The characteristics and related factors of insomnia among postoperative patients with gastric cancer: a cross-sectional survey

Purpose This study aims to explore the characteristics and related factors of insomnia of patients after operation for gastric cancer. Methods A cross-sectional survey was carried out and finally 115 patients with insomnia after operation for gastric cancer were included. The general information, gastric cancer-related information, sleep quality, and other symptoms were investigated. Results ① The Pittsburgh sleep quality index score of most insomnia patients after gastric cancer surgery was 11-15 points, and the sleep quality rating was “poor”. ② The sleep quality of patients with insomnia after surgery for gastric cancer is related to the number of chemotherapy cycles, fatigue, and depression. ③ The probability of reduced sleep quality with the number of chemotherapy cycles >6 is 3.640 times that of ≤6. The probability of reduced sleep quality during moderate to severe fatigue was 4.390 times that of patients with no or mild fatigue. Conclusion Attention to related factors may be associated with improvement of sleep quality in patients with gastric cancer after surgery. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-021-06295-6.


Introduction
According to the World Health Organization (WHO), there were 896.63 million cancer deaths worldwide in 2016, making it the second leading cause of death [1]. Based on GLOBOCAN 2018 statistics, the incidence and death of gastric cancer accounted for the 5th and 3rd of all malignant tumors all over the world, respectively [2]. Anti-tumor tends to be comprehensive measures [3][4][5]. With the continuous improvement of treatment, the survival period of cancer patients has been prolonged. Improving the quality of life of cancer patients has gradually become the focus of attention and urgent problems to be solved for patients, families, society, and clinicians. Symptom management of tumor patients has gradually become a hot spot for medical personnel and scientific researchers [6,7].
Insomnia can lead to adverse health problems. In addition to the potential for physical, psychological, and social problems, they are more likely to contribute to the development of diseases, including cardiovascular disease and cancer [8]. Patients with insomnia have a moderate risk of developing cancer [8][9][10][11]. Studies have shown that insomnia damages DNA and reduces the body's ability to repair it, possibly increasing the risk of cancer [12]. In addition, short sleep duration has been linked to cancer mortality [13]. The incidence of insomnia in patients with malignant tumors is 52.6-67.4%, which is twice that of the general population [14,15]. However, if effective intervention is not given, chronic insomnia often develops [16,17]. It will increase the psychological burden of cancer patients, reduce the effect of anti-tumor treatment, and seriously affect the health of patients [18,19]. Researches, in recent years, have found that insomnia became Juan Li contributed equally with Guang-hui Zhu, and is the co-first author of this article. a common clinical symptom in cancer patients, but patients and doctors did not pay enough attention and treatment to insomnia [17,20]. Early intervention may reduce the severity or longevity of these problems during treatment [21].
In 1986, Spielman et al. have introduced the behavioral perspective on insomnia (the "3P" model), and conceptualized the influencing factors of insomnia into three categories: predisposing factors for insomnia, precipitating factors for insomnia attacks, and perpetuating factors for maintaining long-term insomnia [22]. At present, the "3P" model is still a popular model for the pathogenesis of chronic insomnia [23]. This model believes that individual susceptibility and innate tendency (such as high arousal or anxiety), and encounter predisposing factors (such as stressful events or diseases), will lead to acute insomnia. However, negative thoughts and non-adaptive coping behaviors (such as excessive concern and worry about insomnia) will produce conditioned arousal, and chronic insomnia will occur after repeated [24]. Most studies have included small sample sizes of participants with different characteristics, which may make it impossible to conduct subgroup analysis and identify potential related factors for insomnia [25]. Although a number of factors have been linked to the development of insomnia in cancer patients (e.g., gender, age, cancer treatment), the results have been mixed when it comes to related factors [26]. Surgical resection is the preferred treatment for gastric cancer [27]. Wang X. et al. found that the incidence of disturbed sleep was 90.48% and the risk of symptoms was about 4 points through investigation and analysis of the symptoms of patients after gastric cancer [28]. However, no studies have explored the characteristics and influencing factors of insomnia in postoperative patients with gastric cancer.
Recent studies have shown that insomnia is linked to other symptoms. The simultaneous occurrence of at least two symptoms can be classified into clusters of symptoms that are clinically significant and interrelated [29,30]. Different clusters of sleeprelated symptoms, including fatigue and depression, have been reported in cancer patients [31][32][33]. However, due to the limitations of previous studies, the association between insomnia and other symptoms has not been fully studied, including the lack of effective questionnaires to measure insomnia [31][32][33][34][35].
Based on the "3P" model of insomnia, we started this study in order to understand the characteristics of postoperative insomnia in patients with gastric cancer, find out the possible related factors for insomnia, and explore the interaction between insomnia and other symptoms.

Participants
The cross-sectional study included patients who attended the Oncology Clinic of Guang'anmen Hospital, China Academy of Chinese Medical Sciences between April 2019 and January 2020. The diagnosis of gastric cancer refers to "Regulations for Diagnosis and Treatment of Gastric Cancer (2018 Edition)" [3] and "American Joint Committee on Cancer (AJCC) gastric cancer TNM staging (the 8th version)" [36]. Insomnia is diagnosed on the "Chinese Classification and Diagnostic Criteria for Mental Disorders" (the 3rd version) [37]: ① difficulty falling asleep, ② often awakening and unstable sleep, ③ difficulty falling asleep again after waking up, awakening prematurely in the morning, ④ sleeping less than 6 h, lack of energy during the day, and drowsiness, and ⑤ history of repeated attacks, occurring ≥3 times a week and lasting ≥1 month.
The cases were screened according to the following: ① The patients diagnosed with gastric cancer, and the staging being T 1-4 N X M 0 ; ② within 6-8 months after standard radical gastrectomy; ③ meeting the diagnostic criteria for insomnia, and the Pittsburgh sleep quality index (PSQI) score being > 5 points; ④ no symptoms of insomnia within 1 month before surgery and not taking drugs with sleeping effects (based on clinical records or as reported by patient); ⑤ over 18 years old; ⑥ Karnofsky (KPS) score being ≥ 60 points; ⑦ having sufficient cognitive ability to complete the survey; and ⑧ signing the informed consent form voluntarily.

Procedures
This study was part of a project of Beijing Science and Technology Commission. The proposal was approved by the Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences (NO. 2016-118-KY-02). Potential participants were approached and invited to the study on the first day they were admitted to the hospital. This was a convenience sample. The method and purpose of the research were explained to them. After the patients signing the informed consent form, the inclusion criteria were determined, and information was collected for patients who met the inclusion criteria.

Measurements
(1) General information includes age, gender, and KPS score; (2) relevant data of gastric cancer are pathological type, differentiation grade, Lauren grade, clinical staging, TNM staging, lesion location, surgical method, and number of chemotherapy cycles; (3) main observation index is PSQI scale score; (4) other observation indicators are Piper Fatigue Scale-Chinese Version (PFS-CV) score, and Hospital Anxiety and Depression Scale (HADS) score.

PSQI
The PSQI scale is used to evaluate sleep quality. It consists of self-evaluation and other-evaluated items, and only 19 self-evaluation items participated in the scoring, including 7 components [38]. Every component is scored on a scale of 0-3, and the total score ranges from 0 to 21. PSQI score = component (A + B + C + D + E + F + G). Table 1 presents the correlation between total PSQI score and sleep quality. The score is higher, the worse the quality of sleep. The diagnostic sensitivity of this scale is 89.6%, and the specificity is 86.5% (kappa = 0.75, P ≤ 0.001) [21].

PFS-CV
The PFS-CV was translated by scholars from Hong Kong in 2003, including 4 dimensions of behavior, emotion, feeling, and cognition, with a total of 22 contents. The repeat test reliability is 0.98 [39]. Every content contains 11 points (0-10 points). Patients are scored according to the degree of their fatigue. Among them, there are 5 items for evaluating feelings and emotions, and 6 items for evaluating cognition and behaviors. The final score is derived from the average score of 4 dimensions. The score is higher, the heavier the fatigue; 0 means asymptomatic, 1-3 means mild, 4-6 means moderate, and 7-10 means severe.

HADS
In 1983, Zigmond AS. et al. designed HADS [40]. After tested, the anxiety subscale (A), depression subscale (D), and HADS total score have good retest consistency [41]. There are a total of 14 questions in the table. Among them, the seven questions of A test are used to evaluate anxiety, and the seven questions of D test are used to evaluate depression. Every question is counted as 0-3 points according to the degree level. The score is higher, the more severe the degree; 0-7 is asymptomatic, 8-10 is suspicious, and 11-21 is symptomatic. It is divided into 8 boundaries, <8 is negative, and ≥ 8 is positive.
② Statistical inference method: When the data conforms to the normal distribution and the variance is uniform, the independent sample t test is used to compare the samples between groups. When the variance is not uniform, the independent sample approximate t test is used. Non-normally distributed samples between groups use non-parametric test (Mann-Whitney U test). One-way ANOVA test or Kruskal-Wallis test was used for sample comparison among multiple groups. Multivariate binary unconditional logistic regression analysis is used to analyze categorical variables. Pearson correlation coefficient is used for correlation analysis of numerical variables.
The SPSS 24.0 software was used for statistical analysis of all data, using a two-sided difference test. P ≤ 0.05 is considered statistically significant.

Results
A total of 141 cases of postoperative patients with gastric cancer were initially screened, and 115 cases were finally included. According to the rough estimation method of sample size, the sample size is 5-10 times the number of variables [42]. The number of variables in this study is 15, requiring a sample size of 75-150 cases, so the number of cases included in this study met the requirements. Figure 1 presents the process of recruiting study participants. General data, gastric cancer data, and other symptom data of the included cases were presented in Table 2.

The characteristics
There were 60 cases (52.17%) with a PSQI score of 11-15, 37 cases (32.17%) with a score of 7-10, and 18 cases (15.65%) with a score of 16-21. The average score of the PSQI score was 12.05 ± 3.25. Among them, the "daytime dysfunction" component had the highest score, and the hypnotic drug component had the lowest score (see Table 3).

General information
The independent sample t test was used to compare the PSQI scores of gender and age groups, t = −0.010 and −1.092, P all >0.05. The PSQI score of KPS group was subjected to nonparametric test (Mann-Whitney U test), Z = −0.010, P > 0.05; Table 4.

Fatigue, depression, and anxiety
The Pearson correlation coefficients between the total PSQI score and the final score of the PFS-CV scale, between the total PSQI score and the HADS scale (depression subscale) score, and between the total PSQI score and the HADS scale (anxiety subscale) score were respectively 0.428, 0.261, and 0.060. P = 0.000, 0.005, and 0.527; Supplementary Figure 1

Related factors
The PSQI score was used as the dependent variable and assigned a value: 0 = "PSQI score <11 points (sleep quality is general)" and 1 = "PSQI score ≥11 points" (sleep quality is poor or very poor). The above related factors with P < 0.05 (the number of cycles of chemotherapy, the PFS-CV scale, the HADS scale (depression subscale)) were used as independent variables and assigned values: 0 = "the number of chemotherapy cycles ≤6," 1 = "the number of chemotherapy cycles >6"; 0 = "PFS-CV scale ≤4 points," 1 = "PFS-CV scale >4 points"; and 0 = "HADS scale (depression subscale) <8 points," 1 = "HADS scale (depression subscale) ≥ 8 points". A  Fig. 1 Flowchart of the study recruitment multivariate binary unconditional logistic regression model was established, and the forward method was used to select and eliminate independent variables. The regression analysis showed that the number of chemotherapy cycles and fatigue was significant related factors for the reduction of sleep quality in patients with insomnia (P < 0.05). Compared with the number of chemotherapy cycles ≤ 6, when the number of previous chemotherapy cycles after gastric cancer surgery is greater than 6, the risk of reduced sleep quality is increased (OR = 3.640, 95% CI: 1.416-9.357, P = 0.007). Compared with patients with no or mild fatigue, patients with moderate or severe fatigue after gastric cancer surgery have an increased risk of sleep quality (OR = 4.390, 95% CI:1.843-10.460, P = 0.001; Supplementary Table 2).

Discussion
This study investigated the characteristics of sleep quality included in patients. It was found that poor sleep quality accounted for 52.17%; patients with very poor sleep quality accounted for 15.65%. In the analysis of related factors, the total PSQI score was not statistically different among the groups of gender, age, KPS score, gastric cancer lesion location, differentiation grade, Lauren classification, clinical stage, T stage, and N stage (P > 0.05). That showed that the severity of insomnia in patients after gastric cancer surgery was not significantly related to the above factors. At present, some studies have concluded that gender, age, cancer stage, and other factors have nothing to do with the degree of insomnia in the included cases, which was the same as the results of this study [20,21,43]. However, there were still studies that differ from the results of this study. Ohayon MM et al. believed that gender and age were factors that induce insomnia in cancer patients [44]. We will need to design a prospective study including a larger sample size to verify the conclusions.
By analyzing the influence of the number of chemotherapy cycles on the degree of insomnia, it was found that the total PSQI score of patients with chemotherapy cycles > 6 [13 (12,16)] was significantly higher than that of patients with chemotherapy cycles ≤ 6 [10 (8, 12)] (P = 0.000). The multivariate binary unconditional logistic regression analysis showed that the number of chemotherapy cycles > 6 was a significant related factor for reduced sleep quality in patients with insomnia after operation for gastric cancer (P < 0.05). The risk of reduced sleep quality with the number of chemotherapy cycles >6 is 3.640 times that of ≤6. Chemotherapy, as one of the main anti-tumor treatments, has a certain cytotoxic effect, causing patients to have side effects such as anorexia, nausea, vomiting, fatigue, pain, and bone marrow suppression. As a result, the patient loses confidence in the treatment effect, and insomnia also occurs or worsens [45,46]. The result of a cross-sectional study looking at new-onset insomnia in cancer patients during chemotherapy showed that 42.8% of the 213 patients surveyed reported insomnia, and 31.9% of them reported severe insomnia [6]. In addition, the cerebral toxicity caused by the use of chemotherapeutic drugs contributes to the progression of brain inflammation by affecting the production and distribution of pro-inflammatory cytokines [47]. With the prolonged use of chemotherapeutic drugs, the tendency of insomnia in patients was aggravated. An 18-month study found that insomnia in cancer patients receiving chemotherapy increased with the length of time they took the drug [48].
The sleep quality of insomnia patients after gastric cancer surgery was positively correlated with fatigue and depression (Pearson = 0.428 and 0.261, P = 0.000 and 0.005), but not correlated with anxiety (P = 0.527). Hoang HTX et al. also found that the incidence and severity of insomnia in cancer patients had nothing to do with the characteristics of the participants, cancer information, or treatment factors, but were related to the emotional score of the participants [6]. The results of a systematic review also pointed out that patients with insomnia and mood have a two-way effect [49]. The hypothalamus, hippocampus, and other brain tissues regulate emotion and sleep at the same time by secreting neuropeptides and neurotransmitters, so that the two are connected [50,51]. A Chinese study also found that when a patient suffered from depression and insomnia, the level of neuropeptide Y in the body was lower than that of healthy people, and the level of substance P was higher than that of healthy people [52]. In addition, insomnia and fatigue often occur simultaneously in cancer patients. Xu JN's study included 60 patients with cancer-related fatigue and found that 70% of them suffered from insomnia [53]. Moreover, this study established a multivariate binary unconditional logistic regression analysis to show that the risk of reduced sleep quality in patients with moderate or severe fatigue after gastric cancer surgery was 4.390 times that of patients with no or mild fatigue (P = 0.001). The advantage of this study was to specifically select patients with insomnia after operation for gastric cancer to explore their sleep quality characteristics and related factors.

Study limitations
However, this study was a cross-sectional study. There is no control group to give the finding perspective or relevance for the findings of prevalence and severity. Due to its inherent limitations, this study cannot point out how insomnia and its related symptoms affect each other before they appear and how they change throughout the course of the disease. In addition, the insomnia of the included patients in this study was judged based on the history collection and the evaluation of the PSQI, but it may be caused by the error of patients' recollection that caused the wrong judgment of insomnia. Thirdly, due to limited research funds and time, this study did not observe other symptoms of patients, such as postoperative pain, sleep apnea, and dyspnea, which is a defect of this study. Finally, this study was only a single-center study, so there was certain selection error.

Clinical implications
This study confirmed that the sleep quality of insomnia patients after operation for gastric cancer was mainly "poor". That was correlated with the number of chemotherapy cycles, depression, and fatigue. The number of chemotherapy cycles >6 and moderate to severe fatigue was the negative correlation factors for reducing sleep quality in insomnia patients after operation for gastric cancer. Conclusions indicated that the quality of sleep in cancer patients might be related to previous treatments. Early assessment of insomnia and immediate intervention will be needed to improve the quality of life of cancer patients and their treatment compliance. Because insomnia may occur in all stages of cancer development and treatment, some patients have insomnia symptoms in the early stage of the tumor. In the course of treatment, early interventions may reduce the severity or longevity of these problems, such as exercise therapy, psychotherapy, or medication, to prevent the insomnia from worsening with anti-tumor therapy [21,54]. Cancer patients may have symptom clusters including insomnia, depression, and fatigue, and they may affect each other. Therefore, further research can be carried out to explore the incidence and characteristics of insomnia in cancer patients at different treatment stages.

Conclusion
Attention to related factors may be associated with improvement of sleep quality in patients with gastric cancer after surgery.
Code availability Not applicable.
Author contribution GZ and Juan L contributed equally to this work. Jie L was involved in study concept and design. GZ and Juan L wrote the first draft. Jie L, BX, MD, HW, XW, and JH contributed to the revision of the final report. All authors read and approved the final manuscript.
Funding This work was supported by grants from the Beijing Science and Technology Project (No. D161100005116004).
Data Availability Not applicable.

Declarations
Ethical approval The study obtained ethical approval from the Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences.
Consent to participate Informed consent was obtained from all individual participants included in the study.
Consent for publication Written informed consent for publication was obtained from all participants.

Conflict of interest The authors declare no competing interests.
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