Introduction
Sleep problems are among the most frequently reported complaints in cancer patients across all stages of the disease (i.e., before, during, and after treatment) [
1,
2]. This issue has received research attention in patients with solid tumors but has rarely been investigated in hematological cancer patients [
3‐
5].
Rather than being considered an independent issue, sleep problems in hematological cancer patients are considered to be a consequence of symptoms such as cancer-related fatigue [
5]. Indeed, previous assessment of sleep problems emerged in part while evaluating other problems linked to hematological cancer, describing it as one of the five symptoms affecting leukemia patients [
6]. Sleep problems in cancer patients are influenced by several factors, including hospitalization in an unfamiliar environment, a situation that adds concerns compared to receiving ambulatory therapy. Interestingly, sleep problems have been associated with lower survival chances [
4,
7] and overall quality of life [
5]. In regard to alleviating impaired sleep, studies have demonstrated how regular physical activity and body-mind disciplines can improve sleep quality [
8‐
12].
Less time spent in physical activity is another complaint described by both solid and hematological cancer patients [
13]. Indeed, patients affected by leukemia are reported to be less physically active even before the diagnosis [
14]. As it has been shown that maintaining and improving one’s physical capabilities can reduce several side effects of the disease and its treatment, an increase in physical activity levels is recommended before, during, and after medical therapy [
15,
16]. However, investigations on both sleep and physical activity are mainly conducted during and after medical treatments, whereas studies during the onset of medical therapies are lacking.
Sleep problems and reduced physical activity are two factors that strongly link to the sensation of cancer-related fatigue in leukemia patients, which can interfere with chemotherapy toleration and survival outcomes [
16,
17]. Cancer-related fatigue in leukemia patients is a multifactorial symptom that is often already present at the time of diagnosis and during the onset of therapies [
18,
19]. In addition to the adverse effects of therapies, also muscle dysfunction could increase cancer-related fatigue perception in hematological cancer patients. Reduced physical activity can augment cancer-related fatigue as it contributes to progressive deconditioning of muscle and strength [
20]. Together, cancer-related fatigue and reduced physical activity act in a vicious circle, in which higher cancer-related fatigue reduces one’s physical activity while lower levels of physical activity reciprocally increase one’s sensation of cancer-related fatigue [
21].
In summary, leukemia patients are often identified as fatigued subjects that report sleep and physical activity impairments at the time of diagnosis [
16]. To date, no studies have tried to assess how sleep, physical activity, and fatigue interact and interfere with each other during the onset of chemotherapy. However, such studies are necessary to better understand the relationship between these factors and to develop efficient supportive treatments to reduce this complex of symptoms.
In view of this, the present study considers individuals with hematological malignancies during the onset of high-dose chemotherapy. It focuses on the role of sleep on physical activity and fatigue levels between those classified as good or bad sleepers. Additionally, a mediation model will be used to investigate interactions between sleep, physical activity, and fatigue.
Discussion
To the best of our knowledge, this is the first study to provide an in-depth analysis of sleep problems and their consequences during the onset of therapy in newly-diagnosed patients with hematological cancer diseases.
Based on the cut-off levels of the PSQI, and compared to healthy sample norms [
24], our results reveal that sleep problems affected a considerable proportion (ca 75%) of the study population. These findings are in line with those of previous studies that report sleep problems in comparable populations, although these studies mainly focus on later stages of the disease and its treatment (e.g., during or after medical treatment) [
4,
34]. In contrast, the present study results highlight that sleep problems may occur at the onset, and, more precisely, during the first two weeks of medical therapy.
Comparing individuals classified as either “good” or “bad” sleepers provides an initial suggestion as to the potential causes of sleep problems. On the one hand, the pathology and its symptoms could exert a compromising effect on sleep. Indeed, individuals identified as “bad” sleepers reported significantly increased pain and other symptoms, even though not significant, such as nausea and vomiting, constipation, and diarrhea symptoms. Pain especially is a symptom that has already been found to interfere with sleep by causing awakening during nights [
5,
35]. On the other hand, psychological distress (anxiety and depressive symptoms) due to diagnosis could negatively affect sleep as patients worry about their future and the imminent therapy. In fact, bad sleepers reported higher anxiety levels in the present study. Based on the results of previous studies, we can suppose that anxiety and depression could negatively affect sleep by increasing the difficulty of falling asleep and subsequently maintaining sleep [
2,
36]. The combination of disturbed sleep, distress, anxiety, and pain could negatively impact one’s overall perception of quality of life. Indeed, bad sleepers in the present sample reported a slightly compromised perception of global health compared to good sleepers, even though the analysis showed no significance. Other factors impacting sleep and that should be taken into account are the new and unfamiliar hospital environment and daytime napping. Regarding the former, being hospitalized could represent an additional problem that could negatively affect sleep compared to day hospital care and therapy. However, due to the covered period by PSQI (30 days), sleep problems in the present sample could be mainly anxiety-induced by the disease manifestation and testing prior to the diagnosis and less to chemotherapy side effects. Focusing on daytime napping, even though we did not investigate naps habits or opportunities, based on previous results [
37], we could speculate that usual naps during the day could disrupt nighttime sleep and, consequently, increasing self-perceived fatigue.
Interestingly, bad sleepers also reported decreased physical performance, physical activity levels, and increased sensation of cancer-related fatigue. Leukemia patients have previously been described as physically impaired because the higher fatigue level likely provokes tiredness, weakness, and fatigability, which may contribute to a lower level of physical activity [
16]. Furthermore, specific circumstances of this patient population (for example being connected to infusion for several hours) reduce their ability to move around. Regarding physical activity, to date, studies have investigated the influence of physical activity and exercise on cancer-related fatigue in persons with cancer. In addition, sleep problems have been found to influence physical activity and physical performance. However, cancer-related fatigue has been previously defined as an independent symptom that cannot be attenuated by a sufficient amount of sleep [
38]. To determine the potential interaction between these three factors, we created the mediation model based on the relevant variables identified in the correlation analysis. The mediation analysis identified physical activity in everyday life as a mediating factor between sleep and general fatigue. This indicates that sleep problems affect fatigue indirectly through physical activity. In other words, better sleep positively affects physical activity level, which in turn improves one’s sensation of fatigue. In light of previous works, it is possible to suppose that subjects would feel more inclined to be more physically active if they suffered less from sleep problems. [
39,
40]. Thus, the combined action of sleep and physical activity could be a useful and effective tool to improve sensation of cancer-related fatigue during the onset of hematological cancer treatments. Our suppositions are in line with the statement that even a night of prolonged restorative rest or sleep is insufficient to reduce cancer-related fatigue [
38]. Furthermore, the National Comprehensive Cancer Network recommends practicing physical activity regularly (despite the effort required to fight the effects of fatigue) [
38].
Regarding fatigue, patients with sleep problems reported elevated general fatigue. Previous studies have often generalized that leukemia patients report cancer-related fatigue without considering differences in sleep problems [
41], but we have demonstrated cancer-related fatigue differences based on sleep problems.
Physical activity levels are mostly assessed during hospitalization to improve patients' well-being or quality of life. In this context, baseline data are necessary to show the changes after the hospitalization or the intervention protocol, but not to describe the dissimilarities among patients during the onset of chemotherapy. Increasing physical activity will reduce the burden of cancer-related fatigue symptoms–including sleep problems–and decrease the risk of all-cause mortality [
42‐
44]. The present study results advance the idea that the same process is applicable since the onset of therapy. In view of this, recommendations to practice more physical activity are particularly valuable because a good level of physical functioning could help to combat cancer-related fatigue and positively interact with treatment outcomes, as stated in a recent study by Möller and colleagues (2020) [
45].
The results of the present study should be considered in the context of its strengths and limitations.
Its strengths comprise addressing an underinvestigated population and the administration of a well-established sleep assessment (PSQI). In studies of leukemia patients, questionnaires usually assess sleep as a component of quality of life instead of using a specific questionnaire for sleep [
6,
44,
46]. Additionally, the period of assessment is a unique aspect of the present study. Early knowledge about patient conditions, such as fatigue and sleep problems, is essential because it may predict/influence therapy tolerance and prognosis [
47,
48].
The significance of this study is limited by its cross-sectional design. We describe sleep problems as influencing physical activity. Although the relationship between physical activity and sleep is mostly described in this way (i.e., the former influencing the quality of the latter [
12]), the bi-directional relationship between sleep and physical activity is still debated. Objective assessments for sleep and physical activity should be used in further investigations. Finally, the time frame assessment is different depending on the questionnaire. Indeed, the lack of significance could be addressed to different time frames of the questionnaires (e.g. 30 days for the PSQI and one week for EORTC QLQ-C30). Notwithstanding the difficulties in finding appropriate methods for this population and questionnaires investigating the identical timeframe, we could speculate that the result could be even bigger and significant with a perfect timeframe overlap.
In conclusion, this study identified sleep problems, which may be driven by distress and other symptoms (e.g., anxiety and pain), as an important issue in hematological patients during the onset of the therapy.
Sleep problems represent an issue that could leave subjects with lower energy reserves (preventing physical activity) and ultimately result in cancer-related fatigue. Besides physical activity, sleep problems should be considered as a confounding factor and toehold in further studies investigating cancer-related fatigue in persons with hematological diseases and cancer. Future studies should consider more and other influencing factors linked to sleep, physical activity, and sleep, such as weight and BMI. Indeed, body composition parameters and nutritional status (even though not significant in the present study) are known to interact with sleep disturbances [
49,
50]. Furthermore, upcoming studies should consider investigating sleep more broadly and also in its biological components and objective parameters. For example, cortisol should be taken into account because its low level could interact with fatigue and cytokines production. Moreover, both cortisol and melatonin, the hormone predisposing to sleep, show a circadian rhythm and their altered rhythmicity could predispose to the pathology or be affected by cancer treatments [
51]. In this view, rest-activity circadian rhythm analysis and cortisol and melatonin 24-h dosages could help describe sleep problems and their causes or consequences.
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