and Ellen F. Manzullo1
(1)
Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Chapter Overview
Fatigue is a common symptom experienced by cancer survivors. It is important for the clinician to question the patient about the presence of this symptom because patients are often hesitant to mention it. In addition, cancer-related fatigue (CRF) commonly clusters with other symptoms, such as sleep disturbance, pain, depression, and anxiety. Patients with moderate to severe CRF should undergo a comprehensive evaluation that includes a history, physical examination, laboratory evaluation, and an assessment of their fatigue and possible associated symptoms. Nonpharmacologic interventions for the treatment of CRF include psychosocial interventions, activity enhancement, dietary management, and sleep management; pharmacologic interventions include agents such as stimulants. Further research is needed to elucidate the actual pathophysiology of CRF and better tailor treatment strategies.
Introduction
As strides have been made with earlier diagnosis of and more effective treatments for cancer, the number of cancer survivors has increased. Clinicians in both academic and community settings are more frequently seeing patients who have been treated for cancer with a variety of modalities, including surgery, chemotherapy, and radiotherapy. Although these patients are considered free of cancer, they often present with sequelae resulting from their treatment. One of the most common and distressing symptoms these patients experience is fatigue. Cancer-related fatigue (CRF) is defined as a distressing, persistent, and subjective sense of physical, emotional, or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning (Mock et al. 2000). Cancer patients as well as survivors can experience CRF to such an extent that it interferes with their everyday life. The prevalence of CRF among cancer survivors is 17–21%, using the ICD-10 criteria for diagnosis. However, if other criteria are used, such as fatigue scale scores, the prevalence may be as high as 33–53%.
CRF is an important symptom that has often been overlooked for several reasons. First, clinicians working in an outpatient setting are usually very busy and experience time constraints related to assessing CRF. In addition, clinicians often lack knowledge related to the evaluation and formulation of a treatment plan for this common symptom. Moreover, cancer survivors may be hesitant to mention CRF for fear that it could indicate disease recurrence or that it is simply an expected treatment effect. As a result, the clinician must make a definite effort to inquire about CRF with cancer survivors. Health care providers should also be familiar with methods of assessing and treating CRF. Cancer survivors and their families should be advised that if this symptom is present, they should alert their physician so that an evaluation can be done and a treatment plan can be formulated. CRF may decrease the cancer survivor’s overall quality of life and ability to maintain a career or fulfill other responsibilities.
CRF rarely occurs alone. In fact, CRF commonly occurs with other symptoms. It is important to assess the patient for the presence of other symptoms, as well as the severity of the symptoms. In the CRF Clinic at MD Anderson, patients with severe CRF have also been found to have increased levels of sleep disturbance, pain, depression, and anxiety (Escalante et al. 2010).
Etiology and Proposed Mechanisms of Cancer-Related Fatigue
Because of the high prevalence of fatigue among cancer patients and survivors, better understanding of the causal mechanism of CRF is needed. Unfortunately, the etiology of CRF is poorly understood. Several possible mechanisms have been proposed:
1.
Serotonin dysregulation: cancer or cancer treatment leads to an increase in brain serotonin levels or upregulation of 5-HT receptors, resulting in reduced somatomotor drive, modified hypothalamic-pituitary-adrenal axis function, and a feeling of reduced capacity due to physical work.
2.
Disturbance of the hypothalamic-pituitary-adrenal axis: cancer or cancer treatment alters the hypothalamic-pituitary-adrenal axis, resulting in endocrine changes, such as low cortisol levels, that result in fatigue.
3.
Circadian rhythm disruption: changes in circadian function result in alteration of endocrine function and metabolic processes, as well as sleep disorders.
4.
ATP dysfunction: cancer or cancer treatment leads to a defect in the regeneration of ATP in skeletal muscle, thereby resulting in decreased ability to perform mechanical tasks.
5.
Peripheral release of neuroactive agents: release of these agents leads to activation of vagal afferent nerves, resulting in suppression of somatic muscle activity and “sickness behavior.”
6.
Dysregulation of cytokines: dysregulated levels of cytokines such as tumor necrosis factor-alpha or interleukin-beta can lead to increased fatigue.
A patient’s CRF could be caused by any or all of these potential mechanisms. Further research on the causes of CRF is needed so that better prevention and treatment modalities may be established.
Fatigue Measurement
It is important to screen cancer survivors for CRF so that if it is present, an appropriate evaluation may be performed and an individualized treatment program may be created. The National Comprehensive Cancer Network recommends the following screening question: How would you rate your fatigue on a scale of 0–10 over the past 7 days? Mild fatigue is scored as 1–3; moderate fatigue, 4–6; and severe fatigue, 7–10. The National Comprehensive Cancer Network recommends using the words none, mild, moderate, and severe to describe fatigue for patients who are unable to assign a number to it. In the CRF Clinic at MD Anderson, we use the Brief Fatigue Inventory (Mendoza et al. 1999), which consists of nine questions. This inventory evaluates the patient’s present, usual, and worst levels of fatigue and its impact on the patient’s daily life. Answers to the questions are scored as described above and individual question scores are summed and averaged to produce a final score. The scoring system for the final scores is as follows: mild fatigue, <4; moderate fatigue, 4–6; severe fatigue, ≥7.
Evaluation
When a clinician evaluates a cancer survivor with CRF, the clinician must obtain a complete history and perform a physical examination. It is vital to note the patient’s cancer diagnosis and the treatment received, such as surgery, chemotherapy, radiotherapy, bone marrow transplantation, or hormonal treatment, in the patient’s history. Cancer survivors should also be assessed during the clinic visit for the presence of comorbid conditions and other factors contributing to CRF. It is important to keep in mind that a multitude of comorbid conditions may result in fatigue. For example, cardiac disease, pulmonary dysfunction, hepatic disease, renal insufficiency, hypothyroidism, and anemia are just a few of the medical issues that may contribute to the patient’s fatigue (Table 22.1).
Table 22.1
Factors contributing to cancer-related fatigue
Medical issues |
Anemia |
Endocrine dysfunction |
Hypothyroidism |
Hypogonadism |
Diabetes mellitus |
Adrenal insufficiency |
Neurologic dysfunction |
Cardiac dysfunction |
Pulmonary dysfunction |
Hepatic dysfunction |
Renal dysfunction |
Rheumatologic disorders |
Physical function changes |
Physical inactivity |
Physical deconditioning |
Nutritional imbalances |
Medications |
Sedating agents (e.g., hypnotics, narcotics, neuropathic agents) |
Beta-blockers |
Other (drug interactions and other medication side effects) |
Cancer treatment effects |
Chemotherapy |
Radiotherapy |
Surgery |
Bone marrow transplantation |
Biologic response modifiers |
Hormonal treatment |
Sleep dysfunction |
Obstructive sleep apnea |
Restless leg syndrome |
Narcolepsy |
Insomnia |
Symptom burden |
Pain |
Anxiety and depression |
Stress |
Another important component of the patient’s history is a thorough evaluation of medications the patient is taking. Certain medications such as sedating agents and beta blockers may add to increased fatigue. Another key aspect of medication review is an assessment of any over-the-counter medications the patient may be taking, including vitamins, supplements, and herbal therapy. Polypharmacy and drug interactions may also be a factor in the CRF. Additionally, inquiry into alcohol and illicit drug usage is necessary. These behaviors may impact the patient’s overall medical condition.
A complete review of systems is also necessary because this can provide valuable clues to the presence of comorbid conditions that have not been diagnosed or are being inadequately treated. For instance, questions regarding sleep quality may aid in the assessment of sleep disturbances such as insomnia, narcolepsy, restless leg syndrome, and obstructive sleep apnea.
A detailed history regarding the patient’s CRF should also be attained. It may be very helpful to establish when the patient began to experience fatigue, its pattern over time, factors that have alleviated the fatigue or made it worse, and its overall impact on the patient’s daily life. By asking a patient to describe a typical day, the clinician may begin to assess the patient’s overall activity level. It is important to inquire whether employed patients are having difficulty fulfilling their job duties and whether the patient is or has recently been on short-term or long-term disability.
Inquiries should be made regarding whether the patient exercises; regular daily exercise can be beneficial to many patients with CRF. Finally, a complete physical examination is required for those with moderate to severe fatigue. The National Comprehensive Cancer Network has developed a practice guideline for CRF that may be helpful to practitioners (Mock et al. 2007).
At MD Anderson, a clinic is dedicated to the evaluation, treatment, and long-term follow-up of cancer patients and survivors with CRF. During the initial clinic visit, patients undergo a complete history and physical examination as detailed above. In addition, patients are required to complete a packet of survey tools in an effort to assess not only the severity of the fatigue, but also the presence and degree of other symptoms that normally cluster with fatigue, such as pain, anxiety, depression, stress, and poor sleep quality. Each patient undergoes an initial workup that includes a complete blood count, chemistry panel, and tests to measure electrolyte levels and thyroid-stimulating hormone levels. The thyroid-stimulating hormone test should be performed within 6 months of the initial clinic visit and the additional tests within 2 months of the visit, especially in patients who have not recently undergone diagnostic testing. Further studies may need to be requested to determine whether comorbid conditions may be a factor in the patient’s CRF. Then, an initial treatment plan is formulated and a subsequent visit is arranged.
Treatment Interventions
All cancer patients should be educated on general strategies for the management of CRF, regardless of the patient’s level of fatigue. These approaches are often helpful to patients and families. General strategies for managing CRF include energy conservation and distraction. Examples of energy conservation include setting priorities, delegating activities, and scheduling activities at times of peak energy. Distraction may include playing games, working on puzzles and listening to music, or visiting family or friends.
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