Practical strategies for management of fatigue and sleep disorders in people with brain tumors

“It makes me feel good to know that I'm not the only [one] having fatigue and no energy. I can't get my positive mind and my fatigued body on the same page. Frustrating. I used to be a jet before cancer, and I am still adapting to being a sailboat after diagnosis. I just want to do more, like my old self.”

It is well known that symptoms seldom occur in isolation and that most patients with a solid tumor malignancy report multiple concurrent symptoms. Fatigue and alterations in sleep are 2 of the most common symptoms reported in patients with solid tumors, and research describing these symptoms has indicated that they may form a cluster or complex.^1,2 These symptom clusters are theorized to have shared biologic pathways, and it is postulated that interventions could be developed to target multiple symptoms by targeting the underlying biologic mechanisms.³ Although cancer-related fatigue and cancer-related sleep disturbances are distinct concepts, the majority of studies in patients with cancer that have assessed both sleep and fatigue support a strong correlation between fatigue and various sleep disorders, including poor sleep quality, disrupted initiation and maintenance of sleep, nighttime awakening, restless sleep, and excessive daytime sleepiness.^4–6 The significance of the relationship between fatigue and altered sleep is supported by several reports that concluded that insomnia disorders “added additional risk for experiencing intense and persistent fatigue after cancer treatment (p. 895).”^7,8

The underlying biologic mechanisms of both fatigue and sleep in specific populations are still being interrogated and will assuredly influence treatment. Current management of both symptoms requires a multi-modal approach, including evaluation of comorbid conditions and concomitant medications, current behavioral habits and activities, and physical/psychological stressors. Interventions may include both pharmacologic and non-pharmacologic approaches for an individualized approach to care. This review will provide a general overview of both fatigue and sleep in patients with primary brain tumors, focusing on current strategies for assessment and management.

Fatigue

Fatigue is defined as the perception of unusual tiredness that varies in pattern or severity and has a negative impact on ability to function.⁹ Fatigue is not only one of the most common, but also it is one of the most severe, symptoms in patients with solid tumors, including those with primary brain tumors. Cross-sectional studies have reported fatigue as the most prevalent symptom, with 40%–70% of patients with primary brain tumor reporting having fatigue throughout the illness trajectory.^10,11 In addition, fatigue has been reported to be the most troublesome symptom to patients,¹² with a high percentage of patients reporting very low energy levels¹¹ or rating their fatigue as moderate to severe.¹⁰

Although fatigue is prevalent throughout the disease trajectory, cranial radiation remains the most common and significant cause, with >80% of patients with primary brain tumor reporting fatigue during the course of radiation (Lovely, Miaskowski et al. 1999). Although fatigue has been reported to occur as early as the first week of treatment, the incidence and severity of fatigue markedly increases with cumulative radiation and often continues well into the postradiation period.¹³ Faithfull et al. described a somnolence syndrome occurring during and immediately following cranial radiation therapy in patients with malignant glioma that included fatigue, excessive drowsiness, feeling clumsy, and inability to concentrate.¹⁴ These symptoms had a cyclical pattern, with increased severity on days 1–21 and then again during days 30–35 after the start of radiation. However, although less common, the fatigue can be chronic in nature, often extending into the period of survivorship after therapy has been completed. This can occur regardless of the tumor grade, with one report indicating that 39% of patients with low-grade glioma reported severe fatigue >8 years after completion of therapy.¹⁵

Fatigue is nebulous by it's nature and can encompass mental, physical, and/or psychological components, resulting in a wide variation among patients in the associated symptoms and influence on daily activity. Fatigue can also be difficult to distinguish from other conditions and can be a manifestation of an underlying metabolic or psychiatric condition, most commonly depression. In the population with primary brain tumor, depression and anxiety has been reported to occur in 16%–50% of patients during the early stages of the disease and may be difficult to distinguish from fatigue in this patient population.¹⁶ As indicated above, the cancer therapy itself can be associated with fatigue, but other concomitant medications, such as anticonvulsants and corticosteroids, have also been reported to have a negative impact on fatigue in this patient population.¹⁵ In summary, fatigue occurs commonly as the consequence of multiple etiologies and may be difficult to distinguish from other conditions.

Sleep-Wake Disturbance

Sleep-wake disturbances are defined as perceived or actual alterations in night sleep with resultant daytime impairment.¹⁷ Sleep-wake disturbances occur in 15%–20% of the general population and 33%–57% of those with solid tumors,^7,18 including brain.¹⁹ There are a limited number of studies exploring factors associated with alterations in sleep in patients with primary brain tumor, with most of the published reports involving children. These studies have indicated that, in adult survivors of childhood brain tumors, treatment with a radiation dose >3500 cGy, younger age at treatment and those children with craniopharyngioma report significant problems with sleep as adults.²⁰

There are several types of sleep-wake disturbances, including the broad classifications of insomnia, sleep-related breathing disorders, hypersomnias, circadian rhyhtym sleep disorders, parasomnias, and sleep-related movement disorders. To establish a definitive diagnosis, referral to sleep specialist for formal testing is required. This article will focus on insomnias and hypersomnias, because these are most common sleep disturbances seen in patients with solid tumor and can often be evaluated and managed based on clinical symptoms. The American Academy of Sleep Medicine has established criteria for insomnia,²¹ as outlined in Box 1.

1. Complaints of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is chronically non-restorative

2. Sleep difficulty occurs despite adequate opportunities for sleep

3. At least one of the following daytime impairments:

   • Fatigue or malaise
   • Attention, concentration or memory impairment
   • Social or vocational dysfunction
   • Mood disturbance or irritability
   • Daytime sleepiness
   • Reduced motivation, energy or initiative
   • Proneness for errors or accidents at work or driving
   • Tension, headache, or gastrointestinal symptoms
   • Concerns or worries about sleep

Mechanisms/Models of Fatigue and Sleep Disturbance

Work in other patients with solid tumors has led to the hypothesis that inflammatory pathways may be involved in the production of fatigue and sleep disturbance. Reports indicate that elevated levels of cytokines, including interleukin 6 (IL-6), have been found to be associated with fatigue.^22,23 The role of cytokines in the production of these symptoms is an area of active investigation and has generated support for the concept that a sickness behavior occurs in patients with cancer who experience these symptoms. Models have been developed to describe potential biologic pathways resulting in these symptoms. These developed models using inflammatory pathways (sickness behavior) indicate that IL-1 and IL-6 may lead to induction of corticotrophin-releasing hormone (CRH) and stimulate the pituitary-hypothalamic axis (HPA). CRH may induce adrenocorticotropin hormone (ACTH) and glucocorticoid hormones from the adrenal medulla, perpetuating an inflammatory response, or alternatively, IFN-alpha may result in alterations norepinephrine, serotonin, and dopamine release.³

In the case of brain radiation, neuroinflammation may be the underlying mechanism leading to fatigue and the cascade of additional symptoms that form this cluster of fatigue and sleep disturbance. Existing models propose that variations in melatonin production leads to alterations in the central molecular clock, resulting in aberrant neurotransmitter and cytokine production resulting in symptoms, such as insomnia and fatigue.^24,25 It has been postulated that this aberrant central molecular clock activity results in symptom clusters, including fatigue in patients with other solid tumor malignancies.^26,27 We performed a pilot study on a small subset of patients with brain tumors that led us to hypothesize that this neuroinflammation may result in aberrant production of melatonin as an immunomodulating response (Fig. 1). The secondary effects from the altered melatonin kinetics may contribute to the excessive daytime sleepiness and worsening of the inflammatory-related fatigue.²⁸ Outside our pilot work, altered melatonin secretion has been reported to be associated with excessive daytime sleepiness in children previously treated with cranial radiation²⁹ and postulated to occur in adult glioma survivors.³⁰ Animal models exploring the impact of cranial radiation on melatonin have reported a 2-phase reaction, with an immediate reduction in melatonin synthesis followed quickly by an increase in melatonin synthesis and circulating melatonin.³¹ In addition, this increase in melatonin secretion has also been reported in other inflammatory disease states known to affect the brain.^32,33 This is a continued area of active investigation in patients with primary brain tumors.

Fig. 1.

Proposed model of the Pathophysiology of radiation induced fatigue-sleep cluster.

Neuroimaging studies evaluating alterations in perfusion and biochemical activity in the brain have recently been reported in patients with other neurologic diseases and are now being evaluated in patients with solid tumors. These early reports of brain imaging studies have indicated that brain atrophy and reduced connectivity may occur in patients with underlying neurologic diseases who experience fatigue. For example, functional MRI in multiple sclerosis shows reduced perfusion to the frontal and basal ganglia, and others have shown reduced perfusion of the basal ganglia and thalamus indicating decreased coordination between cortical and subocoritcal systems.³⁴ The implications of these changes are still under investigation.

Measurement

Because of the subjective nature of these symptoms, use of the patient report of the occurrence and severity of both fatigue and insomnia are common. Several patient-reported outcome (PRO) questionnaires with demonstrated reliability and validity are available for use in patients with cancer. Agasi-Idenburg et al. provide an overview of the quality and user-friendliness of available scales for fatigue.³⁵ These instruments have the patient's personally rate their fatigue and it's components on Likert-type scales. Depending on the conceptual underpinnings of the scales, fatigue is either viewed as a unidimensional or multidimensional construct. Selection of an appropriate measure for use is dependent on the study intent, potential for confounding variables, and careful selection of the times to measure.³⁶ For fatigue, there are several options for instruments that are validated in the population with solid tumor include the Brief Fatigue Inventory (BFI),⁸ the Piper Fatigue Scale,³⁷ the PROMIS fatigue scales,³⁸ as well as more broad scope instruments that include fatigue and other symptoms, such as the Edmonton Symptom Assessment System³⁹ and the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT),⁴⁰ among others. PRO scales for sleep wake disturbance are also available, including the Epworth Sleepiness Scale (ESS), which is an 8-item questionnaire designed to asses general level of daytime sleepiness.⁴¹ The ESS has been used in studies that have examined daytime sleepiness in medical interns, chronically ill, and in those with sleep apnea.⁴² Additional tools include the Pittsburgh Sleep Quality Index⁴³ and sleep diaries.^44,45

Objective measures of activity and sleep are also available. Polysomnography is considered to be the gold standard for evaluation of sleep disturbances for diagnostic purposes. Actigraphy is often used for research purposes as a surrogate measure of sleep and daytime activity because of ease of use and significant cost advantages. Actigraphy is the measurement of physical movement using motion sensors and can reliable report several descriptive sleep measures, including the sleep onset latency (SOL), numbers of awakenings (NWAK), wake after sleep onset (WASO), total sleep time (TSTS), and sleep efficiency (SE). As discussed in a major review⁴⁶ and a practice parameter,⁴⁷ actigraphy provides an objective estimate of sleep and the 24 h sleep wake rhythm and can detect circadian disturbances. Actigraphy can also be used to identify patients with sleep disorders who are overly active near bedtime or generally inactive throughout the day.⁴⁸ Actigrapahy is often used in conjunction with a sleep diary to corroborate patient reported data, but will provide objective measures of activity during a 24-hour period. These measures are primarily used for research purposes or in the case of polysomnography, to diagnosis the specific type of sleep disorder.

Management of Fatigue

The National Comprehensive Cancer Network (NCCN) guidelines (2011) include recommendations for the assessment and management of cancer-related fatigue (CRF).⁴⁹ For patients reporting moderate to severe fatigue, the guidelines recommend first evaluating for contributing and treatable factors, including pain, emotional distress, anemia, altered sleep hygiene, nutritional deficiencies, and comorbid conditions, such as thyroid dysfunction. Once these have been evaluated and treatment initiated, if indicated, general strategies to manage fatigue include energy conservation techniques such as setting priorities, delegating activities which drain energy, structuring the daily routine, using labor-saving devices, and use of distraction are recommended. Naps should be limited to <1 h to avoid interfering with the normal sleep-wake cycle. Nonpharmacologic methods to treat fatigue include activity enhancement (such as exercise) use of physical based therapies (including massage), psychosocial interventions, nutritional consultation, and use of cognitive behavioral therapy for sleep hygiene. Efficacy of these various interventions in relation to the patient's current treatment status (receiving active treatment, during follow-up, or at the end of life) are provided in Table 1.

Table 1.

Efficacy of fatigue interventions based on stage of treatment

Stage of treatment	Activity Enhancement	Physically-based Therapy	Psychosocial Interventions	Nutritional Consultation	Cognitive Behavioral Therapy for Sleep
On Active Treatment	X	X	X	X	X
Post Treatment	X		X	X	X
End of Life			X	X

*Based on NCCN Guidelines (2011).

Exercise

Exercise as an intervention to improve CRF has been explored in several studies in patients with other solid tumors, especially breast cancer, but not in the population witn primary brain tumors. Cramp and Daniel⁵⁰ published a meta-analysis of randomized controlled trials (RCTs) and reported that there were statistically and clinically significant improvements in reducing CRF during and following cancer treatments. The effect size (standardized mean difference [SMD],^51,52 −0.23 [95% CI, −0.33 to −0.13]) favored fatigue interventions (n = 28 RCTs) versus control (n = 2083). Kangas et al.⁵³ also reported a meta-analysis of 17 RCTs comparing prescribed exercise with standard of care for CRF, and only 6 (30%) were positive (overall ES 0.33 to −1.09, weighted pooled ES −0.42; z = −4.41; P < .001); they found this to be moderate and clinically meaningful. Both of these analyses report significant issues with methodological quality, including sample size, blinding, withdrawals, and adherence in most studies. Characteristics of exercise programs that were successful included containing walking and resistance training, multiple exercise components, at least partially home-based, individualized, 8 weeks or longer in duration, and started during active treatment. Specific limitations in the population with primary brain tumor, including potential hemiparesis or cognitive deficits, may limit the applicability of these findings for some patients.

There are also reports of psychosocial interventions for CRF in the patient population with solid tumors.^53,54 Gangas reported that there were 119 studies (RCT and non RCT) with CRF outcome (n = 3620). A meta-analysis of 41 RCTs was completed, including those labeled heterogeneous interventions, cognitive behavioral therapy (CBT)/behavioral therapy (BT), problem-solving, and stress management, as well as psycho educational/educational therapies, which included self-care and coping techniques, activity management, and energy conservation. The effect size was considered to be in the small/moderate range (SMD = −0.31[0.43 to −1.10]). As a result, the authors concluded that psychosocial interventions provided clinically meaningful benefits. The most promising approach was interventions specifically designed to treat fatigue that included education about fatigue, self-care, or coping techniques and balancing activity and rest (4/5 = 80%). The interventions were most promising when they were brief (3–5 sessions vs longer), delivered following treatment, and designed with fatigue as the primary outcome.

Drug Treatment

The use of pharmacologic treatment of fatigue has also been evaluated in numerous studies in patients with solid tumors other than patients with primary brain tumors. When updating their guidelines, the NCCN reviewed studies looking at pharmacologic treatment of fatigue, including psychostimulants, hemopoietic growth factors, antidepressants, and progestational steroids. Only psychostimulants (i.e., methylphenidate) showed a small but significant improvement in fatigue (Z = 2.83, P = .005).^55,56 Other agents evaluated as part of the NCCN review did not have sufficient evidence to support use in patients with CRF, including antidepressants (no efficacy in solid tumors), corticosteroids (temporary responses only), L-carnitine (improvement only if subjects were deficient), and donepezil (no improvement in advanced cancer). There were no published reports regarding the use of amantadine, although use in multiple sclerosis, Parkinson's disease, and hepatitis has demonstrated that this agent may improve fatigue.^51,52,57 More recently, an open-label randomized pilot trial of 4-week efficacy of methylphenidate and modafinil in 24 patients with brain tumors (Gehring, Patwardha, Collins, et al, 2011) reported improvement in fatigue as measured by the BFI total score (P < .04) and POMS-FATIGUE instrument (P < .01) with either methylphenidate or modafinil, adding further support of the use of these agents in patients with primary brain tumors.

Management of Insomnia

The American Academy of Sleep Medicine has published a document titled “General Principles of Management of Insomnia.”²¹ In this report, they recommend first evaluating for a treatable underlying cause and emphasize the importance of sleep hygiene alone or in addition to pharmacologic management. In patients with primary brain tumors, the impact of medications (i.e. timing of corticosteroid use, routine use of anxiolytics) may contribute to daytime sleepiness and/or insomnia. In addition, patients with chronic steroid use are at increased risk for sleep apnea. In addition, neurologic consequences of the tumor, such as bowel and bladder dysfunction, as well as emotional stressors related to the diagnosis and treatment may also contribute to insomnia in this patient population.

Specific recommendations to improve sleep hygiene have been set forth in several practice guidelines^21,58 and include the following 7 points for patients having difficulty falling or staying asleep as outlined in Box 1.

In 2009, Berger reported on a meta-analysis of published studies evaluating non-pharmacologic interventions for sleep in patients with cancer.⁵⁹ Cognitive behavioral therapy was found to be effective when designed to eliminate perpetuating likely not to be likely factors and decondition the hyperarousal response. Complementary therapies including mindfulness-based stress reduction (MBSR)—combination of relaxation, meditative techniques and yoga, healing touch, autogenic training, progressive muscle relaxation, massage, and haptotherapy; educational information; and exercise—were interventions for which the effectiveness could not be established.

There are numerous pharmacological interventions for insomnia, but few RCTs in oncology comparing the efficacy of available agents have been completed.⁶⁰ However several basic principles for the use of pharmacologic agents for insomnia have been widely accepted. These include avoiding the isolated use of hypnotics, instead combine these agents with CBT, if drugs are deemed to be necessary, start with a low dose and titrate up, avoid long-term administration of benzodiazepines and use this class of agents very cautiously in those with abuse history, consider the comprehensive medical situation particularly concurrent symptoms/comorbid conditions that may influence the choice of agent, and to institute a tapering schedule when stopping the agent to avoid withdrawal insomnia. Table 2 outlines characteristics of pharmacologic agents commonly used to treat insomnia.⁶¹

Table 2.

Pharmacologic treatment of Insomnia

Agent	Mechanism of action	Standard dose/Half life	Side effects/Comments
Benzodiazepine Hypnotics	Binds to post synaptic GABA receptors	Dependent on specific agents	Sedation, hangover effect, amnesia, potential for addiction
Halcion, Restoril, Lorazepam, & flurazepam (Dalmane)
Nonbenzodiazepine Hypnotics			OVERALL: Lower amnesia, daytime sleepiness and falls
Zolpidem (Ambien, Ambien CR)	Selective binding to alpha-1 subunit of GABA	5–10 mg/2.5 (6.24–12.5 h)
Zaleplon (Sonata)	Selective binding to alpha-1 subunit of GABA	5–10 mg/1 h	Rapid absorption – less hangover effect
Eszopiclone (Lunesta)	Unknown -thought to interact w/GABA receptor	1–3 mg/6 h	Longer half life-should have 8 h in bed.
Ramelteon (Rozerem)	Melatonin receptor agonist	8 mg/1.5	High fat food impact absorption

In addition, over the counter (OTC) medications and supplements have also been evaluated in treatment of insomnia with mixed results. Melatonin, at a typical dose of 3 mg nightly, has been prescribed for insomnia; however, there are concerns that the pharmacokinetics including metabolism and bioavailability of this agent may vary by manufacturer potentially contributing to the variable efficacy reported.⁶² Antihistamines, including diphenhydramine, are the major ingredients in most OTC sleep aids. Although modest success in preventing insomnia has been reported, they are associated with a 10%–25% report of morning hangover.⁶¹ Kava Kava has been reported as a sleep aid, but there have been reports of severe hepatotoxicity associated with its use and this agent cannot be recommended.⁶¹

Summary and Conclusions

Fatigue and insomnia are common problems in the general population and in the patient population with primary brain tumors. Guidelines have been developed for the assessment and management of these complaints in the general population and those with other solid tumor malignancies. However, patients with primary brain tumors have not routinely been included in these descriptive studies or in RCT evaluating pharmacologic and nonpharmacologic management. Given the impact of fatigue and insomnia on function and quality of life, focused studies are needed to explore the biologic basis of both fatigue and insomnia in this patient population. Greater insight into the underlying biologic mechanisms of these important symptoms will permit the development of specific interventions that may either prevent or treat these symptoms.