Sleep Disorders in Cancer—A Systematic Review

Introduction: Sleep disorders, especially insomnia, are very common in different kinds of cancers, but their prevalence and incidence are not well-known. Disturbed sleep in cancer is caused by different reasons and usually appears as a comorbid disorder to different somatic and psychiatric diagnoses, psychological disturbances and treatment methods. There can be many different predictors for sleep disturbances in these vulnerable groups, such as pre-existing sleep disorders, caused by the mental status in cancer or as side effect of the cancer treatment. Methods: A systematic literature review of 8073 studies was conducted on the topic of sleep and sleep disorders in cancer patients. The articles were identified though PubMed, PsycInfo and Web of Knowledge, and a total number of 89 publications were qualified for analysis. Results: The identified eighty-nine studies were analyzed on the topic of sleep and sleep disorders in cancer, twenty-six studies on sleep and fatigue in cancer and sixty-one studies on the topic of sleep disorders in cancer. The prevalence of sleep disturbences and/or sleep disorders in cancer was up to 95%. Discussion: Sleep disturbances and sleep disorders (such as insomnia, OSAS, narcolepsy and RLS; REM-SBD) in cancer patients can be associated with different conditions. Side effects of cancer treatment and cancer-related psychological dysfunctions can be instigated by sleep disturbances and sleep disorders in these patients, especially insomnia and OSAS are common. An evidence-based treatment is necessary for concomitant mental and/or physical states.


Introduction
Sleep disturbances and different sleep disorders (e.g., insomnia and sleep-related breathing disorder (SRBD)/obstructive sleep apnea syndrome (OSAS)) are common and considerable complaints of cancer patients. Narcolepsy, restless legs syndrome (RLS) and REM-sleep behavior disorder (REM-SBD) are rarely found. Up to 95% of cancer patients complain of sleep disturbances/disorders during diagnosis, treatment and after 10 years of survivorship. Sleep disturbances/disorders and excessive daytime sleepiness (EDS) have been reported to influence fatigue  and its perceptions. Savard et al. studied cancer survivors and showed that 52% of them reported sleeping difficulties, and 58% reported that cancer either caused or aggravated their sleeping problems , especially [58].
Disturbed sleep appears before, while and after cancer diseases. The personalized treatment of the most frequent sleep disorders, e.g., insomnia or sleep-related breathing disorder, could improve both their mental and physical health, specifically for diseases such as cancer. The analyses for this review were very challenging, specifically with regards to systematizing the complex and nonhomogeneous literature about sleep, sleep disturbances and different sleep disorders, their prevalence and the severity of sleep complaints in cancer patients, especially because the cancer population is very heterogenous.
The aim of this systematic review was to evaluate critically the prevalence, severity and efficacy of treatments in cancer-related sleep disorders (CRSD).

Sleep Disturbances in the Case of Cancer-Related Fatigue (CrF)
In spite of severe cancer-related fatigue (CrF)  and its perceptions [43,54,58,63,64,67] in cancer patients, there is often also a high prevalence of sleep disturbances (30-50%) in which the proportion of poor sleep or bad sleep quality is significantly higher than in the general population [6,21,23,58,64] (Table 2). Due to frequent "naps" during the day caused by CrF, an additional increase in nocturnal problems can observed [1].
For the research of sleep and quality of sleep, the easy-to-use actigraphy is commonly used [89,90]. Actigraphy data from various studies have shown that there is a strong correlation between the changes in subjectively experienced CrF and sleep quality [2,10,16]. Therefore, CrF-induced sleep disorders can be used as a well-quantifiable CrF-induced event to diagnose and control the course of CrF. Table 1 shows the four sleep-specific phenotypes according to which patients with chronic fatigue syndrome can be classified by means of the more elaborate, but more informative, polysomnography [11]. Table 1. Sleep-specific phenotypes of fatigue (according to Reference [11]

Sleep-Related Breathing Disorder (SRBD)/Obstructive Sleep Apnea Syndrome (OSAS) in Cancer
Sleep-related breathing disorders (SRBD), especially obstructive sleep apnea syndrome, (OSAS) are common disorders that are characterised by repetitive interruptions of ventilation during sleep. They are caused by recurrent (upper) airway collapses and follwed by sleep fragmentation, intermitted hypoxia and oxidative stress. Systemic and vascular inflammations with endothelial dysfunctions cause diverse multiorgan chronic morbidities and mortalities that affect the cerebrovascular, cardiovascular and metabolic systems in the progress to cancer. Sleep-related breathing disorders are an independent risk factor for cerebrovascular diseases, cardiovascular diseases, metabolic diseases and cognitive decline and are associated with high rates of morbidity and mortality [72][73][74][75][76][77][78][79][80][81][82].
Chronic and intermittent hypoxias seem to play a key role in the regulation of various stages of tumor formation and their progressions. In recent years, some important studies have shown that OSAS patients tend to have a higher prevalence and incidence of cancer and even a higher prevalence of cancer-related mortality [72][73][74][75][76][77][78][79][80][81][82]. One article was able to show that early CPAP treatment can reduce these prevalences: In vitro studies have shown that, in OSAS, there are pro-oncogenic hypoxia properties that are mediate mainly by enhanced posttranslational HIF effects. Intermittant hypoxia results in the increased expression of vascular endothelial growth factor (VEGF) and in tumor growth and metastasis. An effective OSAS treatment coud prevent cancer, its growth and/or metastasis [74] ( Tables 3 and 6).

Narcolepsy in Cancer
The cancer risk as a comorbidity profile of narcoleptic patients has been rarely analyzed [83][84][85] (Tables 3 and 7). There exist only two case studies, and one evaluated the Taiwan nationwide database. Tseng et al. researched the risk of cancer (incidence) among adult narcoleptics [85]. They found that adult narcoleptic patients have a higher risk for developing cancer, but the study was not able to describe the underlying mechanisms for this [83][84][85]. Further research is needed to understand the association between narcolepsy and the development of cancer.

Restless Legs Syndrome (RLS) in Cancer
Decreased sleep quality, sleep disturbences and/or sleep disruption are very common in cancer patients, especially when they receive chemotherapy   (Tables 3 and 7). Until now the processes and their pathophysiology have not been completely understood, but most likely, they are multifactorial [86]. Additionally, disturbed sleep and sleep disorders like insomnia and OSAS as disorders and/or diseases with pain, fatigue and mood disturbances often occur in clusters. These clusters can negatively impact the quality of life and the outcome of diseases . Sleep disturbance, fatigue and mood disorders (like depression and anxiety) can be based on distinct biologic processes. These processes could be the trigger for inflammatory signaling as a contributing factor of restless legs syndrome (RLS) [86]. The prevalence and/or incidence of restless legs syndrome in cancer is insufficiently researched. A recent study of Saini et al. showed that RLS is frequent in patients with cancer during chemotherapy. They demonstrated that the prevalence is approximately double compared to the normal population (around 18%). In most cases, restless legs syndrome was correlated with depression, anxiety and a decreased quality of life [86].

REM Sleep Behavior Disorder in Cancer
Rapid Eye Movement Sleep Behavior Disorders (REM-SBD) and cancer are very seldom reported [83,87,88] (Tables 3 and 9). REM-SBD are forms of parasomnias. They are characterised by severe dream-related behavior and increased abnormal electromyographic activity during REM sleep. Sometimes, they are associated with nightmares and parvor nocturnus [83,87,88]. The excessive electromyographic activity during REM sleep reflects the dysfunction of the brainstem structures in REM-SBD patients [87]; acutely, they can be caused by different medications, such as antidepressants or anticholinergic drugs [88].

Data Sources
This review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting process where applicable [91].

Types of Studies
Randomized controlled trials (RCTs) and quasi-randomized controlled trials (qRCTs), prospective and retrospective studies, cross-sectional surveys, uncontrolled studies and controlled trials without randomization methods, a special article and case studies were included in this systematic review, because important literature was very rare and inconsistent. We only excluded any forms of qualitative studies. The search terms included the following keywords and keyword combinations (sleep OR sleep quality OR sleep disorders OR insomnia OR sleep-related breathing disorder OR obstructive sleep apnea syndrome OR narcolepsy OR restless legs syndrome) OR REM sleep behavior disorder (REM-SBD) AND (cancer) (AND (fatigue)) in English. The keywords were combined as pairs, e.g., sleep disorders AND cancer.
In addition, the reference lists of all of the obtained studies were evaluated. Hard copies of all of the articles were obtained, and they were fully read.
For the analyses of sleep disorders in cancer, only studies from the period 1999/2000-2018 were included in the review, with three exceptions: two studies about sleep and cancer-related fatigue (CrF) in cancer from 1983 to 1993 and a study about OSAS and cancer from 1988. For the analysis of sleep and fatigue in cancer, we even included some older ones.
The 8073 publications were found in the three databases-498 articles were read, and a total number of 89 publications were included in the final analysis.

Types of Studies
Randomized controlled trials (RCTs) and quasi-randomized controlled trials (qRCTs), prospective and retrospective studies, cross-sectional surveys, uncontrolled studies and controlled trials without randomization methods, a special article and case studies were included in this systematic review, because important literature was very rare and inconsistent. We only excluded any forms of qualitative studies.

Types of Participants
Participants who were diagnosed with a sleep disorder (insomnia, sleep-related breathing disorder (SRBD)/obstructive sleep apnea syndrome (OSAS), narcolepsy, restless legs syndrome (RLS) and REM-sleep behavior disorder (REM-SBD)) due to cancer (regardless of gender and age) were included.

Types of Intervention
The review included studies that evaluated different types of insomnia interventions:  The prevalence and/or the incidence of sleep disturbences and/or sleep disorders in cancer are measured secondly by subjective measurements-by scales or indices for the sleep quality (e.g., the Pittsburgh Sleep Quality Index (PSQI)) or special sleep disorders: insomnia (e.g., Insomnia Severity Index (ISI), Athens Insomnia Scale (ASI)), OSAS (e.g., Berlin questionnaire), Narcolepsy (e.g., Narcolepsy Symptom Questionnaire (NSQ)) or RLS (International Restless Legs Syndrome Study Group rating scale (IRLS)).

Secondary Outcomes
The effectiveness of insomnia treatments are measured with sleep diaries. Generally, they include various subjective approaches or several items for reflecting the subjective assessment of daily night's sleep, including the total sleep time (TST), time in bed (TIB), sleep efficiency (SE), sleep quality (SQ), satisfaction of sleep onset latency (SOL), wake after sleep onset, total waking time (WASO), number of awakenings and morning woken-up time.

Selection of Studies and Data Extraction
The databases PubMed, PsycInfo and Web of Knowledge were searched and potentially studies screened: After the initial screening with checking the titles and abstracts, all the full-text articles were read. The articles that were included in the review were identified, and the data, according to predefined criteria, were extracted. Information such as samples (e.g., kind and number of participants), interventions (in the case of insomnia), measuring instruments, measuring times, methods, outcomes and results were obtained and documented from each study.

Results
Twenty-six studies for the topic of sleep and fatigue in cancer and sixty-one studies for the topic of sleep disorders in cancer were analyzed, one for sleep disorders generally, forty-four studies for the topic "Insomnia in Cancer" (eight for the "Prevalence of Insomnia in Cancer" and thrirty-six for the "Treatment of Insomnia in Cancer"), twelve studies for the topic "Sleep-Related Breathing Disorder (SRBD)/Obstructive Sleep Apnea Syndrome (OSAS) in Cancer", three studies for the topic "Narcolepsy in Cancer"and one study for the topic "Restless Legs Syndrome (RLS) in Cancer" (Tables 2-9).

Discussion
Sleep disturbances and sleep disorders in cancer patients are very common and have different backgrounds compared with sleep difficulties in normal populations because of the differences in the risk factors, vulnerability and cancer-specific life events.
A personalized treatment of sleep disorders in patients with cancer could improve both their mental and physical health.
The goal of this review was to illuminate approaches that might influence sleep, sleep quality and sleep disorders in cancer patients and treatment possibilities in cancer-related insomnia. However, before treatment trials in different sleep disorders (insomnia, OSAS, narcolepsy, RLS and REM-SBD) can be started, prospective and objective studies are needed to unterstand the baseline levels of sleep, sleep difficulties and circadian rhythm in cancer. Sleep disruption in cancer can be caused by many different reasons, such as stress, mental disorders (like depression and anxiety), pain and treatment side effects.
Bad sleep quality, the degree of sleep disruption and sleep disorders have a very important impact on cancer and can used as predictors. Sleep disruptions and disruptions in the circadian rhythms affecting the sleep quality and the circadian rhythm themselves can result in a variety of psychological and physiological mechanisms, which can foster the developent and persistance of cancer-related fatigue. The role of naps in fatigued cancer patients is unclear; it could be that naps are not helpful to decrease cancer-related fatigue-they could have the opposite effect [17]. In noncancer patients, it is known that daytime naps reduce the nightly sleep quality and total sleep time.
Although the relationship between fatigue, sleep and circadian rhythms in cancer is known, there is a very small quantity of scientific reseach about this topic, and the quality is mostly very poor. The existing literature and research is inhomogeneous, and there are many methodological limitations: the types of studies (e.g., randomized controlled trials, quasi-randomized controlled trials, prospective and retrospective studies, cross-sectional surveys, uncontrolled studies and controlled trials without randomization methods, a special article and case studies); participants (different kinds of cancer patients-e.g., with or without treatment and with different entities); interventions (in the case of insomnia: nonpharmacological and pharmacological interventions); outcomes (objective and/or subjective measurements) are not comparable and the sample sizes are mostly very small. Davidson et al. found in a big sample size with nearly a thousand patients that the total prevalence scores of RLS were present in nearly half of the researched cancer patients, of overly sleepy and of insomnia in around one-third of the patients, of sleeping more than usual and repetitive leg movements in almost one-fifth of them and of breathing interruptions in approximately ten percent [27].
The causes of decreased sleep quality; chronic sleep difficulties and the different sleep disorders (insomnia, OSAS, narcolepsy, RLS and REM-SBD) are multifaceted, and in recent studies, the attention that was paid this problem was too insufficient. Until now, the pathogenesis of cancer-related sleep disorders and the development such as the progression of cancer based on sleep disorders has been unclear. More research about these topics is needed to understand the nature, duration and severity of the different sleep disorders in cancer or their relationship with it.
The prevention of sleep disorders generally and in cancer patients especially and an early personalized treatment can contribute to reducing cancer-related fatigue and severe mental disorders (like depression and anxiety) and can possibily prevent the development, preservation and/or aggravation of cancer.

Expert Recommendations
Sleep disturbances; disruptions of the circadian rhythms and different sleep disorders (e.g., insomnia and sleep-related breathing disorder (SRBD)/obstructive sleep apnea syndrome (OSAS)) could be predictors of cancer development and treatment success (look above). Due to that, cancer patients should be screened by sleep anamnesis and/or by sleep diaries, including the structured exploration of predisposing and precipitating cancer factors, and should be diagnosed-in the case of any kind of sleep-wake difficulties-by polysomnography.
Screening should explore unrefreshing sleep: prolonged sleep latency, frequent awakening and reduced sleep efficiency; daytime sleepiness and fatigue; loud snoring; inadequate nightly behavior and/or nightmares.
Both screening and/or the diagnosis of sleep disturbances; disruptions of the circadian rhythm and/or sleep disorders, as well as adequate sleep health education (including sleep hygiene, rules for good sleep quality and information about the consequences of unhealthy and/or untreated sleep disorders for mental and physical health) should be implemented to minimize the health risks caused by sleep disorders.
Tailored programs are needed and could be helpful to reduce cancer-related fatigue and/or severe mental disorders (like depression and anxiety) to support the outcome of the treatment of patients with cancer and comorbid sleep disorders.
Currently, sleep-wake solutions in cancer are mostly aimed only by responding to emergency reasons and based on isolated and/or fragmented interventions, e.g., the treatment of insomnia: cognitive behavioral therapy for insomnia, nightmares: rehearsal therapy and SRBD: CPAP adherence.
Peronalized medical services for cancer patients should include integrated coaching or the early treatment of the most common sleep disorders and web-based telehealth programs [92] to reduce the preservation and/or aggravation of cancer an/or serious implications, including increased cerebrovascular, cardiovascular and/or metabolic diseases; excessive daytime sleepiness and/or cancer-related fatigue.

Conclusions
Cancer patients can suffer under different sleep disturbances and sleep disorders, and these difficulties can be associated with different mental and/or physical problems. Side effects of cancer treatment and cancer-related psychological dysfunctions can be triggered it. Especially insomnia and OSAS are very common in cancer. Because of it, an evidence-based and tailored treatment is necessary.