Incidence of sleep problems and their mediating role on depression and anxious preoccupation in patients with resected, non-advanced cancer: data from NEOcoping study

Our study analyzes the incidence of sleep problems and their mediating role on depression and anxious preoccupation in patients with resected, non-advanced cancer. A multi-institutional, prospective, observational study was conducted with 750 participants of 14 hospitals in Spain. Participants’ socio-demographic and clinical characteristics were collected using a standardized self-report form and using EORTC QoL-QLQ-C30, BSI, Mini-MAC questionnaires. In women, sleep problems, depression and anxious preoccupation were observed in 65, 41 and 21%, respectively. In men, sleep problems, depression and anxious preoccupation were reported in 51, 29 and 61%, respectively. More sleep problems, depression and anxious preoccupation were found among women than males. Depression was a significant predictor of anxious preoccupation. In males, sleep problems partially mediated this association. This was not confirmed in women. Our findings point toward the importance of developing interventions that decrease depression and sleep problems in cancer.


Introduction
Adjuvant chemotherapy following cancer resection increases survival in patients at risk for recurrence. High levels of anxious preoccupation often emerge during the pre-treatment period due to fear surrounding treatment side effects and recurrence [1]. Likewise, anxious preoccupation has been associated with depression and insomnia [2]. Similarly, depression is also common in oncological patients and can aggravate sleep disturbances [3] and together can contribute to anxious preoccupation, a coping strategy deemed inappropriate [4].
Sleep problems are prevalent in cancer patients [5], nearly two-thirds of patients reported symptoms including long latency periods before falling or staying asleep, frequent nocturnal awakenings, and impaired seep quality [6]. Higher levels of sleep problems predicted for more fatigue, depression and poorer performance status [7].
Few studies have examined anxious preoccupation in individuals about to receive chemotherapy, yet, in our series, it was present in 15.8% [1].
Our objective was to analyze the prevalence of depression, anxious preoccupation and sleep disorders in a population of patients with a resected non-advanced cancer grouped by gender and to know the mediational role of sleep problems in the other two disorders, depression and anxious preoccupation.

Participants and procedures
A multi-institutional, prospective, observational study was conducted with the participation of 14 hospitals in Spain from June 2015 to June 2018. NEOcoping is a cancer patient research program funded by the Continuous Care Group of the Spanish Society of Medical Oncology (SEOM). The study was approved by the Ethics Committee of each institution and by the Spanish Agency of Medicines and Medical Devices (AEMPS). Participants were 18 years of age or older with resected, non-advanced, histologically confirmed, solid cancer and eligible for adjuvant chemotherapy.

Measures
Participants' socio-demographic characteristics were collected using a standardized self-report form. Information related to participants' disease was obtained by reviewing their medical history.
Sleep problems: participant's subjective sleep was measured using the corresponding scale of a multidimensional questionnaire of health related quality of life (HRQoL), the EORTC QoL Questionnaire C30 (QLQ-C30) version 2.0 [8]. The questionnaire involves one straightforward question: 'during the past week, have you had trouble sleeping?' It was considered that patients had subjective sleep problems if they answered, 'a little', 'quite a bit' and 'very much', corresponding to 33.3, 66.7 or 100 values on the scale, respectively. This cut-off point was similar to that used by other authors [5]. In this study, Cronbach's alpha for the scale was 0.88.
Depression was measured using the Brief Symptom Inventory (BSI) 6-item depression subscale [9], designed to assess symptoms of disaffection and dysphoric mood, e.g., those reflecting self-deprecation, anhedonia, hopelessness, and suicidal ideation. Raw scores were converted to T scores [9]. In the present study, internal consistency was 0.75.

Anxious preoccupation
The anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer (Mini-MAC) scale was administered to quantify dysfunctional coping in response to cancer. It was taken from the Spanish version of the Mini-MAC [4] and consists of eight items (e.g., "I worry about the cancer returning or getting worse"), each measuring the tendency toward constant preoccupation with cancer as an event causing feelings of devastation, anxiety, fear, and apprehension. Responses above the 85th percentile (one standard deviation (SD) above the mean) were interpreted as clinically significant for high levels of anxious preoccupation. In this study, Cronbach's alpha for the scale range from 0.55 to 0.80 [10].

Statistical analyses
Chi-square and t test were conducted to compare participants and no-participants' socio-demographic and clinic characteristics. Mediation analyses were performed to determine whether perceived stress mediated in the association of depression and anxious preoccupation-based coping in patients. Separate models were run for anxious preoccupation and path coefficients, and bootstrapped confidence intervals were estimated. Analyses were run on the IBM-SPSS 23.0 statistical software package for Windows PC.

Results
Of the 835 patients recruited, 750 were eligible and the other 85 did not meet the inclusion criteria or met at least some exclusion criteria. No significant intergroup differences were detected regarding socio-demographic and clinical baseline characteristics; see Table 1.

Discussion
This study examines sleep problems in cancer patients who will initiate adjuvant chemotherapy and confirms its high prevalence in both women and men, 65.5% and 51.1%, respectively. Sleep problems (experienced between 12.5% and 56%) is one of the most prevalent symptom in cancer patients and survivors [5,7,11]. The possible causes of this wide range of prevalence may be due to demographic variables such as age, type of tumor, and type of treatment [6,11]. Sleep problems together with depression predicted poor QoL in colorectal patients, the largest group in this series [7].
In the present study, women presented more sleep problems, depression and anxious preoccupation than men. Similar to that found in other studies [12]. Breast cancer patients with a sleep problem were more likely to experienced complications and had longer hospital stays [13], and worse QoL [14].
This study also evaluates a mediation model that hypothesizes that sleep problems mediate the association between  anxious preoccupation and depression. The model was confirmed in men, albeit not in women, indicating that the greater the depression, the more sleep problems leading to increased anxious preoccupation in men. This demonstrates the association between depression and negative consequences for physical and psychological health [15]. Among females, the non-confirmation of the mediation model would indicate that there are other variables that account for anxious preoccupation and should be contemplated in future studies, including fear of deterioration of body image, personality, perceived social and family support. The strengths of this study include its prospective, multicenter design, and a large sample of patients with nonadvanced resected cancer. Its limitations include the modest effect size, use of self-reports that can lead to response biases such as social desirability, memory errors, etc., and the cross-sectional design that prevents directionality from being inferred.
Our findings point toward the importance of developing interventions that decrease depression and sleep problems in men with cancer. This may help them in their coping strategies with evidence-based approaches, such as cognitive and/or behavioral treatments that incorporate relaxation techniques. Future studies should investigate how these states evolve over time and incorporate objective measures of sleep quality.