Despite notable improvements over the last few decades in the efficacy, tolerability, and survival outcomes of cancer therapy, a diagnosis of cancer still causes patients a significant degree of emotional distress. A statistical analysis of ratings and responses made by 1,205 cancer outpatients using the National Comprehensive Cancer Network (NCCN) Distress Thermometer and Problem List identified sleep problems as one of the top five risk factors for distress (other common factors include financial problems, worry, nervousness, and physical difficulties with “getting around”). Patients can experience sleep disruption or sleep-wake disturbances during cancer treatment, for a long time after completing treatment, and even prior to the diagnosis and initial treatment of cancer. A 2017 study of 219 women with breast cancer in Nebraska, for example, found that even before starting chemotherapy, patients reported a cluster of symptoms that included sleep disturbances, anxiety, concerns about appearance, and difficulty concentrating. Although sleep-wake disturbances are common throughout the cancer trajectory, they continue to be underdiagnosed and undertreated.
Consequences of acute and chronic untreated sleep-wake disturbances in individuals with and without cancer include daytime fatigue, irritable mood, and cognitive impairment. When these conditions persist, they may have a negative impact on a person’s social life, daily function at work and at home, and quality of life. In the general population, persistent insomnia has been associated with work absences, life-threatening motor vehicle and work-site accidents, and psychiatric and cardiovascular disorders. Importantly, the economic burden of untreated insomnia is much higher than the costs associated with treating insomnia. For example, in a randomly selected sample of 948 adults in Canada, 76% of all reported insomnia-related expenses resulted from work absences and reduced productivity. Since cancer survivors often depend on employment for economic survival and insurance benefits, access to effective treatments for sleep-wake disturbances, insomnia, and sleep disorders is critical. The personal and societal burden of chronic sleep-wake disturbances, especially in people with cancer, needs to be addressed. To that end, this article describes the etiology, screening, and assessment of sleep-wake disturbances; outlines pharmacologic and nonpharmacologic interventions to manage sleep-wake disturbances; provides expert clinical advice on managing sleep-wake disturbances that occur in the context of cancer; and presents a simplified, user-friendly sleep management algorithm (see Figure).
There is a lack of consistency in the terms and definitions used to describe “sleep disturbances.” Although the terms sleep disorder, acute and chronic insomnia, and sleep-wake disturbance are often used interchangeably, there are distinctions between them. Sleep disorders comprise nearly 100 diagnostic entities described in the International Classification of Sleep Disorders diagnostic and coding manual (third edition, ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders (fifth edition, DSM-5). The most common sleep disorders diagnosed in primary care and oncology populations include chronic insomnia, sleep-disordered breathing (such as obstructive sleep apnea [OSA]), movement disorders (such as restless legs syndrome), and circadian rhythm disorders. Insomnia is defined by the ICSD-3 as persistent difficulty with sleep initiation, maintenance, duration, or quality accompanied by some form of daytime impairment, which occurs despite adequate opportunity for sleep. Insomnia is considered chronic if these problems persist for 3 or more nights per week for at least 3 months; and acute if they have been occurring for less than 3 months. The term sleep-wake disturbances is broader, encompassing perceived or actual alterations in nighttime sleep (quality and duration), with subsequent daytime impairment, without a diagnosis by a provider. Although sleep-wake disturbances often present with the usual features of insomnia—such as difficulty falling asleep (sleep initiation/latency), difficulty staying asleep (sleep maintenance), not feeling restored or refreshed on awakening, and daytime dysfunction—they also include circadian changes, sleep fragmentation, and other sleep alterations. In clinical practice, distinguishing between sleep-wake disturbances and insomnia is less important than identifying the actual sleep disorder and treating it appropriately. It is estimated that 30% to 60% of adults with cancer experience sleep-wake disturbances during diagnosis, treatment, and survivorship.
Maria is a 63-year-old white woman with stage II, estrogen receptor–positive, progesterone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer. Following a lumpectomy with sentinel lymph node biopsy, she completed chemotherapy and radiation therapy, and recently started treatment with an aromatase inhibitor (AI). She works part-time as a receptionist. She presents with an irregular sleep schedule; complaints of difficulty falling asleep; and more than six awakenings per night due to AI-related hot flashes, aches, and pains. The results of her physical examination are unremarkable and her physical status is good. She reports severe fatigue (7 on a scale of 0 to 10) and experiences daytime sleepiness that leads to afternoon naps 3 to 5 days per week. She has a history of anxiety and is very worried about cancer recurrence.
APPLICATION OF THE ALGORITHM
Step 1: Screen – Yes.
Step 2: No.
Step 3: Her Insomnia Severity Index (ISI) score is 16 (due to irregular sleep schedule, hot flashes, anxiety, fatigue, and pain).
Step 4: Focus on regular sleep schedule; better sleep environment; and management of hot flashes, aches, and pain.
Step 5: Exercise program and mindfulness-based stress reduction strategies to reduce anxiety; short-term zolpidem tartrate at 5 mg PRN.
Step 6: Repeat assessment at 12 weeks: ISI = 10; patient rates fatigue and anxiety as moderate (5 on a scale of 0 to 10). Continue to assess; sleep medication not renewed.
The etiology of and risk factors for sleep-wake disturbances comorbid with cancer are numerous, and these conditions often exacerbate prior sleep issues. Sleep-wake disturbances are linked to tumor pathology, advanced stage of cancer, treatments, adjunct medications, environmental factors, psychosocial disturbances, and comorbid medical conditions.[7,11,12] Cancer treatments (chemotherapy, radiation, surgery, biologic agents, hormonal agents, molecularly targeted agents) have sleep-stealing adverse effects and can alter levels of inflammatory cytokines or disrupt circadian rhythms and sleep-wake patterns. Cancer treatments and medications with sedative or stimulant properties (opioids, anxiolytics, anti-emetics, antidepressants, corticosteroids) disrupt sleep latency and maintenance.[13,14] Symptoms related to cancer or its treatment (pain, dyspnea, hot flashes, nausea, diarrhea) and psychological distress (depression, anxiety, and mood alterations) can negatively impact sleep quality and duration.
It is unclear whether specific types of cancer tend to be associated with sleep-wake disturbances. In some studies, the prevalence of sleep-wake disturbances is greatest in patients with breast cancer, compared with other cancer types. OSA has been associated with head and neck cancer. Prostate cancer survivors treated with radiotherapy may experience sleep-wake disturbances resulting from urinary frequency and urgency.
Risk factors for insomnia are categorized as predisposing, precipitating, and perpetuating in Spielman’s “3P” model of insomnia. Predisposing factors are enduring psychological or biological traits that increase the likelihood of developing sleep-wake disturbances during the cancer experience. Predisposing factors include advanced age, female sex, an anxiety-prone personality, a family or personal history of insomnia and/or psychiatric disorder, and genetic characteristics. Precipitating factors are life events and medical, psychological, and environmental factors that trigger insomnia.These include anxiety related to the cancer diagnosis; treatment-related effects of chemotherapy, radiation, and anti-estrogen therapy; and specific side effects/conditions that result in disrupted circadian rhythms, hospitalization, and menopausal symptoms. Perpetuating factors are maladaptive behaviors and beliefs that patients feel help them to cope with sleep difficulties. Detrimental behaviors include spending extended time in bed, taking frequent and long naps, following an irregular sleep schedule, and being physically inactive. Beliefs such as fear of sleeplessness and worries about daytime consequences of poor sleep may delay sleep onset and cause frequent, prolonged awakenings.
How Do We Screen for and Assess Sleep-Wake Disturbances?
Sleep-wake disturbances are recognized through patients’ subjective complaints of insufficient quality or duration of sleep. In addition, patients with sleep disorders such as OSA present with observable signs, such as snoring and apneic episodes during sleep. Prominent groups, including the National Cancer Institute (NCI), NCCN, the Oncology Nursing Society (ONS, in a Putting Evidence into Practice [PEP] resource), and the pan-Canadian expert panel disseminate evidence-based guidelines and resources for screening, assessment, and treatment of sleep-wake disturbances in patients with cancer. Despite the pervasiveness of sleep-wake disturbances and the availability of practice guidelines aimed at addressing symptoms, research suggests that provider communication, assessment, and treatment of sleep-wake disturbances are suboptimal.[24-26] Patient, provider, and system-related barriers hamper the translation of the relevant guidelines into practice. The barriers are similar to issues that impede implemention of guidelines for management of cancer-related fatigue. They include patients’ attitudes and beliefs, clinicians’ tendency to prescribe medications due to a lack of familiarity with and capacity to provide behavioral interventions, and the lack of access to reimbursement and sleep specialists.
Step 1 of the simplified algorithm (Figure) is to identify sleep-wake disturbances in patients with cancer using three brief and standardized screening questions; these need to be asked at regular intervals and when changes occur in the patient’s clinical status. Step 2 is to detect sleep disorders (eg, OSA, restless legs syndrome, hypersomnia) using self-report instruments (Table 1). A referral to a sleep specialist is indicated when a sleep disorder is suspected. Step 3 is a focused assessment. Because of its established use in cancer populations, we suggest using the Insomnia Severity Index (ISI) to determine the severity of sleep-wake disturbances. Identification of treatable risk factors such as comorbidities, medications, symptoms, and irregular sleep-wake patterns is a high priority. Controlling comorbidities and lowering the doses of medications that have stimulating or sedating side effects (eg, corticosteroids, opiates, antidepressants, anti-emetics, antihistamines) may provide immediate benefits. Clinicians need to monitor and treat concurrent symptoms such as pain, fatigue, and depression.
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