Side effects of chemotherapy have been described by cancer patients as more disabling than the cancer itself. Fatigue is increasingly being recognized as an important and pervasive consequence of cancer and chemotherapy. In this article, we review the causes, risk factors and management of cancer and chemotherapy related fatigue.
Fatigue is now increasingly being recognized as an important side effect of chemotherapy. This is partly because of its negative impact on quality of life. Fatigue is understood to be the commonest side effect of chemotherapy and radiotherapy. It has been shown that 82-96% of those undergoing chemotherapy suffer from fatigue during their treatment. Evidence seems to show that fatigue typically improves in the year after treatment. However, in a significant minority of patients, fatigue persists for months or even years after treatment. Studies of long-term survivors of cancer show that fatigue persists in about 25-35% of patients for up to 10 years after cancer diagnosis.
Side Effects of Chemotherapy: Understanding Fatigue
Among the side effects of chemotherapy, fatigue is probably the most difficult to accurately define and measure. What is reasonably certain is that cancer-related fatigue is more severe, more persistent and more debilitating than normal fatigue. Also, cancer or cancer treatment related fatigue is not relieved by adequate sleep or rest unlike normal fatigue which is usually caused by overexertion or inadequate sleep. Cancer related fatigue is multidimensional and likely has physical, mental and emotional components.
Cancer related fatigue is diagnosed when significant fatigue, diminished energy or increased need for rest unrelated to activity levels is present every day or nearly every day for 2 weeks. Symptoms that signal fatigue and support its diagnosis include generalized weakness or limb heaviness, diminished concentration or attention, reduced motivation or interest in usual activities and also insomnia or excessive sleep. Other possible symptoms which aid a diagnosis of fatigue are also known to be side effects of chemotherapy. These include the experience of sleep being non restorative, poor memory, fatigue after exertion lasting several hours and an inability to complete daily tasks. From a mental health perspective, there is often. marked emotional reactivity to feeling fatigued like sadness, frustration and irritability.
Causes of Fatigue
Inflammatory Processes
Overall, research seems to indicate that inflammatory processes are key drivers underlying fatigue in the treatment and post treatment phase. This appears to be especially true for breast cancer, testicular and ovarian cancer survivors. Cytokines are chemical messengers released by cells in the body that modulate inflammation. A lot of research indicates that different families of these cytokines can signal the central nervous system to generate the symptoms of fatigue through neural processes. These cytokines can be released by cancer cells before treatment as well as by chemotherapy damaged tissue. In a study of patients with colorectal, esophageal and non-small cell lung cancer, chemotherapy resulted in marked increases in inflammatory markers. This finding correlated with symptoms of sickness and fatigue in the subjects of the study.
Even in long term survivors of cancer, these inflammatory markers are thought to underlie fatigue. In a sample of 633 breast cancer survivors, higher levels of these markers were associated with increased odds of being classified as fatigued. This finding was seen despite controlling for age, race, menopausal status and medication use. Also of relevance in the long term, gene activation has been seen to occur in breast and prostrate cancer survivors. Activation and expression of genes that code for inflammatory immunological processes and inflammatory markers has been demonstrated in many studies and more are underway.
Neuroendocrine and Autonomic System Changes
Neuroendocrine alterations might also explain cancer related fatigue. Glucocorticoids are cholesterol derived steroid hormones secreted by the adrenal glands that have potent anti inflammatory actions. Research shows that in cancer, there are alterations in the production of these hormones. Glucocorticoid levels have been seen to be abnormal during onset of fatigue with normalization occurring in the post treatment period. In breast cancer patients, a state of hormone resistance has also been observed due to changes in glucocorticoid receptors. This is thought to result in increased levels of pro inflammatory chemicals in the body that might lead to fatigue.
In a study of breast cancer survivors, elevated levels of adrenaline were noted to be associated with fatigue. Elevated levels of adrenaline (or nor-epinephrine) are a sign of sympathetic system over-activity. This finding coincided with the observation that there was reduced heart rate variability which reflects reduced parasympathetic activity. Fatigue and other side effects of chemotherapy could very well be a result of alterations in the activity levels of systems such as the neuroendocrine and the autonomic nervous system. Generally speaking, sympathetic system activity is associated with increased inflammatory activity and parasympathetic system activity with reduced inflammation. This appears to be relevant, and important, in the cancer and cancer treatment context.
Side Effects of Chemotherapy: What Puts You at Risk for Fatigue?
Genes
There is wide variation in the experience of fatigue before, during and after treatment. As pointed out, there is variability in the inflammatory response to treatment which is in turn correlated with variability in fatigue. There are a number of factors that can predispose to fatigue in those with cancer. Genes play an important role in the predilection for fatigue. In two large studies conducted with lung cancer patients alterations in genes controlling cytokine mediated inflammation were found. These alterations were associated with fatigue before as well as after treatment. Alterations in inflammation related genes have been linked to fatigue in breast, lung and prostrate cancer. Interestingly, such changes have been linked to fatigue in other patient populations too suggesting that inflammation promoting genes may serve as a general risk factor for fatigue symptomatology.
Pre-Treatment Fatigue
Pre-treatment fatigue is by far the strongest and most consistent predictor of post-treatment fatigue. It has been found that patients who report fatigue before treatment report elevated fatigue after treatment completion, over the following year and up to 2.5 years later.
Depression
Depression has also been linked to fatigue in cancer. Fatigue can be a symptom of depression as well as a cause for mental illness in the cancer setting since it interferes with social, occupational and leisure activities. There is evidence from several studies that pre-treatment anxiety and depression predict cancer related fatigue before, during and after treatment. A history of major depressive disorder and treatment for mental illness prior to cancer diagnosis predicted post treatment fatigue in many studies with symptoms observed up to 4 years after treatment completion.
Sleep Disturbance
Sleep disturbance has been noted to be a risk factor for fatigue in several studies, including studies of gynecologic and breast cancer. It has been suggested that sleep disturbance may contribute to daytime symptoms of fatigue across cancer populations. Interestingly, getting enough sleep does to necessarily lead to amelioration of fatigue suggesting that other factors contribute to fatigue maintenance over time.
Physical Activity and BMI
Low levels of physical activity and the ensuing decrease in cardiorespiratory fitness are thought to play a very important role in the development and/or persistence of cancer related fatigue. Increased body mass index (BMI) has also been linked with fatigue. In a study of early stage breast cancer, it was found that BMI was one of the key predictors of fatigue at 6 and 42 months post treatment.
Coping and Appraisal
How one responds psychologically to cancer diagnosis is a key element predicting the quality of experience in the following months or years. Patients who engage in negative self-statements and thoughts regarding fatigue report higher levels of fatigue for up to 42 months after treatment. Also, patients who expect to experience fatigue are more likely to report elevated fatigue after treatment. Therefore, having negative expectations and coping strategies early on in the cancer trajectory leads to increased risk of post- treatment fatigue.
There are some other psychological risk factors for cancer related fatigue. These include early life stress, such as neglect and abuse. Early life stress has been linked to fatigue in non cancer populations too. Loneliness in cancer survivors is also associated with higher fatigue and predicts increases in fatigue over time.
Managing Fatigue
A large number of interventions are being studied that might adequately address cancer related fatigue. However, in the absence of a clear understanding of its origins and mechanisms, a definitive treatment is difficult to design. Some approaches that are useful in cancer related fatigue include exercise, psychosocial and mind-body interventions and medications.
Exercise
There is growing evidence that exercise has at least a moderate effect on fatigue. Exercise has been shown to be beneficial during different stages of the cancer trajectory. Exercise can help to buffer the effects of treatment as well as reduce post treatment fatigue. Research shows that aerobic exercise is the most beneficial with evidence being inconclusive for resistance exercises. It is recommended that cancer patients engage in personalized and supervised sessions beginning at modest intensity and increasing gradually in dose and intensity. The American College of Sports Medicine guidelines recommend that cancer patients and survivors undertake at least 150 hours of moderate intensity aerobic exercise each week. Patients should be closely monitored and progress in intensity guided by exercise tolerance and specific diagnosis in order to avoid injury.
Psychosocial Interventions
Psychosocial interventions have been shown to be beneficial in cancer patients especially if they are targeted towards fatigue. Fatigue education and support programs and individualized interventions focusing on fatigue-related thoughts and behavior have been useful in breast cancer patients. A cognitive-behavioral approach combined with hypnosis has also shown promise in reducing fatigue. The Moving Beyond Cancer Trial demonstrated that brief psychoeducational videos help reduce fatigue in breast cancer patients who had recently completed treatment. Multifaceted programs that provided information on cancer-related fatigue, energy conservation, physical activity, sleep hygiene, distress management, nutrition and pain have been shown to be beneficial in decreasing fatigue.
Mind-Body Interventions
There is a growing number of studies that are studying the effects of interventions like acupuncture, mindfulness meditation and yoga on cancer related fatigue. In a trial of 302 patients where 6 weeks of acupuncture was administered, there was significant improvement in fatigue, post chemotherapy. In another study, 100 cancer survivors with severe fatigue were randomized to a 9 week mindfulness based cognitive therapy intervention. The intervention focused specifically on fatigue and instructed the patients on becoming aware of and inhibit unhelpful automatic responses such as feelings, thoughts and behaviors. A significant reduction in fatigue was observed post treatment and this reduction was seen to be maintained over the 6 month follow up. Similarly, studies with restorative and passive yoga poses have been shown to reduce fatigue post treatment.
Pharmacologic Interventions
A considerably large number of studies have investigated the role that specific drugs might play in reducing side effects of chemotherapy and especially fatigue. Evidence appears to indicate that psychostimulants such as methylphenidate (which is an amphetamine based stimulant) could be helpful in reducing fatigue. Interest is growing in Modafanil, which is a non amphetamine based stimulant. Antidepressants such as paroxetine and sertraline have also been studied in the cancer related fatigue context but the results are mixed and somewhat inconclusive.
Based on the research that there is an inflammatory basis of fatigue, several anti-inflammatory drugs have been studied such as steroids like dexamethasone and anti-cytokine drugs such as etanercept and infliximab. All these agents have been shown to have more than a moderate effect on post treatment fatigue. Authoritative and conclusive results on the benefits of anti-inflammatory agents are yet to emerge.
Despite interest in supplements to treat fatigue, there are only a handful of trials studying the potential benefits of these agents. In one trial, the supplement L-carnitine was not seen to have any benefit against fatigue in those receiving cancer treatment. On the other hand, American ginseng was found in one large multisite trial to have beneficial effects, particularly among patients undergoing active cancer treatment.
Fatigue is increasingly being seen as a major impediment to well-being in those with cancer. In order to increase resilience, it is important to be aware of the causes, risk factors and potential management of this common cancer related symptom. We hope this article helped shed some light on this distressing and all too common effect of cancer or its treatment.