, and a tendency to feel tired[17]. CRF is the most common symptom in cancer treatment, and its duration and intensity vary from person to person. Along with experiencing a significant decrease in physical strength, patients with CRF also have other negative symptoms, such as disinterest in their surroundings or self-doubt. These symptoms not only impact their daily lives but also pose a significant threat to their rehabilitation and overall quality of life[18]. This study focused on factors that influence CRF, anxiety, and depression in patients with DLBCL during chemotherapy because our understanding is currently limited and inconclusive.

Chemotherapy is the primary treatment for DLBCL. However, chemotherapy drugs may also kill normal cells. The occurrence of CRF during chemotherapy aggravates patients' negative emotions, which is not conducive to improving quality of life[19]. Most DLBCL patients have sleep disorders during chemotherapy, which may result from negative emotions surrounding the disease and the side effects of chemotherapy[20]. In This study investigated the status of CRF in patients with DLBCL. We observed that the overall average level of CRF in 62 patients with DLBCL during chemotherapy was 5.74 ± 2.51, of which 25 patients had the highest rate of mild fatigue in the cognitive dimension, and 35 patients had the highest moderate fatigue rate in the behavioral dimension. In the emotional dimension, the rate of severe fatigue was the highest in 34 cases. Therefore, it is of great significance to improve patients' cognitive level of fatigue and propose positive and effective measures to improve the degree of fatigue, promote their physical recovery, and improve their quality of life.

Patients with DLBCL must endure pain and discomfort caused by malignant tumors as well as adverse reactions caused by long-term chemotherapy[21]. Additionally, hospitalization can lead to a disruption of interpersonal communication and a sense of isolation, which often result in negative emotions such as anxiety and depression[22]. Previous studies have confirmed that alleviating negative emotions, such as tension, anxiety, and depression, and improving social and family psychological support reduced fatigue and improved their quality of life[23]. In addition, patients with advanced-stage disease may face increased mental stress and worry about the effectiveness of cancer treatment and their prognosis, which aggravates CRF[24]. Our study found that the severity of CRF in patients with DLBCL during chemotherapy in a state of depression and anxiety was significantly higher than it was in patients without depression and anxiety. The level of depression and anxiety significantly influenced CRF. The reason may be that patients with depression and anxiety are in a state of depression and slow thinking for a long time and are more likely to feel tired. Furthermore, antidepressants such as mirtazapine and paroxetine have side effects that make patients tired and sleepy, which might also aggravate CRF.

The results of this study indicate that the CRF score was positively correlated with the cancer experience score in patients with DLBCL during chemotherapy. The reasons might be as follows. The higher the score of the cancer experience, the more serious the hostile experience of patients during chemotherapy, and patients with CRF often experience fatigue in behavior, emotion, feeling, and cognition. Patients experience physical fatigue and weakness that leave them unable to carry out daily tasks, worsening their negative personal, social, and emotional wellbeing, and leading to an increased cancer experience score. Furthermore, we found that the CRF score was negatively correlated with cancer treatment effectiveness in these 62 patients with DLBCL. The reasons might be as follows. Higher cancer treatment efficacy scores reflect stronger belief in disease control, and a more optimistic perception of cancer. Patients with high personal efficacy scores have more vital personal management ability, a more robust ability to control their experience of the disease, better psychological adjustment and self-care, and a reduced degree of CRF.

Our results demonstrated that clinical stage significantly influenced CRF in this group of patients The reasons might be as follows. Patients with advanced-stage disease have lymph node metastasis and distant metastasis, resulting in more severe symptoms of fatigue. As the disease progresses, tumors may invade more organs and tissues, causing damage to multiple systems in the body. This not only increases the complexity of treatment but may also lead to more severe fatigue symptoms[25]. Patients with advanced DLBCL may have more comorbidities and complications, which can themselves lead to fatigue and worsen during chemotherapy. Additionally, the diagnosis and treatment of advanced cancer can have a negative impact on a patient's mental state, resulting in anxiety, depression, and pessimism, which are known risk factors of CRF[26]. Therefore, managing CRF in patients with clinically advanced DLBCL requires a comprehensive approach that includes symptom alleviation strategies, psychological support, rehabilitation training, and measures to improve quality of life. Healthcare professionals should be aware of the seriousness of CRF and consider this important issue in planning treatment to improve patient quality of life and treatment satisfaction.

The study has some limitations. Firstly, the sample size was small. Further research is warranted to validate and expand upon these findings, incorporating larger and more diverse patient populations. Furthermore, the study design might not have accounted for all potential confounding variables that could have influenced the results. Future research should consider controlling for these factors to ensure more accurate and reliable conclusions. Lastly, the findings of this study may be limited by the specific timeframe in which the data was collected. Future research should consider using objective measures to validate the findings.

CONCLUSION

In summary, tumor staging, chemotherapy cycle, self-efficacy level, and anxiety and depression levels were factors related to CRF in patients with DLBCL during chemotherapy. In the clinic, it is necessary to make reasonable treatment and nursing plans for patients with DLBCL combined with the clinical characteristics of CRF to improve their clinical symptoms, treatment effectiveness, and survival rate.