Sleep Disturbance and Fatigue in Cancer Survivorship
About the Lecture
Over two-thirds of the 11.4 million cancer survivors in the United States can expect long-term survival. However, many survivors suffer with ongoing difficulties. Problems with sleep and fatigue, two common problems, often arise during treatment and persist long-term complicating survival and reducing quality of life. In this lecture, the inter-relationships between cancer, sleep disturbance, and fatigue are described. Increasing evidence also links alterations in inflammatory biology dynamics to these long-term effects of cancer diagnosis and treatment. This understanding informs the development of effective strategies to identify those at greatest risk for and the prevention and treatment of sleep disturbance and fatigue in cancer survivors. Interventions in cancer and other populations are described along with new ideas for the future.
Michael Irwin, MD, is the Norman Cousins Professor in the Department of Psychiatry and Biobehavioral Sciences at UCLA and Director of the Cousins Center in Psychoneuroimmunology at the Semel Neuropsychiatric Institute. The Cousins Center fosters research on the bi-directional interactions between the brain and the immune system. Dr. Irwin was also a member of the Advisory Council of the National Center for Complementary and Alternative Medicine, and has a substantial interest in mind-body medicine and how behavioral and alternative medicine practices might influence immune responses and health.
Julienne Bower, PhD, is Associate Professor in the Departments of Psychology and Psychiatry and Biobehavioral Sciences at UCLA, and Research Scientist in the Cousins Center for Psychoneuroimmunology at the Semel Institute for Neuroscience at UCLA. Dr. Bower has conducted pioneering research on the biological mechanisms of fatigue and other side effects of cancer treatment, and developed mind-body interventions to treat these symptoms and improve quality of life in cancer survivors.
This is a summary of a lecture presented on September 10, 2013.
There are over 13.7 million cancer survivors in the United States. Over two-thirds can expect to have long-term survival from this disease. More and more often cancer is treated as a chronic disease for which treatments and consequences can extend over long periods of time. There are some issues that survivors live with as a consequence of the disease and treatment that have been termed the “Sixth Vital Sign,” and include the behavioral co-morbidities or complications that are a result of cancer and its treatment. Three of the behavioral morbidities of a cancer diagnosis and treatments are depression, insomnia, and fatigue. Each of these is a treatable mental health issue that can be assessed and treated to improve patient functioning during and after cancer treatment.
Sleep disturbance can happen to everyone at some time during their lives. Sleep disturbances include having difficulty with sleep-wake cycles after traveling, waking up in the night, or having difficulty going back to sleep because of worries about work or family. It can sometimes include waking up early. Insomnia is defined as having difficulty in one of several areas for more than one month. This includes difficulty initiating sleep, difficulty maintaining sleep or having non-restorative sleep, which means waking in the morning without feeling refreshed and rested – your happy go lucky self. Insomnia can cause significant distress and or impairment in functioning during the day. Insomnia is currently classified in the new Diagnostic and Statistical Manual of Mental Disorders. Insomnia is a disorder that typically occurs with other kinds of disorders including depression and anxiety. The true prevalence of clinical insomnia is not well understood.
In breast cancer survivors, the population in which most of the research has been done because of the large number of survivors, over 50% report insomnia symptoms during treatment and nearly 20% had insomnia as a disorder. There has been some research into the prevalence of insomnia by different cancers with the estimates ranging 38%-43% for breast cancer, 37%-50% for lung cancer, 32% for gastrointestinal cancers, and 29%-32% for gynecologic cancers.
Insomnia is a major problem for cancer survivors. In the general population, insomnia is estimated to be 7-9%. In cancer survivors, it is estimated to range from 27-52%, a 3-fold increase in prevalence.
Being distressed by a cancer diagnosis and/or treatment is a significant factor related to insomnia. The rates of insomnia are highest during this early period. Insomnia, however, persists during treatment. While 59% of patients report insomnia at the start of treatment, 36% report insomnia 18 months later at the end of treatment.
There are some factors that may make someone more “predisposed” to developing insomnia. Women are more likely to develop it, being of younger age, specific cancer types, and whether or not you tend to have an arousability trait. Arousability is that quality of being able to be awakened easily by sound, light or other potentially disturbing stimuli.
Insomnia can begin at any time—after diagnosis, when patients have surgery or when other treatments, such as chemotherapy and radiation, begin. Having dysfunctional beliefs about sleep can also increase the likelihood that sleep disruption becomes more persistent. These include having catastrophic or negative thoughts, such as “If I don’t get to sleep then x, y, z, terrible thing will happen the next day.” Also having unmet needs in one’s daily living environment as well as in one’s physical function can also be a precipitating factor in insomnia. Unmet needs create stress.
While the research in this area is still somewhat limited some of the factors that appear to contribute to persistent insomnia include being on aromatase inhibitors for patients with breast cancer. In prostate cancer, being on an androgen depletion therapy is also a factor. Having less physical activity and less social support are also contributing factors. Having more social strain from your environment can increase insomnia. Also having depressive symptoms increases the likelihood of developing insomnia.
The consequences of insomnia are significant. The most common and obvious is increased amounts of fatigue. In non-cancer populations, there is a 4-fold greater risk of developing depression related to insomnia. There are no prospective longitudinal studies of cancer and depression related to insomnia. In non-cancer samples, there is a 2-fold greater risk of mortality for individuals with insomnia although the risk is not known in cancer populations. There is an association with mortality in both not getting enough sleep, less than 7 hours and if you get more than 9 hours of sleep. Interestingly in a large study called the Nurse’s Health study, erratic work schedules lead to greater sleep disturbance, and they also found a 50% greater risk of breast cancer in this population. Men with insomnia related to shift work have nearly a 2-fold greater risk of developing prostate cancer. In a study of 40,000 people followed over 5 years, having a short or long sleep duration in women led to a 50% greater risk of developing colorectal cancers. Insomnia has a known association with cardiac disease. A short sleep duration can lead to a 2-fold greater risk of stroke. Having short sleep duration is also associated with a 50% greater risk of all chronic diseases of aging.
What is it about sleep disturbance that seems to be related to cancer, mortality, cardiovascular disease, rheumatoid arthritis, depression and diabetes mellitus? The common denominator between all these medical conditions may be that sleep disturbances lead to increased rates of inflammation that create this biologic risk factor. There is some new evidence to suggest that inflammation may be at the intersection of behavior and somatic symptoms. Several studies suggest that inflammatory factors and sleep deprivation are related. In a study where participants were deprived of just 4 hours of sleep, they produced more pro-inflammatory cytokines, and this was especially true for women. In women, sleep disturbance induces activation of nuclear factor kB with shows an increased risk of developing depression and sleep disturbance.
Despite how much more we would like to know about sleep difficulties and cancer, there are some key potential areas of intervention and some data to support them. For example, targeting the sleep-wake cycle can be very important. It is helpful to get people on a regular pattern of awakening and going to sleep at the same time so that a rhythm is established in the body and brain. It is also important to reduce the amount of light exposure to the retina just prior to getting ready for bed. This means using your computer/tablet/phone in bed may not be a good idea if you are prone towards sleep disturbance. Good sleep hygiene includes keeping stimulation out of the bedroom and learning to associate your bed with sleep. Cognitive-behavioral therapies for insomnia integrate these techniques but also help with the potentially negative thoughts that can escalate sleep problems. If you are having difficulty going to sleep, it is better to get up for a short period of time, do something non-stimulating, relaxing in low light and then go back to bed and try again. A good exercise habit, earlier in the day, at least three times per week also is helpful. There is some research to suggest that these efforts combined actually help reduce insomnia and other sleep disturbances. There is, however, only one solid clinical trial in cancer-related insomnia and it showed that a cognitive-behavioral intervention, as described above, was effective in reducing insomnia. There are, however, several studies with adults and older adults that support the efficacy of behavioral treatments for insomnia. There is a growing interest in pro-inflammatory cytokines and their role in sleep disturbance.
It should be noted that there are many interventions that tend to reduce the pro-inflammatory responses and should be considered as potential areas of intervention. For example, targeting stress response mechanisms may have benefits. These include cognitive behavioral therapy approaches that teach stress management. In addition, multi-modal approaches that combine assistance with coping, increased activity, and social support may be helpful. Using supportive and expressive psychotherapy is also helpful. This includes finding meaning. People with a greater purpose have a greater sense of well-being and lower levels of inflammatory cytokines. Techniques such as traditional relaxation exercises, as well as mindfulness-based stress reduction (MBSR), have data to support their benefits.
Some of these whole body treatments may both treat insomnia and the inflammation. Specific research studies to support this include:
- A cognitive behavioral therapy (CBT) in which the benefits of the cellular expression of pro-inflammatory cytokines were found after 16 weeks in person who had an improvement of depression and similar results in those with insomnia.
- Aerobic exercise that included moderate intensity physical activities such as walking for 20-30 minutes per day had benefits on inflammatory markers after 12 months.
- The practice of meditation in which the individual generates spontaneous empathy and compassion for themselves, and others had benefits on inflammatory markers after only six weeks.
- T’ai Chi Chih is a slow moving meditation that combines the practices of 20 aerobic exercises with attentional focus. T’ai Chi Chih (TCC) consists of 19 stand-alone movements and one pose. Research has shown this treatment demonstrated benefits on inflammatory markers after 25 weeks of practice.
- A recent cognitive behaviorally therapy for sleep quality was able to improve sleep and reduce cellular inflammation along with overall improvements in sleep.
Fatigue is among the most common side effects of cancer and its treatment and almost all patients experience some fatigue during treatment. It is typically most severe during chemotherapy, although it is also evident after surgery and during radiation therapy. Patients tend to recover their energy overtime, gradually, and usually within one year after treatment is completed. Fatigue may persist for years after successful treatment in some patients with estimates that some breast cancer survivors, (30%) report fatigue up to 10 years post-treatment and likely beyond.
Cancer-related fatigue is different than “normal” fatigue that you might experience due to lack of sleep or overexertion. It is more pervasive, debilitating, and longer-lasting. It is not relieved by adequate sleep or rest, and it involves physical, mental and emotional components. Patients often indicate that it is a highly distressing symptom associated with cancer and more distress to them than pain or nausea. It also affects all aspects of quality of life including ability to work (61%), ability to care for family (42%), one’s sense of hope of fighting cancer and is related to concerns about survival (33%) and 16% reported that it is as important as treating cancer. There is a consensus that fatigue is under-reported and under-treated.
There is a growing body of literature that is beginning to identify causes or potential causes of fatigue. These include demographic factors, additional illnesses such as cardiovascular disease and obesity, co-morbid symptoms such as pain, menopausal symptoms and sleep disturbance, health behaviors such as extent of physical activity, psychosocial factors such as depression, and coping style as well as biological factors such as anemia and inflammation. Initially, the research focused on anemia. However, now there is a growing body of evidence to suggest that inflammation may be a major factor in the development of persistent fatigue. Fatigue has been correlated with elevated inflammation during radiation and chemotherapy. Cancer survivors with persistent fatigue show elevated markers of inflammatory activity, and this may reflect increased activity of pro-inflammatory cytokines that is the body’s response to stress, infection, etc. , and signals the brain to produce symptoms of fatigue. Individuals who are prone to produce more inflammatory cytokines may be at higher risk for cancer-related fatigue.
Can we treat fatigue?
One of the first steps in treating fatigue is identifying and treating any underlying and contributing factors. Below is a table of possible treatable contributing factors and examples of possible diagnostic evaluations that could be undertaken as clinically appropriate.
|Treatable Contributing Factors||Examples of Possible Diagnostic Evaluation
Should be undertaken only when clinically appropriate
|Cardiac dysfunction (e.g., arrhythmia, hypertension, coronary artery disease, congestive heart failure)||Consider an echocardiogram, exercise test for cardiopulmonary reserve|
|Endocrine dysfunction (e.g., diabetes, hypothyroidism, hypogonadism, adrenal insufficiency)||Consider measuring HgbA1C, thyroid stimulating hormone, glucose, testosterone, or conduct dexamethasone suppression test.|
|Pulmonary dysfunction||Consider chest x-ray, 6 Minute Walk Test, pulmonary function tests, oxygen saturation|
|Renal dysfunction||Consider kidney and electrolyte chemistries|
|Anemia||Consider complete blood count|
|Arthritis||Consider sedimentation rate, serologies|
|Neuromuscular complications (neuromuscular, neuropathy)||Consider grip strength test, neuropathy sensory testing, electromyography|
|Sleep disturbances (e.g., insomnia, sleep apnea, vasomotor symptoms, restless leg syndrome)||Consider assessing sleep with standardized questionnaire and possible sleep study|
|Pain||Evaluate with standardized assessment tool|
|Emotional distress (e.g., anxiety, depression)||Evaluate with standardized assessment tools or diagnostic interview|
While the goal is ultimately to try to treat underlying difficulties with as much precision as possible, if these cannot be identified, then some of the more non-specific interventions may also be helpful and should be considered. These would include behavioral and psychologically based interventions, mind-body approaches, and pharmacologic interventions. Exercise is a behavior-based intervention and patients who exercise during treatment report lower levels of fatigue that is somewhat counter-intuitive. Randomized controlled trials have shown beneficial effects of exercise on fatigue. The general guideline is that 150 minutes of moderate aerobic activity per week combined with 2-3 sessions of strength training will lead to benefits. There have also been benefits found from less intensive walking programs as well.
There are several randomized controlled trials of psychosocial interventions that have found beneficial effects on fatigue. These interventions include psychoeducation and/or individual cognitive behavioral therapy. For example, the Moving Beyond Cancer project created a 30-minute video for breast cancer patients who had completed treatment. The video provided information about what to expect after cancer treatment and modeled active coping, including exercise and seeking support. The video is available for others at www.cancer.gov/beyond-cancer-video. It was beneficial in reducing fatigue. Similarly, a web-based 12-week program for fatigued cancer survivors provided helpful, tailored information about cancer-related fatigue addressing physical activity, sleep hygiene, pain control, distress management, nutrition and energy conservation. Finally, a more intensive 12-week individual therapy program for cancer survivors with severe fatigue was found to be beneficial. In this program, a therapist addressed poor coping with the experience of cancer, fear of disease recurrence, dysfunctional cognitions concerning fatigue, dysregulation of sleep and activity, low social support and negative social interactions.
There is a growing body of research indicating that mind-body treatments such as mindfulness meditation, acupuncture and yoga are beneficial to fatigue in cancer survivors. For example, mindfulness that is the process of bringing attention to the present moment to moment experiences without judgment was used in an 8-week group-based program for breast cancer survivors. Participants did the body scan, gentle yoga-based stretches, and sitting meditation. They also participated in didactic teaching and group discussion on topics including perceptions of and reactions to life events, stress physiology, and mindfulness in ever day life. This program had a variety of benefits and improved fatigue. Similarly, a 12 week Iyengar-based yoga program was found to be beneficial for breast cancer survivors who had significant fatigue. The specially designed Iyengar based program emphasized postures that are thought to reduce fatigue that includes backbends, upside down poses and restorative poses. For patients that had difficulty getting into such poses, props were used to ensure that all participants could enjoy the benefits of the poses. The program decreased fatigue and increased vigor.
There is some evidence that pharmacologic interventions such as psycho-stimulants (methylphenidate) and wakefulness agents (modafinil) may be helpful in improving fatigue in patients with advanced disease or those on active treatment. There is limited evidence for their effectiveness in reducing post-treatment fatigue in cancer survivors.
It is important to discuss your fatigue with your doctor and together you can evaluate possible contributing factors. If appropriate, your doctor can refer you to specific effective cancer-related fatigue treatments that may be helpful. It is important to rule out and treat any underlying conditions. Participation in various mind-body programs may also be helpful. Remember, different programs may work for different individuals so you may need to try different approaches to see what is most useful for you.